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Many women on dialysis quickly developed severe hypocalcemia after starting denosumab (Prolia) for osteoporosis, Medicare data showed.

During the first 12 weeks of treatment, 41.1% of women on denosumab developed severe hypocalcemia compared with 2.0% of those taking oral bisphosphonates, reported a group of largely FDA researchers led by Steven Bird, PhD, PharmD, of the agency offices in Silver Spring, Maryland.

This translated to more than a 20-times higher risk for incident severe hypocalcemia with denosumab (weighted risk ratio 20.7, 95% CI 13.2-41.2), according to the retrospective cohort study in .

Supported by these new findings, the FDA on Friday added a boxed warning over the risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD) taking denosumab for osteoporosis.

The study revealed a sharp decline in calcium levels within the first week of denosumab administration that continued for up to 10 weeks after.

The same was seen in regards to the 12-week weighted cumulative incidence of very severe hypocalcemia, which occurred in 10.9% of denosumab-treated patients versus only 0.4% of those on oral bisphosphonates (weighted RR 26.4, 95% CI 9.7-449.5).

"Stable serum calcium levels observed in this cohort during the 6 months prior to denosumab administration, coupled with the rapid onset and high incidence of severe hypocalcemia post administration, suggest that this association might be causal," they posited. Because of this, the authors said denosumab should only be administered "after careful patients selection and with plans for frequent monitoring."

"This may be due to a confluence of nephrology practice patterns, inadequate communication between physicians, and lack of guidance on osteoporosis management in patients undergoing dialysis," commented authors Pascale Khairallah, MD, of Baylor College of Medicine in Houston, and Thomas Nickolas, MD, MS, of Columbia University Irving Medical Center in New York.

These findings also weren't totally unexpected, Khairallah and Nickolas said, as other global studies reported rates of denosumab-related hypocalcemia of up to 42%.

"The lack of guidance on managing osteoporosis in CKD is shared between the nephrology community and drug regulatory agencies," the editorialists argued. "The broad range of anti-fracture medications being used in patients and the emerging postmarketing adverse event data should prompt medical societies, in conjunction with the ... FDA, to produce relevant guidance on management strategies, including restrictions on drug class usage if warranted by drug safety profiles."

The FDA had issued a safety alert back in November 2022 over denosumab's potential hypocalcemia risk in dialysis-dependent women. In that safety alert, the agency referred to interim results from maker Amgen's ongoing safety study of denosumab, which suggested an increased risk of hypocalcemia in patients with advanced kidney disease. That safety study -- required upon denosumab's initial approval -- was conducted in men and postmenopausal women with osteoporosis.

Bird's group looked at Medicare data on women 65 and older who initiated treatment with denosumab 60 mg (n=1,523) or oral bisphosphonates (n=1,281) including alendronate (Fosamax), risedronate (Actonel, Atelvia), or ibandronate (Boniva) from 2013 through 2020. All women were undergoing long-term hemodialysis or peritoneal dialysis and had a diagnosis of osteoporosis or were receiving treatment for low bone mass after therapy with aromatase inhibitors, gonadotropin-releasing hormone agonists, or high-intensity glucocorticoids. Nearly all had osteoporosis and hyperparathyroidism.

The vast majority of these drugs were prescribed by primary care clinicians, followed by endocrinologists and rheumatologists. Less than 3% of scripts were written by nephrologists.

Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis, while very severe hypocalcemia was considered a serum calcium below 6.5 mg/dL (1.63 mmol/L) or emergent care. Almost all severe hypocalcemia cases were identified based on albumin-corrected serum calcium levels rather than based on emergency department or hospital diagnosis.

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