Musculoskeletal Drugs

Mechanism of Action Absoprtion and Distribution Metabolism and Excretion Adverse Effects and Precautions Therapeutic Use
DRUGS FOR OSTEOPOROSIS
Estrogen
 most potent naturally occurring estrogen in humans, for both ER-α and ER-β mediated actions, is 17-estradiol, followed by estrone and estriol
 Each contains a phenolic A ring with a hydroxyl group at carbon 3, and a β-OH or ketone in position 17 of ring D
 phenolic A = principal structural feature responsible for selective high-affinity binding to both receptors

Effects on bone:
 Have positive effects on bone mass
 Osteoclasts and osteoblasts express both ERα and ER𝛽, with the former apparently playing a greater role; bone also expresses both androgen and progesterone receptors.
 Actions of ERα predominate in bone.
 Directly regulate osteoblasts and increase the synthesis of type I collagen, osteocalcin, osteopontin, osteonectin, alkaline phosphatase, and other markers of differentiated osteoblasts.
 Also increase osteocyte survival by inhibiting apoptosis; anti-apoptotic effects on osteoblasts and osteocytes > may be mediated by rapid signal transduction mechanisms
 Major effect: decrease the number and activity of osteoclasts.
 Much of the action on osteoclasts appears to be mediated by altering cytokine (both paracrine and autocrine) signals from ost eoblasts.
 Decrease osteoblast and stromal cell production of the osteoclast-stimulating cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)- and increase the production of IGF-1, bone
morphogenic protein (BMP)-6, and transforming growth factor (TGF)-, which are anti-resorptive
 Also increase osteoblast production of the cytokine osteoprotegerin (OPG), a soluble non–membrane-bound member of the TNF superfamily > increase osteoclast apoptosis, either directly or by
increasing OPG.
 Affect bone growth and epiphyseal closure in both sexes.

 Enters cell by passive diffusion
through the plasma membrane >
binds to an ER in the nucleus. In
the nucleus [present as an
inactive monomer bound to heat-
shock protein 90 (HSP90)] >
upon binding estrogen, change
in ER conformation dissociates
the heat-shock proteins and
causes receptor dimerization >
increases the affinity and the
rate of receptor binding to DNA
 Homodimers of ERα or ERβ and
ERα /ERβ heterodimers can be
produced depending on the
receptor complement in a given
cell.
 ER/DNA complex recruits a
cascade of co-activator and
other proteins to the promoter
region of target genes
 Lipophilic nature > absorption
generally is good with the
appropriate preparation.
 Aqueous or oil-based esters of
estradiol for IM injection, ranging
in frequency from every week to
once per month.
 Conjugated estrogens > for IV or
IM administration
Oral administration
 Is common and may use
estradiol, conjugated estrogens,
esters of estrone and other
estrogens, and ethinyl estradiol
(in combination with a progestin)
 Addition of ethinyl substituent at
C17 (ethinyl estradiol) inhibits
first-pass hepatic metabolism
 Other common oral preparations
contain: conjugated equine
estrogens (PREMARIN) >
primarily sulfate esters of
estrone, equilin, and other
naturally occurring compounds;
esterified esters (MENEST); or
mixtures of synthetic conjugated
estrogens prepared from plant
derived sources (CENESTIN;
ENJUVIA).
IM
 When dissolved in oil and
injected, esters of estradiol are
well absorbed.
 In general, undergoes rapid
hepatic biotransformation, with a
plasma t1/2 measured in
minutes.
 Estradiol is converted primarily
by 17β-hydroxysteroid
dehydrogenase to estrone,
which undergoes conversion by
16α-hydroxylation and 17-keto
reduction to estriol, the major
urinary metabolite. .
 A variety of sulfate and
glucuronide conjugates also are
excreted in the urine.
 Lesser amounts of estrone or
estradiol are oxidized to the 2-
hydroxycatechols by CYP3A4 in
the liver and by CYP1A in
extrahepatic tissues or to 4-
hydroxycatechols by CYP1B1 in
extrahepatic sites, with the 2-
hydroxycatechol being formed to
a greater extent.
 2- and 4-hydroxycatechols:
largely inactivated by catechol-
O-methyl transferases (COMTs)
 Also undergo enterohepatic
recirculation via (1) sulfate and
glucuronide conjugation in the
liver, (2) biliary secretion of the
conjugates into the intestine, and
(3) hydrolysis in the gut (largely
by bacterial enzymes) followed
by reabsorption
 Risk of developing breast,
endometrial, cervical, and
vaginal cancer is probably the
major concern for the use of
estrogens
 Use during pregnancy also can
increase the incidence of
nonmalignant genital
abnormalities in both male and
female offspring > pregnant
patients should not be given
estrogens because of the
possibility of such reproductive
tract toxicities.
 use of unopposed estrogen for
hormone treatment in
postmenopausal women
increases the risk of endometrial
carcinoma by 5- to 15-fold > can
be prevented if a progestin is co-
administered with the estrogen
(now is the standard practice)
 WHI study: an estrogen-
progestin combination increased
the total risk of breast cancer by
25%; the absolute increase in
attributable cases of disease
was 6 per 1000 women and
required 3 or more years of
treatment
 Estrogens themselves generally
have favorable overall effects on
plasma lipoprotein profiles;
progestins may reduce the
 2 major uses of estrogens are for
menopausal hormone therapy
(MHT) and as components of
combination oral contraceptives
 estrogens have been the most
common agents for
postmenopausal use (0.625
mg/day most often used)
For osteoporosis:
 primary mechanism is to
decrease bone resorption;
consequently, are more effective
at preventing rather than
restoring bone loss
 most effective if treatment is
initiated before significant bone
loss occurs, and maximal
beneficial effects require
continuous use; bone loss
resumes when treatment is
discontinued
 Appropriate diet with adequate
intake of Ca2+ and vitamin D
and weight-bearing exercise
enhance the effects of estrogen
treatment
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Musculoskeletal Drugs
 aryl and alkyl esters of estradiol favorable actions of estrogens
become less polar as the size of Ethinyl estradiol
the substituents increases;  cleared much more slowly due to
correspondingly, rate of decreased hepatic metabolism;
absorption of oily preparations is elimination-phase t1/2 in various
progressively slowed > duration studies ranges from 13 to 27
of action can be prolonged hours.
 single therapeutic dose of  primary route of
compounds such as estradiol biotransformation is via 2-
valerate (DELESTROGEN, hydroxylation and subsequent
others) or estradiol cypionate formation of the corresponding
(DEPO-ESTRADIOL, others) 2- and 3-methyl ethers.
may be absorbed over several
weeks following a single
intramuscular injection.
Selective Estrogen Receptor Modulators and Anti-Estrogens
Selective Estrogen Receptor Modulators: Tamoxifen, Raloxifene, and Toremifene
 Are compounds with tissue-selective actions
 Pharmacological goal: to produce beneficial estrogenic actions in certain tissues (e.g., bone, brain, and liver) during postmenopausal hormone ther apy but antagonist activity in tissues such as breast
and endometrium, where estrogenic actions (e.g., carcinogenesis) might be deleterious.
 Currently approved drugs: tamoxifen citrate, raloxifene hydrochloride (EVISTA), and toremifene (FARESTON), which is chemically related and has similar actions to tamoxifen.
 Tamoxifen and toremifene”for the treatment of breast cancer
 Raloxifene: used primarily for the prevention and treatment of osteoporosis and reduce the risk of invasive breast cancer in high-risk postmenopausal women.

Anti-Estrogens: Clomiphene and Fulvestrant

 Are pure antagonists in all tissues studied
 Clomiphene (CLOMID, SEROPHENE, others):approved for the treatment of infertility in anovulatory women
 fulvestrant (FASLODEX):treatment of breast cancer in women with disease progression after tamoxifen

General MOA:
 All of these agents bind to the ligand-binding pocket of both ER and ER and competitively block estradiol binding
 Distinct ER-ligand conformations recruit different co-activators and co-repressors onto the promoter of a target gene by differential protein-protein interactions at the receptor surface.
 Tissue-specific actions of SERMs explained in part by the distinct conformation of the ER when occupied by different ligands, in com bination with different co-activator and co-repressor levels in
different cell types that together affect the nature of ER complexes formed in a tissue-selective fashion
 Conformation of ERs, especially in the AF-2 domain, determines whether a co-activator or a co-repressor will be recruited to the ER-DNA complex
 Whereas 17-estradiol induces a conformation that recruits co-activators to the receptor, tamoxifen induces a conformation that permits the recruitment of the co-repressor to both ER and ER.
 Agonist activity of tamoxifen seen in tissues such as the endometrium is mediated by the ligand-independent AF-1 transactivation domain of ER ; because ER does not contain a functional AF-1
domain, tamoxifen does not activate ER
Tamoxifen:  Given orally, and peak plasma  Displays 2 elimination phases  Adverse effects: hot flashes, Osteoporosis
 Exhibits anti-estrogenic, levels are reached within 4-7 with half-lives of 7-14 hours and deep vein thrombosis, and leg  Raloxifene reduces the rate of
estrogenic, or mixed activity hours after treatment. 4-11 days. cramps. bone loss and may increase
depending on the species and  Due to prolonged t1/2, 3-4 bone mass at certain sites.
target gene measured. In clinical weeks of treatment are required  In a large clinical trial, increased
tests or laboratory studies with to reach steady-state plasma spinal bone mineral density by
human cells, the drug's activity levels. >2% and reduced the rate of
depends on the tissue and end  Parent drug is converted largely vertebral fractures by 30-50%
point measured to metabolites within 4-6 hours but did not significantly reduce
after oral administration. nonvertebral fractures
 metabolized in humans by  Does not appear to increase the
multiple hepatic CYPs, some of risk of developing endometrial
which it also induces cancer.
 Major route of elimination from  Has beneficial actions on
the body involves N- lipoprotein metabolism, reducing
demethylation and deamination. both total cholesterol and LDL;

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Musculoskeletal Drugs
Raloxifene:
 estrogen agonist in bone, where
it exerts an antiresorptive effect;
reduces the number of vertebral
fractures by up to 50% in a
dose-dependent manner;
 also acts as an estrogen agonist
in reducing total cholesterol and
LDL, but does not increase HDL
or normalize plasminogen-
activator inhibitor 1 in
postmenopausal women
 does not cause proliferation or
thickening of the endometrium
Fulvestrant
 and its less potent forerunner ICI
164,384 have been purely anti-
estrogenic
 binds to ER and ER with a high
affinity comparable to estradiol
but represses
transactivation. It also increases
dramatically the intracellular
proteolytic degradation of ER
while apparently protecting ER
from degradation
Clomiphene increases gonadotropin
secretion and stimulates ovulation. It
increases the amplitude of LH and
FSH pulses without changing pulse
frequency
Progestins
 Compounds with biological activities similar to those of progesterone
 Includes : progesterone, 17-acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives in the estrane series, and norgestrel and related compounds in the gonane
series
 Single gene encodes 2 isoforms
of the progesterone receptor,
PR-A and PR-B. The first 164 N-
terminal amino acids of PR-B
are missing from PR-A; this
 Adsorbed rapidly after oral
administration and has an
absolute bioavailability of 2%.
 Administered monthly by
intramuscular depot injections.
Plasma concentrations reach
maximal levels in 7 days and are
maintained for a month.
 well absorbed following oral
administration,
 Undergoes rapid first-pass
metabolism, but high-dose (e.g.,
100-200 mg) preparations of
micronized progesterone
(PROMETRIUM) are available
 Undergoes enterohepatic however, HDL is not increased.
circulation, and excretion is Adverse effects include hot
primarily in the feces as flashes, deep vein thrombosis,
conjugates of the deaminated and leg cramps.
metabolite.
 Polymorphisms affect the rate of
tamoxifen metabolism to its
more potent 4-hydroxy
metabolite and may impact its
therapeutic activity in breast
cancer
 The drug has a t1/2 of 28 hours
and is eliminated primarily in the
feces after hepatic
glucuronidation; it does not
appear to undergo significant
biotransformation by CYPs.
 Numerous metabolites are
formed in vivo, possibly by
pathways similar to endogenous
estrogen metabolism, but the
drug is eliminated primarily
(90%) via the feces in humans.
 Drug and its metabolites are
eliminated primarily in the feces
and to a lesser extent in the
urine.
 Long plasma t1/2 (5-7 days) is
due largely to plasma-protein
binding, enterohepatic
circulation, and accumulation in
fatty tissues.
 elimination t1/2 = 5 minutes,  2 most frequent uses of
 Metabolized primarily in the liver progestins are for contraception,
to hydroxylated metabolites and either alone or with an estrogen
their sulfate and glucuronide and in combination with estrogen
conjugates, which are eliminated for hormone therapy of
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Musculoskeletal Drugs
occurs by use of two distinct for oral use. Although the in the urine. postmenopausal women.
estrogen-dependent promoters absolute bioavailability of these  A major metabolite specific for
in the PR gene preparations is low, efficacious progesterone is pregnane-3, 20 -
 In the absence of ligand, PR is plasma levels nevertheless may diol; its measurement in urine
present primarily in the nucleus be obtained. Progesterone also and plasma is used as an index
in an inactive monomeric state is available in oil solution for of endogenous progesterone
bound to heat-shock proteins injection, as a vaginal gel secretion. T
(HSP-90, HSP-70, and p59). (CRINONE, PROCHIEVE), as a  Synthetic progestins have much
 When receptors bind slow-release intrauterine device longer half-lives (e.g., 7 hours for
progesterone, the heat-shock (PROGESTASERT) for norethindrone, 16 hours for
proteins dissociate, and the contraception, and as a vaginal norgestrel, 12 hours for
receptors are phosphorylated insert (ENDOMETRIN) for gestodene, and 24 hours for
and subsequently form dimers assisted reproductive MPA).
(homo- and heterodimers) that technology.  Metabolism of synthetic
bind with high selectivity to  In the plasma, progesterone is progestins is thought to be
PREs (progesterone response bound by albumin and primarily hepatic, and elimination
elements) located on target gene corticosteroid-binding globulin is generally via the urine as
 Biological activities of PR-A and but is not appreciably bound to conjugates and various polar
PR-B are distinct and depend on SHBG. 19-Nor compounds, such metabolites, although their
the target gene in question. In as norethindrone, norgestrel, metabolism is not as clearly
most cells, PR-B mediates the and desogestrel, bind to SHBG defined as that of progesterone
stimulatory activities of and albumin, and esters such as
progesterone; PR-A strongly MPA bind primarily to albumin.
inhibits this action of PR-B and is Total binding of all these
also a transcriptional inhibitor of synthetic compounds to plasma
other steroid receptors proteins is extensive, 90%, but
the proteins involved are
compound specific.
Biphosphonates
 Analogs of pyrophosphate that contain two phosphonate groups attached to a geminal (central) carbon that replaces the oxygen in pyrophosphate. Because they form a three-dimensional
structure capable of chelating divalent cations such as Ca2+, the bisphosphonates have a strong affinity for bone, targeting especially bone surfaces undergoing remodeling.
 First-generation bisphosphonates contain minimally modified side chains (medronate, clodronate, and etidronate) or posses a chlorophenol group (tiludronate) They are the least potent and in
some instances cause bone demineralization.
 Second-generation aminobisphosphonates (e.g., alendronate and pamidronate) contain a nitrogen group in the side chain. They are 10-100 times more potent than first-generation compounds.
 Third-generation bisphosphonates (e.g., risedronate and zoledronate) contain a nitrogen atom within a heterocyclic ring and are up to 10,000 times more potent than first-generation agents.
 Concentrate at sites of active  Calcium supplements, antacids,  Excreted primarily by the Oral Preparations  Used extensively in conditions
remodeling. food or medications containing kidneys.  Cause heartburn, esophageal characterized by osteoclast-
 Highly negatively charged, divalent cations, such as iron,  Adjusted doses for patients with irritation, or esophagitis. Other mediated bone resorption,
bisphosphonates are membrane may interfere with intestinal diminished renal function have  Symptoms often abate when including osteoporosis, steroid-
impermeable but are absorption of bisphosphonates. not been determined; taken after an overnight fast, induced osteoporosis, Paget's
incorporated into the bone matrix  All are very poorly absorbed bisphosphonates currently are with tap or filtered water (not disease, tumor-associated
by fluid-phase endocytosis from the intestine and have not recommended for patients mineral water), and remain osteolysis, breast and prostate
 Remain in the matrix until the remarkably limited bioavailability with a creatinine clearance of upright. cancer, and hypercalcemia
bone is remodeled > then (<1% [alendronate, risedronate] <30 mL/minute.  Esophageal complications are  Recent evidence suggests that
released in the acid environment to 6% [etidronate, tiludronate]) > infrequent when the drug is second- and third-generation
of the resorption lacunae should be administered with a taken as described. bisphosphonates also may be
beneath the osteoclast as the full glass of water following an  If symptoms persist, NSAID or effective anticancer drugs
overlying mineral matrix is overnight fast and at least 30 acetaminophen can diminish
dissolved > importance of this minutes before breakfast. these symptoms; a proton pump
process for the antiresorptive  Oral bisphosphonates have not inhibitor at bedtime may be
effect of bisphosphonates is been used widely in children or helpful. Both drugs may be
evidenced by the fact that adolescents because of better tolerated on a once-
calcitonin blocks the uncertainty of long-term effects weekly regimen with no
antiresorptive action of bisphosphonates on the reduction of efficacy.
 antiresorptive action: direct growing skeleton.  Patients with active upper GI

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Musculoskeletal Drugs
inhibitory effects on osteoclasts
rather than strictly
physiochemical effects.
 antiresorptive activity apparently
involves 2 primary mechanisms:
osteoclast apoptosis and
inhibition of components of the
cholesterol biosynthetic
pathway.
Calcitonin
 mediated by the calcitonin
receptor (CTR), which is a
member of the PTH/secretin
subfamily of GPCRs
 hypocalcemic and
hypophosphatemic effects of
calcitonin are caused
predominantly by direct inhibition
of osteoclastic bone resorption.
 Although it inhibits the effects of
PTH on osteolysis, it inhibits
neither PTH activation of bone
cell adenylyl cyclase nor PTH-
induced uptake of Ca2+ into
bone.
disease should not be given oral
bisphosphonates.
 Serious osteonecrosis of the jaw
is associated with use of
bisphosphonates
Parenteral
 Owing to cytokine release, initial
infusion of pamidronate, may
cause skin flushing, flu-like
symptoms, muscle and joint
aches and pains, nausea and
vomiting, abdominal discomfort
and diarrhea (or constipation)
but mainly when given in higher
concentrations or at faster rates
than those recommended.
 Symptoms are short lived and
generally do not recur with
subsequent administration
Zoledronate
 Has more potent effects on
calcium than some other
bisphosphonates and is capable
of causing severe hypocalcemia.
It has been associated with renal
toxicity, deterioration of renal
function, and potential renal
failure.
 Infusion should be given over at
least 15 minutes, and the dose
should be 4 mg.
 Patients who receive
zoledronate should have
standard laboratory and clinical
parameters of renal function
assessed prior to treatment and
periodically after treatment to
monitor for deterioration in renal
function.
 .  Side effects include nausea,  Lowers plasma Ca2+ and
hand swelling, urticaria, and, phosphate concentrations in
rarely, intestinal cramping patients with hypercalcemia >
results from decreased bone
resorption and is greater in
patients in whom bone turnover
rates are high.
 Although effective for up to 6
hours in the initial treatment of
hypercalcemia, patients become
refractory after a few day > likely
due to receptor downregulation
 Use of calcitonin does not
substitute for aggressive fluid
resuscitation, and the
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Musculoskeletal Drugs
 interacts directly with receptors
on osteoclasts to produce a
rapid and profound decrease in
ruffled border surface area,
thereby diminishing resorptive
activity.
Parathyroid hormone
 Continuous administration or high-circulating PTH levels achieved in primary hyperparathyroidism causes bone demineralization and osteopenia. However, intermittent PTH administration promotes
bone growth.
 Synthetic human 34-amino-acid amino-terminal PTH fragment [hPTH(1-34), teriparatide (FORTEO)]
 Full-length human recombinant PTH(1-84) is in phase III trials for hypoparathyroidism, for which teriparatide is not approved.
 Intermittent PTH(1-84) may soon be approved for use in osteoporosis, but its benefits over PTH(1-34) remain to be established
Teriparatide
 Pharmacokinetics and systemic
actions on mineral metabolism
are the same as for PTH.
 Administered by once-daily
subcutaneous injection of 20 g
into the thigh or abdomen.
 With this regimen, serum PTH
concentrations peak at 30
minutes after the injection and
decline to undetectable
concentrations within 3 hours,
whereas the serum calcium
concentration peaks at 4-6 hours
after administration.
 Bioavailability averages 95%.
Fluoride
Teriparatide
 Clearance averages 62 L/hour in
women and 94 L/hour in men,
which exceeds normal liver
plasma flow, consistent with both
hepatic and extrahepatic PTH
removal.
 Serum t1/2 is ~1 hour when
administered subcutaneously
versus 5 minutes when
administered intravenously.
 Longer t1/2 following SQ
administration reflects the time
required for absorption from the
injection site.
PTH(1-34) and full-length PTH
 Elimination proceeds by
nonspecific enzymatic
mechanisms in the liver,
followed by renal excretion.
Teriparatide
 Increased the incidence of
osteosarcoma
 Should not be used in patients
who are at increased baseline
risk for osteosarcoma (including
those with Paget's disease of
bone, unexplained elevations of
alkaline phosphatase, open
epiphyses, or prior radiation
therapy involving the skeleton).
Full-length PTH(1-84)
 Associated with osteosarcomas
in rats; although not in humans.
 Adverse effects include
exacerbation of nephrolithiasis
and elevation of serum uric acid
levels.
bisphosphonates are the
preferred agents.
 Effective in disorders of
increased skeletal remodeling,
such as Paget's disease, and in
some patients with osteoporosis
 Development of antibodies to
calcitonin occurs with prolonged
therapy, but this is not
necessarily associated with
clinical resistance
Teriparatide
 Increases BMD and reduces the
risk of vertebral and nonvertebral
fractures.
 Increased axial bone mineral,
although initial reports of effects
on cortical bone were
disappointing.
 Candidates for treatment:
women who have a history of
osteoporotic fracture, who have
multiple risk factors for fracture,
or who failed or are intolerant of
previous osteoporosis therapy.
Men with primary or
hypogonadal osteoporosis are
also candidates for treatment;
however, the effect on fracture
incidence in this group has not
been established.
Others
 Co-administration of hPTH(1-34)
with estrogen or synthetic
androgen led to impressive
gains in vertebral bone mass or
trabecular bone.
 Most comprehensive studies to
date established value of daily
hPTH(1–34) administration on
total BMD, with significant
elevations of BMD in lumbar
spine and femoral neck and with
significant reductions of vertebral
and nonvertebral fracture risk in
osteoporotic women and men

6