Denosumab increases risk of severe hypocalcemia in women with osteoporosis and chronic kidney disease

1. In this target trial emulation study, denosumab was found to increase the risk of hypocalcemia requiring emergency treatment as compared with bisphosphonates among women with osteoporosis in the setting of chronic kidney disease (CKD).

2. The risk of developing emergently treated hypocalcemia with denosumab increased with worsening CKD stage, particularly in patients with CKD-mineral and bone disorder.

Evidence Rating Level: 2 (Good)

Study Rundown: While oral bisphosphonates and injectable therapies such as denosumab are both commonly used in the treatment of osteoporosis, selection of an agent can be challenging in patients with comorbid chronic kidney disease (CKD). Those with CKD-mineral and bone disorder (CKD-MBD) who typically rely heavily on calcium resorption from the bone may have a higher risk of significant hypocalcemia when treated with potent osteoclast inhibitors such as denosumab. This study aimed to examine the risk of emergently treated hypocalcemia associated with denosumab use in patients with different stages of CKD as well as CKD-MBD. Among women who were given denosumab, the risk of developing emergently treated hypoglycemia was over ten times higher than those given oral bisphosphonates, and nearly five times higher than with IV bisphosphonates. The relative risk appeared to increase with worsening CKD stage, with significant increases particularly among CKD stages 4 and 5 as well as dialysis-dependent CKD. CKD-MBD also appeared to be a significant risk modifier; among patients with advanced CKD, those who also had CKD-MBD had an even greater risk for emergently treated hypocalcemia. Notably, nearly five percent of patients who were given denosumab and required emergent treated for hypocalcemia died of seizures or cardiac arrhythmias, while no deaths were reported in the oral or IV bisphosphonates groups. The generalizability of the study was limited by its lack of male patients and non-Medicare patients, as well as a lack of eGFR levels to verify CKD stages. Nevertheless, this study highlighted the need to account for chronic kidney disease severity when managing treatment for osteoporosis.

Click to read the study in AIM

Relevant Reading: Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients

In-Depth [retrospective cohort]: This target trial emulation aimed to assess the risk of severe hypocalcemia among patients with all stages of CKD, including with CKD-MBD, associated with denosumab, oral bisphosphonates, and IV bisphosphonates. Inclusion criteria included female sex, age 65 years or older, and receiving first-line treatment for osteoporosis, while exclusion criteria included hospitalization, hospice care, other other conditions that might disrupt calcium levels, and recent emergent treatment of hypocalcemia. CKD staging was based on diagnosis codes at baseline; CKD-MBD status was based on diagnosis codes, prescriptions, various laboratory testing abnormalities, and CKD stage 4 or 5. The primary outcome was emergently treated hypocalcemia, defined as diagnosis of hypocalcemia following admission to a hospital or emergency department. A total of 361,453 participants received denosumab, 829,044 oral bisphosphonates, and 160,413 IV bisphosphonates. In the denosumab group, 201 (0.06%) participants developed emergently treated hypocalcemia, compared with 46 (0.01%) participants treated with IV bisphosphonates and 16 (0.004%) participants treated with oral bisphosphonates. This corresponded to a 13.0-fold (95% CI, 7.8 to 27.1) increase in risk of emergently treated hypocalcemia compared with oral bisphosphonates, and a 4.3-fold (95% CI, 2.4 to 9.4) increase compared with IV bisphosphonates. Risk of emergently treated hypocalcemia with denosumab compared with oral bisphosphonates was higher among non-dialysis-dependent (NDD) patients with CKD stages 4 and 5 (risk difference [RD], 0.54%; risk ratio [RR], 17.5 [95% CI, 6.4 to 47.7]) as well as dialysis-dependent patients (RD, 3.01%; RR, 109.8 [95% CI, 6.8 to 1777.9]). Risk of emergently treated hypocalcemia with denosumab compared with IV bisphosphonates was also higher among NDD patients with CKD stages 4 and 5 (RD, 0.46%; RR, 5.2 [95% CI, 2.9 to 9.5]). In patients with CKD stages 4 and 5, the RD and RR of emergently treated hypocalcemia for denosumab compared with oral bisphosphonates were larger among patients with CKD-MBD (RD, 1.51%; RR, 59.0 [95% CI, 14.1 to 247.5]) than among patients without CKD-MBD (RD, 0.19%; RR, 5.8 [95% CI, 1.6 to 21.0]). Within 30 days after emergent treatment of hyperglycemia, 16 (8.0%) patients who had been given denosumab were diagnosed with seizures or cardiac arrhythmias, and 9 (4.5%) patients died; no participants in the oral bisphosphonate and IV bisphosphonate groups died. Overall, this study showed an association between denosumab treatment for osteoporosis and increased risk of emergent treatment hypocalcemia among women with CKD.

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