Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients

Abstract

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility.

Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis.

Design, setting, and participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database.

Exposures: Denosumab, 60 mg, or oral bisphosphonates.

Main outcomes and measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks.

Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]).

Conclusions and relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. 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.

Figure 1.. Total Albumin-Corrected Serum Calcium Levels 6 Months Before and After Initiation of Denosumab or Oral Bisphosphonate Treatment

Median (horizontal lines) and IQR (box tops and bottoms) for total albumin-corrected serum calcium levels each month, with whiskers set at 1.5 times the IQR and circles indicating outside values. Patients with no record of a calcium measurement in a given interval were omitted from that interval. If patients had 1 or more records in the interval, the lower value was used. The oral bisphosphonate cohort was weighted using an inverse probability of treatment weights approach, wherein weights were calculated from a propensity score using covariates listed in Table 1 and eTable 1 in Supplement 1; see text for details.

Figure 2.. Severe Hypocalcemia Incidence Among Patients Treated With Denosumab and Oral Bisphosphonates

In panel A, whiskers represent 95% CIs. Severe hypocalcemia was defined as a serum calcium level below 7.5 mg/dL (1.88 mmol/L) or receipt of emergent care (primary hospital or emergency department admission diagnosis). In both plots, data are from a weighted oral bisphosphonate cohort, formed using the inverse probability of treatment weights approach, wherein weights were calculated from a propensity score using covariates listed in Table 1 and eTable 1 in Supplement 1; see text for details. A total of 6.6% of denosumab-treated patients were censored (for death, 2.4%; end of database, 2.4%; loss to follow-up, 1.1%; and kidney transplant, 0.7%); the remainder had a study outcome (39.9%) or reached the end of the 12-week study (53.7%). A total of 8% of weighted oral bisphosphonate users were censored (for death, 3.4%; end of database, 2.9%; loss to follow-up, 1.5%; and kidney transplant, 0.2%); the remainder had a study outcome (1.9%) or reached the end of the 12-week study (90.0%).

Figure 3.. Lowest Total Albumin-Corrected Serum Calcium Level

Data shown are for 12-week follow-up and based on the weighted oral bisphosphonate cohort, formed using the inverse probability of treatment weights approach, wherein weights were calculated from a propensity score using covariates in Table 1 and eTable 1 in Supplement 1; see text for details. Some patients in the denosumab cohort (3.0% [46 of 1523]) and oral bisphosphonate cohort (3.2% [48 of 1501]) were censored or ended follow-up before a serum calcium level was recorded. All severe hypocalcemia outcomes with oral bisphosphonates (100% [29 of 29]) and nearly all severe hypocalcemia outcomes with denosumab (97.5% [592 of 607]) were based on serum calcium levels rather than hospital or emergency department diagnosis of hypocalcemia.