A Phase 4 interventional study of Denosumab and Placebo in Primary Hyperparathyroidism, sponsored by Columbia University. Terminated at 1 site in United States. Open to female participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2022-11-02.
Sponsored by Columbia University · Phase 4, Interventional, and Treatment
Primary hyperparathyroidism (PHPT), a disease characterized by excess parathyroid hormone (PTH) and high blood calcium, is one of the most common endocrine disorders. PHPT is seen most often in postmenopausal women. Many patients with PHPT have low bone mineral density (BMD) when bone mass is measured by dual energy x-ray absorptiometry (DXA), primarily at the forearm. There is currently no effective medical therapy which increases bone density at the forearm in patients with PHPT.
PTH both builds and breaks down bone, and the pathways by which PTH mediates these actions are beginning to be identified. Prior research suggests that RANKL, a molecule important in bone metabolism, responds to PTH, and that if the RANKL is inactivated, PTH is shifted towards building bone. The investigators will study the effect of Denosumab, a therapeutic agent that binds to and inactivates RANKL, in 28 postmenopausal women with PHPT. Our hypothesis is that Denosumab will increase bone mineral density in primary hyperparathyroidism.
The study will last two years, and subjects will be randomly assigned to receive either placebo or Denosumab for the first year of the study. In the second year, all subjects will receive Denosumab. Denosumab (60 mg) or placebo will be given every 6 months by an injection just under the skin. Study procedures performed will include bone mineral density tests by DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) scans, and assessments of biochemical markers of calcium metabolism and bone turnover using both blood and urine samples of subjects with PHPT.
PTH has both catabolic and anabolic properties, and under normal circumstances, PTH in PHPT is catabolic for bone at the cortical skeleton. Recently, evidence for a direct role of PTH on RANKL expression and osteoclastogenesis in vivo was obtained using mice lacking a distant transcriptional enhancer of the RANKL gene that confers responsiveness to PTH. These observations, supported by additional cross-sectional studies in human subjects make a compelling argument that the catabolic actions of PTH are mediated by RANKL-mediated bone resorption.
The investigators now propose a proof of concept study to test the hypothesis that in PHPT, inhibition of the RANK-L pathway will unmask the anabolic potential of PTH. A therapeutic agent that redirects the actions of PTH in PHPT from one that is primarily catabolic to an anabolic one would fulfill this proof of concept. The investigators hypothesize that Denosumab, a human Immunoglobulin G (IgG) antibody that binds to and inactivates RANKL, will convert skeletal actions of PTH from catabolic to anabolic in primary hyperparathyroidism.
Exclusion Criteria:
Receive active drug for year 1 and year 2 of the study
Drug: Denosumab
Receive placebo for year 1 and active drug for year 2 of the study
Drug: Denosumab · Other: Placebo
The dose of denosumab is 60 mg every 6 months by subcutaneous injection. The 52 subjects will be randomly allocated (2:1) into treatment and placebo arms with the placebo group receiving a subcutaneous injection of vehicle in year 1. In year 2, those who were allocated to the study drug in year 1 will continue in year 2. Those who were allocated to placebo in year 1 will be crossed over to study drug in year 2. Group # 1: Receive active drug for year 1 and year 2 of the study Group #2: Receive placebo for year 1 and active drug for year 2 of the study
Also known as: Prolia, Xgeva
The dose of denosumab is 60 mg every 6 months by subcutaneous injection. The placebo group will receive vehicle injections at the same time interval. The 52 subjects will be randomly allocated (2:1) into treatment and placebo arms with the placebo group receiving a subcutaneous injection of vehicle in year 1. In year 2, those who were allocated to the study drug in year 1 will continue in year 2. Those who were allocated to placebo in year 1 will be crossed over to study drug in year 2. Group # 1: Receive active drug for year 1 and year 2 of the study Group #2: Receive placebo for year 1 and active drug for year 2 of the study
Change in Bone Mineral Density (BMD) at the Lumbar Spine
Percent change from baseline in BMD at the lumbar spine, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
Time frame: Baseline and 12 months
Change in Bone Mineral Density (BMD) at the Distal 1/3 Radius
Percent change from baseline in BMD at the distal 1/3 radius, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
Time frame: 12 months
Change in Bone Mineral Density (BMD) at the Hip
Percent change from baseline in BMD at the hip, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
Time frame: 12 months
| Milestone | Denosumab - Group #1 or Placebo - Group #2 |
|---|---|
| Started | 8 |
| Completed | 1 |
| Not completed | 7 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Study closed due to poor enrollment | 4 |
Percent change from baseline in BMD at the lumbar spine, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
No measurements were reported for this outcome.
Percent change from baseline in BMD at the distal 1/3 radius, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
No measurements were reported for this outcome.
Percent change from baseline in BMD at the hip, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months
No measurements were reported for this outcome.
Collected over Up to 2 years. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Denosumab - Group #1 | 0/8 (0%) | 0/8 (0%) | 0/8 (0%) |
| Placebo - Group #2 | 0/8 (0%) | 0/8 (0%) | 0/8 (0%) |
Study closed prematurely due to poor enrollment. The data were not collected per arm. This study was closed with the Institutional Review Board (IRB) in 2014 and additional analyses cannot be completed.
| Age, Customized(Participants) | Denosumab - Group #1 or Placebo - Group #2 |
|---|---|
| 18-65 years | 3 |
| > 65 years | 5 |
| Sex: Female, Male(Participants) | Denosumab - Group #1 or Placebo - Group #2 |
|---|---|
| Female | 8 |
| Male | 0 |
| Race (NIH/OMB)(Participants) | Denosumab - Group #1 or Placebo - Group #2 |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 8 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Denosumab - Group #1 or Placebo - Group #2 |
|---|---|
| United States | 8 |
Plan to share: No
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Columbia University