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January 23, 2024
On Jan. 19, 2024, the Food and Drug Administration (FDA) announced that a boxed warning — the agency’s most prominent warning — is now required in the prescribing information for the osteoporosis drug denosumab (PROLIA). Denosumab is a monoclonal antibody that is administered by subcutaneous injection every six months. The warning is to alert patients and clinicians that denosumab increases the risk of severe hypocalcemia (low blood calcium) in patients with advanced chronic kidney disease, which can lead to hospitalization and death.[1] Patients on dialysis and those with mineral and bone disorders related to chronic kidney disease are especially at risk. Severe hypocalcemia can be asymptomatic or may present with a variety of serious symptoms, as discussed at the end of this alert.
The decision to add a boxed warning follows an FDA investigation[2] of an increased risk of severe hypocalcemia in patients with advanced kidney disease who are taking denosumab, as discussed in the April 2023 issue of Worst Pills, Best Pills News.[3] Public Citizen's Health Research Group has designated denosumab as Do Not Use because its serious risks (including hypersensitivity reactions, increased risk of serious infections, adverse skin reactions and risk of multiple vertebral fractures after stopping the drug) outweigh its benefits.[4]
The boxed warning is based on the agency’s review of adverse-event reports about denosumab as well as the results of two studies, both of female Medicare patients.[5] The studies found that patients with advanced kidney disease taking denosumab have a significantly increased risk of severe hypocalcemia compared with patients who received bisphosphonates, another class of osteoporosis drugs, including alendronate (BINOSTO, FOSAMAX), ibandronate (generic only) and risedronate (ACTONEL, ATELVIA).
One study of about 2,800 women aged 65 years or older on dialysis found that after 12 weeks of treatment, 41% of subjects who had received denosumab for osteoporosis developed severe hypocalcemia compared with only 2% of those treated with oral bisphosphonates. Although none of the patients in the oral-bisphosphonates group required hospitalization, 11% of denosumab-treated patients with severe hypocalcemia were hospitalized, 5% developed arrhythmias or seizures and 1% died.[6] The second study included over 1.6 million women with chronic kidney disease, including patients with chronic kidney disease and mineral and bone disorders, and it also found that a higher proportion of subjects who received denosumab (242) required treatment for severe hypocalcemia than those who were treated with intravenous (57) or oral (20) bisphosphonates. Among denosumab-treated women with severe hypocalcemia, 9% developed arrhythmias or seizures and 3% died.[7]
In 2010, the FDA approved denosumab to treat osteoporosis in postmenopausal women who are at high risk of fracture.[8] Subsequently, the agency approved the drug for other uses: to increase bone mass in men with osteoporosis, to treat men receiving androgen deprivation therapy for prostate cancer, to treat women at high risk of fracture receiving aromatase inhibitor therapy for breast cancer and to treat men and women with osteoporosis related to the use of glucocorticoids.
If you are taking denosumab for osteoporosis treatment, discuss with your clinician whether you are at increased risk of hypocalcemia, and if so, whether the treatment should be continued. If you also have advanced kidney disease, discuss with your clinician plans for frequent monitoring of calcium in the blood, as well as alternative treatments for osteoporosis. If you also have bone and mineral disorder related to chronic kidney disease, be aware that this condition markedly increases your risk of hypocalcemia.
If you are taking denosumab, talk with your clinician about how to maintain adequate calcium and vitamin D intake. If you are taking denosumab, and especially if you have advanced kidney disease, tell your clinician right away if you experience any symptoms of hypocalcemia, including unusual tingling or numbness in the hands, arms, legs or feet; painful muscle spasms or cramps; confusion; fainting; weakness; seizures; or irregular heart rhythm.
If you are considering denosumab for osteoporosis treatment, talk to your clinician about your kidney function, the risk of severe hypocalcemia and alternative treatments.
Do not stop taking denosumab without consulting your clinician, as a sudden discontinuation can lead to serious adverse effects, such as increasing the risk of bone fracture.
Report any adverse effects caused by denosumab to the FDA’s MedWatch program by calling 1-888-463-6332 or going to https://www.fda.gov/MedWatch.
To see the FDA’s warning, visit the following link: https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery.
References
[1] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed January 22, 2024.
[2] Food and Drug Administration. FDA investigating risk of severe hypocalcemia in patients on dialysis receiving osteoporosis medicine prolia (denosumab). November 22, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-investigating-risk-severe-hypocalcemia-patients-dialysis-receiving-osteoporosis-medicine-prolia. Accessed January 22, 2024.
[3] News Brief: FDA warns that osteoporosis drug may be linked to severe hypocalcemia in certain patients. Worst Pills, Best Pills News. April 2023. https://www.worstpills.org/newsletters/view/1529. Accessed January 22, 2024.
[4] Review of the osteoporosis drug denosumab (PROLIA). Worst Pills, Best Pills News. April 2019. https://www.worstpills.org/newsletters/view/1256. Accessed January 22, 2024.
[5] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed January 22, 2024.
[6] Bird ST, Smith ER, Gelperin K, et al. Severe hypocalcemia with denosumab among older female dialysis-dependent patients. JAMA. Published online January 19, 2024.
[7] Food and Drug Administration. FDA adds boxed warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine prolia (denosumab). January 19, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease?utm_medium=email&utm_source=govdelivery. Accessed January 22, 2024.
[8] Amgen. Label: denosumab (PROLIA). January 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125320s216lbl.pdf. Accessed January 22, 2024.
