Denosumab in Primary Hyperparathyroidism
| Status: | Recruiting |
|---|---|
| Conditions: | Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 40 - Any |
| Updated: | 3/16/2015 |
| Start Date: | January 2012 |
| End Date: | January 2017 |
| Contact: | Wendy Fan, MPH |
| Email: | wf2159@columbia.edu |
| Phone: | 212-305-2900 |
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) 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 IgG antibody that binds to and inactivates RANKL, will convert skeletal
actions of PTH from catabolic to anabolic in primary hyperparathyroidism.
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.
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
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