Download DeLuca et al. 2011 J. Bone Min. Res. 26:538

CLINICAL TRIALS
JBMR
The Vitamin D Analogue 2MD Increases Bone Turnover
but Not BMD in Postmenopausal Women With
Osteopenia: Results of a 1-Year Phase 2 Double-Blind,
Placebo-Controlled, Randomized Clinical Trial
Hector F DeLuca , 1 Wendy Bedale , 1 Neil Binkley , 2 J Chris Gallagher , 3 Michael Bolognese , 4
Munro Peacock , 5 John Aloia , 6 Margaret Clagett-Dame , 1 and Lori Plum1
1
Deltanoid Pharmaceuticals and the Department of Biochemistry, University of Wisconsin–Madison, Madison, WI, USA
Osteoporosis Clinical Center and Research Program and Institute on Aging, University of Wisconsin–Madison, Madison, WI, USA
3
Bone Metabolism Section, Bone Metabolism Unit, Creighton University Medical Center, Omaha, NE, USA
4
Bethesda Health Research Center, Bone Health Center of Bethesda, Bethesda, MD, USA
5
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
6
The Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
2
ABSTRACT
Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation.
2-Methylene-19-nor-(20S)-1a,25-dihydroxyvitamin D3 (2MD) is a vitamin D analogue that potently stimulates bone formation activity in
vitro and in the ovariectomized rat model. In this randomized, double-blind, placebo-controlled study of osteopenic women, the effect of
daily oral treatment with 2MD on bone mineral density (BMD), serum markers of bone turnover, and safety were assessed over 1 year.
Volunteers were randomly assigned to three treatment groups: placebo (n ¼ 50), 220 ng of 2MD (n ¼ 54), and 440 ng of 2MD (n ¼ 53). In
general, 2MD was well tolerated. Although 2MD caused a marked increase in markers of bone formation, it did not significantly increase
BMD. Since 2MD also shows marked activity on bone resorption (as revealed by dose-dependent increases in serum C-telopeptide crosslinks of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone
remodeling. ß 2011 American Society for Bone and Mineral Research.
KEY WORDS: OSTEOPOROSIS; BONE; VITAMIN D; 2MD; BMD
Introduction
O
steoporosis is a debilitating disease whose prevalence is
increasing in an aging population. Osteoporotic fractures in
both men and women are associated with significant morbidity
and mortality. Nearly 1% of women over the age of 65 years
suffer a hip fracture annually, and more than 20% of these
women die within a year of the fracture.(1) Quite clearly,
development of effective therapies that reduce fracture risk in
these patients is a major health goal.
The most commonly used osteoporosis therapies are
antiresorptive agents, including bisphosphonates and selective
estrogen modulators.(2) Less effective antiresorptive agents
include calcitonin,(3) 1-a-hydroxyvitamin D3 [1a(OH)D3],(4,5) and
1a,25-dihydroxyvitamin D3 [1,25(OH)2D3].(6) A new antiresorptive
agent currently under development is the RANKL antibody
denosumab.(7) These drugs inhibit the resorptive component of
the bone-remodeling system, thus reducing the resorbed
surfaces required for new bone synthesis.(8) As a result, new
bone synthesis is inhibited within several months of antiresorptive therapy,(9) limiting further improvement in bone mass after a
year or two of therapy.(10)
Only one anabolic osteoporosis drug, teriparatide, is currently
available in the United States. Teriparatide use is limited perhaps
owing to the delivery method (daily subcutaneous injection),
high cost, and labeling for this drug (boxed warning regarding
osteosarcoma and limitation of therapy duration to 2 years
maximum).(2)
As noted earlier, the hormonal forms of vitamin D,
1,25(OH)2D3, and other vitamin D analogues have been studied
Received in original form June 3, 2010; revised form July 29, 2010; accepted September 16, 2010. Published online October 1, 2010.
Address correspondence to: Hector F DeLuca, PhD, Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA.
E-mail: [email protected]
Journal of Bone and Mineral Research, Vol. 26, No. 3, March 2011, pp 538–545
DOI: 10.1002/jbmr.256
ß 2011 American Society for Bone and Mineral Research
538
46
for possible use in the treatment of osteoporosis and in some
countries are in use for that purpose. For example, 1a(OH)D3 and
1,25(OH)2D3 have been used in Japan for at least two decades.
Clinical evidence of improvements in fracture rates following
1,25(OH)2D3 or 1a(OH)D3 therapy in postmenopausal osteoporosis have been published and debated.(11–16) Thus far, all
vitamin D compounds in use and under development act
primarily by suppression of bone resorption rather than as
anabolic agents at dose levels that are not hypercalcemic.(17,18)
A new series of vitamin D analogues that stimulate new bone
formation has been discovered.(19) One of these, 2-methylene19-nor-(20S)-1a,25-dihydroxyvitamin D3 (2MD or DP001) has
been studied extensively in the ovariectomized (OVX) rat
model.(20–22) 2MD acts as a bone anabolic agent in this model
and is effective in increasing bone mass without hypercalcemia.
Since the OVX rat is an accepted model by regulatory agencies
worldwide,(23–25) it is compelling to consider 2MD as a promising
therapy for osteoporosis. This article presents the results of a
clinical trial designed to test this hypothesis.
Materials and Methods
Study subjects
Postmenopausal women were screened for study enrollment at
nine clinical sites within the United States (Madison, WI,
Indianapolis, IN, Omaha, NE, Mineoloa, NY, West Haverstraw,
NY, Duncansville, PA, Albuquerque, NM, Upland, CA, and
Bethesda, MD).
Included participants were osteopenic women who were
amenorrheic for at least 5 years and between the ages of 55 and
80 years (inclusive). Osteopenia was defined as a lumbar spine
(L1–L4) bone mineral density (BMD) value of 0.937 to 0.772 g/cm2
on Hologic densitometer (Hologic, Inc., Waltham, MA, USA) or
1.060 to 0.880 g/cm2 on GE Healthcare Lunar densitometer (GE
Healthcare, Madison, WI, USA). Other inclusion criteria included
having a body mass index (BMI) of approximately 18 to 35 kg/m2,
being generally healthy, and being willing and able to comply
with the study visits and procedures.
Key exclusion criteria included history of acute or unstable
chronic hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, or neurologic diseases and
current treatment with medications that affect vitamin D
metabolism or absorption or medications affecting calcium
balance or bone turnover (including calcitonin, any prior
intravenous bisphosphonate use, or any past oral bisphosphonate treatment for more than 3 months or any time in the
previous year). Women also were excluded if they had a QTc
value greater than 450 ms, creatinine clearance 50 mL/min,
urinary calcium > 300 mg/24 h, serum 25(OH)D level < 10 ng/mL,
dietary calcium intake > 1000 mg/day, vitamin D intake > 2000
IU/day, or were currently using any illicit drug or had history of
alcohol abuse (Table 1).
The study protocol was approved by institutional review
boards affiliated with the sites or by a central institutional review
board, and all subjects provided written informed consent
before participating in the study. The clinical study was
conducted in accordance with the Declaration of Helsinki. An
2MD INCREASES BONE TURNOVER BUT NOT BMD
independent data safety monitoring board (DSMB) met at
regular intervals during the study and reviewed safety and BMD
data from the study. The study was registered with ClinicalTrials.gov (identifier number NCT00715676).
Study drug
2MD was formulated in soft gel capsules, and the placebo was
formulated identically, except for the absence of 2MD. A
vitamin D3 supplement (600 IU/day) also was provided to each
subject. Both study drug capsules and vitamin D3 supplement
were analyzed for content and stability prior to and during the
study. Placebo or 2MD (220 or 440 ng total daily dose) was taken
orally once daily.
Study design and data collection
The study was a randomized, double-blind, placebo-controlled,
parallel-group study with drug treatment lasting 1 year. The
study enrolled 157 postmenopausal women with osteopenia
between March 2007 and December 2007. Subjects were
randomized in a 1:1:1 ratio to three treatment groups: placebo,
220 ng of 2MD, or 440 ng of 2MD. Study drug and placebo were
prepackaged in identical subject-specific kits by Columbia
University Medical Center Research Pharmacy (CUMCRP, New
York, NY, USA), which also provided the computer-generated
randomization schedule but had no clinical involvement in the
trial. All study participants, the sponsor and data collectors, and
all clinical investigators and support staff were blinded to
treatment assignments throughout the study until after the
study database was locked.
The subjects came to the investigative sites for study
evaluations during weeks 6 to 2 (first screening visit), weeks
4 to 1 (second screening visit), on day 1 (baseline), and during
weeks 2, 4, 8, 13, 20, 26, 33, 39, 46, and 52. Per protocol, the trial
ended when the last remaining subject had completed her final
visit.
Study procedures
BMD assessments were based on duplicate dual-energy X-ray
absorptiometry (DXA) scans at the spine and hip at screening
visit 2, baseline, week 26, and week 52. No analysis of
postscreening DXA scans was performed at the sites; all DXA
scans were sent to Bio-Imaging Technologies (Newtown, PA,
USA) for quality control and BMD analyses.
Laboratory assessments were performed by a central
laboratory (Quest Diagnostics Clinical Trials, Valencia, CA, USA)
except bone marker and postscreening intact parathyroid
hormone (iPTH) analyses, which were performed by the study
sponsor. Serum calcium analysis was performed at all study visits
except for screening visit 2. Twenty-four-hour urinary calcium
measurements were performed for screening visit 2 and the
visits at baseline and weeks 2, 4, 8, 13, 26, 39, and 52.
Bone marker and postscreening iPTH samples were stored at
70 or 808C until the end of the study. Three bone markers
were tested: serum C-terminal cross-linked telopeptide of type I
collagen (s-CTX), osteocalcin, and procollagen I N-terminal
extension peptide (PINP). Bone marker and iPTH analyses were
conducted by Deltanoid Pharmaceuticals (Madison, WI, USA) on
Journal of Bone and Mineral Research
539
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Table 1. Summary of Demographics
Characteristica
Race
White
Black
Hispanic
Asian
Other
Age (years)
Height (cm)
Weight (kg)
Lumbar spine BMD (g/cm2)
Femoral neck BMD (g/cm2)
Total proximal femur BMD (g/cm2)
Trochanter BMD (g/cm2)
Serum 25(OH)D (ng/mL)
Serum iPTH (pg/mL)b
Mean dietary calcium intake at screening (mg/day)
Serum calcium (mg/dL)
24-Hour urinary calcium (mg/24 h)
Mean vitamin D intake (IU/day)
Years postmenopausal
Placebo (n ¼ 49)
220 ng 2MD (n ¼ 54)
440 ng 2MD (n ¼ 53)
39 (80)
1 (2)
9 (18)
0
0
61.1 6.5
159.6 6.7
69.0 11.0
0.889 0.073
0.718 0.097
0.835 0.069
0.634 0.075
29 10
33 13
642 240
9.42 29
153 90
114 105
13.2 7.9
44 (82)
1 (2)
8 (15)
0
1 (2)
61.6 5.5
161.1 6.6
66.2 11.0
0.894 0.078
0.726 0.105
0.825 0.079
0.617 0.067
30 10
34 11
709 299
9.46 31
175 73
132 139
12.5 6.1
42 (79)
2 (4)
9 (17)
0
0
61.9 5.3
160.4 7.1
69.8 12.8
0.899 0.089
0.738 0.094
0.852 0.088
0.647 0.080
32 12
38 16
633 294
9.38 36
146 97
104 101
13.3 6.4
a
Values for racial characteristics represent the number of subjects and the percent of subjects within that group. All other values in the table represent
the mean value SD.
b
The iPTH values reported here were screening values reported by the central laboratory.
coded serum samples collected from fasting subjects between 8
and 11 a.m. at baseline and week 26 visits. Assays were
performed using reagent kits (N-MID Osteocalcin ELISA, UniQ
PINP RIA, Serum CrossLaps ELISA, and Intact PTH ELISA) supplied
by Immunodiagnostics Systems, Ltd. (Scottsdale, AZ, USA)
following the manufacturer’s instructions. Baseline and
week 26 samples were tested at the same time.
Procedures for managing serum or urinary calcium
elevations
Because of the potential for any vitamin D compound to cause
hypercalcemia and hypercalciuria, subjects had laboratory
assessments for serum calcium and 24-hour urinary calcium
performed at each study visit. In addition, criteria and procedures
for dietary modification and/or dose reduction in the case of
confirmed (two consecutive) elevations in serum calcium
(>10.6 mg/dL) or 24-hour urinary calcium (>450 mg/24 h) were
defined in the protocol. The time between initial elevations and
retests varied but usually was greater than 48 hours for serum
calcium elevations and greater than 7 days for urinary calcium
elevations. Dietary modification involved consultation between a
dietitian and the patient to reduce dietary calcium intake by
approximately 400 mg/day, if possible, without reducing dietary
calcium below a total of 400 mg/day. Dose reduction for specific
subjects with hypercalcemia or hypercalciuria did not break the
study blind and involved exchange of study drug bottles to lower
the 440-ng dose to 330 ng and the 220-ng dose to 110 ng.
After approximately 52% of subjects had completed or
discontinued the study, all subjects remaining at the 440-ng dose
540
Journal of Bone and Mineral Research
level (12 of 53 subjects) had their dose adjusted to 330 ng per
recommendation by the DSMB. All dose adjustments were done
in a blinded manner (Fig. 1)
Statistical analysis
The primary efficacy variable was the percent change from
baseline to week 52 in lumbar spine BMD. Secondary endpoints
included the percent change from baseline in lumbar spine BMD
at week 26; the percent changes from baseline in total proximal
femur, femoral neck, and trochanter BMD at weeks 26 and 52;
and the percent change in bone markers at week 26.
The primary analysis was an ANOVA model applied to the
primary endpoint, with contrasts used to determine treatment
effects. The population for this analysis was the full analysis set,
which was defined prospectively as all randomized subjects who
received at least one dose of study drug. Multiple imputation was
used to handle missing data. The Hochberg method was used to
compare dose groups with placebo and control the type 1 error
rate. As a secondary analysis, the same model as the primary
analysis was used, except that it was performed on a perprotocol population, which was defined prospectively as all
randomized subjects who were compliant with study dosing (at
least 80% of study drug taken based on capsule counts) and
completed the study through week 52. Secondary BMD
endpoints were analyzed similarly, except the Hochberg
adjustment was not used.
Subjects were analyzed as part of their original dose group
regardless of whether a subsequent dose reduction occurred.
Bone markers, PTH, and serum and urinary calcium values were
DELUCA ET AL.
48
Fig. 2. (A) Percent change in BMD by treatment group at week 52, fullanalysis set. The mean percent changes from baseline in BMD at week 52
at each anatomic site for each treatment group are shown. Error bars
represent SD. None of the treatment groups showed statistically
significant differences from placebo ( p > .05) at any anatomic site.
(B) Percent change in BMD by treatment group at week 52, per-protocol
set. The mean percent changes from baseline in BMD at week 52 at each
anatomic site for each treatment group are shown. Error bars represent
SD. None of the treatment groups showed statistically significant differences from placebo ( p < .05) at any anatomic site.
Fig. 1. (A) Screening, enrollment, and disposition of study subjects. (B)
Proportion of subjects at 330 or 440 ng of 2MD during study. The number
of subjects originally assigned to the 440-ng dose groups who were still
participating in the study at each specified study visit are shown in this
graph. Subjects who had been dose-reduced to 330 ng 2MD at the time
of that specific visit are shown in white, whereas subjects who remained
at 440 ng 2MD are shown in gray.
Post-hoc analyses of changes in total bone mineral content
and bone area were conducted for the per-protocol population.
No statistically significant changes in bone mineral content or
area were noted at week 26 or week 52 for any treatment group
at any anatomic site (ie, lumbar spine, total proximal femur,
femoral neck, or trochanter; data not shown).
Markers of bone turnover
analyzed using the SAS mixed-model procedure with Dunnett’s
adjustment (SAS Institute, Inc., Cary, NC, USA). Serum and urinary
calcium levels were analyzed as repeated measures, and missing
values were not imputed.
Results
BMD results
The primary endpoint in this study was the percent change from
baseline to week 52 in lumbar spine BMD relative to placebo.
There was no significant change in lumbar spine BMD following 1
year of treatment with 2MD, as shown in Fig. 2A.
No significant changes in BMD were seen at other anatomic
locations (Fig. 2A), at an earlier time point (week 26; data not
shown), or for subjects who completed the study through
week 52 (Fig. 2B).
2MD INCREASES BONE TURNOVER BUT NOT BMD
Serum CTX and osteocalcin showed a dose-dependent increase
( p < .05 for the 440-ng dose group) at week 26 relative to
baseline (Fig. 3A). Serum PINP also showed a trend toward an
increase by week 26 at both 2MD doses relative to baseline;
however, this increase was not statistically significant. These
results suggest overall that bone turnover increased at 26 weeks
of treatment with 2MD.
Bone marker analyses at week 52 were not performed because
the number of subjects completing the study, especially in the
high-dose group, would have been too small to permit
conclusions.
Parathyroid hormone results
iPTH showed a dose-dependent decrease at week 26 (Fig. 3B)
relative to baseline levels. This decrease in PTH level occurred in
parallel with biochemical evidence of increased bone turnover.
Journal of Bone and Mineral Research
541
49
Safety
Fig. 3. (A) Percent change from baseline in bone marker results at week
26. Serum samples for all subjects completing visits at baseline and
week 26 were tested for the bone markers s-CTX, osteocalcin, and PINP.
All serum samples were obtained from fasted subjects between the hours
of 8 and 11 a.m. Baseline and week 26 samples were tested at the same
time on the same immunoassay plate. Data are presented as the mean
with error bars representing SEM. ap < .05 versus placebo. (B) Percent
change from baseline in iPTH results at week 26. Serum samples for all
subjects completing visits at baseline and week 26 were tested for iPTH.
All serum samples were obtained from fasted subjects between the hours
of 8 and 11 a.m. Baseline and week 26 samples were tested at the same
time on the same immunoassay plate. Data are presented as the mean
with error bars representing SEM. ap < .05 versus placebo.
2MD generally was well tolerated, especially at the 220-ng level.
Table 2 presents an overview of the adverse events and notable
laboratory abnormalities that occurred during the study. The
only adverse events consistently judged by investigators to be
related to study drug administration were serum and urinary
calcium elevations in the 440-ng dose group.
Mean serum calcium levels for all dose groups were within the
normal range (Fig. 4A); however, 7 (14%) subjects in the 440-ng
dose group and 2 (4%) subjects in the 220-ng dose group had
confirmed (repeated) serum calcium values greater than
10.6 mg/dL. Once all subjects in the 440-ng group had been
dose-reduced to 330 ng, no more confirmed incidents of serum
calcium levels above the upper limit of normal were reported. All
serum calcium elevations resolved following dose reduction or
discontinuation of study drug.
The 24-hour urinary calcium levels did increase for both the
220- and 440-ng dose groups during the study (Fig. 4B), as
expected for a vitamin D compound. In the 220-ng dose group, 7
subjects (13%) had confirmed urinary calcium elevations over
450 mg/24 hours, whereas 21 subjects (40%) in the 440-ng dose
group had confirmed urinary calcium elevations greater than
450 mg/24 hours. Urinary calcium elevations were asymptomatic
and resolved following dose reduction or discontinuation of
study drug.
Serum and urinary calcium elevations were not limited to time
points early or late in the study but occurred at various times
during the study. Some of the subjects with confirmed serum
calcium elevations had prior unconfirmed urinary calcium
elevations, but others did not. Only one subject, who was in
the 440-ng dose group, had both a confirmed urinary calcium
elevation and a confirmed serum calcium elevation greater than
11.2 mg/dL.
Discussion
In this study, 1 year of treatment with 2MD did not increase BMD
in osteopenic postmenopausal women. This result is in stark
contrast to 2MD’s effects in the OVX rat, where dramatic
increases in BMD were observed.(20,21) The rat skeleton differs
Table 2. Summary of Safety Assessments
Resulta
Number of adverse events (AEs)
Number of subjects with AEs
Number of related AEs
Number of subjects with related AEs
Number of subjects with AEs leading to discontinuation
Number of subjects with confirmed serum calcium
elevations (where at least one value is >10.6 and
11.2 mg/dL and the other >10.6 mg/dL)
Number of subjects with confirmed serum
calcium elevations (>11.2 mg/dL)
Number of subjects with confirmed urinary
calcium elevations (>450 mg/24 h)
Placebo (n ¼ 49)
220 ng 2MD (n ¼ 54)
440 ng 2MD (n ¼ 53)
189
41 (83.7)
14
5 (10.2)
3 (6.1)
0 (0)
162
45 (83.3)
27
16 (29.6)
5 (9.3)
0 (0)
234
46 (86.8)
75
28 (52.8)
21 (39.6)
4 (7.5)
0 (0)
2 (3.7)
3 (5.7)
0 (0)
7 (13.0)
21 (40.0)
a
Values represent number of events or subjects, with numbers in parentheses representing the percentage of subjects within that treatment group.
542
Journal of Bone and Mineral Research
DELUCA ET AL.
50
Fig. 4. (A) Mean serum calcium levels during study by treatment group.
Serum samples were collected from fasted subjects between 8 and 11
a.m. at each study visit. Mean serum calcium (mg/dL) values are shown by
treatment group for each time point. Error bars represent SD. ap < .05
versus mean baseline value for that treatment group. (B) Mean 24-hour
urinary calcium levels during study by treatment group. Twenty-fourhour urine samples were collected from between 8 and 11 a.m. at each
study visit. Mean 24-hour urine calcium levels are shown by treatment
group for each time point. Error bars represent SD. ap < .05 versus mean
baseline value for that treatment group.
from the human skeleton, however.(26–28) The rat skeleton,
especially in younger rats, exhibits little coupled bone remodeling(29) and undergoes a continual modeling sequence where
bone formation is not limited by a lack of resorption surface.(30)
Earlier work indicated that 2MD is not only anabolic but also a
potent stimulator of bone resorption.(22) In fact, its activity on
bone resorption may equal or exceed its activity on bone
synthesis in human subjects, which could explain the failure of
2MD to increase BMD in an adult remodeling system such as
postmenopausal women. The idea that 2MD might markedly
increase bone remodeling is supported in this study by the
marked increase of both bone-formation and bone-resorption
markers.
There is evidence that bone mass by itself is not entirely
predictive of fracture rate.(31,32) It is plausible that increased
remodeling, particularly if driven by an increase in bone
formation, may improve bone quality and reduce fracture rate
without an appreciable increase in bone mass. Unfortunately,
this hypothesis cannot be tested easily because fracture studies
require large numbers of patients and substantial resources. It is
interesting that no fractures occurred in the 2MD-treated groups,
whereas two did occur in the placebo group.
At 440 ng/day, a significant incidence of hypercalciuria/
hypercalcermia occurred that required a reduction of dose to
330 ng/day. This then raises the question of whether the doses
used were too high, causing more bone resorption than at lower
doses. However, preliminary work revealed that 100 ng/day for
2MD INCREASES BONE TURNOVER BUT NOT BMD
6 months did not increase bone mass in postmenopausal
women with osteopenia (unpublished results).
Our results carry an important message in regard to preclinical
models of osteoporosis. The data from our laboratory,(26) as well
as Pfizer’s,(27) demonstrated quite clearly that 2MD is effective in
increasing bone mass in both young and old OVX rats. However,
in postmenopausal women, 2MD produced no significant
increase in bone mass. This demonstrates an inadequacy of
the rat as a model of human osteoporosis. On the other hand,
positive results in this model have been obtained for
teriparatide,(35) the only currently available anabolic therapeutic
in this area. Further, the rat model has been successful in almost
all cases involving bone-resorption inhibitors,(36,37) including
other vitamin D compounds.(17) If our hypothesis is correct, that
is, that 2MD increases bone synthesis and resorption equally,
then because the rat has much less resorptive activity than
formation activity, bone-mass data in the rat can be misleading.
The use of vitamin D compounds for the treatment of
osteoporosis is not universally accepted. Large doses of
vitamin D3 or vitamin D2 had no significant effect on
osteoporotic patients in several recent trials,(38,39) whereas
meta-analyses of vitamin D osteoporosis studies have reached
conflicting conclusions.(40–43) In Japan and other countries where
modest calcium intakes are common (and hypercalcemia and
hypercalciuria therefore less of a concern), 1,25(OH)2D3 or
1a(OH)D3 are used to treat osteoporosis with some success.(44)
Chugai’s investigational vitamin D analogue ED-71 [1a,25dihydroxy-2b-(3-hydroxypropoxy)vitamin D3] was successful in
increasing bone mass in postmenopausal women but occasionally produced hypercalcemia.(45) In contrast to 2MD, ED-71 and
other vitamin D compounds demonstrate significant suppression of bone resorption.(17,45)
Increasing bone turnover might be useful in some conditions.
Patients with higher baseline bone turnover respond better to
bisphosphonates.(46) Patients who discontinue bisphosphonate
have decreased bone turnover, blunting the subsequent
response to other therapies such as PTH(47) and strontium
ranelate.(48) Treatment during bisphosphonate drug holidays
with a drug that would increase bone turnover while preserving
bone mass for a few months may improve subsequent therapy.
Similarly, fracture healing occurs more slowly when bone
turnover is low,(49) and drugs that increase bone turnover have
been shown to improve the rate of fracture healing.(50)
In conclusion, 1 year of treatment with 2MD did not improve
bone mass in postmenopausal women with osteopenia,
although it did increase markers of both bone formation and
bone resorption. These results were not expected given the
striking anabolic activity noted in the OVX rat model. The
discrepancy could be due to the differences in bone metabolism
in rats and humans, highlighting a limitation of the OVX rat
model when developing novel osteoporosis therapies.
Disclosures
HFD, WB, MCD, and LP are officers and own stock in Deltanoid
Pharmaceuticals. NB, JCG, MB, MP, and JA served as consultants
for or received support from Deltanoid Pharmaceuticals for
conducting the clinical trial.
Journal of Bone and Mineral Research
543
51
Acknowledgments
This study was supported by Deltanoid Pharmaceuticals, Inc.,
Madison, WI, USA. The principal investigators for this study were
Neil Binkley, University of Wisconsin–Madison, Osteoporosis
Clinical Research Madison, WI; Munro Peacock, Indiana School
of Medicine University Hospital, Indianapolis, IN; J Chris Gallagher, Creighton University Bone Metabolism Unit, Omaha, NE;
John F Aloia, Winthrop University Hospital Bone Mineral
Research Center, Mineola, NY; Felicia Cosman, Helen Hayes
Hospital Clinical Research Center, West Haverstraw, NY; Frederick
Murphy, Altoona Center for Clinical Research, Duncansville, PA; E
Michael Lewiecki, New Mexico Clinical Research and Osteoporosis Center, Albuquerque, NM; Mohamed Bassam Sebai, Boling
Clinical Trials, Upland, CA; and Michael Bolognese, Bethesda
Health Research, Bethesda, MD
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