ORIGINAL ARTICLE

Differential Effects of Teriparatide and Denosumab

on Intact PTH and Bone Formation Indices: AVA
Osteoporosis Study

David W. Dempster, Hua Zhou, Robert R. Recker, Jacques P. Brown,

Christopher P. Recknor, E. Michael Lewiecki, Paul D. Miller, Sudhaker D. Rao,
David L. Kendler, Robert Lindsay, John H. Krege, Jahangir Alam,

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

Kathleen A. Taylor, Boris Janos, and Valerie A. Ruff*
Context: Denosumab-induced PTH elevation may stimulate early bone formation.

Objective: Our objective was to evaluate whether denosumab-induced changes of intact PTH
(iPTH) result in early anabolic effects according to histomorphometry and bone turnover markers
(BTMs) compared with teriparatide, an established anabolic agent.

Design: This open-label, randomized study used quadruple labeling to label bone before/after
treatment, with a transiliac bone biopsy at 3 months.

Setting: This study took both in both US and Canadian sites.

Participants: Sixty-nine postmenopausal women with osteoporosis were included.

Interventions: Teriparatide (20 ␮g/day) for 6 months and denosumab (60 mg once) were used in
this study.

Main Outcome Measure: Between-treatment comparison of change from baseline to month 3 in

cancellous mineralizing surface/bone surface, histomorphometric indices in four bone envelopes,
and BTM and iPTH at baseline, 1, 3, and 6 months was undertaken.

Results: After denosumab, iPTH peaked at month 1 (P ⬍ .001), then declined, remaining above baseline
through month 6 (P ⱕ .01); after teriparatide, iPTH declined at all time points (P ⬍ .001). From baseline
to month 3, cancellous mineralizing surface/bone surface increased with teriparatide and decreased
with denosumab and at month 3, was higher with teriparatide. Similar results were observed in other
bone envelopes. BTMs increased from baseline in teriparatide-treated subjects (procollagen type 1
N-terminal propeptide at month 1 and carboxyterminal cross-linking telopeptide of type 1 collagen at
month 3); procollagen type 1 N-terminal propeptide and carboxyterminal cross-linking telopeptide of
type 1 collagen decreased from baseline at all time points in denosumab-treated subjects.

Conclusions: Denosumab treatment increased iPTH but inhibited bone formation indices. In con-
trast, teriparatide treatment decreased iPTH but stimulated bone formation indices. These findings
are not consistent with the hypothesis of early indirect anabolic effect with denosumab. (J Clin
Endocrinol Metab 101: 1353–1363, 2016)

steoporosis drugs can be grouped into either anabolic
O or anticatabolic (antiresorptive) classes of bone-ac-
tive agents (1). Teriparatide (recombinant human PTH
analog [1–34]), is currently the only US Food and Drug
Administration–approved agent in the anabolic class (1,
2). The anticatabolic/antiresorptive drug class consists of

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2016 by the Endocrine Society
Received December 8, 2015. Accepted February 1, 2016.
First Published Online February 10, 2016
*Author affiliations listed at the bottom of the next page.
Abbreviations: BFR, bone formation rate; BMD, bone mineral density; BS, bone surface;
BTM, bone turnover marker; BV, bone volume; CTX, carboxyterminal cross-linking telo-
peptide of type 1 collagen; ES, eroded surface; FAS, full analysis set; iPTH, intact PTH; MAR,
mineral apposition rate; MOA, mechanism of action; MS, mineralizing surface; P1NP,
procollagen type 1 N-terminal propeptide; TEAE, treatment-emergent adverse event;
W.Th, wall thickness.

doi: 10.1210/jc.2015-4181 J Clin Endocrinol Metab, April 2016, 101(4):1353–1363 press.endocrine.org/journal/jcem 1353
1354 Dempster et al Teriparatide or Denosumab Bone Effects J Clin Endocrinol Metab, April 2016, 101(4):1353–1363

bisphosphonates, estrogens, selective estrogen receptor
modulators, calcitonin, and denosumab (3–5).
Although denosumab has been characterized as an an-
tiresorptive agent by histomorphometric and bone turn-
over marker (BTM) assessments (6, 7), some effects of this
drug have led to speculation that denosumab may have
distinctive properties with respect to its mechanism of ac-
tion (MOA). Studies have reported that intact PTH (iPTH)
levels are increased in the 1–3 months after denosumab
administration (8 –13). It has been suggested that eleva-
tion of PTH may result in indirect stimulation of bone
lism; history of malignancy in the previous 5 years; signifi-
cantly impaired hepatic or renal function; treatment with sys-
temic glucocorticoids (ⱖ5 mg/day prednisone or equivalent)
in the previous 6 months; and prior or current use of teripa-
ratide, PTH, PTH analog, or denosumab or any IV bisphos-
phonate. Oral bisphosphonate use required a wash-out period
before screening (6 months off for use ⬎2 weeks but ⱕ2
months; 1 year off for use ⬎2 months but ⱕ1 year; 2 years off
for use ⬎1 year).
Study design and treatment
This was an open-label, randomized phase IV study of 6
months’ duration comparing teriparatide (20 ␮g/d) with deno-

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

formation during a time of inhibited osteoclast activity
(12, 14) and in combination with denosumab-induced re-
ductions in cortical porosity (7, 12, 14, 15), may poten-
tially play a role in continuous long-term bone mineral
density (BMD) gains (16) reported with denosumab.
The study objectives were to characterize denosumab-
induced changes in iPTH levels in conjunction with bone
histomorphometric indices and BTMs and compare these
effects with those induced by teriparatide, an anabolic
agent. To achieve these goals, this study used quadruple-
labeled histomorphometry (17) of transiliac biopsies ob-
tained from postmenopausal women with osteoporosis
treated with either denosumab or teriparatide. This is the
first study to use quadruple-labeled histomorphometry
with an antiresorptive agent and to compare directly the
MOAs of an antiresorptive agent and an anabolic agent.
Quadruple labeling allowed both baseline and posttreat-
ment information to be obtained from a single biopsy from
each subject.
Subjects and Methods
Subjects
Ambulatory postmenopausal women with osteoporosis,
aged 55– 89 years, were included if their BMD T-score was at
least 2.5 at the lumbar spine, femoral neck, or total hip; or less
than 1.5 with a prevalent vertebral or nonvertebral fragility frac-
ture. Subjects had laboratory values within reference ranges for
serum calcium, PTH, and alkaline phosphatase.
Subjects were excluded if they had any condition specified
in the teriparatide boxed warning or any treatment contrain-
dications for teriparatide or denosumab (2, 18). Exclusion
criteria included 25-hydroxyvitamin D concentration of less
than 10 ng/ml; treatment with drugs or any active or suspected
disease, except osteoporosis, known to affect bone metabo-
sumab (60 mg once) in postmenopausal women with osteopo-
rosis. The primary endpoint was comparison of change from
baseline to 3 months in mineralizing surface/bone surface (MS/
BS) in the cancellous envelope of transiliac bone biopsies. Biop-
sies were taken at 3 months because iPTH is known to be elevated
at this time point after treatment with denosumab (8 –13). The
iPTH increase may be maximal with the first dose of denosumab
(11–13); therefore, any anabolic properties that are observable
by histomorphometric analyses should be apparent by 3 months
after the first dose. The effect of both teriparatide and deno-
sumab on remodeling also is apparent by this time based on
biochemical marker data (11, 19). Finally, with quadruple-la-
beled histomorphometry, the possibility was considered that
findings in subjects treated with teriparatide might not be reliable
beyond 3 months because some of the initial labels could have
been lost with remodeling. It was thought that loss of the first set
of labels by this mechanism should not be a factor if the biopsy
was obtained at 3 months; however, in a study using quadruple
labeling, the first set of labels was demonstrated to be intact after
3 months of PTH(1– 84) treatment (20). MS/BS was chosen as
the primary endpoint because it is a robust variable that readily
distinguishes between anabolic and antiresorptive MOAs (19).
Other objectives were to characterize changes in: 1) serum iPTH;
2) a panel of histomorphometric indices in 4 bone envelopes
(cancellous, endocortical, intracortical, periosteal), and 3) BTMs
following denosumab or teriparatide treatment, comparing
treatment effects.
To assure a balance in bone turnover between the treatment
groups at baseline, subjects were stratified based on their value
of nonfasting procollagen type 1 N-terminal propeptide (P1NP)
at screening: less than 30 ng/ml, at least 30 ng/ml to less than 50
ng/ml, or more than 50 ng/ml. Using a computer-generated ran-
dom sequence generated by an interactive voice-response system,
subjects were randomly assigned (1:1) to either teriparatide or
denosumab treatment groups based on their stratified baseline
P1NP value. Subjects received elemental calcium (approximately
1000 mg/d) and vitamin D3 or equivalent (800 –1200 IU/day)
throughout the study.
The study received ethical review board approval at all sites,
and subjects gave informed written consent. The study was con-

Regional Bone Center (D.W.D., H.Z., R.L.), Helen Hayes Hospital, West Haverstraw, New York; Department of Pathology and Cell Biology (D.W.D.), College of Physicians and Surgeons
of Columbia University, New York; Department of Medicine (R.R.R.), Division of Endocrinology, School of Medicine, Creighton University, Omaha, Nebraska; Rheumatology and Bone
Diseases Research Group (J.P.B.), CHU de Quebec (CHUL) Research Centre and Department of Medicine, Laval University, Quebec City, Quebec, Canada; United Osteoporosis Centers
(C.P.R.), Gainesville, Georgia; New Mexico Clinical Research & Osteoporosis Center (E.M.L.), Albuquerque, New Mexico; Department of Medicine (P.D.M.), Colorado Center for Bone
Research, Lakewood, Colorado; Bone & Mineral Research Laboratory (S.D.R.), Henry Ford Hospital, Detroit, Michigan; Department of Medicine (Endocrinology) (D.L.K.), University of British
Columbia, Vancouver, British Columbia, Canada; Department of Medicine (R.L.), College of Physicians and Surgeons of Columbia University, New York; Lilly Research Laboratories (J.H.K.,
J.A.), Eli Lilly and Company, Indianapolis, Indiana; Musculoskeletal and Men’s Health (K.A.T., V.A.R.), Lilly USA, LLC, Indianapolis, Indiana; Research and Development – Bio-Medicines
(B.J.), Eli Lilly Canada Inc., Toronto, Ontario, Canada
doi: 10.1210/jc.2015-4181
ducted in accordance with the Declaration of Helsinki and ap-
plicable laws and guidelines.
Assessments
Bone biopsy procedure
Quadruple labeling using the fluorochromes, demeclocy-
cline, and tetracycline was performed (17). Beginning 18 –23
days before randomization, subjects took 150 mg demeclocy-
cline 4 times daily following a 3:12:3 day sequence (baseline
labeling); (Supplemental Appendix 1). One to 5 days after the last
demeclocycline dose, subjects were randomized to either deno-
sumab or teriparatide. Beginning 22–25 days before the bone
biopsy, subjects took 250 mg tetracycline (posttreatment label-
ing) following the same dosing schedule as demeclocycline. The
biopsy was performed 5– 8 days following the last tetracycline
dose.
Transiliac bone biopsies were performed using a Rochester
needle or similar large-bore (6 – 8 mm) manual trephine. Sample
preparation and histomorphometric analyses were performed as
described (19, 21). The central histomorphometry reader was
blinded to treatment assignment and all indices were measured,
calculated, and expressed following American Society for Bone
and Mineral Research Histomorphometric Nomenclature Com-
mittee recommendations (22).
Histomorphometry
Demeclocycline can overestimate the length of fluorochrome
labels relative to tetracycline (23, 24). This artifactual difference
can potentially affect interpretation of data from indices derived
from label length, such as MS/BS, which could be overestimated.
To assess treatment effects accurately and minimize label length
artifacts, demeclocycline and tetracycline were administered for
the first and second labeling periods, respectively (23). The
length of the tetracycline labels in both the teriparatide and de-
nosumab treatment groups was multiplied by a correction factor
(23) of 1.34, which was empirically determined by the histomor-
phometry laboratory assessing the biopsies.
For biopsy samples missing labels, the value of MS/BS was
zero. Mineral apposition rate (MAR) was reported as missing,
and MAR-derived indices, such as bone formation rate, were
assigned a value of zero. For biopsies with a single label only,
MAR and MAR-derived indices were evaluated by two methods:
1) assigned an imputed value of 0.3 ␮m/day or 2) counted as
missing (25). Results from the imputation method only are re-
ported here as results from the 2 methods were similar.
Baseline and 3-month data were obtained for MS/BS, bone
formation rate (BFR)/bone surface (BS), MAR, single-label sur-
face/BS, and double-label surface/BS in all four bone envelopes
defined as described (26). Only 3-month data were obtained for
BFR/bone volume (BV) (cancellous envelope only), activation
frequency, active formation period, adjusted apposition rate,
mineralization lag time, osteoid maturation time, and total for-
mation period (cancellous, endocortical, and intracortical enve-
lopes). Data were only available at month 3 because they require
static components in their derivation, which cannot be separately
assessed at baseline. Static indices measured were osteoid sur-
face/BS, osteoid volume/BV, osteoid thickness, wall thickness
(W.Th), and eroded surface (ES)/BS. These indices were assessed
in the cancellous, endocortical, and intracortical envelopes with
press.endocrine.org/journal/jcem 1355
the exception of osteoid volume/BV, which was assessed in only
the cancellous envelope.
Biochemical markers of bone turnover and intact
PTH
Blood (fasting) was collected at baseline and months 1, 3, and
6 for determination of serum BTM (P1NP and carboxyterminal
cross-linking telopeptide of type 1 collagen [CTX]) and iPTH.
Safety
Clinical chemistry and hematology measurements were per-
formed at the screening visit and vital signs were collected at each
Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021
study visit. Treatment-emergent adverse events (TEAEs) and se-
rious adverse events were recorded at each study visit and at early
discontinuation, if applicable.
Sample size
Twenty completers per group with adequate biopsies would
provide approximately 80% power to detect a significant dif-
ference with a two-sided alpha level of 0.05 using a two-sample
t test. Assuming a 40% dropout or unevaluable biopsy rate, the
total number of randomized subjects needed was 68.
Statistical analyses
All prespecified efficacy and safety analyses were performed
on the full analysis set (FAS) using a modified intent-to-treat
principle. The FAS included data from all randomized subjects
receiving at least one dose of study drug according to the actual
received treatment. Tests of treatment effects were conducted at
a two-sided alpha level of 0.05. No adjustment for multiplicity
was made for primary and secondary analyses. Demographics
and baseline characteristics were summarized by treatment
group. Categorical variables were summarized by frequencies
and percentages. Continuous variables were summarized by
means and standard deviations. Categorical variables were an-
alyzed using Fisher’s exact test, and continuous variables were
analyzed using t test. Efficacy variables were analyzed using an
analysis of covariance model, with treatment group as the main
effect and baseline measurement as a covariate. Paired t tests
were used to assess changes from baseline within each treatment
group. If the normality assumption of efficacy variable was not
satisfied at the 0.01 significance level and if visual inspection of
the data deemed it necessary, an appropriate nonparametric test,
such as the Wilcoxon rank-sum test, was performed to assess
treatment differences; the Wilcoxon signed-rank test was used to
assess changes from baseline within each treatment group.
Results
Baseline demographics and characteristics
Overall, 109 subjects were included from the United
States and Canada; of these, 69 subjects were random-
ized beginning in February 2013 (33 teriparatide; 36
denosumab) (Supplemental Appendix 2). Thirty teripa-
ratide-treated and 34 denosumab-treated subjects com-
pleted the study. The last subject completed the study in
June 2014. Reasons for discontinuation in the teripa-
1356 Dempster et al Teriparatide or Denosumab Bone Effects J Clin Endocrinol Metab, April 2016, 101(4):1353–1363

Table 1. Baseline Characteristics

Teriparatide n ⴝ 33 Denosumab n ⴝ 36
Age, y (mean [SD]) 61.6 (5.8) 65.2 (8.3)a
Race, n (%)
Asian 0 (0) 2 (5.6)
Black or African American 1 (3.0) 2 (5.6)
Multiple 1 (3.0) 1 (2.8)
White 31 (93.9) 31 (86.1)
Body mass index, kg/m2 (mean [SD]) 24.7 (4.6) 24.0 (3.5)
Previous osteoporosis therapy, n (% yes) 11 (33.3) 14 (38.9)
Prevalent clinical fracture, n (% yes) 17 (51.5) 16 (44.4)
Lumbar spine T-score, mean (SD) ⫺2.58 (0.91) ⫺2.45 (0.93)
⫺2.24 (0.92) ⫺2.39 (0.63)

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

Femoral neck T-score, mean (SD)
Total hip T-score, mean (SD) ⫺1.68 (0.93) ⫺1.92 (0.76)
Serum P1NP strata, n (%)
⬍30 ng/ml 0 (0) 2 (5.6)
ⱖ30 ng/ml to ⱕ50 ng/ml 13 (39.4) 14 (38.9)
⬎50 ng/ml 20 (60.6) 20 (55.6)
25-hydroxyvitamin D (mean [SE]), ng/mlb 35.5 (2.5) (n ⫽ 32) 38.0 (3.1) (n ⫽ 35)
iPTH (mean [SE]), pg/mlc 34.8 (2.4) (n ⫽ 33) 33.7 (2.4) (n ⫽ 34)
a
P ⬍ .05 using Fisher’s exact test for categorical variables and using t test for continuous variables.
b
Reference range: ⱖ29 ng/ml for ⬎18 y of age.
c
Reference range: 14 –72 pg/ml for ⬎18 y of age.

ratide group were adverse event (n ⫽ 1) and sponsor
decision (n ⫽ 2), and in the denosumab group, subject
decision (n ⫽ 2). Biopsies were collected from 66 sub-
jects (31 teriparatide; 35 denosumab); all biopsies were
evaluable for all indices with the exception of one bi-
opsy with a missing cortex.
Baseline characteristics between the two treatment
groups were similar with the exception of mean age, which
was higher in the denosumab group than in the teripa-
ratide group (65.2 years vs 61.6 years; P ⫽ .041) (Table 1);
this difference did not affect any treatment outcomes (data
not shown). The groups were balanced with respect to
P1NP stratification.
Of the five significant protocol violations (one each in
three teriparatide-treated subjects; one denosumab-
treated subject with two violations), all involving viola-
tions of inclusion/exclusion criteria, one subject was re-
moved from the study. Analyses excluding these subjects
were performed for the primary endpoint; inclusion of
these subjects in the FAS did not significantly change the
result or conclusions.
iPTH and BTMs
In the denosumab group, iPTH was significantly in-
creased from baseline (89.6 mean percent change; P ⬍
.001) after 1 month of treatment (mean absolute values,

A B

Figure 1. Changes in serum bone turnover markers and intact parathyroid hormone. (A) Denosumab; (B) teriparatide. Mean percent change ⫾ SE
is shown. †P ⬍ .001 for within treatment group comparison from baseline to each time point. *P ⫽ .01 for within treatment group comparison
from baseline to each time point using t test.
doi: 10.1210/jc.2015-4181 press.endocrine.org/journal/jcem 1357

baseline: 38.1 pg/ml; month 1: 63.5 pg/ml; reference
range: 14 –72 pg/ml) (Figure 1A). Thereafter, iPTH levels
declined but were still significantly greater than baseline at
month 3 (68.0%, 51.5 pg/ml) and at month 6 (31.9%,
47.9 pg/ml). However, despite the elevated iPTH levels,
both P1NP and CTX levels were significantly reduced
(P ⬍ .001 vs baseline at all time points). In contrast, after
1 month of teriparatide treatment, there was a significant
reduction from baseline (⫺27.1 mean percent change; P ⬍
.001) in iPTH levels (mean absolute values, baseline: 38.6
pg/ml; month 1: 27.1 pg/ml), continuing through month 6
(month 3: ⫺22.4%, 25.1 pg/ml; month 6: ⫺35.3%, 22.2
(5.22%) and denosumab (4.78%) (Figure 2A, Table 2). At
month 3, median MS/BS was significantly higher in the
teriparatide group (18.73%) than in the denosumab group
(0.96%) (P ⬍ .001). From baseline to month 3, MS/BS in-
creased with teriparatide treatment (P ⬍ .001) and decreased
with denosumab treatment (P ⬍ .001) (median of change,
⫹12.4% vs ⫺2.5%; P ⬍ .001 for between-group compari-
son), indicating increased extent of new bone formation with
teriparatide and decreased extent with denosumab. Similar
results for MS/BS were observed in the endocortical, intra-

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

pg/ml) (Figure 1B). However, both P1NP and CTX levels
increased significantly starting at 1 and 3 months, respec-
tively, and rose through 6 months with P1NP approxi-
mately 400% above baseline at 6 months.
Bone histomorphometry
At baseline, in the cancellous envelope, median MS/BS
values were not significantly different between teriparatide
cortical, and periosteal envelopes (Figure 2, B–D).
Results for supporting histomorphometric indices for
cancellous and other envelopes are shown in Tables 2 and
3. In all bone envelopes, the median month 3 values for
most dynamic and static indices of bone formation were
significantly different between treatment groups and were
greater for teriparatide vs denosumab. The static index of
bone resorption, ES/BS, was significantly lower in the de-

A B

C D

Figure 2. Changes in mineralizing surface. Median and interquartile range (Q1, Q3) are shown for the four bone envelopes at baseline and 3
months: (A) cancellous; (B) endocortical; (C) intracortical; and (D) periosteal. For samples with no label, MS/BS was assigned a value of zero. *P ⬍
.001 for between treatment group comparison at baseline or 3 months in each envelope using Wilcoxon rank-sum test. †P ⬍ .001 for within
treatment group comparison from baseline to 3 months in each envelope using Wilcoxon signed-rank test. ¥P ⬍ .01 for within treatment group
comparison from baseline to 3 months in each envelope using Wilcoxon signed-rank test.
1358 Dempster et al Teriparatide or Denosumab Bone Effects J Clin Endocrinol Metab, April 2016, 101(4):1353–1363

Table 2. Histomorphometric Indices (Baseline to Month 3)a,b

Cancellous Endocorticalc

Indices, Baseline Month 3 Baseline Month 3

Median
(Q1, Q3) TPTD DMAb TPTD DMAb TPTD DMAb TPTD DMAb
MS/BS, %d 5.22 4.78 18.73e 0.96e,f 8.73 8.54 39.50e 5.42f,g
(2.63, 7.39) (2.68, 6.19) (11.13, 26.64) (0.44, 1.93) (5.90, 15.64) (5.62, 12.44) (23.92, 60.39) (2.63, 10.15)
n ⫽ 31 n ⫽ 35 n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
BFR/BS, 0.0096 0.0091 0.0366e 0.0014e,f 0.0201 0.0169 0.0889e 0.0096e,f
mm3/mm2/yh (0.0051, 0.0148) (0.0048, 0.0115) (0.0226, 0.0543) (0.0005, 0.0033) (0.0096, 0.0353) (0.0092, 0.0241) (0.0445, 0.1501) (0.0029, 0.0193)
n ⫽ 31 n ⫽ 35 n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
MAR, 0.55 0.52i 0.57 0.41e,f 0.56 0.50i 0.60j 0.45e,f
␮m/dayh (0.48, 0.58) (0.45, 0.54) (0.49, 0.59) (0.30, 0.48) (0.52, 0.61) (0.46, 0.55) (0.53, 0.63) (0.32, 0.50)
n ⫽ 31 n ⫽ 35 n ⫽ 31 n ⫽ 33 n ⫽ 29 n ⫽ 34 n ⫽ 30 n ⫽ 31

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

sLS/BS, % 4.68 4.13 15.44e 1.28e,f 7.80 7.90 24.24e 7.18f
(2.71, 7.19) (2.90, 6.29) (10.16, 18.53) (0.66, 2.62) (5.93, 12.59) (5.69, 9.93) (14.65, 30.32) (4.13, 10.58)
n ⫽ 31 n ⫽ 35 n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
dLS/BS, % 2.47 2.43 10.44e 0.22e,f 5.11 4.72 28.84e 1.68e,f
(1.54, 3.16) (1.19, 3.31) (6.00, 15.41) (0.00, 0.79) (2.21, 8.57) (3.33, 7.47) (12.83, 43.96) (0.00, 5.08)
n ⫽ 31 n ⫽ 35 n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35

Abbreviations: dLS/BS, double labels per bone surface; DMAb, denosumab; sLS/BS, single labels per bone surface; TPTD, teriparatide. Median
values are in bold.
a
Baseline values were derived from demeclocycline labels.
b
Month 3 values were derived from tetracycline labels.
c
One sample (teriparatide group) had a missing cortex and was not included in analysis of cortical envelopes.
d
For samples with no label, MS/BS was assigned a value of zero.
e
P ⬍ .001 for within treatment group comparison from baseline to 3 months in each envelope using Wilcoxon signed-rank test.
f
P ⬍ .001 for between treatment group comparison at baseline or 3 months in each envelope using Wilcoxon rank-sum test.
g
P ⬍ .01 for within treatment group comparison from baseline to 3 months in each envelope using Wilcoxon signed-rank test.
h
For MAR and BFR/BS derived from MAR, MAR measured on samples with double label and on samples with single label only that were imputed
to 0.3 ␮m/day (samples with no label reported as missing for MAR and assigned a value of zero for BFR/BS).
i
P ⬍ .05 for between treatment group comparison at baseline or 3 months in each envelope using Wilcoxon rank-sum test.
j
P ⬍ .05 for within treatment group comparison from baseline to 3 months in each envelope using Wilcoxon signed-rank test.

nosumab vs teriparatide group (P ⬍ .001) at month 3 in all
envelopes.
For indices with baseline and month 3 data, the direc-
tional change with treatment was generally consistent across
envelopes (increased with teriparatide; decreased with deno-
sumab), with the exception of MAR. In the cancellous en-
velope, there was no significant longitudinal change in me-
dian MAR for the teriparatide group (P ⫽ .311), but a
significant decrease was observed for the denosumab group
(P ⬍ .001). Consequently, MAR was higher with teripa-
ratide than with denosumab at 3 months (P ⬍ .001). In the
endocortical and intracortical envelopes, MAR increased
with teriparatide and decreased with denosumab. There was
no change in MAR with either treatment in the periosteal
envelope, perhaps because of a lower number of samples
with labels in this envelope than in the other envelopes.
Figure 3 shows representative images from two subjects
each in the teriparatide and denosumab groups. These
subjects were chosen because their MS/BS values were sim-
ilar to the median value for their assigned treatment group.
There are many more posttreatment labels (red arrows) in
the teriparatide subject (Figure 3A) than in the denosumab
subject (Figure 3B), and the labels are longer in the teripa-
ratide subject. Additionally, with teriparatide treatment,
the posttreatment label is shifted downward with respect
to the baseline label (Figure 3C, see asterisk), confirming
that the mineralization front was moving laterally during
the bone formation phase.
Safety
There were no deaths in this trial. Two subjects in each
group reported serious adverse events (teriparatide: chest
pain and lung adenocarcinoma; denosumab: appendicitis
and deep vein thrombosis); none of these events were con-
sidered related to teriparatide or denosumab treatment,
and none led to study discontinuation. One teriparatide-
treated subject discontinued because of an adverse event of
abdominal pain, which was considered by the investigator
to be unrelated to teriparatide.
At least one TEAE was experienced by 27 (81.8%)
teriparatide-treated and 23 (63.9%) denosumab-treated
subjects. The most common TEAEs experienced by teripa-
ratide-treated subjects were contusion related to the bi-
opsy procedure (30.3%); arthralgia (15.2%); and nausea,
fatigue, and headache (12.1% each). The most common
TEAEs experienced by denosumab-treated subjects were
doi: 10.1210/jc.2015-4181 press.endocrine.org/journal/jcem 1359

Table 2. Continued
Intracorticalc Periostealc

Indices, Baseline Month 3 Baseline Month 3

Median
(Q1, Q3) TPTD DMAb TPTD DMAb TPTD DMAb TPTD DMAb
MS/BS, %d 8.99 10.16 21.69e 3.05e,f 0.73 0.48 4.69e 0.00e,f
(5.74, 11.84) (6.85, 16.95) (15.61, 30.17) (2.03, 7.38) (0.00, 3.25) (0.00, 1.76) (1.24, 8.98) (0.00, 0.00)
n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
BFR/BS, 0.0216 0.0229 0.0668e 0.0048e,f 0.0008 0.0005 0.0051e 0.0000e,f
mm3/mm2/yh (0.0127, 0.0295) (0.0144, 0.0376) (0.0465, 0.0950) (0.0025, 0.0099) (0.0000, 0.0033) (0.0000, 0.0023) (0.0014, 0.0111) (0.0000, 0.0000)
n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
MAR, 0.63 0.63 0.84e 0.40e,f 0.30 0.30 0.30 0.30
␮m/dayh (0.54, 0.70) (0.54, 0.70) (0.78, 0.90) (0.30, 0.45) (0.30, 0.43) (0.30, 0.37) (0.30, 0.33) (0.30, 0.30)
n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 34 n ⫽ 20 n ⫽ 25 n ⫽ 29 n⫽5

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

sLS/BS, % 8.34 11.69 15.28e 4.66e,f 1.45 0.77 9.37e 0.00e,f
(5.75, 11.24) (7.09, 13.89) (11.17, 17.26) (2.54, 9.57) (0.00, 5.50) (0.00, 3.50) (2.47, 13.92) (0.00, 0.00)
n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
dLS/BS, % 4.72 5.82 14.96e 0.83e,f 0.00 0.00 0.00 0.00i,g
(2.61, 6.36) (2.80, 9.73) (10.55, 19.69) (0.00, 1.87) (0.00, 0.39) (0.00, 0.29) (0.00, 0.62) (0.00, 0.00)
n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35

constipation, contusion, and postprocedural discomfort
(11.1% each). TEAEs were generally mild or moderate in
severity with the exception of one subject in the teripa-
ratide group (lung adenocarcinoma) and two subjects in
the denosumab group (appendicitis and carpal tunnel syn-
drome), whose events were considered severe.
Discussion
Our results confirm previous observations that iPTH lev-
els are elevated after a single administration of deno-
sumab. The response profile is consistent with these stud-
ies, with maximal iPTH elevations occurring at 1 month
and then declining toward baseline through 6 months
(10 –13). Although we did not assess the kinetics of en-
dogenous PTH in this study, it is unlikely that they would
be similar to the pulsatile increments that occur with daily
subcutaneous injection of PTH peptides and have been
associated with bone anabolism (27). The increase in PTH
that we observed in our study is not unique to denosumab
and may be an attribute of the antiresorptive drug class
because iPTH also increases in response to alendronate
and zoledronic acid treatment (11, 12, 28, 29). It is likely
that PTH increases are compensatory responses to main-
tain serum calcium levels, which decrease with antiresorp-
tive treatment (8 –11, 13, 28, 29). In this study, we could
not address this hypothesis because serum calcium was
assessed at screening only. Likewise, our finding that iPTH
levels decrease during teriparatide treatment has been re-
ported previously (28, 30, 31). This effect is expected and
is likely because of teriparatide-mediated suppression of
endogenous PTH release from the parathyroid glands.
Theoretically, to be defined as a bone anabolic agent,
treatment must result in a significant increase in bone mass
because of an increase in bone remodeling with a positive
basic multicellular unit balance in which bone formation
is greater than resorption (1, 25). In the presence of an
anabolic agent, indices of bone formation, including MS/
BS, BFR/BS, osteoid surface/BS, and W.Th, are expected to
increase relative to placebo or baseline because they reflect
an increase in osteoblast number and activity. Despite the
significant elevation in serum iPTH levels during 6 months
of denosumab treatment, these four indices (except W.Th
in the intracortical envelope), along with others, including
MAR (except in the periosteal envelope), were signifi-
cantly lower with denosumab compared to teriparatide at
1360 Dempster et al Teriparatide or Denosumab Bone Effects J Clin Endocrinol Metab, April 2016, 101(4):1353–1363

Table 3. Histomorphometric Indices (Month 3)a

Cancellous Endocorticalb Intracorticalb
Indices, Median
(Q1, Q3)c TPTD DMAb TPTD DMAb TPTD DMAb
Dynamic
BFR/BV, % per y 0.66 0.03d
(0.45, 0.88) (0.01, 0.07) NM NM NM NM
n ⫽ 31 n ⫽ 35
Ac.f, cycle/y 1.41 0.06d 2.77 0.34d 1.88 0.12d
(0.88, 2.02) (0.02, 0.14) (1.48, 4.31) (0.09, 0.59) (1.13, 2.48) (0.06, 0.27)
n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
a.FP, y 0.13 0.16d 0.15 0.19d 0.13 0.26d

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

(0.12, 0.14) (0.14, 0.20) (0.14, 0.16) (0.16, 0.22) (0.11, 0.14) (0.22, 0.35)
n ⫽ 31 n ⫽ 33 n ⫽ 30 n ⫽ 31 n ⫽ 30 n ⫽ 34
Aj.AR, ␮m/day 0.58 0.14d 0.76 0.58e 1.03 0.35d
(0.46, 0.67) (0.08, 0.33) (0.56, 0.88) (0.22, 0.81) (0.88, 1.18) (0.19, 0.73)
n ⫽ 31 n ⫽ 33 n ⫽ 30 n ⫽ 30 n ⫽ 30 n ⫽ 33
Mlt, day 10.93 21.68f 9.28 9.15 7.21 12.04f
(9.66, 13.78) (12.20, 48.83) (7.37, 11.46) (5.50, 18.00) (5.92, 8.52) (7.08, 24.94)
n ⫽ 31 n ⫽ 33 n ⫽ 30 n ⫽ 31 n ⫽ 30 n ⫽ 34
Omt, day 10.88 9.86e 11.43 10.76 8.40 11.45d
(10.11, 11.97) (8.28, 11.80) (9.94, 12.87) (7.89, 12.92) (7.45, 9.48) (9.45, 13.73)
n ⫽ 31 n ⫽ 33 n ⫽ 30 n ⫽ 31 n ⫽ 30 n ⫽ 34
Tt.FP, y 0.12 0.47d 0.12 0.15 0.10 0.30d
(0.11, 0.15) (0.21, 0.91) (0.10, 0.15) (0.11, 0.38) (0.09, 0.12) (0.16, 0.52)
n ⫽ 31 n ⫽ 33 n ⫽ 30 n ⫽ 31 n ⫽ 30 n ⫽ 33
Static
OV/BV, % 2.58 0.39d
(1.67, 3.51) (0.17, 0.65) NM NM NM NM
n ⫽ 31 n ⫽ 35
OS/BS, % 20.51 3.46d 30.85 6.95d 17.81 4.34d
(12.50, 24.13) (2.05, 5.40) (21.47, 48.02) (2.82, 10.88) (11.89, 22.50) (2.07, 6.17)
n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
O.Th, ␮m 6.12 3.78d 6.99 4.33d 7.08 4.68d
(5.52, 6.71) (3.49, 4.18) (5.61, 7.99) (3.49, 4.78) (6.15, 7.92) (3.68, 5.13)
n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
W.Th, ␮m 26.29 24.03d 31.88 30.08e 38.25 37.80
(25.58, 27.84) (22.79, 25.23) (29.75, 32.99) (27.61, 32.03) (33.87, 39.84) (34.61, 40.15)
n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
ES/BS, % 3.73 1.52d 3.79 1.65d 11.19 1.27d
(2.95, 6.05) (0.92, 2.87) (2.79, 6.25) (0.78, 2.47) (7.37, 13.71) (0.90, 3.82)
n ⫽ 31 n ⫽ 35 n ⫽ 30 n ⫽ 35 n ⫽ 30 n ⫽ 35
Abbreviations: a.FP, active formation period; Ac.f, activation frequency; Aj.AR, adjusted apposition rate; DMAb, denosumab; Mlt, mineralization
lag time; NM, not measured; O.Th, osteoid thickness; Omt, osteoid maturation time; OS, osteoid surface; OV, osteoid volume; Tt.FP, total
formation period; TPTD, teriparatide. Median values are in bold.
a
Month 3 values were derived from tetracycline labels.
b
One sample (teriparatide group) had a missing cortex and was not included in the analysis of cortical envelopes.
c
For dynamic parameters derived from MAR, MAR measured on samples with double label and on samples with single label only imputed to 0.3
␮m/day (samples with no label reported as missing with the exception of BFR/BV and Ac.f, which were assigned a value of zero).
d
P ⬍ .001 for between treatment group comparison using Wilcoxon rank-sum test.
e
P ⬍ .05 for between treatment group comparison using Wilcoxon rank-sum test.
f
P ⬍ .01 for between treatment group comparison using Wilcoxon rank-sum test.

3 months. In addition, with quadruple labeling, we dem-
onstrated that MS/BS and BFR/BS decreased from baseline
to 3 months with denosumab treatment, whereas these
indices increased with teriparatide treatment.
The finding that teriparatide treatment resulted in sig-
nificant increases in MS/BS and BFR/BS in the periosteal
envelope is interesting and adds to the current body of
evidence for this effect (32, 33). Using quadruple labeling,
these results provide for the first time direct evidence in a
single biopsy for stimulation of bone formation in the peri-
osteal envelope with teriparatide. These same indices,
however, decreased with denosumab treatment.
The median baseline value for MAR was significantly
different between treatment groups in the cancellous and
endocortical envelopes, being higher with teriparatide
treatment. This difference does not appear to be the result
doi: 10.1210/jc.2015-4181 press.endocrine.org/journal/jcem 1361

greater proportion of the formation

A B sites with denosumab treatment will
be at a later stage in the bone forma-
tion phase, and, therefore, MAR
would be expected to be lower. By
contrast, more remodeling units will
be initiated with teriparatide with a
greater proportion of formation sites
at an earlier stage in the bone forma-
tion phase, and MAR would be ex-
C D pected to be higher. Treatment ef-

Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021

fects on osteoblasts are not needed to
explain these findings; this could be
explained by different effects of de-
nosumab and teriparatide on activa-
tion frequency.
This study has several strengths.
The ability to measure baseline his-
Figure 3. Quadruple labeling in teriparatide- and denosumab-treated subjects in cancellous bone. tomorphometric data as a result of
Low- (top) and high-power (bottom) images of samples, each from a different subject, representative using quadruple-labeling allowed
of the month 3 median values for MS/BS for each treatment group (18.73% teriparatide vs 0.96%
for a head-to-head comparison of di-
denosumab). The white arrows indicate first labeling period (demeclocycline) at baseline; red arrows
indicate second labeling period (tetracycline) at 3 months. A, Teriparatide, low power; B, Denosumab rectional changes, providing a more
low power; C, Teriparatide, high power; D, Denosumab, high power. accurate and robust picture of drug
effects on bone metabolism and
MOA. Additionally, although this
of differences in baseline bone remodeling rate, because study was powered for MS/BS, a full panel of supporting
there were no differences in the distribution of subjects in histomorphometric indices was assessed across four bone
the two treatment groups among the P1NP strata at ran- envelopes providing a comprehensive assessment of the
domization. After adjusting for baseline MAR, results for effects of these drugs on bone at an early time point. More-
primary and secondary endpoints were similar to the orig- over, based on preclinical findings that suggest a role for
inal findings and conclusions remained the same. MAR modeling-based bone formation in the MOA of denosumab
increased with teriparatide in the endocortical and intra- (37), we have the ability to assess both modeling- and re-
cortical envelopes, whereas it decreased with denosumab modeling-based formation in all four envelopes in these hu-
in the cancellous, endocortical, and intracortical enve- man biopsy samples. This work is ongoing. Finally, changes
lopes. The current finding that teriparatide is able to stim- in iPTH, histomorphometric indices, and BTMs were as-
ulate MAR as previously reported (17, 32) and that de- sessed during the same time frame in the same subjects. This
nosumab reduced MAR is of interest. This is the first study study was, however, limited by a short duration with a bone
to use quadruple labeling to assess the effects of an anti- biopsy taken after 3 months of treatment.
resorptive agent, and it is the first prospective demonstra- In conclusion, denosumab-induced increases in iPTH,
tion of an inhibitory effect of an antiresorptive agent on when examined in parallel with changes in BTMs and a
MAR. It is important to note that this decrease in MAR full panel of histomorphometric indices across four bone
with denosumab remains significant when only the data envelopes, are not consistent with and do not support
from subjects with double label were used (data not early bone-forming activity of this drug. Our data suggest
shown). The mechanism for such an effect is unclear, but that the sustained and substantial increases in BMD seen
there are possible explanations. One could be because of with denosumab treatment are not explained by indirect
denosumab’s action to reduce osteoclast number and ac- anabolic action induced by increases in endogenous PTH
tivity, resulting in a decrease in osteoclast-derived osteo- and must be caused by other mechanism(s).
blast stimulating factors or “clastokines” (34). A second
possibility relates to the decline of MAR over time during
the bone formation phase (35, 36). Early in antiresorptive
Acknowledgments
treatment, there is a rapid reduction of initiation of new We thank the study investigators, site personnel, and patients
remodeling, and sites that were active before treatment and their families. Medical writing support was provided by Lori
complete their formation phase (1). Consequently, a Kornberg (INC Research, Raleigh, NC).
1362 Dempster et al Teriparatide or Denosumab Bone Effects
Address all correspondence and requests for reprints to:
David W. Dempster, Regional Bone Center, Helen Hayes Hos-
pital, Route 9W, West Haverstraw, New York 10993. E-mail:
ddempster9@aol.com.
This work was sponsored by Eli Lilly and Company.
Trial Registration: ClinicalTrials.gov: NCT01753856.
Disclosure Summary: D.W.D. has received research grants
from and serves as a consultant and speaker for Eli Lilly and
Company and Amgen, and is a consultant for Merck, Tarsa
Pharmaceuticals, and Radius Health. R.R.R. receives research
grants from and is a consultant for Eli Lilly and Company and
Merck. J.P.B. receives research grants from Amgen, Eli Lilly and
Company, and Novartis; serves as a consultant for Amgen, Eli
Lilly and Company, and Radius; and is a speaker for Amgen and
Eli Lilly and Company. C.P.R. has received grant/research sup-
port from Amgen, Merck, and Eli Lilly and Company and No-
vartis, and has served on scientific advisory boards for Amgen,
Merck, Eli Lilly and Company, NPS, and Novartis and receives
honorarium and travel expenses for advisory boards. E.M.L. has
received institutional grant/research support from Amgen,
Merck, and Eli Lilly and Company; has served on scientific ad-
visory boards for Amgen, Merck, Eli Lilly and Company, Radius
Health, AgNovos Healthcare, Alexion, NPS, and AbbVie; and
receives honorarium and travel expenses for advisory boards.
P.D.M. serves on scientific advisory boards for Alexion, Amgen,
AgNovos, Lilly, Merck, Radius Pharma, and Roche; receives
research grants from Amgen, Boehringer Ingelheim, Immunodi-
agnostics, Lilly, Merck, Merck Serrano, Novartis, Novo Nor-
disk, Radius Pharma, Roche Diagnostics, and Takeda; and is a
speaker for Alexion Pharmaceuticals and Radius Health. S.D.R.
receives research grants from Eli Lilly and Company. D.L.K.
receives research grants, consultancies, and/or honoraria from
Amgen, Eli Lilly and Company, Pfizer, GSK, Astra Zeneca, and
Astalis. R.L. is a speaker for Eli Lilly and Company. J.H.K., J.A.,
K.A.T., B.J., and V.A.R. are employees of Eli Lilly and Company
and own stock. H.Z. has nothing to declare.
References
1. Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical
need for a uniform nomenclature based on their action on bone
remodeling. J Bone Miner Res. 2005;20:177–184.
2. Forteo Prescribing Information. Eli Lilly and Company. Indianap-
olis, IN, 2012. http://pi.lilly.com/us/forteo-pi.pdf. Accessed Novem-
ber 30, 2015.
3. Recker RR, Armas L. The effect of antiresorptives on bone quality.
Clin Orthop Relat Res. 2011;469:2207–2214.
4. Reginster JY, Neuprez A, Dardenne N, Beaudart C, Emonts P,
Bruyere O. Efficacy and safety of currently marketed anti-osteopo-
rosis medications. Best Pract Res Clin Endocrinol Metab. 2014;28:
809 – 834.
5. Tella SH, Gallagher JC. Prevention and treatment of postmeno-
pausal osteoporosis. J Steroid Biochem Mol Biol. 2014;142:155–
170.
6. Cummings SR, San Martin J, McClung MR, et al. FREEDOM Trial.
Denosumab for prevention of fractures in postmenopausal women
with osteoporosis. N Engl J Med. 2009;361:756 –765.
7. Reid IR, Miller PD, Brown JP, et al. Denosumab Phase 3 Bone His-
tology Study Group. Effects of denosumab on bone histomorphom-
etry: the FREEDOM and STAND studies. J Bone Miner Res. 2010;
25:2256 –2265.
8. Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S,
J Clin Endocrinol Metab, April 2016, 101(4):1353–1363
Makras P. Comparative effect of zoledronic acid versus denosumab
on serum sclerostin and dickkopf-1 levels of naive postmenopausal
women with low bone mass: a randomized, head-to-head clinical
trial. J Clin Endocrinol Metab. 2013;98:3206 –3212.
9. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose pla-
cebo-controlled study of AMG 162, a fully human monoclonal an-
tibody to RANKL, in postmenopausal women. J Bone Miner Res.
2004;19:1059 –1066.
10. Makras P, Polyzos SA, Papatheodorou A, Kokkoris P, Chatzifotia-
dis D, Anastasilakis AD. Parathyroid hormone changes following
denosumab treatment in postmenopausal osteoporosis. Clin Endo-
crinol (Oxf). 2013;79:499 –503.
11. McClung MR, Lewiecki EM, Cohen SB, et al. AMG 162 Bone Loss
Study Group. Denosumab in postmenopausal women with low
Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021
bone mineral density. N Engl J Med. 2006;354:821– 831.
12. Seeman E, Libanati C, Austin M, et al. The transitory increase in
PTH following denosumab administration is associated with re-
duced intracortical porosity: a distinctive attribute of denosumab
therapy. J Bone Miner Res. 2011; 26(Suppl 1) (presentation 1064).
13. Sugimoto T, Matsumoto T, Hosoi T, et al. Three-year denosumab
treatment in postmenopausal Japanese women and men with os-
teoporosis: results from a 1-year open-label extension of the Deno-
sumab Fracture Intervention Randomized Placebo Controlled Trial
(DIRECT). Osteoporos Int. 2015;26:765–774.
14. Seeman E, Libanati C, Austin M, et al. Association between tran-
sitory increase in PTH following denosumab administration and
reduced intracortical porosity is a distinctive attribute of denosumab
therapy. Bone. 2012;50:S162.
15. Zebaze RM, Libanati C, Austin M, et al. Differing effects of deno-
sumab and alendronate on cortical and trabecular bone. Bone.
2014;59:173–179.
16. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years
of denosumab treatment in postmenopausal women with osteopo-
rosis: results from the FREEDOM Extension study. Osteoporos Int.
2015;26:2773–2783.
17. Lindsay R, Cosman F, Zhou H, et al. A novel tetracycline labeling
schedule for longitudinal evaluation of the short-term effects of an-
abolic therapy with a single iliac crest bone biopsy: early actions of
teriparatide. J Bone Miner Res. 2006;21:366 –373.
18. Prolia Prescribing Information. Amgen. Thousand Oaks, CA, USA,
2015. http://pi.amgen.com/united_states/prolia/prolia_pi.pdf. Ac-
cessed November 30, 2015.
19. Dempster DW, Zhou H, Recker RR, et al. Skeletal histomorphom-
etry in subjects on teriparatide or zoledronic acid therapy (SHOTZ)
study: a randomized controlled trial. J Clin Endocrinol Metab.
2012;97:2799 –2808.
20. Rubin MR, Dempster DW, Sliney J Jr., Zhou H, et al. PTH(1– 84)
administration reverses abnormal bone-remodeling dynamics and
structure in hypoparathyroidism. J Bone Miner Res. 2011;26:2727–
2736.
21. Dempster DW. Bone quantification and dynamics of bone turnover
by histomorphometric analysis. In: KL Becker, ed. Principles and
Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia:
J. B. Lippincott Co.; 1995:491– 498.
22. Dempster DW, Compston JE, Drezner MK, et al. Standardized no-
menclature, symbols, and units for bone histomorphometry: a 2012
update of the report of the ASBMR Histomorphometry Nomencla-
ture Committee. J Bone Miner Res. 2013;28:2–17.
23. Lindsay R, Zhou H, Cosman F, Nieves J, Dempster D. Double and
quadruple tetracycline labeling of bone: impact of the label itself.
J Bone Miner Res. 2013;28:222–223.
24. Parfitt AM, Foldes J, Villanueva AR, Shih MS. Difference in label
length between demethylchlortetracycline and oxytetracycline: im-
plications for the interpretation of bone histomorphometric data.
Calcif Tissue Int. 1991;48:74 –77.
25. Recker RR, Kimmel DB, Dempster D, Weinstein RS, Wronski TJ,
Burr DB. Issues in modern bone histomorphometry. Bone. 2011;
49:955–964.
doi: 10.1210/jc.2015-4181
26. Dempster DW, Zhou H, Recker RR, et al. A longitudinal study of
skeletal histomorphometry at 6 and 24 months across four bone
envelopes in postmenopausal women with osteoporosis receiving
teriparatide or zoledronic acid in the SHOTZ trial [published online
February 3, 2016]. J Bone Miner Res. doi:10.1002/jbmr.2804.
27. Dobnig H, Turner RT. The effects of programmed administration
of human parathyroid fragment (1–34) on bone histomorphometry
and serum chemistry in rats. Endocrinology. 1997;138:4607– 4612.
28. Anastasilakis AD, Polyzos SA, Makras P, et al. Circulating sema-
phorin-4D and plexin-B1 levels in postmenopausal women with low
bone mass: the 3-month effect of zoledronic acid, denosumab or
teriparatide treatment. Expert Opin Ther Targets. 2015;19:299 –
306.
29. Polyzos SA, Anastasilakis AD, Terpos E. Transient secondary hy-
perparathyroidism following intravenous infusion of zoledronic
acid. Support Care Cancer. 2009;17:1329 –1330.
30. Anastasilakis AD, Polyzos SA, Goulis DG, et al. Endogenous intact
PTH is suppressed during Teriparatide (rhPTH 1–34) administra-
tion in postmenopausal women with established osteoporosis. En-
docr J. 2008;55:613– 616.
31. Anastasilakis AD, Polyzos SA, Makras P, et al. Circulating irisin is
associated with osteoporotic fractures in postmenopausal women
with low bone mass but is not affected by either teriparatide or
press.endocrine.org/journal/jcem 1363
denosumab treatment for 3 months. Osteoporos Int. 2014;25:
1633–1642.
32. Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman
AB. Effects of a one-month treatment with PTH(1–34) on bone
formation on cancellous, endocortical, and periosteal surfaces of the
human ilium. J Bone Miner Res. 2007;22:495–502.
33. Ma YL, Zeng Q, Donley DW, et al. Teriparatide increases bone
formation in modeling and remodeling osteons and enhances IGF-II
immunoreactivity in postmenopausal women with osteoporosis.
J Bone Miner Res. 2006;21:855– 864.
34. Shiwaku Y, Neff L, Nagano K, et al. The crosstalk between oste-
oclasts and osteoblasts is dependent upon the composition and
structure of biphasic calcium phosphates. PloS One. 2015;10:
e0132903.
35. Eriksen EF. Normal and pathological remodeling of human trabec-
Downloaded from https://academic.oup.com/jcem/article/101/4/1353/2804498 by guest on 10 February 2021
ular bone: three dimensional reconstruction of the remodeling se-
quence in normals and in metabolic bone disease. Endocr Rev. 1986;
7:379 – 408.
36. Parfitt AM. The cellular basis of bone remodeling: the quantum
concept reexamined in light of recent advances in the cell biology of
bone. Calcif Tissue Int. 1984;36:S37–S45.
37. Ominsky MS, Libanati C, Niu QT, et al. Sustained modeling-based
bone formation during adulthood in cynomolgus monkeys may con-
tribute to continuous BMD gains with denosumab. J Bone Miner
Res. 2015;30:1280 –1289.