FDA adds boxed warning of increased severe hypocalcemia risk for denosumab
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Key takeaways:
- The FDA issued a boxed warning stating denosumab increases severe hypocalcemia risk for adults with advanced CKD.
- Incidence rates of severe hypocalcemia are higher for denosumab vs. oral bisphosphonates.
The FDA has added a boxed warning for denosumab to advise patients with advanced chronic kidney disease of an increased risk for severe hypocalcemia, according to an FDA drug safety communication.
On Jan. 19, the FDA said it had concluded that denosumab (Prolia, Amgen) increases the risk for severe hypocalcemia for people with advanced CKD, particularly those on dialysis. The announcement came less than 2 months after the agency announced in November that it would be investigating the risk for severe hypocalcemia among people receiving denosumab. The drug safety communication was issued after the publication of a study in JAMA that found an increased severe hypocalcemia risk among older women with advanced CKD initiating denosumab.
“Based on a completed U.S. FDA review of available information, we have concluded that the osteoporosis medicine Prolia increases the risk of severe hypocalcemia, very low blood calcium levels, in patients with advanced CKD, particularly patients on dialysis,” the FDA stated in the drug safety communication. “Severe hypocalcemia appears to be more common in patients with CKD who also have a condition known as mineral and bone disorder. In patients with advanced CKD taking Prolia, severe hypocalcemia resulted in serious harm, including hospitalization, life-threatening events and death. As a result, we are revising the Prolia prescribing information to include a new boxed warning, FDA’s most prominent warning, communicating this increased risk.”
Severe hypocalcemia risk with denosumab
In the JAMA study, researchers reviewed data from Medicare beneficiaries who were women aged 65 years and older receiving ongoing dialysis who initiated treatment with either 60 mg denosumab or an oral bisphosphonate between August 2013 and August 2020. Women who were enrolled in Medicare Parts A, B and D for at least 15 months continuously, had at least two laboratory values available in the three prior months and had an albumin-corrected serum calcium level of at least 7.5 mg/dL at treatment initiation were included. Severe hypocalcemia was defined as a serum calcium level of less than 7.5 mg/dL or a hospital or emergency department diagnosis of hypocalcemia. Analysis was limited to the first 12 weeks of treatment.
There were 1,523 women receiving denosumab (mean age, 74.5 years) and 1,281 receiving oral bisphosphonates (mean age, 73.8 years) in the study. Of the oral bisphosphonate group, 91.8% were receiving alendronate. The proportion of women with osteoporosis was 98.4% in the denosumab group and 97.8% in the bisphosphonate group. Median total serum calcium levels were similar between the groups at baseline.
After treatment initiation, women in the denosumab group had a sharp drop in median serum calcium levels that remained below baseline for 4 months. Levels reached as low as 4.7 mg/dL for denosumab users. The oral bisphosphonate group had no change in levels.
In unweighted data, severe hypocalcemia occurred in 39.9% of the denosumab group and 1.8% of the bisphosphonate group. The weighted cumulative incidence of severe hypocalcemia reached 41.1% in the denosumab group vs. 2% in the oral bisphosphonate group at 12 weeks. Very severe hypocalcemia occurred in 10.9% of the denosumab group vs. 0.4% of the oral bisphosphonate group at 12 weeks.
Among the denosumab group, women who had a serum calcium level of 7.5 mg/dL to 8.4 mg/dL at baseline had a higher incidence of severe hypocalcemia than those with a serum calcium of 8.5 mg/dL or higher at baseline (62.9% vs. 38%).
“Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring,” Steven T. Bird, PhD, a pharmacoepidemiologist in the office of pharmacovigilance and epidemiology, center for drug evaluation and research at the FDA, and colleagues wrote.
Closely monitor calcium levels with denosumab
In the drug safety communication, the FDA advised patients considering denosumab for osteoporosis treatment to discuss their kidney function and severe hypocalcemia risk with their provider. Those already taking denosumab are advised to maintain adequate calcium and vitamin D intake while receiving the medication. Adults with advanced CKD, especially those on dialysis, should frequently monitor their calcium level, especially for the first 2 to 10 weeks after each denosumab injection. Adults receiving denosumab should not stop taking the drug without talking with their provider. Patients should advise their provider if they have symptoms suggestive of hypocalcemia, including confusion, seizures, irregular heart rhythm, fainting, face twitching, uncontrolled muscle spasms or weakness, tingling, or numbness in parts of the body.
The FDA advises that before prescribing denosumab, providers assess the patient’s kidney function. The risk for severe hypocalcemia should be considered in the context of other available treatments for osteoporosis for people with advanced CKD. If denosumab is still prescribed for adults with advanced CKD on dialysis, calcium blood levels should be checked, and patients should be assessed for CKD mineral and bone disorder.
Reference:
Bird ST, et al. JAMA. 2024;doi:10.1001/jama.2023.28239.
Perspective
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Rachel Pessah-Pollack, MD, FACE
Denosumab is a potent inhibitor of bone turnover. The newly issued boxed warning regarding an increased risk for severe hypocalcemia with denosumab in patients with advanced CKD, especially those on dialysis, is very important, albeit a known entity to those who treat osteoporosis. The warning comes after a review of data from a retrospective cohort study by Bird and colleagues highlighting the strikingly increased risk for severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older on denosumab compared with oral bisphosphonates (treatment-weighted cumulative incidence of severe hypocalcemia 41.1% with denosumab vs. 2% with oral bisphosphonates and of very severe hypocalcemia 10.9% vs. 0.4%, respectively).
In patients with normal renal function adequately supplemented with calcium and vitamin D, hypocalcemia is a rare occurrence. However, in patients with conditions predisposing to hypocalcemia, such as CKD, hypoparathyroidism and malabsorption syndromes, the risk for severely low calcium exists and denosumab should not be given until hypocalcemia is corrected. In fact, there are an increasing number of case reports utilizing denosumab to manage hypercalcemia of malignancy (particularly if there is persistent hypercalcemia despite bisphosphonates).
It is important to note that patients with advanced CKD have a higher risk for fractures compared with the general population, and our options for bone treatments are limited. Compared with bisphosphonates, which are cleared by the kidney, denosumab is not cleared by the kidney and can be used with a creatinine clearance below 35 mL/min. However, the serious hypocalcemia that can be seen in dialysis patients warrants attention and monitoring, and the FDA boxed warning brings this important potential complication to a greater public awareness. It is vital to monitor calcium levels in this population both before and after treatment to tailor denosumab to the carefully selected CKD patient, with a goal of increasing bone mineral density, reducing the risk for fractures and minimizing complications such as severe hypocalcemia.
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FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease. Published Jan. 19, 2024. Accessed Jan. 19, 2024.
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