Risks of Hypocalcemia and Other Bone Mineral Disorders for Denosumab Versus Zoledronate Across the Spectrum of Kidney...

Denosumab, an osteoporosis medication, may induce hypocalcemia, secondary hyperparathyroidism (SHPT), and hypophosphatemia. We studied these risks compared with zoledronate and whether the risks differ based on underlying kidney function.

Observational study, new-user design with active comparator.

Patients aged 50 year or older initiating denosumab (n = 5,085) or zoledronate (n = 3,599) in Stockholm, Sweden (2011-2021).

Denosumab or zoledronate initiation.

Hypocalcemia, with secondary outcomes of SHPT and hypophosphatemia assessed within 180 days of dispensing of study medications.

Cox regression to estimate hazard ratios (HRs), Aalen-Johansen estimators to compute absolute risks (ARs) and risk differences (RDs), and splines to explore effect modification by baseline estimated glomerular filtration rate (eGFR).

Twenty-five percent of the study population had eGFR < 60 mL/min/1.73 m² (chronic kidney disease [CKD] stage 3a [15%] and 3b [8%]). Compared with zoledronate, denosumab initiation was associated with higher rates of hypocalcemia (HR, 2.10 [95% CI, 1.28-4.33]; RD, 0.72% [95% CI, 0.26-1.18]), SHPT (HR, 2.85 [95% CI, 1.94-5.48]; RD, 1.33% [95% CI, 0.91-1.85]), and hypophosphatemia (HR, 1.96 [95% CI, 1.30-3.38]; RD, 0.85% [95% CI, 0.33-1.38]), which occurred mainly within the first 2 weeks of treatment. Adverse event rates were greater with lower kidney function and mainly limited to people with eGFR < 60 mL/min/1.73 m². The denosumab-associated absolute risk differences for hypocalcemia (RD, 2.12% versus 0.19%; P for interaction = 0.04) and SHPT (RD, 4.84% versus 0.03%; P for interaction < 0.001) were greater in patients with eGFR < 60 versus ≥60 mL/min/1.73 m². For hypophosphatemia, the RDs were numerically higher, but no multiplicative interaction was observed across lower eGFR strata (P for interaction = 0.1). The results were similar when restricting previous users of oral bisphosphonates, when requiring sustained abnormal laboratory values, and across different testing rate scenarios.

Residual confounding inherent to observational studies and lack of generalizability to other populations.

Compared with zoledronate, denosumab was associated with higher risks of hypocalcemia, SHPT, and hypophosphatemia, particularly among users with moderate-to-advanced CKD, highlighting the need for careful monitoring of these parameters, especially immediately after treatment initiation.

Denosumab is a drug used to prevent fractures, but it can affect calcium, phosphate, and parathyroid hormone levels in the blood. We studied adults aged 50 years or older in Stockholm, Sweden, to examine whether these risks differ by kidney function. Compared with zoledronate, denosumab was associated with higher risks of low calcium, low phosphate, and high parathyroid hormone levels. These adverse events occurred mainly within the first 2 weeks after starting treatment and were largely limited to people with moderate to advanced chronic kidney disease. Our findings suggest that patients with chronic kidney disease treated with denosumab should receive careful monitoring of mineral and hormone levels, especially at treatment initiation.