JOURNAL OF BONE AND MINERAL RESEARCH

Volume 18, Number 11, 2003

© 2003 American Society for Bone and Mineral Research

Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] Improves

Both Cortical and Cancellous Bone Structure

YEBIN JIANG,1 JENNY J ZHAO,1 BRUCE H MITLAK,2 OUHONG WANG,2

HARRY K GENANT,1 and ERIK F ERIKSEN2

ABSTRACT

Histomorphometry and ␮CT of 51 paired iliac crest biopsy specimens from women treated with teriparatide
revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone
plate-like structure, and cortical thickness, and a reduction in marrow star volume.

Introduction: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both
cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal
women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after
treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural
data.
Methods: Fifty-one paired iliac crest bone biopsy specimens (placebo [n ⫽ 19], 20 ␮g teriparatide [n ⫽ 18], and 40
␮g teriparatide [n ⫽ 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional
(3D) microcomputed tomography (␮CT). Data for both teriparatide treatment groups were pooled for analysis.
Results and Conclusions: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone
volume (median percent change: teriparatide, 14%; placebo, ⫺24%; p ⫽ 0.001) and reduced marrow star volume
(teriparatide, ⫺16%; placebo, 112%; p ⫽ 0.004). Teriparatide administration was not associated with osteomalacia
or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous
and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index
(teriparatide, ⫺12%; placebo, 7%; p ⫽ 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo,
⫺14%; p ⫽ 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p ⫽ 0.012). These data show
that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone
volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and
increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve
biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral
fractures during administration of teriparatide.
J Bone Miner Res 2003;18:1932–1941

Key words: iliac crest, biopsy specimens, histomorphometry, teriparatide, microstructure

INTRODUCTION mass.(1) After the first report in 1929 of increased skeletal

NCE-DAILY ADMINISTRATION OF parathyroid hormone
O (PTH), the major hormonal regulator of calcium ho-
meostasis, causes increased bone formation and bone
Dr Jiang received a research grant from Eli Lilly and Company
for this study. Dr Genant is on the speaking bureau at Eli Lilly and
Company. Drs Mitlak and Wang are employees and shareholders of Eli
Lilly and Company. Dr Eriksen is an employee of Eli Lilly and Company.
calcium in rats after injection of parathyroid extract,(2) pre-
clinical studies and small clinical trials have shown pro-
nounced anabolic effects of intermittent PTH administration
on bone.(3,4)
Most recently, a large randomized double-blind multi-
center study, the Fracture Prevention Trial tested recombi-
nant human PTH(1-34) [teriparatide, rhPTH(1-34), TPTD]
versus placebo for treatment of osteoporosis in 1637 post-

1
Osteoporosis and Arthritis Research Group, Department of Radiology, University of California, San Francisco, California, USA.
2
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

1932
TERIPARATIDE IMPROVES BONE MICROSTRUCTURE
menopausal women.(5) Daily injections of 20 or 40 ␮g of
teriparatide over a mean of 19 months increased bone min-
eral density (BMD) at the lumbar spine and proximal femur
and significantly decreased the incidence of vertebral and
nonvertebral fractures.(5)
The effect of injected PTH on human cortical bone is
controversial. Some small early clinical studies found that
appendicular BMD was reduced by PTH treatment, whereas
vertebral BMD increased.(6 – 8) In other studies, BMD at the
predominantly distal radius or femoral neck(9) changed little
during PTH administration.(10 –12) These findings led to
speculation that the anabolic effects of teriparatide on can-
cellous bone may be obtained at the expense of cortical
bone.
In most studies of PTH peptides to treat osteoporosis, the
primary endpoint was a change in BMD. Only four such
studies have examined the effects of PTH peptides on iliac
crest bone histology.(13–16) However, those were small, used
different protocols, and had variable results. Three stud-
ies(13,14,17) found that PTH peptides significantly increase
cancellous bone volume, and the other two studies found
significant increases in cortical thickness by two-
dimensional (2D)(15) and three-dimensional (3D)(16) analy-
ses.
Stereological analysis of iliac crest bone structure based
on 2D sections can potentially yield 3D structural informa-
tion. However, the amount of tissue available for analysis is
small, because only a few thin sections of the biopsy core
are used. This leads to pronounced variation of calculated
structural indices and various possible biases.(18,19) Analysis
of 3D structure of bone biopsy specimens is now possible
using a variety of X-ray– or nuclear magnetic resonance
(NMR)-based techniques, among which the most widely
used is microcomputed tomography (␮CT).(19) These tech-
niques permit measurements of the entire biopsy core and
therefore may provide more stable and unbiased estimates
of bone structural indices.
This study presents quantitative microstructural data from
a substudy of the Fracture Prevention Trial, in which a
subset of patients randomized to placebo or teriparatide
injections underwent iliac crest biopsies before and after
teriparatide administration. Based on the antifracture effi-
cacy observed in these patients, it was hypothesized that
teriparatide treatment would improve both cancellous and
cortical bone in postmenopausal women with osteoporosis.
Changes in bone remodeling and trabecular and cortical
microstructure in paired iliac crest bone biopsy specimens
were analyzed using both 2D histomorphometry(20) and 3D
␮CT.(19)
MATERIALS AND METHODS
Subjects
One hundred and two patients participated in the biopsy
study, and a total of 51 paired iliac crest biopsy specimens,
of sufficient quality for analysis, were obtained from sub-
jects at 11 sites in five countries participating in the ran-
domized, multicenter, double-blind, placebo-controlled
Fracture Prevention Trial. BMD and fracture incidence were
the primary clinical outcomes of this trial. The characteris-
1933
tics of these patients and primary outcomes of the study
have been previously described in detail.(5) Briefly, women
were eligible for enrollment if a period of at least 5 years
had elapsed since menopause, and if they had at least one
moderate or two mild atraumatic vertebral fractures on
radiographs of the thoracic and lumbar spine, and an am-
bulatory status. For women with fewer than two moderate
fractures, an additional criterion for enrollment was a value
for BMD of the hip or lumbar spine that was at least 1 SD
below the mean value in normal premenopausal white
women (age range, 20 –35 years). BMD was measured by
DXA. Women were excluded from the study if they had
illnesses that affect bone or calcium metabolism.
Patients signed informed consent to the treatment and
investigation protocol, which was approved by the Institu-
tional Review Board for Research Involving Human Sub-
jects, at each participating center.
Treatment
Teriparatide was synthesized at Lilly Research Laborato-
ries using recombinant DNA technology, lyophilized, and
stored at ⫺20°C. All enrolled subjects were supplemented
with a daily intake of 1000 mg of elemental calcium and
400-1200 IU of vitamin D3. The women administered a
once-daily self-injection of placebo for 2 weeks and were
then randomly assigned to receive placebo or 20 or 40 ␮g of
teriparatide daily. Bone mass was measured by DXA of the
lumbar spine, total hip region, and forearm.
Specimens
Transiliac crest bone biopsy specimens were obtained
from 102 women, enrolled in the Fracture Prevention Trial,
using a Bordier needle trephine system (8 mm inner diam-
eter) after in vivo double labeling with tetracycline fluoro-
chromes given orally in a 3:12:3 day sequence. All sites
performing biopsy specimens were instructed to use sites 2
cm behind and 2 cm below the anterior superior iliac spine.
They were also instructed to insure that the biopsy was
taken perpendicular to the axis of the ilium in that area. The
first biopsy was taken at baseline and the second from the
contralateral iliac crest after 12 months of treatment or at
treatment endpoint. Treatment duration for these women at
the time of the second biopsy was 18 ⫾ 5 months (range,
11–24 months). The biopsy specimens were fixed in 70%
ethanol, dehydrated in a graded series of alcohols (70 –
100%, two changes per grade, each for 4 h under vacuum),
and placed in xylene and infiltrated with methylmethacry-
late under vacuum at 20 psi on a 2 h/step and 24 h infiltra-
tion cycle. The samples were then embedded in methyl
methacrylate and sectioned on a heavy-duty microtome
(Jung K2). Fifty-one paired iliac crest biopsy specimens
(placebo [n ⫽ 19], 20 ␮g teriparatide [n ⫽ 18], and 40 ␮g
teriparatide [n ⫽ 14]) were found to be complete and of
sufficient quality to be analyzed by both histomorphometry
and ␮CT. The criterion to reject a biopsy sample was the
loss of one cortex.
Histomorphometry
Biopsy specimens were measured without the knowledge
of sample treatment group. All static parameters of remod-
1934
eling activity were measured under light microscopy on
5-␮m-thick biopsy sections stained with Goldner’s
trichrome. Dynamic parameters of bone formation were also
measured under fluorescent microscopy of unstained 15-
␮m-thick biopsy sections at 125⫻ magnification.(20) Point
counting and intersection-based assessments were used to
measure most static and dynamic parameters, and a digitizer
was used to measure the distance between tetracycline la-
bels and osteoid thickness. All measurements represent the
mean of four sections with 100-␮m spacing. Measured and
derived variables were expressed according to the standard
nomenclature and formulas recommended by the American
Society of Bone and Mineral Research nomenclature com-
mittee.(18)
The static histomorphometric parameters for trabecular
bone included total bone volume per tissue volume (BV/
TV, %), fraction of trabecular surface covered by osteoid
(OS/BS, %), and total erosion surface (ES/BS, %). Mean
wall thickness (W.Th, ␮m) of completed osteons was de-
rived from measurements between the cement line and
quiescent bone surface. Erosion depth (E.De, ␮m) was
assessed by lamellar counting as described by Eriksen.(20)
Trabecular diameter (Tb.Dm, ␮m), trabecular number
(Tb.N, mm⫺1), and trabecular separation (Tb.Sp, ␮m) were
calculated indirectly from the bone surface to volume ratio
and BV/TV. Marrow star volume (Ma.St.V, mm3), an index
of trabecular connectivity, was measured at a 15-fold mag-
nification using a projection microscope and computed as
the sum of the lengths of rays projected from randomly
selected points in the marrow space toward trabeculae.
Static histomorphometric parameters for cortical bone
were measured for the inner and outer cortex and averaged
for each biopsy. Cortical tissue was analyzed between the
periosteal and endosteal surfaces. The junction between
endosteal and trabecular bone was selected to exclude en-
docortical trabeculae. Cortical thickness (Ct.Th, ␮m) was
expressed as the average of grid intersection-based, evenly
spaced, orthogonal intercepts across each of the two corti-
ces. Cortical porosity (Ct.Po/Ct.V, %) was expressed as the
average percent area occupied by Haversian canals within
the inner and outer cortical tissue and was assessed by point
counting.
Both double and single tetracycline-labeled surfaces
(dLS/BS, %; sLS/BS, %) were measured to obtain the
mineralizing surface (MS/BS, %), using the correction for
“label escape” (dLS ⫹ 0.5 ⫻ sLS). Dynamic parameters
also included mineral apposition rate (MAR, ␮m/day).
␮CT imaging acquisition
Non-decalcified specimens embedded in methyl methac-
rylate were trimmed to fit the specimen holder and exam-
ined using a compact fan-beam-type ␮CT scanner (Scanco
Medical AG, Bassersdorf, Switzerland), which can work in
either a spiral scanning or multislice mode. A small X-ray
tube with a 10-␮m nominal diameter ␮focal spot was used
as a source. The detector consisted of a linear charge-
coupled device (CCD) array. A scout view scan was ob-
tained for selection of the examination volume of the spec-
imens, by automatic positioning, measurement, and offline
reconstruction.(21)
JIANG ET AL.
For each sample, a total of approximately 600 microto-
mographic sections were acquired with a slice increment of
17 ␮m. The field of view was 17 ⫻ 17 mm2, and the matrix
size was 1024 ⫻ 1024. Images with isotropic resolution of
17 ␮m3 were obtained.
␮CT imaging processing and analysis
␮CT image acquisition and analysis of the biopsy spec-
imens were performed without the knowledge of sample
treatment group. For subsequent image analyses, subvol-
umes of the library of 600 sections originally obtained were
selected. Each selected volume of interest (VOI) contained
either trabecular bone or cortical bone. To exclude endocor-
tical trabeculae, the trabeculae within 0.5 mm of the en-
docortical surface were excluded as the junction between
endosteal and trabecular bone. To avoid the risk of subvol-
ume selection bias, precautions were taken to exclude a
buffer zone at the junction between endosteal and trabecular
bone consisting of endocortical trabeculae of 0.5 mm width
starting from endocortical surface. The volumetric data
were recorded in binary data.
3D trabecular structural parameters were measured di-
rectly, as previously described.(19) Because the X-ray atten-
uation throughout a non-homogeneous material is not uni-
form and there may exist trabeculae of varying densities
throughout the specimen, the selection of one commonly
used global and local gray-scaled threshold value, or con-
straint region growing segmentation method, to create a
binary image was inappropriate.(22,23) Mineralized bone was
separated from bone marrow with a 3D segmentation algo-
rithm based on the analysis of the steepest gradient calcu-
lated from a continuous polynomial fit least-squares approx-
imation of the originally discrete CT volume to find digital
edges, which were most commonly characterized by inten-
sity changes in a local image neighborhood. For example,
smooth transitions between neighboring intensities are
called roof edges, representing points of change from in-
creasing to decreasing intensities or vice versa, whereas a
sudden change between neighboring intensities is termed
step edge, which describes the borderline between two
adjacent regions with considerably different intensities.(23)
Bone surface area was determined using the matching cubes
method to triangulate the surface of the mineralized bone
phase using an interpolating 3D surface reconstruction al-
gorithm.(23) The marching cube algorithm decides how a
cube made of neighboring voxels is intersected by the
original rugged surface. The resulting surface is a polygon
represented by triangles. A voxel within a cube can either
belong to the object or to the background. Various triangu-
lated surfaces result from the intersection of the surface and
the cube, depending on the voxel configurations with a
cube. The algorithm marches on to the next cube, after
detecting the surface of the investigated cube in the discrete
data set. This approach smooths the surface, which has a 3D
polygonal representation consisting exclusively of triangles.
BV was calculated using tetrahedrons corresponding to
the enclosed volume of the triangulated surface. TV was the
volume of the sample that was examined. A normalized
index, BV/TV, was used to compare samples of varying
size. The methods used for calculating trabecular thickness
TERIPARATIDE IMPROVES BONE MICROSTRUCTURE
TABLE 1. BASELINE CHARACTERISTICS OF A SUBSET OF WOMEN FROM
n Placebo
Age (years) 19 67.6 ⫾ 6.8
Years since menopause 17 19.5 ⫾ 8.5
BMD (g/cm2)
Femoral neck 19 0.65 ⫾ 0.10
Intertrochanter 18 0.89 ⫾ 0.14
Lumbar spine 19 0.86 ⫾ 0.19
Radius shaft 19 0.58 ⫾ 0.11
Distal radius 19 0.33 ⫾ 0.09
No. vertebral fractures 19 2.2 ⫾ 1.6
Data are presented as mean ⫾ SD.
(Tb.Th), Tb.Sp, Tb.N, and structural model index (SMI)
have been described previously.(19)
In aging and postmenopausal osteoporosis, the deteriora-
tion of trabecular bone structure is characterized by a
change from plate elements to rod elements. SMI quantifies
the characteristic form of a 3D structure in terms of the
amount of plates and rods composing the structure. The SMI
is based on a differential analysis of the triangulated bone
surface. The SMI value is 0 and 3 for an ideal plate structure
and a perfect cylindrical rod structure, respectively, inde-
pendent of the physical dimensions. For a structure with
both plates and rods of equal thickness the value lies be-
tween 0 and 3, depending on the volume ratio of rods and
plates. Morphological measures such as the Euler number, a
measure of the maximum number of branches that could be
removed before the structure was divided into multiple
pieces, was determined in the ␮CT data set without prior
skeletonization. The connectivity (C) of a two-component
system, i.e., bone and marrow, was derived directly from the
Euler number, by C ⫽ 1 ⫺ E, if all the trabeculae and bone
marrow cavities are connected without isolated marrow
cavities inside the bone.(24) It was normalized by examined
tissue volume and reported as connectivity density (CD).
Ct.Th was expressed as the average thickness of the 3D
cortex on the inner and outer cortical surfaces of the biopsy
specimens. A semiautomatic contouring algorithm defined
the cortical margins with a manual tracing correction locat-
ing periosteal and endosteal surfaces or the most probable
edge of the inner and outer cortical surfaces. Filling maxi-
mal spheres in the whole cortex with the distance transfor-
mation, then calculating the average thickness of all bone
voxels determined Ct.Th. Cortical porosity (Ct.Po) was the
nonbone in the binary image and was calculated with the
same procedure as for BV/TV.
To determine reproducibility of the ␮CT examination, 20
specimens from different groups were rescanned and rean-
alyzed. The root mean square CV of the measurements was
2.6% (BV/TV), 3.6% (Tb.N), 5.9% (Tb.Th), 4.0% (Tb.Sp),
3.3% (DA), 2.1% (SMI), 3.9% (CD), 2.7% (Ct.Po), and
2.9% (Ct.Th).
Statistical analysis
Recently, the antifracture efficacy of teriparatide was
reported,(5) and treatment with either 20 or 40 ␮g/day of
1935
THE FRACTURE PREVENTION TRIAL WHO PROVIDED PAIRED BIOPSIES
n TPTD20 n TPTD40
18 67.8 ⫾ 5.5 14 67.8 ⫾ 7.6
15 21.3 ⫾ 8.1 11 22.0 ⫾ 9.4
18 0.61 ⫾ 0.10 14 0.62 ⫾ 0.10
17 0.81 ⫾ 0.13 14 0.82 ⫾ 0.16
18 0.77 ⫾ 0.15 14 0.84 ⫾ 0.17
18 0.54 ⫾ 0.10 14 0.59 ⫾ 0.12
18 0.30 ⫾ 0.06 14 0.34 ⫾ 0.08
18 2.6 ⫾ 1.6 14 2.5 ⫾ 1.5
teriparatide was shown to have similar antifracture efficacy.
In addition, this biopsy substudy did not reveal any signif-
icant difference in structural variables between the two
teriparatide treatment groups. Therefore, because of the
small sample size, the data for both doses of teriparatide
were pooled for the analyses of 2D and 3D structural
parameters. Patient demographics were compared across
treatment groups and with the total population of the Frac-
ture Prevention Trial, using the Pearson ␹2 test for discrete
variables and t-test for continuous variables. For each mea-
sured variable, individual patient’s paired baseline and end-
point data were analyzed to construct percent change from
baseline values, and these data were summarized for both
the placebo group and the pooled teriparatide group. The 2D
and 3D biopsy data were not normally distributed; therefore,
rank transformation was applied before statistical analyses
were performed. The placebo and teriparatide treatment
groups were compared using t-test (based on ranked or
unranked data), and the summary statistics for biopsy spec-
imens were expressed as median and interquartile range
(25th, 75th) for each individual group.
RESULTS
The baseline demographic (Table 1) and bone structural
characteristics (Tables 2 and 3) of study participants were
similar across all study groups. Baseline demographics for
this substudy population did not differ from those of the
total Fracture Prevention Trial population.(5) Pairwise com-
parisons between 20 and 40 ␮g teriparatide treatment
groups showed no significant p values for 2D (p ⬎ 0.05) or
3D (p ⬎ 0.1) structural variables. Therefore, the data for the
teriparatide treatment groups were pooled for all analyses.
BMD
Baseline and endpoint measurements of BMD were ob-
tained for all biopsy study participants, and data for the 51
patients with complete paired biopsy specimens are shown
in Table 4. Data from patients with incomplete biopsy
specimens were not significantly different from patients
with paired biopsy specimens. There was a significant in-
crease in BMD for the teriparatide treatment group com-
pared with placebo at the lumbar spine (teriparatide,
⫹14.4% ⫾ 1.3%; placebo, ⫹0.3% ⫾ 1.6%; p ⬍ 0.001),
1936 JIANG ET AL.

TABLE 2. PERCENT CHANGE FROM BASELINE OF 2D TRABECULAR AND CORTICAL BONE HISTOMORPHOMETRY VALUES

Placebo Pooled TPTD

† † †
n Baseline Endpoint Percent change* n Baseline Endpoint† Percent change* p Value

ES/BS 17 0.041 0.036 12.5 (⫺24.5, 92.5) 28 0.038 0.042 38.0 (⫺51.2, 126.9) 0.782
E.De (␮m) 17 48.3 47.4 15.5 (⫺4.6, 25.5) 28 46.4 49.2 ⫺2.6 (⫺23.1, 37.4) 0.406
OS/BS 17 0.10 0.07 20.5 (⫺44.5, 140.3) 29 0.07 0.10 34.7 (⫺22.4, 133.3) 0.363
MS/BS 17 0.09 0.07 ⫺15.9 (⫺40.8, 67.4) 28 0.06 0.04 ⫺18.9 (⫺64.9, 54.1) 0.343
MAR (␮m/day) 17 0.58 0.57 ⫺4.1 (⫺10.3, 7.0) 24 0.49 0.56 4.7 (⫺14.5, 34.2) 0.260
W.Th (␮m) 18 41.2 41.0 ⫺0.2 (⫺4.3, 7.0) 29 38.5 41.7 4.6 (⫺9.1, 11.7) 0.463
O.Th (␮m) 17 10.3 10.1 ⫺0.6 (⫺12.4, 8.6) 29 9.7 9.2 ⫺3.6 (⫺21.3, 21.6) 0.849
BV/TV 15 0.19 0.14 ⫺24.0 (⫺48.1, 7.7) 25 0.14 0.18 14.3 (0.0, 50.0) 0.001
Ma.St.V (mm3) 14 11.4 33.3 112.2 (10.9, 212.4) 23 16.1 15.2 ⫺15.9 (⫺41.6, 47.0) 0.004
Tb.Dm (␮m) 18 276.2 251.0 ⫺2.9 (⫺27.8, 28.6) 27 250.0 285.7 11.8 (⫺6.7, 27.3) 0.111
Tb.N (mm⫺1) 15 1.94 1.85 ⫺8.6 (⫺19.3, 15.8) 25 2.0 1.9 ⫺3.4 (⫺11.4, 12.5) 0.880
Tb.Sp (␮m) 15 515.2 540.4 9.4 (⫺13.6, 23.8) 25 503.8 540.8 3.6 (⫺11.1, 12.9) 0.880
Ct.Po 15 0.054 0.055 23.4 (⫺29.6, 56.3) 26 0.048 0.072 51.8 (20.7, 117.5) 0.094
Ct.Th, ␮m 15 966.0 753.0 ⫺10.8 (⫺32.4, 13.2) 27 927.0 1008.0 0.9 (⫺14.7, 39.5) 0.197

* Data are presented as median percent change (25th, 75th interquartile range).
†
Data are presented as median.
Ct.Po, cortical porosity; Ct.Th, cortical thickness; MAR, mineral appositional rate; MS/BS, mineralization surface; OS/BS, osteoid surface; O.Th, osteoid
thickness; BV/TV, trabecular volume; Ma.St.V, marrow star volume; W.Th, wall thickness; Tb.Dm, trabecular diameter; Tb.N, trabecular number; Tb.Sp,
trabecular separation; ES/BS, total erosion surface; E.De, erosion depth.

TABLE 3. PERCENT CHANGE FROM BASELINE IN 3D TRABECULAR AND CORTICAL BONE MICROSTRUCTURE

Placebo Pooled TPTD

† † †
n Baseline Endpoint Percent change* n Baseline Endpoint† Percent change* p Value

BV/TV 19 0.13 0.11 ⫺5.0 (⫺40.2, 37.8) 32 0.12 0.13 7.2 (⫺14.7, 99.0) 0.098
Tb.N (mm⫺1) 19 1.27 1.26 ⫺0.1 (⫺6.3, 9.5) 32 1.27 1.31 3.3 (⫺7.8, 22.5) 0.335
Tb.Th (␮m) 19 0.15 0.14 0.8 (⫺16.0, 9.0) 32 0.14 0.15 ⫺0.9 (⫺11.5, 21.1) 0.408
Tb.Sp (␮m) 19 0.80 0.79 ⫺0.7 (⫺8.6, 6.2) 32 0.76 0.76 ⫺2.1 (⫺11.7, 9.2) 0.526
DA 19 1.42 1.39 0.1 (⫺7.4, 9.0) 32 1.42 1.38 ⫺1.9 (⫺7.2, 6.9) 0.773
SMI 19 1.7 2.0 7.1 (⫺13.7, 38.8) 32 2.0 1.5 ⫺12.2 (⫺43.2, 11.4) 0.025
CD (mm⫺3) 19 5.6 4.5 ⫺14.0 (⫺31.7, 31.8) 32 3.7 4.5 19.1 (⫺14.6, 84.4) 0.034
Ct.Po 17 0.18 0.16 ⫺21.0 (⫺23.7, 10.4) 25 0.16 0.16 0.69 (⫺11.2, 16.0) 0.457
Ct.Th (mm) 17 0.84 0.74 2.9 (⫺18.5, 13.2) 25 0.74 0.92 22.0 (7.0, 40.8) 0.012

* Data are presented as median percent change (25th, 75th interquartile range).
†
Data are presented as median.
BV/TV, bone volume/total volume; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; DA, degree of anisotropy; SMI,
structure model index; CD, connectivity density; Ct.Po, cortical porosity; Ct.Th, cortical thickness.

femoral neck (teriparatide, ⫹6.3 ⫾ 0.9; placebo, ⫺2.4% ⫾
0.9; p ⬍ 0.001), and intertrocanter (teriparatide, ⫹6.1 ⫾
0.9; placebo, ⫺1.9% ⫾ 0.7; p ⬍ 0.001). Measurements of
BMD at the radius shaft and distal radius were not signifi-
cantly different between placebo and teriparatide treatment
groups.
2D histomorphometry
Qualitative analysis of the biopsy specimens (Fig. 1)
revealed no osteomalacia or woven bone in the teriparatide
groups. Increased trabecular and cortical thickness was also
observed in most post-treatment biopsy specimens. How-
ever, in biopsy specimens obtained from women treated
with 40 ␮g teriparatide, marrow fibrosis (2/14) and tunnel-
ing resorption (4/14) were seen. Changes in histomorpho-
metric indices reflecting activity and turnover (ES/BS, OS/
BS, MS/BS, MAR, and Ac.F) did not differ between groups.
Neither did changes in erosion depth (E.De) or wall thick-
ness (W.Th; Table 2).
Analysis of structural indices (Table 2) revealed a signif-
icant increase in cancellous bone volume in the pooled
teriparatide group versus placebo (teriparatide, 14% [0%,
50%] [median percent change, 25th, 75th interquartile
range]; placebo, ⫺24% [⫺48%, 8%]; p ⫽ 0.001). Teripa-
ratide also caused reductions in marrow star volume (teripa-
ratide, 16% [⫺42%, 47%]; placebo, 112% [11%, 212%];
p ⫽ 0.004). In the placebo group, cortical thickness de-
creased, whereas it increased in the pooled teriparatide
group. However, because of the pronounced variation in this
index, this trend did not reach significance. No significant
TERIPARATIDE IMPROVES BONE MICROSTRUCTURE 1937

TABLE 4. PERCENT CHANGE IN BMD FROM BASELINE FOR PLACEBO AND POOLED TERIPARATIDE TREATMENT GROUPS*
2
BMD (g/cm ) n Placebo n Pooled TPTD p Value

Lumbar spine 19 0.3 ⫾ 1.6 32 14.4 ⫾ 1.3 ⬍0.001

Femoral neck 19 ⫺2.4 ⫾ 0.9 31 6.3 ⫾ 0.9 ⬍0.001
Intertrochanter 18 ⫺1.9 ⫾ 0.7 30 6.1 ⫾ 0.9 ⬍0.001
Radius shaft 19 ⫺0.9 ⫾ 0.8 32 ⫺3.3 ⫾ 0.9 0.067
Distal radius 19 ⫺3.0 ⫾ 2.0 32 ⫺2.6 ⫾ 1.2 0.841

Data are presented as mean ⫾ SEM.

* For the 51 patients who provided paired biopsies.

FIG. 1. 2D sections of two sets

of paired iliac crest bone biopsy
specimens. Improved trabecular
connectivity as well as increased
cortical thickness after teripa-
ratide treatment is seen in both
sections. A significant increase in
BV/TV and decrease in Ma.St.V
were observed after treatment
with teriparatide (p ⬍ 0.05). A
and C are baseline samples, and
B and D are samples after treat-
ment with (A and B) 20 ␮g
teriparatide or (C and D) 40 ␮g
teriparatide.

increase in cortical porosity was observed in the pooled
teriparatide-treated group.
3D ␮CT
A representative picture derived from the ␮CT analysis of
one paired teriparatide biopsy sample is shown in Fig. 2. In
the post-treatment biopsy, an improvement of the osteopo-
rotic trabecular structure is seen compared with the pretreat-
ment biopsy, with a change toward more plate-like mor-
phology and an increase in cortical thickness. The
percentage decrease in SMI (teriparatide, ⫺12% [⫺43%,
11%] [median % change, 25th, 75th interquartile range];
placebo, 7% [⫺14%, 39%]), increase in CD (teriparatide,
19% [⫺15%, 84%]; placebo, ⫺14% [⫺32%, 32%]), and
increase in Ct.Th (teriparatide, 22% [7%, 41%]; placebo 3%
[⫺19%, 13%]) were found to be significant (p ⬍ 0.05) after
teriparatide treatment, based on the calculation of percent-
age change from each individual patient (Table 3). How-
ever, no significant increase in 3D trabecular bone volume
fraction was demonstratable (teriparatide, 7% [⫺15%,
99%]; placebo, ⫺5% [⫺40%, 38%]; p ⫽ 0.098; Table 3).
There was no statistically significant difference in cortical
porosity between placebo and pooled teriparatide-treated
patients.
DISCUSSION
In this study, both 2D histomorphometry and 3D ␮CT
techniques were used to analyze biopsy specimens from a
subset of postmenopausal women with osteoporosis en-
rolled in the Fracture Prevention Trial. This approach pro-
vided quantitative data to assess changes in bone structural
indices and clearly showed that teriparatide treatment was
able to improve both cancellous and cortical bone structure.
This is the first report of quantitative microstructural data
from paired biopsy specimens obtained from patients
treated with teriparatide.
In contrast to a large increase in BMD observed in these
patients after treatment with teriparatide,(5) this biopsy study
revealed no significant changes in cancellous bone remod-
eling indices, bone resorption indices (erosion surface, ero-
sion depth, and resorption period), bone formation rates, or
labeling indices after 18 months of teriparatide treatment.
From previous short-term studies, where biopsy specimens
1938
FIG. 2. 3D ␮CT reconstructions of a paired iliac crest bone biopsy.
The cortical bone of the iliac crest and trabecular microstructure and
connectivity between the cortex can be observed in these images.
Compared with the (A) baseline biopsy, treatment with (B) 20 ␮g of
teriparatide increased trabecular bone volume, trabecular connectivity,
and cortical thickness. Note also the change in trabecular morphology
from a rod-like structure to a more plate-like pattern in the post-
treatment biopsy. This paired biopsy sample was obtained from a
65-year-old woman who was treated with 20 ␮g teriparatide for 21
months.
were obtained after 1 month,(16) we know that teriparatide is
able to increase labeled surface and increase bone formation
very rapidly on quiescent surfaces. Lindsay et al. has re-
ported that biochemical markers of bone resorption and
formation reached a maximum level after 1– 6 months of
teriparatide treatment, which gradually returned to baseline
over the duration of the study.(12) The lack of increase in
bone turnover in our study is probably explained by the late
timing of the biopsy specimens in relation to initiation of
therapy (11–24 months). At this time, bone turnover may
JIANG ET AL.
have been reduced toward baseline levels. We were also
unable to show significant increases in wall thickness, albeit
a positive trend was seen. It may be that early in the
treatment cycle, cancellous packets of increased thickness
may have been laid down and were then subsequently
covered with packets of more normal thickness by the time
of the second biopsy. Dempster et al. previously reported an
increased width of endocortical walls but also found the
width of trabecular packets to be unchanged.(16) The lack of
change in trabecular wall thickness in both studies may be
explained by several factors. First, wall thickness was as-
sessed over the bone surface as a whole, which means that
a significant proportion of walls measured were formed
before teriparatide treatment was initiated. Second, a large
proportion of new bone formation in the early phases of
teriparatide therapy may occur on quiescent surfaces, not
previously resorbed.(16,25) This may contribute to the im-
provement in trabecular structural indices but not necessar-
ily an increase in wall thickness.
Previously, PTH, like other anabolic agents such as so-
dium fluoride,(26) was thought to exert its effect mainly on
cancellous bone. Moreover, there are unresolved questions
that PTH might exert deleterious effects on cortical bone in
terms of cortical thinning(6,8,13,27) because of an increase in
intracortical and endocortical resorption.(28) Our study
shows that teriparatide actually improved cortical bone
structure, reflected in a 22% increase in cortical thickness.
The images obtained during the ␮CT analysis suggest that
the increased cortical thickness resulted from increased
bone formation at both the periosteal and endosteal surfaces.
Potentially, the early increases in bone turnover seen during
intermittent teriparatide therapy could exert negative effects
on cortical bone strength through an increase in porosity.
However, in rabbits, although intracortical remodeling was
significantly increased by teriparatide treatment, the subse-
quent increase in intracortical porosity did not compromise
the mechanical strength of the bone.(29) It seemed that the
increased porosity occurred primarily at the endocortex,
which has been proven to have a lesser effect on the me-
chanical properties of bone than if this transient loss of bone
were to occur at the periosteal surface.(24) Similar observa-
tions of conserved bone strength despite increased cortical
porosity have also been reported after teriparatide treatment
in a cynomolgus monkey model.(30) Finally, the clinical
experience with teriparatide during the Fracture Interven-
tion Trial found a tendency for nonvertebral fractures to be
reduced after the ninth month of the study.(5)
Discrepancies between the histomorphometric and ␮CT
analysis for indices of cortical thickness and cancellous
bone volume may be explained by amount of tissue exam-
ined using the two different techniques and by the segmen-
tation threshold based on mineralization density that is used
in ␮CT imaging. The newly formed bone on the cancellous
bone surface may not be optimally mineralized, and there-
fore not as dense as the segmentation threshold, and unable
to be detected by ␮CT. However this new, relatively hy-
pomineralized bone could be detected by histological stain-
ing. On the other hand, the mineralization of the cortical
bone was much denser than the cancellous bone, and even
the newly formed cortical bone could be detected by ␮CT.
TERIPARATIDE IMPROVES BONE MICROSTRUCTURE
Failure of histology to detect the change in cortical thick-
ness could be caused by the limited amount of tissue exam-
ined.
Studies in human bone reported by Dempster et al.(16)
showed that an increase in cortical bone was accompanied
by increased endocortical wall width and reduced erosion
perimeter, suggesting a positive balance at the endosteal
envelope. Our in vivo assessment of bone structure using
peripheral quantitative computed tomography (pQCT)(31)
and radiogrammetry(32) also demonstrated improved corti-
cal structure in two different subgroups of women in the
Fracture Prevention Trial. Zanchetta et al.(31) demonstrated
increased diameter but unchanged cortical thickness of the
radius after treatment with teriparatide using pQCT mea-
surements, leading to significant increases in axial and polar
moments of inertia. Furthermore, using radiogrammetry,
Hyldstrup et al. (32) demonstrated increased cortical thick-
ness of metacarpals and the radius and reduced marrow
diameter, suggesting both increased endosteal and perios-
teal bone formation. Finally, a structural analysis of hip
geometry by Uusi-Rasi et al.,(33) based on DXA scans from
the Fracture Prevention Trial, also revealed significant in-
creases in cortical thickness. Increased cortical thickness
contributes substantially to bone strength even at skeletal
sites such as the vertebrae, where cancellous bone has
traditionally been thought to play the dominant role in
determining strength.(34,35) One study reported that cortical
bone is responsible for up to two-thirds of the mechanical
strength of vertebrae in osteoporotic patients.(35)
Teriparatide also improved trabecular architecture and
increased trabecular bone volume, reflected in significant
improvements of several 2D and 3D indices. Large incre-
ments in bone volume fraction are one of the most striking
and consistent findings in ovariectomized rats treated with
PTH and are associated with increased biomechanical
strength.(36,37) Previous reports on changes in cancellous
bone volume in humans after PTH treatment have, however,
been conflicting. Three previous studies of human iliac crest
biopsy specimens using traditional 2D bone histomorphom-
etry reported an increase,(13,14,17) but two other studies were
unable to show an increase in cancellous bone volume.(15,16)
These discrepancies are probably caused by the limited
number of samples available for assessment in these studies.
Treatment with teriparatide for 6 months was found to
induce a 2-fold increase in bone volume fraction,(13) and a
50% increase was observed in estrogenized women after 1
year of teriparatide treatment.(14) Also, two indices reflect-
ing connectivity of the trabecular network, marrow star
volume assessed by 2D methods and connectivity index
assessed by 3D ␮CT, showed significant improvement.
Increased 2D trabecular connectivity after teriparatide
treatment has been demonstrated in rats(38) and monkeys.(39)
Greater 2D trabecular connectivity has also been found in
patients with mild primary hyperparathyroidism when they
were compared with age- and sex-matched controls.(40) The
increased 3D connectivity density after teriparatide treat-
ment in these studies support data in a recent report where
a similar observation was made based on a limited number
of iliac specimens.(16) Improvement of connectivity indices
does not directly prove reconnection of perforated trabecu-
1939
lae. Trabecular thickening may also cause a decrease of
marrow star volume, and the connectivity index may actu-
ally increase in the early phases of perforation of trabecular
plates in young bone.(41) Another possibility of increasing
connectivity density is intratrabecular tunneling(39,42) or tra-
becular perforation.(43) Intratrabecular tunneling in iliac
crest and vertebral sections has been described in monkeys
after teriparatide treatment,(39) possibly as a remodeling
mechanism to maintain trabecular thickness. Tunneling of
thickened individual trabeculae would convert them into
multiple trabeculae, resulting in a normalization of trabec-
ular thickness but an increase in the number of 3D spatial
connections. However, when analyzing our images obtained
from the ␮CT analysis, increased connectivity and a rever-
sal of rod-like structure to a plate-like pattern can be ob-
served. This is also reflected quantitatively in the decrease
in structure model index in biopsy specimens from women
treated with teriparatide.
The structural changes accompanying age-dependent
bone loss and osteoporosis are loss of trabecular connectiv-
ity caused by trabecular perforations and cortical
thinning.(44 – 46) The trabecular perforations also cause a
transition of trabecular morphology from the plate-like ap-
pearance in younger individuals to a more rod like appear-
ance. Our qualitative and quantitative data show that teripa-
ratide not only increases bone volume but also reverses the
osteoporotic changes in trabecular morphology and cortical
geometry. Earlier studies on human vertebral specimens
have demonstrated that the combination of trabecular bone
volume fraction with other 2D structural parameters im-
proves the prediction of bone strength in a multiple regres-
sion model.(47) At this time, only limited data are available
for humans, although the association of bone volume
fraction with bone biomechanical properties is well docu-
mented.(19)
One study in ovariectomized rats on estrogen replacement
therapy reported that the SMI and 3D connectivity density
predicted vertebral compressive strength. Another aging
study in pigs has demonstrated that inclusion of connectiv-
ity density with bone volume in a regression analysis im-
proved the prediction of both maximum vertebral stress
from compressive testing and apparent modulus from finite
element modeling.(48)
In our analysis, the changes of more simple 2D indices
pertaining to cancellous bone structure, Tb.N, Tb.Th, and
Tb.Sp, did not reach significance after teriparatide treat-
ment. However, more stereologically correct indices, like
marrow star volume and ␮CT-based 3D indices revealed
significant changes, further corroborating the superiority of
these techniques for structural analysis of small samples
such as bone biopsy specimens.
When material properties change, such as in rats on
low-dose long-term sodium fluoride treatment, structural
parameters fail to predict biomechanical properties.(49)
However, for teriparatide, clear correlations between im-
provement of structure and biomechanical properties have
been reported in monkeys.(30,50) Using a combination of
QCT, microfinite element analysis, and compression test-
ing, significant improvements in biomechanical competence
of vertebrae from monkeys treated with teriparatide for 6
1940
months have been demonstrated. Thus, teriparatide does not
negatively impact the material properties of bone that would
offset the positive effects on bone architecture.
In conclusion, teriparatide treatment stimulates both tra-
becular and cortical bone formation, resulting in increased
cortical thickness and cancellous bone volume, improved
cancellous bone connectivity, and a shift from rod-like to
plate-like trabecular morphology. These changes constitute
a reversal of osteoporotic bone structural changes and ex-
plain the pronounced decrease in vertebral and nonvertebral
fracture rates observed after teriparatide treatment.
ACKNOWLEDGMENTS
The authors thank Karen V Pinette for manuscript prep-
aration and Anette Baatrup for preparation and sectioning of
bone samples. This study was supported by Eli Lilly and
Company, Indianapolis, Indiana, USA.
REFERENCES
1. Podbesek R, Edouard C, Meunier PJ, Parsons JA, Reeve J, Steven-
son RW, Zanelli JM 1983 Effects of two treatment regimes with
synthetic human parathyroid hormone fragment on bone formation
and the tissue balance of trabecular bone in greyhounds. Endocri-
nology 112:1000 –1006.
2. Bauer E, Aub J, Albright JF 1929 Studies of calcium and phos-
phorus metabolism: Study of bone trabeculae as readily available
reserve supply of calcium. J Exp Med 49:145–162.
3. Rubin MR, Cosman F, Lindsay R, Bilezikian JP 2002 The anabolic
effects of parathyroid hormone. Osteoporos Int 13:267–277.
4. Turner CH 2002 Biomechanics of bone: Determinants of skeletal
fragility and bone quality. Osteoporos Int 13:97–104.
5. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Regin-
ster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK,
Wang O, Mitlak BH 2001 Effect of parathyroid hormone (1-34) on
fractures and bone mineral density in postmenopausal women with
osteoporosis. N Engl J Med 344:1434 –1441.
6. Hodsman AB, Steer BM, Fraher LJ, Drost DJ 1991 Bone densi-
tometric and histomorphometric responses to sequential human
parathyroid hormone (1–38) and salmon calcitonin in osteoporotic
patients. Bone Miner 14:67– 83.
7. Reeve J, Bradbeer JN, Arlot M, Davies UM, Green JR, Hampton
L, Edouard C, Hesp R, Hulme P, Ashby JP 1991 hPTH 1–34
treatment of osteoporosis with added hormone replacement ther-
apy: Biochemical, kinetic and histological responses. Osteoporos
Int 1:162–170
8. Slovik DM, Rosenthal DI, Doppelt SH, Potts JT Jr, Daly MA,
Campbell JA, Neer RM 1986 Restoration of spinal bone in osteo-
porotic men by treatment with human parathyroid hormone (1-34)
and 1,25-dihydroxyvitamin D. J Bone Miner Res 1:377–381.
9. Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD,
Neer RM 1998 Prevention of estrogen deficiency-related bone loss
with human parathyroid hormone (1-34): A randomized controlled
trial. JAMA 280:1067–1073.
10. Hodsman AB, Fraher LJ, Watson PH, Ostbye T, Stitt LW, Adachi
JD, Taves DH, Drost D 1997 A randomized controlled trial to
compare the efficacy of cyclical parathyroid hormone versus cy-
clical parathyroid hormone and sequential calcitonin to improve
bone mass in postmenopausal women with osteoporosis. J Clin
Endocrinol Metab 82:620 – 628.
11. Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud
CD 1998 Parathyroid hormone treatment can reverse corti-
costeroid-induced osteoporosis. Results of a randomized controlled
clinical trial. J Clin Invest 102:1627–1633.
12. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen
V, Dempster D, Cosman F 1997 Randomised controlled study of
effect of parathyroid hormone on vertebral-bone mass and fracture
incidence among postmenopausal women on oestrogen with os-
teoporosis. Lancet 350:550 –555.
13. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron
P, Edouard C, Klenerman L, Neer RM, Renier JC, Slovik D,
JIANG ET AL.
Vismans FJ, Potts JT Jr 1980 Anabolic effect of human parathyroid
hormone fragment on trabecular bone in involutional osteoporosis:
A multicentre trial. BMJ 280:1340 –1344
14. Bradbeer JN, Arlot ME, Meunier PJ, Reeve J 1992 Treatment of
osteoporosis with parathyroid peptide (hPTH 1–34) and oestrogen:
Increase in volumetric density of iliac cancellous bone may depend
on reduced trabecular spacing as well as increased thickness of
packets of newly formed bone. Clin Endocrinol (Oxf) 37:282–289.
15. Hodsman AB, Kisiel M, Adachi JD, Fraher LJ, Watson PH 2000
Histomorphometric evidence for increased bone turnover without
change in cortical thickness or porosity after 2 years of cyclical
hPTH(1-34) therapy in women with severe osteoporosis. Bone
27:311–318.
16. Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J,
Woelfert L, Shane E, Plavetic K, Muller R, Bilezikian J, Lindsay
R 2001 Effects of daily treatment with parathyroid hormone on
bone microarchitecture and turnover in patients with osteoporosis:
A paired biopsy study. J Bone Miner Res 16:1846 –1853.
17. Vogel M, Hesch RD, Delling G 1990 Morphologic study of iliac
crest spongiosa in patients with osteoporosis treated with combi-
nation therapy of pulsatile administration of parathyroid hormone
(1–38 hPTH) and sequential addition of calcitonin nasal spray.
Med Klin 85:82– 86.
18. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H,
Meunier PJ, Ott SM, Recker RR 1987 Bone histomorphometry:
Standardization of nomenclature, symbols, and units. Report of the
ASBMR Histomorphometry Nomenclature Committee. J Bone
Miner Res 2:595– 610.
19. Jiang Y, Zhao J, Genant HK 2002 Macro and micro imaging of
bone architecture. In: Bilezikian JP, Raisz LG, Rodan GA (eds.)
Principles of Bone Biology, 2nd ed. Academic Press, San Diego,
CA, USA, pp. 1599 –1623.
20. Eriksen EF 1986 Normal and pathological remodeling of human
trabecular bone: Three dimensional reconstruction of the remod-
eling sequence in normals and in metabolic bone disease. Endocr
Rev 7:379 – 408.
21. Jiang Y, Zhao J, White JL, Genant HK 2000 Micro CT and micro
MR imaging of the 3D architecture of animal skeleton. J Muscu-
loskeletal Neuronal Interactions 1:45–51.
22. Goulet RW, Goldstein SA, Ciarelli MJ, Kuhn JL, Brown MB,
Feldkamp LA 1994 The relationship between the structural and
orthogonal compressive properties of trabecular bone. J Biomech
27:375–389.
23. Muller R, Hildebrand T, Ruegsegger P 1994 Non-invasive bone
biopsy: A new method to analyze and display the three-
dimensional structure of trabecular bone. Phys Med Biol 39:145–
164.
24. Mashiba T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM 2001
Effects of human parathyroid hormone (1-34), LY333334, on bone
mass, remodeling, and mechanical properties of cortical bone
during the first remodeling cycle in rabbits. Bone 28:538 –547.
25. Turner RT, Evans GL, Cavolina JM, Halloran B, Morey-Holton E
1998 Programmed administration of parathyroid hormone in-
creases bone formation and reduces bone loss in hindlimb-
unloaded ovariectomized rats. Endocrinology 139:4086 – 4091.
26. Jiang Y, Zhao J, Van Audekercke R, Dequeker J, Geusens P 1996
Effects of low-dose long-term sodium fluoride preventive treat-
ment on rat bone mass and biomechanical properties. Calcif Tissue
Int 58:30 –39.
27. Horwitz M, Stewart A, Greenspan SL 2000 Sequential parathyroid
hormone/alendronate therapy for osteoporosis—robbing Peter to
pay Paul? J Clin Endocrinol Metab 85:2127–2128.
28. Neer M, Slovik DM, Daly M, Potts T Jr, Nussbaum SR 1993
Treatment of postmenopausal osteoporosis with daily parathyroid
hormone plus calcitriol. Osteoporos Int 3(Suppl 1):204 –205.
29. Hirano T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM 1999
Anabolic effects of human biosynthetic parathyroid hormone frag-
ment (1-34), LY333334, on remodeling and mechanical properties
of cortical bone in rabbits. J Bone Miner Res 14:536 –545.
30. Burr DB, Hirano T, Turner CH, Hotchkiss C, Brommage R, Hock
JM 2001 Intermittently administered human parathyroid hormone
(1-34) treatment increases intracortical bone turnover and porosity
without reducing bone strength in the humerus of ovariectomized
cynomolgus monkeys. J Bone Miner Res 16:157–165.
31. Zanchetta JR, Bogado C, Ferretti JL, Wang O, Sato M, Gaich GA
2002 Effects of ly 333334 [recombinant human parathyroid hor-
TERIPARATIDE IMPROVES BONE MICROSTRUCTURE
mone (1-34)] on cortical bone strength indices as assessed by
peripheral quantitative computed tomography. Bone 28:S86.
32. Hyldstrup L, Jorgensen JT, Gaich G 2002 Assessment of effects of
ly333334 [recombinant human parathyroid hormone (1-34)] on
cortical bone using digital x-ray radiogrammetry. Bone 28:S97.
33. Uusi-Rasi K, Beck TJ, Oreskovic TL, Sato M, Bogado CE,
Zanchetta JR 2002 Teriparatide [rhPTH(1-34)] improves the struc-
tural geometry of the hip. J Bone Miner Res 17:S208.
34. Rockoff SD, Sweet E, Bleustein J 1969 The relative contribution of
trabecular and cortical bone to the strength of human lumbar
vertebrae. Calcif Tissue Res 3:163–175.
35. Faulkner KG, Cann CE, Hasegawa BH 1991 Effect of bone dis-
tribution on vertebral strength: Assessment with patient-specific
nonlinear finite element analysis. Radiology 179:669 – 674.
36. Ejersted C, Andreassen TT, Nilsson MH, Oxlund H 1994 Human
parathyroid hormone (1-34) increases bone formation and strength
of cortical bone in aged rats. Eur J Endocrinol 130:201–207.
37. Sogaard CH, Wronski TJ, McOsker JE, Mosekilde L 1994 The
positive effect of parathyroid hormone on femoral neck bone
strength in ovariectomized rats is more pronounced than that of
estrogen or bisphosphonates. Endocrinology 134:650 – 657.
38. Sato M, Zeng GQ, Turner CH 1997 Biosynthetic human parathy-
roid hormone (1-34) effects on bone quality in aged ovariecto-
mized rats. Endocrinology 138:4330 – 4337.
39. Jerome CP, Burr DB, Van Bibber T, Hock JM, Brommage R 2001
Treatment with human parathyroid hormone (1-34) for 18 months
increases cancellous bone volume and improves trabecular archi-
tecture in ovariectomized cynomolgus monkeys (Macaca fascicu-
laris). Bone 28:150 –159.
40. Parisien M, Cosman F, Mellish RW, Schnitzer M, Nieves J,
Silverberg SJ, Shane E, Kimmel D, Recker RR, Bilezikian JP 1995
Bone structure in postmenopausal hyperparathyroid, osteoporotic,
and normal women. J Bone Miner Res 10:1393–1399.
41. Boyce RW, Ebert DC, Youngs TA, Paddock CL, Mosekilde L,
Stevens ML, Gundersen HJ 1995 Unbiased estimation of vertebral
trabecular connectivity in calcium-restricted ovariectomized
minipigs. Bone 16:637– 642.
42. Boyce RW, Paddock CL, Franks AF, Jankowsky ML, Eriksen EF
1996 Effects of intermittent hPTH(1-34) alone and in combination
with 1,25(OH)(2)D(3) or risedronate on endosteal bone remodel-
ing in canine cancellous and cortical bone. J Bone Miner Res
11:600 – 613.
43. Boyce RW, Wronski TJ, Ebert DC, Stevens ML, Paddock CL,
Youngs TA, Gundersen HJ 1995 Direct stereological estimation of
three-dimensional connectivity in rat vertebrae: Effect of estrogen,
etidronate and risedronate following ovariectomy. Bone 16:209 –
213.
1941
44. Parisien MV, McMahon D, Pushparaj N, Dempster DW 1988
Trabecular architecture in iliac crest bone biopsies: Infra-
individual variability in structural parameters and changes with
age. Bone 9:289 –295.
45. Johnston CC, Norton J, Khairi MR, Kernek C, Edouard C, Arlot
M, Meunier PJ 1985 Heterogeneity of fracture syndromes in post-
menopausal women. J Clin Endocrinol Metab 61:551–556.
46. Parfitt AM 1984 Age-related structural changes in trabecular and
cortical bone: Cellular mechanisms and biomechanical conse-
quences. Calcif Tissue Int 36(Suppl 1):S123–S128.
47. Jiang Y, Zhao J, Augat P, Ouyang X, Lu Y, Majumdar S, Genant
HK 1998 Trabecular bone mineral and calculated structure of
human bone specimens scanned by peripheral quantitative com-
puted tomography: Relation to biomechanical properties. J Bone
Miner Res 13:1783–1790.
48. Borah B, Dufresne TE, Cockman MD, Gross GJ, Sod EW, Myers
WR, Combs KS, Higgins RE, Pierce SA, Stevens ML 2000 Eval-
uation of changes in trabecular bone architecture and mechanical
properties of minipig vertebrae by three-dimensional magnetic
resonance microimaging and finite element modeling. J Bone
Miner Res 15:1786 –1797.
49. Zhao J, Jiang Y, Prevrhal S, Genant HK 2000 Effects of low dose
long-term sodium fluoride on three-dimensional trabecular micro-
structure, bone mineral, and biomechanical properties of rat body.
J Bone Miner Res 15:816.
50. Sato M, Westmore M, Clendenon J, Smith S, Hannum B, Zeng
GQ, Brommage R, Turner CH 2000 Three-dimensional modeling
of the effects of parathyroid hormone on bone distribution in
lumbar vertebrae of ovariectomized cynomolgus macaques. Osteo-
poros Int 11:871– 880.
Address reprint requests to:
Yebin Jiang, MD, PhD
Osteoporosis and Arthritis Research Group
Department of Radiology
University of California
San Francisco, CA 94143-0628, USA
E-mail: Yebin.Jiang@oarg.ucsf.edu
Received in original form January 16, 2003; in revised form May
2, 2003; accepted July 8, 2003.