SECTION VI

DISORDERS OF
BONE AND CALCIUM
METABOLISM

Ha rris on_Endocrinology_Ch32_p423-p441.indd 423 27/07/16 11:04 a m

 CH AP TER 3 2
BONE AND MINERAL METABOLISM IN HEALTH
AND DISEASE
F. Richard Bringhurst ■ Marie B. Dem ay ■ Step hen M. Krane
■ Henry M. Kronenb erg
BO NE STRUCTURE AND METABO LISM
Bone is dyn ic tissue th t is re odeled const ntly
throughout li e. T e rr nge ent o co p ct nd c n-
cellous bone provides strength nd density suit ble or
both obility nd protection. In ddition, bone pro-
vides reservoir or c lciu , gnesiu , phospho-
rus, sodiu , nd other ions necess ry or ho eost tic
unctions. Bone lso hosts nd regul tes he topoiesis
by providing niches or he topoietic cell proli er -
tion nd di erenti tion. T e skeleton is highly v scul r
nd receives bout 10% o the c rdi c output. Re odel-
ing o bone is cco plished by two distinct cell types:
osteobl sts produce bone trix, nd osteocl sts resorb
the trix.
T e extr cellul r co ponents o bone consist o
solid iner l ph se in close ssoci tion with n org nic
trix, o which 90–95% is type I coll gen. T e noncol-
l genous portion o the org nic trix is heterogeneous
nd cont ins seru proteins such s lbu in s well
s ny loc lly produced proteins, whose unctions
re inco pletely understood. T ose proteins include
cell tt ch ent/sign ling proteins such s thro bos-
pondin, osteopontin, nd bronectin; c lciu -binding
proteins such s trix gl protein nd osteoc lcin; nd
proteoglyc ns such s biglyc n nd decorin. So e o
the proteins org nize coll gen brils; others in uence
iner liz tion nd binding o the iner l ph se to the
trix.
T e iner l ph se is de up o c lciu nd
phosph te nd is best ch r cterized s poorly crys-
t lline hydroxy p tite. T e iner l ph se o bone
is deposited initi lly in inti te rel tion to the col-
l gen brils nd is ound in speci c loc tions in the
“holes” between the coll gen brils. T is rchitec-
tur l rr nge ent o iner l nd trix results in
424
Ha rris on_Endocrinology_Ch32_p423-p441.indd 424
two-ph se teri l well suited to withst nd ech ni-
c l stresses. T e org niz tion o coll gen in uences
the ount nd type o iner l ph se or ed in bone.
Although the pri ry structures o type I coll gen in
skin nd bone tissues re si il r, there re di erences
in posttr nsl tion l odi c tions nd distribution
o inter olecul r cross-links. T e holes in the p ck-
ing structure o the coll gen re l rger in iner lized
coll gen o bone nd dentin th n in un iner lized
coll gens such s those in tendon. Single ino cid
substitutions in the helic l portion o either the α1
(COL1A1) or α2 (COL1A2) ch ins o type I coll -
gen disrupt the org niz tion o bone in osteogenesis
i per ect . T e severe skelet l r gility ssoci ted with
this group o disorders highlights the i port nce o
the brill r trix in the structure o bone.
Osteoblasts synthesize nd secrete the org nic trix
nd regul te its iner liz tion. T ey re derived ro
cells o esenchy l origin (Fig. 32-1A). Active osteo-
bl sts re ound on the sur ce o newly or ing bone.
As n osteobl st secretes trix, which then is iner-
lized, the cell beco es n osteocyte, still connected
with its blood supply through series o c n liculi.
Osteocytes ccount or the v st jority o the cells in
bone. T ey re thought to be the ech nosensors in
bone th t co unic te sign ls to sur ce osteobl sts
nd their progenitors through the c n licul r network
nd thereby serve s ster regul tors o bone or -
tion nd resorption. Re rk bly, osteocytes lso secrete
brobl st growth ctor 23 (FGF23), jor regul tor
o phosph te et bolis (see below). Miner liz tion o
the trix, both in tr becul r bone nd in osteones o
co p ct cortic l bone (Haversian systems), begins soon
er the trix is secreted (pri ry iner liz tion) but
is not co pleted or sever l weeks or even longer (sec-
ond ry iner liz tion). Although this iner liz tion
27/07/16 11:04 a m
 BMP s P TH, Vit D, IGFs, 425
BMP s, Wnts

Me s e nchyma l Os te obla s t Active

os te obla s t pre curs or os te obla s t
proge nitor
Runx 2 Colla ge n (I)
Alka line phos pha ta s e
Os te oca lcin, os te opontin

C
Bone s ia loprote in

H
A

A
P
T
E
R
M-CS F RANK Liga nd M-CS F RANK Liga nd

3
2
RANK Liga nd IL-1
IL-1,IL-6

B
o
Co mmitme nt Diffe re ntiatio n Fus io n

n
e
a
He ma topoie tic Os te ocla s t Mononucle a r Quie s ce nt Active

n
d
os te ocla s t pre curs or os te ocla s t os te ocla s t os te ocla s t

M
proge nitor

i
n
P U-1+ c-fos + c-s rc+

e
r
a
NKκB+ β3 inte grin+

l
M
TRAF+ PYK2 kina s e +

e
Ca the ps in K+

t
a
b
TRAF+

o
l
Ca rbonic a nhydra s e II+

i
s
B

m
i
n
FIGURE 3 2 -1

H
e
Pa th wa ys re g u la t in g d e ve lo p m e n t o f A o ste o b la st s a n d actor; NFκB, nuclear actor κB; PTH, parathyroid hormone; PU-1,

a
l
t
B o ste o cla sts. Hormones, cytokines, and growth actors that a monocyte- and B lymphocyte–speci c ets amily transcription

h
a
n
control cell proli eration and di erentiation are shown above the actor; RANK ligand, receptor activator o NFκB ligand; Runx2,

d
D
arrows. Transcription actors and other markers speci c or various Runt-related transcription actor 2; TRAF, tumor necrosis actor

i
s
e
stages o development are depicted below the arrows. BMPs, bone receptor–associated actors; Vit D, vitamin D; wnts, wingless-type

a
s
e
morphogenic proteins; IGFs, insulin-like growth actors; IL-1, inter- mouse mammary tumor virus integration site. (Modif ed rom
leukin 1; IL-6, interleukin 6; M-CSF, macrophage colony-stimulating TSuda et al: Endocr Rev 20:345, 1999, with permission.)

t kes dv nt ge o the high concentr tions o c l-
ciu nd phosph te, lre dy ne r s tur tion in seru ,
iner liz tion is c re ully regul ted process th t is
dependent on the ctivity o osteobl st-derived lk -
line phosph t se, which prob bly works by hydrolyzing
inhibitors o iner liz tion.
Genetic studies in hu ns nd ice h ve identi ed
sever l key genes th t control osteobl st develop ent.
Runx2 is tr nscription ctor expressed speci -
c lly in chondrocyte (c rtil ge cells) nd osteobl st
progenitors s well s in hypertrophic chondrocytes
nd ture osteobl sts. Runx2 regul tes the expres-
sion o sever l i port nt osteobl st proteins, includ-
ing osterix ( nother tr nscription ctor needed or
osteobl st tur tion), osteopontin, bone si loprotein,
type I coll gen, osteoc lcin, nd receptor- ctiv tor o
NFκB (RANK) lig nd. Runx2 expression is regul ted
in p rt by bone orphogenic proteins (BMPs). Runx2-
de cient ice re devoid o osteobl sts, where s ice
with deletion o only one llele (Runx2 +/−) exhibit
del y in or tion o the cl vicles nd so e cr ni l
bones. T e l tter bnor lities re si il r to those in
the hu n disorder cleidocranial dysplasia, which is
lso c used by heterozygous in ctiv ting ut tions in
Runx2.
T e p r crine sign ling olecule, Indi n hedge-
hog (Ihh), lso pl ys critic l role in osteobl st devel-
op ent, s evidenced by Ihh-de cient ice th t l ck
osteobl sts in the type o bone or ed on c rtil ge
old (endochondr l ossi c tion). Sign ls origin ting
ro e bers o the wnt (wingless-type ouse -
ry tu or virus integr tion site) ily o p r crine
ctors re lso i port nt or osteobl st proli er tion
nd di erenti tion. Nu erous other growth-regul tory
ctors ect osteobl st unction, including the three
closely rel ted tr ns or ing growth ctor βs, brobl st
growth ctors (FGFs) 2 nd 18, pl telet-derived growth
ctor, nd insulin-like growth ctors (IGFs) I nd II.
Hor ones such s p r thyroid hor one (P H) nd
1,25-dihydroxyvit in D (1,25[OH]2D) ctiv te recep-
tors expressed by osteobl sts to ssure iner l ho eo-
st sis nd in uence v riety o bone cell unctions.

Ha rris on_Endocrinology_Ch32_p423-p441.indd 425 27/07/16 11:04 a m

 426 Resorption o bone is c rried out inly by osteoclasts, or tion, chondrocytes proli er te, secrete nd in-
ultinucle ted cells th t re or ed by usion o cells er lize trix, enl rge (hypertrophy), nd then die,
derived ro the co on precursor o croph ges enl rging bone nd providing the trix nd ctors
nd osteocl sts. T us, these cells derive ro the he - th t sti ul te endochondr l bone or tion. T is pro-
topoietic line ge, quite di erent ro the esenchy l gr is regul ted by both loc l ctors, such s IGF-I
cells th t beco e osteobl sts. Multiple ctors th t regu- nd -II, Ihh, P H-rel ted peptide (P HrP), nd FGFs,
l te osteocl st develop ent h ve been identi ed (Fig. nd by syste ic hor ones, such s growth hor one,
32-1B). F ctors produced by osteobl sts or rrow stro- glucocorticoids, nd estrogen.
l cells llow osteobl sts to control osteocl st develop- New bone, whether or ed in in nts or in dults dur-
ent nd ctivity. M croph ge colony-sti ul ting ctor ing rep ir, h s rel tively high r tio o cells to trix
S
E
(M-CSF) pl ys critic l role during sever l steps in the nd is ch r cterized by co rse ber bundles o coll -
C
T
I
p thw y nd ulti tely le ds to usion o osteocl st pro- gen th t re interl ced nd r ndo ly dispersed (woven
O
N
genitor cells to or ultinucle ted, ctive osteocl sts. bone). In dults, the ore ture bone is org nized with
V
I
RANK lig nd, e ber o the tu or necrosis ctor ber bundles regul rly rr nged in p r llel or concen-
( NF) ily, is expressed on the sur ce o osteobl st tric sheets (l ell r bone). In long bones, deposition o
progenitors nd stro l brobl sts. In process involv- l ell r bone in concentric rr nge ent round blood
D
i
s
ing cell-cell inter ctions, RANK lig nd binds to the vessels or s the H versi n syste s. Growth in length o
o
r
d
RANK receptor on osteocl st progenitors, sti ul ting bones is dependent on proli er tion o c rtil ge cells nd
e
r
s
osteocl st di erenti tion nd ctiv tion. Altern tively, the endochondr l sequence t the growth pl te. Growth
o
f
B
soluble decoy receptor, re erred to s osteoprotegerin, c n in width nd thickness is cco plished by or tion o
o
n
e
bind RANK lig nd nd inhibit osteocl st di erenti tion. bone t the perioste l sur ce nd by resorption t the
a
n
Sever l growth ctors nd cytokines (including inter- endoste l sur ce, with the r te o or tion exceeding
d
C
leukins 1, 6, nd 11; NF; nd inter eron γ) odul te th t o resorption. In dults, er the growth pl tes o
a
l
c
i
osteocl st di erenti tion nd unction. Most hor ones c rtil ge close, growth in length nd endochondr l bone
u
m
th t in uence osteocl st unction do not t rget these cells or tion ce se except or so e ctivity in the c rtil ge
M
e
directly but inste d ct on cells o the osteobl st line ge cells bene th the rticul r sur ce. Even in dults, how-
t
a
b
to incre se production o M-CSF nd RANK. Both P H ever, re odeling o bone (within H versi n syste s s
o
l
i
s
nd 1,25(OH)2D incre se osteocl st nu ber nd ctiv- well s long the sur ces o tr becul r bone) continues
m
ity by this indirect ech nis . C lcitonin, in contr st, throughout li e. In dults, ~4% o the sur ce o tr becu-
binds to its receptor on the b s l sur ce o osteocl sts l r bone (such s ili c crest) is involved in ctive resorp-
nd directly inhibits osteocl st unction. Estr diol h s tion, where s 10–15% o tr becul r sur ces re covered
ultiple cellul r t rgets in bone, including osteocl sts, with osteoid, un iner lized new bone or ed by osteo-
i une cells, nd osteobl sts; ctions on ll these cells bl sts. R dioisotope studies indic te th t s uch s 18%
serve to decre se osteocl st nu ber nd decre se bone o the tot l skelet l c lciu is deposited nd re oved
resorption. e ch ye r. T us, bone is n ctive et bolizing tissue
Osteocl st- edi ted resorption o bone t kes pl ce th t requires n int ct blood supply. T e cycle o bone
in sc lloped sp ces (Howship’s lacunae) where the resorption nd or tion is highly orchestr ted pro-
osteocl sts re tt ched through speci c αvβ3 integrin cess c rried out by the b sic ulticellul r unit, which
to co ponents o the bone trix such s osteopon- is co posed o group o osteocl sts nd osteobl sts
tin. T e osteocl st or s tight se l to the underlying (Fig. 32-2).
trix nd secretes protons, chloride, nd protein ses T e response o bone to r ctures, in ection, nd
into con ned sp ce th t h s been likened to n extr - interruption o blood supply nd to exp nding lesions
cellul r lysoso e. T e ctive osteocl st sur ce or s is rel tively li ited. De d bone ust be resorbed, nd
ru ed border th t cont ins speci lized proton pu p new bone ust be or ed, process c rried out in
A P se th t secretes cid nd solubilizes the iner l ssoci tion with growth o new blood vessels into the
ph se. C rbonic nhydr se (type II isoenzy e) within involved re . In injuries th t disrupt the org niz tion
the osteocl st gener tes the needed protons. T e bone o the tissue such s r cture in which pposition o
trix is resorbed in the cid environ ent dj cent to r g ents is poor or when otion exists t the r cture
the ru ed border by prote ses, such s c thepsin K, site, progenitor stro l cells rec pitul te the endochon-
th t ct t low pH. dr l bone or tion o e rly develop ent nd or
In the e bryo nd the growing child, bone develops c rtil ge th t is repl ced by bone nd, v ri bly, brous
ostly by re odeling nd repl cing previously c lci ed tissue. When there is good pposition with x tion nd
c rtil ge (endochondr l bone or tion) or, in ew little otion t the r cture site, rep ir occurs predo i-
bones, is or ed without c rtil ge trix (intr e - n ntly by or tion o new bone without other edi t-
br nous bone or tion). During endochondr l bone ing tissue.

Ha rris on_Endocrinology_Ch32_p423-p441.indd 426 27/07/16 11:04 a m

 Os te ocla s t 427
pre curs or Os te obla s t
pre curs ors
Os te ocla s t Active os te ocla s t Os te obla s t Bo ne
re mo de ling
Lining ce lls unit

Re s ting
Os te oid
bone Ce me nt
s urfa ce Re s orption line
Ac tivatio n Reve rs al Bo ne fo rmatio n Mine ralizatio n
Os te ocyte
~3 we e ks ~3 months

C
H
A
FIGURE 3 2 -2

P
T
Sch e m atic re p re sen tatio n of b o n e rem o d e lin g. The cycle o Osteoclasts adhere to bone and subsequently remove it by acidi -

E
R
bone remodeling is carried out by the basic multicellular unit (BMU), cation and proteolytic digestion. As the BMU advances, osteoclasts

which consists o a group o osteoclasts and osteoblasts. In cortical
bone, the BMUs tunnel through the tissue, whereas in cancellous
bone, they move across the trabecular sur ace. The process o bone
3
2
leave the resorption site and osteoblasts move in to cover the exca-
vated area and begin the process o new bone ormation by secret-
ing osteoid, which eventually is mineralized into new bone. A ter

B
o
n
remodeling is initiated by contraction o the lining cells and the osteoid mineralization, osteoblasts atten and orm a layer o lining

e
a
recruitment o osteoclast precursors. These precursors use to orm cells over new bone.

n
d
multinucleated, active osteoclasts that mediate bone resorption.

M
i
n
e
r
a
Re odeling o bone occurs long lines o orce gen- provides ech nic l st bility nd serves s reservoir

l
M
e
er ted by ech nic l stress. T e sign ls ro these so eti es needed to int in extr cellul r uid (ECF)

t
a
b
ech nic l stresses re sensed by osteocytes, which c lciu concentr tion (Fig. 32-3). Skelet l c lciu

o
l
i
tr ns it sign ls to osteocl sts nd osteobl sts or their ccretion rst beco es signi c nt during the third tri-

s
m
precursors. One such sign l de by osteocytes is ester o et l li e, cceler tes throughout childhood

i
n
H
sclerostin, n inhibitor o wnt sign ling. Mech nic l nd dolescence, re ches pe k in e rly dulthood, nd

e
a
l
orces suppress sclerostin production nd thus incre se gr du lly declines there er t r tes th t r rely exceed

t
h
a
bone or tion by osteobl sts. Exp nding lesions in

n
d
bone such s tu ors induce resorption t the sur-

D
i
s
ce in cont ct with the tu or by producing lig nds

e
0.4–1.5 g

a
s
e
such s P HrP th t sti ul te osteocl st di erenti -
tion nd unction. Even in disorder s rchitectur-
lly disruptive s P get’s dise se, re odeling is dict ted 0.25–0.5 g 0.25–0.5 g
by ech nic l orces. T us, bone pl sticity re ects ECF
1000–2000 g
0.1–0.2 g 1–2 g 0.25–0.5 g
the inter ction o cells with e ch other nd with the
environ ent.
Me sure ent o the products o osteobl st nd 8–10 g 7.9–9.7 g
osteocl st ctivity c n ssist in the di gnosis nd n- Inte s tine Bo ne
ge ent o bone dise ses. Osteobl st ctivity c n be
ssessed by e suring seru bone-speci c lk line
0.3–1 g
phosph t se. Si il rly, osteoc lcin, protein secreted
ro osteobl sts, is de virtu lly only by osteobl sts.
Osteocl st ctivity c n be ssessed by e sure ent o
Kidne y
products o coll gen degr d tion. Coll gen olecules
re cov lently linked to e ch other in the extr cellul r
trix through the or tion o hydroxypyridiniu 0.15–.3 g
cross-links. A er digestion by osteocl sts, these cross- FIGURE 3 2 -3
linked peptides c n be e sured both in urine nd in Ca lciu m h o m e o st a sis. Schematic illustration o calcium con-
blood. tent o extracellular uid (ECF) and bone as well as o diet and
eces; magnitude o calcium ux per day as calculated by various
methods is shown at sites o transport in intestine, kidney, and
CALCIUM METABO LISM bone. Ranges o values shown are approximate and were chosen
to illustrate certain points discussed in the text. In conditions o
Over 99% o the 1–2 kg o c lciu present nor lly in calcium balance, rates o calcium release rom and uptake into
the dult hu n body resides in the skeleton, where it bone are equal.

Ha rris on_Endocrinology_Ch32_p423-p441.indd 427 27/07/16 11:04 a m

 428 1–2% per ye r. T ese slow ch nges in tot l skelet l c l- Nor l diet ry c lciu int ke in the United St tes
ciu content contr st with rel tively high d ily r tes o v ries widely, r nging ro 10–37 ol/d (400–1500
closely tched uxes o c lciu into nd out o bone g/d). An Institute o Medicine report reco ends
(~250–500 g e ch), process edi ted by coupled d ily llow nce o 25–30 ol (1000–1200 g) or
osteobl stic nd osteocl stic ctivity. Another 0.5–1% o ost dults. Intestin l bsorption o ingested c lciu
skelet l c lciu is reely exch nge ble (e.g., in che ic l involves both ctive (tr nscellul r) nd p ssive (p r cel-
equilibriu ) with th t in the ECF. lul r) ech nis s. P ssive c lciu bsorption is non-
T e concentr tion o ionized c lciu in the ECF s tur ble nd pproxi tes 5% o d ily c lciu int ke,
ust be int ined within n rrow r nge bec use o where s ctive bsorption involves pic l c lciu entry
the critic l role c lciu pl ys in wide rr y o cel- vi speci c ion ch nnels ( RPV5 nd RPV6), whose
S
E
lul r unctions, especi lly those involved in neuro- expression is controlled princip lly by 1,25(OH)2D, nd
C
T
I
uscul r ctivity, secretion, nd sign l tr nsduction. nor lly r nges ro 20 to 70%. Active c lciu tr ns-
O
N
Intr cellul r cytosolic ree c lciu levels re ~100 port occurs inly in the proxi l s ll bowel (duo-
V
I
n ol/L nd re 10,000- old lower th n ionized c l- denu nd proxi l jejunu ), lthough so e ctive
ciu concentr tions in the blood nd ECF (1.1–1.3 c lciu bsorption occurs in ost seg ents o the
ol/L). Cytosolic c lciu does not pl y the struc- s ll intestine. Opti l r tes o c lciu bsorption
D
i
s
tur l role pl yed by extr cellul r c lciu ; inste d, it require g stric cid. T is is especi lly true or we kly
o
r
d
serves sign ling unction. T e steep che ic l gr - dissoci ble c lciu supple ents such s c lciu c r-
e
r
s
dient o c lciu ro outside to inside the cell pro- bon te. In ct, l rge boluses o c lciu c rbon te re
o
f
B
otes r pid c lciu in ux through v rious e br ne poorly bsorbed bec use o their neutr lizing e ect
o
n
e
c lciu ch nnels th t c n be ctiv ted by hor ones, on g stric cid. In chlorhydric subjects nd or those
a
n
et bolites, or neurotr ns itters, swi ly ch nging t king drugs th t inhibit g stric cid secretion, supple-
d
C
cellul r unction. In blood, tot l c lciu concentr - ents should be t ken with e ls to opti ize their
a
l
c
i
tion is nor lly 2.2–2.6 M (8.5–10.5 g/dL), o bsorption. Use o c lciu citr te y be pre er ble in
u
m
which ~50% is ionized. T e re inder is bound ioni- these circu st nces. C lciu bsorption y lso be
M
e
c lly to neg tively ch rged proteins (predo in ntly blunted in dise se st tes such s p ncre tic or bili ry
t
a
b
lbu in nd i unoglobulins) or loosely co plexed insuf ciency, in which ingested c lciu re ins bound
o
l
i
s
with phosph te, citr te, sul te, or other nions. Alter- to un bsorbed tty cids or other ood constituents. At
m
tions in seru protein concentr tions directly ect high levels o c lciu int ke, synthesis o 1,25(OH)2D
the tot l blood c lciu concentr tion even i the ion- is reduced; this decre ses the r te o ctive intestin l
ized c lciu concentr tion re ins nor l. An lgo- c lciu bsorption. T e opposite occurs with diet ry
rith to correct or protein ch nges djusts the tot l c lciu restriction. So e c lciu , ~2.5–5 ol/d
seru c lciu (in g/dL) upw rd by 0.8 ti es the (100–200 g/d), is excreted s n oblig te co ponent
de cit in seru lbu in (g/dL) or by 0.5 ti es the o intestin l secretions nd is not regul ted by c lciotro-
de cit in seru i unoglobulin (in g/dL). Such cor- pic hor ones.
rections provide only rough pproxi tions o ctu l T e eedb ck-controlled hor on l regul tion
ree c lciu concentr tions, however, nd y be o intestin l bsorptive ef ciency results in rel -
isle ding, p rticul rly during cute illness. Acidosis tively const nt d ily net c lciu bsorption o ~5–7.5
lso lters ionized c lciu by reducing its ssoci tion ol/d (200–400 g/d) despite l rge ch nges in d ily
with proteins. T e best pr ctice is to e sure blood diet ry c lciu int ke. T is d ily lo d o bsorbed
ionized c lciu directly by ethod th t e ploys c lciu is excreted by the kidneys in nner th t is
c lciu -selective electrodes in cute settings during lso tightly regul ted by the concentr tion o ionized
which c lciu bnor lities ight occur. c lciu in the blood. Approxi tely 8–10 g/d o c l-
Control o the ionized c lciu concentr tion in the ciu is ltered by the glo eruli, o which only 2–3%
ECF ordin rily is cco plished by djusting the r tes o ppe rs in the urine. Most ltered c lciu (65%) is
c lciu ove ent cross intestin l nd ren l epitheli . re bsorbed in the proxi l tubules vi p ssive, p r -
T ese djust ents re edi ted inly vi ch nges in cellul r route th t is coupled to conco it nt N Cl
blood levels o the hor ones, P H nd 1,25(OH)2D. re bsorption nd not speci c lly regul ted. T e corti-
Blood ionized c lciu directly suppresses P H secre- c l thick scending li b o Henle’s loop (c AL) re b-
tion by ctiv ting c lciu -sensing receptors (C SRs) sorbs roughly nother 20% o ltered c lciu , lso vi
in p r thyroid cells. Also, ionized c lciu indirectly p r cellul r ech nis . C lciu re bsorption in the
ects P H secretion by lowering 1,25(OH)2D produc- c AL requires tight-junction l protein c lled p r -
tion. T is ctive vit in D et bolite inhibits P H cellin-1 nd is inhibited by incre sed blood concentr -
production by n inco pletely understood ech nis tions o c lciu or gnesiu , cting vi the C SR,
o neg tive eedb ck (Chap. 34). which is highly expressed on b sol ter l e br nes

Ha rris on_Endocrinology_Ch32_p423-p441.indd 428 27/07/16 11:04 a m

 in this nephron seg ent. Oper tion o the ren l C SR
provides ech nis , independent o those eng ged
directly by P H or 1,25(OH)2D, by which seru ion-
ized c lciu c n control ren l c lciu re bsorption.
Fin lly, ~10% o ltered c lciu is re bsorbed in the
dist l convoluted tubules (DC s) by tr nscellul r
ech nis . C lciu enters the lu in l sur ce o the
cell through speci c pic l c lciu ch nnels ( RPV5),
whose nu ber is regul ted. It then oves cross the
cell in ssoci tion with speci c c lciu -binding pro-
intr cellul r constituent both s the ree nion(s) nd 429
s co ponent o nu erous org nophosph te co -
pounds, including structur l proteins, enzy es, tr n-
scription ctors, c rbohydr te nd lipid inter edi tes,
high-energy stores ( denosine triphosph te [A P],
cre tine phosph te), nd nucleic cids. Unlike c lciu ,
phosphorus exists intr cellul rly t concentr tions close
to those present in ECF (e.g., 1–2 ol/L). In cells nd
in the ECF, phosphorus exists in sever l or s, pre-
do in ntly s H 2PO4− or N HPO4−, with perh ps 10%

C
H
A
tein (c lbindin-D28k) th t bu ers cytosolic c lciu s HPO42−. T is ixture o nions will be re erred to

P
T
concentr tions ro the l rge ss o tr nsported c l- here s “phosph te.” In seru , bout 12% o phospho-

E
R
ciu . C 2+-A P ses nd N +/C 2+ exch ngers ctively rus is bound to proteins. Concentr tions o phosph tes

3
2
extrude c lciu cross the b sol ter l sur ce nd in blood nd ECF gener lly re expressed in ter s o
thereby int in the tr nscellul r c lciu gr dient. ele ent l phosphorus, with the nor l r nge in dults
All these processes re sti ul ted directly or indi- being 0.75–1.45 ol/L (2.5–4.5 g/dL). Bec use the

B
o
n
rectly by P H. T e DC is lso the site o ction o volu e o the intr cellul r uid co p rt ent is twice

e
a
thi zide diuretics, which lower urin ry c lciu excre- th t o the ECF, e sure ents o ECF phosph te y

n
d
tion by inducing sodiu depletion nd thereby ug- not ccur tely re ect phosph te v il bility within cells

M
i
n
enting proxi l c lciu re bsorption. Conversely, th t ollows even odest shi s o phosph te ro one

e
r
a
diet ry sodiu lo ds, or incre sed dist l sodiu deliv- co p rt ent to the other.

l
M
ery c used by loop diuretics or s line in usion, induce Phosph te is widely v il ble in oods nd is

e
t
a
c lciuresis. bsorbed ef ciently (65%) by the s ll intestine even

b
o
l
i
T e ho eost tic ech nis s th t nor lly in- in the bsence o vit in D. However, phosph te

s
m
t in const nt seru ionized c lciu concentr tion bsorptive ef ciency y be enh nced (to 85–90%)

i
n
H
y il t extre es o c lciu int ke or when the vi ctive tr nsport ech nis s th t re sti ul ted by

e
a
l
hor on l syste s or org ns involved re co pro- 1,25(OH)2D. T ese ech nis s involve ctiv tion o

t
h
a
ised. T us, even with xi l ctivity o the vit in N +/PO42− co-tr nsporters th t ove phosph te into

n
d
D–dependent intestin l ctive tr nsport syste , sus- intestin l cells g inst n un vor ble electroche i-

D
i
s
t ined c lciu int kes <5 ol/d (<200 g/d) c n- c l gr dient. D ily net intestin l phosph te bsorp-

e
a
s
not provide enough net c lciu bsorption to repl ce tion v ries widely with the co position o the diet but

oblig te losses vi the intestine, the kidney, swe t, nd
other secretions. In this c se, incre sed blood levels o
P H nd 1,25(OH)2D ctiv te osteocl stic bone resorp-
tion to obt in needed c lciu ro bone, which le ds
to progressive bone loss nd neg tive c lciu b l nce.
Incre sed P H nd 1,25(OH)2D lso enh nce ren l c l-
ciu re bsorption, nd 1,25(OH)2D enh nces c lciu
bsorption in the gut. At very high c lciu int kes
(>100 ol/d [>4 g/d]), p ssive intestin l bsorp-
tion continues to deliver c lciu into the ECF despite
xi lly downregul ted intestin l ctive tr nsport
nd ren l tubul r c lciu re bsorption. T is c n c use
severe hyperc lciuri , nephroc lcinosis, progressive
ren l ilure, nd hyperc lce i (e.g., “ ilk- lk li syn-
dro e”). De ciency or excess o P H or vit in D,
intestin l dise se, nd ren l ilure represent other
co only encountered ch llenges to nor l c lciu
ho eost sis (Chap. 34).
P HO SP HO RUS METABO LISM
Although 85% o the ~600 g o body phosphorus is
present in bone iner l, phosphorus is lso jor
e
is gener lly in the r nge o 500–1000 g/d. Phosph te
bsorption c n be inhibited by l rge doses o c lciu
s lts or by sevel er hydrochloride (Ren gel), str te-
gies co only used to control levels o seru phos-
ph te in ren l ilure. Alu inu hydroxide nt cids
lso reduce phosph te bsorption but re used less
co only bec use o the potenti l or lu inu tox-
icity. Low seru phosph te sti ul tes ren l proxi l
tubul r synthesis o 1,25(OH)2D, perh ps by suppress-
ing blood levels o FGF23 (see below).
Seru phosph te levels v ry by s uch s 50% on
nor l d y. T is re ects the e ect o ood int ke but
lso n underlying circ di n rhyth th t produces
n dir between 7:00 nd 10:00 a .m. C rbohydr te
d inistr tion, especi lly s IV dextrose solutions in
sting subjects, c n decre se seru phosph te by >0.7
ol/L (2 g/dL) due to r pid upt ke into nd utiliz -
tion by cells. A si il r response is observed in the tre t-
ent o di betic keto cidosis nd during et bolic or
respir tory lk losis. Bec use o this wide v ri tion in
seru phosph te, it is best to per or e sure ents in
the b s l, sting st te.
Control o seru phosph te is deter ined inly
by the r te o ren l tubul r re bsorption o the ltered

Ha rris on_Endocrinology_Ch32_p423-p441.indd 429 27/07/16 11:04 a m

 430 lo d, which is ~4–6 g/d. Bec use intestin l phos- TABLE 3 2 -1
ph te bsorption is highly ef cient, urin ry excretion CAUSES OF HYPOPHOSPHATEMIA
is not const nt but v ries directly with diet ry int ke. I. Reduced renal tubular phosphate reabsorption
T e r ction l excretion o phosph te (r tio o phos- A. PTH/PTHrP-dependent
ph te to cre tinine cle r nce) is gener lly in the r nge 1. Primary hyperparathyroidism
o 10–15%. T e proxi l tubule is the princip l site t
2. Secondary hyperparathyroidism
which ren l phosph te re bsorption is regul ted. T is is
cco plished by ch nges in the levels o pic l expres- a. Vitamin D de ciency/resistance
sion nd ctivity o speci c N +/PO42− co-tr nsporters b. Calcium starvation/malabsorption
(N Pi-2 nd N Pi-2c) in the proxi l tubule. Levels
S
c. Bartter’s syndrome
E
o these tr nsporters t the pic l sur ce o these cells
C
T
d. Autosomal recessive renal hypercalciuria with
I
re reduced r pidly by P H, jor hor on l regu-
O
hypomagnesemia
N
l tor o ren l phosph te excretion. FGF23 c n i p ir
V
3. PTHrP-dependent hypercalcemia o malignancy
I
phosph te re bsorption dr tic lly by si il r ech-
4. Familial hypocalciuric hypercalcemia
nis . Activ ting FGF23 ut tions c use the r re dis-
order utoso l do in nt hypophosph te ic rickets. B. PTH/PTHrP-independent
D
i
s
In contr st to P H, FGF23 lso le ds to reduced syn-
o
1. Excess FGF23 or other “phosphatonins”
r
d
thesis o 1,25(OH)2D, which y worsen the resulting
e
a. X-linked hypophosphatemic rickets (XLH)
r
s
hypophosph te i by lowering intestin l phosph te
o
f
b. Autosomal recessive hypophosphatemia (ARHP)
B
bsorption. Ren l re bsorption o phosph te is respon-
o
n
c. Autosomal dominant hypophosphatemic rickets
e
sive to ch nges in diet ry int ke such th t experi ent l
a
(ADHR) (DMP1, ENPP1 de ciency)
n
diet ry phosph te restriction le ds to dr tic lower-
d
d. Tumor-induced osteomalacia syndrome (TIO)
C
ing o urin ry phosph te within hours, preceding ny
a
l
c
e. McCune-Albright syndrome ( brous dysplasia)
i
decline in seru phosph te (e.g., ltered lo d). T is
u
m
physiologic ren l d pt tion to ch nges in diet ry phos- . Epidermal nevus syndrome
M
e
ph te v il bility occurs independently o P H nd
t
2. Intrinsic renal disease
a
b
y be edi ted in p rt by ch nges in levels o seru
o
a. Fanconi’s syndrome(s)
l
i
s
FGF23. Findings in FGF23-knockout ice suggest th t
m
b. Cystinosis
FGF23 nor lly cts to lower blood phosph te nd
c. Wilson’s disease
1,25(OH)2D levels. In turn, elev tion o blood phos-
ph te incre ses blood levels o FGF23. d. NaPi-2a or NaPi-2c mutations
Ren l phosph te re bsorption is i p ired by hypo- 3. Other systemic disorders
c lce i , hypo gnese i , nd severe hypophosph - a. Poorly controlled diabetes mellitus
te i . Phosph te cle r nce is enh nced by ECF volu e b. Alcoholism
exp nsion nd i p ired by dehydr tion. Phosph te
c. Hyperaldosteronism
retention is n i port nt p thophysiologic e ture o
ren l insuf ciency. d. Hypomagnesemia
e. Amyloidosis
. Hemolytic-uremic syndrome
HYPOPHOSPHATEMIA
g. Renal transplantation or partial liver resection
Ca u ses h. Rewarming or induced hyperthermia
Hypophosph te i c n occur by one or ore o three 4. Drugs or toxins
pri ry ech nis s: (1) in dequ te intestin l phos- a. Ethanol
ph te bsorption, (2) excessive ren l phosph te excre- b. Acetazolamide, other diuretics
tion, nd (3) r pid redistribution o phosph te ro
c. High-dose estrogens or glucocorticoids
the ECF into bone or so tissue (Table 32-1). Bec use
phosph te is so bund nt in oods, in dequ te intestin l d. Heavy metals (lead, cadmium, saccharated erric
oxide)
bsorption is l ost never observed now th t lu inu
hydroxide nt cids, which bind phosph te in the gut, re e. Toluene, N-methyl ormamide
no longer widely used. F sting or st rv tion, however, . Cisplatin, i os amide, oscarnet, rapamycin
y result in depletion o body phosph te nd predis- II. Impaired intestinal phosphate absorption
pose to subsequent hypophosph te i during re eeding, A. Aluminum-containing antacids
especi lly i this is cco plished with IV glucose lone.
B. Sevelamer
Chronic hypophosph te i usu lly signi es per-
sistent ren l tubul r phosph te-w sting disorder. (continued)

Ha rris on_Endocrinology_Ch32_p423-p441.indd 430 27/07/16 11:04 a m

 TABLE 3 2 -1
CAUSES OF HYPOPHOSPHATEMIA (CONTINUED)
III. Shi ts o extracellular phosphate into cells
A. Intravenous glucose
B. Insulin therapy or prolonged hyperglycemia or diabetic
ketoacidosis
C. Catecholamines (epinephrine, dopamine, albuterol)
D. Acute respiratory alkalosis
in ctiv tion o int ct FGF23. Sever l other genetic dis- 431
orders exhibit elev ted FGF23 nd hypophosph te i .
T e ost co on o these is X-linked hypophosph -
te ic rickets (XLH), which results ro in ctiv ting
ut tions in n endopeptid se ter ed PHEX (phos-
ph te-regul ting gene with ho ologies to endopep-
tid ses on the X chro oso e) th t is expressed ost
bund ntly on the sur ce o osteocytes nd ture
osteobl sts. P tients with XLH usu lly h ve high FGF23

C
E. Gram-negative sepsis, toxic shock syndrome levels, nd bl tion o the FGF23 gene reverses the

H
A
F. Recovery rom starvation or acidosis hypophosph te i ound in the ouse version o XLH.

P
T
How in ctiv tion o PHEX le ds to incre sed levels o

E
G. Rapid cellular proli eration

R
FGF23 h s not been deter ined. wo r re utoso l

3
1. Leukemic blast crisis

2
recessive hypophosph te ic syndro es ssoci ted
2. Intensive erythropoietin, other growth actor therapy with elev ted FGF23 re due to in ctiv ting ut tions
IV. Accelerated net bone ormation o dentin trix protein-1 (DMP1) nd ectonucleotide

B
o
n
A. A ter parathyroidectomy pyrophosph t se/phosphodiester se 1 (ENPP1), both

e
a
o which nor lly re highly expressed in bone nd

n
B. Treatment o vitamin D de ciency, Paget’s disease

d
regul te FGF23 production. An unusu l hypophosph -

M
C. Osteoblastic metastases

i
n
te ic disorder, tu or-induced osteo l ci ( IO), is

e
r
a
n cquired disorder in which tu ors, usu lly o es-

l
M
Ab brevia tio n s: PTH, parathyroid hormone; PTHrP, parathyroid hor-
enchy l origin nd gener lly histologic lly benign,

e
mone–related peptide.

t
a
b
secrete FGF23 nd/or other olecules th t induce ren l

o
l
i
phosph te w sting. T e hypophosph te ic syndro e

s
m
Excessive ctiv tion o P H/P HrP receptors in the resolves co pletely within hours to d ys er success-

i
n
H
proxi l tubule s result o pri ry or second- ul resection o the responsible tu or. Such tu ors

e
a
l
ry hyperp r thyroidis or bec use o the P HrP- typic lly express l rge ounts o FGF23 RNA, nd

t
h
a
edi ted hyperc lce i syndro e in lign ncy p tients with IO usu lly exhibit elev tions o FGF23 in

n
d
(Chap. 34) is ong the ore co on c uses o ren l their blood.

D
i
s
hypophosph te i , especi lly bec use o the high Dent’s dise se is n X-linked recessive disorder

e
a
s
prev lence o vit in D de ciency in older A eri- c used by in ctiv ting ut tions in CLCN5, chloride

c ns. F ili l hypoc lciuric hyperc lce i nd J nsen’s
chondrodystrophy re r re ex ples o genetic disor-
ders in this c tegory (Chap. 34).
Sever l genetic nd cquired dise ses c use P H/
P HrP-independent tubul r phosph te w sting with
ssoci ted rickets nd osteo l ci . All these dise ses
ni est severe hypophosph te i ; ren l phosph te
w sting, so eti es cco p nied by ino ciduri ;
in ppropri tely low blood levels o 1,25(OH)2D; low-
nor l seru levels o c lciu ; nd evidence o
i p ired c rtil ge or bone iner liz tion. An lysis
o these dise ses led to the discovery o the hor one
FGF23, which is n i port nt physiologic regul tor o
phosph te et bolis . FGF23 decre ses phosph te
re bsorption in the proxi l tubule nd lso sup-
presses the 1α-hydroxyl se responsible or synthesis o
1,25(OH)2D. FGF23 is synthesized by cells o the osteo-
bl st line ge, pri rily osteocytes. High-phosph te
diets incre se FGF23 levels, nd low-phosph te diets
decre se the . Autoso l do in nt hypophosph -
te ic rickets (ADHR) w s the rst dise se linked to
bnor lities in FGF23. ADHR results ro ctiv t-
ing ut tions in the gene th t encodes FGF23. T ese
ut tions lter cle v ge site th t ordin rily llows or
e
tr nsporter expressed in endoso es o the proxi l
tubule; e tures include hyperc lciuri , hypophosph -
te i , nd recurrent kidney stones. Ren l phosph te
w sting is co on ong poorly controlled di betic
p tients nd lcoholics, who there ore re t risk or
i trogenic hypophosph te i when tre ted with insu-
lin or IV glucose, respectively. Diuretics nd cert in
other drugs nd toxins c n c use de ective ren l tubul r
phosph te re bsorption ( ble 32-1).
In hospit lized p tients, hypophosph te i is o en
ttribut ble to ssive redistribution o phosph te ro
the ECF into cells. Insulin ther py or di betic keto-
cidosis is p r dig or this pheno enon, in which
the severity o the hypophosph te i is rel ted to the
extent o ntecedent depletion o phosph te nd other
electrolytes (Chap. 23). T e hypophosph te i is usu-
lly gre test t point ny hours er initi tion o
insulin ther py nd is dif cult to predict ro b seline
e sure ents o seru phosph te t the ti e o pre-
sent tion, when preren l zote i c n obscure sig-
ni c nt phosph te depletion. Other ctors th t y
contribute to such cute redistributive hypophosph -
te i include ntecedent st rv tion or lnutrition,
d inistr tion o IV glucose without other nutrients,

Ha rris on_Endocrinology_Ch32_p423-p441.indd 431 27/07/16 11:04 a m

 432 elev ted blood c techol ines (endogenous or exog- con usion, nd seizures re likely only t phosph te
enous), respir tory lk losis, nd recovery ro et - concentr tions <0.25 ol/L (<0.8 g/dL). Rh b-
bolic cidosis. do yolysis y develop during r pidly progressive
Hypophosph te i lso c n occur tr nsiently (over hypophosph te i . T e di gnosis o hypophosph te-
weeks to onths) during the ph se o cceler ted net i -induced rh bdo yolysis y be overlooked, s
bone or tion th t ollows p r thyroidecto y or up to 30% o p tients with cute hypophosph te i
severe pri ry hyperp r thyroidis or during tre t- (<0.7 M) h ve cre tine phosphokin se elev tions th t
ent o vit in D de ciency or lytic P get’s dise se. pe k 1–2 d ys er the n dir in seru phosph te, when
T is is usu lly ost pro inent in p tients who pre- the rele se o phosph te ro injured yocytes y
oper tively h ve evidence o high bone turnover (e.g., h ve led to ne r nor liz tion o circul ting levels o
S
E
high seru levels o lk line phosph t se). Osteobl stic phosph te.
C
T
I
et st ses c n lso le d to this syndro e. Respir tory ilure nd c rdi c dys unction, which
O
N
re reversible with phosph te tre t ent, y occur
V
I
Clin ica l a n d la b o ra to ry f nd in g s t seru phosph te levels o 0.5–0.8 ol/L (1.5–2.5
g/dL). Ren l tubul r de ects, including tubul r ci-
T e clinic l ni est tions o severe hypophosph te i dosis, glycosuri , nd i p ired re bsorption o sodiu
D
i
s
re ect gener lized de ect in cellul r energy et bo- nd c lciu , y occur. He tologic bnor li-
o
r
d
lis bec use o A P depletion, shi ro oxid tive ties correl te with reductions in intr cellul r A P nd
e
r
s
phosphoryl tion tow rd glycolysis, nd ssoci ted tis- 2,3-diphosphoglycer te nd y include erythrocyte
o
f
sue or org n dys unction. Acute, severe hypophos-
B
icrospherocytosis nd he olysis; i p ired oxyhe-
o
n
ph te i occurs inly or exclusively in hospit lized
e
oglobin dissoci tion; de ective leukocyte che ot xis,
a
p tients with underlying serious edic l or surgi-
n
ph gocytosis, nd b cteri l killing; nd pl telet dys-
d
C
c l illness nd preexisting phosph te depletion due to unction with spont neous g strointestin l he orrh ge.
a
l
c
excessive urin ry losses, severe l bsorption, or l-
i
u
m
nutrition. Chronic hypophosph te i tends to be less
M
e
severe, with clinic l present tion do in ted by us-
t
a
b
culoskelet l co pl ints such s bone p in, osteo l - TREATMENT Hypophosphatemia
o
l
i
ci , pseudo r ctures, nd proxi l uscle we kness or,
s
m
in children, rickets nd short st ture. Severe hypophosph te i (<0.75 ol/L [<2 g/dL]), p r-
Neuro uscul r ni est tions o severe hypophos- ticul rly in the setting o underlying phosph te depletion,
ph te i re v ri ble but y include uscle we k- constitutes d ngerous electrolyte bnor lity th t should
ness, leth rgy, con usion, disorient tion, h llucin tions, be corrected pro ptly. Un ortun tely, the cu ul tive de cit
dys rthri , dysph gi , oculo otor p lsies, nisoco- in body phosph te c nnot be predicted e sily ro knowl-
ri , nyst g us, t xi , cerebell r tre or, b llis us, edge o the circul ting level o phosph te, nd ther py ust
hypore exi , i p ired sphincter control, dist l sen- be ppro ched e piric lly. T e threshold or IV phosph te
sory de cits, p resthesi , hyperesthesi , gener lized or ther py nd the dose d inistered should re ect consid-
Guill in-B rré–like scending p r lysis, seizures, co , er tion o ren l unction, the likely severity nd dur tion o
nd even de th. Serious sequel e such s p r lysis, the underlying phosph te depletion, nd the presence nd

TABLE 3 2 -2
INTRAVENOUS THERAPY FOR HYPOPHOSPHATEMIA
Co n sid e r
Likely severity o underlying phosphate depletion
Concurrent parenteral glucose administration
Presence o neuromuscular, cardiopulmonary, or hematologic complications o hypophosphatemia
Renal unction (reduce dose by 50% i serum creatinine >220 µmol/L [>2.5 mg/dL])
Serum calcium level (correct hypocalcemia rst; reduce dose by 50% in hypercalcemia)
Guidelines
Serum Phosp h oru s, m M m g/d L Ra te o f In fu sio n , m m o l/h Du ra t io n , h To t a l Ad m in iste re d , m m o l
<0.8 (<2.5) 2 6 12
<0.5 (<1.5) 4 6 24
<0.3 (<1) 8 6 48

No te: Rates shown are calculated or a 70-kg person; levels o serum calcium and phosphorus must be measured every 6–12 h during therapy; in usions
can be repeated to achieve stable serum phosphorus levels >0.8 mmol/L (>2.5 mg/dL); most ormulations available in the United States provide
3 mmol/mL o sodium or potassium phosphate.

Ha rris on_Endocrinology_Ch32_p423-p441.indd 432 27/07/16 11:04 a m

 severity o sy pto s consistent with those o hypophos- TABLE 3 2 -3 433
ph te i . In dults, phosph te y be s ely d inistered CAUSES OF HYPERPHOSPHATEMIA
IV s neutr l ixtures o sodiu or pot ssiu phosph te I. Impaired renal phosphate excretion
s lts t initi l doses o 0.2–0.8 ol/kg o ele ent l phos- A. Renal insuf ciency
phorus over 6 h (e.g., 10–50 ol over 6 h), with doses B. Hypoparathyroidism
>20 ol/6 h reserved or those who h ve seru levels 1. Developmental
<0.5 ol/L (1.5 g/dL) nd nor l ren l unction. A sug- 2. Autoimmune
gested ppro ch is presented in Table 32-2. Seru levels o 3. A ter neck surgery or radiation
4. Activating mutations o the calcium-sensing receptor
phosph te nd c lciu ust be onitored closely (every
C. Parathyroid suppression

C
6–12 h) throughout tre t ent. It is necess ry to void 1. Parathyroid-independent hypercalcemia

H
A
seru c lciu -phosphorus product >50 to reduce the risk a. Vitamin D or vitamin A intoxication

P
T
o heterotopic c lci c tion. Hypoc lce i , i present, should b. Sarcoidosis, other granulomatous diseases

E
R
be corrected be ore d inistering IV phosph te. Less severe c. Immobilization, osteolytic metastases

3
2
hypophosph te i , in the r nge o 0.5–0.8 ol/L (1.5–2.5 d. Milk-alkali syndrome
g/dL), usu lly c n be tre ted with or l phosph te in divided 2. Severe hypermagnesemia or hypomagnesemia
D. Pseudohypoparathyroidism
doses o 750–2000 g/d s ele ent l phosphorus; higher

B
o
E. Acromegaly

n
doses c n c use blo ting nd di rrhe .

e
F. Tumoral calcinosis

a
M n ge ent o chronic hypophosph te i requires

n
G. Heparin therapy

d
knowledge o the c use(s) o the disorder. Hypophosph te-

M
II. Massive extracellular uid phosphate loads

i
n
i rel ted to the second ry hyperp r thyroidis o vit - A. Rapid administration o exogenous phosphate (intrave-

e
r
a
in D de ciency usu lly responds to tre t ent with vit in nous, oral, rectal)

l
M
D nd c lciu lone. XLH, ADHR, IO, nd rel ted ren l B. Extensive cellular injury or necrosis

e
t
a
1. Crush injuries

b
tubul r disorders usu lly re n ged with divided or l

o
2. Rhabdomyolysis

l
i
doses o phosph te, o en with c lciu nd 1,25(OH)2D sup-

s
m
3. Hyperthermia
ple ents to byp ss the block in ren l 1,25(OH)2D synthesis

i
n
4. Fulminant hepatitis

H
nd prevent second ry hyperp r thyroidis c used by sup- 5. Cytotoxic therapy

e
a
l
pression o ECF c lciu levels. T i zide diuretics y be 6. Severe hemolytic anemia

t
h
a
used to prevent nephroc lcinosis in p tients who re n- C. Transcellular phosphate shi ts

n
d
ged this w y. Co plete nor liz tion o hypophosph te i 1. Metabolic acidosis

D
i
2. Respiratory acidosis

s
is gener lly not possible in these conditions. Opti l ther py

e
a
s
or IO is extirp tion o the responsible tu or, which y

be loc lized by r diogr phic skelet l survey or bone sc n
( ny re loc ted in bone) or by r dionuclide sc nning
using sest ibi or l beled octreotide. Success ul tre t ent
o IO-induced hypophosph te i with octreotide h s been
reported in s ll nu ber o p tients.
HYPERPHOSPHATEMIA
Ca u ses
When the ltered lo d o phosph te nd glo erul r l-
tr tion r te (GFR) re nor l, control o seru phos-
ph te levels is chieved by djusting the r te t which
phosph te is re bsorbed by the proxi l tubul r N Pi-2
co-tr nsporters. T e princip l hor on l regul tors o
N Pi-2 ctivity re P H nd FGF23. Hyperphosph -
te i , de ned in dults s sting seru phosph te
concentr tion >1.8 ol/L (5.5 g/dL), usu lly results
ro i p ired glo erul r ltr tion, hypop r thyroid-
is , excessive delivery o phosph te into the ECF ( ro
bone, gut, or p renter l phosph te ther py), or co -
bin tion o these ctors (Table 32-3). T e upper li it
o nor l seru phosph te concentr tions is higher
in children nd neon tes (2.4 ol/L [7 g/dL]). It
e
is use ul to distinguish hyperphosph te i c used by
i p ired ren l phosph te excretion ro th t which
results ro excessive delivery o phosph te into the
ECF ( ble 32-3).
In chronic ren l insuf ciency, reduced GFR le ds to
phosph te retention. Hyperphosph te i in turn ur-
ther i p irs ren l synthesis o 1,25(OH)2D, incre ses
FGF23 levels, nd sti ul tes P H secretion nd hyper-
trophy both directly nd indirectly (by lowering blood
ionized c lciu levels). T us, hyperphosph te i is
jor c use o the second ry hyperp r thyroidis o
ren l ilure nd ust be ddressed e rly in the course
o the dise se (Chap. 34).
Hypop r thyroidis le ds to hyperphosph te i
vi incre sed expression o N Pi-2 co-tr nsporters in
the proxi l tubule. Hypop r thyroidis , or p r thy-
roid suppression, h s ultiple potenti l c uses, includ-
ing utoi une dise se; develop ent l, surgic l,
or r di tion-induced bsence o unction l p r thy-
roid tissue; vit in D intoxic tion or other c uses o
P H-independent hyperc lce i ; cellul r P H resis-
t nce (pseudohypop r thyroidis or hypo gnese-
i ); in ltr tive disorders such s Wilson’s dise se nd

Ha rris on_Endocrinology_Ch32_p423-p441.indd 433 27/07/16 11:04 a m

 434 he ochro tosis; nd i p ired P H secretion c used y be help ul in chel ting nd li iting bsorption o o ending
by hyper gnese i , severe hypo gnese i , or phosph te s lts present in the intestine. He odi lysis is the ost
ctiv ting ut tions in the C SR. Hypoc lce i y e ective ther peutic str tegy nd should be considered e rly in
lso contribute directly to i p ired phosph te cle r- the course o severe hyperphosph te i , especi lly in the setting
nce, s c lciu in usion c n induce phosph turi in o ren l ilure nd sy pto tic hypoc lce i .
hypop r thyroid subjects. Incre sed tubul r phosph te
re bsorption lso occurs in cro eg ly, during hep -
rin d inistr tion, nd in tu or l c lcinosis. u or l
MAGNESIUM METABO LISM
c lcinosis is c used by r re group o genetic disor-
ders in which FGF23 is processed in w y th t le ds M gnesiu is the jor intr cellul r div lent c tion.
S
E
to low levels o ctive FGF23 in the bloodstre . T is
C
Nor l concentr tions o extr cellul r gnesiu nd
T
I
y result ro ut tions in the FGF23 sequence or
O
c lciu re cruci l or nor l neuro uscul r ctivity.
N
vi in ctiv ting ut tions in the GALNT3 gene, which Intr cellul r gnesiu or s key co plex with A P
V
I
encodes g l ctos inyl tr ns er se th t nor lly nd is n i port nt co ctor or wide r nge o enzy es,
dds sug r residues to FGF23 th t slow its proteoly- tr nsporters, nd nucleic cids required or nor l cel-
sis. A si il r syndro e results ro FGF23 resist nce
D
lul r unction, replic tion, nd energy et bolis . T e
i
s
due to in ctiv ting ut tions o the FGF23 co-receptor
o
concentr tion o gnesiu in seru is closely regu-
r
d
Klotho. T ese bnor lities c use elev ted seru
e
l ted within the r nge o 0.7–1 ol/L (1.5–2 eq/L;
r
s
1,25(OH)2D, p r thyroid suppression, incre sed intes-
o
1.7–2.4 g/dL), o which 30% is protein-bound nd
f
B
tin l c lciu bsorption, nd oc l hyperostosis with
o
nother 15% is loosely co plexed to phosph te nd
n
e
l rge, lobul ted peri rticul r heterotopic ossi c tions other nions. One-h l o the 25 g (1000 ol) o tot l
a
n
(especi lly t shoulders or hips) nd re cco p nied
d
body gnesiu is loc ted in bone, only one-h l o
C
by hyperphosph te i . In so e or s o tu or l c lci-
a
which is insoluble in the iner l ph se. Al ost ll
l
c
i
nosis, seru phosphorus levels re nor l.
u
extr skelet l gnesiu is present within cells, where
m
When l rge ounts o phosph te re delivered r p-
M
the tot l concentr tion is 5 M, 95% o which is bound
e
idly into the ECF, hyperphosph te i c n occur despite
t
to proteins nd other cro olecules. Bec use only 1%
a
b
nor l ren l unction. Ex ples include overze lous IV
o
o body gnesiu resides in the ECF, e sure ents o
l
i
s
phosph te ther py, or l or rect l d inistr tion o l rge
m
seru gnesiu levels y not ccur tely re ect the
ounts o phosph te-cont ining l x tives or ene s level o tot l body gnesiu stores.
(especi lly in children), extensive so tissue injury or Diet ry gnesiu content nor lly r nges ro
necrosis (crush injuries, rh bdo yolysis, hyperther i , 6 to 15 ol/d (140–360 g/d), o which 30–40% is
ul in nt hep titis, cytotoxic che other py), extensive bsorbed, inly in the jejunu nd ileu . Intesti-
he olytic ne i , nd tr nscellul r phosph te shi s n l gnesiu bsorptive ef ciency is sti ul ted by
induced by severe et bolic or respir tory cidosis. 1,25(OH)2D nd c n re ch 70% during gnesiu
depriv tion. Urin ry gnesiu excretion nor lly
Clin ica l f nd in g s tches net intestin l bsorption nd is ~4 ol/d (100
g/d). Regul tion o seru gnesiu concentr tions
T e clinic l consequences o cute, severe hyperphos- is chieved inly by control o ren l gnesiu re b-
ph te i re due inly to the or tion o wide- sorption. Only 20% o ltered gnesiu is re bsorbed
spre d c lciu phosph te precipit tes nd resulting in the proxi l tubule, where s 60% is recl i ed in the
hypoc lce i . T us, tet ny, seizures, cceler ted neph- c AL nd nother 5–10% in the DC . M gnesiu re b-
roc lcinosis (with ren l ilure, hyperk le i , hyper- sorption in the c AL occurs vi p r cellul r route th t
urice i , nd et bolic cidosis), nd pul on ry or requires both lu en-positive potenti l, cre ted by N Cl
c rdi c c lci c tions (including develop ent o cute re bsorption, nd tight-junction proteins encoded by
he rt block) y occur. T e severity o these co plic - e bers o the Cl udin gene ily. M gnesiu re b-
tions rel tes to the elev tion o seru phosph te levels, sorption in the c AL is incre sed by P H but inhibited
which c n re ch concentr tions s high s 7 ol/L by hyperc lce i or hyper gnese i , both o which
(20 g/dL) in inst nces o ssive so tissue injury or ctiv te the C SR in this nephron seg ent.
tu or lysis syndro e.

HYPOMAGNESEMIA
TREATMENT Hyperphosphatemia Ca u ses
T er peutic options or n ge ent o severe hyperphosph - Hypo gnese i usu lly signi es subst nti l deple-
te i re li ited. Volu e exp nsion y enh nce ren l phos- tion o body gnesiu stores (0.5–1 ol/kg). Hypo-
ph te cle r nce. Alu inu hydroxide nt cids or sevel er gnese i c n result ro intestin l l bsorption;

Ha rris on_Endocrinology_Ch32_p423-p441.indd 434 27/07/16 11:04 a m

 protr cted vo iting, di rrhe , or intestin l dr in ge; gnesiu l bsorption h s been described (pri ry 435
de ective ren l tubul r gnesiu re bsorption; or r pid in ntile hypo gnese i ). Another r re inherited dis-
shi s o gnesiu ro the ECF into cells, bone, or order (hypo gnese i with second ry hypoc lce i )
third sp ces (Table 32-4). Diet ry gnesiu de ciency is c used by ut tions in the gene encoding RPM6,
is unlikely except possibly in the setting o lcoholis . protein th t, long with RPM7, or s ch nnel i por-
A r re genetic disorder th t c uses selective intestin l t nt or both intestin l nd dist l-tubul r ren l tr nscel-
lul r gnesiu tr nsport. M l bsorptive st tes, o en
TABLE 3 2 -4 co pounded by vit in D de ciency, c n critic lly li it
CAUSES OF HYPOMAGNESEMIA gnesiu bsorption nd produce hypo gnese i
despite the co pens tory e ects o second ry hyperp r -

C
H
I. Impaired intestinal absorption

A
thyroidis nd o hypoc lce i nd hypo gnese i

P
A. Hypomagnesemia with secondary hypocalcemia (TRPM6

T
to enh nce c AL gnesiu re bsorption. Di rrhe or

E
mutations)

R
B. Malabsorption syndromes surgic l dr in ge uid y cont in ≥5 ol/L o g-

3
2
C. Vitamin D de ciency nesiu . Proton pu p inhibitors (o epr zole nd others)
D. Proton pump inhibitors y produce hypo gnese i by n unknown ech -
II. Increased intestinal losses nis th t does not involve ren l w sting o gnesiu .

B
o
A. Protracted vomiting/diarrhea

n
Sever l genetic gnesiu -w sting syndro es h ve

e
B. Intestinal drainage, stulas

a
been described, including in ctiv ting ut tions o genes

n
d
III. Impaired renal tubular reabsorption
encoding the DC N Cl co-tr nsporter (Gitel n’s syn-

M
A. Genetic magnesium-wasting syndromes

i
n
dro e), proteins required or c AL N -K-2Cl tr nsport

e
1. Gitelman’s syndrome

r
a
(B rtter’s syndro e), cl udin 16 or cl udin 19 ( utoso l

l
2. Bartter’s syndrome

M
recessive ren l hypo gnese i with hyperc lciuri ),

e
3. Claudin 16 or 19 mutations

t
a
4. Potassium channel mutations (Kv1.1, Kir4.1) DC N +, K+-A P se γ-subunit ( utoso l do i-

b
o
l
5. Na +, K+-ATPase γ-subunit mutations (FXYD2)

i
n nt ren l hypo gnese i with hypoc lciuri ), DC

s
m
B. Acquired renal disease
K+ ch nnels (Kv1.1, Kir4.1), nd itochondri l gene

i
n
1. Tubulointerstitial disease

H
encoding tRNA. Activ ting ut tions o the C SR c n

e
2. Postobstruction, ATN (diuretic phase)

a
l
c use hypo gnese i s well s hypoc lce i . ECF

t
3. Renal transplantation

h
a
C. Drugs and toxins exp nsion, hyperc lce i , nd severe phosph te deple-

n
d
1. Ethanol tion y i p ir gnesiu re bsorption, s c n v ri-

D
i
s
2. Diuretics (loop, thiazide, osmotic) ous or s o ren l injury, including those c used by drugs

e
a
s
3. Cisplatin such s cispl tin, cyclosporine, inoglycosides, nd

e
4. Pentamidine, oscarnet
pent idine s well s the epider l growth ctor (EGF)
5. Cyclosporine
6. Aminoglycosides, amphotericin B
receptor inhibitory ntibody, cetuxi b (EGF ction is
7. Cetuximab required or nor l DC pic l expression o RPM6)
D. Other ( ble 32-4). A rising blood concentr tion o eth nol
1. Extracellular uid volume expansion directly i p irs tubul r gnesiu re bsorption, nd
2. Hyperaldosteronism persistent glycosuri with os otic diuresis le ds to g-
3. SIADH nesiu w sting nd prob bly contributes to the high re-
4. Diabetes mellitus quency o hypo gnese i in poorly controlled di betic
5. Hypercalcemia
6. Phosphate depletion
p tients. M gnesiu depletion is ggr v ted by et bolic
7. Metabolic acidosis cidosis, which c uses intr cellul r losses s well.
8. Hyperthyroidism Hypo gnese i due to r pid shi s o gnesiu
IV. Rapid shi ts rom extracellular uid ro ECF into the intr cellul r co p rt ent c n occur
A. Intracellular redistribution during recovery ro di betic keto cidosis, st rv tion,
1. Recovery rom diabetic ketoacidosis or respir tory cidosis. Less cute shi s y be seen
2. Re eeding syndrome during r pid bone or tion er p r thyroidecto y,
3. Correction o respiratory acidosis
with tre t ent o vit in D de ciency, or with osteo-
4. Catecholamines
B. Accelerated bone ormation bl stic et st ses. L rge ounts o gnesiu y
1. Postparathyroidectomy be lost with cute p ncre titis, extensive burns, or pro-
2. Treatment o vitamin D de ciency tr cted nd severe swe ting nd during pregn ncy nd
3. Osteoblastic metastases l ct tion.
C. Other
1. Pancreatitis, burns, excessive sweating
2. Pregnancy (third trimester) and lactation Clin ica l a n d la b o ra to ry f n d in g s
Abb revia tio ns: ATN, acute tubular necrosis; SIADH, syndrome o inap- Hypo gnese i y c use gener lized lter tions
propriate antidiuretic hormone. in neuro uscul r unction, including tet ny, tre or,

Ha rris on_Endocrinology_Ch32_p423-p441.indd 435 27/07/16 11:04 a m

 436 seizures, uscle we kness, t xi , nyst g us, vertigo, due to r pid sti ul tion o P H secretion. T is is voided by
p thy, depression, irrit bility, deliriu , nd psycho- d inistering both c lciu nd gnesiu .
sis. P tients re usu lly sy pto tic when seru
gnesiu concentr tions re >0.5 ol/L (1 eq/L;
1.2 g/dL), lthough the severity o sy pto s y
not correl te with seru gnesiu levels. C rdi c HYPERMAGNESEMIA
rrhyth i s y occur, including sinus t chyc rdi , Ca u ses
other supr ventricul r t chyc rdi s, nd ventricul r
rrhyth i s. Electroc rdiogr phic bnor lities y Hyper gnese i is r rely seen in the bsence o
include prolonged PR or Q interv ls, -w ve tten- ren l insuf ciency, s nor l kidneys c n excrete l rge
S
E
ing or inversion, nd S str ightening. Sensitivity to ounts (250 ol/d) o gnesiu . Mild hyper -
C
T
gnese i due to excessive re bsorption in the c AL
I
digit lis toxicity y be enh nced.
O
N
Other electrolyte bnor lities o en seen with occurs with C SR ut tions in ili l hypoc lciuric
V
hyperc lce i nd h s been described in so e p tients
I
hypo gnese i , including hypoc lce i (with hypo-
c lciuri ) nd hypok le i , y not be e sily corrected with dren l insuf ciency, hypothyroidis , or hypo-
unless gnesiu is d inistered s well. T e hypo- ther i . M ssive exogenous gnesiu exposures,
D
i
usu lly vi the g strointestin l tr ct, c n overwhel
s
c lce i y be result o concurrent vit in D de -
o
r
d
ciency, lthough hypo gnese i c n c use i p ired ren l excretory c p city nd c use li e-thre tening
e
r
s
synthesis o 1,25(OH)2D, cellul r resist nce to P H, hyper gnese i (Table 32-5). A not ble ex ple o
o
f
this is prolonged retention o even nor l ounts o
B
nd, t very low seru gnesiu (<0.4 ol/L [0.8
o
n
gnesiu -cont ining c th rtics in p tients with intes-
e
eq/L; <1 g/dL]), de ect in P H secretion; these
a
tin l ileus, obstruction, or per or tion. Extensive so
n
bnor lities re reversible with ther py.
d
C
tissue injury or necrosis c n lso deliver l rge ounts
a
l
c
o gnesiu into the ECF in p tients who h ve su -
i
u
m
ered tr u , shock, sepsis, c rdi c rrest, or severe
M
burns.
e
TREATMENT Hypomagnesemia
t
a
b
o
l
i
Mild, sy pto tic hypo gnese i y be tre ted with
s
Clin ica l a n d la b o ra to ry f n d in g s
m
or l gnesiu s lts (MgCl2, MgO, Mg[OH]2) in divided
doses tot ling 20–30 ol/d (40–60 eq/d). Di rrhe T e ost pro inent clinic l ni est tions o hyper-
y occur with l rger doses. More severe hypo gnese i gnese i re v sodil tion nd neuro uscul r
should be tre ted p renter lly, pre er bly with IV MgCl2, block de, which y ppe r t seru gnesiu
which c n be d inistered s ely s continuous in usion concentr tions >2 ol/L (>4 eq/L; >4.8 g/dL).
o 50 ol/d (100 eq Mg2+/d) i ren l unction is nor- Hypotension th t is re r ctory to v sopressors or vol-
l. I GFR is reduced, the in usion r te should be lowered u e exp nsion y be n e rly sign. N use , leth-
by 50–75%. Use o IM MgSO4 is discour ged; the injections rgy, nd we kness y progress to respir tory ilure,
re p in ul nd provide rel tively little gnesiu (2 L o p r lysis, nd co , with hypo ctive tendon re exes,
50% MgSO4 supplies only 4 ol). MgSO4 y be given IV t seru gnesiu levels >4 ol/L. Other nd-
inste d o MgCl2, lthough the sul te nions y bind c l- ings y include g strointestin l hypo otility or ileus;
ciu in seru nd urine nd ggr v te hypoc lce i . Seru
gnesiu should be onitored t interv ls o 12–24 h dur-
TABLE 3 2 -5
ing ther py, which y continue or sever l d ys bec use o
CAUSES OF HYPERMAGNESEMIA
i p ired ren l conserv tion o gnesiu (only 50–70% o
the d ily IV gnesiu dose is ret ined) nd del yed reple- I. Excessive magnesium intake
A. Cathartics, urologic irrigants
tion o intr cellul r de cits, which y be s high s 1–1.5
B. Parenteral magnesium administration
ol/kg (2–3 eq/kg). II. Rapid mobilization rom so t tissues
It is i port nt to consider the need or c lciu , pot s- A. Trauma, shock, sepsis
siu , nd phosph te supple ent tion in p tients with B. Cardiac arrest
hypo gnese i . Vit in D de ciency requently coex- C. Burns
ists nd should be tre ted with or l or p renter l vit in D III. Impaired magnesium excretion
or 25(OH)D (but not with 1,25[OH]2D, which y i p ir A. Renal ailure
B. Familial hypocalciuric hypercalcemia
tubul r gnesiu re bsorption, possibly vi P H suppres-
IV. Other
sion). In severely hypo gnese ic p tients with conco i- A. Adrenal insuf ciency
t nt hypoc lce i nd hypophosph te i , d inistr tion B. Hypothyroidism
o IV gnesiu lone y worsen hypophosph te i , C. Hypothermia
provoking neuro uscul r sy pto s or rh bdo yolysis,

Ha rris on_Endocrinology_Ch32_p423-p441.indd 436 27/07/16 11:04 a m

 ci l ushing; pupill ry dil tion; p r doxic l br dyc r- Vita min D 437
di ; prolong tion o PR, QRS, nd Q interv ls; he rt
block; nd, t seru gnesiu levels ppro ching 10
ol/L, systole.
Hyper gnese i , cting vi the C SR, c uses
hypoc lce i nd hyperc lciuri due to both p r -
thyroid suppression nd i p ired c AL c lciu
re bsorption.

C
H
S kin Gut

A
TREATMENT Hypermagnesemia 7-De hydrochole s te rol

P
T
E
R
Success ul tre t ent o hyper gnese i gener lly involves

3
2
Vita min D
identi ying nd interrupting the source o gnesiu nd
e ploying e sures to incre se gnesiu cle r nce ro

B
the ECF. Use o gnesiu - ree c th rtics or ene s y

o
n
be help ul in cle ring ingested gnesiu ro the g stro-

e
a
n
intestin l tr ct. Vigorous IV hydr tion should be tte pted,

d
Live r

M
i ppropri te. He odi lysis is e ective nd y be required

i
n
in p tients with signi c nt ren l insuf ciency. C lciu ,

e
25(OH)D

r
a
l
d inistered IV in doses o 100–200 g over 1–2 h, h s been

M
e
reported to provide te por ry i prove ent in signs nd

t
a
b
sy pto s o hyper gnese i .

o
l
i
s
m
i
n
H
e
Kidne y
VITAMIN D

a
l
t
h
a
SYNTHESIS AND METABOLISM

n
d
D
1,25(OH)2 D

i
1,25-Dihydroxyvit in D (1,25[OH]2D) is the jor

s
e
a
steroid hor one involved in iner l ion ho eost sis

s
FIGURE 3 2 -4

regul tion. Vit in D nd its et bolites re hor ones
nd hor one precursors r ther th n vit ins, since
in the proper biologic setting, they c n be synthesized
endogenously (Fig. 32-4). In response to ultr violet
r di tion o the skin, photoche ic l cle v ge results
in the or tion o vit in D ro 7-dehydrocholes-
terol. Cut neous production o vit in D is decre sed
by el nin nd high sol r protection ctor sunblocks,
which e ectively i p ir skin penetr tion by ultr violet
light. T e incre sed use o sunblocks in North A eric
nd Western Europe nd reduction in the gnitude
o sol r exposure o the gener l popul tion over the
l st sever l dec des h s led to n incre sed reli nce on
diet ry sources o vit in D. In the United St tes nd
C n d , these sources l rgely consist o orti ed cere-
ls nd d iry products, in ddition to sh oils nd egg
yolks. Vit in D ro pl nt sources is in the or o
vit in D2, where s th t ro ni l sources is vit -
in D3. T ese two or s h ve equiv lent biologic
ctivity nd re ctiv ted equ lly well by the vit in D
hydroxyl ses in hu ns. Vit in D enters the circul -
tion, whether bsorbed ro the intestine or synthe-
sized cut neously, bound to vit in D–binding protein,
n α-globulin synthesized in the liver. Vit in D is sub-
sequently 25-hydroxyl ted in the liver by cytochro e
e
Vit a m in D syn t h e sis a n d a ct iva t io n . Vitamin D is synthe-
sized in the skin in response to ultraviolet radiation and also is
absorbed rom the diet. It is then transported to the liver, where
it undergoes 25-hydroxylation. This metabolite is the major cir-
culating orm o vitamin D. The nal step in hormone activation,
1α-hydroxylation, occurs in the kidney.
P450–like enzy es in the itochondri nd icro-
so es. T e ctivity o this hydroxyl se is not tightly
regul ted, nd the result nt et bolite, 25-hydroxyvi-
t in D (25[OH]D), is the jor circul ting nd stor-
ge or o vit in D. Approxi tely 88% o 25(OH)
D circul tes bound to the vit in D–binding protein,
0.03% is ree, nd the rest circul tes bound to lbu in.
T e h l -li e o 25(OH)D is pproxi tely 2–3 weeks;
however, it is shortened dr tic lly when vit in D–
binding protein levels re reduced, s c n occur with
incre sed urin ry losses in the nephrotic syndro e.
T e second hydroxyl tion, required or the or-
tion o the ture hor one, occurs in the kidney
(Fig. 32-5). T e 25-hydroxyvit in D-1α-hydroxyl se
is tightly regul ted cytochro e P450–like ixed-
unction oxid se expressed in the proxi l convoluted
tubule cells o the kidney. P H nd hypophosph te i

Ha rris on_Endocrinology_Ch32_p423-p441.indd 437 27/07/16 11:04 a m

 438 Vita min D3 hyperc lce i with glucocorticoids, ketocon zole,
or chloroquine reduces 1,25(OH)2D production nd
Vita min D-
e ectively lowers seru c lciu . In contr st, chloro-
25 hydroxyla s e quine h s not been shown to lower the elev ted seru
1,25(OH)2D levels in p tients with ly pho .
T e jor p thw y or in ctiv tion o vit in D
et bolites is n ddition l hydroxyl tion step by the
– vit in D 24-hydroxyl se, n enzy e th t is expressed
Live r in ost tissues. 1,25(OH)2D is the jor inducer o
this enzy e; there ore, this hor one pro otes its own
S
25(OH)D3
E
in ctiv tion, thereby li iting its biologic e ects. Mut -
C
T
I
tions o the gene encoding this enzy e (CYP24A1)
O
25(OH)D-1α -
N
P i a nd hydroxyla s e c n le d to in ntile hyperc lce i nd, in those less
V
I
othe r fa ctors
severely ected, long-st nding hyperc lciuri , nephro-
–/+ Kidney – c lcinosis, nd nephrolithi sis.
Pol r et bolites o 1,25(OH)2D re secreted into
D
i
s
D3
the bile nd re bsorbed vi the enterohep tic circul -
o
r
)2
1,25(OH)2 D3
d
H

tion. I p ir ent o this recircul tion, which is seen

e
(O
r
s
5
,2

with dise ses o the ter in l ileu , le ds to cceler ted

o
1
f
P TH
B
losses o vit in D et bolites.
o
–
n
e
a
n
d
ACTIONS OF 1 ,25 (OH)2 D
C
a
P TH
l
Bo ne
c
1,25(OH)2D edi tes its biologic e ects by binding to
i
u
m
e ber o the nucle r receptor super ily, the vit -
M
Parathyro id
e
in D receptor (VDR). T is receptor belongs to the
t
a
g lands
b
sub ily th t includes the thyroid hor one receptors,
C
o
a
2
l
Inte s tine
+
C
i
the retinoid receptors, nd the peroxiso e proli er tor–
s
a

H
m
lc

P
ifi

4 2–
–

ctiv ted receptors; however, in contr st to the other

2
ca

O4
tio

HP
n
2+
Ca
Blood
ca lcium
FIGURE 3 2 -5
Sch e m a t ic re p re se n t a t io n o f t h e h o rm o n a l co n t ro l lo o p
fo r vit a m in D m e t a b o lism a n d fu n ct io n . A reduction in the
serum calcium below ~2.2 mmol/L (8.8 mg/dL) prompts a propor-
tional increase in the secretion o parathyroid hormone (PTH) and
so mobilizes additional calcium rom the bone. PTH promotes the
synthesis o 1,25(OH)2D in the kidney, which in turn stimulates
the mobilization o calcium rom bone and intestine and regu-
lates the synthesis o PTH by negative eedback.
re the jor inducers o this icroso l enzy e,
where s c lciu , FGF23, nd the enzy e’s product,
1,25(OH)2D, repress it. T e 25-hydroxyvit in D-1α-
hydroxyl se is lso present in epider l ker tinocytes,
but ker tinocyte production o 1,25(OH)2D is not
thought to contribute to circul ting levels o this hor-
one. In ddition to being present in the trophobl stic
l yer o the pl cent , the 1α-hydroxyl se is produced by
croph ges ssoci ted with gr nulo s nd ly pho-
s. In these l tter p thologic st tes, the ctivity o the
enzy e is induced by inter eron γ nd NF-α but is not
regul ted by c lciu or 1,25(OH)2D; there ore, hyper-
c lce i , ssoci ted with elev ted levels o 1,25(OH)2D,
y be observed. re t ent o s rcoidosis- ssoci ted
e bers o this sub ily, only one VDR iso or h s
been isol ted. T e VDR binds to t rget DNA sequences
s heterodi er with the retinoid X receptor, recruit-
ing series o co ctiv tors th t odi y chro tin nd
pproxi te the VDR to the b s l tr nscription l pp -
r tus, resulting in the induction o t rget gene expres-
sion. T e ech nis o tr nscription l repression by
the VDR v ries with di erent t rget genes but h s been
shown to involve either inter erence with the ction o
ctiv ting tr nscription ctors or the recruit ent o
novel proteins to the VDR co plex, resulting in tr n-
scription l repression.
T e f nity o the VDR or 1,25(OH)2D is pproxi-
tely three orders o gnitude higher th n th t or
other vit in D et bolites. In nor l physiologic
circu st nces, these other et bolites re not thought
to sti ul te receptor-dependent ctions. However, in
st tes o vit in D toxicity, the rkedly elev ted levels
o 25(OH)D y le d to hyperc lce i by inter cting
directly with the VDR nd by displ cing 1,25(OH)2D
ro vit in D–binding protein, resulting in incre sed
bio v il bility o the ctive hor one.
T e VDR is expressed in wide r nge o cells nd
tissues. T e olecul r ctions o 1,25(OH)2D h ve
been studied ost extensively in tissues involved in the
regul tion o iner l ion ho eost sis. T is hor one
is jor inducer o c lbindin 9K, c lciu -binding

Ha rris on_Endocrinology_Ch32_p423-p441.indd 438 27/07/16 11:04 a m

 protein expressed in the intestine, which is thought to
pl y n i port nt role in the ctive tr nsport o c l-
ciu cross the enterocyte. T e two jor c lciu
tr nsporters expressed by intestin l epitheli , RPV5
nd RPV6 (tr nsient receptor potenti l v nilloid),
re lso vit in D responsive. By inducing the expres-
sion o these nd other genes in the s ll intestine,
1,25(OH)2D incre ses the ef ciency o intestin l c l-
ciu bsorption, nd it lso h s been shown to h ve
sever l i port nt ctions in the skeleton. T e VDR
skin, l ck o diet ry int ke, cceler ted losses o vit - 439
in D, i p ired vit in D ctiv tion, or resist nce to
the biologic e ects o 1,25(OH)2D (Table 32-6). T e
elderly nd nursing ho e residents re p rticul rly t
risk or vit in D de ciency, since both the ef ciency
o vit in D synthesis in the skin nd the bsorp-
tion o vit in D ro the intestine decline with ge.
Si il rly, intestin l l bsorption o diet ry ts nd
short bowel syndro e, including th t ssoci ted with
intestin l byp ss surgery, c n le d to vit in D de -

C
H
A
is expressed in osteobl sts nd regul tes the expres- ciency. T is is urther ex cerb ted in the presence o

P
T
sion o sever l genes in this cell. T ese genes include ter in l ile l dise se, which results in i p ired entero-

E
R
the bone trix proteins osteoc lcin nd osteopontin, hep tic circul tion o vit in D et bolites. In ddi-

which re upregul ted by 1,25(OH)2D, in ddition to
type I coll gen, which is tr nscription lly repressed by
1,25(OH)2D. Both 1,25(OH)2D nd P H induce the
3
2
tion to intestin l dise ses, cceler ted in ctiv tion o
vit in D et bolites c n be seen with drugs th t
induce hep tic cytochro e P450 ixed- unction oxi-

B
o
n
expression o RANK lig nd, which pro otes osteo- d ses such s b rbitur tes, phenytoin, nd ri pin.

e
a
cl st di erenti tion nd incre ses osteocl st ctivity, I p ired 25-hydroxyl tion, ssoci ted with severe

n
d
by binding to RANK on osteocl st progenitors nd liver dise se or isoni zid, is n unco on c use o

M
i
n
ture osteocl sts. T is is the ech nis by which vit in D de ciency. A ut tion in the gene respon-

e
r
a
1,25(OH)2D induces bone resorption. However, the sible or 25-hydroxyl tion h s been identi ed in one

l
M
skelet l e tures ssoci ted with VDR-knockout ice kindred. I p ired 1α-hydroxyl tion is prev lent in the

e
t
a
(rickets, osteo l ci ) re l rgely corrected by incre s- popul tion with pro ound ren l dys unction due to

b
o
l
i
ing c lciu nd phosphorus int ke, underscoring the n incre se in circul ting FGF23 levels nd decre se

s
m
i port nce o vit in D ction in the gut. in unction l ren l ss. T us, ther peutic interven-

i
n
H
T e VDR is expressed in the p r thyroid gl nd, nd tions should be considered in p tients whose cre tinine

e
a
l
1,25(OH)2D h s been shown to h ve ntiproli er tive cle r nce is <0.5 L/s (30 L/ in). Mut tions in the

t
h
a
e ects on p r thyroid cells nd to suppress the tr n- ren l 1α-hydroxyl se re the b sis or the genetic dis-

n
d
scription o the P H gene. T ese e ects o 1,25(OH)2D order, pseudovit in D–de ciency rickets. T is uto-

D
i
s
on the p r thyroid gl nd re n i port nt p rt o the so l recessive disorder presents with the syndro e

e
a
s
r tion le or current ther pies directed t preventing o vit in D de ciency in the rst ye r o li e. P tients

e
nd tre ting hyperp r thyroidis ssoci ted with ren l present with growth ret rd tion, rickets, nd hypo-
insuf ciency. c lce ic seizures. Seru 1,25(OH)2D levels re low
T e VDR is lso expressed in tissues nd org ns th t
do not pl y role in iner l ion ho eost sis. Not ble
in this respect is the observ tion th t 1,25(OH)2D h s
n ntiproli er tive e ect on sever l cell types, includ- TABLE 3 2 -6
ing ker tinocytes, bre st c ncer cells, nd prost te c n-
CAUSES OF IMPAIRED VITAMIN D ACTION
cer cells. T e e ects o 1,25(OH)2D nd the VDR on
ker tinocytes re p rticul rly intriguing. Alopeci is Vitamin D de ciency Impaired 1α-hydroxylation
seen in hu ns nd ice with ut nt VDRs but is not Impaired cutaneous Hypoparathyroidism
e ture o vit in D de ciency; thus, the e ects o the production
VDR on the h ir ollicle re lig nd-independent. Dietary absence Renal ailure
Malabsorption Ketoconazole
Accelerated loss o vitamin D 1α-hydroxylase mutation
VITAMIN D DEFICIENCY Increased metabolism Oncogenic osteomalacia
(barbiturates, phenytoin, X-linked hypophospha-
T e ounting concern bout the rel tionship between
ri ampin) temic rickets
sol r exposure nd the develop ent o skin c ncer h s
led to incre sed reli nce on diet ry sources o vit in Impaired enterohepatic Target organ resistance
circulation
D. Although the prev lence o vit in D de ciency
v ries, the third N tion l He lth nd Nutrition Ex i- Nephrotic syndrome Vitamin D receptor
mutation
n tion Survey (NHANES III) reve led th t vit in D
de ciency is prev lent throughout the United St tes. Impaired 25-hydroxylation Phenytoin
T e clinic l syndro e o vit in D de ciency c n Liver disease, isoniazid
be result o de cient production o vit in D in the

Ha rris on_Endocrinology_Ch32_p423-p441.indd 439 27/07/16 11:04 a m

 440 despite nor l 25(OH)D levels nd elev ted P H lev- endochondr l bone or tion. Investig tions in urine
els. re t ent with vit in D et bolites th t do not odels de onstr te th t hypophosph te i , which
require 1α-hydroxyl tion results in dise se re ission, in vit in D de ciency is consequence o second ry
lthough li elong ther py is required. A second utoso- hyperp r thyroidis , is key etiologic ctor in the
l recessive disorder, heredit ry vit in D–resist nt develop ent o the r chitic growth pl te.
rickets, consequence o vit in D receptor ut tions, T e hypoc lce i nd hypophosph te i th t
is gre ter ther peutic ch llenge. T ese p tients pres- cco p ny vit in D de ciency result in i p ired
ent in si il r shion during the rst ye r o li e, but iner liz tion o bone trix proteins, condition
lopeci o en cco p nies the disorder, de onstr ting known s osteomalacia. Osteo l ci is lso e ture o
unction l role o the VDR in postn t l h ir regen- long-st nding hypophosph te i , which y be con-
S
E
er tion. Seru levels o 1,25(OH)2D re dr tic lly sequence o ren l phosph te w sting or chronic use o
C
T
I
elev ted in these individu ls both bec use o incre sed etidron te or phosph te-binding nt cids. T is hypo-
O
N
production due to sti ul tion o 1α-hydroxyl se ctiv- iner lized trix is bio ech nic lly in erior to nor-
V
I
ity s consequence o second ry hyperp r thyroidis l bone; s result, p tients with vit in D de ciency
nd bec use o i p ired in ctiv tion, since induction re prone to bowing o weight-be ring extre ities nd
o the 24-hydroxyl se by 1,25(OH)2D requires n int ct skelet l r ctures. Vit in D nd c lciu supple ent -
D
i
s
VDR. Bec use the receptor ut tion results in hor- tion h ve been shown to decre se the incidence o hip
o
r
d
one resist nce, d ily c lciu nd phosphorus in u- r cture ong bul tory nursing ho e residents in
e
r
s
sions y be required to byp ss the de ect in intestin l Fr nce, suggesting th t under iner liz tion o bone con-
o
f
B
iner l ion bsorption. tributes signi c ntly to orbidity in the elderly. Proxi l
o
n
e
Reg rdless o the c use, the clinic l ni est tions yop thy is striking e ture o severe vit in D de -
a
n
o vit in D de ciency re l rgely consequence o ciency both in children nd in dults. R pid resolution o
d
C
i p ired intestin l c lciu bsorption. Mild to od- the yop thy is observed upon vit in D tre t ent.
a
l
c
i
er te vit in D de ciency is sy pto tic, where s Although vit in D de ciency is the ost co -
u
m
long-st nding vit in D de ciency results in hypoc l- on c use o rickets nd osteo l ci , ny disorders
M
e
ce i cco p nied by second ry hyperp r thyroidis , le d to in dequ te iner liz tion o the growth pl te
t
a
b
i p ired iner liz tion o the skeleton (osteopeni on nd bone. C lciu de ciency without vit in D de -
o
l
i
s
x-r y or decre sed bone iner l density), nd proxi l ciency, the disorders o vit in D et bolis previ-
m
yop thy. Vit in D de ciency lso h s been shown ously discussed, nd hypophosph te i c n ll le d to
to be ssoci ted with n incre se in over ll ort l- inef cient iner liz tion. Even in the presence o nor-
ity, including c rdiov scul r c uses. In the bsence o l c lciu nd phosph te levels, chronic cidosis nd
n intercurrent illness, the hypoc lce i ssoci ted drugs such s bisphosphon tes c n le d to osteo l -
with long-st nding vit in D de ciency r rely pres- ci . T e inorg nic c lciu /phosph te iner l ph se
ents with cute sy pto s o hypoc lce i such s o bone c nnot or t low pH, nd bisphosphon tes
nu bness, tingling, nd seizures. However, the concur- bind to nd prevent iner l cryst l growth. Bec use
rent develop ent o hypo gnese i , which i p irs lk line phosph t se is necess ry or nor l iner l
p r thyroid unction, or the d inistr tion o potent deposition, prob bly bec use the enzy e c n hydrolyze
bisphosphon tes, which i p ir bone resorption, c n inhibitors o iner liz tion such s inorg nic pyro-
le d to cute sy pto tic hypoc lce i in vit in D– phosph te, genetic in ctiv tion o the lk line phosph -
de cient individu ls. t se gene (heredit ry hypophosph t si ) lso c n le d
to osteo l ci in the setting o nor l c lciu nd
Rickets a n d o steo m a la cia phosph te levels.

In children, be ore epiphyse l usion, vit in D de -

ciency results in growth ret rd tion ssoci ted with n
exp nsion o the growth pl te known s rickets. T ree
l yers o chondrocytes re present in the nor l growth
pl te: the reserve zone, the proli er ting zone, nd the
hypertrophic zone. Rickets ssoci ted with i p ired
vit in D ction is ch r cterized by exp nsion o the
hypertrophic chondrocyte l yer. T e proli er tion
nd di erenti tion o the chondrocytes in the r chitic
growth pl te re nor l, nd the exp nsion o the
growth pl te is consequence o i p ired poptosis o
the l te hypertrophic chondrocytes, n event th t pre-
cedes repl ce ent o these cells by osteobl sts during
Dia g n o sis o vita m in D d ef cien cy, rickets, a n d
o steo m a la cia
T e ost speci c screening test or vit in D de -
ciency in otherwise he lthy individu ls is seru
25(OH)D level. Although the nor l r nges v ry, lev-
els o 25(OH)D <37 n ol/L (<15 ng/ L) re ssoci ted
with incre sing P H levels nd lower bone density. T e
Institute o Medicine h s de ned vit in D suf ciency
s vit in D level >50 n ol/L (>20 ng/ L), lthough
higher levels y be required to opti ize intesti-
n l c lciu bsorption in the elderly nd those with
underlying dise se st tes. Vit in D de ciency le ds

Ha rris on_Endocrinology_Ch32_p423-p441.indd 440 27/07/16 11:04 a m

 to i p ired intestin l bsorption o c lciu , resulting 441
in decre sed seru tot l nd ionized c lciu v lues. TREATMENT Vitamin DDef ciency
T is hypoc lce i results in second ry hyperp r thy-
B sed on the Institute o Medicine 2010 report, the rec-
roidis , ho eost tic response th t initi lly int ins
o ended d ily int ke o vit in D is 600 IU ro 1 to
seru c lciu levels t the expense o the skeleton.
70 ye rs o ge, nd 800 IU or those over 70. B sed on the
Due to the P H-induced incre se in bone turnover,
observ tion th t 800 IU o vit in D, with c lciu supple-
lk line phosph t se levels re o en incre sed. In ddi-
ent tion, decre ses the risk o hip r ctures in elderly
tion to incre sing bone resorption, P H decre ses uri-
wo en, this higher dose is thought to be n ppropri te d ily
n ry c lciu excretion while pro oting phosph turi .
int ke or prevention o vit in D de ciency in dults. T e
T is results in hypophosph te i , which ex cerb tes

C
H
s ety rgin or vit in D is l rge, nd vit in D toxic-

A
the iner liz tion de ect in the skeleton. With pro-

P
ity usu lly is observed only in p tients t king doses in the

T
longed vit in D de ciency resulting in osteo l -

E
r nge o 40,000 IU d ily. re t ent o vit in D de ciency

R
ci , c lciu stores in the skeleton beco e rel tively

3
should be directed t the underlying disorder, i possible,

2
in ccessible, since osteocl sts c nnot resorb un in-
nd lso should be t ilored to the severity o the condition.
er lized osteoid, nd r nk hypoc lce i ensues.
Vit in D should lw ys be repleted in conjunction with
Bec use P H is jor sti ulus or the ren l 25(OH)

B
c lciu supple ent tion bec use ost o the consequences

o
n
D 1α-hydroxyl se, there is incre sed synthesis o the

e
o vit in D de ciency re result o i p ired iner l

a
ctive hor one, 1,25(OH)2D. P r doxic lly, levels o

n
d
ion ho eost sis. In p tients in who 1α-hydroxyl tion is
this hor one re o en nor l in severe vit in D de -

M
i p ired, et bolites th t do not require this ctiv tion step

i
n
ciency. T ere ore, e sure ents o 1,25(OH)2D re not

e
re the tre t ent o choice. T ey include 1,25(OH)2D3 (c l-

r
a
ccur te re ections o vit in D stores nd should not

l
M
citriol [Roc ltrol], 0.25–0.5 µg/d) nd 1α-hydroxyvit in D2
be used to di gnose vit in D de ciency in p tients

e
t
(Hectorol, 2.5–5 µg/d). I the p thw y required or ctiv -

a
with nor l ren l unction.

b
o
tion o vit in D is int ct, severe vit in D de ciency c n

l
i
R diologic e tures o vit in D de ciency in chil-

s
m
be tre ted with ph r cologic repletion initi lly (50,000 IU
dren include widened, exp nded growth pl te th t

i
n
weekly or 3–12 weeks), ollowed by inten nce ther py

H
is ch r cteristic o rickets. T ese ndings not only re

e
(800 IU d ily). Ph r cologic doses y be required or

a
l
pp rent in the long bones but lso re present t the

t
h
inten nce ther py in p tients who re t king edic tions,

a
costochondr l junction, where the exp nsion o the

n
such s b rbitur tes or phenytoin, th t cceler te et bolis

d
growth pl te le ds to swellings known s the “r chitic

D
o or c use resist nce to 1,25(OH)2D. C lciu supple ent -

i
s
ros ry.” I p ir ent o intr e br nous bone iner-

e
a
tion should include 1.5–2 g/d o ele ent l c lciu . Nor o-

s
liz tion le ds to del yed usion o the c lv ri l sutures

e
c lce i is usu lly observed within 1 week o the institution
nd decre se in the r diop city o cortic l bone in the
o ther py, lthough incre ses in P H nd lk line phosph -
long bones. I vit in D de ciency occurs er epiphy-
t se levels y persist or 3–6 onths. T e ost ef c cious
se l usion, the in r diologic nding is decre se
ethods to onitor tre t ent nd resolution o vit in D
in cortic l thickness nd rel tive r diolucency o the
de ciency re seru nd urin ry c lciu e sure ents. In
skeleton. A speci c r diologic e ture o osteo l ci ,
p tients who re vit in D replete nd re t king dequ te
whether ssoci ted with phosph te w sting or vit in
c lciu supple ent tion, the 24-h urin ry c lciu excre-
D de ciency, is pseudo r ctures, or Looser’s zones.
tion should be in the r nge o 100–250 g/24 h. Lower levels
T ese re r diolucent lines th t occur where l rge rter-
suggest proble s with dherence to the tre t ent regi en or
ies re in cont ct with the underlying skelet l ele ents;
with bsorption o c lciu or vit in D supple ents. Lev-
it is thought th t the rteri l puls tions le d to the
els >250 g/24 h predispose to nephrolithi sis nd should
r diolucencies. As result, these pseudo r ctures re
le d to reduction in vit in D dos ge nd/or c lciu
usu lly ew illi eters wide, re sever l centi eters
supple ent tion.
long, nd re seen p rticul rly in the sc pul , the pelvis,
nd the e or l neck.

Ha rris on_Endocrinology_Ch32_p423-p441.indd 441 27/07/16 11:04 a m

 CH AP TER 3 3
HYPERCALCEMIA AND HYPOCALCEMIA
Su n d e e p Kh o sla
T e calcium ion plays a critical role in normal cellu-
lar unction and signaling, regulating diverse physi-
ologic processes such as neuromuscular signaling,
cardiac contractility, hormone secretion, and blood
coagulation. T us, extracellular calcium concentra-
tions are maintained within an exquisitely narrow range
through a series o eedback mechanisms that involve
parathyroid hormone (P H) and the active vitamin
D metabolite 1,25-dihydroxyvitmin D [1,25(OH)2D].
T ese eedback mechanisms are orchestrated by inte-
grating signals between the parathyroid glands, kidney,
intestine, and bone (Fig. 33-1; Chap. 32). Disorders o
serum calcium concentration are relatively common
and o en serve as a harbinger o underlying disease.
T is chapter provides a brie summary o the approach
to patients with altered serum calcium levels. See Chap.
34 for a detailed discussion of this topic.
HYP ERCALCEMIA
ETIOLOGY
T e causes o hypercalcemia can be understood
and classi ed based on derangements in the normal
eedback mechanisms that regulate serum calcium
(Table 33-1). Excess P H production, which is not
appropriately suppressed by increased serum calcium
concentrations, occurs in primary neoplastic disor-
ders o the parathyroid glands (parathyroid adenomas;
hyperplasia; or, rarely, carcinoma) that are associated
with increased parathyroid cell mass and impaired
eedback inhibition by calcium. Inappropriate P H
secretion or the ambient level o serum calcium also
occurs with heterozygous inactivating calcium sensor
receptor (CaSR) or G protein mutations, which impair
extracellular calcium sensing by the parathyroid glands
and the kidneys, resulting in amilial hypocalciuric
hypercalcemia (FHH). Although P H secretion by
442
Ha rris on_Endocrinology_Ch33_p442-p445.indd 442
tumors is extremely rare, many solid tumors produce
P H-related peptide (P HrP), which shares homol-
ogy with P H in the rst 13 amino acids and binds the
P H receptor, thus mimicking e ects o P H on bone
and the kidney. In P HrP-mediated hypercalcemia
o malignancy, P H levels are suppressed by the high
serum calcium levels. Hypercalcemia associated with
granulomatous disease (e.g., sarcoidosis) or lympho-
mas is caused by enhanced conversion o 25(OH)D to
the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D
enhances intestinal calcium absorption, resulting in
hypercalcemia and suppressed P H. Disorders that
directly increase calcium mobilization rom bone, such
as hyperthyroidism or osteolytic metastases, also lead
to hypercalcemia with suppressed P H secretion as
does exogenous calcium overload, as in milk-alkali syn-
drome, or total parenteral nutrition with excessive cal-
cium supplementation.
CLINICAL MANIFESTATIONS
Mild hypercalcemia (up to 11–11.5 mg/dL) is usually
asymptomatic and recognized only on routine calcium
measurements. Some patients may complain o vague
neuropsychiatric symptoms, including trouble concen-
trating, personality changes, or depression. Other pre-
senting symptoms may include peptic ulcer disease or
nephrolithiasis, and racture risk may be increased. More
severe hypercalcemia (>12–13 mg/dL), particularly i it
develops acutely, may result in lethargy, stupor, or coma,
as well as gastrointestinal symptoms (nausea, anorexia,
constipation, or pancreatitis). Hypercalcemia decreases
renal concentrating ability, which may cause polyuria
and polydipsia. With long-standing hyperparathyroid-
ism, patients may present with bone pain or pathologic
ractures. Finally, hypercalcemia can result in signi cant
electrocardiographic changes, including bradycardia, AV
block, and short Q interval; changes in serum calcium
can be monitored by ollowing the Q interval.
27/07/16 11:05 a m

Parathyro id g lands
2 P TH
1
TABLE 3 3 -1 443
CAUSES OF HYPERCALCEMIA
Excessive PTH production
Primary hyperparathyroidism (adenoma, hyperplasia, rarely
carcinoma)
Tertiary hyperparathyroidism (long-term stimulation o PTH
secretion in renal insu ciency)
2
Ectopic PTH secretion (very rare)
Inactivating mutations in the CaSR or in G proteins (FHH)

C
H
A
ECF Ca 2+ Alterations in CaSR unction (lithium therapy)

P
T
Hypercalcemia o malignancy

E
R
3

3
Kidney Overproduction o PTHrP (many solid tumors)

3
Bo ne 4 Lytic skeletal metastases (breast, myeloma)
1,25 (OH)2 D
Excessive 1,25(OH)2D production

H
y
Granulomatous diseases (sarcoidosis, tuberculosis, silicosis)

p
e
r
c
Lymphomas

a
l
c
e
Vitamin D intoxication

m
i
a
Primary increase in bone resorption

a
n
d
Inte s tine Hyperthyroidism

H
y
p
FIGURE 3 3 -1 Immobilization

o
c
Fe e d b a ck m e ch a n ism s m a in t a in in g e xt ra ce llu la r ca lciu m

a
Excessive calcium intake

l
c
e
co n ce n t ra t io n s wit h in a n a rro w, p h ysio lo g ic ra n g e (8.9–

m
Milk-alkali syndrome

i
10.1 m g /d L [2.2–2.5 m M]). A decrease in extracellular (ECF)

a
calcium (Ca 2+) triggers an increase in parathyroid hormone (PTH) Total parenteral nutrition
secretion (1) via the calcium sensor receptor on parathyroid cells. Other causes
PTH, in turn, results in increased tubular reabsorption o calcium Endocrine disorders (adrenal insu ciency, pheochromocy-
by the kidney (2) and resorption o calcium rom bone (2) and toma, VIPoma)
also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in Medications (thiazides, vitamin A, antiestrogens)
turn, acts principally on the intestine to increase calcium absorp-
tion (4). Collectively, these homeostatic mechanisms serve to Abb revia tio ns: CaSR, calcium sensor receptor; FHH, amilial hypocalciu-
restore serum calcium levels to normal. ric hypercalcemia; PTH, parathyroid hormone; PTHrP, PTH-related peptide.

DIAGNOSTIC APPROACH
T e rst step in the diagnostic evaluation o hyper- or
hypocalcemia is to ensure that the alteration in serum
calcium levels is not due to abnormal albumin concen-
trations. About 50% o total calcium is ionized, and the
rest is bound principally to albumin. Although direct
measurements o ionized calcium are possible, they are
easily in uenced by collection methods and other arti-
acts; thus, it is generally pre erable to measure total cal-
cium and albumin to “correct” the serum calcium. When
serum albumin concentrations are reduced, a corrected
calcium concentration is calculated by adding 0.2 mM
(0.8 mg/dL) to the total calcium level or every decre-
ment in serum albumin o 1.0 g/dL below the re erence
value o 4.1 g/dL or albumin, and, conversely, or eleva-
tions in serum albumin.
A detailed history may provide important
clues regarding the etiology o the hypercalcemia
( able 33-1). Chronic hypercalcemia is most commonly
caused by primary hyperparathyroidism, as opposed to
the second most common etiology o hypercalcemia,
an underlying malignancy. T e history should include
medication use, previous neck surgery, and systemic
symptoms suggestive o sarcoidosis or lymphoma.
Once true hypercalcemia is established, the second
most important laboratory test in the diagnostic evalu-
ation is a P H level using a two-site assay or the intact
hormone. Increases in P H are o en accompanied
by hypophosphatemia. In addition, serum creatinine
should be measured to assess renal unction; hypercal-
cemia may impair renal unction, and renal clearance
o P H may be altered depending on the ragments
detected by the assay. I the P H level is increased (or
“inappropriately normal”) in the setting o elevated
calcium and low phosphorus, the diagnosis is almost
always primary hyperparathyroidism. Because individ-
uals with FHH may also present with mildly elevated
P H levels and hypercalcemia, this diagnosis should be
considered and excluded because parathyroid surgery is
ine ective in this condition. A calcium/creatinine clear-
ance ratio (calculated as urine calcium/serum calcium
divided by urine creatinine/serum creatinine) o <0.01

Ha rris on_Endocrinology_Ch33_p442-p445.indd 443 27/07/16 11:05 a m

 444 is suggestive o FHH, particularly when there is a amily chloroquine, and hydroxychloroquine, may also decrease
history o mild, asymptomatic hypercalcemia. In addi- 1,25(OH)2D production and are used occasionally.
tion, sequence analysis o the CaSR gene is now com-
monly per ormed or the de nitive diagnosis o FHH,
although in some amilies, FHH may be caused by
mutations in G proteins that mediate signaling by the HYP O CALCEMIA
CaSR. Ectopic P H secretion is extremely rare.
A suppressed P H level in the ace o hypercalcemia ETIOLOGY
is consistent with non-parathyroid-mediated hyper-
T e causes o hypocalcemia can be di erentiated
calcemia, most o en due to underlying malignancy.
S
according to whether serum P H levels are low (hypo-
E
Although a tumor that causes hypercalcemia is gener-
C
T
parathyroidism) or high (secondary hyperparathy-
I
ally overt, a P HrP level may be needed to establish
O
roidism). Although there are many potential causes o
N
the diagnosis o hypercalcemia o malignancy. Serum
V
hypocalcemia, impaired P H production and impaired
I
1,25(OH)2D levels are increased in granulomatous dis-
vitamin D production are the most common etiolo-
orders, and clinical evaluation in combination with lab-
gies (Table 33-2) (Chap. 34). Because P H is the main
oratory testing will generally provide a diagnosis or the
D
de ense against hypocalcemia, disorders associated with
i
s
various disorders listed in able 33-1.
o
r
de cient P H production or secretion may be associ-
d
e
r
ated with pro ound, li e-threatening hypocalcemia. In
s
o
f
adults, hypoparathyroidism most commonly results
B
TREATMENT Hypercalcemia
o
rom inadvertent damage to all our glands during thy-
n
e
a
roid or parathyroid gland surgery. Hypoparathyroidism
n
Mild, asymptomatic hypercalcemia does not require imme-
d
is a cardinal eature o autoimmune endocrinopathies
C
diate therapy, and management should be dictated by the
a
l
(Chap. 29); rarely, it may be associated with in ltrative
c
underlying diagnosis. By contrast, signi cant, symptom-
i
u
m
atic hypercalcemia usually requires therapeutic intervention diseases such as sarcoidosis. Impaired P H secretion
M
may be secondary to magnesium de ciency or to acti-
e
independent o the etiology o hypercalcemia. Initial therapy
t
a
vating mutations in the CaSR or in the G proteins that
b
o signi cant hypercalcemia begins with volume expansion
o
l
mediate CaSR signaling, which suppress P H, leading
i
s
because hypercalcemia invariably leads to dehydration; 4–6
m
L o intravenous saline may be required over the rst 24 h, to e ects that are opposite to those that occur in FHH.
keeping in mind that underlying comorbidities (e.g., con- Vitamin D de ciency, impaired 1,25(OH)2D pro-
gestive heart ailure) may require the use o loop diuretics duction (primarily secondary to renal insuf ciency),
to enhance sodium and calcium excretion. However, loop or vitamin D resistance also cause hypocalcemia.
diuretics should not be initiated until the volume status has However, the degree o hypocalcemia in these disor-
been restored to normal. I there is increased calcium mobi- ders is generally not as severe as that seen with hypo-
lization rom bone (as in malignancy or severe hyperpara- parathyroidism because the parathyroids are capable o
thyroidism), drugs that inhibit bone resorption should be mounting a compensatory increase in P H secretion.
considered. Zoledronic acid (e.g., 4 mg intravenously over Hypocalcemia may also occur in conditions associated
30 min), pamidronate (e.g., 60–90 mg intravenously over with severe tissue injury such as burns, rhabdomyoly-
2–4 h), and ibandronate (2 mg intravenously over 2 h) are sis, tumor lysis, or pancreatitis. T e cause o hypocalce-
bisphosphonates that are commonly used or the treatment mia in these settings may include a combination o low
o hypercalcemia o malignancy in adults. Onset o action is albumin, hyperphosphatemia, tissue deposition o cal-
within 1–3 days, with normalization o serum calcium levels cium, and impaired P H secretion.
occurring in 60–90% o patients. Bisphosphonate in usions
may need to be repeated i hypercalcemia relapses. An alter-
CLINICAL MANIFESTATIONS
native to the bisphosphonates is gallium nitrate (200 mg/m 2
intravenously daily or 5 days), which is also e ective, but has Patients with hypocalcemia may be asymptomatic i
potential nephrotoxicity. In rare instances, dialysis may be the decreases in serum calcium are relatively mild and
necessary. Finally, although intravenous phosphate chelates chronic, or they may present with li e-threatening com-
calcium and decreases serum calcium levels, this therapy can plications. Moderate to severe hypocalcemia is associ-
be toxic because calcium-phosphate complexes may deposit ated with paresthesias, usually o the ngers, toes, and
in tissues and cause extensive organ damage. circumoral regions, and is caused by increased neu-
In patients with 1,25(OH)2D-mediated hypercalcemia, romuscular irritability. On physical examination, a
glucocorticoids are the pre erred therapy, as they decrease Chvostek’s sign (twitching o the circumoral muscles
1,25(OH)2D production. Intravenous hydrocortisone (100– in response to gentle tapping o the acial nerve just
300 mg daily) or oral prednisone (40–60 mg daily) or 3–7 anterior to the ear) may be elicited, although it is also
days is used most o en. Other drugs, such as ketoconazole, present in 10% o normal individuals. Carpal spasm

Ha rris on_Endocrinology_Ch33_p442-p445.indd 444 27/07/16 11:05 a m

 TABLE 3 3 -2
CAUSES OF HYPOCALCEMIA
Lo w Pa ra t h yro id Ho rm o n e Le ve ls
(Hyp o p a ra t h yro id ism )
Parathyroid agenesis
Isolated
DiGeorge’s syndrome
Parathyroid destruction
Surgical
Radiation
Inf ltration by metastases or systemic diseases
Autoimmune
Reduced parathyroid unction
Hypomagnesemia
Activating CaSR or G protein mutations
Hig h Pa ra t h yro id Ho rm o n e Le ve ls
(Se co n d a ry Hyp e rp a ra t h yro id ism )
Vitamin D def ciency or impaired 1,25(OH)2D production/action
Nutritional vitamin D def ciency (poor intake or absorption)
Renal insu ciency with impaired 1,25(OH)2D production
Vitamin D resistance, including receptor de ects
Parathyroid hormone resistance syndromes
PTH receptor mutations
Pseudohypoparathyroidism (G protein mutations)
Drugs
Calcium chelators
Inhibitors o bone resorption (bisphosphonates, plicamycin)
Altered vitamin D metabolism (phenytoin, ketoconazole)
Miscellaneous causes
Acute pancreatitis
Acute rhabdomyolysis
Hungry bone syndrome a ter parathyroidectomy
Osteoblastic metastases with marked stimulation o bone
ormation (prostate cancer)
Abbrevia tions: CaSR, calcium sensor receptor; PTH, parathyroid hormone.
may be induced by in ation o a blood pressure cu
to 20 mmHg above the patient’s systolic blood pres-
sure or 3 min ( rousseau’s sign). Severe hypocalcemia
can induce seizures, carpopedal spasm, bronchospasm,
laryngospasm, and prolongation o the Q interval.
DIAGNOSTIC APPROACH
In addition to measuring serum calcium, it is use ul to
determine albumin, phosphorus, and magnesium levels. As
or the evaluation o hypercalcemia, determining the P H
level is central to the evaluation o hypocalcemia. A sup-
pressed (or “inappropriately low”) P H level in the setting
Ha rris on_Endocrinology_Ch33_p442-p445.indd 445
o hypocalcemia establishes absent or reduced P H secre- 445
tion (hypoparathyroidism) as the cause o the hypocalce-
mia. Further history will o en elicit the underlying cause
(i.e., parathyroid agenesis vs. destruction). By contrast,
an elevated P H level (secondary hyperparathyroidism)
should direct attention to the vitamin D axis as the cause
o the hypocalcemia. Nutritional vitamin D de ciency is
best assessed by obtaining serum 25-hydroxyvitamin D
levels, which re ect vitamin D stores. In the setting o renal
C
insuf ciency or suspected vitamin D resistance, serum
H
A
1,25(OH)2D levels are in ormative.
P
T
E
R
3
3
TREATMENT Hypocalcemia
T e approach to treatment depends on the severity o the
H
y
hypocalcemia, the rapidity with which it develops, and the
p
e
r
accompanying complications (e.g., seizures, laryngospasm).
c
a
l
c
Acute, symptomatic hypocalcemia is initially managed with
e
m
calcium gluconate, 10 mL 10% wt/vol (90 mg or 2.2 mmol)
i
a
a
intravenously, diluted in 50 mL o 5% dextrose or 0.9% sodium
n
d
chloride, given intravenously over 5 min. Continuing hypocal-
H
y
p
cemia o en requires a constant intravenous in usion (typically
o
c
a
10 ampules o calcium gluconate or 900 mg o calcium in 1 L o
l
c
e
5% dextrose or 0.9% sodium chloride administered over 24 h).
m
i
a
Accompanying hypomagnesemia, i present, should be treated
with appropriate magnesium supplementation.
Chronic hypocalcemia due to hypoparathyroidism is
treated with calcium supplements (1000–1500 mg/d elemen-
tal calcium in divided doses) and either vitamin D2 or D3
(25,000–100,000 U daily) or calcitriol [1,25(OH)2D, 0.25–2
µg/d]. Other vitamin D metabolites (dihydrotachysterol, al a-
calcidiol) are now used less requently. Vitamin D de ciency,
however, is best treated using vitamin D supplementation,
with the dose depending on the severity o the de cit and the
underlying cause. T us, nutritional vitamin D de ciency gen-
erally responds to relatively low doses o vitamin D (50,000
U, 2–3 times per week or several months), whereas vitamin
D de ciency due to malabsorption may require much higher
doses (100,000 U/d or more). T e treatment goal is to bring
serum calcium into the low normal range and to avoid hyper-
calciuria, which may lead to nephrolithiasis.
GLOBAL CONSIDERATIONS
In countries with more limited access to health
care or screening laboratory testing o serum
calcium levels, primary hyperparathyroidism
o en presents in its severe orm with skeletal complica-
tions (osteitis brosa cystica) in contrast to the asymp-
tomatic orm that is common in developed countries. In
addition, vitamin D de ciency is paradoxically com-
mon in some countries despite extensive sunlight (e.g.,
India) due to avoidance o sun exposure and poor
dietary vitamin D intake.
27/07/16 11:05 a m
 CH AP TER 3 4
DISORDERS OF THE PARATHYROID GLAND
AND CALCIUM HOMEOSTASIS
Jo h n T. Po tts, Jr.
T e our parathyroid glands are located posterior to
the thyroid gland. T ey produce parathyroid hormone
(P H), which is the primary regulator o calcium physi-
ology. P H acts directly on bone, where it induces cal-
cium release; on the kidney, where it enhances calcium
reabsorption in the distal tubules; and in the proximal
renal tubules, where it synthesizes 1,25-dihydroxyvi-
tamin D (1,25[OH]2D), a hormone that increases gas-
trointestinal calcium absorption. Serum P H levels are
tightly regulated by a negative eedback loop. Calcium,
acting through the calcium-sensing receptor, and vita-
min D, acting through its nuclear receptor, reduce P H
release and synthesis. Additional evidence indicates
that broblast growth actor 23 (FGF23), a phosphatu-
ric hormone, can suppress P H secretion. Understand-
ing the hormonal pathways that regulate calcium levels
and bone metabolism is essential or e ective diag-
nosis and management o a wide array o hyper- and
hypocalcemic disorders.
Hyperparathyroidism, characterized by excess pro-
duction o P H, is a common cause o hypercalcemia
and is usually the result o autonomously unctioning
adenomas or hyperplasia. Surgery or this disorder is
highly e ective and has been shown to reverse some o
the deleterious e ects o long-standing P H excess on
bone density. Humoral hypercalcemia o malignancy
is also common and is usually due to the overproduc-
tion o parathyroid hormone–related peptide (P HrP)
by cancer cells. T e similarities in the biochemical
characteristics o hyperparathyroidism and humoral
hypercalcemia o malignancy, rst noted by Albright
in 1941, are now known to re ect the actions o P H
and P HrP through the same G protein–coupled P H/
P HrP receptor.
T e genetic basis o multiple endocrine neoplasia
(MEN) types 1 and 2, amilial hypocalciuric hypercalce-
mia (FHH), di erent orms o pseudohypoparathyroidism,
Ha rris on_Endocrinology_Ch34_p446-p479.indd 446
■ Hara ld Jü p p n e r
Jansen’s syndrome, disorders o vitamin D synthesis and
action, and the molecular events associated with para-
thyroid gland neoplasia have provided new insights into
the regulation o calcium homeostasis. P H and possibly
some o its analogues are promising therapeutic agents
or the treatment o postmenopausal or senile osteoporo-
sis, and calcimimetic agents, which activate the calcium-
sensing receptor, have provided new approaches or P H
suppression.
PARATHYRO ID HO RMO NE
PHYSIOLOGY
T e primary unction o P H is to maintain the extra-
cellular uid (ECF) calcium concentration within a nar-
row normal range. T e hormone acts directly on bone
and kidney and indirectly on the intestine through its
e ects on synthesis o 1,25(OH)2D to increase serum
calcium concentrations; in turn, P H production is
closely regulated by the concentration o serum ion-
ized calcium. T is eedback system is the critical
homeostatic mechanism or maintenance o ECF cal-
cium. Any tendency toward hypocalcemia, as might
be induced by calcium- or vitamin D–de cient diets,
is counteracted by an increased secretion o P H. T is
in turn (1) increases the rate o dissolution o bone
mineral, thereby increasing the ow o calcium rom
bone into blood; (2) reduces the renal clearance o cal-
cium, returning more o the calcium and phosphate
ltered at the glomerulus into ECF; and (3) increases
the e ciency o calcium absorption in the intestine by
stimulating the production o 1,25(OH)2D. Immedi-
ate control o blood calcium is due to P H e ects on
bone and, to a lesser extent, on renal calcium clear-
ance. Maintenance o steady-state calcium balance,
446
20/05/16 9:33 a m
 on the other hand, probably results rom the e ects o can reduce, directly or indirectly, some o the biologic 447
1,25(OH)2D on calcium absorption (Chap. 32). T e actions o ull-length P H (1–84) and o P H (1–34).
renal actions o the hormone are exerted at multiple
sites and include inhibition o phosphate transport
(proximal tubule), augmentation o calcium reabsorp- BIOSYNTHESIS, SECRETION,
tion (distal tubule), and stimulation o the renal AND METABOLISM
25(OH)D-1α-hydroxylase. As much as 12 mmol (500 Syn th esis
mg) o calcium is trans erred between the ECF and
Parathyroid cells have multiple methods o adapting
bone each day (a large amount in relation to the total
to increased needs or P H production. Most rapid
ECF calcium pool), and P H has a major e ect on this

C
H
(within minutes) is secretion o pre ormed hormone in

A
trans er. T e homeostatic role o the hormone can pre-

P
response to hypocalcemia. Second, within hours, P H

T
serve calcium concentration in blood at the cost o bone

E
mRNA expression is induced by sustained hypocalce-

R
demineralization.

3
mia. Finally, protracted challenge leads within days to

P H has multiple actions on bone, some direct and
some indirect. P H-mediated changes in bone calcium
release can be seen within minutes. T e chronic e ects
4
cellular replication to increase parathyroid gland mass.
P H is initially synthesized as a larger molecule

D
(preproparathyroid hormone, consisting o 115 amino

i
s
o P H are to increase the number o bone cells, both

o
r
acids). A er a rst cleavage step to remove the “pre”

d
osteoblasts and osteoclasts, and to increase the remod-

e
r
sequence o 25 amino acid residues, a second cleavage

s
eling o bone; these e ects are apparent within hours

o
f
step removes the “pro” sequence o 6 amino acid resi-

t
a er the hormone is given and persist or hours a er

h
e
dues be ore secretion o the mature peptide comprising

P
P H is withdrawn. Continuous exposure to elevated

a
84 residues. Mutations in the preprotein region o the

r
a
P H (as in hyperparathyroidism or long-term in usions

t
h
gene can cause hypoparathyroidism by inter ering with

y
in animals) leads to increased osteoclast-mediated bone

r
o
hormone synthesis, transport, or secretion.

i
d
resorption. However, the intermittent administration o

G
ranscriptional suppression o the P H gene by cal-

l
P H, elevating hormone levels or 1–2 h each day, leads

a
n
cium is nearly maximal at physiologic calcium con-

d
to a net stimulation o bone ormation rather than bone

a
centrations. Hypocalcemia increases transcriptional

n
breakdown. Striking increases, especially in trabecular

d
activity within hours. 1,25(OH)2D strongly suppresses

C
a
bone in the spine and hip, have been reported with the

l
c
P H gene transcription. In patients with renal ail-

i
u
use o P H in combination with estrogen. P H (1–34)

m
ure, IV administration o supraphysiologic levels o
as monotherapy caused a highly signi cant reduction

H
o
1,25(OH)2D or analogues o this active metabolite can

m
in racture incidence in a worldwide placebo-controlled

e
dramatically suppress P H overproduction, which is

o
trial.

s
t
sometimes di cult to control due to severe second-

a
Osteoblasts (or stromal cell precursors), which have

P H/P HrP receptors, are crucial to this bone- orming
e ect o P H; osteoclasts, which mediate bone break-
down, lack such receptors. P H-mediated stimula-
tion o osteoclasts is indirect, acting in part through
cytokines released rom osteoblasts to activate osteo-
clasts; in experimental studies o bone resorption in
vitro, osteoblasts must be present or P H to activate
osteoclasts to resorb bone (Chap. 32).
STRUCTURE
P H is an 84-amino-acid single-chain peptide. T e
amino-terminal portion, P H (1–34), is highly con-
served and is critical or the biologic actions o the
molecule. Modi ed synthetic ragments o the amino-
terminal sequence as small as P H (1–11) are su -
cient to activate the P H/P HrP receptor (see below).
T e carboxyl-terminal region o the ull-length P H
(1–84) molecule also can bind to a separate binding
protein/receptor (cP H-R), but this receptor has been
incompletely characterized. Fragments shortened at
the amino-terminus possibly by binding to cP H-R
s
i
s
ary hyperparathyroidism. Regulation o proteolytic
destruction o pre ormed hormone (posttranslational
regulation o hormone production) is an important
mechanism or mediating rapid (within minutes)
changes in hormone availability. High calcium increases
and low calcium inhibit the proteolytic destruction o
stored hormone.
Reg u la tio n o PTH se cretio n
P H secretion increases steeply to a maximum value
o about ve times the basal rate o secretion as the
calcium concentration alls rom normal to the range o
1.9–2.0 mmol/L (7.6–8.0 mg/dL; measured as total cal-
cium). However, the ionized raction o blood calcium
is the important determinant o hormone secretion.
Severe intracellular magnesium de ciency impairs P H
secretion (see below).
ECF calcium controls P H secretion by interaction
with a calcium-sensing receptor (CaSR), a G protein–
coupled receptor (GPCR) or which Ca2+ ions act as the
primary ligand (see below). T is receptor is a member
o a distinctive subgroup o the GPCR super amily that

Ha rris on_Endocrinology_Ch34_p446-p479.indd 447 20/05/16 9:33 a m

 448 mediates its actions through the alpha-subunits o two some o these assays detect, besides the intact molecule,
related signaling G proteins, namely Gq and G11, and large amino-terminally truncated orms o P H, which
is characterized by a large extracellular domain suit- are present in normal and uremic individuals in addi-
able or “clamping” the small-molecule ligand. Stimu- tion to P H(1–84). T e concentration o these rag-
lation o the CaSR by high calcium levels suppresses ments relative to that o intact P H(1–84) is higher with
P H secretion. T e CaSR is present in parathyroid induced hypercalcemia than in eucalcemic or hypocal-
glands and the calcitonin-secreting cells o the thyroid cemic conditions and is higher in patients with impaired
(C cells), as well as in multiple other sites, including renal unction. P H(7–84) has been identi ed as a major
brain and kidney. Genetic evidence has revealed a key component o these amino-terminally truncated rag-
biologic role or the CaSR in parathyroid gland respon- ments. Growing evidence suggests that the P H(7–84)
S
E
siveness to calcium and in renal calcium clearance. Het- (and probably related amino-terminally truncated rag-
C
T
I
erozygous loss-o - unction mutations in CaSR cause the ments) can act, through yet unde ned mechanisms,
O
N
syndrome o FHH, in which the blood calcium abnor- as an inhibitor o P H action and may be o clinical
V
I
mality resembles that observed in hyperparathyroid- signi cance, particularly in patients with chronic kid-
ism but with hypocalciuria; two more recently de ned ney disease. In this group o patients, e orts to prevent
variants o FHH, FHH2 and FHH3, are caused either secondary hyperparathyroidism by a variety o mea-
D
i
s
by heterozygous mutations in G11, one o the signaling sures (vitamin D analogues, higher calcium intake,
o
r
d
proteins downstream o the CaSR, or by heterozygous higher dialysate calcium, phosphate-lowering strate-
e
r
s
mutations in AP2S1. Homozygous loss-o - unction gies, and calcimetic drugs) can lead to oversuppression
o
f
B
mutations in the CaSR are the cause o severe neona- o the parathyroid glands since some amino-terminally
o
n
e
tal hyperparathyroidism, a disorder that can be lethal truncated P H ragments, such as P H(7–84), react in
a
n
i not treated within the rst days o li e. On the other many immunometric P H assays (now termed second-
d
C
hand, heterozygous gain-o - unction mutations cause a generation assays; see below under “Diagnosis”), thus
a
l
c
i
orm o hypocalcemia resembling hypoparathyroidism overestimating the levels o biologically active, intact
u
m
(see below). P H. Such excessive parathyroid gland suppression in
M
e
chronic kidney disease can lead to adynamic bone dis-
t
a
b
ease (see below), which has been associated with ur-
o
Meta b o lism
l
i
s
ther impaired growth in children and increased bone
m
T e secreted orm o P H is indistinguishable by racture rates in adults, and can urthermore lead to
immunologic criteria and by molecular size rom the signi cant hypercalcemia. T e measurement o P H
84-amino-acid peptide (P H[1–84]) extracted rom with newer third-generation immunoassays, which use
glands. However, much o the immunoreactive material detection antibodies directed against extreme amino-
ound in the circulation is smaller than the extracted or terminal P H epitopes and thus detect only ull-length
secreted hormone. T e principal circulating ragments P H(1–84), may provide some advantage to prevent
o immunoreactive hormone lack a portion o the criti- bone disease in chronic kidney disease.
cal amino-terminal sequence required or biologic
activity and, hence, are biologically inactive ragments
(so-called middle and carboxyl-terminal ragments).
Much o the proteolysis o the hormone occurs in the PARATHYRO ID HO RMO NE–RELATED
liver and kidney. Peripheral metabolism o P H does P ROTEIN (P THr P )
not appear to be regulated by physiologic states (high
versus low calcium, etc.); hence, peripheral metabolism P HrP is responsible or most instances o humoral
o hormone, although responsible or rapid clearance hypercalcemia o malignancy (Chap. 31), a syn-
o secreted hormone, appears to be a high-capacity, drome that resembles primary hyperparathyroidism
metabolically invariant catabolic process. but without elevated P H levels. Most cell types nor-
T e rate o clearance o the secreted 84-amino-acid mally produce P HrP, including brain, pancreas, heart,
peptide rom blood is more rapid than the rate o clear- lung, mammary tissue, placenta, endothelial cells,
ance o the biologically inactive ragment(s) corre- and smooth muscle. In etal animals, P HrP directs
sponding to the middle and carboxyl-terminal regions transplacental calcium trans er, and high concentra-
o P H. Consequently, the interpretation o results tions o P HrP are produced in mammary tissue and
obtained with earlier P H radioimmunoassays was secreted into milk, but the biologic signi cance o the
in uenced by the nature o the peptide ragments very high concentrations o this hormone in breast
detected by the antibodies. milk is unknown. P HrP also plays an essential role in
Although the problems inherent in P H measure- endochondral bone ormation and in branching mor-
ments have been largely circumvented by use o double- phogenesis o the breast, and possibly in uterine con-
antibody immunometric assays, it is now known that traction and other biologic unctions.

Ha rris on_Endocrinology_Ch34_p446-p479.indd 448 20/05/16 9:33 a m

 1 5 10 15 20 25 30 449
hPTH SER VAL SER GLU I LE GLN LEU MET HI S ASN LEU GLY LYS HI S LEU ASN SER MET GLU ARG VAL GLU TRP LEU ARG LYS LYS LEU GLN ASP
hPTHr p ALA – – – HI S – – LEU – ASP LYS – – SER I LE GLN ASP LEU ARG – ARG PHE PHE – HI S HI S LEU I LE ALA GLU

hPTH hPTHrP

1 30 84 1 30 84 144
Amino a cid re s idue s Amino a cid re s idue s

FIGURE 3 4 -1

C
H
Schem atic d iagram to illustrate sim ilarities and d if erences in is only 84 residues long; a ter residue 30, there is little structural homo-

A
P
stru ctu re o h um an p arathyroid h orm on e PTH an d h um an logy between the two. Dashed lines in the PTHrP sequence indicate

T
E
PTH related p ep tid e PTHrP . Close structural (and unctional) identity; underlined residues, although di erent rom those o PTH, still

R
3
homology exists between the rst 30 amino acids o hPTH and hPTHrP. represent conservative changes (charge or polarity preserved). Ten

4
The PTHrP sequence may be ≥144 amino acid residues in length. PTH amino acids are identical, and a total o 20 o 30 are homologues.

D
i
s
o
r
P H and P HrP, although products o di erent P H, originally termed the PTH-2 receptor (P H2R), is

d
e
r
s
genes, exhibit considerable unctional and structural primarily expressed in brain, pancreas, and testis. Di er-

o
f
homology (Fig. 34-1) and have evolved rom a shared ent mammalian P H1Rs respond equivalently to P H

t
h
e
ancestral gene. T e structure o the gene encoding and P HrP, at least when tested with traditional assays,

P
a
r
human P HrP, however, is more complex than that o whereas only the human P H2R responds e ciently to

a
t
h
P H, containing multiple additional exons, which can P H (but not to P HrP). P H2Rs rom other species

y
r
o
undergo alternate splicing patterns during ormation show little or no stimulation o second-messenger or-

i
d
G
o the mature mRNA. Protein products o 139, 141, mation in response to P H or P HrP. T e endogenous

l
a
n
and 173 amino acids are produced, and other molecu- ligand o the P H2R was shown to be a hypothalamic

d
a
lar orms may result rom tissue-speci c degradation peptide re erred to as tubular in undibular peptide o

n
d
C
at accessible internal cleavage sites. T e biologic roles 39 residues, IP39, that is distantly related to P H and

a
l
c
o these various molecular species and the nature o P HrP. T e P H1R and the P H2R can be traced back-

i
u
m
the circulating orms o P HrP are unclear. In act, it is ward in evolutionary time to sh; in act, the zebra sh

H
o
uncertain whether P HrP circulates at any signi cant genome contains, in addition to the P H1R and the

m
e
level in adults. As a paracrine actor, P HrP may be P H2R orthologs, a third receptor, the P H3R, that is

o
s
t
produced, act, and be destroyed locally within tissues. more closely related to the sh P H1R than to the sh

In adults, P HrP appears to have little in uence on cal-
cium homeostasis, except in disease states, when large
tumors, especially o the squamous cell type as well as
renal cell carcinomas, lead to massive overproduction
o the hormone and hypercalcemia.
PTH AND PTHrP HORMONE ACTION
Both P H and P HrP bind to and activate the P H/
P HrP receptor. T e P H/P HrP receptor (also known
as the P H-1 receptor, P H1R) belongs to a sub amily
o GPCRs that includes the receptors or calcitonin, glu-
cagon, secretin, vasoactive intestinal peptide, and other
peptides. Although both ligands activate the P H1R, the
two peptides induce distinct responses in the receptor,
which explains how a single receptor without iso orms
can serve two biologic roles. T e extracellular regions o
the receptor are involved in hormone binding, and the
intracellular domains, a er hormone activation, bind
G protein subunits to transduce hormone signaling
into cellular responses through the stimulation o sec-
ond messenger ormation. A second receptor that binds
a
s
i
s
P H2R. T e evolutionary conservation o structure
and unction suggests important biologic roles or these
receptors, even in sh, which lack discrete parathy-
roid glands but produce two molecules that are closely
related to mammalian P H.
Studies using the cloned P H1R con rm that it can
be coupled to more than one G protein and second-
messenger pathway, apparently explaining the mul-
tiplicity o pathways stimulated by P H. Activation
o protein kinases (A and C) and calcium transport
channels is associated with a variety o hormone-
speci c tissue responses. T ese responses include
inhibition o phosphate and bicarbonate transport,
stimulation o calcium transport, and activation o renal
1α-hydroxylase in the kidney. T e responses in bone
include e ects on collagen synthesis, alkaline phos-
phatase, ornithine decarboxylase, citrate decarboxyl-
ase, and glucose-6-phosphate dehydrogenase activities;
phospholipid synthesis; and calcium and phosphate
transport. Ultimately, these biochemical events lead
to an integrated hormonal response in bone turnover
and calcium homeostasis. P H also activates Na+/Ca2+
exchangers at renal distal tubular sites and stimulates

Ha rris on_Endocrinology_Ch34_p446-p479.indd 449 20/05/16 9:33 a m

 450 translocation o pre ormed calcium transport channels,
CALCITO NIN
moving them rom the interior to the apical sur ace to
increase tubular uptake o calcium. P H-dependent (See also Chap. 29) Calcitonin is a hypocalcemic pep-
stimulation o phosphate excretion (reducing reabsorp- tide hormone that in several mammalian species acts
tion—the opposite e ect rom actions on calcium in the as an indirect antagonist to the calcemic actions o
kidney) involves the downregulation o two sodium- P H. Calcitonin seems to be o limited physiologic
dependent phosphate co-transporters, NP 2a and signi cance in humans, at least with regard to calcium
NP 2c, and their expression at the apical membrane, homeostasis. It is o medical signi cance because o
thereby reducing phosphate reabsorption in the proxi- its role as a tumor marker in sporadic and hereditary
mal renal tubules. Similar mechanisms may be involved cases o medullary carcinoma and its medical use as an
S
E
in other renal tubular transporters that are in uenced
C
adjunctive treatment in severe hypercalcemia and in
T
I
by P H. Recent studies rea rm the critical linkage o
O
Paget’s disease o bone.
N
blood phosphate lowering to net calcium entry into T e hypocalcemic activity o calcitonin is accounted
V
I
blood by P H action and emphasize the participa- or primarily by inhibition o osteoclast-mediated bone
tion o bone cells other than osteoclasts in the rapid resorption and secondarily by stimulation o renal cal-
calcium-elevating actions o P H.
D
cium clearance. T ese e ects are mediated by receptors
i
s
P HrP exerts important developmental in uences
o
on osteoclasts and renal tubular cells. Calcitonin exerts
r
d
on etal bone development and in adult physiology. A
e
additional e ects through receptors present in the
r
s
homozygous ablation o the gene encoding P HrP (or
o
brain, the gastrointestinal tract, and the immune sys-
f
B
disruption o the P H1R gene) in mice causes a lethal
o
tem. T e hormone, or example, exerts analgesic e ects
n
e
phenotype in which animals are born with pronounced directly on cells in the hypothalamus and related struc-
a
n
acceleration o chondrocyte maturation that resembles
d
tures, possibly by interacting with receptors or related
C
a lethal orm o chondrodysplasia in humans that is
a
peptide hormones such as calcitonin gene–related
l
c
i
caused by homozygous or compound heterozygous,
u
peptide (CGRP) or amylin. Both o these ligands have
m
inactivating P H1R mutations (Fig. 34-2). Heterozy-
M
speci c high-a nity receptors that share consider-
e
gous P H1R mutations in humans urthermore can
t
able structural similarity with the P H1R and can also
a
b
be a cause o delayed tooth eruption, and mice that are
o
bind to and activate calcitonin receptors. T e calcitonin
l
i
s
heterozygous or ablation o the P HrP gene display
m
receptor shares considerable structural similarity with
reduced mineral density consistent with osteoporosis. the P H1R.
Experiments with these mouse models point to a hith- T e thyroid is the major source o the hormone, and
erto unappreciated role o P HrP as a paracrine/auto- the cells involved in calcitonin synthesis arise rom
crine actor that modulates bone metabolism in adults neural crest tissue. During embryogenesis, these cells
as well as during bone development. migrate into the ultimobranchial body, derived rom
the last branchial pouch. In submammalian vertebrates,
the ultimobranchial body constitutes a discrete organ,
anatomically separate rom the thyroid gland; in mam-
Ma ny
orga ns P a ra thyroids mals, the ultimobranchial gland uses with and is incor-
porated into the thyroid gland.
P THrP P TH T e naturally occurring calcitonins consist o a pep-
Ca 2+ tide chain o 32 amino acids. T ere is considerable
sequence variability among species. Calcitonin rom
salmon, which is used therapeutically, is 10–100 times
Growth P la te more potent than mammalian orms in lowering serum
Bre a s t Kidne y calcium.
Bra in
S mooth mus cle Bone T ere are two calcitonin genes, α and β; the tran-
S kin scriptional control o these genes is complex. wo di -
erent mRNA molecules are transcribed rom the α
Parac rine Ac tio ns Calc ium Ho me o s tas is
gene; one is translated into the precursor or calcito-
FIGURE 3 4 -2 nin, and the other message is translated into an alter-
Du a l ro le o r t h e a ct io n s o t h e PTH/PTHrP re ce p t o r native product, CGRP. CGRP is synthesized wherever
PTH1R . Parathyroid hormone (PTH; endocrine-calcium homeo- the calcitonin mRNA is expressed (e.g., in medullary
stasis) and PTH-related peptide (PTHrP; paracrine–multiple tissue carcinoma o the thyroid). T e β, or CGRP-2, gene
actions including growth plate cartilage in developing bone) use is transcribed into the mRNA or CGRP in the cen-
the single receptor or their disparate unctions mediated by the tral nervous system (CNS); this gene does not pro-
amino-terminal 34 residues o either peptide. Other regions o
duce calcitonin, however. CGRP has cardiovascular
both ligands interact with other receptors (not shown).

Ha rris on_Endocrinology_Ch34_p446-p479.indd 450 20/05/16 9:33 a m

 actions and may serve as a neurotransmitter or play a TABLE 3 4 -1 451
developmental role in the CNS. CLASSIFICATION OF CAUSES OF HYPERCALCEMIA
T e circulating level o calcitonin in humans is I. Parathyroid-Related
lower than that in many other species. In humans, even A. Primary hyperparathyroidism
extreme variations in calcitonin production do not 1. Adenoma(s)
change calcium and phosphate metabolism; no de nite 2. Multiple endocrine neoplasia
e ects are attributable to calcitonin de ciency (totally 3. Carcinoma
B. Lithium therapy
thyroidectomized patients receiving only replacement
C. Familial hypocalciuric hypercalcemia
thyroxine) or excess (patients with medullary carci- II. Malignancy-Related
noma o the thyroid, a calcitonin-secreting tumor)

C
A. Solid tumor with metastases (breast)

H
A
(Chap. 29). Calcitonin has been a use ul pharmaco- B. Solid tumor with humoral mediation o hypercalcemia

P
T
logic agent to suppress bone resorption in Paget’s dis- (lung, kidney)

E
R
ease (Chap. 36) and osteoporosis (Chap. 35) and in the C. Hematologic malignancies (multiple myeloma, lym-

3
4
treatment o hypercalcemia o malignancy (see below). phoma, leukemia)
III. Vitamin D–Related
However, bisphosphonates are usually more e ective,
A. Vitamin D intoxication
and the physiologic role, i any, o calcitonin in humans

D
B. ↑ 1,25(OH)2D; sarcoidosis and other granulomatous

i
s
is uncertain. On the other hand, ablation o the calcito-

o
r
diseases

d
nin gene (combined because o the close proximity with

e
C. ↑ 1,25(OH)2D; impaired 1,25(OH)2D metabolism due to

r
s
ablation o the CGRP gene) in mice leads to reduced

o
24-hydroxylase de ciency

f
t
bone mineral density, suggesting that its biologic role in

h
IV. Associated with High Bone Turnover

e
P
mammals is still not ully understood. A. Hyperthyroidism

a
r
B. Immobilization

a
t
h
C. Thiazides

y
r
o
D. Vitamin A intoxication

i
d
HYP ERCALCEMIA

G
E. Fat necrosis

l
a
V. Associated with Renal Failure

n
(See also Chap. 33) Hypercalcemia can be a mani es-

d
A. Severe secondary hyperparathyroidism

a
n
tation o a serious illness such as malignancy or can

d
B. Aluminum intoxication

C
be detected coincidentally by laboratory testing in a

a
C. Milk-alkali syndrome

l
c
i
patient with no obvious illness. T e number o patients

u
m
recognized with asymptomatic hypercalcemia, usually

H
o
hyperparathyroidism, increased in the late twentieth

m
e
century. patient to the physician, and hypercalcemia is discov-

o
s
t
ered during the evaluation. In such patients, the interval

a
Whenever hypercalcemia is con rmed, a de nitive

diagnosis must be established. Although hyperparathy-
roidism, a requent cause o asymptomatic hypercal-
cemia, is a chronic disorder in which mani estations,
i any, may be expressed only a er months or years,
hypercalcemia can also be the earliest mani estation o
malignancy, the second most common cause o hyper-
calcemia in the adult. T e causes o hypercalcemia are
numerous (Table 34-1), but hyperparathyroidism and
cancer account or 90% o all cases.
Be ore undertaking a diagnostic workup, it is essen-
tial to be sure that true hypercalcemia, not a alse-
positive laboratory test, is present. A alse-positive
diagnosis o hypercalcemia is usually the result o inad-
vertent hemoconcentration during blood collection or
elevation in serum proteins such as albumin. Hyper-
calcemia is a chronic problem, and it is cost-e ective to
obtain several serum calcium measurements; these tests
need not be in the asting state.
Clinical eatures are help ul in di erential diagno-
sis. Hypercalcemia in an adult who is asymptomatic is
usually due to primary hyperparathyroidism. In malig-
nancy-associated hypercalcemia, the disease is usually
not occult; rather, symptoms o malignancy bring the
s
i
s
between detection o hypercalcemia and death, espe-
cially without vigorous treatment, is o en <6 months.
Accordingly, i an asymptomatic individual has had
hypercalcemia or some mani estation o hypercalcemia
such as kidney stones or more than 1 or 2 years, it is
unlikely that malignancy is the cause. Nevertheless, di -
erentiating primary hyperparathyroidism rom occult
malignancy can occasionally be di cult, and care ul
evaluation is required, particularly when the duration
o the hypercalcemia is unknown. Hypercalcemia not
due to hyperparathyroidism or malignancy can result
rom excessive vitamin D action, impaired metabolism
o 1,25(OH)2D, high bone turnover rom any o sev-
eral causes, or renal ailure ( able 34-1). Dietary his-
tory and a history o ingestion o vitamins or drugs are
o en help ul in diagnosing some o the less requent
causes. Immunometric P H assays serve as the princi-
pal laboratory test in establishing the diagnosis.
Hypercalcemia rom any cause can result in atigue,
depression, mental con usion, anorexia, nausea, vomiting,
constipation, reversible renal tubular de ects, increased
urine output, a short Q interval in the electrocardio-
gram, and, in some patients, cardiac arrhythmias. T ere

Ha rris on_Endocrinology_Ch34_p446-p479.indd 451 20/05/16 9:33 a m

 452 is a variable relation rom one patient to the next between may also arise in hereditary syndromes such as MEN
the severity o hypercalcemia and the symptoms. Gener- syndromes. Parathyroid tumors may also arise as sec-
ally, symptoms are more common at calcium levels >2.9– ondary to underlying disease (excessive stimulation
3.0 mmol/L (11.6–12.0 mg/dL), but some patients, even in secondary hyperparathyroidism, especially chronic
at this level, are asymptomatic. When the calcium level is renal ailure) or a er other orms o excessive stimu-
>3.2 mmol/L (12.8 mg/dL), calci cation in kidneys, skin, lation such as lithium therapy. T ese etiologies are
vessels, lungs, heart, and stomach occurs and renal insu - discussed below.
ciency may develop, particularly i blood phosphate lev-
So lita ry a d e n o m a s
els are normal or elevated due to impaired renal excretion.
A single abnormal gland is the cause in ~80% o
Severe hypercalcemia, usually de ned as ≥3.7–4.5 mmol/L
S
patients; the abnormality in the gland is usually a
E
(14.8–18.0 mg/dL), can be a medical emergency; coma
C
T
benign neoplasm or adenoma and rarely a parathyroid
I
and cardiac arrest can occur.
O
N
Acute management o the hypercalcemia is usually carcinoma. Some surgeons and pathologists report that
V
the enlargement o multiple glands is common; double
I
success ul. T e type o treatment is based on the sever-
ity o the hypercalcemia and the nature o associated adenomas are reported. In ~15% o patients, all glands
are hyper unctioning; chie cell parathyroid hyperpla-
symptoms, as outlined below.
D
sia is usually hereditary and requently associated with
i
s
o
r
other endocrine abnormalities.
d
e
r
s
PRIMARY HYPERPARATHYROIDISM
o
He re d ita ry syn d ro m e s a n d m u ltip le
f
B
p a rath yro id tu m o rs
o
Na tu ra l h isto ry a n d in cid en ce
n
e
Hereditary hyperparathyroidism can occur without
a
n
Primary hyperparathyroidism is a generalized disorder other endocrine abnormalities but is usually part o a
d
C
o calcium, phosphate, and bone metabolism due to an multiple endocrine neoplasia (MEN) syndrome (Chap.
a
l
c
i
increased secretion o P H. T e elevation o circulating 29). MEN 1 (Wermer’s syndrome) consists o hyper-
u
m
hormone usually leads to hypercalcemia and hypophos- parathyroidism and tumors o the pituitary and pan-
M
e
phatemia. T ere is great variation in the mani estations. creas, o en associated with gastric hypersecretion and
t
a
b
Patients may present with multiple signs and symptoms, peptic ulcer disease (Zollinger-Ellison syndrome).
o
l
i
s
including recurrent nephrolithiasis, peptic ulcers, men- MEN 2A is characterized by pheochromocytoma and
m
tal changes, and, less requently, extensive bone resorp- medullary carcinoma o the thyroid, as well as hyper-
tion. However, with greater awareness o the disease and parathyroidism; MEN 2B has additional associated
wider use o multiphasic screening tests, including mea- eatures such as multiple neuromas but usually lacks
surements o blood calcium, the diagnosis is requently hyperparathyroidism. Each o these MEN syndromes is
made in patients who have no symptoms and minimal, transmitted in an apparent autosomal dominant man-
i any, signs o the disease other than hypercalcemia and ner, although, as noted below, the genetic basis o MEN
elevated levels o P H. T e mani estations may be sub- 1 involves biallelic loss o a tumor suppressor.
tle, and the disease may have a benign course or many T e hyperparathyroidism jaw tumor (HP -J ) syn-
years or a li etime. T is milder orm o the disease is usu- drome occurs in amilies with parathyroid tumors
ally termed asymptomatic hyperparathyroidism. Rarely, (sometimes carcinomas) in association with benign
hyperparathyroidism develops or worsens abruptly and jaw tumors. T is disorder is caused by mutations in
causes severe complications such as marked dehydration CDC73 (HRPT2), and mutations in this gene are also
and coma, so-called hypercalcemic parathyroid crisis. observed in parathyroid cancers. Some kindreds exhibit
T e annual incidence o the disease is calculated to hereditary hyperparathyroidism without other endocri-
be as high as 0.2% in patients >60, with an estimated nopathies. T is disorder is o en termed nonsyndromic
prevalence, including undiscovered asymptomatic amilial isolated hyperparathyroidism (FIHP). T ere is
patients, o ≥1%; some reports suggest the incidence speculation that these amilies may be examples o vari-
may be declining. I con rmed, these changing esti- able expression o the other syndromes such as MEN 1,
mates may re ect less requent routine testing o serum MEN 2, or the HP -J syndrome, but they may also
calcium in recent years, earlier overestimates in inci- have distinctive, still unidenti ed genetic causes.
dence, or unknown actors. T e disease has a peak inci-
dence between the third and h decades but occurs in Pa th o lo gy
young children and in the elderly.
Adenomas are most o en located in the in erior para-
thyroid glands, but in 6–10% o patients, parathyroid
Etio lo g y
adenomas may be located in the thymus, the thyroid,
Parathyroid tumors are most o en encountered as iso- the pericardium, or behind the esophagus. Adeno-
lated adenomas without other endocrinopathy. T ey mas are usually 0.5–5 g in size but may be as large as

Ha rris on_Endocrinology_Ch34_p446-p479.indd 452 20/05/16 9:33 a m

 10–20 g (normal glands weigh 25 mg on average). Chie
cells are predominant in both hyperplasia and ade-
noma. With chie cell hyperplasia, the enlargement may
be so asymmetric that some involved glands appear
grossly normal. I generalized hyperplasia is present,
however, histologic examination reveals a uni orm pat-
tern o chie cells and disappearance o at even in the
absence o an increase in gland weight. T us, micro-
scopic examination o biopsy specimens o several
glands is essential to interpret ndings at surgery.
o one mutated allele in this hereditary syndrome, ol- 453
lowed by loss o the other allele via somatic cell muta-
tion, leads to monoclonal expansion and tumor
development. Also, in ~15–20% o sporadic parathyroid
adenomas, both alleles o the MEN1 locus on chromo-
some 11 are somatically deleted, implying that the same
de ect responsible or MEN 1 can also cause the spo-
radic disease (Fig. 34-3A). Consistent with the Knudson
hypothesis or two-step neoplasia in certain inherited

C
cancer syndromes, the earlier onset o hyperparathy-

H
A
Parathyroid carcinoma is o en not aggressive. roidism in the hereditary syndromes re ects the need

P
T
Long-term survival without recurrence is common i or only one mutational event to trigger the monoclonal

E
R
at initial surgery the entire gland is removed without outgrowth. In sporadic adenomas, typically occurring

rupture o the capsule. Recurrent parathyroid carci-
noma is usually slow-growing with local spread in the
neck, and surgical correction o recurrent disease may
3
4
later in li e, two di erent somatic events must occur
be ore the MEN1 gene is silenced.
Other presumptive anti-oncogenes involved in

D
i
s
be easible. Occasionally, however, parathyroid carci- hyperparathyroidism include a still unidenti ed gene

o
r
d
noma is more aggressive, with distant metastases (lung,

e
mapped to chromosome 1p seen in 40% o sporadic

r
s
liver, and bone) ound at the time o initial operation. parathyroid adenomas and a gene mapped to chromo-

o
f
t
It may be di cult to appreciate initially that a primary

h
some Xp11 in patients with secondary hyperparathy-

e
P
tumor is carcinoma; increased numbers o mitotic g- roidism and renal ailure, who progressed to “tertiary”

a
r
a
ures and increased brosis o the gland stroma may hyperparathyroidism, now known to re ect monoclo-

t
h
y
precede invasion. T e diagnosis o carcinoma is o en nal outgrowths within previously hyperplastic glands.

r
o
i
d
made in retrospect. Hyperparathyroidism rom a para- A more complex pattern, still incompletely resolved,

G
l
thyroid carcinoma may be indistinguishable rom other arises with genetic de ects and carcinoma o the para-

a
n
d
orms o primary hyperparathyroidism but is usually thyroids. T is appears to be due to biallelic loss o a

a
n
more severe clinically. A potential clue to the diagnosis unctioning copy o a gene, HRPT2 (or CDC73), origi-

d
C
a
is o ered by the degree o calcium elevation. Calcium nally identi ed as the cause o the HP -J syndrome.

l
c
i
u
values o 3.5–3.7 mmol/L (14–15 mg/dL) are requent Several inactivating mutations have been identi ed

m
with carcinoma and may alert the surgeon to remove in HRPT2 (located on chromosome 1q21-31), which

H
o
m
the abnormal gland with care to avoid capsular rupture. encodes a 531-amino-acid protein called para bromin.

e
o
Recent ndings concerning the genetic basis o para- T e responsible genetic mutations in HRPT2 appear to

s
t
a
thyroid carcinoma (distinct rom that o benign adeno- be necessary, but not su cient, or parathyroid cancer.

mas) indicate the need, in these kindreds, or amily
screening (see below).
GENETIC DEFECTS ASSOCIATED WITH
HYPERPARATHYROIDISM
As in many other types o neoplasia, two unda-
mental types o genetic de ects have been identi-
ed in parathyroid gland tumors: (1) overactivity
o protooncogenes and (2) loss o unction o tumor-
suppressor genes. T e ormer, by de nition, can lead to
uncontrolled cellular growth and unction by activation
(gain-o - unction mutation) o a single allele o the
responsible gene, whereas the latter requires loss o
unction o both allelic copies. Biallelic loss o unction
o a tumor-suppressor gene is usually characterized by a
germline de ect (all cells) and an additional somatic
deletion/mutation in the tumor (Fig. 34-3).
Mutations in the MEN1 gene locus, encoding the
protein MENIN, on chromosome 11q13 are responsible
or causing MEN 1; the normal allele o this gene ts
the de nition o a tumor-suppressor gene. Inheritance
s
i
s
In general, the detection o additional genetic de ects
in these parathyroid tumor–related syndromes and the
variations seen in phenotypic expression/penetrance
indicate the multiplicity o the genetic actors respon-
sible. Nonetheless, the ability to detect the presence o
the major genetic contributors has greatly aided a more
in ormed management o amily members o patients
identi ed in the hereditary syndromes such as MEN 1,
MEN 2, and HP -J .
An important contribution rom studies on the
genetic origin o parathyroid carcinoma has been the
realization that the mutations involve a di erent path-
way than that involved with the benign gland enlarge-
ments. Unlike the pathogenesis o genetic alterations
seen in colon cancer, where lesions evolve rom benign
adenomas to malignant disease by progressive genetic
changes, the alterations commonly seen in most para-
thyroid cancers (HRPT2 mutations) are in requently
seen in sporadic parathyroid adenomas.
Abnormalities at the Rb gene were the rst to be
noted in parathyroid cancer. T e Rb gene, a tumor-
suppressor gene located on chromosome 13q14, was

Ha rris on_Endocrinology_Ch34_p446-p479.indd 453 20/05/16 9:33 a m

 454 Chromos ome 11

S oma tic Be nign

de le tion/muta tion tumor
Norma l Muta nt of re ma ining
copy copy norma l a lle le

Muta nt copy of puta tive tumor Clona l proge nitor ce ll la cks P TH P TH

s uppre s s or ge ne on 11q13 is functiona l ge ne product Coding Coding
inhe rite d in MEN-1 a nd pre s e nt P TH 5'
in a ll pa ra thyroid ce lls Bre a k Re gula tory

Muta tion of one a lle le of s a me

Ce ntrome re
S
ge ne ma y occur s oma tica lly in
E
C
othe r pa tie nts , pre s e nt in s pe cific P TH 5'
T
pa ra thyroid ce ll(s ) Re gula tory
I
O
P RAD1
N
Bre a k P RAD1
V
I
Chromos ome 1 S oma tic
de le tion/muta tion P a ra thyroid Norma l Inve rte d
Norma l Muta nt of re ma ining ca rcinoma
norma l a lle le
D
copy copy
i
s
o
r
d
e
S oma tic muta tion of one copy of the Clona l proge nitor ce ll la cks
r
s
HRP T2 tumor s uppre s s or ge ne on functiona l HRP T2 ge ne product
o
f
1q21–31 no a dve rs e cons e que nce s
B
o
A to pa ra thyroid ce ll B
n
e
a
FIGURE 3 4 -3
n
d
A. Schematic diagram indicating molecular events in tumor sus- gene termed HRPT2 is involved in the pathogenesis o parathy-
C
a
l
ceptibility. The patient with the hereditary abnormality (multiple roid carcinoma. (From A Arnold: J Clin Endocrine Metab 77:1108,
c
i
u
endocrine neoplasia [MEN]) is envisioned as having one de ective 1993. Copyright 1993, The Endocrine Society.) B. Schematic illustra-
m
M
gene inherited rom the a ected parent on chromosome 11, but tion o the mechanism and consequences o gene rearrangement
e
t
one copy o the normal gene is present rom the other parent. and overexpression o the PRAD1 protooncogene (pericentro-
a
b
o
In the monoclonal tumor (benign tumor), a somatic event, here meric inversion o chromosome 11) in parathyroid adenomas.
l
i
s
m
partial chromosomal deletion, removes the remaining normal The excessive expression o PRAD1 (a cell cycle control protein,
gene rom a cell. In nonhereditary tumors, two successive somatic cyclin D1) by the highly active parathyroid hormone (PTH) gene
mutations must occur, a process that takes a longer time. By promoter in the parathyroid cell contributes to excess cellu-
either pathway, the cell, deprived o growth-regulating in uence lar proli eration. (From J Habener et al, in L DeGroot, JL Jameson
rom this gene, has unregulated growth and becomes a tumor. A [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, 2001; with
di erent genetic locus also involving loss o a tumor-suppressor permission.)

initially associated with retinoblastoma but has since
been implicated in other neoplasias, including parathy-
roid carcinoma. Early studies implicated allelic dele-
tions o the Rb gene in many parathyroid carcinomas
and decreased or absent expression o the Rb protein.
However, because there are o en large deletions in
chromosome 13 that include many genes in addition
to the Rb locus (with similar ndings in some pituitary
carcinomas), it remains possible that other tumor-sup-
pressor genes on chromosome 13 may be playing a role
in parathyroid carcinoma.
Study o the parathyroid cancers ound in some
patients with the HP -J syndrome has led to identi -
cation o a much larger role or mutations in the HRPT2
gene in most parathyroid carcinomas, including those
that arise sporadically, without apparent association
with the HP -J syndrome. Mutations in the coding
region have been identi ed in 75–80% o all parathy-
roid cancers analyzed, leading to the conclusion that,
with addition o presumed mutations in the noncoding
regions, this genetic de ect may be seen in essentially
all parathyroid carcinomas. O special importance was
the discovery that, in some sporadic parathyroid can-
cers, germline mutations have been ound; this, in turn,
has led to care ul investigation o the amilies o these
patients and a new clinical indication or genetic testing
in this setting.
Hypercalcemia occurring in amily members (who
are also ound to have the germline mutations) can lead
to the nding, at parathyroid surgery, o premalignant
parathyroid tumors.
Overall, it seems there are multiple actors in para-
thyroid cancer, in addition to the HRPT2 and Rb gene,
although the HRPT2 gene mutation is the most invariant
abnormality. RET encodes a tyrosine kinase type recep-
tor; speci c inherited germline mutations lead to a con-
stitutive activation o the receptor, thereby explaining the
autosomal dominant mode o transmission and the rela-
tively early onset o neoplasia. In the MEN 2 syndrome,
the RET protooncogene may be responsible or the

Ha rris on_Endocrinology_Ch34_p446-p479.indd 454 20/05/16 9:33 a m

 earliest disorder detected, the polyclonal disorder (C cell
hyperplasia, which then is trans ormed into a clonal out-
growth—a medullary carcinoma with the participation
o other, still uncharacterized genetic de ects).
In some parathyroid adenomas, activation o a proto-
oncogene has been identi ed (Fig. 34-3B). A reciprocal
translocation involving chromosome 11 has been iden-
ti ed that juxtaposes the PTH gene promoter upstream
o a gene product termed PRAD-1, encoding a cyclin
D protein that plays a key role in normal cell division.
bone density in the extremities can be quanti ed by 455
densitometry o the hip or o the distal radius at a site
chosen to be primarily cortical. Computed tomography
(C ) is a very sensitive technique or estimating spinal
bone density, but reproducibility o standard C is no
better than 5%. Newer C techniques (spiral, “extreme”
C ) are more reproducible but are currently avail-
able in a limited number o medical centers. Cortical
bone density is reduced while cancellous bone density,
especially in the spine, is relatively preserved. In symp-

C
H
A
T is translocation plus other mechanisms that cause tomatic patients, dys unctions o the CNS, peripheral

P
T
an equivalent overexpression o cyclin D1 are ound in nerve and muscle, gastrointestinal tract, and joints also

E
R
20–40% o parathyroid adenomas. occur. It has been reported that severe neuropsychiatric

Mouse models have con rmed the role o several o
the major identi ed genetic de ects in parathyroid dis-
ease and the MEN syndromes. Loss o the MEN1 gene
3
4
mani estations may be reversed by parathyroidectomy.
When present in symptomatic patients, neuromuscular
mani estations may include proximal muscle weakness,

D
i
s
locus or overexpression o the PRAD-1 protooncogene easy atigability, and atrophy o muscles and may be so

o
r
d
or the mutated RET protooncogene have been analyzed striking as to suggest a primary neuromuscular disor-

e
r
s
by genetic manipulation in mice, with the expected der. T e distinguishing eature is the complete regres-

o
f
t
onset o parathyroid tumors or medullary carcinoma, sion o neuromuscular disease a er surgical correction

h
e
P
respectively. o the hyperparathyroidism.

a
r
a
Gastrointestinal mani estations are sometimes subtle

t
h
y
and include vague abdominal complaints and disorders

r
o
Sig n s a n d sym p to m s

i
d
o the stomach and pancreas. Again, cause and e ect are

G
l
Many patients with hyperparathyroidism are asymp- unclear. In MEN 1 patients with hyperparathyroidism,

a
n
d
tomatic. Mani estations o hyperparathyroidism involve duodenal ulcer may be the result o associated pancre-

a
n
primarily the kidneys and the skeletal system. Kidney atic tumors that secrete excessive quantities o gastrin

d
C
a
involvement, due either to deposition o calcium in (Zollinger-Ellison syndrome). Pancreatitis has been

l
c
i
u
the renal parenchyma or to recurrent nephrolithiasis, reported in association with hyperparathyroidism, but

m
was present in 60–70% o patients prior to 1970. With the incidence and the mechanism are not established.

H
o
m
earlier detection, renal complications occur in <20% Much attention has been paid in recent years to the

e
o
o patients in many large series. Renal stones are usu- mani estations o and optimum management strategies

s
t
a
ally composed o either calcium oxalate or calcium or asymptomatic hyperparathyroidism. T is is now the

phosphate. In occasional patients, repeated episodes
o nephrolithiasis or the ormation o large calculi may
lead to urinary tract obstruction, in ection, and loss
o renal unction. Nephrocalcinosis may also cause
decreased renal unction and phosphate retention.
T e distinctive bone mani estation o hyperpara-
thyroidism is osteitis brosa cystica, which occurred in
10–25% o patients in series reported 50 years ago. His-
tologically, the pathognomonic eatures are an increase
in the giant multinucleated osteoclasts in scalloped
areas on the sur ace o the bone (Howship’s lacunae)
and a replacement o the normal cellular and mar-
row elements by brous tissue. X-ray changes include
resorption o the phalangeal tu s and replacement o
the usually sharp cortical outline o the bone in the dig-
its by an irregular outline (subperiosteal resorption). In
recent years, osteitis brosa cystica is very rare in pri-
mary hyperparathyroidism, probably due to the earlier
detection o the disease.
Dual-energy x-ray absorptiometry (DEXA) o the
spine provides reproducible quantitative estimates
(within a ew percent) o spinal bone density. Similarly,
s
i
s
most prevalent orm o the disease. Asymptomatic pri-
mary hyperparathyroidism is de ned as biochemically
con rmed hyperparathyroidism (elevated or inappro-
priately normal P H levels despite hypercalcemia) with
the absence o signs and symptoms typically associated
with more severe hyperparathyroidism such as eatures
o renal or bone disease.
T ree con erences on the topic have been held in
the United States over the past two decades, with the
most recent in 2008. T e published proceedings include
discussion o more subtle mani estations o disease,
its natural history (without parathyroidectomy), and
guidelines both or indications or surgery and medical
monitoring in nonoperated patients.
Issues o concern include the potential or cardiovas-
cular deterioration, the presence o subtle neuropsychi-
atric symptoms, and the longer-term status o skeletal
integrity in patients not treated surgically. T e current
consensus is that medical monitoring rather than surgi-
cal correction o hyperparathyroidism may be justi ed
in certain patients. T e current recommendation is that
patients who show mild disease, as de ned by speci c

Ha rris on_Endocrinology_Ch34_p446-p479.indd 455 20/05/16 9:33 a m

 456 TABLE 3 4 -2 cardiovascular eatures in those with milder disease.
GUIDELINES FOR SURGERY IN ASYMPTOMATIC T ere are reports o endothelial dys unction in patients
PRIMARY HYPERPARATHYROIDISM a with mild asymptomatic hyperparathyroidism, but
PARAMETER GUIDELINE the expert panels concluded that more observation is
needed, especially regarding whether there is reversibil-
Serum calcium (above >1 mg/dL
ity with surgery.
normal)
A topic o considerable interest and some debate
24-h urinary calcium No indication
is assessment o neuropsychiatric status and health-
Creatinine clearance I <60 mL/min related quality o li e (QOL) status in hyperparathyroid
(calculated)b patients both be ore surgery and in response to para-
S
E
T score <−2.5 at any o 3 sitesc thyroidectomy. Several observational studies suggest
C
Bone density
T
I
considerable improvements in symptom score a er
O
Age <50
N
surgery. Randomized studies o surgery versus observa-
V
I
a
JP Bilezikian et al: Guidelines or the management o asymptomatic pri- tion, however, have yielded inconclusive results, espe-
mary hyperparathyroidism: Summary statement rom the third interna- cially regarding bene ts o surgery. Most studies report
tional workshop. J Clin Endocrinol Metab 94:335, 2009.
that hyperparathyroidism is associated with increased
D
b
i
Creatinine clearance calculated by Cockcro t-Gault equation or Modi ca-
s
neuropsychiatric symptoms, so the issue remains a
o
r
tion o Diet in Renal Disease (MDRD) equation.
d
signi cant actor in decisions regarding the impact o
e
c
Spine, distal radius, hip.
r
s
surgery in this disease.
o
f
B
o
n
criteria (Table 34-2), can be sa ely ollowed under man-
e
a
agement guidelines (Table 34-3). T ere is, however,
n
d
growing uncertainty about subtle disease mani esta- DIAGNOSIS
C
a
l
c
tions and whether surgery is there ore indicated in most T e diagnosis is typically made by detecting an elevated
i
u
m
patients. Among the issues is the evidence o eventual immunoreactive P H level in a patient with asymptom-
M
(>8 years) deterioration in bone mineral density a er atic hypercalcemia (see “Di erential Diagnosis: Special
e
t
a
a decade o relative stability. T ere is concern that this
b
ests,” below). Serum phosphate is usually low but may
o
l
late-onset deterioration in bone density in nonoper-
i
be normal, especially i renal ailure has developed.
s
m
ated patients could contribute signi cantly to the well- Several modi cations in P H assays have been intro-
known age-dependent racture risk (osteoporosis). One duced in e orts to improve their utility in light o in or-
study reported signi cant and sustained improvements mation about metabolism o P H (as discussed above).
in bone mineral density a er success ul parathyroid- First-generation assays were based on displacement o
ectomy, again raising the issue regarding bene ts o radiolabeled P H rom antibodies that reacted with P H
surgery. Other randomized studies, however, did not (o en also P H ragments). Double-antibody or immu-
report major gains a er surgery. nometric assays (one antibody that is usually directed
Cardiovascular disease including le ventricular against the carboxyl-terminal portion o intact P H to
hypertrophy, cardiac unctional de ects, and endothe- capture the hormone and a second radio- or enzyme-
lial dys unction have been reported as reversible in labeled antibody that is usually directed against the
European patients with more severe symptomatic dis- amino-terminal portion o intact P H) greatly improved
ease a er surgery, leading to numerous studies o these the diagnostic discrimination o the tests by eliminating
inter erence rom circulating biologically inactive rag-
TABLE 3 4 -3 ments, detected by the original rst-generation assays.
GUIDELINES FOR MONITORING IN ASYMPTOMATIC Double-antibody assays are now re erred to as second-
PRIMARY HYPERPARATHYROIDISM a generation. Such P H assays have in some centers and
testing laboratories been replaced by third-generation
PARAMETER GUIDELINE
assays a er it was discovered that large P H rag-
Serum calcium Annually ments, devoid o only the extreme amino-terminal por-
24-h urinary calcium Recommended tion o the P H molecule, are also present in blood and
Creatinine clearance Recommended are detected, incorrectly, as intact P H. T ese amino-
terminally truncated P H ragments were prevented
Serum creatinine b Annually
rom registering in the newer third-generation assays by
Bone density Annually (3 sites)a use o a detection antibody directed against the extreme
a
amino-terminal epitope. T ese assays may be use ul or
Updates guidelines (JP Bilezikian et al: J Clin Endocrinol Metab 2014;
epub ahead o print).
clinical research studies as in management o chronic
b
Creatinine clearance calculated by Cockcro t-Gault equation or Modi ca- renal disease, but the consensus is that either second-
tion o Diet in Renal Disease (MDRD) equation. or third-generation assays are use ul in the diagnosis o

Ha rris on_Endocrinology_Ch34_p446-p479.indd 456 20/05/16 9:33 a m

 1000 Hype rpa ra thyroidis m
wo surgical approaches are generally practiced. T e con- 457
Hype rca lce mia of ma ligna ncy ventional parathyroidectomy procedure was neck explora-
800 Hypopa ra thyroidis m
600
tion with general anesthesia; this procedure is being replaced
500 in many centers, whenever easible, by an outpatient pro-
cedure with local anesthesia, termed minimally invasive
parathyroidectomy.
Parathyroid exploration is challenging and should be
)
L
400
m
undertaken by an experienced surgeon. Certain eatures help
/
g
p
(
in predicting the pathology (e.g., multiple abnormal glands
4
8
C
in amilial cases). However, some critical decisions regarding
–
H
1
300

A
e
management can be made only during the operation.
n
P
o
T
m
With conventional surgery, one approach is still based

E
r
R
o
on the view that typically only one gland (the adenoma)
h
3
d
4
i
is abnormal. I an enlarged gland is ound, a normal gland
o
200
r
y
h
should be sought. In this view, i a biopsy o a normal-sized
t
a
r
second gland con rms its histologic (and presumed unc-
a
D
P
i
s
tional) normality, no urther exploration, biopsy, or excision

o
r
100

d
e
is needed. At the other extreme is the minority viewpoint that

r
s
all our glands be sought and that most o the total parathy-

o
f
t
h
20 roid tissue mass be removed. T e concern with the ormer

e
P
approach is that the recurrence rate o hyperparathyroidism

a
r
1

a
may be high i a second abnormal gland is missed; the latter

t
0

h
y
approach could involve unnecessary surgery and an unac-

r
0 6 7 8 9 10 11 12 13 14 15 16 18 19

o
i
d
Ca lcium (mg/dL) ceptable rate o hypoparathyroidism. When normal glands

G
l
are ound in association with one enlarged gland, excision o

a
FIGURE 3 4 -4

n
d
Le ve ls o im m u n o re a ct ive p a ra t h yro id h o rm o n e PTH the single adenoma usually leads to cure or at least years ree

a
n
o symptoms. Long-term ollow-up studies to establish true

d
d e t e cte d in p a t ie n t s with primary hyperparathyroidism, hyper-

C
a
calcemia o malignancy, and hypoparathyroidism. Boxed area rates o recurrence are limited.

l
c
i
u
represents the upper and normal limits o blood calcium and/or Recently, there has been growing experience with new

m
surgical strategies that eature a minimally invasive approach

H
immunoreactive PTH. (From SR Nussbaum, JT Potts, Jr, in LDeGroot,

o
m
JL Jameson [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, guided by improved preoperative localization and intraop-

e
o
2001; with permission.) erative monitoring by P H assays. Preoperative 99m c ses-

s
t
a
tamibi scans with single-photon emission C (SPEC ) are

primary hyperparathyroidism and or the diagnosis o
high-turnover bone disease in chronic kidney disease.
Many tests based on renal responses to excess P H
(renal calcium and phosphate clearance; blood phos-
phate, chloride, magnesium; urinary or nephrogenous
cyclic AMP [cAMP]) were used in earlier decades.
T ese tests have low speci city or hyperparathyroid-
ism and are there ore not cost-e ective; they have been
replaced by P H immunometric assays combined with
simultaneous blood calcium measurements (Fig. 34-4).
TREATMENT Hyperparathyroidism
Surgical excision o the abnormal parathyroid tissue is the
de nitive therapy or this disease. As noted above, medical
surveillance without operation or patients with mild, asymp-
tomatic disease is, however, still pre erred by some physicians
and patients, particularly when the patients are more elderly.
Evidence avoring surgery, i medically easible, is grow-
ing because o concerns about skeletal, cardiovascular, and
neuropsychiatric disease, even in mild hyperparathyroidism.
s
i
s
used to predict the location o an abnormal gland and intra-
operative sampling o P H be ore and at 5-min intervals
a er removal o a suspected adenoma to con rm a rapid all
(>50%) to normal levels o P H. In several centers, a com-
bination o preoperative sestamibi imaging, cervical block
anesthesia, minimal surgical incision, and intraoperative
P H measurements has allowed success ul outpatient sur-
gical management with a clear-cut cost bene t compared to
general anesthesia and more extensive neck surgery. T e use
o these minimally invasive approaches requires clinical judg-
ment to select patients unlikely to have multiple gland disease
(e.g., MEN or secondary hyperparathyroidism). T e grow-
ing acceptance o the technique and its relative ease or the
patient has lowered the threshold or surgery.
Severe hypercalcemia may provide a preoperative clue to
the presence o parathyroid carcinoma. In such cases, when
neck exploration is undertaken, the tissue should be widely
excised; care is taken to avoid rupture o the capsule to
prevent local seeding o tumor cells.
Multiple-gland hyperplasia, as predicted in amilial cases,
poses more di cult questions o surgical management. Once
a diagnosis o hyperplasia is established, all the glands must

Ha rris on_Endocrinology_Ch34_p446-p479.indd 457 20/05/16 9:33 a m

 458 be identi ed. wo schemes have been proposed or surgical should be considered, because it inter eres with P H secre-
management. One is to totally remove three glands with par- tion and causes unctional hypoparathyroidism (Chap. 32).
tial excision o the ourth gland; care is taken to leave a good Signs o hypocalcemia include symptoms such as muscle
blood supply or the remaining gland. Other surgeons advo- twitching, a general sense o anxiety, and positive Chvostek’s
cate total parathyroidectomy with immediate transplantation and rousseau’s signs coupled with serum calcium consis-
o a portion o a removed, minced parathyroid gland into the tently <2 mmol/L (8 mg/dL). Parenteral calcium replace-
muscles o the orearm, with the view that surgical excision ment at a low level should be instituted when hypocalcemia is
is easier rom the ectopic site in the arm i there is recurrent symptomatic. T e rate and duration o IV therapy are deter-
hyper unction. mined by the severity o the symptoms and the response o
In a minority o cases, i no abnormal parathyroid glands the serum calcium to treatment. An in usion o 0.5–2 mg/
S
E
are ound in the neck, the issue o urther exploration must kg per hour or 30–100 mL/h o a 1-mg/mL solution usually
C
T
I
be decided. T ere are documented cases o ve or six para- su ces to relieve symptoms. Usually, parenteral therapy is
O
N
thyroid glands and o unusual locations or adenomas such as required or only a ew days. I symptoms worsen or i par-
V
I
in the mediastinum. enteral calcium is needed or >2–3 days, therapy with a vita-
When a second parathyroid exploration is indicated, the min D analogue and/or oral calcium (2–4 g/d) should be
minimally invasive techniques or preoperative localiza- started (see below). It is cost-e ective to use calcitriol (doses
D
i
s
tion such as ultrasound, C scan, and isotope scanning are o 0.5–1 µg/d) because o the rapidity o onset o e ect and
o
r
d
combined with venous sampling and/or selective digital arte-
e
prompt cessation o action when stopped, in comparison to
r
s
riography in one o the centers specializing in these proce- other orms o vitamin D. A rise in blood calcium a er sev-
o
f
B
dures. Intraoperative monitoring o P H levels by rapid P H eral months o vitamin D replacement may indicate restora-
o
n
e
immunoassays may be use ul in guiding the surgery. At one tion o parathyroid unction to normal. It is also appropriate
a
n
center, long-term cures have been achieved with selective to monitor serum P H serially to estimate gland unction in
d
C
embolization or injection o large amounts o contrast mate- such patients.
a
l
c
i
rial into the end-arterial circulation eeding the parathyroid I magnesium de ciency was present, it can complicate
u
m
tumor. the postoperative course since magnesium de ciency impairs
M
e
A decline in serum calcium occurs within 24 h a er suc- the secretion o P H. Hypomagnesemia should be corrected
t
a
b
cess ul surgery; usually blood calcium alls to low-normal whenever detected. Magnesium replacement can be e ective
o
l
i
s
values or 3–5 days until the remaining parathyroid tissue orally (e.g., MgCl2, MgOH2), but parenteral repletion is usual
m
resumes ull hormone secretion. Acute postoperative hypo- to ensure postoperative recovery, i magnesium de ciency is
calcemia is likely only i severe bone mineral de cits are pres- suspected due to low blood magnesium levels. Because the
ent or i injury to all the normal parathyroid glands occurs depressant e ect o magnesium on central and peripheral nerve
during surgery. In general, there are ew problems encoun- unctions does not occur at levels <2 mmol/L (normal range
tered in patients with uncomplicated disease such as a single 0.8–1.2 mmol/L), parenteral replacement can be given rapidly.
adenoma (the clear majority), who do not have symptomatic A cumulative dose as great as 0.5–1 mmol/kg o body weight
bone disease or a large de cit in bone mineral, who are vita- can be administered i severe hypomagnesemia is present;
min D and magnesium su cient, and who have good renal o en, however, total doses o 20–40 mmol are su cient.
and gastrointestinal unction. T e extent o postoperative
hypocalcemia varies with the surgical approach. I all glands MEDICAL MANAGEMENT T e guidelines or recommending
are biopsied, hypocalcemia may be transiently symptom- surgical intervention, i easible ( able 34-2), as well as or
atic and more prolonged. Hypocalcemia is more likely to be monitoring patients with asymptomatic hyperparathyroid-
symptomatic a er second parathyroid explorations, particu- ism who elect not to undergo parathyroidectomy ( able
larly when normal parathyroid tissue was removed at the ini- 34-3), re ect the changes over time since the rst con erence
tial operation and when the manipulation and/or biopsy o on the topic in 1990. Medical monitoring rather than cor-
the remaining normal glands are more extensive in the search rective surgery is still acceptable, but it is clear that surgical
or the missing adenoma. intervention is the more requently recommended option
Patients with hyperparathyroidism have e cient intestinal or the reasons noted above. ightened guidelines avor-
calcium absorption due to the increased levels o 1,25(OH)2D ing surgery include lowering the recommended level o
stimulated by P H excess. Once hypocalcemia signi es suc- serum calcium elevation, more care ul attention to skeletal
cess ul surgery, patients can be put on a high-calcium intake integrity through re erence to peak skeletal mass at baseline
or be given oral calcium supplements. Despite mild hypo- ( scores) rather than age-adjusted bone density (Z scores),
calcemia, most patients do not require parenteral therapy. I as well as the presence o any ragility racture. T e other
the serum calcium alls to <2 mmol/L (8 mg/dL), and i the changes noted in the two guidelines ( ables 34-2 and 34-3)
phosphate level rises simultaneously, the possibility that sur- re ect accumulated experience and practical consideration,
gery has caused hypoparathyroidism must be considered. such as a di culty in quantity o urine collections. Despite
With unexpected hypocalcemia, coexistent hypomagnesemia the use ulness o the guidelines, the importance o individual

Ha rris on_Endocrinology_Ch34_p446-p479.indd 458 20/05/16 9:33 a m

 patient and physician judgment and pre erence is clear in all
recommendations.
When surgery is not selected, or not medically easible,
there is interest in the potential value o speci c medical
therapies. T ere is no long-term experience regarding speci c
clinical outcomes such as racture prevention, but it has been
established that bisphosphonates increase bone mineral den-
sity signi cantly without changing serum calcium (as does
estrogen, but the latter is not avored because o reported
(see below), leading to inappropriately normal or even 459
increased secretion o P H, whereas another hyper-
calcemic disorder, namely the exceedingly rare Jansen’s
disease, is caused by a constitutively active P H/P HrP
receptor in target tissues. Neither FHH1 nor Jansen’s
disease, however, is a growth disorder o the parathy-
roids. Other orms o FHH are caused either by hetero-
zygous mutations in GNA11 (encoding G11), one o the
signaling proteins downstream o the CaSR (FHH2), or

C
adverse e ects in other organ systems). Calcimimetics that by mutations in AP2S1 (FHH3).

H
A
lower P H secretion lower calcium but do not a ect bone T e pathophysiology o FHH1 is now understood.

P
T
mineral density. T e primary de ect is abnormal sensing o the blood

E
R
calcium by the parathyroid gland and renal tubule,

OTHER PARATHYROID-RELATED CAUSES
3
4
causing inappropriate secretion o P H and excessive
reabsorption o calcium in the distal renal tubules. T e
CaSR is a member o the third amily o GPCRs (type

D
OF HYPERCALCEMIA

i
s
C or type III). T e receptor responds to increased ECF

o
r
d
Lithium thera py

e
calcium concentration by suppressing P H secretion

r
s
through second-messenger signaling involving the G

o
Lithium, used in the management o bipolar depression

f
t
h
and other psychiatric disorders, causes hypercalcemia in protein alpha-subunits G11 and Gq, thereby providing

e
P
negative- eedback regulation o P H secretion. Many

a
~10% o treated patients. T e hypercalcemia is depen-

r
a
di erent inactivating CaSR mutations have been identi-

t
dent on continued lithium treatment, remitting and

h
y
ed in patients with FHH1. T ese mutations lower the

r
recurring when lithium is stopped and restarted. T e

o
i
d
parathyroid adenomas reported in some hypercalcemic capacity o the sensor to bind calcium, and the mutant

G
l
receptors unction as though blood calcium levels were

a
patients with lithium therapy may re ect the presence o

n
d
an independently occurring parathyroid tumor; a perma- low; excessive secretion o P H occurs rom an oth-

a
n
erwise normal gland. Approximately two-thirds o

d
nent e ect o lithium on parathyroid gland growth need

C
a
patients with FHH have mutations within the protein-

l
not be implicated as most patients have complete rever-

c
i
u
sal o hypercalcemia when lithium is stopped. However, coding region o the CaSR gene. T e remaining one-

m
third o kindreds may have mutations in the promoter

H
long-standing stimulation o parathyroid cell replication

o
m
by lithium may predispose to development o adenomas o the CaSR gene or are caused by mutations in other

e
o
genes.

s
(as is documented in secondary hyperparathyroidism

t
a
Even be ore elucidation o the pathophysiology o

s
and renal ailure).

At the levels achieved in blood in treated patients,
lithium can be shown in vitro to shi the P H secretion
curve to the right in response to calcium; i.e., higher
calcium levels are required to lower P H secretion,
probably acting at the calcium sensor (see below). T is
e ect can cause elevated P H levels and consequent
hypercalcemia in otherwise normal individuals. For-
tunately, there are usually alternative medications or
the underlying psychiatric illness. Parathyroid surgery
should not be recommended unless hypercalcemia and
elevated P H levels persist a er lithium is discontinued.
GENETIC DISORDERS CAUSING
HYPERPARATHYROID-LIKE SYNDROMES
Fa m ilia l hyp o ca lciuric hyp erca lcem ia
FHH (also called amilial benign hypercalcemia) is
inherited as an autosomal dominant trait. A ected indi-
viduals are discovered because o asymptomatic hyper-
calcemia. Most cases o FHH (FHH1) are caused by
an inactivating mutation in a single allele o the CaSR
i
s
FHH, abundant clinical evidence served to separate
the disorder rom primary hyperparathyroidism; these
clinical eatures are still use ul in di erential diagnosis.
Patients with primary hyperparathyroidism have <99%
renal calcium reabsorption, whereas most patients
with FHH have >99% reabsorption. T e hypercalce-
mia in FHH is o en detectable in a ected members o
the kindreds in the rst decade o li e, whereas hyper-
calcemia rarely occurs in patients with primary hyper-
parathyroidism or the MEN syndromes who are age
<10 years. P H may be elevated in the di erent orms
o FHH, but the values are usually normal or lower or
the same degree o calcium elevation than is observed
in patients with primary hyperparathyroidism. Para-
thyroid surgery per ormed in a ew patients with FHH
be ore the nature o the syndrome was understood led
to permanent hypoparathyroidism; nevertheless, hypo-
calciuria persisted, establishing that hypocalciuria is not
P H-dependent (now known to be due to the abnormal
CaSR in the kidney).
Few clinical signs or symptoms are present in patients
with FHH, whereas other endocrine abnormalities

Ha rris on_Endocrinology_Ch34_p446-p479.indd 459 20/05/16 9:33 a m

 460 are not. Most patients are detected as a result o amily occasions, di cult to distinguish rom primary hyper-
screening a er hypercalcemia is detected in a proband. parathyroidism. Although malignancy is o en clinically
In those patients inadvertently operated upon or pri- obvious or readily detectable by medical history, hyper-
mary hyperparathyroidism, the parathyroids appeared calcemia can occasionally be due to an occult tumor.
normal or moderately hyperplastic. Parathyroid surgery Previously, hypercalcemia associated with malignancy
is not appropriate, nor, in view o the lack o symptoms, was thought to be due to local invasion and destruc-
does medical treatment seem needed to lower the cal- tion o bone by tumor cells; many cases are now known
cium. One striking exception to the rule against parathy- to result rom the elaboration by the malignant cells
roid surgery in this syndrome is the occurrence, usually o humoral mediators o hypercalcemia. P HrP is the
in consanguineous marriages (due to the rarity o the responsible humoral agent in most solid tumors that
S
E
gene mutation), o a homozygous or compound het- cause hypercalcemia.
C
T
I
erozygote state, resulting in severe impairment o CaSR T e histologic character o the tumor is more impor-
O
N
unction. In this condition, neonatal severe hypercal- tant than the extent o skeletal metastases in predicting
V
I
cemia, total parathyroidectomy is mandatory, but cal- hypercalcemia. Small-cell carcinoma (oat cell) and ade-
cimetics have been used as a temporary measure. Rare nocarcinoma o the lung, although the most common
but well-documented cases o acquired hypocalciuric lung tumors associated with skeletal metastases, rarely
D
i
s
hypercalcemia are reported due to antibodies against the cause hypercalcemia. By contrast, many patients with
o
r
d
CaSR. T ey appear to be a complication o an underlying squamous cell carcinoma o the lung develop hypercal-
e
r
s
autoimmune disorder and respond to therapies directed cemia. Histologic studies o bone in patients with squa-
o
f
B
against the underlying disorder. mous cell or epidermoid carcinoma o the lung, in sites
o
n
e
invaded by tumor as well as areas remote rom tumor
a
n
Ja n sen’s d isea se invasion, reveal increased bone resorption.
d
C
wo main mechanisms o hypercalcemia are opera-
a
l
Activating mutations in the P H/P HrP receptor
c
i
tive in cancer hypercalcemia. Many solid tumors asso-
u
m
(P H1R) have been identi ed as the cause o this rare
ciated with hypercalcemia, particularly squamous cell
M
autosomal dominant syndrome. Because the mutations
e
and renal tumors, produce and secrete P HrP that
t
a
lead to constitutive activation o receptor unction, one
b
causes increased bone resorption and mediate the
o
l
abnormal copy o the mutant receptor is su cient to
i
s
hypercalcemia through systemic actions on the skel-
m
cause the disease, thereby accounting or its dominant
eton. Alternatively, direct bone marrow invasion occurs
mode o transmission. T e disorder leads to short-
with hematologic malignancies such as leukemia, lym-
limbed dwar sm due to abnormal regulation o chon-
phoma, and multiple myeloma. Lymphokines and cyto-
drocyte maturation in the growth plates o the bone
kines (including P HrP) produced by cells involved in
that are ormed through the endochondral process. In
the marrow response to the tumors promote resorp-
adult li e, there are numerous abnormalities in bone,
tion o bone through local destruction. Several hor-
including multiple cystic resorptive areas resembling
mones, hormone analogues, cytokines, and growth
those seen in severe hyperparathyroidism. Hypercalce-
actors have been implicated as the result o clinical
mia and hypophosphatemia with undetectable or low
assays, in vitro tests, or chemical isolation. T e etio-
P H levels are typically observed. T e pathogenesis o
logic actor produced by activated normal lymphocytes
the growth plate abnormalities in Jansen’s disease has
and by myeloma and lymphoma cells, originally termed
been con rmed by transgenic experiments in which
osteoclast activation actor, now appears to represent
targeted expression o the mutant P H/P HrP receptor
the biologic action o several di erent cytokines, prob-
to the proli erating chondrocyte layer o growth plate
ably interleukin 1 and lymphotoxin or tumor necro-
emulated several eatures o the human disorder. Some
sis actor ( NF). In some lymphomas, there is a third
o these genetic mutations in the parathyroid gland or
mechanism, caused by an increased blood level o
P H target cells that a ect Ca2+ metabolism are illus-
1,25(OH)2D, produced by the abnormal lymphocytes.
trated in Fig. 34-5.
In the more common mechanism, usually termed
humoral hypercalcemia o malignancy, solid tumors
MALIGNANCY-RELATED HYPERCALCEMIA (cancers o the lung and kidney, in particular), in which
bone metastases are absent, minimal, or not detect-
Clin ica l synd ro m es a n d m e ch a n ism s able clinically, secrete P HrP measurable by immuno-
o hyp erca lcem ia
assay. Secretion by the tumors o the P H-like actor,
Hypercalcemia due to malignancy is common (occur- P HrP, activates the P H1R, resulting in a patho-
ring in as many as 20% o cancer patients, especially physiology closely resembling hyperparathyroidism,
with certain types o tumor such as lung carcinoma), but with normal or suppressed P H levels. T e clini-
o en severe and di cult to manage, and, on rare cal picture resembles primary hyperparathyroidism

Ha rris on_Endocrinology_Ch34_p446-p479.indd 460 20/05/16 9:33 a m

 Lo s s -o f-func tio n FHH1, Bloms tra nd’s le tha l 461
NS HP T chondrodys pla s ia
Ja ns e n’s me ta phys e a l
Gain-o f-func tio n ADHH
chondrodys pla s ia
P s e udo-
Ca 2+ hypopa ra thyroidis m
Ca S R McCune -Albright
syndrome
P LC Gq/11
cAMP AMP Acrodys os tos is

C
AC without hormona l

H
P IP 2 IP 3 re s is ta nce (ADOP 4)

A
Re gula tory Ca ta lytic P DE4D

P
P TH/P THrP G
Gs s ubunit s ubunit

T
Proto-oncoge ne s a nd ATP Active

E
(P RKAR1A)
re ce ptor cAMP P KA

R
tumor-s upre s s or ge ne s Ce llula r eve nts,

3
R C R C

4
P TH including HDAC4
R C R a ctiva tion
Tra ns cription fa ctors, e.g. C
P IP 2 Ina ctive P KA
GATA3, GCM2, AIRE, FAM111A Gq/11
P THrP

D
i
IP 3 + DAG Acrodys os tos is with

s
P LC

o
hormona l re s is ta nce

r
d
e
(ADOHR)

r
s
o
PARATHYROID CELL TARGET CELL

f
t
h
(e.g. kidney, bone, or ca rtila ge )

e
P
a
FIGURE 3 4 -5

r
a
t
Illu st ra t io n o so m e g e n e t ic m u t a t io n s that alter calcium and severe neonatal hyperparathyroidism (NSHPT); heterozy-

h
y
r
metabolism by e ects on the parathyroid cell or target cells o gous gain-o - unction causes autosomal dominant hypercalciuric

o
i
d
parathyroid hormone (PTH) action. Alterations in PTH production hypocalcemia (ADHH). Other de ects in parathyroid cell unction

G
l
a
by the parathyroid cell can be caused by changes in the response that occur at the level o gene regulation (oncogenes or tumor-

n
d
to extracellular uid calcium (Ca 2+) that are detected by the cal- suppressor genes) or transcription actors are discussed in the

a
n
d
cium-sensing receptor (CaSR). Furthermore, PTH (or PTH-related text. Blomstrand’s lethal chondrodysplasia is due to homozygous

C
a
peptide [PTHrP]) can show altered ef cacy in target cells such as or compound heterozygous loss-o - unction mutations in the

l
c
i
u
in proximal tubular cells, by altered unction o its receptor (PTH/ PTH/PTHrP receptor, a neonatally lethal disorder, while pseudohy-

m
PTHrP receptor) or the signal transduction proteins, G proteins poparathyroidism involves inactivation at the level o the G pro-

H
o
m
such as Gsα, which is linked to adenylate cyclase (AC), the enzyme teins, speci cally mutations that eliminate or reduce Gsα activity

e
o
responsible or producing cyclic AMP (cAMP) (also illustrated are in the kidney (see text or details). Acrodysostosis can occur with

s
t
a
Gq/11, which activate an alternate pathway o receptor signal (acrodysostosis with hormonal resistance [ADOHR]; mutant regu-

transmission involving the generation o inositol triphosphate
[IP3] or diacylglycerol [DAG]). Heterozygous loss-o - unction
mutations in the CaSR cause amilial benign hypocalciuric hyper-
calcemia (FBHH), homozygous mutations (both alleles mutated),
s
i
s
latory subunit o PKA) or without hormonal resistance (ADOP4;
mutant PDE4D). Jansen’s metaphyseal chondrodysplasia and
McCune-Albright syndrome represent gain-o - unction mutations
in the PTH/PTHrP receptor and Gsα protein, respectively.

(hypophosphatemia accompanies hypercalcemia), and
elimination or regression o the primary tumor leads to
disappearance o the hypercalcemia.
As in hyperparathyroidism, patients with the
humoral hypercalcemia o malignancy have elevated
urinary nephrogenous cAMP excretion, hypophos-
phatemia, and increased urinary phosphate clearance.
However, in humoral hypercalcemia o malignancy,
immunoreactive P H is undetectable or suppressed,
making the di erential diagnosis easier. Other eatures
o the disorder di er rom those o true hyperpara-
thyroidism. Although the biologic actions o P H and
P HrP are exerted through the same receptor, subtle
di erences in receptor activation by the two ligands
must account or some o the discordance in patho-
physiology, when an excess o one or the other peptide
occurs. Other cytokines elaborated by the malignancy
may contribute to the variations rom hyperparathy-
roidism in these patients as well. Patients with humoral
hypercalcemia o malignancy may have low to nor-
mal levels o 1,25(OH)2D instead o elevated levels as
in true hyperparathyroidism. In some patients with
the humoral hypercalcemia o malignancy, osteoclas-
tic resorption is unaccompanied by an osteoblastic or
bone- orming response, implying inhibition o the nor-
mal coupling o bone ormation and resorption.
Several di erent assays (single- or double-antibody,
di erent epitopes) have been developed to detect
P HrP. Most data indicate that circulating P HrP
levels are undetectable (or low) in normal individu-
als except perhaps in pregnancy (high in human milk)
and elevated in most cancer patients with the humoral

Ha rris on_Endocrinology_Ch34_p446-p479.indd 461 20/05/16 9:33 a m

 462 syndrome. T e etiologic mechanisms in cancer hyper- late stages o a tumor that is resistant to antitumor therapy,
calcemia may be multiple in the same patient. For the treatment o the hypercalcemia should be judicious as
example, in breast carcinoma (metastatic to bone) and high calcium levels can have a mild sedating e ect. Standard
in a distinctive type o cell lymphoma/leukemia ini- therapies or hypercalcemia (discussed below) are applicable
tiated by human cell lymphotropic virus I, hypercal- to patients with malignancy.
cemia is caused by direct local lysis o bone as well as
by a humoral mechanism involving excess production
o P HrP. Hyperparathyroidism has been reported to VITAMIN D–RELATED HYPERCALCEMIA
coexist with the humoral cancer syndrome, and rarely,
ectopic hyperparathyroidism due to tumor elaboration Hypercalcemia caused by vitamin D can be due to
S
E
o true P H is reported. excessive ingestion or abnormal metabolism o the
C
T
I
vitamin. Abnormal metabolism o the vitamin is
O
N
usually acquired in association with a widespread
V
Dia g n o stic issu es
I
granulomatous disorder. Vitamin D metabolism is
Levels o P H measured by the double-antibody tech- care ully regulated, particularly the activity o renal
nique are undetectable or extremely low in tumor 1α-hydroxylase, the enzyme responsible or the pro-
D
i
s
hypercalcemia, as would be expected with the media- duction o 1,25(OH)2D (Chap. 32). T e regulation o
o
r
d
tion o the hypercalcemia by a actor other than P H 1α-hydroxylase and the normal eedback suppression
e
r
s
(the hypercalcemia suppresses the normal parathy- by 1,25(OH)2D seem to work less well in in ants than
o
f
B
roid glands). In a patient with minimal symptoms in adults and to operate poorly, i at all, in sites other
o
n
re erred or hypercalcemia, low or undetectable P H than the renal tubule; these phenomena may explain
e
a
n
levels would ocus attention on a possible occult the occurrence o hypercalcemia secondary to exces-
d
C
malignancy (except or very rare cases o ectopic sive 1,25(OH)2D production in in ants with Williams’
a
l
c
hyperparathyroidism).
i
syndrome (see below) and in adults with sarcoidosis or
u
m
Ordinarily, the diagnosis o cancer hypercalcemia is lymphoma.
M
e
not di cult because tumor symptoms are prominent
t
a
b
when hypercalcemia is detected. Indeed, hypercalce-
o
Vita m in D in toxica tio n
l
i
s
mia may be noted incidentally during the workup o a
m
patient with known or suspected malignancy. Clinical Chronic ingestion o 40–100 times the normal physi-
suspicion that malignancy is the cause o the hyper- ologic requirement o vitamin D (amounts >40,000–
calcemia is heightened when there are other signs or 100,000 U/d) is usually required to produce signi cant
symptoms o a paraneoplastic process such as weight hypercalcemia in otherwise healthy individuals. T e
loss, atigue, muscle weakness, or unexplained skin stated upper limit o sa e dietary intake is 2000 U/d
rash, or when symptoms speci c or a particular tumor (50 µg/d) in adults because o concerns about poten-
are present. Squamous cell tumors are most requently tial toxic e ects o cumulative supraphysiologic doses.
associated with hypercalcemia, particularly tumors o T ese recommendations are now regarded as too
the lung, kidney, head and neck, and urogenital tract. restrictive, because some estimates are that in elderly
Radiologic examinations can ocus on these areas when individuals in northern latitudes, 2000 U/d or more
clinical evidence is unclear. Bone scans with techne- may be necessary to avoid vitamin D insu ciency.
tium-labeled bisphosphonate are use ul or detection o Hypercalcemia in vitamin D intoxication is due to
osteolytic metastases; the sensitivity is high, but speci- an excessive biologic action o the vitamin, perhaps
city is low; results must be con rmed by conventional the consequence o increased levels o 25(OH)D rather
x-rays to be certain that areas o increased uptake are than merely increased levels o the active metabolite
due to osteolytic metastases per se. Bone marrow biop- 1,25(OH)2D (the latter may not be elevated in vitamin
sies are help ul in patients with anemia or abnormal D intoxication). 25(OH)D has de nite, i low, biologic
peripheral blood smears. activity in the intestine and bone. T e production o
25(OH)D is less tightly regulated than is the production
o 1,25(OH)2D. Hence concentrations o 25(OH)D are
TREATMENT Malignancy-Related Hypercalcemia elevated several- old in patients with excess vitamin D
intake.
reatment o the hypercalcemia o malignancy is rst T e diagnosis is substantiated by documenting ele-
directed to control o tumor; reduction o tumor mass usually vated levels o 25(OH)D >100 mg/mL. Hypercalcemia
corrects hypercalcemia. I a patient has severe hypercalcemia is usually controlled by restriction o dietary calcium
yet has a good chance or e ective tumor therapy, treatment intake and appropriate attention to hydration. T ese
o the hypercalcemia should be vigorous while awaiting the measures, plus discontinuation o vitamin D, usually
results o de nitive therapy. I hypercalcemia occurs in the lead to resolution o hypercalcemia. However, vitamin

Ha rris on_Endocrinology_Ch34_p446-p479.indd 462 20/05/16 9:33 a m

 D stores in at may be substantial, and vitamin D intoxi-
cation may persist or weeks a er vitamin D ingestion
is terminated. Such patients are responsive to glucocor-
ticoids, which in doses o 100 mg/d o hydrocortisone
or its equivalent usually return serum calcium levels
to normal over several days; severe intoxication may
require intensive therapy.
Sa rco ido sis a nd o th er g ra nulo m a to us disea ses
not described until later. Levels o 1,25(OH)2D can be 463
elevated, ranging rom 46 to 120 nmol/L (150–500 pg/
mL). T e mechanism o the abnormal sensitivity to
vitamin D and o the increased circulating levels o
1,25(OH)2D is still unclear. Studies suggest that genetic
mutations involving microdeletions at the elastin locus
and perhaps other genes on chromosome 7 may play a
role in the pathogenesis. Another cause o hypercalce-
mia in in ants and young children is a 24-hydroxylase
de ciency that impairs metabolism o 1,25(OH)2D.

C
H
In patients with sarcoidosis and other granulomatous

A
P
T
diseases, such as tuberculosis and ungal in ections,

E
R
excess 1,25(OH)2D is synthesized in macrophages HYPERCALCEMIA ASSOCIATED WITH

3
4
or other cells in the granulomas. Indeed, increased HIGH BONE TURNOVER
1,25(OH)2D levels have been reported in anephric
patients with sarcoidosis and hypercalcemia. Macro- Hyp erthyro id ism

D
i
s
phages obtained rom granulomatous tissue convert

o
As many as 20% o hyperthyroid patients have high-

r
d
25(OH)D to 1,25(OH)2D at an increased rate. T ere is a

e
normal or mildly elevated serum calcium concen-

r
s
positive correlation in patients with sarcoidosis between

o
trations; hypercalciuria is even more common. T e

f
t
25(OH)D levels (re ecting vitamin D intake) and the

h
hypercalcemia is due to increased bone turnover, with

e
circulating concentrations o 1,25(OH)2D, whereas nor-

P
bone resorption exceeding bone ormation. Severe cal-

a
r
a
mally there is no increase in 1,25(OH)2D with increas- cium elevations are not typical, and the presence o

t
h
y
ing 25(OH)D levels due to multiple eedback controls such suggests a concomitant disease such as hyperpara-

r
o
i
on renal 1α-hydroxylase (Chap. 32). T e usual regula-

d
thyroidism. Usually, the diagnosis is obvious, but signs

G
l
tion o active metabolite production by calcium and

a
o hyperthyroidism may occasionally be occult, partic-

n
d
phosphate or by P H does not operate in these patients. ularly in the elderly (Chap. 7). Hypercalcemia is man-

a
n
Clearance o 1,25(OH)2D rom blood may be decreased

d
aged by treatment o the hyperthyroidism. Reports that

C
in sarcoidosis as well. P H levels are usually low and

a
thyroid-stimulating hormone ( SH) itsel normally has

l
c
i
1,25(OH)2D levels are elevated, but primary hyper-

u
a bone-protective e ect suggest that suppressed SH

m
parathyroidism and sarcoidosis may coexist in some

H
levels also play a role in hypercalcemia.

o
m
patients.

e
o
Management o the hypercalcemia can o en be

s
Im m o b iliza tio n

t
a
accomplished by avoiding excessive sunlight exposure

and limiting vitamin D and calcium intake. Presum-
ably, however, the abnormal sensitivity to vitamin D
and abnormal regulation o 1,25(OH)2D synthesis will
persist as long as the disease is active. Alternatively, glu-
cocorticoids in the equivalent o 100 mg/d o hydrocor-
tisone or equivalent doses o glucocorticoids may help
control hypercalcemia. Glucocorticoids appear to act by
blocking excessive production o 1,25(OH)2D, as well as
the response to it in target organs.
Id io p a th ic hyp erca lcem ia o in a n cy
T is rare disorder, usually re erred to as Williams’ syn-
drome, is an autosomal dominant disorder charac-
terized by multiple congenital development de ects,
including supravalvular aortic stenosis, mental retarda-
tion, and an el n acies, in association with hypercal-
cemia due to abnormal sensitivity to vitamin D. T e
hypercalcemia associated with the syndrome was rst
recognized in England a er orti cation o milk with
vitamin D. T e cardiac and developmental abnormali-
ties were independently described, but the connec-
tion between these de ects and hypercalcemia were
s
i
s
Immobilization is a rare cause o hypercalcemia in
adults in the absence o an associated disease but may
cause hypercalcemia in children and adolescents, par-
ticularly a er spinal cord injury and paraplegia or
quadriplegia. With resumption o ambulation, the
hypercalcemia in children usually returns to normal.
T e mechanism appears to involve a dispropor-
tion between bone ormation and bone resorption; the
ormer decreased and the latter increased. Hypercalci-
uria and increased mobilization o skeletal calcium can
develop in normal volunteers subjected to extensive
bed rest, although hypercalcemia is unusual. Immobi-
lization o an adult with a disease associated with high
bone turnover, however, such as Paget’s disease, may
cause hypercalcemia.
Thia zides
Administration o benzothiadiazines (thiazides) can
cause hypercalcemia in patients with high rates o
bone turnover. raditionally, thiazides are associated
with aggravation o hypercalcemia in primary hyper-
parathyroidism, but this e ect can be seen in other

Ha rris on_Endocrinology_Ch34_p446-p479.indd 463 20/05/16 9:33 a m

 464 high-bone-turnover states as well. T e mechanism o which, in turn, is a stimulus to parathyroid gland
thiazide action is complex. Chronic thiazide admin- enlargement. However, recent ndings have indicated
istration leads to reduction in urinary calcium; the that an increase o FGF23 production by osteocytes
hypocalciuric e ect appears to re ect the enhance- (and possibly osteoblasts) in bone occurs well be ore an
ment o proximal tubular resorption o sodium and elevation in P H is detected. FGF23 is a potent inhibi-
calcium in response to sodium depletion. Some o this tor o the renal 1-alpha hydroxylase, and the FGF23-
renal e ect is due to augmentation o P H action and dependent reduction in 1,25(OH)2 vitamin D seems to
is more pronounced in individuals with intact P H be an important stimulus or the development o sec-
secretion. However, thiazides cause hypocalciuria in ondary hyperparathyroidism.
hypoparathyroid patients on high-dose vitamin D and Secondary hyperparathyroidism occurs not only in
S
E
oral calcium replacement i sodium intake is restricted. patients with renal ailure but also in those with osteo-
C
T
I
T is nding is the rationale or the use o thiazides as malacia due to multiple causes (Chap. 32), including
O
N
an adjunct to therapy in hypoparathyroid patients, as de ciency o vitamin D action and pseudohypopara-
V
I
discussed below. T iazide administration to normal thyroidism (de cient response to P H downstream o
individuals causes a transient increase in blood calcium P HR1). For both disorders, hypocalcemia seems to
(usually within the high-normal range) that reverts be the common denominator in initiating the devel-
D
i
s
to preexisting levels a er a week or more o continued opment o secondary hyperparathyroidism. Primary
o
r
d
administration. I hormonal unction and calcium and (1°) and secondary (2°) hyperparathyroidism can be
e
r
s
bone metabolism are normal, homeostatic controls are distinguished conceptually by the autonomous growth
o
f
B
reset to counteract the calcium-elevating e ect o the o the parathyroid glands in primary hyperparathy-
o
n
e
thiazides. In the presence o hyperparathyroidism or roidism (presumably irreversible) and the adaptive
a
n
increased bone turnover rom another cause, homeo- response o the parathyroids in secondary hyperpara-
d
C
static mechanisms are ine ective. T e abnormal e ects thyroidism (typically reversible). In act, reversal over
a
l
c
i
o the thiazide on calcium metabolism disappear within weeks rom an abnormal pattern o secretion, presum-
u
m
days o cessation o the drug. ably accompanied by involution o parathyroid gland
M
e
mass to normal, occurs in patients with osteomala-
t
a
b
Vita m in A in toxica tio n cia who have been treated e ectively with calcium
o
l
i
s
and vitamin D. However, it is now recognized that a
m
Vitamin A intoxication is a rare cause o hypercalcemia
true clonal outgrowth (irreversible) can arise in long-
and is most commonly a side e ect o dietary addism.
standing, inadequately treated chronic kidney disease
Calcium levels can be elevated into the 3–3.5-mmol/L
(e.g., tertiary [3°] hyperparathyroidism; see below).
(12–14 mg/dL) range a er the ingestion o 50,000–
Patients with secondary hyperparathyroidism may
100,000 units o vitamin A daily (10–20 times the mini-
develop bone pain, ectopic calci cation, and pruri-
mum daily requirement). ypical eatures o severe
tus. T e bone disease seen in patients with secondary
hypercalcemia include atigue, anorexia, and, in some,
hyperparathyroidism and chronic kidney disease is
severe muscle and bone pain. Excess vitamin A intake is
termed renal osteodystrophy and a ects primarily bone
presumed to increase bone resorption.
turnover. However, osteomalacia is requently encoun-
T e diagnosis can be established by history and by
tered as well and may be related to the circulating levels
measurement o vitamin A levels in serum. Occasion-
o FGF23.
ally, skeletal x-rays reveal periosteal calci cations, par-
wo other skeletal disorders have been requently
ticularly in the hands. Withdrawal o the vitamin is
associated in the past with chronic kidney disease
usually associated with prompt disappearance o the
(CKD) patients treated by long-term dialysis, who
hypercalcemia and reversal o the skeletal changes. As
received aluminum-containing phosphate bind-
in vitamin D intoxication, administration o 100 mg/d
ers. Aluminum deposition in bone (see below) leads
o hydrocortisone or its equivalent leads to a rapid
to an osteomalacia-like picture. T e other entity is
return o the serum calcium to normal.
a low-turnover bone disease termed “aplastic” or
“adynamic” bone disease; P H levels are lower than
HYPERCALCEMIA ASSOCIATED typically observed in CKD patients with secondary
WITH RENAL FAILURE hyperparathyroidism. It is believed that the condi-
tion is caused, at least in part, by excessive P H sup-
Severe se co n d a ry hyp erp a ra thyro id ism
pression, which may be even greater than previously
T e pathogenesis o secondary hyperparathyroidism appreciated in light o evidence that some o the
in chronic kidney disease is incompletely understood. immunoreactive P H detected by most commercially
Resistance to the normal level o P H is a major ac- available P H assays is not the ull-length biologically
tor contributing to the development o hypocalcemia, active molecule (as discussed above) but may consist

Ha rris on_Endocrinology_Ch34_p446-p479.indd 464 20/05/16 9:33 a m

 o amino-terminally truncated ragments that do not avoidance o aluminum-containing antacids or alumi- 465
activate the P H1R. num excess in the dialysis regimen.

Milk-a lka li syn d ro m e

TREATMENT SecondaryHyperparathyroidism
Medical therapy to reverse secondary hyperparathyroidism
in CKD includes reduction o excessive blood phosphate by
restriction o dietary phosphate, the use o nonabsorbable
T e milk-alkali syndrome is due to excessive ingestion
o calcium and absorbable antacids such as milk or cal-
cium carbonate. It is much less requent since proton
pump inhibitors and other treatments became avail-
able or peptic ulcer disease. For a time, the increased

C
phosphate binders, and care ul, selective addition o cal-

H
use o calcium carbonate in the management o sec-

A
citriol (0.25–2 µg/d) or related analogues. Calcium carbon-

P
ondary hyperparathyroidism led to reappearance o the

T
ate became pre erred over aluminum-containing antacids to

E
R
prevent aluminum-induced bone disease. However, synthetic syndrome. Several clinical presentations—acute, sub-

gels that also bind phosphate (such as sevelamer) are now
widely used, with the advantage o avoiding not only alumi-
3
4
acute, and chronic—have been described, all o which
eature hypercalcemia, alkalosis, and renal ailure. T e
chronic orm o the disease, termed Burnett’s syndrome,

D
num retention, but also excess calcium loading, which may

i
s
is associated with irreversible renal damage. T e acute

o
contribute to cardiovascular calci cations. Intravenous cal-

r
d
syndromes reverse i the excess calcium and absorbable

e
citriol (or related analogues), administered as several pulses

r
s
alkali are stopped.

o
each week, helps control secondary hyperparathyroidism.

f
t
Individual susceptibility is important in the patho-

h
Aggressive but care ully administered medical therapy can

e
genesis, because some patients are treated with cal-

P
o en, but not always, reverse hyperparathyroidism and its

a
r
a
cium carbonate and alkali regimens without developing

t
symptoms and mani estations.

h
y
the syndrome. One variable is the ractional calcium

r
Occasional patients develop severe mani estations o sec-

o
i
absorption as a unction o calcium intake. Some indi-

d
ondary hyperparathyroidism, including hypercalcemia, pru-

G
viduals absorb a high raction o calcium, even with

l
a
ritus, extraskeletal calci cations, and pain ul bones, despite

n
d
aggressive medical e orts to suppress the hyperparathyroid- intakes ≥2 g o elemental calcium per day, instead o

a
n
reducing calcium absorption with high intake, as occurs

d
ism. P H hypersecretion no longer responsive to medical

C
in most normal individuals. Resultant mild hypercal-

a
therapy, a state o severe hyperparathyroidism in patients

l
c
i
cemia a er meals in such patients is postulated to con-

u
with CKD that requires surgery, has been re erred to as ter-

m
tribute to the generation o alkalosis. Development o

H
tiary hyperparathyroidism. Parathyroid surgery is neces-

o
hypercalcemia causes increased sodium excretion and

m
sary to control this condition. Based on genetic evidence

e
o
some depletion o total-body water. T ese phenomena

s
rom examination o tumor samples in these patients, the

t
a
and perhaps some suppression o endogenous P H

s
emergence o autonomous parathyroid unction is due to a

monoclonal outgrowth o one or more previously hyperplas-
tic parathyroid glands. T e adaptive response has become
an independent contributor to disease; this nding seems to
emphasize the importance o optimal medical management
to reduce the proli erative response o the parathyroid cells
that enables the irreversible genetic change.
Alum inum intoxica tio n
Aluminum intoxication (and o en hypercalcemia as a
complication o medical treatment) in the past occurred
in patients on chronic dialysis; mani estations included
acute dementia and unresponsive and severe osteoma-
lacia. Bone pain, multiple nonhealing ractures, partic-
ularly o the ribs and pelvis, and a proximal myopathy
occur. Hypercalcemia develops when these patients are
treated with vitamin D or calcitriol because o impaired
skeletal responsiveness. Aluminum is present at the
site o osteoid mineralization, osteoblastic activity is
minimal, and calcium incorporation into the skeleton
is impaired. T e disorder is now rare because o the
i
s
secretion due to mild hypercalcemia lead to increased
bicarbonate resorption and to alkalosis in the ace o
continued calcium carbonate ingestion. Alkalosis per
se selectively enhances calcium resorption in the distal
nephron, thus aggravating the hypercalcemia. T e cycle
o mild hypercalcemia →bicarbonate retention →alka-
losis →renal calcium retention →severe hypercalcemia
perpetuates and aggravates hypercalcemia and alkalosis
as long as calcium and absorbable alkali are ingested.
DIFFERENTIAL DIAGNOSIS: SPECIAL TESTS
Di erential diagnosis o hypercalcemia is best achieved
by using clinical criteria, but immunometric assays to
measure P H are especially use ul in distinguishing
among major causes (Fig. 34-6). T e clinical eatures
that deserve emphasis are the presence or absence o
symptoms or signs o disease and evidence o chro-
nicity. I one discounts atigue or depression, >90%
o patients with primary hyperparathyroidism have
asymptomatic hypercalcemia; symptoms o malignancy
are usually present in cancer-associated hypercalcemia.

Ha rris on_Endocrinology_Ch34_p446-p479.indd 465 20/05/16 9:33 a m

 466
EVALUATION OF P ATIENTS WITH HYPERCALCEMIA
Hype rc alc e mia

Ke y his torica l cons ide ra tions

• Confirm if ↑ Ca 2+ chronic
• Clue s from his tory a nd phys ica l findings

Ac ute (o r unkno wn) duratio n Chro nic duratio n (mo nths )

S
P TH hig h P TH low P TH low P TH hig h
E
C
T
S cre e n
I
O
1˚ Hype rpa ra - Cons ide r ne ga tive Othe r ca us e s Hype rpa ra -
N
thyroidis m ma ligna ncy Gra nuloma tous thyroidis m
V
Cons ide r MEN P THrP a s s a y dis e a s e Cons ide r MEN
I
s yndrome s Clinica l e va lua tion FHH s yndrome s
Milk-a lka li s yndrome
Me dica tions
D
(lithium, thia zide s )
i
s
o
Immobiliza tion
r
d
Vit D or Vit A
e
r
intoxica tion
s
o
Adre na l ins ufficie ncy
f
B
Hype rthyroidis m
o
n
e
a
n
FIGURE 3 4 -6
d
C
a
Alg o rit h m o r t h e e va lu a t io n o p a t ie n t s wit h h yp e rca lce m ia . See text or details. FHH, amilial hypocalciuric hypercalcemia; MEN,
l
c
i
u
multiple endocrine neoplasia; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide.
m
M
e
t
a
b
o
l
i
Disorders other than hyperparathyroidism and malig- In summary, P H values are elevated in >90% o
s
m
nancy cause <10% o cases o hypercalcemia, and some parathyroid-related causes o hypercalcemia, unde-
o the nonparathyroid causes are associated with clear- tectable or low in malignancy-related hypercalcemia,
cut mani estations such as renal ailure. and undetectable or normal in vitamin D–related and
Hyperparathyroidism is the likely diagnosis in high-bone-turnover causes o hypercalcemia. In view
patients with chronic hypercalcemia. I hypercalcemia o the speci city o the P H immunoassay and the
has been mani est or >1 year, malignancy can usually high requency o hyperparathyroidism in hypercal-
be excluded as the cause. A striking eature o malig- cemic patients, it is cost-e ective to measure the P H
nancy-associated hypercalcemia is the rapidity o the level in all hypercalcemic patients unless malignancy
course, whereby signs and symptoms o the under- or a speci c nonparathyroid disease is obvious. False-
lying malignancy are evident within months o the positive P H assay results are rare. Immunoassays
detection o hypercalcemia. Although clinical consid- or P HrP are help ul in diagnosing certain types o
erations are help ul in arriving at the correct diagnosis malignancy-associated hypercalcemia. Although FHH
o the cause o hypercalcemia, appropriate laboratory is parathyroid-related, the disease should be managed
testing is essential or de nitive diagnosis. T e immu- distinctively rom hyperparathyroidism. Clinical ea-
noassay or P H usually separates hyperparathyroid- tures and the low urinary calcium excretion can help
ism rom all other causes o hypercalcemia (exceptions make the distinction. Because the incidence o malig-
are very rare reports o ectopic production o excess nancy and hyperparathyroidism both increase with
P H by nonparathyroid tumors). Patients with hyper- age, they can coexist as two independent causes o
parathyroidism have elevated P H levels despite hypercalcemia.
hypercalcemia, whereas patients with malignancy 1,25(OH)2D levels are elevated in many (but not
and the other causes o hypercalcemia (except or all) patients with primary hyperparathyroidism. In
disorders mediated by P H such as lithium-induced other disorders associated with hypercalcemia, con-
hypercalcemia) have levels o hormone below normal centrations o 1,25(OH)2D are low or, at the most, nor-
or undetectable levels. Assays based on the double- mal. However, this test is o low speci city and is not
antibody method or P H exhibit very high sensi- cost-e ective, as not all patients with hyperparathy-
tivity (especially i serum calcium is simultaneously roidism have elevated 1,25(OH)2D levels and not all
evaluated) and speci city or the diagnosis o primary nonparathyroid hypercalcemic patients have suppressed
hyperparathyroidism (Fig. 34-4). 1,25(OH)2D. Measurement o 1,25(OH)2D is, however,

Ha rris on_Endocrinology_Ch34_p446-p479.indd 466 20/05/16 9:33 a m

 critically valuable in establishing the cause o hypercal-
cemia in sarcoidosis and certain lymphomas.
A use ul general approach is outlined in Fig. 34-6.
I the patient is asymptomatic and there is evidence o
chronicity to the hypercalcemia, hyperparathyroidism is
almost certainly the cause. I P H levels (usually mea-
sured at least twice) are elevated, the clinical impression
is con rmed and little additional evaluation is neces-
sary. I there is only a short history or no data as to the
duration o the hypercalcemia, occult malignancy must
hypercalcemia, even though increased bone resorption per- 467
sists. As outlined below, the more severe the hypercalcemia,
the greater the number o combined therapies that should be
used. Rapid-acting (hours) approaches—rehydration, orced
diuresis, and calcitonin—can be used with the most e ective
antiresorptive agents such as bisphosphonates (since severe
hypercalcemia usually involves excessive bone resorption).
HYDRATION, INCREASED SALT INTAKE, MILD AND FORCED DIURESIS T e
rst principle o treatment is to restore normal hydration.

C
H
Many hypercalcemic patients are dehydrated because o vom-

A
be considered; i the P H levels are not elevated, then a

P
iting, inanition, and/or hypercalcemia-induced de ects in uri-

T
thorough workup must be undertaken or malignancy,

E
R
including chest x-ray, C o chest and abdomen, and nary concentrating ability. T e resultant drop in glomerular

bone scan. Immunoassays or P HrP may be espe-
cially use ul in such situations. Attention should also
be paid to clues or underlying hematologic disorders
3
4
ltration rate is accompanied by an additional decrease in
renal tubular sodium and calcium clearance. Restoring a nor-
mal ECF volume corrects these abnormalities and increases

D
i
s
such as anemia, increased plasma globulin, and abnor- urine calcium excretion by 2.5–7.5 mmol/d (100–300 mg/d).

o
r
d
mal serum immunoelectrophoresis; bone scans can Increasing urinary sodium excretion to 400–500 mmol/d

e
r
s
be negative in some patients with metastases such as increases urinary calcium excretion even urther than simple

o
f
t
in multiple myeloma. Finally, i a patient with chronic rehydration. A er rehydration has been achieved, saline can

h
e
be administered, or urosemide or ethacrynic acid can be

P
hypercalcemia is asymptomatic and malignancy there-

a
r
given twice daily to depress the tubular reabsorptive mecha-

a
ore seems unlikely on clinical grounds, but P H values

t
h
y
are not elevated, it is use ul to search or other chronic nism or calcium (care must be taken to prevent dehydra-

r
o
i
tion). T e combined use o these therapies can increase

d
causes o hypercalcemia such as occult sarcoidosis. A

G
urinary calcium excretion to ≥12.5 mmol/d (500 mg/d) in

l
care ul history o dietary supplements and drug use

a
n
d
may suggest intoxication with vitamin D or vitamin A most hypercalcemic patients. Because this is a substantial

a
n
or the use o thiazides. percentage o the exchangeable calcium pool, the serum cal-

d
C
cium concentration usually alls 0.25–0.75 mmol/L (1–3

a
l
c
i
mg/dL) within 24 h. Precautions should be taken to prevent

u
m
TREATMENT HypercalcemicStates potassium and magnesium depletion; calcium-containing

H
o
renal calculi are a potential complication.

m
e
T e approach to medical treatment o hypercalcemia var-

o
Under li e-threatening circumstances, the preceding

s
t
a
ies with its severity (Table 34-4). Mild hypercalcemia, approach can be pursued more aggressively, but the avail-

<3 mmol/L (12 mg/dL), can be managed by hydration. More
severe hypercalcemia (levels o 3.2–3.7 mmol/L [13–15 mg/
dL]) must be managed aggressively; above that level, hyper-
calcemia can be li e-threatening and requires emergency
measures. By using a combination o approaches in severe
hypercalcemia, the serum calcium concentration can be
decreased by 0.7–2.2 mmol/L (3–9 mg/dL) within 24–48 h
in most patients, enough to relieve acute symptoms, pre-
vent death rom hypercalcemic crisis, and permit diagnostic
evaluation. T erapy can then be directed at the underlying
disorder—the second priority.
Hypercalcemia develops because o excessive skeletal cal-
cium release, increased intestinal calcium absorption, or inad-
equate renal calcium excretion. Understanding the particular
pathogenesis helps guide therapy. For example, hypercalce-
mia in patients with malignancy is primarily due to excessive
skeletal calcium release and is, there ore, minimally improved
by restriction o dietary calcium. On the other hand, patients
with vitamin D hypersensitivity or vitamin D intoxication
have excessive intestinal calcium absorption, and restric-
tion o dietary calcium is bene cial. Decreased renal unc-
tion or ECF depletion decreases urinary calcium excretion. In
such situations, rehydration may rapidly reduce or reverse the
s
i
s
ability o e ective agents to block bone resorption (such as
bisphosphonates) has reduced the need or extreme diuresis
regimens ( able 34-4). Depletion o potassium and magne-
sium is inevitable unless replacements are given; pulmonary
edema can be precipitated. T e potential complications can
be reduced by care ul monitoring o central venous pres-
sure and plasma or urine electrolytes; catheterization o the
bladder may be necessary. Dialysis treatment may be needed
when renal unction is compromised.
BISPHOSPHONATES T e bisphosphonates are analogues o
pyrophosphate, with high a nity or bone, especially in areas
o increased bone turnover, where they are power ul inhibi-
tors o bone resorption. T ese bone-seeking compounds are
stable in vivo because phosphatase enzymes cannot hydrolyze
the central carbon-phosphorus-carbon bond. T e bisphos-
phonates are concentrated in areas o high bone turnover and
are taken up by and inhibit osteoclast action; the mechanism
o action is complex. T e bisphosphonate molecules that con-
tain amino groups in the side chain structure (see below)
inter ere with prenylation o proteins and can lead to cellu-
lar apoptosis. T e highly active nonamino group–containing
bisphosphonates are also metabolized to cytotoxic products.

Ha rris on_Endocrinology_Ch34_p446-p479.indd 467 20/05/16 9:33 a m

 468 TABLE 3 4 -4
THERAPIES FOR SEVERE HYPERCALCEMIA
TREATMENT ONSET OF ACTION DURATION OF ACTION ADVANTAGES DISADVANTAGES

Mo st Use u l Th e ra p ie s
Hydration with saline Hours During in usion Rehydration invariably Volume overload
needed
Forced diuresis; saline Hours During treatment Rapid action Volume overload, car-
plus loop diuretic diac decompensation,
intensive monitoring,
S
E
electrolyte disturbance,
C
T
inconvenience
I
O
N
Pamidronate 1–2 days 10–14 days to weeks High potency; interme- Fever in 20%, hypo-
V
diate onset o action phosphatemia,
I
hypocalcemia, hypo-
magnesemia, rarely jaw
D
necrosis
i
s
o
r
Zoledronate 1–2 days >3 weeks Same as or pamidro- Same as pamidronate
d
e
nate (may last longer) above
r
s
o
f
Calcitonin Hours 1–2 days Rapid onset o action; Rapid tachyphylaxis
B
o
use ul as adjunct in
n
e
severe hypercalcemia
a
n
d
Sp e cia l Use Th e ra p ie s
C
a
l
c
Phosphate oral 24 h During use Chronic management Limited use except as
i
u
m
(with hypophospha- adjuvant or chronic
M
temia); low toxicity i therapy
e
t
phosphate <4 mg/dL
a
b
o
l
Glucocorticoids Days Days, weeks Oral therapy, antitumor Active only in certain
i
s
m
agent malignancies, vitamin
D excess and sarcoid-
osis; glucocorticoid
side e ects
Dialysis Hours During use and 24–48 h Use ul in renal ailure; Complex procedure,
a terward onset o e ect in reserved or extreme or
hours; can immediately special circumstances
reverse li e-threatening
hypercalcemia

T e initial bisphosphonate widely used in clinical prac-
tice, etidronate, was e ective but had several disadvantages,
including the capacity to inhibit bone ormation as well as
blocking resorption. Subsequently, a number o second- or
third-generation compounds have become the mainstays o
antiresorptive therapy or treatment o hypercalcemia and
osteoporosis. T e newer bisphosphonates have a highly avor-
able ratio o blocking resorption versus inhibiting bone or-
mation; they inhibit osteoclast-mediated skeletal resorption
yet do not cause mineralization de ects at ordinary doses.
Although the bisphosphonates have similar structures, the
routes o administration, e cacy, toxicity, and side e ects
vary. T e potency o the compounds or inhibition o bone
resorption varies more than 10,000- old, increasing in the
order o etidronate, tiludronate, pamidronate, alendronate,
risedronate, and zoledronate. T e IV use o pamidronate and
zoledronate is approved or the treatment o hypercalcemia;
between 30 and 90 mg pamidronate, given as a single IV dose
over a ew hours, returns serum calcium to normal within
24–48 h with an e ect that lasts or weeks in 80–100% o
patients. Zoledronate given in doses o 4 or 8 mg/5-min in u-
sion has a more rapid and more sustained e ect than pami-
dronate in direct comparison.
T ese drugs are used extensively in cancer patients.
Absolute survival improvements are noted with pamidro-
nate and zoledronate in multiple myeloma, or example.
However, although still rare, there are increasing reports o
jaw necrosis, especially a er dental surgery, mainly in can-
cer patients treated with multiple doses o the more potent
bisphosphonates.
CALCITONIN Calcitonin acts within a ew hours o its adminis-
tration, principally through receptors on osteoclasts, to block
bone resorption. Calcitonin, a er 24 h o use, is no longer
e ective in lowering calcium. achyphylaxis, a known phe-
nomenon with this drug, seems to explain the results, since

Ha rris on_Endocrinology_Ch34_p446-p479.indd 468 20/05/16 9:33 a m

 the drug is o en e ective in the rst 24 h o use. T ere ore, in
li e-threatening hypercalcemia, calcitonin can be used e ec-
tively within the rst 24 h in combination with rehydration
and saline diuresis while waiting or more sustained e ects
rom a simultaneously administered bisphosphonate such as
pamidronate. Usual doses o calcitonin are 2–8 U/kg o body
weight IV, SC, or IM every 6–12 h.
OTHER THERAPIES Denosumab, an antibody that blocks the
Phosphate therapy, PO or IV, has a limited role in cer- 469
tain circumstances (Chap. 32). Correcting hypophospha-
temia lowers the serum calcium concentration by several
mechanisms, including bone/calcium exchange. T e usual
oral treatment is 1–1.5 g o phosphorus per day or several
days, given in divided doses. It is generally believed, but not
established, that toxicity does not occur i therapy is limited
to restoring serum inorganic phosphate concentrations to
normal.

C
RANK ligand (RANKL) and dramatically reduces osteoclast Raising the serum inorganic phosphate concentration

H
A
number and unction, is approved or therapy o osteopo- above normal decreases serum calcium levels, sometimes

P
T
rosis. It also appears to be an e ective treatment to reverse strikingly. Intravenous phosphate is one o the most dramati-

E
R
hypercalcemia o malignancy, but is not yet approved or cally e ective treatments available or severe hypercalcemia

this indication. Plicamycin ( ormerly mithramycin), which
inhibits bone resorption, and gallium nitrate, which exerts
a hypocalcemic action also by inhibiting bone resorption,
3
4
but is toxic and even dangerous ( atal hypocalcemia). For
these reasons, it is used rarely and only in severely hypercal-
cemic patients with cardiac or renal ailure where dialysis, the

D
i
s
pre erable alternative, is not easible or is unavailable.

o
are no longer used because o superior alternatives such as

r
d
e
bisphosphonates.

r
s
SUMMARY T e various therapies or hypercalcemia are listed

o
Glucocorticoids have utility, especially in hypercalcemia

f
t
in able 34-4. T e choice depends on the underlying dis-

h
complicating certain malignancies. T ey increase urinary

e
ease, the severity o the hypercalcemia, the serum inorganic

P
calcium excretion and decrease intestinal calcium absorp-

a
r
phosphate level, and the renal, hepatic, and bone marrow

a
tion when given in pharmacologic doses, but they also cause

t
h
y
negative skeletal calcium balance. In normal individuals and unction. Mild hypercalcemia (≤3 mmol/L [12 mg/dL]) can

r
o
i
usually be managed by hydration. Severe hypercalcemia (≥3.7

d
in patients with primary hyperparathyroidism, glucocorti-

G
mmol/L [15 mg/dL]) requires rapid correction. Calcitonin

l
a
coids neither increase nor decrease the serum calcium con-

n
d
centration. In patients with hypercalcemia due to certain should be given or its rapid, albeit short-lived, blockade o

a
n
bone resorption, and IV pamidronate or zoledronate should

d
osteolytic malignancies, however, glucocorticoids may be

C
be administered, although its onset o action is delayed

a
e ective as a result o antitumor e ects. T e malignancies

l
c
i
or 1–2 days. In addition, or the rst 24–48 h, aggressive

u
in which hypercalcemia responds to glucocorticoids include

m
multiple myeloma, leukemia, Hodgkin’s disease, other lym- sodium-calcium diuresis with IV saline should be given and,

H
o
ollowing rehydration, large doses o urosemide or ethac-

m
phomas, and carcinoma o the breast, at least early in the

e
o
course o the disease. Glucocorticoids are also e ective in rynic acid, but only i appropriate monitoring is available and

s
t
a
cardiac and renal unction are adequate. Intermediate degrees

s
treating hypercalcemia due to vitamin D intoxication and

sarcoidosis. Glucocorticoids are also use ul in the rare orm
o hypercalcemia, now recognized in certain autoimmune
disorders in which inactivating antibodies against the recep-
tor imitate FHH. Elevated P H and calcium levels are e ec-
tively lowered by the glucocorticoids. In all the preceding
situations, the hypocalcemic e ect develops over several days,
and the usual glucocorticoid dosage is 40–100 mg prednisone
(or its equivalent) daily in our divided doses. T e side e ects
o chronic glucocorticoid therapy may be acceptable in some
circumstances.
Dialysis is o en the treatment o choice or severe hyper-
calcemia complicated by renal ailure, which is di cult to
manage medically. Peritoneal dialysis with calcium- ree
dialysis uid can remove 5–12.5 mmol (200–500 mg) o cal-
cium in 24–48 h and lower the serum calcium concentration
by 0.7–3 mmol/L (3–12 mg/dL). Large quantities o phos-
phate are lost during dialysis, and serum inorganic phosphate
concentration usually alls, potentially aggravating hyper-
calcemia. T ere ore, the serum inorganic phosphate con-
centration should be measured a er dialysis, and phosphate
supplements should be added to the diet or to dialysis uids
i necessary.
i
s
o hypercalcemia between 3 and 3.7 mmol/L (12 and 15 mg/
dL) should be approached with vigorous hydration and then
the most appropriate selection or the patient o the combina-
tions used with severe hypercalcemia.
HYP O CALCEMIA
(See also Chap. 33)
PATHOPHYSIOLOGY OF HYPOCALCEMIA:
CLASSIFICATION BASED ON MECHANISM
Chronic hypocalcemia is less common than hypercalcemia;
causes include chronic renal ailure, hereditary and acquired
hypoparathyroidism, vitamin D de ciency, pseudohypo-
parathyroidism, and hypomagnesemia (Table 34-5).
Acute rather than chronic hypocalcemia is seen
in critically ill patients or as a consequence o cer-
tain medications and o en does not require speci c

Ha rris on_Endocrinology_Ch34_p446-p479.indd 469 20/05/16 9:33 a m

 470 TABLE 3 4 -5 without obvious cause and with a paucity o symptoms;
FUNCTIONAL CLASSIFICATION OF HYPOCALCEMIA the pathogenesis is unclear.
(EXCLUDING NEONATAL CONDITIONS) Chronic hypocalcemia, however, is usually symp-
PTH Ab se n t tomatic and requires treatment. Neuromuscular and
Hereditary Hypomagnesemia neurologic mani estations o chronic hypocalcemia
hypoparathyroidism include muscle spasms, carpopedal spasm, acial gri-
Acquired hypoparathyroidism macing, and, in extreme cases, laryngeal spasm and
convulsions. Respiratory arrest may occur. Increased
PTH In e f e ct ive
intracranial pressure occurs in some patients with long-
Chronic kidney disease Active vitamin D ine ective standing hypocalcemia, o en in association with papill-
S
E
Active vitamin D lacking Intestinal malabsorption edema. Mental changes include irritability, depression,
C
T
I
and psychosis. T e Q interval on the electrocardio-
O
↓ Dietary intake or sunlight Vitamin D–dependent
N
rickets type II gram is prolonged, in contrast to its shortening with
V
I
De ective metabolism: Pseudohypoparathyroidism hypercalcemia. Arrhythmias occur, and digitalis e ec-
Anticonvulsant therapy tiveness may be reduced. Intestinal cramps and chronic
malabsorption may occur. Chvostek’s or rousseau’s
D
i
Vitamin D–dependent
s
sign can be used to con rm latent tetany.
o
r
rickets type I
d
T e classi cation o hypocalcemia shown in able
e
r
s
PTH Ove rwh e lm e d
34-5 is based on an organizationally use ul premise that
o
f
B
Severe, acute Osteitis brosa a ter P H is responsible or minute-to-minute regulation
o
n
hyperphosphatemia parathyroidectomy
e
o plasma calcium concentration and, there ore, that
a
n
Tumor lysis the occurrence o hypocalcemia must mean a ailure
d
C
o the homeostatic action o P H. Failure o the P H
a
Acute kidney injury
l
c
i
response can occur i there is hereditary or acquired
u
Rhabdomyolysis
m
parathyroid gland ailure, i P H is ine ective in target
M
e
organs, or i the action o the hormone is overwhelmed
t
Abb revia tio n: PTH, parathyroid hormone.
a
b
by the loss o calcium rom the ECF at a rate aster than
o
l
i
s
it can be replaced.
m
treatment. ransient hypocalcemia is seen with severe
sepsis, burns, acute kidney injury, and extensive trans-
PTH ABSENT
usions with citrated blood. Although as many as one-
hal o patients in an intensive care setting are reported Whether hereditary or acquired, hypoparathyroid-
to have calcium concentrations o <2.1 mmol/L (8.5 ism has a number o common components. Symptoms
mg/dL), most do not have a reduction in ionized cal- o untreated hypocalcemia are shared by both types o
cium. Patients with severe sepsis may have a decrease hypoparathyroidism, although the onset o hereditary
in ionized calcium (true hypocalcemia), but in other hypoparathyroidism can be more gradual and associ-
severely ill individuals, hypoalbuminemia is the pri- ated with other developmental de ects. Basal ganglia
mary cause o the reduced total calcium concentration. calci cation and extrapyramidal syndromes are more
Alkalosis increases calcium binding to proteins, and in common and earlier in onset in hereditary hypopara-
this setting, direct measurements o ionized calcium thyroidism. In previous decades, acquired hypopara-
should be made. thyroidism secondary to surgery in the neck was more
Medications such as protamine, heparin, and gluca- common than hereditary hypoparathyroidism, but the
gon may cause transient hypocalcemia. T ese orms o requency o surgically induced parathyroid ailure has
hypocalcemia are usually not associated with tetany and diminished as a result o improved surgical techniques
resolve with improvement in the overall medical condi- that spare the parathyroid glands and increased use o
tion. T e hypocalcemia a er repeated trans usions o nonsurgical therapy or hyperthyroidism. Pseudohypo-
citrated blood usually resolves quickly. parathyroidism, an example o ine ective P H action
Patients with acute pancreatitis have hypocalcemia rather than a ailure o parathyroid gland production,
that persists during the acute in ammation and varies may share several eatures with hypoparathyroidism,
in degree with disease severity. T e cause o hypocalce- including extraosseous calci cation and extrapyramidal
mia remains unclear. P H values are reported to be low, mani estations such as choreoathetotic movements and
normal, or elevated, and both resistance to P H and dystonia.
impaired P H secretion have been postulated. Occa- Papilledema and raised intracranial pressure may
sionally, a chronic low total calcium and low ionized occur in both hereditary and acquired hypoparathy-
calcium concentration are detected in an elderly patient roidism, as do chronic changes in ngernails and hair

Ha rris on_Endocrinology_Ch34_p446-p479.indd 470 20/05/16 9:33 a m

 and lenticular cataracts, the latter usually reversible
with treatment o hypocalcemia. Certain skin mani es-
tations, including alopecia and candidiasis, are char-
acteristic o hereditary hypoparathyroidism associated
with autoimmune polyglandular ailure (Chap. 29).
Hypocalcemia associated with hypomagnesemia
is associated with both de cient P H release and
impaired responsiveness to the hormone. Patients with
hypocalcemia secondary to hypomagnesemia have
absent or low levels o circulating P H, indicative o
recognized—now called DSG2. T e phenotypes seem 471
similar. Studies on the chromosome 22 de ect have
pinpointed a transcription actor, BX1. Deletions o
the orthologous mouse gene show a phenotype similar
to the human syndrome.
Another autosomal dominant developmental de ect,
eaturing hypoparathyroidism, dea ness, and renal dys-
plasia (HDR), has been studied at the genetic level.
Cytogenetic abnormalities in some, but not all kindreds,
point to translocation de ects on chromosome 10, as in

C
H
A
diminished hormone release despite a maximum physi- DiGeorge syndrome. However, the lack o immuno-

P
T
ologic stimulus by hypocalcemia. Plasma P H levels de ciency and heart de ects distinguishes the two syn-

E
R
return to normal with correction o the hypomagne- dromes. Mouse models, as well as deletional analysis

semia. T us hypoparathyroidism with low levels o
P H in blood can be due to hereditary gland ailure,
acquired gland ailure, or acute but reversible gland
3
4
in some HDR patients, has identi ed the transcription
actor GA A3, which is important in embryonic devel-
opment and is expressed in developing kidney, ear struc-

D
i
s
dys unction (hypomagnesemia). tures, and the parathyroids.

o
r
d
Another pair o linked developmental disorders

e
r
s
involving the parathyroids is recognized. Kenney-

o
f
Gen etic a bn o rm a lities a n d here d ita ry

t
Caf ey syndrome type I eatures hypoparathyroidism,

h
e
hyp o p a ra thyro id ism

P
short stature, osteosclerosis, and thick cortical bones.

a
r
a
Hereditary hypoparathyroidism can occur as an iso- A de ect seen in Middle Eastern patients, particularly

t
h
y
lated entity without other endocrine or dermatologic in Saudi Arabia, termed Sanjad-Sakati syndrome, also

r
o
i
d
mani estations. More typically, it occurs in association exhibits growth ailure and other dysmorphic eatures.

G
l
with other abnormalities such as de ective development T is syndrome, which is clearly autosomal recessive,

a
n
d
o the thymus or ailure o other endocrine organs such involves a gene on chromosome 1q42-q43. Both syn-

a
n
as the adrenal, thyroid, or ovary (Chap. 29). Hereditary dromes apparently involve a chaperone protein, called

d
C
a
hypoparathyroidism is o en mani est within the rst TBCE, relevant to tubulin unction. Recently, a de ect in

l
c
i
u
decade but may appear later. FAM111A was identi ed as the cause o Kenney-Caf ey

m
Genetic de ects associated with hypoparathyroid- syndrome type 2.

H
o
m
ism serve to illuminate the complexity o organ devel- Hypoparathyroidism can occur in association with

e
o
opment, hormonal biosynthesis and secretion, and a complex hereditary autoimmune syndrome involv-

s
t
a
tissue-speci c patterns o endocrine e ector unction ing ailure o the adrenals, the ovaries, the immune

(Fig. 34-5). O en, hypoparathyroidism is isolated, sig-
ni ying a highly speci c unctional disturbance. When
hypoparathyroidism is associated with other develop-
mental or organ de ects, treatment o the hypocalcemia
can still be e ective.
A orm o hypoparathyroidism associated with
de ective development o both the thymus and the
parathyroid glands is termed the DiGeorge syndrome,
or the velocardio acial syndrome. Congenital cardio-
vascular, acial, and other developmental de ects are
present, and patients may die in early childhood with
severe in ections, hypocalcemia and seizures, or car-
diovascular complications. Patients can survive into
adulthood, and milder, incomplete orms occur. Most
cases are sporadic, but an autosomal dominant orm
involving microdeletions o chromosome 22q11.2 has
been described. Smaller deletions in chromosome 22
are seen in incomplete orms o the DiGeorge syn-
drome, appearing in childhood or adolescence, that
are mani est primarily by parathyroid gland ailure.
T e chromosome 22 de ect is now termed DSG1;
more recently, a de ect in chromosome 10p is also
s
i
s
system, and the parathyroids in association with recur-
rent mucocutaneous candidiasis, alopecia, vitiligo, and
pernicious anemia (Chap. 29). T e responsible gene on
chromosome 21q22.3 has been identi ed. T e protein
product, which resembles a transcription actor, has
been termed the autoimmune regulator, or AIRE. A stop
codon mutation occurs in many Finnish amilies with
the disorder, commonly re erred to as polyglandular
autoimmune type 1 de ciency, whereas another AIRE
mutation (Y85C) is typically observed in Jews o Iraqi
and Iranian descent.
Hypoparathyroidism is seen in two disorders asso-
ciated with mitochondrial dys unction and myopathy,
one termed the Kearns-Sayre syndrome (KSS), with
ophthalmoplegia and pigmentary retinopathy, and the
other termed the MELAS syndrome (mitochondrial
encephalopathy, lactic acidosis, and stroke-like epi-
sodes). Mutations or deletions in mitochondrial genes
have been identi ed.
Several orms o hypoparathyroidism, each rare
in requency, are seen as isolated de ects; the genetic
mechanisms are varied. T e inheritance includes

Ha rris on_Endocrinology_Ch34_p446-p479.indd 471 20/05/16 9:33 a m

 472 autosomal dominant, autosomal recessive, and X-linked As with autoimmune disorders that block the CaSR
modes. T ree separate autosomal de ects involving the (discussed above under hypercalcemic conditions),
parathyroid gene have been recognized: one is domi- there are autoantibodies that at least transiently acti-
nant and the other two are recessive. T e dominant vate the CaSR, leading to suppressed P H secretion and
orm has a point mutation in the signal sequence, a hypocalcemia. T is disorder may wax and wane.
critical region involved in intracellular transport o the
hormone precursor. An Arg or Cys mutation inter- Acq u ire d hyp o p a ra thyro id ism
eres with processing o the precursor and is believed
to trigger an apoptotic cellular response, hence acting Acquired chronic hypoparathyroidism is usually the
as a dominant negative. T e other two orms are reces- result o inadvertent surgical removal o all the para-
S
E
sive. One point mutation also blocks cleavage o the thyroid glands; in some instances, not all the tissue is
C
T
I
P H precursor but requires both alleles to cause hypo- removed, but the remainder undergoes vascular supply
O
N
parathyroidism. T e third involves a single-nucleotide compromise secondary to brotic changes in the neck
V
I
base change that results in an exon splicing de ect; the a er surgery. In the past, the most requent cause o
lost exon contains the promoter—hence, the gene is acquired hypoparathyroidism was surgery or hyperthy-
silenced. An X-linked recessive orm o hypoparathy- roidism. Hypoparathyroidism now usually occurs a er
D
i
s
roidism has been described in males, and the de ect surgery or hyperparathyroidism when the surgeon,
o
r
d
has been localized to chromosome Xq26-q27, perhaps acing the dilemma o removing too little tissue and
e
r
s
involving the SOX3 gene. thus not curing the hyperparathyroidism, removes too
o
f
B
Abnormalities in the CaSR are detected in three distinc- much. Parathyroid unction may not be totally absent in
o
n
all patients with postoperative hypoparathyroidism.
e
tive hypocalcemic disorders. All are rare, but more than
a
n
10 di erent gain-o - unction mutations have been ound Rare causes o acquired chronic hypoparathyroidism
d
C
in one orm o hypocalcemia termed autosomal dominant include radiation-induced damage subsequent to radio-
a
l
c
iodine therapy o hyperthyroidism and glandular dam-
i
hypocalcemic hypercalciuria (ADHH). T e receptor senses
u
m
the ambient calcium level as excessive and suppresses P H age in patients with hemochromatosis or hemosiderosis
M
e
secretion, leading to hypocalcemia. T e hypocalcemia is a er repeated blood trans usions. In ection may involve
t
a
b
aggravated by constitutive receptor activity in the renal one or more o the parathyroids but usually does not
o
l
i
s
tubule causing excretion o inappropriate amounts o cal- cause hypoparathyroidism because all our glands are
m
cium. Recognition o the syndrome is important because rarely involved.
e orts to treat the hypocalcemia with vitamin D analogues Transient hypoparathyroidism is requent ollow-
and increased oral calcium exacerbate the already exces- ing surgery or hyperparathyroidism. A er a variable
sive urinary calcium excretion (several grams or more per period o hypoparathyroidism, normal parathyroid
24 h), leading to irreversible renal damage rom stones and unction may return due to hyperplasia or recovery o
ectopic calci cation. remaining tissue. Occasionally, recovery occurs months
Other causes o isolated hypoparathyroidism include a er surgery.
homozygous, inactivating mutations in the parathyroid-
speci c transcription actor GCM2, which lead to an
autosomal recessive orm o the disease, or heterozy- TREATMENT Acquired and Hereditary Hypoparathyroidism
gous point mutations in GCM2, which have a dominant
negative e ect on the wild-type protein and thus lead reatment involves replacement with vitamin D or
to an autosomal dominant orm o hypoparathyroid- 1,25(OH)2D (calcitriol) combined with a high oral calcium
ism. Furthermore, heterozygous mutations in G11, one intake. In most patients, blood calcium and phosphate levels
o the two signaling proteins downstream o the CaSR, are satis actorily regulated, but some patients show resistance
have been identi ed as a cause o autosomal dominant and a brittleness, with a tendency to alternate between hypo-
hypoparathyroidism. calcemia and hypercalcemia. For many patients, vitamin D
Bartter’s syndrome is a group o disorders associ- in doses o 40,000–120,000 U/d (1–3 mg/d) combined with
ated with disturbances in electrolyte and acid/base ≥1 g elemental calcium is satis actory. T e wide dosage range
balance, sometimes with nephrocalcinosis and other re ects the variation encountered rom patient to patient;
eatures. Several types o ion channels or transporters precise regulation o each patient is required. Compared
are involved. Curiously, Bartter’s syndrome type V has to typical daily requirements in euparathyroid patients o
the electrolyte and pH disturbances seen in the other 200 U/d (or in older patients as high as 800 U/d), the high
syndromes but appears to be due to a gain o unc- dose o vitamin D (as much as 100- old higher) re ects the
tion in the CaSR. T e de ect may be more severe than reduced conversion o vitamin D to 1,25(OH)2D. Many phy-
in ADHH and explains the additional eatures seen sicians now use 0.5–1 µg o calcitriol in management o such
beyond hypocalcemia and hypercalciuria. patients, especially i they are di cult to control. Because

Ha rris on_Endocrinology_Ch34_p446-p479.indd 472 20/05/16 9:33 a m

 o its storage in at, when vitamin D is withdrawn, weeks
are required or the disappearance o the biologic e ects,
compared with a ew days or calcitriol, which has a rapid
turnover.
Oral calcium and vitamin D restore the overall calcium-
phosphate balance but do not reverse the lowered urinary
calcium reabsorption typical o hypoparathyroidism. T ere-
ore, care must be taken to avoid excessive urinary calcium
excretion a er vitamin D and calcium replacement therapy;
to a rapid increase in P H level. Serum phosphate 473
levels are o en not elevated, in contrast to the situa-
tion with acquired or idiopathic hypoparathyroidism,
probably because phosphate de ciency is o en seen in
hypomagnesmia.
Diminished peripheral responsiveness to P H also
occurs in some patients, as documented by subnormal
response in urinary phosphorus and urinary cAMP
excretion a er administration o exogenous P H to

C
otherwise, nephrocalcinosis and kidney stones can develop, patients who are hypocalcemic and hypomagnesemic.

H
A
and the risk o CKD is increased. T iazide diuretics lower Both blunted P H secretion and lack o renal response

P
T
urine calcium by as much as 100 mg/d in hypoparathyroid to administered P H can occur in the same patient.

E
R
patients on vitamin D, provided they are maintained on a When acute magnesium repletion is undertaken, the

3
4
low-sodium diet. Use o thiazides seems to be o bene t in restoration o P H levels to normal or supranormal
mitigating hypercalciuria and easing the daily management may precede restoration o normal serum calcium by
o these patients. several days.

D
i
s
T ere are now trials o parenterally administered P H

o
r
d
e
(either P H[1–34] or P H[1–84]) in patients with hypo-

r
s
parathyroidism providing greater ease o maintaining serum

o
TREATMENT Hypomagnesemia

f
t
h
calcium and reducing urinary calcium excretion (desirable

e
P
to protect any renal damage). However, P H therapy or the Repletion o magnesium cures the condition. Repletion

a
r
a
treatment o hypoparathyroidism is not approved as o yet.

t
should be parenteral. Attention must be given to restoring

h
y
r
the intracellular de cit, which may be considerable. A er IV

o
i
d
magnesium administration, serum magnesium may return

G
l
a
transiently to the normal range, but unless replacement ther-

n
Hyp o m a g nesem ia

d
apy is adequate, serum magnesium will again all. I the cause

a
n
d
Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) o the hypomagnesemia is renal magnesium wasting, magne-

C
a
is associated with hypocalcemia (Chap. 32). Restora- sium may have to be given long-term to prevent recurrence

l
c
i
u
tion o the total-body magnesium de cit leads to rapid (Chap. 32).

m
H
reversal o hypocalcemia. T ere are at least two causes

o
m
o the hypocalcemia—impaired P H secretion and

e
o
reduced responsiveness to P H. For further discus-

s
t
PTH INEFFECTIVE

a
s
sion of causes and treatment of hypomagnesemia, see

Chap. 32.
T e e ects o magnesium on P H secretion are simi-
lar to those o calcium; hypermagnesemia suppresses
and hypomagnesemia stimulates P H secretion. T e
e ects o magnesium on P H secretion are normally o
little signi cance, however, because the calcium e ects
dominate. Greater change in magnesium than in cal-
cium is needed to in uence hormone secretion. None-
theless, hypomagnesemia might be expected to increase
hormone secretion. It is there ore surprising to nd
that severe hypomagnesemia is associated with blunted
secretion o P H. T e explanation or the paradox is
that severe, chronic hypomagnesemia leads to intra-
cellular magnesium de ciency, which inter eres with
secretion and peripheral responses to P H. T e mecha-
nism o the cellular abnormalities caused by hypomag-
nesemia is unknown, although e ects on adenylate
cyclase ( or which magnesium is a co actor) have been
proposed.
P H levels are undetectable or inappropriately low in
severe hypomagnesemia despite the stimulus o severe
hypocalcemia, and acute repletion o magnesium leads
i
s
P H is not su ciently active to ully prevent hypocalce-
mia (although retaining phosphaturic activity, or exam-
ple). T is problem occurs when the P H1R–signaling
protein complex is de ective (as in the di erent orms o
pseudohypoparathyroidism [PHP], discussed below);
when P H action to promote calcium absorption rom
the diet via the synthesis o 1,25(OH)2D is insu cient
because o vitamin D de ciency or because vitamin D
is ine ective (de ects in vitamin D receptor or vitamin
D synthesis); or in CKD in which the calcium-elevating
action o P H is impaired.
ypically, hypophosphatemia is more severe than
hypocalcemia in vitamin D de ciency states because o
the increased secretion o P H, which, although only
partly e ective in elevating blood calcium, is readily
capable o promoting urinary phosphate excretion.
PHP, on the other hand, has a pathophysiology
that is di erent rom the other disorders o ine ective
P H action. PHP resembles hypoparathyroidism (in
which P H synthesis is de cient) and is mani ested
by hypocalcemia and hyperphosphatemia, yet ele-
vated P H levels. T e cause o the disorder is de ective

Ha rris on_Endocrinology_Ch34_p446-p479.indd 473 20/05/16 9:33 a m

 474 P H-dependent activation o the stimulatory G pro- evidence o genetic changes and monoclonal outgrowths o
tein complex or the downstream e ector protein kinase parathyroid glands in CKD patients, to prevent secondary
A, resulting in ailure o P H to increase intracellu- hyperparathyroidism rom becoming autonomous hyperpara-
lar cAMP or to respond to elevated cAMP levels (see thyroidism. Reduction o hyperphosphatemia and restora-
below). tion o normal intestinal calcium absorption by calcitriol can
improve blood calcium levels and reduce the mani estations o
Chro n ic kid n ey disea se secondary hyperparathyroidism. Because adynamic bone dis-
ease can occur in association with low P H levels, it is impor-
Improved medical management o CKD now allows tant to avoid excessive suppression o the parathyroid glands
many patients to survive or decades and hence allows while recognizing the bene cial e ects o controlling the sec-
S
time enough to develop eatures o renal osteodys-
E
ondary hyperparathyroidism. T ese patients should probably
C
T
trophy, which must be controlled to avoid additional
I
be closely monitored with P H assays that detect only the ull-
O
N
morbidity. Impaired production o 1,25(OH)2D is now length P H(1–84) to ensure that biologically active P H and
V
thought to be the principal actor that causes calcium
I
not inactive, inhibitory P H ragments are measured. Use o
de ciency, secondary hyperparathyroidism, and bone phosphate-binding agents such as sevelamer is approved only
disease; hyperphosphatemia typically occurs only in in end-stage renal disease, but it may be necessary to initi-
D
i
the later stages o the disease. Low levels o 1,25(OH)2D
s
ate such treatment much earlier during the course o kidney
o
r
due to increased FGF23 production in bone are criti-
d
e
disease to prevent the increase in FGF23 and its “o -target”
r
s
cal in the development o hypocalcemia. T e uremic e ects.
o
f
state also causes impairment o intestinal absorption by
B
o
n
mechanisms other than de ects in vitamin D metabo-
e
a
lism. Nonetheless, treatment with supraphysiologic
n
d
amounts o vitamin D or calcitriol can correct the Vita m in D d ef cien cy d ue to in a d e q ua te
C
a
d iet a n d /o r su n lig h t
l
c
impaired calcium absorption. Because increased FGF23
i
u
m
levels are seen even in early stages o CKD and have Vitamin D de ciency due to inadequate intake o dairy
M
been reported to correlate with increased mortality products enriched with vitamin D, lack o vitamin
e
t
a
and le ventricular hypertrophy, there is current inter-
b
supplementation, and reduced sunlight exposure in
o
l
est in approaches to lower intestinal phosphate absorp-
i
the elderly, particularly during winter in northern lati-
s
m
tion early during the course o kidney disease and to tudes, is more common in the United States than pre-
thereby lower FGF23 levels. However, there is concern viously recognized. Biopsies o bone in elderly patients
as to whether vitamin D supplementation increases the with hip racture (documenting osteomalacia) and
circulating FGF23 levels in CKD patients. Although abnormal levels o vitamin D metabolites, P H, cal-
vitamin D analogs improve survival in this patient pop- cium, and phosphate indicate that vitamin D de ciency
ulation, it is notable that there are o en dramatic eleva- may occur in as many as 25% o elderly patients, par-
tions o FGF23. ticularly in northern latitudes in the United States. Con-
Hyperphosphatemia in CKD lowers blood calcium centrations o 25(OH)D are low or low-normal in these
levels by several mechanisms, including extraosseous patients. Quantitative histomorphometric analysis o
deposition o calcium and phosphate, impairment o bone biopsy specimens rom such individuals reveals
the bone-resorbing action o P H, and reduction in widened osteoid seams consistent with osteomalacia
1,25(OH)2D production by remaining renal tissue. (Chap. 32). P H hypersecretion compensates or the
tendency or the blood calcium to all but also increases
renal phosphate excretion and thus causes osteomalacia.
TREATMENT ChronicKidneyDisease reatment involves adequate replacement with vita-
min D and calcium until the de ciencies are corrected.
T erapy o CKD involves appropriate management o patients Severe hypocalcemia rarely occurs in moderately severe
prior to dialysis and adjustment o regimens once dialysis is vitamin D de ciency o the elderly, but vitamin D de -
initiated. Attention should be paid to restriction o phosphate ciency must be considered in the di erential diagnosis
in the diet; avoidance o aluminum-containing phosphate- o mild hypocalcemia.
binding antacids to prevent the problem o aluminum intoxi- Mild hypocalcemia, secondary hyperparathyroidism,
cation; provision o an adequate calcium intake by mouth, severe hypophosphatemia, and a variety o nutritional
usually 1–2 g/d; and supplementation with 0.25–1 µg/d cal- de ciencies occur with gastrointestinal diseases. Hepa-
citriol or other activated orms o vitamin D. Each patient must tocellular dys unction can lead to reduction in 25(OH)D
be monitored closely. T e aim o therapy is to restore normal levels, as in portal or biliary cirrhosis o the liver, and
calcium balance to prevent osteomalacia and severe second- malabsorption o vitamin D and its metabolites, includ-
ary hyperparathyroidism (it is usually recommended to main- ing 1,25(OH)2D, may occur in a variety o bowel diseases,
tain P H levels between 100 and 300 pg/mL) and, in light o hereditary or acquired. Hypocalcemia itsel can lead to

Ha rris on_Endocrinology_Ch34_p446-p479.indd 474 20/05/16 9:33 a m

 steatorrhea, due to de cient production o pancreatic
enzymes and bile salts. Depending on the disorder, vita-
min D or its metabolites can be given parenterally, guaran-
teeing adequate blood levels o active metabolites.
De e ctive vita m in D m eta b o lism
An tico n vu lsa n t th e ra p y
Anti-convulsant therapy with any o several agents
Vita m in D–d e p e n d e n t ricke ts t yp e II 475
Vitamin D–dependent rickets type II results rom end-
organ resistance to the active metabolite 1,25(OH)2D.
T e clinical eatures resemble those o the type I dis-
order and include hypocalcemia, hypophosphatemia,
secondary hyperparathyroidism, and rickets but also
partial or total alopecia. Plasma levels o 1,25(OH)2D
are elevated, in keeping with the re ractoriness o the
end organs. T is disorder is caused by mutations in the
gene encoding the vitamin D receptor; treatment is di -

C
induces acquired vitamin D de ciency by increasing the

H
A
conversion o vitamin D to inactive compounds and/or cult and requires regular, usually nocturnal calcium

P
T
causing resistance to its action. T e more marginal the in usions, which dramatically improve growth but do

E
R
vitamin D intake in the diet, the more likely that anti- not restore hair growth (Chap. 32).

3
4
convulsant therapy will lead to abnormal mineral and
bone metabolism. Pseu d o hyp o p a ra thyro id ism

D
i
Vita m in D–d e p e n d e n t ricke ts t yp e I

s
PHP re ers to a group o distinct inherited disorders.

o
r
d
Vitamin D–dependent rickets type I, previously termed Patients a ected by PHP type Ia (PHP-Ia) are character-

e
r
s
pseudo-vitamin D–resistant rickets, di ers rom true vita- ized by symptoms and signs o hypocalcemia in associa-

o
f
min D–resistant rickets (vitamin D–dependent rickets

t
tion with distinctive skeletal and developmental de ects.

h
e
type II, see below) in that it is typically less severe and T e hypocalcemia is due to a de cient response to

P
a
r
the biochemical and radiographic abnormalities can be

a
P H, which is probably restricted to the proximal renal

t
h
reversed with appropriate doses o the vitamin’s active

y
tubules. Hyperplasia o the parathyroids, a response to

r
o
metabolite, 1,25(OH)2D. Physiologic amounts o cal-

i
hormone-resistant hypocalcemia, causes elevation o

d
G
citriol cure the disease (Chap. 32). T is nding ts with

l
P H levels. Studies, both clinical and basic, have clari-

a
n
the pathophysiology o the disorder, which is autosomal

d
ed some aspects o these disorders, including the vari-

a
recessive, and is now known to be caused by mutations in

n
able clinical spectrum, the pathophysiology, the genetic

d
C
the gene encoding 25(OH)D-1α-hydroxylase. Both alleles de ects, and their mode o inheritance.

a
l
c
are inactivated in a ected patients, and compound het-

i
A working classi cation o the various orms o PHP

u
m
erozygotes, harboring distinct mutations, are common. is given in Table 34-6. T e classi cation scheme is based

H
o
Clinical eatures include hypocalcemia, o en with

m
on the signs o ine ective P H action (low calcium and

e
tetany or convulsions, hypophosphatemia, secondary

o
high phosphate), low or normal urinary cAMP response

s
t
hyperparathyroidism, and osteomalacia, o en associ-

a
to exogenous P H, the presence or absence o Albright’s

s
i
s
ated with skeletal de ormities and increased alkaline hereditary osteodystrophy (AHO), and assays to measure
phosphatase. reatment involves physiologic replace- the concentration o the Gsα subunit o the adenylate
ment doses o 1,25(OH)2D (Chap. 32). cyclase enzyme. Using these criteria, there are our types:

TABLE 3 4 -6
CLASSIFICATION OF PSEUDOHYPOPARATHYROIDISM (PHP) AND PSEUDOPSEUDOHYPOPARATHYROIDISM
(PPHP)
RESISTANCE
RESPONSE OF TO HORMONES
HYPOCALCEMIA, URINARY cAMP G Sα SUBUNIT OTHER THAN
TYPE HYPERPHOSPHATEMIA TO PTH SERUM PTH DEFICIENCY AHO PTH

PHP-Ia Yes ↓ ↑ Yes Yes Yes

PPHP No Normal Normal Yes Yes No
PHP-Ib Yes ↓ ↑ No No Yes (in some
patients)
PHP-II Yes Normal ↑ No No No
Acrodysostosis Yes Normal (but ↓ ↑ No Yes Yes
with hormonal phosphaturic
resistance response)

Ab brevia tio n s: ↓, decreased; ↑ , increased; AHO, Albright’s hereditary osteodystrophy; PTH, parathyroid hormone.

Ha rris on_Endocrinology_Ch34_p446-p479.indd 475 20/05/16 9:33 a m

 476 PHP types Ia and Ib; pseudopseudohypoparathyroidism thyroid; consequently, inheritance o a de ective pater-
(PPHP), and PHP-II. nal allele has no implications with regard to hormonal
unction. T us, emales a ected by either PHP-Ia or
PHP-IA a n d PHP-IB
PPHP will have o spring with PHP-Ia, i these chil-
Individuals with PHP-I, the most common o the dis-
dren inherit the allele carrying the GNAS mutation; in
orders, show a de cient urinary cAMP response to
contrast, i the mutant allele is inherited rom a male
administration o exogenous P H. Patients with PHP-I
a ected by either disorder, the o spring will exhibit
are divided into type Ia and type Ib. Patients with PHP-
PPHP. Consistent with these data in humans, gene-abla-
Ia show evidence or AHO and reduced amounts o Gsα
tion studies in mice have shown that inheritance o the
protein/activity, as determined in readily accessible tis-
mutant Gsα allele rom the emale causes much reduced
S
sues such as erythrocytes, lymphocytes, and broblasts.
E
Gsα protein in renal cortex, hypocalcemia, and resis-
C
T
Patients with PHP-Ib typically lack evidence or AHO
I
tance to P H. O spring inheriting the mutant allele
O
N
and they have normal Gsα activity. PHP-Ic, sometimes rom the male showed no evidence o P H resistance or
V
listed as a third orm o PHP-I, is really a variant o
I
hypocalcemia.
PHP-Ia, although the mutant Gsα shows normal activity Imprinting is tissue selective. Paternal Gsα expression
in certain in vitro assays.
is not silenced in most tissues. It seems likely, there ore,
D
Most patients who have PHP-Ia reveal characteristic
i
s
that the AHO phenotype recognized in PPHP as well as
o
r
eatures o AHO, which consist o short stature, round
d
PHP-Ia re ects Gsα haploinsu ciency during embry-
e
r
ace, obesity, skeletal anomalies (brachydactyly), intel-
s
onic or postnatal development.
o
f
lectual impairment, and/or heterotopic calci cations.
B
T e complex mechanisms that control the GNAS
o
n
Patients have low calcium and high phosphate levels, as
e
gene contribute to challenges involved in unraveling
a
with true hypoparathyroidism. P H levels, however, are
n
the pathogenesis o these disorders, especially that o
d
elevated, re ecting resistance to hormone action.
C
PHP-Ib. Much intensive work with amilies in which
a
l
Amorphous deposits o calcium and phosphate are
c
i
u
m
ound in the basal ganglia in about one-hal o patients.
M
T e de ects in metacarpal and metatarsal bones are
e
t
a
sometimes accompanied by short phalanges as well,
b
o
l
possibly re ecting premature closing o the epiphyses.
i
s
m
T e typical ndings are short ourth and h metacar-
pals and metatarsals. T e de ects are usually bilateral.
Exostoses and radius curvus are requent.

In h erita n ce a n d g en etic d e ects

Multiple de ects at the GNAS locus have now been iden-
ti ed in PHP-Ia, PHP-Ib, and PPHP patients. T is gene,
which is located on chromosome 20q13.3, encodes the
α-subunit o the stimulatory G protein (Gsα), among
other products (see below). Mutations include abnor-
malities in splice junctions associated with de cient
mRNA production, point mutations, insertions, and/
or deletion that all result in a protein with de ective
unction resulting in a 50% reduction o Gsα activity in
erythrocytes or other cells.
Detailed analyses o disease transmission in a ected
kindreds have clari ed many eatures o PHP-Ia, PPHP,
and PHP-Ib (Fig. 34-7). T e ormer two entities, o en
traced through multiple generations, have an inheri-
tance pattern consistent with genetic imprinting. T e
phenomenon o gene imprinting, involving methylation
o genetic loci, independent o any mutation, impairs
transcription rom either the maternal or the paternal
allele. T e Gsα transcript is biallelically expressed in
most tissues; expression rom paternal allele is silenced
through as-o -yet unknown mechanisms in some tis-
sues including the proximal renal tubules and the
P HP -Ia P HP P
Urina ry P TH (+ AHO) P TH (+ AHO)
cyclic AMP /
phos pha te
FIGURE 3 4 -7
Pa t e rn a l im p rin t in g o re n a l p a ra t h yro id h o rm o n e PTH
re sist a n ce . An impaired excretion o urinary cyclic AMP and
phosphate is observed in patients with pseudohypoparathyroid-
ism type Ia (PHP-Ia). In the renal cortex, there is selective silencing
o paternal Gsα expression. The disease becomes mani est only in
patients who inherit the de ective gene rom an obligate emale
carrier (left). I the genetic de ect is inherited rom an obligate
male gene carrier, there is no biochemical abnormality; admin-
istration o PTH causes an appropriate increase in the urinary
cyclic AMP and phosphate concentration (pseudo-PHP [PPHP];
right). Both patterns o inheritance lead to Albright’s hereditary
osteodystrophy (AHO), perhaps because o haplotype insuf -
ciency—i.e., both copies o Gsα must be active or normal bone
development.

Ha rris on_Endocrinology_Ch34_p446-p479.indd 476 20/05/16 9:33 a m

 multiple members are a ected by PHP-Ib, as well as
studies o the complex regulation o the GNAS gene
locus, have now shown that PHP-Ib is caused by micro-
deletions within or upstream o the GNAS locus, which
are associated with a loss o DNA methylation at one or
several loci o the maternal allele ( able 34-6). T ese
abnormalities in methylation silence the expression
o the gene. T is leads in the proximal renal tubules—
where Gsα appears to be expressed exclusively rom the
maternal allele—to P H resistance.
distal tubules—hence, urinary calcium clearance is typically 477
reduced, and they are not at risk o developing nephrocalci-
nosis as are patients with true hypoparathyroidism, unless
overtreatment occurs, or example, a er the completion o
pubertal development and skeletal mutation, when calcium
and 1,25(OH)2D treatment should be reduced. Variability in
response makes it necessary to establish the optimal regimen
or each patient, based on maintaining appropriate blood cal-
cium level and urinary calcium excretion and keeping the

C
P H level within or slightly above the normal range.

H
A
PHP-Ib, lacking the AHO phenotype in most instances,

P
T
shares with PHP-Ia the hypocalcemia and hyperphospha-

E
R
temia caused by P H resistance, and thus the blunted uri-

3
PTH OVERWHELMED

4
nary cAMP response to administered P H, a standard test
to assess the presence or absence o hormone resistance Occasionally, loss o calcium rom the ECF is so severe
( able 34-6). Furthermore, these endocrine abnormali- that P H cannot compensate. Such situations include

D
i
s
ties become apparent only i the disease-causing muta-

o
acute pancreatitis and severe, acute hyperphosphate-

r
d
tion is inherited maternally. Bone responsiveness may be

e
mia, o en in association with renal ailure, conditions

r
s
excessive rather than blunted in PHP-Ib (and in PHP-Ia)

o
in which there is rapid ef ux o calcium rom the ECF.

f
t
patients, based on case reports that have emphasized an

h
Severe hypocalcemia can occur quickly; P H rises in

e
P
osteitis brosa–like pattern in several PHP-Ib patients. response to hypocalcemia but does not return blood

a
r
a
PHP-II re ers to patients with hypocalcemia and calcium to normal.

t
h
y
hyperphosphatemia, who have a normal urinary cAMP

r
o
i
d
but an impaired urinary phosphaturic response to

G
Severe, a cu te hyp erp h o sp h a tem ia

l
P H. In a PHP-II variant, re erred to as acrodysosto-

a
n
d
sis with hormonal resistance (ADOHR), patients have Severe hyperphosphatemia is associated with extensive

a
n
a de ect in the regulatory subunit o PKA (PRKAR1A) tissue damage or cell destruction (Chap. 32). T e com-

d
C
a
that mediates the response to P H distal to cAMP pro- bination o increased release o phosphate rom muscle

l
c
i
u
duction. Acrodysostosis without hormonal resistance and impaired ability to excrete phosphorus because o

m
is caused by mutations in the cAMP-selective phos- renal ailure causes moderate to severe hyperphosphate-

H
o
m
phodiesterase 4 (ADOP4). It remains unclear why the mia, the latter causing calcium loss rom the blood and

e
o
P H-resistance in some patients, labeled as PHP-II mild to moderate hypocalcemia. Hypocalcemia is usu-

s
t
a
without bony abnormalities, resolves upon treatment ally reversed with tissue repair and restoration o renal

with vitamin D supplements.
T e diagnosis o these hormone-resistant states can
usually be made without di culty when there is a posi-
tive amily history or eatures o AHO, in association
with the signs and symptoms o hypocalcemia. In both
categories—PHP-Ia and PHP-Ib—serum P H levels
are elevated, particularly when patients are hypocalce-
mic. However, patients with PHP-Ib or PHP-II with-
out acrodysostosis present only with hypocalcemia and
high P H levels, as evidence or hormone resistance. In
PHP-Ia and PHP-Ib, the response o urinary cAMP to
the administration o exogenous P H is blunted. T e
diagnosis o PHP-II, in the absence o acrodysostosis,
is more complex, and vitamin D de ciency must be
excluded be ore such a diagnosis can be entertained.
s
i
s
unction as phosphorus and creatinine values return
to normal. T ere may even be a mild hypercalcemic
period in the oliguric phase o renal unction recovery.
T is sequence, severe hypocalcemia ollowed by mild
hypercalcemia, re ects widespread deposition o cal-
cium in muscle and subsequent redistribution o some
o the calcium to the ECF a er phosphate levels return
to normal.
Other causes o hyperphosphatemia include
hypothermia, massive hepatic ailure, and hemato-
logic malignancies, either because o high cell turn-
over o malignancy or because o cell destruction by
chemotherapy.

TREATMENT Severe, Acute Hyperphosphatemia

TREATMENT Pseudohypoparathyroidism reatment is directed toward lowering o blood phosphate by

the administration o phosphate-binding antacids or dialy-
reatment o PHP is similar to that o hypoparathyroid- sis, o en needed or the management o CKD. Although
ism, except that calcium and vitamin D doses are usually calcium replacement may be necessary i hypocalcemia is
higher. Patients with PHP show no P H-resistance in the severe and symptomatic, calcium administration during the

Ha rris on_Endocrinology_Ch34_p446-p479.indd 477 20/05/16 9:33 a m

 478 hyperphosphatemic period tends to increase extraosseous or ine ective vitamin D, thereby impairing the action
calcium deposition and aggravate tissue damage. T e levels o P H on calcium metabolism (but not phosphate
o 1,25(OH)2D may be low during the hyperphosphatemic clearance). T e relative ine ectiveness o P H in cal-
phase and return to normal during the oliguric phase o cium homeostasis in vitamin D de ciency, anticonvul-
recovery. sant therapy, gastrointestinal disorders, and hereditary
de ects in vitamin D metabolism leads to secondary
hyperparathyroidism as a compensation. T e excess
Osteitis f bro sa a ter p a ra thyro id e cto my P H on renal tubule phosphate transport accounts or
Severe hypocalcemia a er parathyroid surgery is rare renal phosphate wasting and hypophosphatemia.
Exceptions to these patterns may occur. Most orms
S
now that osteitis brosa cystica is an in requent mani-
E
o hypomagnesemia are due to long-standing nutri-
C
estation o hyperparathyroidism. When osteitis brosa
T
I
tional de ciency as seen in chronic alcoholics. Despite
O
cystica is severe, however, bone mineral de cits can be
N
the act that the hypocalcemia is principally due to an
V
large. A er parathyroidectomy, hypocalcemia can per-
I
sist or days i calcium replacement is inadequate. reat- acute absence o P H, phosphate levels are usually
ment may require parenteral administration o calcium; low, rather than elevated, as in hypoparathyroidism.
Chronic renal ailure is o en associated with hypo-
D
addition o calcitriol and oral calcium supplementation
i
s
calcemia and hyperphosphatemia, despite secondary
o
is sometimes needed or weeks to a month or two until
r
d
hyperparathyroidism.
e
bone de ects are lled (which, o course, is o therapeu-
r
s
Diagnosis is usually established by application o the
o
tic bene t in the skeleton), making it possible to discon-
f
B
P H immunoassay, tests or vitamin D metabolites, and
o
tinue parenteral calcium and/or reduce the amount.
n
e
measurements o the urinary cAMP response to exog-
a
n
enous P H. In hereditary and acquired hypoparathy-
d
C
roidism and in severe hypomagnesemia, P H is either
a
l
c
DIFFERENTIAL DIAGNOSIS OF
i
undetectable or inappropriately in the normal range
u
m
HYPOCALCEMIA (Fig. 34-4). T is nding in a hypocalcemic patient is
M
e
supportive o hypoparathyroidism, as distinct rom
t
Care must be taken to ensure that true hypocalcemia is
a
b
ine ective P H action, in which even mild hypocal-
o
present; in addition, acute transient hypocalcemia can
l
i
s
cemia is associated with elevated P H levels. Hence
m
be a mani estation o a variety o severe, acute illnesses,
as discussed above. Chronic hypocalcemia, however, can a ailure to detect elevated P H levels establishes the
usually be ascribed to a ew disorders associated with diagnosis o hypoparathyroidism; elevated levels sug-
absent or ine ective P H. Important clinical criteria gest the presence o secondary hyperparathyroidism, as
include the duration o the illness, signs or symptoms ound in many o the situations in which the hormone
o associated disorders, and the presence o eatures that is ine ective due to associated abnormalities in vitamin
suggest a hereditary abnormality. A nutritional history D action. Assays or 25(OH)D can be help ul. Low or
can be help ul in recognizing a low intake o vitamin low-normal 25(OH)D indicates vitamin D de ciency
D and calcium in the elderly, and a history o excessive due to lack o sunlight, inadequate vitamin D intake, or
alcohol intake may suggest magnesium de ciency. intestinal malabsorption. Recognition that mild hypo-
Hypoparathyroidism and PHP are typically li e- calcemia, rickets, and hypophosphatemia are due to
long illnesses, usually (but not always) appearing by anticonvulsant therapy is made by history.
adolescence; hence, a recent onset o hypocalcemia
in an adult is more likely due to nutritional de cien-
cies, renal ailure, or intestinal disorders that result in TREATMENT HypocalcemicStates
de cient or ine ective vitamin D. Neck surgery, even
long past, however, can be associated with a delayed T e management o hypoparathyroidism, PHP, chronic renal
onset o postoperative hypoparathyroidism. A history ailure, and hereditary de ects in vitamin D metabolism
o seizure disorder raises the issue o anticonvulsive involves the use o vitamin D or vitamin D metabolites and
medication. Developmental de ects may point to the calcium supplementation. Vitamin D itsel is the least expen-
diagnosis o PHP. Rickets and a variety o neuromus- sive orm o vitamin D replacement and is requently used in
cular syndromes and de ormities may indicate ine ec- the management o uncomplicated hypoparathyroidism and
tive vitamin D action, either due to de ects in vitamin D some disorders associated with ine ective vitamin D action.
metabolism or to vitamin D de ciency. When vitamin D is used prophylactically, as in the elderly
A pattern o low calcium with high phosphorus in the or in those with chronic anticonvulsant therapy, there is a
absence o renal ailure or massive tissue destruction wider margin o sa ety than with the more potent metabo-
almost invariably means hypoparathyroidism or PHP. A lites. However, most o the conditions in which vitamin D is
low calcium and low phosphorus pattern points to absent administered chronically or hypocalcemia require amounts

Ha rris on_Endocrinology_Ch34_p446-p479.indd 478 20/05/16 9:33 a m

 50–100 times the daily replacement dose because the orma-
tion o 1,25(OH)2D is de cient. In such situations, vitamin D
is no sa er than the active metabolite because intoxication can
occur with high-dose therapy (because o storage in at). Cal-
citriol is more rapid in onset o action and also has a short
biologic hal -li e.
Vitamin D (at least 1000 U/d [2–3 µg/d] [higher lev-
els required in older persons]) or calcitriol (0.25–1 µg/d) is
required to prevent rickets in normal individuals. In contrast,
also used in disorders o 25(OH)D-1α-hydroxylase; vitamin 479
D receptor de ects are much more di cult to treat.
Patients with hypoparathyroidism should be given 2–3 g
o elemental calcium PO each day. T e two agents, vitamin
D or calcitriol and oral calcium, can be varied independently.
Urinary calcium excretion needs to be monitored care ully.
I hypocalcemia alternates with episodes o hypercalcemia in
high-brittleness patients with hypoparathyroidism, adminis-
tration o calcitriol and use o thiazides, as discussed above,

C
40,000–120,000 U (1–3 mg) o vitamin D2 or D3 is typically may make management easier. Clinical trials with P H(1–

H
A
required in hypoparathyroidism. T e dose o calcitriol is 34) or P H(1–84) are promising, but these alternative treat-

P
T
unchanged in hypoparathyroidism, because the de ect is in ments have not yet been approved.

E
R
hydroxylation by the 25(OH)D-1α-hydroxylase. Calcitriol is

3
4
D
i
s
o
r
d
e
r
s
o
f
t
h
e
P
a
r
a
t
h
y
r
o
i
d
G
l
a
n
d
a
n
d
C
a
l
c
i
u
m
H
o
m
e
o
s
t
a
s
i
s
Ha rris on_Endocrinology_Ch34_p446-p479.indd 479 20/05/16 9:33 a m
 CH AP TER 3 5
OSTEOPOROSIS
Ro b e rt Lin d say
Osteoporosis, a condition characterized by decreased
bone strength, is prevalent among postmenopausal
women but also occurs in men and women with under-
lying conditions or major risk actors associated with
bone demineralization. Its chie clinical mani estations
are vertebral and hip ractures, although ractures can
occur at almost any skeletal site. Osteoporosis a ects
almost 10 million individuals in the United States, but
only a small proportion are diagnosed and treated.
DEFINITIO N
Osteoporosis is de ned as a reduction in the strength o
bone that leads to an increased risk o ractures. Loss
o bone tissue is associated with deterioration in skel-
etal microarchitecture. T e World Health Organization
(WHO) operationally de nes osteoporosis as a bone
density that alls 2.5 standard deviations (SD) below the
mean or young healthy adults o the same sex—also
re erred to as a T-score o –2.5. Postmenopausal women
who all at the lower end o the young normal range (a
-score <–1.0) are de ned as having low bone density
and are also at increased risk o osteoporosis. Although
risk is lower in this group, more than 50% o ractures
among postmenopausal women, including hip ractures,
occur in this group with low bone density, because the
number o individuals in this category is so much larger
than that in the osteoporosis range. As a result, there are
ongoing attempts to identi y individuals within the low
bone density range who are at high risk o racture and
might bene t rom pharmacologic intervention. Fur-
thermore, some have advocated using racture risk as the
“diagnostic” criterion or osteoporosis.
EP IDEMIO LO GY
In the United States, as many as 9 million adults have
osteoporosis ( -score <–2.5 in either spine or hip),
Ha rris on_Endocrinology_Ch35_p480-p502.indd 480
■ Fe licia Co sm a n
and an additional 48 million individuals have bone
mass levels that put them at increased risk o devel-
oping osteoporosis (e.g., bone mass -score <–1.0).
Osteoporosis occurs more requently with increas-
ing age as bone tissue is lost progressively. In women,
the loss o ovarian unction at menopause (typically
about age 50) precipitates rapid bone loss so that
most women meet the diagnostic criterion or osteo-
porosis by age 70–80. As the population continues to
age, the number o individuals with osteoporosis and
ractures will also continue to increase, despite a rec-
ognized reduction in age-speci c risk. It is estimated
that about 2 million ractures occur each year in the
United States as a consequence o osteoporosis, and
that number is expected to increase as the population
continues to age.
T e epidemiology o ractures ollows the trend
or loss o bone density, with exponential increases in
both hip and vertebral ractures with age. Fractures o
the distal radius have a somewhat di erent epidemiol-
ogy, increasing in requency be ore age 50 and plateau-
ing by age 60, with only a modest age-related increase
therea er. In contrast, incidence rates or hip ractures
double every 5 years a er age 70 (Fig. 35-1). T is dis-
tinct epidemiology may be related to the way the elderly
all as they age, with ewer alls on an outstretched hand
and more alls directly on the hip. About 300,000 hip
ractures occur each year in the United States, most o
which require hospital admission and surgical interven-
tion. T e probability that a 50-year-old white individual
will have a hip racture during his or her li etime is 14%
or women and 5% or men; the risk or A rican Ameri-
cans is lower (about one-hal those rates), and the risk
or Asians is roughly equal to that or whites. Hip rac-
tures are associated with a high incidence o deep vein
thrombosis and pulmonary embolism (20–50%) and a
mortality rate between 5 and 20% during the year a er
surgery. T ere is also signi cant morbidity, with about
20–40% o survivors requiring long-term care, and
480
20/05/16 9:36 a m
 Wome n to height loss (o en o several inches), kyphosis, and 481
3,000 secondary pain and discom ort related to altered bio-
Hip mechanics o the back. T oracic ractures can be asso-
ciated with restrictive lung disease, whereas lumbar
r
a
e
y
ractures are associated with abdominal symptoms that
-
n
o
include distention, early satiety, and constipation.
s
2,000
r
e
Ve rte bra e
Approximately 400,000 wrist ractures and 135,000
p
0
0
pelvic ractures occur in the United States each year.
0
,
0
Fractures o the humerus and other bones (estimated to
0
1
/
C
be about 675,000 per year) also occur with osteoporo-
e
c
H
n
1,000

A
sis; this is not surprising in light o the act that bone
e
d
P
i
c
T
loss is a systemic phenomenon. Although some rac-
n
E
I
R
tures result rom major trauma, the threshold or rac-

3
Colle s ’

5
ture is reduced or an osteoporotic bone (Fig. 35-3). In
addition to bone density, there are a number o risk ac-
35–39 ≥85
tors or racture; the common ones are summarized in

O
Age group, ye a r

s
t
Table 35-1 Age, prior ractures (especially recent rac-

e
o
FIGURE 3 5 -1

p
tures), a amily history o osteoporosis-related ractures,

o
r
Ep id e m io lo g y o ve r t e b ra l, h ip , a n d Co lle s’ ra ct u re s wit h

o
low body weight, smoking, and excessive alcohol use

a g e . (Adapted from C Cooper, LJ Melton III: Trends Endocrinol Metab
3:224, 1992; with permission.)
many who are unable to unction as they did be ore the
racture.
T ere are about 550,000 vertebral crush ractures per
year in the United States. Only a raction (estimated to
be one-third) o them are recognized clinically, because
many are relatively asymptomatic and are identi ed
incidentally during radiography or other purposes
(Fig. 35-2). Vertebral ractures rarely require hospital-
ization but are associated with long-term morbidity and
a slight increase in mortality rates, primarily related to
pulmonary disease. Multiple vertebral ractures lead
s
i
s
are all independent predictors o racture. Chronic dis-
eases with in ammatory components that increase skel-
etal remodeling such as rheumatoid arthritis, increase
the risk o osteoporosis, as do diseases associated with
malabsorption. Chronic diseases that increase the risk
o alling or railty, including dementia, Parkinson’s dis-
ease, and multiple sclerosis, also increase racture risk.
In the United States and Europe, osteoporosis-related
ractures are more common among women than men,
presumably due to a lower peak bone mass as well as
postmenopausal bone loss in women. However, this sex
di erence in bone density and age-related increase in
hip ractures is not as apparent in some other cultures,
possibly due to genetics, physical activity level, or diet.
Fractures are themselves risk actors or uture rac-
tures ( able 35-1). Vertebral ractures increase the risk
o other vertebral ractures as well as ractures o the
peripheral skeleton such as the hip and wrist. Wrist rac-
tures also increase the risk o vertebral and hip ractures.
T e risk or subsequent ractures is particularly high in
the rst several years a er the rst racture, and the risk

FACTORS LEADING TO FRACTURE

Othe r ris k
Aging Me nopa us e
fa ctors

Incre a s e d Low pe a k
bone los s bone ma s s
Low bone
de ns ity

Prope ns ity Poor bone

to fa ll qua lity
Fra cture s
FIGURE 3 5 -2
La t e ra l sp in e x-ra y showing severe osteopenia and a severe FIGURE 3 5 -3
wedge-type de ormity (severe anterior compression). Fa ct o rs le a d in g t o o st e o p o ro t ic ra ct u re s.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 481 20/05/16 9:36 a m

 482 TABLE 3 5 -1
CONDITIONS, DISEASES, AND MEDICATIONS THAT CONTRIBUTE TO OSTEOPOROSIS AND FRACTURES
Li e st yle a cto rs
Alcohol abuse High salt intake Falling
Low calcium intake Inadequate physical activity Excessive thinness
Vitamin D insu ciency Immobilization Prior ractures
Excess vitamin A Smoking (active or passive)
Ge n e t ic a ct o rs
Cystic brosis Homocystinuria Osteogenesis imper ecta
Ehlers-Danlos syndrome Hypophosphatasia Parental history o hip racture
S
E
Gaucher’s disease Idiopathic hypercalciuria Porphyria
C
T
Glycogen storage diseases Mar an’s syndrome Riley-Day syndrome
I
O
Hemochromatosis Menkes’steely hair syndrome
N
V
Hyp o g o n a d a l st a t e s
I
Androgen insensitivity Hyperprolactinemia Athletic amenorrhea
Anorexia nervosa and bulimia Premature menopause Panhypopituitarism
Premature ovarian ailure
D
i
s
Turner’s & Kline elter’s syndromes
o
r
d
En d o crin e d iso rd e rs
e
r
s
o
Adrenal insu ciency Cushing’s syndrome Central adiposity
f
B
Diabetes mellitus (types 1 and 2) Hyperparathyroidism Thyrotoxicosis
o
n
e
Ga st ro in t e st in a l d iso rd e rs
a
n
Celiac disease In ammatory bowel disease Primary biliary cirrhosis
d
C
Gastric bypass Malabsorption
a
l
c
Gastrointestinal surgery Pancreatic disease
i
u
m
He m a to lo g ic d iso rd e rs
M
e
Multiple myeloma Monoclonal gammopathies Sickle cell disease
t
a
b
Hemophilia Leukemia and lymphomas Systemic mastocytosis
o
l
Thalassemia
i
s
m
Rh e u m a t o lo g ic a n d a u t o im m u n e d ise a se s
Ankylosing spondylitis Lupus Rheumatoid arthritis
Other rheumatic and autoimmune diseases
Ce n t ra l n e rvo u s syst e m d iso rd e rs
Epilepsy Parkinson’s disease Stroke
Multiple sclerosis Spinal cord injury
Misce lla n e o u s co n d it io n s a n d d ise a se s
AIDS/HIV Congestive heart ailure Posttransplant bone disease
Alcoholism Depression Sarcoidosis
Amyloidosis End-stage renal disease
Weight loss
Chronic metabolic acidosis Hypercalciuria
Chronic obstructive lung disease Idiopathic scoliosis
Muscular dystrophy
Me d ica t io n s
Aluminum (in antacids) Glucocorticoids (≥5 mg/d prednisone or Tamoxi en (premenopausal use)
Anticoagulants (heparin) equivalent or ≥3 months) Thiazolidinediones (such as pioglitazone
Anticonvulsants Gonadotropin-releasing hormone antag- and rosiglitazone)
Aromatase inhibitors onists and agonists Thyroid hormones (in excess)
Barbiturates Lithium Parenteral nutrition
Cancer chemotherapeutic drugs Methotrexate
Cyclosporine A and tacrolimus Proton pump inhibitors
Depo-medroxyprogesterone (premeno- Selective serotonin reuptake inhibitors
pausal contraception)

So u rce: From the 2014 National Osteoporosis Foundation Clinician’s Guide to the Prevention and Treatment o Osteoporosis. © National Osteoporosis
Foundation.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 482 20/05/16 9:36 a m

 wanes considerably therea er. Consequently, among
individuals over age 50, any racture should be consid-
ered as potentially related to osteoporosis regardless o
the circumstances o the racture. Osteoporotic bone is
more likely to racture than normal bone at any level o
trauma, and a racture in a person over 50 should trig-
ger evaluation or osteoporosis. T is o en does not occur
because post racture care is not always well coordinated.
ormation, activation, and li e span as well as suppres- 483
sion o osteoclast activity, thereby increasing bone or-
mation. T e osteocyte product, sclerostin, is a negative
inhibitor o Wnt signaling.
Pre os te ocla s t

C
H
PATHO P HYSIO LO GY

A
P
BMU

T
E
A
BONE REMODELING

R
3
Pre os te obla s t

5
Osteoporosis results rom bone loss due to age-related
changes in bone remodeling as well as extrinsic and
intrinsic actors that exaggerate this process. T ese

O
s
t
changes may be superimposed on a low peak bone

e
o
p
mass. Consequently, understanding the bone remodel-

o
Os te ocla s t

r
B

o
ing process is undamental to understanding the patho-

s
i
s
physiology o osteoporosis (Chap. 32). During growth,
the skeleton increases in size by linear growth and by
apposition o new bone tissue on the outer sur aces o
the cortex (Fig. 35-4). T e latter process is called mod- C Os te obla s ts
eling, a process that also allows the long bones to adapt Os te oid
in shape to the stresses placed on them. Increased sex
hormone production at puberty is required or skeletal
maturation, which reaches maximum mass and density
in early adulthood. It is around puberty that the sexual
dimorphism in skeletal size becomes obvious, although D
true bone density remains similar between the sexes.
Nutrition and li estyle also play an important role in
growth, although genetic actors primarily determine
peak skeletal mass and density. Numerous genes control
skeletal growth, peak bone mass, and body size, as well E
as skeletal structure and density. Heritability estimates
o 50–80% or bone density and size have been derived
on the basis o twin studies. Although peak bone mass
is o en lower among individuals with a amily his-
F
tory o osteoporosis, association studies o candidate
genes (vitamin D receptor; type I collagen, the estrogen
FIGURE 3 5 -4
receptor [ER], and interleukin 6 [IL-6]; and insulin-like
Me ch a n ism o b o n e re m o d e lin g . The basic molecular unit
growth actor I [IGF-I]) and bone mass, bone turnover,
(BMU) moves along the trabecular sur ace at a rate o about
and racture prevalence have been inconsistent. Link-
10 µm/d. The gure depicts remodeling over ~120 days. A.
age studies suggest that a genetic locus on chromosome Origination o BMU-lining cells contracts to expose collagen and
11 is associated with high bone mass. Families with attract preosteoclasts. B. Osteoclasts use into multinucleated
high bone mass and without much apparent age-related cells that resorb a cavity. Mononuclear cells continue resorption,
bone loss have been shown to have a point mutation in and preosteoblasts are stimulated to proli erate. C. Osteoblasts
LRP5, a low-density lipoprotein receptor–related pro- align at bottom o cavity and start orming osteoid (black). D.
tein. T e role o this gene in the general population is Osteoblasts continue ormation and mineralization. Previous
not clear, although a non unctional mutation results in osteoid starts to mineralize (horizontal lines). E. Osteoblasts begin
osteoporosis-pseudoglioma syndrome, and LRP5 sig- to atten. F. Osteoblasts turn into lining cells; bone remodeling
naling appears to be important in controlling bone or- at initial sur ace (left of drawing) is now complete, but BMU is still
mation. LRP5 acts through the Wnt signaling pathway. advancing (to the right). (Adapted from SM Ott, in JP Bilezikian et al
With LRP5 and Wnt activation, beta-catenin is translo- [eds]: Principles of Bone Biology, vol. 18. San Diego, Academic Press,
cated to the nucleus, allowing stimulation o osteoblast 1996, pp 231–241.)

Ha rris on_Endocrinology_Ch35_p480-p502.indd 483 20/05/16 9:36 a m

 484 Genome-wide scans or low bone mass suggest mul- prostaglandins, and members o the tumor necro-
tiple genes are involved, many o which are also impli- sis actor ( NF) super amily. T ese actors primar-
cated in control o body size. ily modulate the rate at which new remodeling sites
In adults, bone remodeling, not modeling, is the are activated, a process that results initially in bone
principal metabolic skeletal process. Bone remodeling resorption by osteoclasts, ollowed by a period o
has two primary unctions: (1) to repair microdamage repair during which new bone tissue is synthesized by
within the skeleton to maintain skeletal strength and osteoblasts. T e cytokine responsible or communica-
ensure the relative youth o the skeleton and (2) to sup- tion between the osteoblasts, other marrow cells, and
ply calcium rom the skeleton to maintain serum cal- osteoclasts is RANK ligand (RANKL; receptor activa-
cium. Remodeling may be activated by microdamage tor o nuclear actor-κB [NF-κB]). RANKL, a mem-
S
E
to bone as a result o excessive or accumulated stress. ber o the NF amily, is secreted by osteoblasts and
C
T
I
Acute demands or calcium involve osteoclast-medi- certain cells o the immune system (Chap. 32). T e
O
N
ated resorption as well as calcium transport by osteo- osteoclast receptor or this protein is re erred to as
V
I
cytes. Chronic demands or calcium result in secondary RANK. Activation o RANK by RANKL is a nal com-
hyperparathyroidism, increased bone remodeling, and mon path in osteoclast development, activation, and
overall loss o bone tissue. li e span. A humoral decoy or RANKL, also secreted
D
i
s
Bone remodeling also is regulated by several cir- by osteoblasts, is osteoprotegerin (Fig. 35-5). Modula-
o
r
d
culating hormones, including estrogens, androgens, tion o osteoclast recruitment and activity appears to
e
r
s
vitamin D, and parathyroid hormone (P H), as well be related to the interplay among these three actors.
o
f
B
as locally produced growth actors such as IGF-I and It appears that estrogens are pivotal in modulating
o
n
e
immunoreactive growth hormone II (IGH-II), trans- secretion o osteoprotegerin (OPG) and perhaps also
a
n
orming growth actor β ( GF-β), parathyroid hor- RANKL. Additional in uences include nutrition (par-
d
C
mone–related peptide (P HrP), interleukins (ILs), ticularly calcium intake) and physical activity level.
a
l
c
i
u
m
M
A CFU-GM B
e
OP G
t
Activa te d
a
RANKL Activa te d T
b
synovia l
o
lymphocyte s M-CS F M-CS F
l
RANK
i
fibrobla s ts
s
m
Pre os te ocla s t

Activa te d
de ndritic
ce lls

T T
Multinucle a te d
os te ocla s t

Os te obla s ts or bone Bone

ma rrow s troma l ce lls Activa te d Apoptotic
os te ocla s t os te ocla s t

Prore s orptive a nd 1,25(OH)2 vita min D3 . P TH, P THrP, P GE 2 , IL-1, Ana bolic or a nti- Es troge ns, ca lcitonin, BMP 2/4, TGF-β, TP O, IL-17,
ca lciotropic fa ctors IL-6, TNF, prola ctin, corticos te roids, oncos ta tin M, LIF re s orptive fa ctors P DGF, ca lcium

FIGURE 3 5 -5
Ho rm o n a l co n t ro l o b o n e re so rp t io n . A. Proresorptive
and calciotropic actors. B. Anabolic and antiosteoclastic ac-
tors. RANK ligand (RANKL) expression is induced in osteo-
blasts, activated T cells, synovial broblasts, and bone marrow
stromal cells. It binds to membrane-bound receptor RANK to
promote osteoclast dif erentiation, activation, and survival.
Conversely, osteoprotegerin (OPG) expression is induced by
actors that block bone catabolism and promote anabolic
ef ects. OPG binds and neutralizes RANKL, leading to a block
in osteoclastogenesis and decreased survival o preexisting
osteoclasts. CFU-GM, colony- orming units, granulocyte mac-
rophage; IL, interleukin; LIF, leukemia inhibitory actor; M-CSF,
macrophage colony-stimulating actor; OPG-L, osteoprotegerin-
ligand; PDGF, platelet-derived growth actor; PGE2, prostaglan-
din E2; PTH, parathyroid hormone; RANKL, receptor activator o
nuclear actor nuclear actor-κB; TGF-β, trans orming growth
actor β; TNF, tumor necrosis actor; TPO, thrombospondin.
(From WJ Boyle et al: Nature 423: 337, 2003.)

Ha rris on_Endocrinology_Ch35_p480-p502.indd 484 20/05/16 9:36 a m

 In young adults, resorbed bone is replaced by an
equal amount o new bone tissue. T us, the mass o
the skeleton remains constant a er peak bone mass is
achieved in adulthood. A er age 30–45, however, the
resorption and ormation processes become imbal-
anced, and resorption exceeds ormation. T is imbal-
ance may begin at di erent ages and varies at di erent
skeletal sites; it becomes exaggerated in women a er
menopause. Excessive bone loss can be due to an
increase in osteoclastic activity and/or a decrease in
osteoblastic activity. In addition, an increase in remod-
eling activation requency, and thus the number o
remodeling sites, can magni y the small imbalance
seen at each remodeling unit. Increased recruitment o
bone remodeling sites produces a reversible reduction
in bone tissue but also can result in permanent loss o
tissue and disrupted skeletal architecture. In trabecu-
lar bone, i the osteoclasts penetrate trabeculae, they
leave no template or new bone ormation to occur, and,
consequently, rapid bone loss ensues and cancellous
connectivity becomes impaired. A higher number o
remodeling sites increases the likelihood o this event.
In cortical bone, increased activation o remodeling
creates more porous bone. T e e ect o this increased
porosity on cortical bone strength may be modest i the
overall diameter o the bone is not changed. However,
decreased apposition o new bone on the periosteal
sur ace coupled with increased endocortical resorp-
tion o bone decreases the biomechanical strength o
long bones. Even a slight exaggeration in normal bone
loss increases the risk o osteoporosis-related ractures
because o the architectural changes that occur, and
osteoporosis is primarily a disease o disordered skeletal
architecture. T e main clinically available tool (dual-
energy x-ray absorptiometry) measures mass not archi-
tecture. Emerging data rom high-resolution peripheral
quantitative computed tomography (C ) scans suggest
that aging is associated with changes in microstructure
o bone tissue, including increased cortical porosity and
reduced cortical thickness.
CALCIUM NUTRITION
Peak bone mass may be impaired by inadequate cal-
cium intake during growth among other nutritional ac-
tors (calories, protein, and other minerals), leading to
increased risk o osteoporosis later in li e. During the
adult phase o li e, insu cient calcium intake contrib-
utes to relative secondary hyperparathyroidism and an
increase in the rate o bone remodeling to maintain nor-
mal serum calcium levels. P H stimulates the hydrox-
ylation o vitamin D in the kidney, leading to increased
levels o 1,25-dihydroxyvitamin D [1,25(OH)2D] and
enhanced gastrointestinal calcium absorption. P H
also reduces renal calcium loss. Although these are all
Ha rris on_Endocrinology_Ch35_p480-p502.indd 485
appropriate compensatory homeostatic responses or 485
adjusting calcium economy, the long-term e ects are det-
rimental to the skeleton because the increased remodel-
ing rates and the ongoing imbalance between resorption
and ormation at remodeling sites combine to accelerate
loss o bone tissue.
otal daily calcium intakes <400 mg are detrimental
to the skeleton, and intakes in the range o 600–800 mg,
which is about the average intake among adults in the
C
United States, are also probably suboptimal. T e rec-
H
A
ommended daily required intake o 1000–1200 mg or
P
T
adults accommodates population heterogeneity in con-
E
R
trolling calcium balance. Such intakes should pre er-
3
5
entially come rom dietary sources, and supplements
should be used only when dietary intakes all short. T e
supplement should contain enough calcium to bring
O
s
t
total intake to about 1200 mg/d.
e
o
p
o
r
o
s
i
s
VITAMIN D
(See also Chap. 32) Severe vitamin D de ciency causes
rickets in children and osteomalacia in adults. However,
there is accumulating evidence that vitamin D insu -
ciency may be more prevalent than previously thought,
particularly among individuals at increased risk such as
the elderly; those living in northern latitudes; and indi-
viduals with poor nutrition, malabsorption, or chronic
liver or renal disease. Dark-skinned individuals are also
at high risk o vitamin D de ciency. T ere is controversy
regarding optimal levels o serum 25-hydroxy-vitamin
D [25(OH)D], with some advocating levels >20 ng/
mL and others advocating optimal targets >75 nmol/L
(30 ng/mL). o achieve this level or most adults requires
an intake o 800–1000 units/d, particularly in individuals
who avoid sunlight or routinely use ultra-violet-blocking
lotions. Vitamin D insu ciency leads to compensatory
secondary hyperparathyroidism and is an important risk
actor or osteoporosis and ractures. Some studies have
shown that >50% o inpatients on a general medical ser-
vice exhibit biochemical eatures o vitamin D de ciency,
including increased levels o P H and alkaline phospha-
tase and lower levels o ionized calcium. In women living
in northern latitudes, vitamin D levels decline during the
winter months. T is is associated with seasonal bone loss,
re ecting increased bone turnover. Even among healthy
ambulatory individuals, mild vitamin D de ciency is
increasing in prevalence, in part due to decreased expo-
sure to sunlight coupled with increased use o potent
sunscreens. reatment with vitamin D can return levels
to normal and prevent the associated increase in bone
remodeling, bone loss, and ractures. Improved muscle
unction and gait associated with reduced alls and rac-
ture rates also have been documented among individu-
als in northern latitudes who have greater vitamin D
intake and higher 25(OH)D levels (see below). Vitamin
20/05/16 9:36 a m
 486 D adequacy also may a ect risk and/or severity o other have higher bone mass than does the general popula-
diseases, including cancers (colorectal, prostate, and tion. T ese changes in skeletal mass are most marked
breast), autoimmune diseases, and diabetes; however, when the stimulus begins during growth and be ore
many observational studies suggesting these potential the age o puberty. Adults are less capable than chil-
extraskeletal bene ts have not been con rmed with ran- dren o increasing bone mass a er restoration o physi-
domized controlled trials. cal activity. Epidemiologic data support the bene cial
e ects on the skeleton o chronic high levels o physi-
cal activity. Fracture risk is lower in rural communities
ESTROGEN STATUS and in countries where physical activity is maintained
into old age. However, when exercise is initiated during
S
Estrogen de ciency probably causes bone loss by two
E
adult li e, the e ects o moderate exercise on the skel-
C
distinct but interrelated mechanisms: (1) activation o
T
I
eton are modest, with a bone mass increase o 1–2% in
O
new bone remodeling sites and (2) exaggeration o the
N
short-term studies o <2 years in duration. It is argued
V
imbalance between bone ormation and resorption. T e
I
change in activation requency causes a transient bone that more active individuals are less likely to all and
loss until a new steady state between resorption and or- are more capable o protecting themselves upon alling,
thereby reducing racture risk.
D
mation is achieved. T e remodeling imbalance, however,
i
s
o
results in a permanent decrement in mass. In addition,
r
d
e
the very presence o more remodeling sites in the skel-
r
s
CHRONIC DISEASE
o
eton increases the probability that trabeculae will be pen-
f
B
o
etrated, eliminating the template on which new bone can Various genetic and acquired diseases are associated
n
e
be ormed and accelerating the loss o bony tissue. with an increase in the risk o osteoporosis ( able 35-1).
a
n
d
T e most common estrogen-de cient state is the ces- Mechanisms that contribute to bone loss are unique or
C
a
sation o ovarian unction at the time o menopause,
l
each disease and typically result rom multiple actors,
c
i
u
which occurs on average at age 51 (Chap. 16). T us, with including nutrition, reduced physical activity levels, and
m
M
current li e expectancy, an average woman will spend actors that a ect rates o bone remodeling. In most, but
e
t
about 30 years without an ovarian supply o estrogen.
a
not all, circumstances the primary diagnosis is made
b
o
T e mechanism by which estrogen de ciency causes be ore osteoporosis presents clinically.
l
i
s
m
bone loss is summarized in Fig. 35-5. Marrow cells (mac-
rophages, monocytes, osteoclast precursors, mast cells)
as well as bone cells (osteoblasts, osteocytes, osteoclasts) MEDICATIONS
express ERs α and β. Loss o estrogen increases produc- A large number o medications used in clinical prac-
tion o RANKL and may reduce production o OPG, tice have potentially detrimental e ects on the skeleton
increasing osteoclast recruitment. Estrogen also may play ( able 35-1). Glucocorticoids are the most common
an important role in determining the li e span o bone cause o medication-induced osteoporosis. It is o en
cells by controlling the rate o apoptosis. T us, in situa- not possible to determine the extent to which osteo-
tions o estrogen deprivation, the li e span o osteoblasts porosis is related to glucocorticoids or to other actors,
may be decreased, whereas the longevity and activity o because treatment is superimposed on the e ects o the
osteoclasts are increased. T e rate and duration o bone primary disease, which in itsel may be associated with
loss a er menopause are heterogeneous and unpredict- bone loss (e.g., rheumatoid arthritis). Excessive doses o
able. Once sur aces are lost in cancellous bone, the rate o thyroid hormone can accelerate bone remodeling and
bone loss must decline. In cortical bone, loss is slower but result in bone loss.
continues or a longer time period. Other medications have less detrimental e ects on
Because remodeling is initiated at the sur ace o the skeleton than pharmacologic doses o glucocor-
bone, it ollows that trabecular bone—which has a con- ticoids. Anticonvulsants are thought to increase the
siderably larger sur ace area (80% o the total) than cor- risk o osteoporosis, although many a ected individu-
tical bone—will be a ected pre erentially by estrogen als have concomitant insu ciency o 1,25(OH)2D, as
de ciency. Fractures occur earliest at sites where tra- some anticonvulsants induce the cytochrome P450
becular bone contributes most to bone strength; conse- system and vitamin D metabolism. Patients undergo-
quently, vertebral ractures are the most common early ing transplantation are at high risk or rapid bone loss
consequence o estrogen de ciency. and racture not only rom glucocorticoids but also
rom treatment with other immunosuppressants such as
cyclosporine and tacrolimus (FK506). In addition, these
PHYSICAL ACTIVITY
patients o en have underlying metabolic abnormalities,
Inactivity, such as prolonged bed rest or paralysis, such as hepatic or renal ailure, that predispose to bone
results in signi cant bone loss. Concordantly, athletes loss.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 486 20/05/16 9:36 a m

 Aromatase inhibitors, which potently block the aro-
matase enzyme that converts androgens and other
adrenal precursors to estrogen, reduce circulating post-
menopausal estrogen levels dramatically. T ese agents,
which are used in various stages or breast cancer treat-
ment, also have been shown to have a detrimental e ect
on bone density and risk o racture. More recently
a variety o agents have been implicated in increased
bone loss and ractures. T ese include selective sero-
tonin reuptake inhibitors, proton pump inhibitors, and
the spine and are a particular problem in measuring the 487
spine in older individuals. Because DXA instrumenta-
tion is provided by several di erent manu acturers, the
output varies in absolute terms. Consequently, it has
become standard practice to relate the results to “nor-
mal” values by using -scores (a -score o 1 equals 1
SD), which compare individual results to those in a
young population that is matched or race and sex.
Z-scores (also measured in SD) compare individual

C
results to those o an age-matched population that

H
A
thiazolidinediones. It is di cult in some cases to sepa- also is matched or race and sex. T us, a 60-year-old

P
T
rate the risk accrued by the underlying disease rom woman with a Z-score o –1 (1 SD below mean or age)

E
R
that attributable to the medication. For example, both has a -score o –2.5 (2.5 SD below mean or a young

depression and diabetes are risk actors or racture by
themselves.
3
5
control group) (Fig. 35-6). A -score below –2.5 in
the lumbar spine, emoral neck, or total hip has been
de ned as a diagnosis o osteoporosis. As noted above,

O
s
t
because more than 50% o ractures occur in individu-

e
o
CIGARETTE CONSUMPTION

p
als with low bone mass rather than BMD osteoporosis,

o
r
o
attempts are ongoing to rede ne the disease as a rac-

s
T e use o cigarettes over a long period has detrimen-

tal e ects on bone mass. T ese e ects may be mediated
directly by toxic e ects on osteoblasts or indirectly by
modi ying estrogen metabolism. On average, cigarette
smokers reach menopause 1–2 years earlier than the
general population. Cigarette smoking also produces
secondary e ects that can modulate skeletal status,
including intercurrent respiratory and other illnesses,
railty, decreased exercise, poor nutrition, and the need
or additional medications (e.g., glucocorticoids or
lung disease).
MEASUREMENT O F BO NE MASS
Several noninvasive techniques are available or esti-
mating skeletal mass or density. T ey include dual-
energy x-ray absorptiometry (DXA), single-energy
x-ray absorptiometry (SXA), quantitative C , and ultra-
sound (US). DXA is a highly accurate x-ray technique
that has become the standard or measuring bone den-
sity. Although it can be used or measurement in any
skeletal site, clinical determinations usually are made
o the lumbar spine and hip. DXA also can be used to
measure body composition. In the DXA technique, two
x-ray energies are used to estimate the area o mineral-
i
s
ture risk rather than a speci c BMD. Consistent with
this concept, ractures o the spine and hip that occur
in the absence o major trauma would be considered
to be su cient to diagnose osteoporosis, regardless o
BMD. Fractures o other sites, such as pelvis, proximal
humerus, and wrist, would be tantamount to an osteo-
porosis diagnosis in the presence o low BMD. C can
also be used to measure the spine and the hip, but is
rarely used clinically, in part because o higher radia-
tion exposure and cost, in addition to a lesser body o
data con rming its ability to predict racture risk, com-
pared with BMD by DXA. High-resolution peripheral
C is used to measure bone in the orearm or tibia as
a research tool to noninvasively provide some measure
o skeletal architecture. Magnetic resonance imaging
(MRI) can also be used in research settings to obtain
some architectural in ormation on the orearm and per-
haps the hip.
DXA equipment can also be used to obtain lateral
images o the spine, rom 4 through L4, a technique
called vertebral racture assessment (VFA). Although
Z- a nd T-S core s
3
2

ized tissue, and the mineral content is divided by the 1

e
r
area, which partially corrects or body size. However,
o
0
c
S
this correction is only partial because DXA is a two-
D
–1
M
dimensional scanning technique and cannot estimate
B
–2 T-S core = –2.5
+1 S D
the depth or posteroanterior length o the bone. T us, –3 Z-S core =-1 0
small slim people tend to have lower than average bone –1 SD
mineral density (BMD), a eature that is important in 20 30 40 50 60 70 80 90
interpreting BMD measurements when per ormed in Age

young adults, and something that must be taken into FIGURE 3 5 -6

account at any age. Bone spurs, which are common in Re la t io n sh ip b e t we e n Z-sco re s a n d T-sco re s in a 60-year-
osteoarthritis, tend to alsely increase bone density o old woman. BMD, bone mineral density; SD, standard deviation.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 487 20/05/16 9:37 a m

 488 not as de nitive as radiography, it is a use ul screening TABLE 3 5 -2
tool when height loss, back pain, or postural change INDICATIONS FOR BONE DENSITY TESTING
suggests the presence o an undiagnosed vertebral rac- Consider BMD testing in the ollowing individuals:
ture. Furthermore, because vertebral ractures are so • Women age 65 and older and men age 70 and older, regard-
prevalent with advancing age, screening vertebral imag- less o clinical risk actors
ing is recommended in women and men with low bone • Younger postmenopausal women, women in the meno-
mass ( -score <1) by age 70 and 80, respectively. pausal transition and men age 50–69 with clinical risk ac-
tors or racture
US is used to measure bone mass by calculating the
• Adults who have a racture a ter age 50
attenuation o the signal as it passes through bone or • Adults with a condition (e.g., rheumatoid arthritis) or taking
the speed with which it traverses the bone. It is unclear
S
a medication (e.g., glucocorticoids in a daily dose ≥5 mg
E
whether US assesses properties o bone other than mass
C
prednisone or equivalent or ≥3 months) associated with
T
I
(e.g., quality), but this is a potential advantage o the
O
low bone mass or bone loss
N
technique. Because o its relatively low cost and mobil-
V
I
ity, US is amenable or use as a screening procedure in So u rce : From the 2014 National Osteoporosis Foundation Clinician’s
stores or at health airs. Guide to the Prevention and Treatment o Osteoporosis. © National Osteo-
porosis Foundation.
All o these techniques or measuring BMD have
D
i
s
been approved by the U.S. Food and Drug Administra-
o
r
d
tion (FDA) on the basis o their capacity to predict rac-
e
r
excessive alcohol use, steroid use, and rheumatoid
s
ture risk. T e hip is the pre erred site o measurement
o
arthritis) can be combined with BMD to assess the
f
B
in most individuals, because it predicts the risk o hip
o
likelihood o a racture over a 5- or 10-year period.
n
e
racture, the most important consequence o osteopo- reatment threshold depends on cost-e ectiveness
a
n
rosis, better than any other bone density measurement
d
analyses but probably is ~1% per year o risk in the
C
site. When hip measurements are per ormed by DXA,
a
United States.
l
c
i
the spine can be measured at the same time. In younger
u
m
individuals such as perimenopausal or early postmeno-
M
e
pausal women, spine measurements may be the most APPROACHTOTHEPATIENT:
t
a
b
sensitive indicator o bone loss. A risk assessment tool
o
Osteoporosis
l
i
s
(FRAX) incorporates emoral neck BMD to assess
m
10-year racture risk (see below). T e perimenopausal transition is a good opportunity
to initiate a discussion about risk actors or osteopo-
rosis and consideration o indications or a BMD test.
WHEN TO MEASURE BONE MASS A care ul history and physical examination should
be per ormed to identi y risk actors or osteoporo-
Clinical guidelines have been developed or the use o sis. A low Z-score increases the suspicion o a second-
bone densitometry in clinical practice. T e original ary disease. Height loss >2.5–3.8 cm (>1–1.5 in.) is
National Osteoporosis Foundation guidelines recom- an indication or VFA by DXA or radiography to rule
mend bone mass measurements in postmenopausal out asymptomatic vertebral ractures, as is the pres-
women, assuming they have one or more risk actors ence o signi cant kyphosis or back pain, particularly
or osteoporosis in addition to age, sex, and estrogen i it began a er menopause. In appropriate individu-
de ciency. T e guidelines urther recommend that als, screening BMD and screening vertebral imaging
bone mass measurement be considered in all women by should be recommended as above, even in the absence
age 65, a position rati ed by the U.S. Preventive Health o any speci c risk actors (Table 35-3). For patients
Services ask Force. Criteria approved or Medicare who present with ractures, it is important to ensure
reimbursement o BMD are summarized in Table 35-2. that the ractures are not caused by an underlying
malignancy. Usually this is clear on routine radiogra-
phy, but on occasion, C , MRI, or radionuclide scans
WHEN TO TREAT BASED ON BONE MASS may be necessary.
RESULTS
ROUTINE LABORATORYEVALUATION T ere is no established
Most guidelines suggest that patients be considered algorithm or the evaluation o women who present
or treatment when BMD is >2.5 SD below the mean with osteoporosis. A general evaluation that includes
value or young adults ( -score ≤–2.5), in either spine, complete blood count, serum and 24-h urine calcium,
total hip, or emoral neck. reatment also should also renal and hepatic unction tests, and a 25(OH)D level
be considered in postmenopausal women with rac- is use ul or identi ying selected secondary causes o
ture risk actors even i BMD is not in the osteoporosis low bone mass, particularly or women with ractures
range. Risk actors (age, prior racture, amily history o or very low Z-scores. An elevated serum calcium level
hip racture, low body weight, cigarette consumption,

Ha rris on_Endocrinology_Ch35_p480-p502.indd 488 20/05/16 9:37 a m

 TABLE 3 5 -3
INDICATIONS FOR VERTEBRAL IMAGING
Consider vertebral imaging tests in the ollowing individuals:
• In all women age 70 and older and all men age 80 and older
i bone mineral density (BMD) T-score is –1.0 or below
• In women age 65–69 and men age 75–79 i BMD T-score is
–1.5 or below
• In postmenopausal women age 50–64 and men age 50–69
with speci c risk actors:
• Low-trauma racture
• Historical height loss o 1.5 in. or more (4 cm)
• Prospective height loss o 0.8 in. or more (2 cm)
• Recent or ongoing long-term glucocorticoid treatment
So u rce : From the 2014 National Osteoporosis Foundation Clinician’s
Guide to the Prevention and Treatment o Osteoporosis. © National Osteo-
porosis Foundation.
suggests hyperparathyroidism or malignancy, whereas
a reduced serum calcium level may re ect malnutrition
and osteomalacia. In the presence o hypercalcemia,
a serum P H level di erentiates between hyperpara-
thyroidism (P H↑ ) and malignancy (P H↓ ), and a
high P HrP level can help document the presence o
humoral hypercalcemia o malignancy (Chap. 34). A
low urine calcium (<50 mg/24 h) suggests osteomala-
cia, malnutrition, or malabsorption; a high urine cal-
cium (>300 mg/24 h) is indicative o hypercalciuria
and must be investigated urther. Hypercalciuria occurs
primarily in three situations: (1) a renal calcium leak,
which is more common in males with osteoporosis; (2)
absorptive hypercalciuria, which can be idiopathic or
associated with increased 1,25(OH)2D in granuloma-
tous disease; or (3) hematologic malignancies or con-
ditions associated with excessive bone turnover such
as Paget’s disease, hyperparathyroidism, and hyperthy-
roidism. Renal hypercalciuria is treated with thiazide
diuretics, which lower urine calcium and help improve
calcium economy.
Individuals who have osteoporosis-related ractures
or bone density in the osteoporotic range should have
a measurement o serum 25(OH)D level, because the
intake o vitamin D required to achieve a target level
>20–30 ng/mL is highly variable. Vitamin D levels
should be optimized in all individuals being treated or
osteoporosis. Hyperthyroidism should be evaluated by
measuring thyroid-stimulating hormone ( SH).
When there is clinical suspicion o Cushing’s syn-
drome, urinary ree cortisol levels or a asting serum
cortisol should be measured a er overnight dexa-
methasone. When bowel disease, malabsorption, or
malnutrition is suspected, serum albumin, choles-
terol, and a complete blood count should be checked.
Asymptomatic malabsorption may be heralded by
anemia (macrocytic—vitamin B12 or olate de ciency;
Ha rris on_Endocrinology_Ch35_p480-p502.indd 489
489
microcytic—iron de ciency) or low serum cholesterol
or urinary calcium levels. I these or other eatures
suggest malabsorption, urther evaluation is required.
Asymptomatic celiac disease with selective malab-
sorption is being ound with increasing requency; the
diagnosis can be made by testing or antigliadin, anti-
endomysial, or transglutaminase antibodies but may
require endoscopic biopsy. A trial o a gluten- ree diet
can be con rmatory. When osteoporosis is ound asso-
C
H
ciated with symptoms o rash, multiple allergies, diar-
A
P
rhea, or ushing, mastocytosis should be excluded
T
E
by using 24-h urine histamine collection or serum
R
3
tryptase.
5
Myeloma can masquerade as generalized osteo-
porosis, although it more commonly presents with
O
bone pain and characteristic “punched-out” lesions
s
t
e
o
on radiography. Serum and urine electrophoresis and
p
o
or serum ree light chains are required to exclude this
r
o
s
i
diagnosis. More commonly, a monoclonal gammopa-
s
thy o unclear signi cance (MGUS) is ound, and the
patient is subsequently monitored to ensure that this
is not an incipient myeloma. Approximately 1% o
patients with MGUS progress to myeloma each year.
A bone marrow biopsy may be required to rule out
myeloma (in patients with equivocal electrophoretic
results) and also can be used to exclude mastocyto-
sis, leukemia, and other marrow in ltrative disorders
such as Gaucher’s disease. MGUS syndromes, although
benign, may also be associated with reduced bone mass
and elevated bone turnover.
BONE BIOPSY etracycline labeling o the skeleton
allows determination o the rate o remodeling as well
as evaluation or other metabolic bone diseases. T e
current use o BMD tests, in combination with hor-
monal evaluation and biochemical markers o bone
remodeling, has largely replaced the clinical use o
bone biopsy, although it remains an important tool
in clinical research and assessment o mechanism o
action o medication or osteoporosis.
BIOCHEMICALMARKERS Several biochemical tests are avail-
able that provide an index o the overall rate o bone
remodeling (Table 35-4). Biochemical markers usually
are characterized as those related primarily to bone for-
mation or bone resorption. T ese tests measure the over-
all state o bone remodeling at a single point in time.
Clinical use o these tests has been hampered by biologic
variability (in part related to circadian rhythm) as well as
analytic variability, although the latter is improving.
Biochemical markers o bone resorption may help in
the prediction o racture risk, independently o bone
density, particularly in older individuals. In women
≥65 years, when bone density results are greater than
the usual treatment thresholds noted above, a high
level o bone resorption should prompt consideration
20/05/16 9:37 a m
 490 TABLE 3 5 -4 ractures almost always require surgical repair i the patient
INDICATIONS FOR BIOCHEMICAL MARKERS is to become ambulatory again. Depending on the loca-
Biochemical markers o bone turnover may: tion and severity o the racture, condition o the neighbor-
• Predict risk o racture independently o bone density. ing joint, and general status o the patient, procedures may
• Predict extent o racture risk reduction when repeated include open reduction and internal xation with pins and
a ter 3–6 months o treatment with FDA-approved plates, hemiarthroplasties, and total arthroplasties. T ese
therapies. surgical procedures are ollowed by intense rehabilitation in
• Predict magnitude o BMD increases with FDA-approved
an attempt to return patients to their pre racture unctional
therapies.
• Predict rapidity o bone loss. level. Long bone ractures (e.g., wrist) o en require either
external or internal xation. Other ractures (e.g., vertebral,
S
• Help determine adequacy o patient compliance and
E
rib, and pelvic ractures) usually are managed with support-
C
persistence with osteoporosis therapy.
T
I
• Help determine duration o “drug holiday” (data are quite ive care, requiring no speci c orthopedic treatment.
O
N
limited to support this use, but studies are under way). Only ~25–30% o vertebral compression ractures present
V
I
with sudden-onset back pain. For acutely symptomatic rac-
Abb revia tio ns: BMD, bone mineral density; FDA, U.S. Food and Drug tures, treatment with analgesics is required, including non-
Administration.
steroidal anti-in ammatory agents and/or acetaminophen,
D
So u rce : Adapted rom the 2014 National Osteoporosis Foundation Clini-
i
s
sometimes with the addition o a narcotic agent (codeine
o
cian’s Guide to the Prevention and Treatment o Osteoporosis. © National
r
d
e
Osteoporosis Foundation. or oxycodone). A ew small, randomized clinical trials sug-
r
s
gest that calcitonin may reduce pain related to acute verte-
o
f
B
bral compression racture. Percutaneous injection o arti cial
o
o treatment. T e primary use o biochemical markers
n
e
is or monitoring the response to treatment. With the cement (polymethylmethacrylate) into the vertebral body
a
n
(vertebroplasty or kyphoplasty) may o er signi cant imme-
d
introduction o antiresorptive therapeutic agents, bone
C
diate pain relie in patients with severe pain rom acute or
a
remodeling declines rapidly, with the all in resorption
l
c
i
subacute vertebral ractures. Sa ety concerns include extrava-
u
occurring earlier than the all in ormation. Inhibition
m
sation o cement with neurologic sequelae and increased risk
M
o bone resorption is maximal within 3 months or so.
e
o racture in neighboring vertebrae due to mechanical rigid-
t
T us, measurement o bone resorption (C-telopeptide
a
b
ity o the treated bone. Exactly which patients are the optimal
o
[C X] is the pre erred marker) be ore initiating ther-
l
i
s
candidates or this procedure remains unknown. Short peri-
m
apy and 3–6 months a er starting therapy provides
an earlier estimate o patient response than does bone ods o bed rest may be help ul or pain management, but in
densitometry. A decline in resorptive markers can be general, early mobilization is recommended because it helps
ascertained a er treatment with potent antiresorp- prevent urther bone loss associated with immobilization.
tive agents such as bisphosphonates, denosumab, or Occasionally, use o a so elastic-style brace may acilitate
standard-dose estrogen; this e ect is less marked a er earlier mobilization. Muscle spasms o en occur with acute
treatment with weaker agents such as raloxi ene or compression ractures and can be treated with muscle relax-
intranasal calcitonin. A biochemical marker response ants and heat treatments.
to therapy is particularly use ul or asymptomatic Severe pain usually resolves within 6–10 weeks. More
patients and may help ensure long-term adherence to chronic severe pain might suggest the possibility o multiple
treatment. Bone turnover markers are also use ul in myeloma or underlying metastatic disease. Chronic pain
monitoring the e ects o osteoanabolic agents such as ollowing vertebral racture is probably not bony in origin;
1-34hP H, or teriparatide, which rapidly increases instead, it is related to abnormal strain on muscles, ligaments,
bone ormation (P1NP is pre erred, but osteocalcin is and tendons and to secondary acet-joint arthritis associ-
a reasonable alternative) and later bone resorption. ated with alterations in thoracic and/or abdominal shape.
T e recent suggestion o “drug holidays” (see below) Chronic pain is di cult to treat e ectively and may require
has created another use or biochemical markers, analgesics, sometimes including narcotic analgesics. Frequent
allowing evaluation o the o e ect o drugs such as intermittent rest in a supine or semireclining position is o en
bisphosphonates. required to allow the so tissues, which are under tension,
to relax. Back-strengthening exercises (paraspinal) may be
bene cial. Heat treatments help relax muscles and reduce the
muscular component o discom ort. Various physical modali-
ties, such as US and transcutaneous nerve stimulation, may
TREATMENT Osteoporosis be bene cial in some patients. Pain also occurs in the neck
region, not as a result o compression ractures (which almost
MANAGEMENTOF PATIENTS WITHFRACTURES reatment o a patient never occur in the cervical spine as a result o osteoporosis)
with osteoporosis requently involves management o acute but because o chronic strain associated with trying to elevate
ractures as well as treatment o the underlying disease. Hip the head in a person with a signi cant thoracic kyphosis.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 490 20/05/16 9:37 a m

 Multiple vertebral ractures o en are associated with
psychological symptoms; this is not always appreciated.
T e changes in body con guration and back pain can lead
to marked loss o sel -image and a secondary depression.
Altered balance, precipitated by the kyphosis and the ante-
rior movement o the body’s center o gravity, leads to a ear
o alling, a consequent tendency to remain indoors, and the
onset o social isolation. T ese symptoms sometimes can be
alleviated by amily support and/or psychotherapy. Medica-
tion may be necessary when depressive eatures are present.
Multiple thoracic vertebral ractures may be associated with
restrictive lung disease symptoms and increased pulmonary
in ections. Multiple lumbar vertebral ractures are o en asso-
ciated with abdominal pain, constipation, protuberance, and
early satiety. Multiple vertebral ractures are associated with
greater age-speci c mortality.
Multiple studies show that the majority o patients pre-
senting in adulthood with ractures are not evaluated or
treated or osteoporosis. Estimates suggest only about 20%
o racture patients receive ollow-up care. Patients who sus-
tain acute ractures are at dramatically elevated risk or more
ractures, particularly within the rst several years, and phar-
macologic intervention can reduce that risk substantially.
Recently, several studies have demonstrated the e ectiveness
o a relatively simple and inexpensive program that reduces
the risk o subsequent ractures. In the Kaiser system, it is
estimated that a 20% decline in hip racture occurrence was
seen with the introduction o what is called a racture liai-
son service. T is typically involves a health care pro essional
(usually a nurse) whose job is to coordinate ollow-up care
and education o racture patients. I the Kaiser experience
can be repeated, there would be signi cant savings o health
care dollars, as well as a dramatic drop in hip racture inci-
dence and a marked improvement in morbidity and mortality
among the aging population.
MANAGEMENT OF THE UNDERLYING DISEASE Patients present-
ing with typical osteoporosis-related ractures (certainly hip
and spine) can be assumed to have osteoporosis and can be
treated appropriately. Patients with osteoporosis by BMD
are handled in a similar ashion. Other racture patients
and those with reduced bone mass can be classi ed accord-
ing to their uture risk o racture and treated i that risk is
su ciently high. It must be emphasized, however, that risk
assessment is an inexact science when applied to individual
patients. Fractures are chance occurrences that can happen to
anyone. Patients o en do not understand the relative bene ts
o medications, compared to the perceived risks o the medi-
cations themselves.
Risk Factor Reduction Several tools exist or risk assessment.
T e most commonly available is the FRAX tool, developed
by a working party or the WHO, and available as part o the
report rom many DXA machines. It is also available online
(http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9)
(Fig. 35-7). In the United States, it has been estimated that
Ha rris on_Endocrinology_Ch35_p480-p502.indd 491
it is cost-e ective to treat a patient i the 10-year major rac- 491
ture risk (including hip, clinical spine, proximal humerus,
and tibia) rom FRAX is ≥20% and/or the 10-year risk o
hip racture is ≥3%. FRAX is an imper ect tool because it
does not include any assessment o all risk and secondary
causes are excluded when BMD is entered. Moreover, it does
not include any term or multiple ractures or recent versus
remote racture. Nonetheless, it is use ul as an educational
tool or patients.
C
A er risk assessment, patients should be thoroughly edu-
H
A
cated to reduce the impact o modi able risk actors associ-
P
T
ated with bone loss and alling. All medications that increase
E
R
risk o alls, bone loss, or ractures should be reviewed to
3
5
ensure that they are necessary and being used at the lowest
required dose. For those on thyroid hormone replacement,
SH testing should be per ormed to con rm that an exces-
O
s
t
sive dose is not being used, because biochemical and symp-
e
o
p
tomatic thyrotoxicosis can be associated with increased bone
o
r
o
loss. In patients who smoke, e orts should be made to acili-
s
i
s
tate smoking cessation. Reducing risk actors or alling also
include alcohol abuse treatment and a review o the medical
regimen or any drugs that might be associated with ortho-
static hypotension and/or sedation, including hypnotics
and anxiolytics. I nocturia occurs, the requency should be
reduced, i possible (e.g., by decreasing or modi ying diuretic
use), because arising in the middle o sleep is a common pre-
cipitant o a all. Patients should be instructed about envi-
ronmental sa ety with regard to eliminating exposed wires,
curtain strings, slippery rugs, and mobile tables. Avoid-
ing stocking eet on wood oors, checking carpet condition
(particularly on stairs), and providing good light in paths to
bathrooms and outside the home are important preventive
measures. reatment or impaired vision is recommended,
particularly a problem with depth perception, which is spe-
ci cally associated with increased alling risk. Elderly patients
with neurologic impairment (e.g., stroke, Parkinson’s disease,
Alzheimer’s disease) are particularly at risk o alling and
require specialized supervision and care.
Nutritional Recommendations
Calcium A large body o data indicates that optimal calcium
intake reduces bone loss and suppresses bone turnover.
Recommended intakes rom an Institute o Medicine report
are shown in Table 35-5.
T e National Health and Nutrition Examination Sur-
veys (NHANES) have consistently documented that average
calcium intakes all considerably short o these recommen-
dations. Food sources o calcium are dairy products (milk,
yogurt, and cheese) and orti ed oods such as certain cere-
als, waf es, snacks, juices, and crackers. Some o these or-
ti ed oods contain as much calcium per serving as milk.
Green lea y vegetables and nuts, particularly almonds, are
also sources o calcium, although their bioavailability may be
lower than with dairy products. Calcium intake rom the diet
can also be assessed (Table 35-6) and calculators are available
at NOF.org or NYSOPEP.org.
20/05/16 9:37 a m
 492
S
E
C
T
I
O
N
V
I
D
i
s
o
r
d
e
r
s
o
f
B
o
n
e
a
n
d
C
a
l
c
i
u
m
M
e
t
a
b
o
l
i
s
m
FIGURE 3 5 -7
FRAX ca lcu la t io n t o o l. When the answers to the indicated http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) also can risk
questions are lled in, the calculator can be used to assess the adjust or various ethnic groups.
10-year probability o racture. The calculator (available online at

TABLE 3 5 -5
I a calcium supplement is required, it should be taken
ADEQUATE CALCIUM INTAKE in doses su cient to supplement dietary intake to bring
ESTIMATED ADEQUATE total intake to the required level (1000–1200 mg/d). Doses
DAILY CALCIUM INTAKE, o supplements should be ≤600 mg at a time, because the
LIFE STAGE GROUP MG/D
calcium absorption raction decreases at higher doses.
Young children (1–3 years) 500 Calcium supplements should be calculated on the basis o
Older children (4–8 years) 800 the elemental calcium content o the supplement, not the
Adolescents and young adults 1300 weight o the calcium salt. Calcium supplements contain-
(9–18 years) ing carbonate are best taken with ood because they require
Men and women (19–50 1000 acid or solubility. Calcium citrate supplements can be taken
years) at any time. o con rm bioavailability, calcium supplements
Men and women (51 and 1200 can be placed in distilled vinegar. T ey should dissolve
older) within 30 min.
Several controlled clinical trials o calcium, mostly plus
No te: Pregnancy and lactation needs are the same as or nonpregnant vitamin D, have con rmed reductions in clinical ractures,
women (e.g., 1300 mg/d or adolescents/young adults and 1000 mg/d or including ractures o the hip (~20–30% risk reduction). All
≥19 years). recent studies o pharmacologic agents have been conducted
So u rce : Adapted rom the Standing Committee on the Scienti c Evalu-
ation o Dietary Re erence Intakes. Food and Nutrition Board. Institute o in the context o calcium replacement (± vitamin D). T us,
Medicine. Washington, DC, 1997, National Academy Press. it is standard practice to ensure an adequate calcium and

Ha rris on_Endocrinology_Ch35_p480-p502.indd 492 20/05/16 9:37 a m

 TABLE 3 5 -6 493
SIMPLE METHOD FOR CALCULATING DIETARY CALCIUM INTAKE
STEP 1: Estimate calcium intake rom calcium-rich oods
Est im a t e d
#o ca lciu m / Ca lciu m in
Pro d u ct Se rvin g s/d se rvin g , in m g mg
Milk (8 oz.) __________ × 300 = __________
Yogurt (6 oz.) __________ × 300 = __________
Cheese (1 oz. or 1 cubic in.) __________ × 200 = __________

C
H
A
Forti ed oods or juices __________ × 80 to 1000 = __________

P
T
Subtotal = __________

E
R
3
STEP 2: Total rom above + 250 mg or nondairy sources

5
= total dietary calcium TOTAL Calcium, in mg = __________

O
So u rce: Adapted rom SM Krane, MF Holick, Chap. 355, in Harrison’s Principles of Internal

s
t
e
Medicine, 14th ed. New York, McGraw-Hill, 1998.

o
p
o
r
o
s
vitamin D intake in patients with osteoporosis whether they Other NutrientsOther nutrients such as salt, high animal

are receiving additional pharmacologic therapy or not. A sys-
tematic review con rmed a greater BMD response to antire-
sorptive therapy when calcium intake was adequate.
Although side e ects rom supplemental calcium are
minimal (eructation and constipation mostly with carbonate
salts), individuals with a history o kidney stones should have
a 24-h urine calcium determination be ore starting increased
calcium to avoid signi cant hypercalciuria. Many studies
con rm a small but signi cant increase in the risk o renal
stones with calcium supplements, but not dietary calcium.
A recent analysis o published data has suggested that high
intakes o calcium rom supplements are associated with an
increase in the risk o heart disease. T is is an evolving story
with additional studies that con rm or re ute this nding.
Because high calcium supplement intakes increase the risk o
renal stones and con er no extra bene t to the skeleton, the
recommendation that total intakes should be between 1000
and 1200 mg/d is reasonable.
Vitamin D Vitamin D is synthesized in skin under the in lu-
ence o heat and ultraviolet light (Chap. 32). However,
large segments o the population do not obtain su icient
vitamin D to maintain what is now considered an adequate
supply [serum 25(OH)D consistently >75 µmol/L (30 ng/
mL)]. Because vitamin D supplementation at doses that
would achieve these serum levels is sa e and inexpensive,
the Institute o Medicine (based on obtaining a serum level
o 20 ng/mL) recommends daily intakes o 200 IU or adults
<50 years o age, 400 IU or those 50–70 years, and 600 IU
or those >70 years. Multivitamin tablets usually contain 400
IU, and many calcium supplements also contain vitamin
D. Some data suggest that higher doses (≥1000 IU) may be
required in the elderly and chronically ill. he Institute o
Medicine report suggests that it is sa e to take up to 4000
IU/d. For those with osteoporosis or those at risk o osteopo-
rosis, 1000–2000 IU/d can usually maintain serum 25(OH)
D above 30 ng/mL.
i
s
protein intakes, and ca eine may have modest e ects on
calcium excretion or absorption. Adequate vitamin K
status is required or optimal carboxylation o osteocal-
cin. States in which vitamin K nutrition or metabolism is
impaired, such as with long-term war arin therapy, have
been associated with reduced bone mass. Research con-
cerning cola intake is controversial but suggests a pos-
sible link to reduced bone mass through actors that are
independent o ca eine. Although dark green lea y veg-
etables such as spinach and kale contain a air amount o
calcium, the high oxalate content reduces absorption o
this calcium (but does not inhibit absorption o calcium
rom other ood eaten simultaneously).
Magnesium is abundant in oods, and magnesium
de ciency is quite rare in the absence o a serious
chronic disease. Magnesium supplementation may be
warranted in patients with in ammatory bowel disease,
celiac disease, chemotherapy, severe diarrhea, malnutri-
tion, or alcoholism. Dietary phytoestrogens, which are
derived primarily rom soy products and legumes (e.g.,
garbanzo beans [chickpeas] and lentils), exert some
estrogenic activity but are insu ciently potent to justi y
their use in place o a pharmacologic agent in the treat-
ment o osteoporosis.
Patients with hip ractures are o en rail and rela-
tively malnourished. Some data suggest an improved
outcome in such patients when they are provided cal-
orie and protein supplementation. Excessive protein
intake can increase renal calcium excretion, but this can
be corrected by an adequate calcium intake.
Exercise Exercise in young individuals increases the likeli-
hood that they will attain the maximal genetically deter-
mined peak bone mass. Meta-analyses o studies per ormed
in postmenopausal women indicate that weight-bearing
exercise helps prevent bone loss but does not appear to
result in substantial gain o bone mass. his bene icial e ect

Ha rris on_Endocrinology_Ch35_p480-p502.indd 493 20/05/16 9:37 a m

 494 wanes i exercise is discontinued. Most o the studies are declines a er discontinuation to the extent that there is no
short term, and a more substantial e ect on bone mass is residual protective e ect against racture by 10 years a er
likely i exercise is continued over a long period. Exercise discontinuation. T e rst clinical trial evaluating ractures
also has bene icial e ects on neuromuscular unction, and as secondary outcomes, the Heart and Estrogen-Progestin
it improves coordination, balance, and strength, thereby Replacement Study (HERS) trial, showed no e ect o hor-
reducing the risk o alling. A walking program is a practi- mone therapy on hip or other clinical ractures in women
cal way to start. Other activities, such as dancing, racquet with established coronary artery disease. T ese data made the
sports, cross-country skiing, and use o gym equipment, results o the Women’s Health Initiative (WHI) exceedingly
are also recommended, depending on the patient’s personal important (Chap. 16). T e estrogen-progestin arm o the
pre erence and general condition. Even women who cannot WHI in >16,000 postmenopausal healthy women indicated
S
E
walk bene it rom swimming or water exercises, not so much that hormone therapy reduces the risk o hip and clinical
C
T
I
or the e ects on bone, which are quite minimal, but because spine racture by 34% and reduces the risk o all clinical rac-
O
N
o e ects on muscle. Exercise habits should be consistent, tures by 24%. T ere was similar anti racture e cacy seen with
V
I
optimally at least three times a week. estrogen alone in women who had had a hysterectomy.
A ew smaller clinical trials have evaluated spine racture
PHARMACOLOGIC THERAPIES Be ore the mid-1990s, estro-
occurrence as an outcome with estrogen therapy. T ey have
D
i
gen treatment, either by itsel or in concert with a proges-
s
consistently shown that estrogen treatment reduces the inci-
o
r
d
tin, was the primary therapeutic agent or prevention or
e
dence o vertebral compression racture.
r
s
treatment o osteoporosis. T ere are now a number o new T e WHI has provided a vast amount o data on the
o
f
medications approved or osteoporosis and more under
B
multisystemic e ects o hormone therapy. Although earlier
o
n
development. Some are agents that speci cally treat osteopo-
e
observational studies suggested that estrogen replacement
a
rosis (bisphosphonates, calcitonin, denosumab, and teripara-
n
might reduce heart disease, the WHI showed that combined
d
tide [1-34hP H]); others, such as selective estrogen response
C
estrogen-progestin treatment increased risk o atal and non-
a
l
c
modulators (SERMs) and, most recently, an estrogen/SERM
i
atal myocardial in arction by ~29%, con rming data rom
u
m
combination medication, have broader e ects. T e availabil- the HERS study. Other important relative risks included a
M
ity o these drugs allows therapy to be tailored to the needs o
e
40% increase in stroke, a 100% increase in venous throm-
t
a
an individual patient.
b
boembolic disease, and a 26% increase in risk o breast can-
o
l
i
s
cer. Subsequent analyses have con rmed the increased risk
m
Estrogens A large body o clinical trial data indicates that vari-
ous types o estrogens (conjugated equine estrogens, estradiol, o stroke and, in a substudy, showed a two old increase in
estrone, esteri ied estrogens, ethinyl estradiol, and mestranol) dementia. Bene ts other than the racture reductions noted
reduce bone turnover, prevent bone loss, and induce small above included a 37% reduction in the risk o colon cancer.
increases in bone mass o the spine, hip, and total body. he T ese relative risks have to be interpreted in light o absolute
e ects o estrogen are seen in women with natural or surgi- risk (Fig. 35-8). For example, out o 10,000 women treated
cal menopause and in late postmenopausal women with or with estrogen-progestin or 1 year, there will be 8 excess heart
without established osteoporosis. Estrogens are e icacious attacks, 8 excess breast cancers, 18 excess venous thrombo-
when administered orally or transdermally. For both oral and embolic events, 5 ewer hip ractures, 44 ewer clinical rac-
transdermal routes o administration, combined estrogen/ tures, and 6 ewer colorectal cancers. T ese numbers must
progestin preparations are now available in many countries, be multiplied by years o hormone treatment. T ere was no
obviating the problem o taking two tablets or using a patch e ect o hormone treatment on the risk o uterine cancer or
and oral progestin. total mortality.
It is important to note that these WHI ndings apply spe-
Dose of Estrogen For oral estrogens, the standard recom-
ci cally to hormone treatment in the orm o conjugated
mended doses have been 0.3 mg/d or esteri ed estrogens,
equine estrogen plus medroxyprogesterone acetate. T e rela-
0.625 mg/d or conjugated equine estrogens, and 5 µg/d or
tive bene ts and risks o unopposed estrogen in women who
ethinyl estradiol. For transdermal estrogen, the commonly
had hysterectomies vary somewhat. T ey still show bene ts
used dose supplies 50 µg estradiol per day, but a lower dose
against racture occurrence and increased risk o venous
may be appropriate or some individuals. Dose-response data
thrombosis and stroke, similar in magnitude to the risks or
or conjugated equine estrogens indicate that lower doses (0.3
combined hormone therapy. In contrast, though, the estro-
and 0.45 mg/d) are e ective. Doses even lower have been
gen-only arm o WHI indicated no increased risk o heart
associated with bone mass protection.
attack or breast cancer. T e data suggest that at least some
Fracture Data Epidemiologic databases indicate that women o the detrimental e ects o combined therapy are related to
who take estrogen replacement have a 50% reduction, on the progestin component. In addition, there is the possibil-
average, o osteoporotic ractures, including hip ractures. ity, suggested by primate data, that the risk accrues mainly
T e bene cial e ect o estrogen is greatest among those who to women who have some years o estrogen de ciency be ore
start replacement early and continue the treatment; the bene t initiating treatment. (T e average woman in the WHI was

Ha rris on_Endocrinology_Ch35_p480-p502.indd 494 20/05/16 9:37 a m

 Ris ks Be ne fits Ne utra l treatment o osteoporosis as well as the prevention o breast 495
60 cancer, and tamoxi en, which is approved or the prevention
50 Additiona l eve nts and treatment o breast cancer. A third SERM, bazedoxi ene,
r
has been complexed with conjugated estrogen, creating a tis-
a
e
7 8 8 18
s
y
e
40 sue selective estrogen complex ( SEC). T is agent has been
/
n
s
a
e
Re duce d
c
m
approved or prevention o osteoporosis.
f
eve nts
o
o
30
w
r
Tamoxifen reduces bone turnover and bone loss in post-
e
0
b
0
m
6 5
0
20 menopausal women compared with placebo groups. T ese
,
u
0
N
1
ndings support the concept that tamoxi en acts as an estro-
n
i
10

C
genic agent in bone. T ere are limited data on the e ect o

H
A
0 tamoxi en on racture risk, but the Breast Cancer Preven-

P
CHD S troke Bre a s t VTE Colore cta l Hip Endome tria l De a ths

T
ca nce r ca nce r fra cture ca nce r tion Study indicated a possible reduction in clinical vertebral,

E
R
hip, and Colles’ ractures. T e major bene t o tamoxi en is

3
FIGURE 3 5 -8

5
Ef e ct s o h o rm o n e t h e ra p y o n e ve n t ra te s: green, placebo; on breast cancer occurrence. T e breast cancer prevention
purple, estrogen and progestin. CHD, coronary heart disease; VTE, trial indicated that tamoxi en administration over 4–5 years
reduced the incidence o new invasive and noninvasive breast

O
venous thromboembolic events. (Adapted from Women’s Health

s
t
cancer by ~45% in women at increased risk o breast can-

e
Initiative. WHI HRT Update. Available at http://www.nhlbi.nih.gov/

o
p
cer. T e incidence o ER-positive breast cancers was reduced

o
health/women/upd2002.htm.)

r
o
by 65%. amoxi en increases the risk o uterine cancer and

more than 10 years rom the last menstrual period). None-
theless, there is reluctance among women to use estrogen/
hormone therapy, and the U.S. Preventive Services ask Force
has speci cally suggested that estrogen/hormone therapy not
be used or disease prevention.
Mode of Action wo subtypes o ERs, α and β, have been iden-
ti ied in bone and other tissues. Cells o monocyte lineage
express both ERα and ERβ, as do osteoblasts. Estrogen-
mediated e ects vary with the receptor type. Using ER knock-
out mouse models, elimination o ERα produces a modest
reduction in bone mass, whereas mutation o ERβ has less o
an e ect on bone. A male patient with a homozygous muta-
tion o ERα had markedly decreased bone density as well as
abnormalities in epiphyseal closure, con irming the impor-
tant role o ERα in bone biology. he mechanism o estrogen
action in bone is an area o active investigation (Fig. 35-5).
Although data are con licting, estrogens may inhibit osteo-
clasts directly. However, the majority o estrogen (and andro-
gen) e ects on bone resorption are mediated through para-
crine actors produced by osteoblasts and osteocytes. hese
actions include decreasing RANKL production and increasing
OPG production by osteoblasts.
Progestins In women with a uterus, daily progestin or cycli-
cal progestins at least 12 days per month are prescribed in
combination with estrogens to reduce the risk o uterine can-
cer. Medroxyprogesterone acetate and norethindrone acetate
blunt the high-density lipoprotein response to estrogen, but
micronized progesterone does not. Neither medroxyproges-
terone acetate nor micronized progesterone appears to have
an independent e ect on bone; at lower doses o estrogen,
norethindrone acetate may have an additive bene it. On breast
tissue, progestins may increase the risk o breast cancer.
SERMs wo SERMs are used currently in postmenopausal
women: raloxi ene, which is approved or the prevention and
s
i
s
increases risk o venous thrombosis, cataracts, and possibly
stroke in postmenopausal women, limiting its use or breast
cancer prevention in women at low or moderate risk.
Raloxifene (60 mg/d) has e ects on bone turnover and
bone mass that are very similar to those o tamoxi en, indi-
cating that this agent is also estrogenic on the skeleton. T e
e ect o raloxi ene on bone density (+1.4–2.8% vs placebo
in the spine, hip, and total body) is somewhat less than that
seen with standard doses o estrogens. Raloxi ene reduces the
occurrence o vertebral racture by 30–50%, depending on
the population; however, there are no data con rming that
raloxi ene can reduce the risk o nonvertebral ractures over 8
years o observation.
Raloxi ene, like tamoxi en and estrogen, has e ects in
other organ systems. T e most bene cial e ect appears to be
a reduction in invasive breast cancer (mainly decreased ER-
positive) occurrence o ~65% in women who take raloxi ene
compared to placebo. In a head-to-head study, raloxi ene
was as e ective as tamoxi en in preventing breast cancer in
high-risk women, and raloxi ene is now FDA approved or
this indication. In a urther study, raloxi ene had no e ect on
heart disease in women with increased risk or this outcome.
In contrast to tamoxi en, raloxi ene is not associated with an
increase in the risk o uterine cancer or benign uterine dis-
ease. Raloxi ene increases the occurrence o hot ashes but
reduces serum total and low-density lipoprotein cholesterol,
lipoprotein(a), and brinogen. Raloxi ene, with positive
e ects on breast cancer and vertebral ractures, has become
a use ul agent or the treatment o the younger asymptomatic
postmenopausal woman. In some women, a recurrence o
menopausal hot ashes may occur. Usually this is evanescent,
but occasionally, it is su ciently impact ul on daily li e and
sleep that the drug must be withdrawn. Raloxi ene increases
the risk o deep vein thrombosis and may increase the risk o
death rom stroke among older women. Consequently, it is
not usually recommended or women over 70 years o age.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 495 20/05/16 9:37 a m

 496 T e main advantage o the bazedoxifene/conjugated estro- irritation. Cases o esophagitis, esophageal ulcer, and
gen compound is that the bazedoxi ene protects uterine tis- esophageal stricture have been described, but the incidence
sue rom the e ects o estrogen and makes it possible to avoid appears to be low. In clinical trials, overall gastrointestinal
taking a progestin, while using an estrogen primarily or con- symptomatology was no di erent with alendronate than
trol o menopausal symptoms. T e SEC prevents bone loss with placebo. Alendronate is also available in a preparation
somewhat more potently than raloxi ene alone and appears that contains vitamin D.
sa e or the breast. Risedronate also reduces bone turnover and increases bone
mass. Controlled clinical trials have demonstrated 40–50%
Mode of Action of Serms All SERMs bind to the ER, but each
reduction in vertebral racture risk over 3 years, accompa-
agent produces a unique receptor-drug con ormation. As a
nied by a 40% reduction in clinical nonspine ractures. T e
S
result, speci ic co-activator or co-repressor proteins are bound
E
only clinical trial speci cally designed to evaluate hip racture
C
T
to the receptor (Chap. 2), resulting in di erential e ects on
I
outcome (HIP) indicated that risedronate reduced hip rac-
O
gene transcription that vary depending on other transcription
N
ture risk in women in their seventies with con rmed osteo-
V
actors present in the cell. Another aspect o selectivity is the
I
porosis by 40%. In contrast, risedronate was not e ective at
a inity o each SERM or the di erent ERα and ERβ subtypes,
reducing hip racture occurrence in older women (80+ years)
which are expressed di erentially in various tissues. hese
without proven osteoporosis. Studies have shown that 35 mg
D
tissue-selective e ects o SERMs o er the possibility o tailor-
i
s
o risedronate administered once weekly is therapeutically
o
r
ing estrogen therapy to best meet the needs and risk actor
d
e
equivalent to 5 mg/d and that 150 mg once monthly is thera-
r
pro ile o an individual patient.
s
peutically equivalent to 35 mg once weekly. Patients should
o
f
B
Bisphosphonates Alendronate, risedronate, ibandronate, and take risedronate with a ull glass o plain water to acilitate
o
n
e
zoledronic acid are approved or the prevention and treatment delivery to the stomach and should not lie down or 30 min
a
n
o postmenopausal osteoporosis. Alendronate, risedronate, a er taking the drug. T e incidence o gastrointestinal side
d
C
and zoledronic acid are also approved or the treatment o e ects in trials with risedronate was similar to that o pla-
a
l
c
i
steroid-induced osteoporosis, and risedronate and zoledronic cebo. A new preparation, which allows risedronate to be
u
m
acid are approved or prevention o steroid-induced osteo- taken with ood, was recently approved.
M
e
porosis. Alendronate, risedronate, and zoledronic acid are Etidronate was the rst bisphosphonate to be approved,
t
a
b
approved or treatment o osteoporosis in men. initially or use in Paget’s disease and hypercalcemia. T is
o
l
i
s
Alendronate has been shown to decrease bone turnover agent has also been used in osteoporosis trials o smaller
m
and increase bone mass in the spine by up to 8% versus pla- magnitude than those per ormed or alendronate and rise-
cebo and by 6% versus placebo in the hip. Multiple trials dronate but is not approved by the FDA or treatment o
have evaluated its e ect on racture occurrence. T e Fracture osteoporosis. Etidronate probably has some e cacy against
Intervention rial provided evidence in >2000 women with vertebral racture when given as an intermittent cyclical regi-
prevalent vertebral ractures that daily alendronate treat- men (2 weeks on, 2.5 months o ). Its e ectiveness against
ment (5 mg/d or 2 years and 10 mg/d or 9 months a er- nonvertebral ractures has not been studied.
ward) reduces vertebral racture risk by about 50%, multiple Ibandronate is the third amino-bisphosphonate approved
vertebral ractures by up to 90%, and hip ractures by up to in the United States. Ibandronate (2.5 mg/d) has been shown
50%. Several subsequent trials have con rmed these ndings in clinical trials to reduce vertebral racture risk by ~40% but
(Fig. 35-9). For example, in a study o >1900 women with with no overall e ect on nonvertebral ractures. In a post
low bone mass treated with alendronate (10 mg/d) versus pla- hoc analysis o subjects with a emoral neck -score o –3
cebo, the incidence o all nonvertebral ractures was reduced or below, ibandronate reduced the risk o nonvertebral rac-
by ~47% a er only 1 year. In the United States, the 10-mg tures by ~60%. In clinical trials, ibandronate doses o 150 mg/
dose is approved or treatment o osteoporosis and 5 mg/d is month PO or 3 mg every 3 months IV had greater e ects on
used or prevention. turnover and bone mass than did 2.5 mg/d. Patients should
rials comparing once-weekly alendronate, 70 mg, with take oral ibandronate in the same way as other bisphospho-
daily 10-mg dosing have shown equivalence with regard nates, but with 1 h elapsing be ore other ood or drink (other
to bone mass and bone turnover responses. Consequently, than plain water).
once-weekly therapy generally is pre erred because o the Zoledronic acid is a potent bisphosphonate with a unique
low incidence o gastrointestinal side e ects and ease o administration regimen (5 mg by slow IV in usion annually).
administration. Alendronate should be given with a ull T e data con rm that it is highly e ective in racture risk
glass o water be ore break ast, because bisphosphonates reduction. In a study o >7000 women ollowed or 3 years,
are poorly absorbed. Because o the potential or esopha- zoledronic acid (three annual in usions) reduced the risk o
geal irritation, alendronate is contraindicated in patients vertebral ractures by 70%, nonvertebral ractures by 25%,
who have stricture or inadequate emptying o the esopha- and hip ractures by 40%. T ese results were associated with
gus. It is recommended that patients remain upright or at less height loss and disability. In the treated population,
least 30 min a er taking the medication to avoid esophageal there was an increased risk o transient postdose symptoms

Ha rris on_Endocrinology_Ch35_p480-p502.indd 496 20/05/16 9:37 a m

 Ve rte bral frac ture s 497
Ale ndrona te Ris e drona te Iba ndrona te Zole drona te
poole d, pos t hoc poole d, pos t hoc pre pla nne d pre pla nne d
4 4 6 3
P LB P LB P LB P LB
ALN RIS IBAN ZOL
3 3
s
t
4 2
n
e
i
45%↓ *
t
a
p
49↓*
2 2
f
o
C
t
H
n
A
77%↓ *
e
*
c
P
2 1
r
*

T
e
69%↓*
P
E
1 * 1

R
*

3
5
* ?
*
0 0 0 0
0 12 24 36 0 6 12 0 12 24 36 0 12 24 36

O
s
t
A Months Months Months Months

e
o
p
No nve rte bral frac ture s

o
r
o
s
Ale ndrona te poole d, pos t hoc Ris e drona te poole d, pos t hoc Zole drona te pre pla nne d

i
s
15 15 15
P LB P LB P LB
ALN RIS ZOL

27%↓ *
s
10 10 10
t
n
e
*
i
t
25%↓ *
a
p
f
*
o
59%↓ *
t
n
e
?
c
5 5
r
5
e
*
P
**
* *
*
** *
*
0 0 0
0 12 24 36 0 12 24 36 0 12 24 36
B Months Months Months
Hip frac ture s

Cumula tive incide nce of hip fra cture s ove r 3 ye a rs

3
)
%
(
2 RRR
e
c
P la ce bo (n = 3861) 41%
n
e
Zole ndrona te (n = 3875)
d
i
c
n
i
e
v
i
t
a
1
l
u
m
u
C
0
0 3 6 9 12 15 18 21 24 27 30 33 36
C Time to firs t hip fra cture (months )

FIGURE 3 5 -9
Ef ects o vario us b isp hosp h onates on clinical vertebral rac- 85:4118, 2000; C Roux et al: Curr Med Res Opin 4:433, 2004; CH Ches-
tures A. nonvertebral ractures B. and hip ractures C. PLB, placebo; nut et al: J Bone Miner Res 19:1241, 2004; DM Black et al: N Engl J Med
RRR, relative risk reduction. (After DM Black et al: J Clin Endocrinol Metab 356:1809, 2007; JTHarrington et al: Calcif Tissue Int 74:129, 2003.)

Ha rris on_Endocrinology_Ch35_p480-p502.indd 497 20/05/16 9:37 a m

 498 (acute-phase reaction) mani ested by ever, arthralgia, myal-
gias, and headache. T e symptoms usually last less than 48 h.
An increased risk o atrial brillation and transient but not
permanent reduction in renal unction was seen in compari-
son to placebo. Detailed evaluation o all bisphosphonates
ailed to con rm that these agents increased the risk o atrial
brillation. Zoledronic acid is the only osteoporosis agent
that has been studied in the elderly with a prior hip racture.
T e risk o all clinical ractures was reduced signi cantly by
about 35%, and there was a trend toward reduced risk o a
S
E
second hip racture (e ect size similar to that seen above).
C
T
I
T ere was also a reduction in mortality o about 30% that was
O
N
A B C D
not completely accounted or the reduced hip racture risk.
V
I
Recently there has been concern about two potential side FIGURE 3 5 -1 0
e ects associated with bisphosphonate use. T e rst is osteo- An a t yp ica l e m u r ra ctu re (AFF) o t h e e m o ra l d ia p hy-
necrosis o the jaw (ONJ). ONJ usually ollows a dental proce- sis. A. Note the transverse racture line in the lateral cortex that
D
i
becomes oblique as it progresses medially across the emur (white
s
dure in which bone is exposed (extractions or dental implants).
o
r
d
arrow). B. On radiograph obtained immediately a ter intramedul-
It is presumed that the exposed bone becomes in ected and
e
r
s
lary rod placement, a small area o periosteal thickening o the lat-
dies. It is not uncommon among cancer victims with mul-
o
f
eral cortex is visible (white arrow). C. On radiograph obtained at 6
B
tiple myeloma or patients receiving high doses o bisphospho-
o
n
weeks, note callus ormation o the racture site (white arrow). D.
e
nates or skeletal metastases, but is rare among persons with
a
On radiograph obtained at 3 months, there is a mature callus that
n
osteoporosis on usual doses o bisphosphonates. T e second
d
has ailed to bridge the cortical gap (white arrow). Note the local-
C
side e ect is called atypical emur racture. T ese are unusual
a
l
ized periosteal and/or endosteal thickening o the lateral cortex at
c
i
ractures that occur distal to the lesser trochanter and any-
u
the racture site (white arrow). (From E Shane et al: J Bone Min Res
m
where along the emoral sha . T ey are o en preceded by pain
M
29:1-23, 2014. Courtesy of Fergus McKiernan.)
e
in the lateral thigh or groin that can be present or weeks or
t
a
b
months be ore the racture. T e ractures occur with trivial
o
end products in the mevalonic acid pathway, by inhibiting the
l
i
s
trauma, sometimes completely spontaneously, and are pri-
m
enzyme arnesyl pyrophosphate synthase. his e ect disrupts
marily transverse, with a medial break when complete and intracellular protein tra icking and ultimately may lead to
minimally comminuted. A localized periosteal reaction, con- apoptosis. Some bisphosphonates have very long retention
sistent with a stress racture, is o en seen in the lateral cortex in the skeleton and may exert long-term e ects. he conse-
(Fig. 35-10). T e overall risk is low (suggested to be about one- quences o this, i any, are unknown.
one hundredth to one-tenth that o hip racture) but appears
Calcitonin Calcitonin is a polypeptide hormone produced by
to increase in incidence with long-term use o bisphospho-
the thyroid gland (Chap. 34). Its physiologic role is unclear
nates. Although the ractures may be bisphosphonate related in
because no skeletal disease has been described in association
many individuals, they clearly occur in patients with no prior
with calcitonin de ciency or excess. Calcitonin preparations
bisphosphonate exposure. When complete, they require surgi-
are approved by the FDA or Paget’s disease, hypercalce-
cal xation and may be di cult to heal. Anabolic medication
mia, and osteoporosis in women >5 years past menopause.
may accelerate healing o these ractures in some patients, and
Concerns have been raised about an increase in the inci-
surgery can sometimes be avoided. Patients initiating bisphos-
dence o cancer associated with calcitonin use. Initially, the
phonates need to be warned that i they develop thigh or groin
cancer noted was o the prostate, but an analysis o all data
pain they must noti y their physician. Routine x-rays will
suggested a more general increase in cancer risk. In Europe,
sometimes pick up cortical thickening or even a stress racture,
the European Medicines Agency (EMA) has removed the
but more commonly MRI or technetium bone scan is required.
osteoporosis indication, and an FDA Advisory Committee has
T e presence o an abnormality requires at minimum a period
voted or a similar change in the United States.
o modi ed weight bearing and may need prophylactic rod-
Injectable calcitonin produces small increments in bone
ding o the emur. It is important to realize that these ractures
mass o the lumbar spine. However, di culty o adminis-
may be bilateral, and when an abnormality is ound, the other
tration and requent reactions, including nausea and acial
emur should be investigated.
ushing, make general use limited. A nasal spray contain-
Mode of Action Bisphosphonates are structurally related to ing calcitonin (200 IU/d) is available or treatment o osteo-
pyrophosphates, compounds that are incorporated into bone porosis in postmenopausal women. One study suggests that
matrix. Bisphosphonates speci ically impair osteoclast unc- nasal calcitonin produces small increments in bone mass and
tion and reduce osteoclast number, in part by inducing apop- a small reduction in new vertebral ractures in calcitonin-
tosis. Recent evidence suggests that the nitrogen-containing treated patients versus those on calcium alone. T ere has
bisphosphonates also inhibit protein prenylation, one o the been no proven e ectiveness against nonvertebral ractures.

Ha rris on_Endocrinology_Ch35_p480-p502.indd 498 20/05/16 9:37 a m

 Calcitonin is not indicated or prevention o osteoporo- A New ve rte bral frac ture
499
sis and is not su ciently potent to prevent bone loss in early P la ce bo De nos uma b
postmenopausal women. Calcitonin might have an analgesic
RR, 0.32 RR, 0.39 RR, 0.22 RR, 0.35
e ect on bone pain, both in the subcutaneous and possibly 8 P < 0.001 P < 0.001 P < 0.001 P < 0.001
the nasal orm. 7

)
6

%
Mode of Action Calcitonin suppresses osteoclast activity by

(
e
5

c
direct action on the osteoclast calcitonin receptor. Osteoclasts

n
e
4

d
exposed to calcitonin cannot maintain their active ru led

i
c
n
i
3
border, which normally maintains close contact with underly-

C
e
d
H
u
ing bone. 2

A
r
C
P
1

T
E
Denosumab A novel agent that was given twice yearly by SC

R
0

3
administration in a randomized controlled trial in postmeno- 0-36 0-12 >12-24 >12-36

5
pausal women with osteoporosis has been shown to increase Month

BMD in the spine, hip, and orearm and reduce vertebral, B Time to firs t no nve rte bral frac ture

O
hip, and nonvertebral ractures over a 3-year period by 70, 9

s
t
e
P la ce bo

o
40, and 20%, respectively (Fig. 35-11). Other clinical trials 8

p
)
%
o
indicate ability to increase bone mass in postmenopausal 7

(
r
o
e
s
c
6

i
women with low bone mass (above osteoporosis range) and

n
s
e
d
5

i
in postmenopausal women with breast cancer treated with De nos uma b

c
n
i
4
hormonal agents. Furthermore, a study o men with pros-
e
v
i
3
t
tate cancer treated with gonadotropin-releasing hormone a
l
u
2
m
(GnRH) agonist therapy indicated the ability o denosumab
u
C
1
to improve bone mass and reduce vertebral racture occur- 0
rence. Denosumab was approved by the FDA in 2010 or the 0 6 12 18 24 30 36
treatment o postmenopausal women who have a high risk Month
or osteoporotic ractures, including those with a history o No . at ris k
P la ce bo 3906 3750 3578 3410 3264 3121 3009
racture or multiple risk actors or racture, and those who De nos uma b 3902 3759 3594 3453 3337 3228 3130
have ailed or are intolerant to other osteoporosis therapy.
C Time to firs t hip frac ture
Denosumab is also approved or the treatment o osteoporo-
1.4
sis in men at high risk, men with prostate cancer on GnRH
1.2 P la ce bo
)
agonist therapy, and women with breast cancer on aromatase
%
(
inhibitor therapy.
e
1.0
c
n
e
0.8
d
i
c
Mode of Action Denosumab is a ully human monoclonal anti-
n
i
0.6
e
body to RANKL, the inal common e ector o osteoclast or-
v
i
t
a
0.4 De nos uma b
mation, activity, and survival. Denosumab binds to RANKL,
l
u
m
inhibiting its ability to initiate ormation o mature osteoclasts
u
0.2
C
rom osteoclast precursors and to bring mature osteoclasts to 0.0
the bone sur ace and initiate bone resorption. Denosumab 0 6 12 18 24 30 36
also plays a role in reducing the survival o the osteoclast. Month
No . at ris k
hrough these actions on the osteoclast, denosumab induces P la ce bo 3906 3799 3672 3538 3430 3311 3221
potent antiresorptive action, as assessed biochemically and De nos uma b 3902 3796 3676 3566 3477 3397 3311
histomorphometrically, and may contribute to the occurrence
o ONJ. Atypical emur ractures have also been noted. Serious FIGURE 3 5 -1 1
Ef e ct s o d e n o su m a b on new vertebral ractures A. and times
adverse reactions include hypocalcemia, skin in ections (usu-
to nonvertebral and hip racture B. and C. RR, relative risk. (After SR
ally cellulitis o the lower extremity), and dermatologic reac-
Cummings et al: N Engl J Med 361:756, 2009.)
tions such as dermatitis, rashes, and eczema. he e ects o
denosumab are rapidly reversible. I denosumab is stopped,
bone will be lost rapidly i another agent is not used.
Parathyroid Hormone Endogenous P H is an 84-amino-acid tion exerts anabolic e ects on bone. eriparatide (1-34hP H)
peptide that is largely responsible or calcium homeostasis is approved or the treatment o osteoporosis in both men and
(Chap. 34). Although chronic elevation o P H, as occurs in women at high risk or racture. In a pivotal study (median
hyperparathyroidism, is associated with bone loss (particularly time o treatment, 19 months’ duration), 20 µg o teriparatide
cortical bone), P H when given exogenously as a daily injec- daily by SC injection reduced vertebral ractures by 65% and

Ha rris on_Endocrinology_Ch35_p480-p502.indd 499 20/05/16 9:37 a m

 500 nonvertebral ractures by 45% (Fig. 35-12). reatment is is not ollowed by an antiresorptive agent, the bone gained is
administered as a single daily injection given or a maximum rapidly lost.
o 2 years. eriparatide produces increases in bone mass and Side e ects o teriparatide are generally mild and can include
mediates architectural improvements in skeletal structure. leg cramps, muscle pain, weakness, dizziness, headache, and
T ese e ects are lower when patients have been exposed nausea. Rodents given prolonged treatment with P H in rela-
previously to bisphosphonates, possibly in proportion to tively high doses developed osteogenic sarcomas. Long-term
the potency o the antiresorptive e ect. When teriparatide surveillance studies suggest no association between 2 years o
is being considered or treatment-naive patients, it is best teriparatide administration and osteosarcoma risk in humans.
administered as monotherapy and ollowed by an antiresorp- P H use may be limited by its mode o administration;
tive agent such as a bisphosphonate. I teriparatide treatment alternative modes o delivery are being investigated. T e opti-
S
E
mal requency o administration also remains to be estab-
C
T
I
lished, and it is possible that P H might be e ective when
O
N
used intermittently. Cost also may be a limiting actor. In
V
I
Effe c t o f te riparatide o n the ris k o f ne w some settings, the e ect o P H might be enhanced by com-
ve rte bral frac ture s bination with an antiresorptive agent. T is might be particu-
larly important in patients who have been treated previously
D
i
s
70 15 with bisphosphonate medications.
o
r
s
d
r
e
o
14
e
r
60
r
u
1
Mode of Action Exogenously administered P H appears to have
s
Ris k re duction
t
c
h
12
o
t
a
f
50
i
direct actions on osteoblast activity, with biochemical and
r
w
n
B
Re la tive : Re la tive :
f
10
e
l
o
n
a
m
65% 69% histomorphometric evidence o de novo bone ormation early
n
40
r
e
b
e
o
m
8
w
e
Abs olute : Abs olute :
a
in response to P H, be ore activation o bone resorption.
o
t
r
n
w
30
f
ve
9.3% 9.9%
o
d
6
f
Subsequently, P H activates bone remodeling but still appears
%
o
C
w
20
a
r
e
4
l
e
to avor bone ormation over bone resorption. P H stimulates
c
n
b
i
u
m
e
10 2
m
r
Wnt signaling, IGF-I, and collagen production and appears
u
o
64 22 19
N
m
M
0 0 to increase osteoblast number by stimulating replication,
e
P la ce bo TP TD20 TP TD40
t
a
enhancing osteoblast recruitment, and inhibiting apoptosis.
b
A (n = 448) (n = 444) (n = 434)
o
l
Unlike all other treatments, P H produces a true increase in
i
s
Effe c t o f te riparatide o n the ris k o f no nve rte bral
m
frag ility frac ture s bone tissue and an apparent restoration o bone microarchi-
35 6 tecture (Fig. 35-13).
s
e
Ris k re duction
r
30 5 Fluoride Fluoride has been available or many years and is
u
h
t
t
i
c
w
Re la tive : Re la tive : a potent stimulator o osteoprogenitor cells when studied
a
25
r
f
n
53% 54% 4
n
y
e
in vitro. It has been used in multiple osteoporosis studies
e
t
m
i
Abs olute : Abs olute :
m
20
l
i
o
g
o
3 with con licting results, in part because o the use o varying
w
2.9% 3.0%
a
w
r
f
f
15
f
o
doses and preparations. Despite increments in bone mass
l
o
a
r
2
r
%
e
b
10 o up to 10%, there are no consistent e ects o luoride on
b
e
m
t
r
u
e
1 vertebral or nonvertebral racture; the latter may actually
N
5
v
n
30 14 14
o
increase when high doses o luoride are used. Fluoride
n
0 0
P la ce bo TP TD20 TP TD40
B (n = 544) (n = 541) (n = 552)
Effe c t o f te riparatide o n the ris k o f no nve rte bral
frag ility frac ture s (time to firs t frac ture )
8
7
6
*
*
*P <0.05 vs . pla ce bo
n
5 P la ce bo
e
m
4
o
w
3 TP TD20
f
o
*
2 * TP TD40
%
1
0
0 2 4 6 8 10 12 14 16 18 20
C Months s ince ra ndomiza tion FIGURE 3 5 -1 3
FIGURE 3 5 -1 2 Ef e ct o p a ra t h yro id h o rm o n e (PTH) t re a t m e n t o n b o n e
Ef e ct s o te rip a ra t id e (TPTD) on new vertebral ractures A. m icro a rch ite ct u re . Paired biopsy specimens rom a 64-year-
and nonvertebral ragility ractures B. and C. (After RM Neer et al: old woman be ore A. and a ter B. treatment with PTH. (From DW
N Engl J Med 344:1434, 2001.) Dempster et al: J Bone Miner Res 16:1846, 2001.)

Ha rris on_Endocrinology_Ch35_p480-p502.indd 500 20/05/16 9:37 a m

 remains an experimental agent despite its long history and
multiple studies.
Strontium Ranelate Strontium ranelate is approved in several
European countries or the treatment o osteoporosis. It
increases bone mass throughout the skeleton; in clinical tri-
als, the drug reduced the risk o vertebral ractures by 37%
and that o nonvertebral ractures by 14%. It appears to be
modestly antiresorptive while at the same time not causing as
much o a decrease in bone ormation (measured biochemi-
cally). Strontium is incorporated into hydroxyapatite, replac-
ing calcium, a eature that might explain some o its racture
bene its. Small increased risks o venous thrombosis, some-
times severe dermatologic reactions, seizures, and abnormal
cognition have been seen and require urther study. An
increase in risk o cardiovascular disease has also been associ-
ated with use o strontium, such that the EMA has restricted
its use at present.
Other Potential Anabolic Agents Several small studies o growth
hormone (GH), alone or in combination with other agents,
have not shown consistent or substantial positive e ects on
skeletal mass. Many o these studies have been relatively
short term, and the e ects o GH, growth hormone–releasing
hormone, and the IGFs are still under investigation. Anabolic
steroids, mostly derivatives o testosterone, act primarily as
antiresorptive agents to reduce bone turnover but also may
stimulate osteoblastic activity. E ects on bone mass remain
unclear but appear weak in general, and use is limited by mas-
culinizing side e ects. Several observational studies suggested
that the statin drugs, used to treat hypercholesterolemia, may
be associated with increased bone mass and reduced ractures,
but conclusions rom clinical trials have been largely negative.
Early studies with sclerostin antibodies, which inhibit scleros-
tin, activate Wnt, and might be highly anabolic to bone, are
under development. Odanacatib is a mixed antiresorptive,
partial bone ormation stimulator that is currently in the late
stages o development.
NONPHARMACOLOGIC APPROACHES In some early studies, pro-
tective pads worn around the outer thigh, which cover the
trochanteric region o the hip, were able to prevent hip rac-
tures in elderly residents in nursing homes. Randomized con-
trolled trials o hip protectors have been unable to con rm
these early ndings. T ere ore, the e cacy o hip protectors
remains controversial at this time.
Kyphoplasty and vertebroplasty are also use ul nonpharma-
cologic approaches or the treatment o pain ul vertebral rac-
tures. However, no long-term data are available.
TREATMENT MONITORING T ere are currently no well-accepted
guidelines or monitoring treatment o osteoporosis. Because
most osteoporosis treatments produce small or moderate
bone mass increments on average, it is reasonable to consider
BMD as a monitoring tool. Changes must exceed ~4% in the
spine and 6% in the hip to be considered signi cant in any
individual. T e hip is the pre erred site due to larger sur ace
Ha rris on_Endocrinology_Ch35_p480-p502.indd 501
area and greater reproducibility. Medication-induced incre- 501
ments may require several years to produce changes o this
magnitude (i they do at all). Consequently, it can be argued
that BMD should be repeated at intervals >2 years. Only sig-
ni cant BMD reductions should prompt a change in medical
regimen, because it is expected that many individuals will not
show responses greater than the detection limits o the cur-
rent measurement techniques.
Biochemical markers o bone turnover may prove use ul
C
or treatment monitoring, but little hard evidence currently
H
A
supports this concept; it remains unclear which endpoint is
P
T
most use ul. I bone turnover markers are used, a determina-
E
R
tion should be made be ore therapy is started and repeated
3
5
≥4 months a er therapy is initiated. In general, a change in
bone turnover markers must be 30–40% lower than the base-
line to be signi cant because o the biologic and technical
O
s
t
variability in these tests. A positive change in biochemical
e
o
p
markers and/or bone density can be use ul to help patients
o
r
o
adhere to treatment regimens.
s
i
s
GLUCO CO RTICO ID-INDUCED
O STEO P O RO SIS
Osteoporotic ractures are a well-characterized con-
sequence o the hypercortisolism associated with
Cushing’s syndrome. However, the therapeutic use o
glucocorticoids is by ar the most common orm o glu-
cocorticoid-induced osteoporosis. Glucocorticoids are
used widely in the treatment o a variety o disorders,
including chronic lung disorders, rheumatoid arthri-
tis and other connective tissue diseases, in ammatory
bowel disease, and a er transplantation. Osteoporosis
and related ractures are serious side e ects o chronic
glucocorticoid therapy. Because the e ects o glucocor-
ticoids on the skeleton are o en superimposed on the
consequences o aging and menopause, it is not sur-
prising that women and the elderly are most requently
a ected. T e skeletal response to steroids is remarkably
heterogeneous, however, and even young, growing indi-
viduals treated with glucocorticoids can present with
ractures.
T e risk o ractures depends on the dose and dura-
tion o glucocorticoid therapy, although recent data
suggest that there may be no completely sa e dose. Bone
loss is more rapid during the early months o treatment,
and trabecular bone is a ected more severely than cor-
tical bone. As a result, ractures have been shown to
increase within 3 months o steroid treatment. T ere
is an increase in racture risk in both the axial skeleton
and the appendicular skeleton, including risk o hip
racture. Bone loss can occur with any route o steroid
administration, including high-dose inhaled gluco-
corticoids and intraarticular injections. Alternate-day
20/05/16 9:37 a m
 502 delivery does not appear to ameliorate the skeletal long-term (>3 months) glucocorticoids should have
e ects o glucocorticoids. measurement o bone mass at both the spine and the
hip using DXA. I only one skeletal site can be mea-
sured, it is best to assess the spine in individuals <60
PATHOPHYSIOLOGY years and the hip in those >60 years.
Glucocorticoids increase bone loss by multiple mecha-
nisms, including (1) inhibition o osteoblast unction
PREVENTION
and an increase in osteoblast apoptosis, resulting in
impaired synthesis o new bone; (2) stimulation o bone Bone loss caused by glucocorticoids can be prevented
resorption, probably as a secondary e ect; (3) impair- and the risk o ractures signi cantly reduced. Strategies
S
E
C
ment o the absorption o calcium across the intes- must include using the lowest dose o glucocorticoid
T
I
O
tine, probably by a vitamin D–independent e ect; (4) or disease management. opical and inhaled routes o
N
increase o urinary calcium loss and perhaps induc- administration are pre erred, where appropriate. Risk
V
I
tion o some degree o secondary hyperparathyroidism; actor reduction is important, including smoking cessa-
(5) reduction o adrenal androgens and suppression o tion, limitation o alcohol consumption, and participa-
D
ovarian and testicular secretion o estrogens and andro- tion in weight-bearing exercise, when appropriate. All
i
s
o
gens; and (6) induction o glucocorticoid myopathy, patients should receive an adequate calcium and vita-
r
d
e
which may exacerbate e ects on skeletal and calcium min D intake rom the diet or rom supplements.
r
s
o
homeostasis as well as increase the risk o alls.
f
B
o
n
e
a
TREATMENT Glucocorticoid-Induced Osteoporosis
n
EVALUATION OF THE PATIENT
d
C
a
Because o the prevalence o glucocorticoid-induced Several bisphosphonates (alendronate, risedronate, and zole-
l
c
i
u
bone loss, it is important to evaluate the status o the dronic acid) have been demonstrated in large clinical trials to
m
M
skeleton in all patients starting or already receiving reduce the risk o vertebral ractures in patients being treated
e
t
long-term glucocorticoid therapy. Modi able risk ac-
a
with glucocorticoids, as well as improve bone mass in spine
b
o
tors should be identi ed, including those or alls. and hip. eriparatide also improves bone mass and reduces
l
i
s
m
Examination should include testing o height and racture risk in glucocorticoid-treated osteoporosis compared
muscle strength. Laboratory evaluation should include to an active comparator (alendronate).
an assessment o 24-h urinary calcium. All patients on

Ha rris on_Endocrinology_Ch35_p480-p502.indd 502 20/05/16 9:37 a m

 CH AP TER 3 6
PAGET’S DISEASE AND OTHER
DYSPLASIAS OF BONE
Mu rray J. Favu s
PAGET’S DISEASE O F BO NE
Paget’s disease is a localized bone-remodeling disor-
der that a ects widespread, noncontiguous areas o the
skeleton. T e pathologic process is initiated by overac-
tive osteoclastic bone resorption ollowed by a com-
pensatory increase in osteoblastic new bone ormation,
resulting in a structurally disorganized mosaic o woven
and lamellar bone. Pagetic bone is expanded, less com-
pact, and more vascular; thus, it is more susceptible to
de ormities and ractures. Although most patients are
asymptomatic, symptoms resulting directly rom bony
involvement (bone pain, secondary arthritis, rac-
tures) or secondarily rom the expansion o bone caus-
ing compression o surrounding neural tissue are not
uncommon.
Ep id em io lo g y
T ere is a marked geographic variation in the re-
quency o Paget’s disease, with high prevalence in
Western Europe (Great Britain, France, and Ger-
many, but not Switzerland or Scandinavia) and among
those who have immigrated to Australia, New Zealand,
South A rica, and North and South America. T e disease
is rare in native populations o the Americas, A rica,
Asia, and the Middle East; when it does occur, the
a ected subjects usually have evidence o European
ancestry, supporting the migration theory. For unclear
reasons, the prevalence and severity o Paget’s disease are
decreasing, and the age o diagnosis is increasing.
T e prevalence is greater in males and increases
with age. Autopsy series reveal Paget’s disease in about
3% o those over age 40. Prevalence o positive skeletal
radiographs in patients over age 55 is 2.5% or men and
1.6% or women. Elevated alkaline phosphatase (ALP)
levels in asymptomatic patients have an age-adjusted
Ha rris on_Endocrinology_Ch36_p503-p514.indd 503
■ Tam a ra J. Vo ke s
incidence o 12.7 and 7 per 100,000 person-years in
men and women, respectively.
Etio lo g y
T e etiology o Paget’s disease o bone remains
unknown, but evidence supports both genetic and viral
etiologies. A positive amily history is ound in 15–25%
o patients and, when present, raises the prevalence
o the disease seven- to ten old among rst-degree
relatives.
A clear genetic basis has been established or several
rare amilial bone disorders that clinically and radio-
graphically resemble Paget’s disease but have more
severe presentation and earlier onset. A homozygous
deletion o the TNFRSF11B gene, which encodes osteo-
protegrin (Fig. 36-1), causes juvenile Paget’s disease,
also known as amilial idiopathic hyperphosphatasia, a
disorder characterized by uncontrolled osteoclastic di -
erentiation and resorption. Familial patterns o disease
in several large kindred are consistent with an auto-
somal dominant pattern o inheritance with variable
penetrance. Familial expansile osteolysis, expansile skel-
etal hyperphosphatasia, and early-onset Paget’s disease
are associated with mutations in TNFRSF11A gene,
which encodes RANK (receptor activator o nuclear
actor-κB), a member o the tumor necrosis ac-
tor super amily critical or osteoclast di erentiation
(Fig. 36-1). Finally, mutations in the gene or valosin-
containing protein cause a rare syndrome with auto-
somal dominant inheritance and variable penetrance
known as inclusion body myopathy with Paget’s disease
and rontotemporal dementia (IBMPFD). T e role o
genetic actors is less clear in the more common orm
o late-onset Paget’s disease. Although a ew amilies
with mutations in the gene encoding RANK have been
reported, the most common mutations identi ed in
503
27/07/16 11:06 a m
 504
Me s e nchyma l ce ll
containing the measles virus nucleocapsid or matrix
genes. However, the viral etiology has been questioned by
M-CS F
c-fms
the inability to culture a live virus rom pagetic bone and
by ailure to clone the ull-length viral genes rom mate-
OP G rial obtained rom patients with Paget’s disease.
+
RANK L Os te ocla s t
pre curs or Pa th o p hysio lo gy
IL-1, IL-6
T e principal abnormality in Paget’s disease is the
IGF-1 RANK increased number and activity o osteoclasts. Pag-
S
IGF-2
E
etic osteoclasts are large, increased 10- to 100- old in
C
T
I
number, and have a greater number o nuclei (as many
O
N
as 100 compared to 3–5 nuclei in the normal osteo-
V
Os te obla s ts
I
Os te obla s ts clast). T e overactive osteoclasts may create a seven old
increase in resorptive sur aces and an erosion rate o 9
µg/d (normal is 1 µg/d). Several causes or the increased
D
Colla ge n
i
s
Os te ocla s t
number and activity o pagetic osteoclasts have been
o
os te oca lcin
r
d
identi ed: (1) osteoclastic precursors are hypersensitive
e
r
FIGURE 3 6 -1
s
to 1,25(OH)2D3; (2) osteoclasts are hyperresponsive to
o
f
Dia g ra m illu stra tin g a cto rs th a t p ro m o te d i e re n tia tio n
B
RANK ligand (RANKL), the osteoclast stimulatory ac-
o
a n d u n ctio n o o ste o cla sts a n d o ste o b la sts a n d th e ro le
n
tor that mediates the e ects o most osteotropic actors
e
a
o th e RANK p a thwa y. Stromal bone marrow (mesenchymal)
n
on osteoclast ormation; (3) marrow stromal cells rom
d
cells and di erentiated osteoblasts produce multiple growth ac-
C
pagetic lesions have increased RANKL expression; (4)
a
tors and cytokines, including macrophage colony-stimulating
l
c
i
osteoclast precursor recruitment is increased by inter-
u
actor (M-CSF), to modulate osteoclastogenesis. RANKL (receptor
m
leukin (IL) 6, which is increased in the blood o patients
M
activator o nuclear actor-κB ligand) is produced by osteoblast pro-
e
with active Paget’s disease and is overexpressed in pagetic
t
genitors and mature osteoblasts and can bind to a soluble decoy
a
b
osteoclasts; (5) expression o the protooncogene c- os,
o
receptor known as OPG (osteoprotegerin) to inhibit RANKL action.
l
i
s
which increases osteoclastic activity, is increased; and
m
Alternatively, a cell-cell interaction between osteoblast and osteo-
clast progenitors allows RANKL to bind to its membrane-bound (6) the antiapoptotic oncogene Bcl-2 in pagetic bone is
receptor, RANK, thereby stimulating osteoclast di erentiation and overexpressed. Numerous osteoblasts are recruited to
unction. RANK binds intracellular proteins called TRAFs (tumor active resorption sites and produce large amounts o new
necrosis actor receptor–associated actors) that mediate receptor bone matrix. As a result, bone turnover is high, and bone
signaling through transcription actors such as NF-κB. M-CSF binds mass is normal or increased, not reduced, unless there is
to its receptor, c- ms, which is the cellular homologue o the fms concomitant de ciency o calcium and/or vitamin D.
oncogene. See text or the potential role o these pathways in dis- T e characteristic eature o Paget’s disease is
orders o osteoclast unction such as Paget’s disease and osteope- increased bone resorption accompanied by accelerated
trosis. IL, interleukin; IGF, insulin-like growth actor. bone ormation. An initial osteolytic phase involves
prominent bone resorption and marked hypervascular-
ization. Radiographically, this mani ests as an advanc-
amilial and sporadic cases o Paget’s disease have been ing lytic wedge, or “blade o grass” lesion. T e second
in the SQSTM1 gene (sequestasome-1 or p62 protein) phase is a period o very active bone ormation and
in the C-terminal ubiquitin-binding domain. T e p62 resorption that replaces normal lamellar bone with
protein is involved in nuclear actor κB (NF-κB) signal- haphazard (woven) bone. Fibrous connective tissue
ing and regulates osteoclastic di erentiation. T e phe- may replace normal bone marrow. In the nal sclerotic
notypic variability in patients with SQSTM1 mutations phase, bone resorption declines progressively and leads
suggests that additional actors, such as other genetic to a hard, dense, less vascular pagetic or mosaic bone,
in uences or viral in ection, may in uence clinical which represents the so-called burned-out phase o
expression o the disease. Paget’s disease. All three phases may be present at the
Several lines o evidence suggest that a viral in ection same time at di erent skeletal sites.
may contribute to the clinical mani estations o Paget’s
disease, including (1) the presence o cytoplasmic and
nuclear inclusions resembling paramyxoviruses (measles Clin ica l m a n i esta tio n s
and respiratory syncytial virus) in pagetic osteoclasts Diagnosis is o en made in asymptomatic patients because
and (2) viral mRNA in precursor and mature osteoclasts. they have elevated ALP levels on routine blood chem-
T e viral etiology is urther supported by conversion o istry testing or an abnormality on a skeletal radiograph
osteoclast precursors to pagetic-like osteoclasts by vectors obtained or another indication. T e skeletal sites most

Ha rris on_Endocrinology_Ch36_p503-p514.indd 504 27/07/16 11:06 a m

 commonly involved are the pelvis, vertebral bodies, skull,
emur, and tibia. Familial cases with an early presentation
o en have numerous active sites o skeletal involvement.
T e most common presenting symptom is pain,
which may result rom increased bony vascularity,
expanding lytic lesions, ractures, bowing, or other
de ormities. Bowing o the emur or tibia causes gait
abnormalities and abnormal mechanical stresses with
secondary osteoarthritis o the hip or knee joints. Long
bone bowing also causes extremity pain by stretching
potent antiresorptive agents. T e majority o tumors are 505
osteosarcomas, which usually present with new pain in
a long-standing pagetic lesion. Osteoclast-rich benign
giant cell tumors may arise in areas adjacent to pagetic
bone, and they respond to glucocorticoid therapy.
Cardiovascular complications may occur in patients
with involvement o large (15–35%) portions o the
skeleton and a high degree o disease activity (ALP
our times above normal). T e extensive arteriovenous
shunting and marked increases in blood ow through

C
H
A
the muscles attached to the bone so ened by the pag- the vascular pagetic bone lead to a high-output state

P
T
etic process. Back pain results rom enlarged pagetic and cardiac enlargement. However, high-output heart

E
R
vertebrae, vertebral compression ractures, spinal steno- ailure is relatively rare and usually develops in patients

sis, degenerative changes o the joints, and altered body
mechanics with kyphosis and orward tilt o the upper
back. Rarely, spinal cord compression may result rom
3
6
with concomitant cardiac pathology. In addition, cal-
ci c aortic stenosis and di use vascular calci cations
have been associated with Paget’s disease.

P
a
g
bone enlargement or rom the vascular steal syndrome.

e
t
’
s
Skull involvement may cause headaches, symmetric Dia g n o sis

D
i
s
or asymmetric enlargement o the parietal or rontal

e
a
T e diagnosis may be suggested on clinical examination

s
bones ( rontal bossing), and increased head size. Cra-

e
a
nial expansion may narrow cranial oramens and cause by the presence o an enlarged skull with rontal boss-

n
d
ing, bowing o an extremity, or short stature with simian

O
neurologic complications including hearing loss rom

t
h
cochlear nerve damage rom temporal bone involve- posturing. An extremity with an area o warmth and ten-

e
r
derness to palpation may suggest an underlying pagetic

D
ment, cranial nerve palsies, and so ening o the base o

y
s
lesion. Other ndings include bony de ormity o the pel-

p
the skull (platybasia) with the risk o brainstem com-

l
a
vis, skull, spine, and extremities; arthritic involvement o

s
pression. Pagetic involvement o the acial bones may

i
a
s
cause acial de ormity; loss o teeth and other dental the joints adjacent to lesions; and leg-length discrepancy

o
f
B
conditions; and, rarely, airway compression. resulting rom de ormities o the long bones.

o
n
Paget’s disease is usually diagnosed rom radiologic

Fractures are serious complications o Paget’s dis-
ease and usually occur in long bones at areas o active
or advancing lytic lesions. Common racture sites are
the emoral sha and subtrochanteric regions. Neo-
plasms arising rom pagetic bone are rare (<0.5%). T e
incidence o sarcoma appears to be decreasing, pos-
sibly because o earlier, more e ective treatment with
e
and biochemical abnormalities. Radiographic nd-
ings typical o Paget’s disease include enlargement
or expansion o an entire bone or area o a long bone,
cortical thickening, coarsening o trabecular markings,
and typical lytic and sclerotic changes. Skull radio-
graphs (Fig. 36-2) reveal regions o “cotton wool,” or

FIGURE 3 6 -2
A 4 8-ye a r-o ld wo m a n wit h Pa g e t ’s d ise a se o t h e sku ll. and lateral views o the skull showing di use isotope uptake by
Le t. Lateral radiograph showing areas o both bone resorption the rontal, parietal, occipital, and petrous bones.
and sclerosis. Rig h t. 99mTc HDP bone scan with anterior, posterior,

Ha rris on_Endocrinology_Ch36_p503-p514.indd 505 27/07/16 11:06 a m

 506 osteoporosis circumscripta, thickening o diploic areas, bone marker elevation re ects the extent and severity
and enlargement and sclerosis o a portion or all o one o the disease. Patients with the highest elevation o
or more skull bones. Vertebral cortical thickening o ALP (10 × the upper limit o normal) typically have
the superior and in erior end plates creates a “picture involvement o the skull and at least one other skeletal
rame” vertebra. Di use radiodense enlargement o a site. Lower values suggest less extensive involvement
vertebra is re erred to as “ivory vertebra.” Pelvic radio- or a quiescent phase o the disease. For most patients,
graphs may demonstrate disruption or usion o the serum total ALP remains the test o choice both or
sacroiliac joints; porotic and radiodense lesions o the diagnosis and assessing response to therapy. Occasion-
ilium with whorls o coarse trabeculation; thickened ally, a symptomatic patient with evidence o progres-
and sclerotic iliopectineal line (brim sign); and so en- sion at a single site may have a normal total ALP level
S
E
ing with protrusio acetabuli, with axial migration o the but increased bone-speci c ALP. For unclear reasons,
C
T
I
hips and unctional exion contracture. Radiographs serum osteocalcin, another marker o bone ormation,
O
N
o long bones reveal bowing de ormity and typical pag- is not always elevated and is not recommended or use
V
I
etic changes o cortical thickening and expansion and in diagnosis or management o Paget’s disease. Bone
areas o lucency and sclerosis (Fig. 36-3). Radionuclide resorption markers (serum or urine N-telopeptide or
99m
c bone scans are less speci c but are more sensitive C-telopeptide measured in the blood or urine) are also
D
i
s
than standard radiographs or identi ying sites o active elevated in active Paget’s disease and decrease more
o
r
d
skeletal lesions. Although computed tomography (C ) rapidly in response to therapy than does ALP.
e
r
s
and magnetic resonance imaging (MRI) studies are Serum calcium and phosphate levels are normal in
o
f
B
not necessary in most cases, C may be use ul or the Paget’s disease. Immobilization o a patient with active
o
n
e
assessment o possible racture, and MRI is necessary Paget’s disease may rarely cause hypercalcemia and
a
n
to assess the possibility o sarcoma, giant cell tumor, or hypercalciuria and increase the risk or nephrolithia-
d
C
metastatic disease in pagetic bone. De nitive diagnosis sis. However, the discovery o hypercalcemia, even in
a
l
c
i
o malignancy o en requires bone biopsy. the presence o immobilization, should prompt a search
u
m
Biochemical evaluation is use ul in the diagno- or another cause o hypercalcemia. In contrast, hypo-
M
e
sis and management o Paget’s disease. T e marked calcemia or mild secondary hyperparathyroidism may
t
a
b
increase in bone turnover can be monitored using develop in Paget’s patients with very active bone or-
o
l
i
s
biochemical markers o bone ormation and resorp- mation and insu cient calcium and vitamin D intake,
m
tion. T e parallel rise in markers o bone ormation particularly during bisphosphonate therapy when bone
and resorption con rms the coupling o bone orma- resorption is rapidly suppressed and active bone or-
tion and resorption in Paget’s disease. T e degree o mation continues. T ere ore, adequate calcium and
vitamin D intake should be instituted prior to adminis-
tration o bisphosphonates.

TREATMENT Paget’s Disease of Bone

T e development o e ective and potent pharmacologic

FIGURE 3 6 -3
Ra d io g ra p h o a 73-ye a r-o ld m a n wit h Pa g e t ’s d ise a se o
th e rig h t p roxim a l e m u r. Note the coarsening o the trabecu-
lar pattern with marked cortical thickening and narrowing o the
joint space consistent with osteoarthritis secondary to pagetic
de ormity o the right emur.
agents (Table 36-1) has changed the treatment philosophy
rom treating only symptomatic patients to treating asymp-
tomatic patients who are at risk or complications. Pharma-
cologic therapy is indicated in the ollowing circumstances:
to control symptoms caused by metabolically active Paget’s
disease such as bone pain, racture, headache, pain rom
pagetic radiculopathy or arthropathy, or neurologic compli-
cations; to decrease local blood ow and minimize operative
blood loss in patients who need surgery at an active pagetic
site; to reduce hypercalciuria that may occur during immo-
bilization; and to decrease the risk o complications when
disease activity is high (elevated ALP) and when the site o
involvement involves weight-bearing bones, areas adjacent to
major joints, vertebral bodies, and the skull. Whether or not
early therapy prevents late complications remains to be deter-
mined. A randomized study o over 1200 patients rom the
United Kingdom showed no di erence in bone pain, racture

Ha rris on_Endocrinology_Ch36_p503-p514.indd 506 27/07/16 11:06 a m

 TABLE 3 6 -1 or 30–60 min. T e e cacy o di erent agents, based on their 507
PHARMACOLOGIC AGENTS APPROVED FOR ability to normalize or decrease ALP levels, is summarized in
TREATMENT OF PAGET’S DISEASE able 36-1, although the response rates are not comparable
DOSE AND MODE NORMALIZATION because they are obtained rom di erent studies.
NAME OF DELIVERY OF ALP Intravenous bisphosphonates approved or Paget’s dis-
Zoledronic acid 5 mg IV over 15 90% o patients at ease include pamidronate and zoledronic acid. Although the
min 6 mo recommended dose or pamidronate is 30 mg dissolved in
500 mL o normal saline or dextrose IV over 4 h on 3 con-
Pamidronate 30 mg IV/d over ~50% o patients
4 h on 3 days secutive days, a more commonly used simpler regimen is

C
a single in usion o 60–90 mg in patients with mild eleva-

H
Risedronate 30 mg PO/d or 73% o patients

A
tion o serum ALP and multiple 90-mg in usions in those

P
2 mo

T
with higher levels o ALP. In many patients, particularly

E
Alendronate 40 mg PO/d or 63% o patients

R
those who have severe disease or need rapid normaliza-

3
6 mo

6
tion o bone turnover (neurologic symptoms, severe bone
Tiludronate 800 mg PO daily 35% o patients
pain due to a lytic lesion, risk o an impending racture, or
or 3 mo
pretreatment prior to elective surgery in an area o active

P
a
Etidronate 200–400 mg PO/d 15% o patients

g
disease), treatment with zoledronic acid is the rst choice. It

e
t
× 6 mo

’
s
normalizes ALP in about 90% o patients by 6 months, and

D
i
Calcitonin 100 U SC daily or (Reduction o ALP

s
the therapeutic e ect persists or at least 6 more months in

e
a
(Miacalcin) 6–18 mo (may by up to 50%)

s
most patients. About 10–20% o patients experience a ulike

e
reduce to 50 U

a
syndrome a er the rst in usion, which can be partly ame-

n
3 × per wk)

d
O
liorated by pretreatment with acetaminophen or nonsteroi-

t
h
dal anti-in ammatory drugs (NSAIDs). In patients with high

e
r
D
bone turnover, vitamin D and calcium should be provided

y
s
p
to prevent hypocalcemia and secondary hyperparathyroid-

l
a
s
rates, quality o li e, and hearing loss between patients who ism. Remission ollowing treatment with IV bisphosphonates,

i
a
s
received pharmacologic therapy to control symptoms (bone

o
particularly zoledronic acid, may persist or well over 1 year.

f
B
pain) and those receiving bisphosphonates to normalize Bisphosphonates should not be used in patients with renal

o
n
serum ALP. However, the most potent agent (zoledronic acid)

was not used, and the duration o observation (mean o 3
years with a range o 2 to 5 years) may not be long enough
to assess the impact o treatment on long-term outcomes. It
seems likely that the restoration o normal bone architecture
ollowing suppression o pagetic activity will prevent urther
de ormities and complications.
Agents approved or treatment o Paget’s disease sup-
press the very high rates o bone resorption and secondarily
decrease the high rates o bone ormation ( able 36-1). As
a result o decreasing bone turnover, pagetic structural pat-
terns, including areas o poorly mineralized woven bone,
are replaced by more normal cancellous or lamellar bone.
Reduced bone turnover can be documented by a decline
in serum ALP and urine or serum resorption markers
(N-telopeptide, C-telopeptide).
T e rst clinically use ul agent, etidronate, is now rarely
used because the doses required to suppress bone resorp-
tion may impair mineralization, necessitating that the drug
be given or a maximum o 6 months ollowed by a 6-month
drug- ree period. T e second-generation oral bisphospho-
nates—tiludronate, alendronate, and risedronate—are more
potent than etidronate in controlling bone turnover and,
thus, induce a longer remission at a lower dose. T e lower
doses reduce the risks o impaired mineralization and osteo-
malacia. Oral bisphosphonates should be taken rst thing in
the morning on an empty stomach, ollowed by maintenance
o upright posture with no ood, drink, or other medications
e
insu ciency (glomerular ltration rate <35 mL/min).
T e subcutaneous injectable orm o salmon calcitonin is
approved or the treatment o Paget’s disease. T e common
side e ects o calcitonin therapy are nausea and acial ush-
ing. Secondary resistance a er prolonged use may be due to
either the ormation o anticalcitonin antibodies or down-
regulation o osteoclastic cell–sur ace calcitonin receptors.
T e lower potency and injectable mode o delivery make
this agent a less attractive treatment option that should be
reserved or patients who either do not tolerate bisphospho-
nates or have a contraindication to their use. In early reports,
denosumab, an antibody to RANKL, has shown promise but
has not been approved or this indication.
SCLERO SING BO NE DISO RDERS
OSTEOPETROSIS
Osteopetrosis re ers to a group o disorders caused by
severe impairment o osteoclast-mediated bone resorp-
tion. Other terms that are o en used include marble
bone disease, which captures the solid x-ray appearance
o the involved skeleton, and Albers-Schonberg disease,
which re ers to the milder, adult orm o osteopetrosis
also known as autosomal dominant osteopetrosis type
II. T e major types o osteopetrosis include malignant

Ha rris on_Endocrinology_Ch36_p503-p514.indd 507 27/07/16 11:06 a m

 508 (severe, in antile, autosomal recessive) osteopetrosis
and benign (adult, autosomal dominant) osteopetrosis
types I and II. A rare autosomal recessive intermediate
orm has a more benign prognosis. Autosomal recessive
carbonic anhydrase (CA) II de ciency produces osteo-
petrosis o intermediate severity associated with renal
tubular acidosis and cerebral calci cation.
by loss o vision, dea ness, psychomotor delay, man-
dibular osteomyelitis, and other complications usually
associated with the juvenile orm. In some kindred,
nonpenetrance results in skip generations, while in
other amilies, severely a ected children are born into
amilies with benign disease. T e milder orm o the
disease does not usually require treatment.

Etio lo g y a n d g en etics Ra d io g ra p hy
S
E
C
Naturally occurring and gene-knockout animal mod- ypically, there are generalized symmetric increases in
T
I
O
els with phenotypes similar to those o the human dis- bone mass with thickening o both cortical and trabec-
N
V
orders have been used to explore the genetic basis o ular bone. Diaphyses and metaphyses are broadened,
I
osteopetrosis. T e primary de ect in osteopetrosis is the and alternating sclerotic and lucent bands may be seen
loss o osteoclastic bone resorption and preservation o in the iliac crests, at the ends o long bones, and in ver-
D
normal osteoblastic bone ormation. Osteoprotegerin tebral bodies. T e cranium is usually thickened, par-
i
s
o
(OPG) is a soluble decoy receptor that binds osteoblast- ticularly at the base o the skull, and the paranasal and
r
d
e
derived RANK ligand, which mediates osteoclast di - mastoid sinuses are underpneumatized.
r
s
o
erentiation and activation (Fig. 36-1). ransgenic mice
f
B
o
that overexpress OPG develop osteopetrosis, presum-
n
e
ably by blocking RANK ligand. Mice de cient in RANK La b o ra to ry f nd ing s
a
n
d
lack osteoclasts and develop severe osteopetrosis. T e only signi cant laboratory ndings are elevated
C
a
Recessive mutations o CA II prevent osteoclasts
l
c
serum levels o osteoclast-derived tartrate-resistant acid
i
u
rom generating an acid environment in the clear zone
m
phosphatase ( RAP) and the brain isoenzyme o creatine
M
between its ruf ed border and the adjacent mineral sur- kinase. Serum calcium may be low in severe disease, and
e
t
ace. Absence o CA II, there ore, impairs osteoclastic
a
parathyroid hormone and 1,25-dihydroxyvitamin D lev-
b
o
bone resorption. Other orms o human disease have
l
i
els may be elevated in response to hypocalcemia.
s
m
less clear genetic de ects. About one-hal o the patients
with malignant in antile osteopetrosis have a mutation
in the TCIRG1 gene encoding the osteoclast-speci c
subunit o the vacuolar proton pump, which mediates TREATMENT Osteopetrosis
the acidi cation o the inter ace between bone min-
Allogeneic HLA-identical bone marrow transplantation has
eral and the osteoclast ruf ed border. Mutations in the
been success ul in some children. Following transplantation,
CICN7 chloride channel gene cause autosomal domi- the marrow contains progenitor cells and normally unctioning
nant osteopetrosis type II.
osteoclasts. A cure is most likely when children are transplanted
be ore age 4. Marrow transplantation rom nonidentical HLA-
Clin ica l p resen ta tio n matched donors has a much higher ailure rate. Limited studies
in small numbers o patients have suggested variable bene ts ol-
T e incidence o autosomal recessive severe (malignant) lowing treatment with inter eron γ-1β, 1,25-dihydroxyvitamin D
osteopetrosis ranges rom 1 in 200,000 to 1 in 500,000 (which stimulates osteoclasts directly), methylprednisolone, and
live births. As bone and cartilage ail to undergo model- a low-calcium/high-phosphate diet.
ing, paralysis o one or more cranial nerves may occur Surgical intervention is indicated to decompress optic
due to narrowing o the cranial oramens. Failure o or auditory nerve compression. Orthopedic management is
skeletal modeling also results in inadequate marrow required or the surgical treatment o ractures and their com-
space, leading to extramedullary hematopoiesis with plications including malunion and post racture de ormity.
hypersplenism and pancytopenia. Hypocalcemia due
to lack o osteoclastic bone resorption may occur in
in ants and young children. T e untreated in antile dis-
ease is atal, o en be ore age 5.
Adult (benign) osteopetrosis is an autosomal domi-
PYKNODYSOSTOSIS
nant disease that is usually diagnosed by the discovery T is is an autosomal recessive orm o osteosclerosis
o typical skeletal changes in young adults who undergo that is believed to have a ected the French impression-
radiologic evaluation o a racture. T e prevalence is ist painter Henri de oulouse-Lautrec. T e molecu-
1 in 100,000 to 1 in 500,000 adults. T e course is not lar basis involves mutations in the gene that encodes
always benign, because ractures may be accompanied cathepsin K, a lysosomal metalloproteinase highly

Ha rris on_Endocrinology_Ch36_p503-p514.indd 508 27/07/16 11:06 a m

 expressed in osteoclasts and important or bone-matrix
degradation. Osteoclasts are present but do not unc-
tion normally. Pyknodysostosis is a orm o short-limb
dwar sm that presents with requent ractures but usu-
ally a normal li e span. Clinical eatures include short
stature; kyphoscoliosis and de ormities o the chest;
high arched palate; proptosis; blue sclerae; dysmorphic
eatures including small ace and chin, rontooccipital
prominence, pointed beaked nose, large cranium, and
obtuse mandibular angle; and small, square hands with
Intermittent bisphosphonate therapy has produced clinical 509
improvement in a limited number o patients.
HYPEROSTOSIS CORTICALIS
GENERALISATA
T is is also known as van Buchem’s disease; it is an auto-
somal recessive disorder characterized by endosteal
hyperostosis in which osteosclerosis involves the skull,

C
mandible, clavicles, and ribs. T e major mani esta-

H
A
hypoplastic nails. Radiographs demonstrate a general- tions are due to narrowed cranial oramens with neu-

P
T
ized increase in bone density, but in contrast to osteo- ral compressions that may result in optic atrophy, acial

E
R
petrosis, the long bones are normally shaped. Separated paralysis, and dea ness. Adults may have an enlarged

3
6
cranial sutures, including the persistent patency o the mandible. Serum ALP levels may be elevated, which
anterior ontanel, are characteristic o the disorder. re ect the uncoupled bone remodeling with high osteo-
T ere may also be hypoplasia o the sinuses, mandible,

P
blastic ormation rates and low osteoclastic resorption.

a
g
distal clavicles, and terminal phalanges. Persistence o

e
As a result, there is increased accumulation o normal

t
’
s
deciduous teeth and sclerosis o the calvarium and base bone. Endosteal hyperostosis with syndactyly, known as

D
i
s
o the skull are also common. Histologic evaluation sclerosteosis, is a more severe orm. T e genetic de ects

e
a
s
shows normal cortical bone architecture with decreased

e
or both sclerosteosis and van Buchem’s disease have

a
osteoblastic and osteoclastic activities. Serum chemis-

n
been assigned to the same region o the chromosome

d
O
tries are normal, and unlike osteopetrosis, there is no 17q12-q21. It is possible that both conditions may have

t
h
anemia. T ere is no known treatment or this condition,

e
deactivating mutations in the BEER (bone-expressed

r
D
and there are no reports o attempted bone marrow

y
equilibrium regulator) gene.

s
p
transplant.

l
a
s
i
a
s
MELORHEOSTOSIS

o
f
B
o
PROGRESSIVE DIAPHYSEAL DYSPLASIA Melorheostosis (Greek, “ owing hyperostosis”) may

Also known as Camurati-Engelmann disease, pro-
gressive diaphyseal dysplasia is an autosomal domi-
nant disorder that is characterized radiographically by
diaphyseal hyperostosis and a symmetric thickening
and increased diameter o the endosteal and periosteal
sur aces o the diaphyses o the long bones, particularly
the emur and tibia, and, less o en, the bula, radius,
and ulna. T e genetic de ect responsible or the disease
has been localized to the area o chromosome 19q13.2
encoding tumor growth actor ( GF) β1. T e muta-
tion promotes activation o GF-β1. T e clinical sever-
ity is variable. T e most common presenting symptoms
are pain and tenderness o the involved areas, atigue,
muscle wasting, and gait disturbance. T e weakness
may be mistaken or muscular dystrophy. Characteris-
tic body habitus includes thin limbs with little muscle
mass yet prominent and palpable bones and, when the
skull is involved, large head with prominent orehead
and proptosis. Patients may also display signs o cranial
nerve palsies, hydrocephalus, central hypogonadism,
and Raynaud’s phenomenon. Radiographically, patchy
progressive endosteal and periosteal new bone orma-
tion is observed along the diaphyses o the long bones.
Bone scintigraphy shows increased radiotracer uptake
in involved areas.
reatment with low-dose glucocorticoids relieves bone
pain and may reverse the abnormal bone ormation.
n
e
occur sporadically or ollow a pattern consistent with
an autosomal recessive disorder. T e major mani-
estation is progressive linear hyperostosis in one or
more bones o one limb, usually a lower extremity.
T e name comes rom the radiographic appearance o
the involved bone, which resembles melted wax that
has dripped down a candle. Symptoms appear dur-
ing childhood as pain or sti ness in the area o scle-
rotic bone. T ere may be associated ectopic so tissue
masses, composed o cartilage or osseous tissue, and
skin changes overlying the involved bone, consisting
o scleroderma-like areas and hypertrichosis. T e dis-
ease does not progress in adults, but pain and sti ness
may persist. Laboratory tests are unremarkable. No spe-
ci c etiology is known. T ere is no speci c treatment.
Surgical interventions to correct contractures are o en
unsuccess ul.
OSTEOPOIKILOSIS
T e literal translation o osteopoikilosis is “spotted
bones”; it is a benign autosomal dominant condition in
which numerous small, variably shaped (usually round
or oval) oci o bony sclerosis are seen in the epiphy-
ses and adjacent metaphyses. T e lesions may involve
any bone except the skull, ribs, and vertebrae. T ey
may be misidenti ed as metastatic lesions. T e main

Ha rris on_Endocrinology_Ch36_p503-p514.indd 509 27/07/16 11:06 a m

 510 di erentiating points are that bony lesions o osteo- pyridoxal 5′-phosphate (PLP). T e accumulation o PPi
poikilosis are stable over time and do not accumulate inter eres with mineralization through its action as a
radionucleotide on bone scanning. In some kindred, potent inhibitor o hydroxyapatite crystal growth.
osteopoikilosis is associated with connective tissue Perinatal hypophosphatasia becomes mani est dur-
nevi known as dermato brosis lenticularis disseminata, ing pregnancy and is o en complicated by polyhydram-
also known as Buschke-Ollendorf syndrome. Histologic nios and intrauterine death. T e in antile orm becomes
inspection reveals thickened but otherwise normal tra- clinically apparent be ore the age o 6 months with
beculae and islands o normal cortical bone. No treat- ailure to thrive, rachitic de ormities, unctional cra-
ment is indicated. niosynostosis despite widely open ontanels (which are
actually hypomineralized areas o the calvarium), raised
S
E
C
intracranial pressure, and ail chest with predisposition
T
HEPATITIS C–ASSOCIATED
I
to pneumonia. Hypercalcemia and hypercalciuria are
O
N
OSTEOSCLEROSIS common. T is orm has a mortality rate o about 50%.
V
I
Hepatitis C–associated osteosclerosis (HCAO) is a Prognosis seems to improve or the children who sur-
rare acquired di use osteosclerosis in adults with prior vive in ancy. Childhood hypophosphatasia has variable
clinical presentation. Premature loss o deciduous teeth
D
hepatitis C in ection. A er a latent period o several
i
s
(be ore age 5) is the hallmark o the disease. Rickets
o
years, patients develop di use appendicular bone pain
r
d
e
and a generalized increase in bone mass with elevated causes delayed walking with waddling gait, short stat-
r
s
ure, and dolichocephalic skull with rontal bossing. T e
o
serum ALP. Bone biopsy and histomorphometry reveal
f
B
increased rates o bone ormation, decreased bone disease o en improves during puberty but may recur in
o
n
e
resorption with a marked decrease in osteoclasts, and adult li e. Adult hypophosphatasia presents during mid-
a
n
dle age with pain ul, poorly healing metatarsal stress
d
dense lamellar bone. One patient had increased serum
C
ractures or thigh pain due to emoral pseudo ractures.
a
OPG levels, and bone biopsy showed large numbers
l
c
i
Laboratory investigation reveals low ALP levels and
u
o osteoblasts positive or OPG and reduced osteo-
m
clast number. Empirical therapy includes pain control, normal or elevated levels o serum calcium and phos-
M
e
phorus despite clinical and radiologic evidence o
t
and there may be bene cial response to bisphospho-
a
b
rickets or osteomalacia. Serum parathyroid hormone,
o
nate. Long-term antiviral therapy may reverse the bone
l
i
s
25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D
m
disease.
levels are normal. T e elevation o PLP is speci c or
the disease and may even be present in asymptomatic
parents o severely a ected children. Because vitamin
DISO RDERS ASSO CIATED WITH
B6 increases PLP levels, vitamin B6 supplements should
DEFECTIVE MINERALIZATIO N be discontinued 1 week be ore testing. Clinical testing is
HYPOPHOSPHATASIA available to detect loss-o - unction mutation(s) within
the ALPL gene that encodes NSALP.
T is is a rare inherited disorder that presents as rickets T ere is no established medical therapy. In contrast
in in ants and children or osteomalacia in adults with to other orms o rickets and osteomalacia, calcium and
paradoxically low serum levels o ALP. T e requency vitamin D supplementation should be avoided because
o the severe neonatal and in antile orms is about 1 in they may aggravate hypercalcemia and hypercalciuria.
100,000 live births in Canada, where the disease is most A low-calcium diet, glucocorticoids, and calcitonin
common because o its high prevalence among Men- have been used in a small number o patients with vari-
nonites and Hutterites. It is rare in A rican Americans. able responses. Because racture healing is poor, place-
T e severity o the disease is remarkably variable, rang- ment o intramedullary rods is best or acute racture
ing rom intrauterine death associated with pro ound repair and or prophylactic prevention o ractures.
skeletal hypomineralization at one extreme to prema-
ture tooth loss as the only mani estation in some adults.
Severe cases are inherited in an autosomal recessive
AXIAL OSTEOMALACIA
manner, but the genetic patterns are less clear or the
milder orms. T e disease is caused by a de ciency o T is is a rare disorder characterized by de ective skel-
tissue nonspeci c (bone/liver/kidney) ALP ( NSALP), etal mineralization despite normal serum calcium and
which, although ubiquitous, results only in bone abnor- phosphate levels. Clinically, the disorder presents in
malities. Protein levels and unctions o the other ALP middle-aged or elderly men with chronic axial skeletal
isozymes (germ cell, intestinal, placental) are normal. discom ort. Cervical spine pain may also be present.
De ective ALP permits accumulation o its major nat- Radiographic ndings are mainly osteosclerosis due
urally occurring substrates including phosphoetha- to coarsened trabecular patterns typical o osteomala-
nolamine (PEA), inorganic pyrophosphate (PPi), and cia. Spine, pelvis, and ribs are most commonly a ected.

Ha rris on_Endocrinology_Ch36_p503-p514.indd 510 27/07/16 11:06 a m

 Histologic changes show de ective mineralization and
at, inactive osteoblasts. T e primary de ect appears to
be an acquired de ect in osteoblast unction. T e course
is benign, and there is no established treatment. Cal-
cium and vitamin D therapies are not e ective.
FIBROGENESIS IMPERFECTA OSSIUM
T is is a rare condition o unknown etiology. It presents
into woven bone. Calci cation may occur in some 511
areas. In other areas, cells have eatures o chondrocytes
and produce cartilage-like extracellular matrix.
CLINICAL PRESENTATION
Fibrous dysplasia occurs with equal requency in both
sexes, whereas MAS with precocious puberty is more
common (10:1) in girls. T e monostotic orm is the most

C
in both sexes; in middle age or later; and with progres- common and is usually diagnosed in patients between 20

H
A
sive, intractable skeletal pain and ractures; worsening and 30 years o age without associated skin lesions. T e

P
T
immobilization; and a debilitating course. Radiographic polyostotic orm typically mani ests in children <10 years

E
R
evaluation reveals generalized osteomalacia, osteope- old and may progress with age. Early-onset disease is

3
6
nia, and occasional pseudo ractures. Histologic eatures generally more severe. Lesions may become quiescent in
include a tangled pattern o collagen brils with abun- puberty and progress during pregnancy or with estrogen

P
dant osteoblasts and osteoclasts. T ere is no e ective therapy. In polyostotic brous dysplasia, the lesions most

a
g
treatment. Spontaneous remission has been reported

e
commonly involve the maxilla and other cranio acial

t
’
s
in a small number o patients. Calcium and vitamin D bones, ribs, and metaphyseal or diaphyseal portions o

D
i
s
have not been bene cial. the proximal emur or tibia. Expanding bone lesions may

e
a
s
e
cause pain, de ormity, ractures, and nerve entrapment.

a
n
Sarcomatous degeneration involving the acial bones or

d
O
emur is in requent (<1%). T e risk o malignant trans-

t
h
FIBRO US DYSP LASIA AND MCCUNE-

e
ormation is increased by radiation, which has proven to

r
D
ALBRIGHT SYNDRO ME

y
be ine ective treatment. In rare patients with widespread

s
p
l
lesions, renal phosphate wasting and hypophosphatemia

a
Fibrous dysplasia is a sporadic disorder characterized

s
i
a
may cause rickets or osteomalacia. Hypophosphatemia

s
by the presence o one (monostotic) or more (poly-

o
may be due to production o a phosphaturic actor by the

f
B
ostotic) expanding brous skeletal lesions composed

o
abnormal brous tissue.

n
o bone- orming mesenchyme. T e association o the

polyostotic orm with ca é au lait spots and hyper unc-
tion o an endocrine system such as pseudoprecocious
puberty o ovarian origin is known as McCune-Albright
syndrome (MAS). A spectrum o the phenotypes is
caused by activating mutations in the GNAS1 gene,
which encodes the α subunit o the stimulatory G pro-
tein (Gsα). As the postzygotic mutations occur at di er-
ent stages o early development, the extent and type o
tissue a ected are variable and explain the mosaic pat-
tern o skin and bone changes. G P binding activates
the Gsα regulatory protein and mutations in regions
o Gsα that selectively inhibit G Pase activity, which
results in constitutive stimulation o the cyclic AMP–
protein kinase A signal transduction pathway. Such
mutations o the Gsα protein–coupled receptor may
cause autonomous unction in bone (parathyroid hor-
mone receptor); skin (melanocyte-stimulating hormone
receptor); and various endocrine glands including
ovary ( ollicle-stimulating hormone receptor), thy-
roid (thyroid-stimulating hormone receptor), adrenal
(adrenocorticotropic hormone receptor), and pituitary
(growth hormone–releasing hormone receptor). T e
skeletal lesions are composed largely o mesenchymal
cells that do not di erentiate into osteoblasts, resulting
in the ormation o imper ect bone. In some areas o
bone, broblast-like cells develop eatures o osteoblasts
in that they produce extracellular matrix that organizes
e
MAS patients may have ca é au lait spots, which are
at, hyperpigmented skin lesions that have rough bor-
ders (“coast o Maine”) in contrast to the ca é au lait
lesions o neuro bromatosis that have smooth borders
(“coast o Cali ornia”). T e most common endocri-
nopathy is isosexual pseudoprecocious puberty in girls.
Other less common endocrine disorders include thyro-
toxicosis, Cushing’s syndrome, acromegaly, hyperpara-
thyroidism, hyperprolactinemia, and pseudoprecocious
puberty in boys.
RADIOGRAPHIC FINDINGS
In long bones, the brous dysplastic lesions are typically
well-de ned, radiolucent areas with thin cortices and a
ground-glass appearance. Lesions may be lobulated with
trabeculated areas o radiolucency (Fig. 36-4). Involve-
ment o acial bones usually presents as radiodense
lesions, which may create a leonine appearance (leontia-
sis osea). Expansile cranial lesions may narrow oramens
and cause optic lesions, reduce hearing, and create other
mani estations o cranial nerve compression.
LABORATORY RESULTS
Serum ALP is occasionally elevated but calcium,
parathyroid hormone, 25-hydroxyvitamin D, and

Ha rris on_Endocrinology_Ch36_p503-p514.indd 511 27/07/16 11:06 a m

 512 that involves the distal extremities. T e lesions present
as clubbing o the digits and hyperhidrosis and thicken-
ing o the skin, primarily o the ace and orehead. T e
changes usually appear during adolescence, progress
over the next decade, and then become quiescent. Dur-
ing the active phase, progressive enlargement o the
hands and eet produces a paw-like appearance, which
may be mistaken or acromegaly. Arthralgias, pseudo-
gout, and limited mobility may also occur. T e disorder
must be di erentiated rom secondary hypertrophic oste-
S
E
opathy that develops during the course o serious pulmo-
C
T
I
nary disorders. T e two conditions can be di erentiated
O
N
by standard radiography o the digits in which second-
V
I
ary pachydermoperiostosis has exuberant periosteal new
bone ormation and a smooth and undulating sur ace. In
contrast, primary hypertrophic osteopathy has an irregu-
D
i
s
lar periosteal sur ace.
o
r
d
T ere are no diagnostic blood or urine tests. Synovial
e
r
s
uid does not have an in ammatory pro le. T ere is no
o
f
B
speci c therapy, although a limited experience with colchi-
o
n
e
cine suggests some bene t in controlling the arthralgias.
a
n
FIGURE 3 6 -4
d
C
Ra d io g ra p h o a 16-ye a r-o ld m a le wit h f b ro u s d ysp la sia
a
l
c
o t h e rig h t p roxim a l e m u r. Note the multiple cystic lesions,
i
OSTEOCHONDRODYSPLASIAS
u
m
including the large lucent lesion in the proximal midsha t with
M
scalloping o the interior sur ace. The emoral neck contains two T ese include several hundred heritable disorders o con-
e
t
a
lucent cystic lesions. nective tissue. T ese primary abnormalities o cartilage
b
o
l
mani est as disturbances in cartilage and bone growth.
i
s
m
Selected growth-plate chondrodysplasias are described
1,25-dihydroxy-vitamin D levels are normal. Patients
here.
with extensive polyostotic lesions may have hypophos-
phatemia, hyperphosphaturia, and osteomalacia. T e
hypophosphatemia and phosphaturia are directly related Ach o n d ro d ysp la sia
to the levels o broblast growth actor 23 (FGF23). Bio- T is is a relatively common orm o short-limb dwar -
chemical markers o bone turnover may be elevated. ism that occurs in 1 in 15,000 to 1 in 40,000 live births.
T e disease is caused by a mutation o the broblast
growth actor receptor 3 (FGFR3) gene that results in
TREATMENT Fibrous Dysplasia and McCune-Albright Syndrome a gain-o - unction state. Most cases are sporadic muta-
tions. However, when the disorder appears in amilies,
Spontaneous healing o the lesions does not occur, and there the inheritance pattern is consistent with an autoso-
is no established e ective treatment. Improvement in bone mal dominant disorder. T e primary de ect is abnor-
pain and partial or complete resolution o radiographic mal chondrocyte proli eration at the growth plate that
lesions have been reported a er IV bisphosphonate therapy. causes development o short, but proportionately thick,
Surgical stabilization is used to prevent pathologic racture or long bones. Other regions o the long bones may be rel-
destruction o a major joint space and to relieve nerve root or atively una ected. T e disorder is mani est by the pres-
cranial nerve compression or sinus obstruction. ence o short limbs (particularly the proximal portions),
normal trunk, large head, saddle nose, and an exagger-
ated lumbar lordosis. Severe spinal de ormity may lead
to cord compression. T e homozygous disorder is more
OTHER DYSP LASIAS O F BO NE serious than the sporadic orm and may cause neona-
AND CARTILAGE tal death. Pseudoachondroplasia clinically resembles
achondrodysplasia but has no skull abnormalities.
PACHYDERMOPERIOSTOSIS
En ch o n d ro m a to sis
Pachydermoperiostosis, or hypertrophic osteoarthropa-
thy (primary or idiopathic), is an autosomal dominant T is is also called dyschondroplasia or Ollier’s disease; it is
disorder characterized by periosteal new bone ormation also a disorder o the growth plate in which the primary

Ha rris on_Endocrinology_Ch36_p503-p514.indd 512 27/07/16 11:06 a m

 cartilage is not resorbed. Cartilage ossi cation proceeds TABLE 3 6 -2 513
normally, but it is not resorbed normally, leading to car- DISEASES AND CONDITIONS ASSOCIATED WITH
tilage accumulation. T e changes are most marked at the ECTOPIC CALCIFICATION AND OSSIFICATION
ends o long bones, where the highest growth rates occur. Metastatic calci cation Dystrophic calci cation
Chondrosarcoma develops in requently. T e association Hypercalcemic states Inf ammatory disorders
o enchondromatosis and cavernous hemangiomas o Primary Scleroderma
the skin and so tissues is known as Maf ucci’s syndrome. hyperparathyroidism Dermatomyositis
Sarcoidosis Systemic lupus
Both Ollier’s disease and Ma ucci’s syndrome are associ-
Vitamin D intoxication erythematosus
ated with various malignancies, including granulosa cell Milk-alkali syndrome Trauma-induced
tumor o the ovary and cerebral glioma.

C
Renal ailure Ectopic ossi cation

H
A
Hyperphosphatemia Myositis ossi cans

P
T
Tumoral calcinosis Postsurgery

E
Mu ltip le exo sto ses

R
Secondary Burns

3
6
T is is also called diaphyseal aclasis or osteochondro- hyperparathyroidism Neurologic injury
matosis; it is a genetic disorder that ollows an autoso- Pseudohypoparathyroidism Other trauma
mal dominant pattern o inheritance. In this condition, Renal ailure Fibrodysplasia ossi cans

P
a
Hemodialysis progressiva
areas o growth plates become displaced, presumably

g
e
Cell lysis ollowing

t
’
by growing through a de ect in the perichondrium.

s
chemotherapy

D
i
T e lesion begins with vascular invasion o the growth-

s
Therapy with vitamin D

e
a
plate cartilage, resulting in a characteristic radiographic

s
and phosphate

e
a
nding o a mass that is in direct communication with

n
d
the marrow cavity o the parent bone. T e underly-

O
t
h
ing cortex is resorbed. T e disease is caused by inacti-

e
r
or both. In addition, vitamin D and phosphate treat-

D
vating mutations o the EXT1 and EXT2 genes, whose

y
s
products normally regulate processing o chondrocyte ments or calcium administration in the presence o mild

p
l
a
hyperphosphatemia, such as during hemodialysis, may

s
cytoskeletal proteins. T e products o the EXT gene

i
a
s
likely unction as tumor suppressors, with the loss-o - induce ectopic calci cation. Calcium phosphate pre-

o
f
cipitation may complicate any disorder when the serum

B
unction mutation resulting in abnormal proli eration

o
n
o growth-plate cartilage. Solitary or multiple lesions calcium × phosphate concentration product is >75. T e

are located in the metaphyses o long bones. Although
usually asymptomatic, the lesions may inter ere with
joint or tendon unction or compress peripheral nerves.
T e lesions stop growing when growth ceases but may
recur during pregnancy. T ere is a small risk or malig-
nant trans ormation into chondrosarcoma.
EXTRASKELETAL (ECTO P IC)
CALCIFICATIO N AND O SSIFICATIO N
e
initial calcium phosphate deposition is in the orm o
small, poorly organized crystals, which subsequently
organize into hydroxyapatite crystals. Calci cations that
occur in hypercalcemic states with normal or low phos-
phate have a predilection or kidney, lungs, and gastric
mucosa. Hyperphosphatemia with normal or low serum
calcium may promote so tissue calci cation with pre-
dilection or the kidney and arteries. T e disturbances
o calcium and phosphate in renal ailure and hemo-
dialysis are common causes o so tissue (metastatic)
calci cation.

Deposition o calcium phosphate crystals (calci cation) or

ormation o true bone (ossi cation) in nonosseous so tis-
sue may occur by one o three mechanisms: (1) metastatic
calci cation due to a supranormal calcium × phosphate
concentration product in extracellular uid; (2) dystrophic
calci cation due to mineral deposition into metabolically
impaired or dead tissue despite normal serum levels o cal-
cium and phosphate; and (3) ectopic ossi cation, or true
bone ormation. Disorders that may cause extraskeletal
calci cation or ossi cation are listed in Table 36-2.
METASTATIC CALCIFICATION
So tissue calci cation may complicate diseases associ-
ated with signi cant hypercalcemia, hyperphosphatemia,
TUMORAL CALCINOSIS
T is is a rare genetic disorder characterized by masses
o metastatic calci cations in so tissues around major
joints, most o en shoulders, hips, and ankles. umoral
calcinosis di ers rom other disorders in that the peri-
articular masses contain hydroxyapatite crystals or
amorphous calcium phosphate complexes, while in
brodysplasia ossi cans progressiva (below), true bone
is ormed in so tissues. About one-third o tumoral
calcinosis cases are amilial, with both autosomal reces-
sive and autosomal dominant modes o inheritance
reported. T e disease is also associated with a variably
expressed abnormality o dentition marked by short
bulbous roots, pulp calci cation, and radicular dentin

Ha rris on_Endocrinology_Ch36_p503-p514.indd 513 27/07/16 11:06 a m

 514 deposited in swirls. T e primary de ect responsible or DYSTROPHIC CALCIFICATION
the metastatic calci cation appears to be hyperphos-
Posttraumatic calci cation may occur with normal
phatemia resulting rom the increased capacity o the
serum calcium and phosphate levels and normal ion-
renal tubule to reabsorb ltered phosphate. Sponta-
solubility product. T e deposited mineral is either in the
neous so tissue calci cation is related to the elevated
orm o amorphous calcium phosphate or hydroxyapatite
serum phosphate, which, along with normal serum cal-
crystals. So tissue calci cation complicating connective
cium, exceeds the concentration product o 75.
tissue disorders such as scleroderma, dermatomyositis,
All o the North American patients reported have
and systemic lupus erythematosus may involve local-
been A rican American. T e disease usually presents
ized areas o the skin or deeper subcutaneous tissue and
in childhood and continues throughout the patient’s
S
is re erred to as calcinosis circumscripta. Mineral deposi-
E
li e. T e calci c masses are typically painless and grow
C
T
tion at sites o deeper tissue injury including periarticular
I
at variable rates, sometimes becoming large and bulky.
O
sites is called calcinosis universalis.
N
T e masses are o en located near major joints but
V
I
remain extracapsular. Joint range o motion is not usu-
ally restricted unless the tumors are very large. Compli-
cations include compression o neural structures and ECTOPIC OSSIFICATION
D
i
s
ulceration o the overlying skin with drainage o chalky
o
rue extraskeletal bone ormation that begins in areas
r
d
uid and risk o secondary in ection. Small deposits
e
o asciitis ollowing surgery, trauma, burns, or neu-
r
s
not detected by standard radiographs may be detected
o
rologic injury is re erred to as myositis ossi cans. T e
f
B
by 99m c bone scanning. T e most common laboratory
o
bone ormed is organized as lamellar or trabecular, with
n
e
ndings are hyperphosphatemia and elevated serum normal osteoblasts and osteoclasts conducting active
a
n
1,25-dihydroxyvitamin D levels. Serum calcium, parathy-
d
remodeling. Well-developed haversian systems and
C
roid hormone, and ALP levels are usually normal. Renal
a
marrow elements may be present. A second cause o
l
c
i
unction is also usually normal. Urine calcium and phos-
u
ectopic bone ormation occurs in an inherited disorder,
m
phate excretions are low, and calcium and phosphate bal- brodysplasia ossi cans progressiva.
M
e
ances are positive.
t
a
b
An acquired orm o the disease may occur with
o
l
i
s
other causes o hyperphosphatemia, such as second-
m
FIBRODYSPLASIA OSSIFICANS
ary hyperparathyroidism associated with hemodialysis, PROGRESSIVA
hypoparathyroidism, pseudohypoparathyroidism, and
massive cell lysis ollowing chemotherapy or leukemia. T is is also called myositis ossi cans progressiva; it is a
issue trauma rom joint movement may contribute to rare autosomal dominant disorder characterized by
the periarticular calci cations. Metastatic calci cations congenital de ormities o the hands and eet and epi-
are also seen in conditions associated with hypercal- sodic so tissue swellings that ossi y. Ectopic bone
cemia, such as in sarcoidosis, vitamin D intoxication, ormation occurs in ascia, tendons, ligaments, and
milk-alkali syndrome, and primary hyperparathyroid- connective tissue within voluntary muscles. ender,
ism. In these conditions, however, mineral deposits are rubbery induration, sometimes precipitated by trauma,
more likely to occur in proton-transporting organs such develops in the so tissue and gradually calci es. Even-
as kidney, lungs, and gastric mucosa in which an alka- tually, heterotopic bone orms at these sites o so tissue
line milieu is generated by the proton pumps. trauma. Morbidity results rom heterotopic bone inter-
ering with normal movement and unction o muscle
and other so tissues. Mortality is usually related to
restrictive lung disease caused by an inability o the
TREATMENT Tumoral Calcinosis chest to expand. Laboratory tests are unremarkable.
T ere is no e ective medical therapy. Bisphospho-
T erapeutic successes have been achieved with surgical nates, glucocorticoids, and a low-calcium diet have
removal o subcutaneous calci ed masses, which tend not to largely been ine ective in halting progression o the
recur i all calci cation is removed rom the site. Reduction ossi cation. Surgical removal o ectopic bone is not rec-
o serum phosphate by chronic phosphorus restriction may ommended, because the trauma o surgery may precipi-
be accomplished using low dietary phosphorus intake alone tate ormation o new areas o heterotopic bone. Dental
or in combination with oral phosphate binders. T e addition complications including rozen jaw may occur ollow-
o the phosphaturic agent acetazolamide may be use ul. Lim- ing injection o local anesthetics. T us, C imaging o
ited experience using the phosphaturic action o calcitonin the mandible should be undertaken to detect early sites
deserves urther testing. o so tissue ossi cation be ore they are appreciated by
standard radiography.

Ha rris on_Endocrinology_Ch36_p503-p514.indd 514 27/07/16 11:06 a m