Denosumab in Primary Hyperparathyroidism

Sponsor

John P. Bilezikian (Other)

Overall Status

Completed

CT.gov ID

NCT01558115

Collaborator

National Institutes of Health (NIH) (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Amgen (Industry)

Enrollment

Location

Arms

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Hyperparathyroidism	Drug: Denosumab Other: Placebo	Phase 4

Detailed Description

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 IgG antibody that binds to and inactivates RANKL, will convert skeletal actions of PTH from catabolic to anabolic in primary hyperparathyroidism.

Study Design

Study Type:

Interventional

Actual Enrollment :

8 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Denosumab in Primary Hyperparathyroidism

Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Oct 1, 2014

Actual Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab - Group #1 Receive active drug for year 1 and year 2 of the study	Drug: Denosumab 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 (35 patients): Receive active drug for year 1 and year 2 of the study Group #2 (17 patients): Receive placebo for year 1 and active drug for year 2 of the study Other Names: Prolia Xgeva
Placebo Comparator: Placebo - Group #2 Receive placebo for year 1 and active drug for year 2 of the study	Drug: Denosumab 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 (35 patients): Receive active drug for year 1 and year 2 of the study Group #2 (17 patients): Receive placebo for year 1 and active drug for year 2 of the study Other Names: Prolia Xgeva Other: Placebo 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 (35 patients): Receive active drug for year 1 and year 2 of the study Group #2 (17 patients): Receive placebo for year 1 and active drug for year 2 of the study

Arm

Intervention/Treatment

Experimental: Denosumab - Group #1

Receive active drug for year 1 and year 2 of the study

Drug: Denosumab

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 (35 patients): Receive active drug for year 1 and year 2 of the study Group #2 (17 patients): Receive placebo for year 1 and active drug for year 2 of the study

Other Names:

Prolia

Xgeva

Placebo Comparator: Placebo - Group #2

Receive placebo for year 1 and active drug for year 2 of the study

Drug: Denosumab

Other Names:

Prolia

Xgeva

Other: Placebo

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 (35 patients): Receive active drug for year 1 and year 2 of the study Group #2 (17 patients): Receive placebo for year 1 and active drug for year 2 of the study

Outcome Measures

Primary Outcome Measures

Change in Bone Mineral Density (BMD) at the lumbar spine [Baseline and 12 months]
Percent change from baseline in BMD at the lumbar spine, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months

Secondary Outcome Measures

Change in Bone Mineral Density (BMD) at the distal 1/3 radius [12 months]
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
Change in Bone Mineral Density (BMD) at the hip [12 months]
Percent change from baseline in BMD at the hip, as measured by Dual-emission X-ray absorptiometry (DXA) scan at 12 months

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmed hypercalcemic PHPT in postmenopausal women with serum calcium >10.2 mg/dL and < 12.0 mg/dL (nl: 8.6-10.2)
T-score between -1.5 and -2.5 at any site. If the T-score is <-2.5, patients become candidates for parathyroid surgery. They will be enrolled only if they refuse the parathyroid surgery

Exclusion Criteria:

25-hydroxyvitamin D level < 20 ng/ml
Previous use of the bisphosphonate zoledronic acid (ever), alendronate or risedronate (within 12 months) or ibandronate (within 6 months)
Current use of PTH, glucocorticoids, SERMS, estrogen (other than vaginal), calcitonin or pharmacological amounts of calcitriol Current or previous use of cinacalcet (within 6 months)
Hyperthyroidism
Rheumatoid arthritis or any other inflammatory joint disease
Paget's disease of bone
Malabsorption
T-score <-3.5 at any site
Signs of symptomatic PHPT (e.g, kidney stones within the past 5 years; fragility fracture within the past 2 years)
Physical or mental handicapping condition that precludes ability to complete the protocol and/or provide informed consent.
Subjects on Antiviral HIV therapy or subjects with compromised immune systems
Premenopausal women or men
Stage 5 CKD or anyone on dialysis
Creatinine clearance < 30 cc/min unless the patient is not a candidate for surgery or if the patient refuses surgery