Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies

Abstract

The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29-55%, I = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (≥ 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, - 0.30 to 0.69 mg/dL) and - 0.10 mg/dL (95% CI, - 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of - 0.65 (95% CI - 1.13 to - 0.16) and - 1.89 (95% CI - 3.44 to - 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available.

Contrasting PTH Response of Denosumab Use in Dialysis Patients: A Report of 2 Cases

“…The authors stated that the decrease in PTH levels may be a result of supplements initiation (calcium and active vitamin D) after initial PTH increase within the first month. Consequently, post-treatment PTH levels were significantly lower than the baseline PTH levels [6].…”

“…Lastly, a recent meta-analysis study by Thongprayoon et al used six observational studies to determine the incidence of hypocalcemia and the effects on BMD after denosumab use in ESRD patients [6]. The pooled estimated hypocalcemia incident was 42% (95% CI 29%-55%, I2 = 0%) after using denosumab in this special population.…”

“…The U.S. Food and Drug Administration approved denosumab as an antiresorptive therapy in patients with osteoporosis and renal impairment [4]. Denosumab-associated severe hypocalcemia is a common adverse effect in the general population as well as patients with advanced CKD [5][6][7][8][9]. As a result, an increase in iPTH level is also commonly seen in order to compensate for a decrease in calcium [10,11].…”

Risk of hip fracture in patients on hemodialysis versus peritoneal dialysis: A meta‐analysis of observational studies

“…Lastly, although our studies demonstrated an association between HD status and the higher risk of hip fracture, data on BMD among ESRD patients in included studies were limited. In addition, current evidence on the benefits of interventions to improve BMD on the improvement of fracture rates in ESRD patients remains controversial . However, the findings of our study highlight the need for future studies on the prevention of hip fractures among ESRD patients undergoing HD.…”

Innovative rheumatologische und osteologische Medikation im Kontext der chronischen Niereninsuffizienz – Was ist möglich?

“…Beim Einsatz in einer high turnover Situation ist unsere derzeitige Kenntnis über die Dauer der Therapie mit der Gefahr der Entwicklung eines low turnovers in der Langzeitanwendung einerseits und der Gefahr einer Steigerung des Knochenmassenverlustes nach dem Abschluss der Therapie andererseits sehr begrenzt [41,42]. Zudem wurde die Induktion einer schweren Hypocalcämie nach der Denosumab Applikation bei einer chronischen Niereninsuffizienz im Stadium CKD G4 und G5 wiederholt beschrieben [43,44].…”