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Calcium-sensing receptor antagonist did not improve BMD in postmenopausal women
Transient pulses of parathyroid hormone occurred in postmenopausal women with osteoporosis treated with the orally bioavailable calcium-sensing receptor antagonist MK-5442, according to research published in The Journal of Clinical Endocrinology & Metabolism.
“Administration of MK-5442 resulted in a dose-dependent transient increase in serum parathyroid hormone, an increase in biomarkers of bone formation, and a later more modest rise in markers of bone resorption,” the researchers wrote. “However, despite the biochemical marker effects, there was no increase in bone mineral density.”
Johan Halse, MD, PhD, of Osteoporoseklinikken is Oslo, Norway, and colleagues from other institutions conducted a randomized, double-blind, placebo-controlled, parallel-group trial involving 383 women (aged 45 to 85 years, at least 5 years in post menopause) recruited from private or institutional practices. They all had osteoporosis and were naïve to therapy except for 25-Hydroxyvitamin D.
The researchers assigned patients to MK-5442 (2.5, 5, 7.5, 10 or 15 mg) or placebo daily to identify a dose that would produces osteoanabolic effects without excessive hypercalcemia. Serum parathyroid hormone (PTH) and calcium, bone turnover markers, areal bone mineral density (BMD) and safety were evaluated.
Patients demonstrated dose-dependent transient increases in PTH that lasted longer than 3.5 hours after receiving MK-5442. Significant increases in bone formation markers (serum procollagen 1 N-terminal peptide, bone-specific alkaline phosphatase) were seen by 6 months compared with placebo. Bone resorption markers (serum beta-Crosslaps, urine N-telopeptides of type 1 collagen) decreased initially, then showed significant increases by the same time.
Although biochemical marker changes pointed to an anabolic response, no statistically significant differences existed between any dose of MK-5442 and placebo in percent change from baseline at 6 months in any of the BMD endpoints. Hypercalcemia (trough serum calcium ≥10.8 mg/dL) was seen more frequently with higher MK-5442 doses.
“It is likely the relatively small peak PTH concentration and persistent PTH secretion were the major factors, but it is possible that interaction of MK-5442 at the bone cell level may have contributed to its lack of osteoanabolic efficacy,” the researchers wrote.
Disclosures: Please see study for full list of disclosures.