Denosumab helps improve BMD in primary hyperparathyroidism

The antiresorptive agent denosumab, used alone or in combination with the calcimimetic agent cinacalcet, improves BMD and reduces bone turnover in patients with primary hyperparathyroidism (PHPT) — providing a potential treatment option for patients in whom surgery is undesirable, the DENOCINA* trials has shown.

“[While] surgery remains the treatment of choice in all who meet the criteria as suggested by [guidelines] … most patients do not fulfill [the] criteria for surgical treatment at diagnosis, and others do not wish to have surgery or are ineligible because of comorbidities,” explained the researchers. “Therefore, pharmaceutical alternatives to surgery are desirable.”

“This treatment, [however,] is not an alternative to curative surgery when indicated, but can constitute an option for those who cannot or will not have surgery,” they added.

After 1 year, denosumab monotherapy led to significantly improved BMD compared with placebo at all sites measured (except the third distal forearm), including lumbar spine (percentage change vs placebo, 6.9 percent; p<0.0001), total hip (4.1 percent; p<0.0001), and femoral neck (3.8 percent; p=0.0022). [Lancet Diabetes Endocrinol 2020;8:407-417]

Similar findings were seen when denosumab was used in combination with cinacalcet: BMD improved by 5.4 percent (p<0.0001) in lumbar spine, 5.0 percent (p<0.0001) in total hip, and 4.5 percent in femoral neck (p=0.0008); compared with placebo.   

These results from BMD were further supported by significant improvements in volumetric BMD of the lumbar spine, as measured by quantitative CT, with mono- or combined therapy containing denosumab.

BMD changes at the third distal forearm, however, were of borderline significance with denosumab monotherapy (1.8 percent; p=0.04) and combined therapy with cinacalcet (1.9 percent; p=0.06).

Biochemistry profile

In the phase III, proof-of-concept, single-centre, double-blind trial, 46 patients (mean age above 65 years) with PHPT were randomized 1:1:1 to receive subcutaneous injections of denosumab 60 mg Q6M alone, or in combination with oral cinacalcet 30 mg daily, or matching placebo (n=15; placebo group) for 1 year.

“Plasma PTH increases with initiation of denosumab therapy irrespective of addition of cinacalcet, but this effect might be temporary,” the researchers noted.

While plasma calcium was normalized in the combined therapy group (63.8 percent of all visits throughout the treatment period), initial decrease in the levels seen with denosumab monotherapy eventually returned to baseline levels.

“The combination of cinacalcet and denosumab seems safe, and the few cases of hypocalcaemia were corrected by calcium supplementations,” said the researchers.

In terms of safety, there were six nonfatal serious adverse events (AEs), comprising two events in the combination group, one event in the monotherapy group, and three events in the placebo group. The overall prevalence of AEs was not significantly different among groups, although nausea and paresthesia appeared more commonly in both active treatment groups. No fatal AEs were reported.

Filling the gap

“The main message derived from this investigation is the availability of a pharmacological option to protect the skeleton in patients with PHPT who are conservatively managed; this finding is especially important for those with kidney failure, in whom bisphosphonates cannot be used,” wrote Drs Salvatore Minisola, Cristiana Cipriani, and Jessica Pepe from Rome University in Rome, Italy, in a commentary. [Lancet Diabetes Endocrinol 2020;8:352-353]

According to the investigators, the cost and reversibility of the effect of denosumab upon treatment discontinuation were drawbacks of the treatment.

“Notwithstanding these bounds, the study filled a gap in an underinvestigated area — ie, skeleton protection in patients with PHPT who are ineligible or unwilling to have surgery,” highlighted Minisola and co-authors.