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Keywords:

  • OSTEOPOROSIS;
  • BONE;
  • VITAMIN D;
  • 2MD;
  • BMD

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation. 2-Methylene-19-nor-(20S)-1α,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 = 50), 220 ng of 2MD (n = 54), and 440 ng of 2MD (n = 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 cross-links of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone remodeling. © 2011 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Osteoporosis 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-α-hydroxyvitamin D3 [1α(OH)D3],4, 5 and 1α,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 for possible use in the treatment of osteoporosis and in some countries are in use for that purpose. For example, 1α(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 1α(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-methylene-19-nor-(20S)-1α,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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

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).

Table 1. Summary of Demographics
CharacteristicaPlacebo (n = 49)220 ng 2MD (n = 54)440 ng 2MD (n = 53)
  • 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.

Race
 White39 (80)44 (82)42 (79)
 Black1 (2)1 (2)2 (4)
 Hispanic9 (18)8 (15)9 (17)
 Asian000
 Other01 (2)0
Age (years)61.1 ± 6.561.6 ± 5.561.9 ± 5.3
Height (cm)159.6 ± 6.7161.1 ± 6.6160.4 ± 7.1
Weight (kg)69.0 ± 11.066.2 ± 11.069.8 ± 12.8
Lumbar spine BMD (g/cm2)0.889 ± 0.0730.894 ± 0.0780.899 ± 0.089
Femoral neck BMD (g/cm2)0.718 ± 0.0970.726 ± 0.1050.738 ± 0.094
Total proximal femur BMD (g/cm2)0.835 ± 0.0690.825 ± 0.0790.852 ± 0.088
Trochanter BMD (g/cm2)0.634 ± 0.0750.617 ± 0.0670.647 ± 0.080
Serum 25(OH)D (ng/mL)29 ± 1030 ± 1032 ± 12
Serum iPTH (pg/mL)b33 ± 1334 ± 1138 ± 16
Mean dietary calcium intake at screening (mg/day)642 ± 240709 ± 299633 ± 294
Serum calcium (mg/dL)9.42 ± 299.46 ± 319.38 ± 36
24-Hour urinary calcium (mg/24 h)153 ± 90175 ± 73146 ± 97
Mean vitamin D intake (IU/day)114 ± 105132 ± 139104 ± 101
Years postmenopausal13.2 ± 7.912.5 ± 6.113.3 ± 6.4

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 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 −80°C 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 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 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)

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Figure 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.

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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 per-protocol 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 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

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.

thumbnail image

Figure 2. (A) Percent change in BMD by treatment group at week 52, full-analysis 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.

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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).

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

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.

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Figure 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.

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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.

Safety

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.

Table 2. Summary of Safety Assessments
ResultaPlacebo (n = 49)220 ng 2MD (n = 54)440 ng 2MD (n = 53)
  • a

    Values represent number of events or subjects, with numbers in parentheses representing the percentage of subjects within that treatment group.

Number of adverse events (AEs)189162234
Number of subjects with AEs41 (83.7)45 (83.3)46 (86.8)
Number of related AEs142775
Number of subjects with related AEs5 (10.2)16 (29.6)28 (52.8)
Number of subjects with AEs leading to discontinuation3 (6.1)5 (9.3)21 (39.6)
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)0 (0)0 (0)4 (7.5)
Number of subjects with confirmed serum calcium elevations (>11.2 mg/dL)0 (0)2 (3.7)3 (5.7)
Number of subjects with confirmed urinary calcium elevations (>450 mg/24 h)0 (0)7 (13.0)21 (40.0)

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.

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Figure 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-four-hour 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.

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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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

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 from the human skeleton, however.26–28 The rat skeleton, especially in younger rats, exhibits little coupled bone remodeling29 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 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 1α(OH)D3 are used to treat osteoporosis with some success.44 Chugai's investigational vitamin D analogue ED-71 [1α,25-dihydroxy-2β-(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 PTH47 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

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

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References