medwireNews: Women with worsening chronic kidney disease (CKD) have an increased risk for emergently treated hypocalcemia after treatment with the osteoporosis drug denosumab, a study suggests.
Among women beginning osteoporosis treatments, those taking denosumab (n=361,453) saw a higher risk for hypocalcemia requiring admission to the emergency department or hospital after 12 weeks than those given intravenous (iv) bisphosphonates (n=353,510) or oral bisphosphonates (n=353,510), with corresponding rates of 0.06%, 0.01%, and 0.004%.
There was also a significant link between the stage of CKD and the incidence of denosumab-induced emergent hypocalcemia. In particular, denosumab treatment relative to oral bisphosphonates showed risk ratios ranging from 5.9 among patients without CKD or CKD stage 1 and 2 to 109.8 among dialysis-dependent patients and 59.0 among those with CKD stage 4 to 5 with CKD–mineral and bone disorder (CKD–MBD), a common complication of advanced CKD.
“Osteoporosis and CKD are common comorbidities, increasing the relevance of this study question to the approximately 3 million postmenopausal women in the United States with osteoporosis and CKD,” write Steven Bird (US Food and Drug Administration, Silver Spring, Maryland, USA) and colleagues in the Annals of Internal Medicine.
Until now, data on the effectiveness of antiresorptive treatments have been “very limited in patients with advanced CKD,” the researchers say. While injectable antiresorptive therapies such as denosumab may be more convenient than other treatments, they also have potential for a greater hypocalcemic effect, they add.
The investigators emulated a target clinical trial using observational data from Medicare for female outpatients aged 65 years and older who were beginning first-line treatment for osteoporosis and had at least 15 months of healthcare use at baseline.
The stages of CKD ranged from stage 1, with an estimated glomerular filtration rate (eGFR) of 90 mL/min per 1.73 m² or more, to stage 5 with an eGFR of less than 15 mL/min per 1.73 m². Patients with stage 1 and 2 met additional criteria for CKD, such as albuminuria, urinary sediment abnormalities, or imaging.
The patient groups received either 60 mg of denosumab, oral bisphosphonates, such as alendronate, ibandronate, and risedronate, or iv bisphosphonates, including zoledronic acid and ibandronate.
The patients were aged an average of 77 years and 90% were White, 97% had osteoporosis and around 87–88% had either no CKD or stage 1 or 2 disease.
The incidence of emergently treated hypocalcemia in the denosumab group peaked at week 2 and remained higher than for the other treatment groups before returning to baseline at week 10. This timing “corresponds to the expected nadir for total serum calcium after denosumab administration,” the investigators add.
By contrast, the incidence of emergently treated hypocalcemia with iv bisphosphonates increased over the first 2 weeks only and did not change from baseline for those given oral therapy.
Patients given denosumab also saw a 13.0-fold higher cumulative risk of emergently treated hypocalcemia compared with those on oral bisphosphonates and a 4.3 increase compared with the iv bisphosphonates group. Meanwhile, iv bisphosphonates were associated with a threefold increased cumulative risk relative to their oral counterparts.
A total of 42.8% of non-dialysis-dependent participants with stages 4 and 5 CKD and 98.9% of dialysis-dependent patients had CKD-MBD.
Non-dialysis-dependent patients with CKD stages 4–5 and CKD–MBD had a 28.3-fold higher risk for emergently treated hypocalcemia with denosumab than with oral bisphosphonates (1.01 vs 0.03%). And this risk was 59.0-fold greater among dialysis-dependent patients with CKD–MBD (1.53 vs 0.02%).
A similar trend was evident when comparing denosumab with iv bisphosphonates, with risk ratios of 1.8, 52.9, and 5.2 among patients without CKD or CKD stage 1 and 2, those with CKD stage 3, and those with stage 4 or 5 CKD with CKD-MBD, respectively.
A total of 8.0% of patients given denosumab had a diagnosis of seizure or cardiac arrhythmia within 30 days of emergent treatment of hypocalcemia and 4.5% died. By contrast, there were no deaths seen after use of iv or oral bisphosphonates.
“Diagnosis and management of skeletal fragility in these high-risk patients is complex, requiring careful patient selection, adequate supplementation with calcium and vitamin D, and frequent monitoring of serum calcium under supervision of a clinician with expert knowledge and experience treating CKD-MBD,” write Bird and colleagues.
Nevertheless, the authors acknowledge limitations in the study, including that the outcome “captures emergently treated hypocalcemia but does not ascertain cases treated in nonemergent care settings or undiagnosed cases among patients whose serum calcium is not routinely monitored.”
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