The Efficacy and Safety of Bisphosphonate Therapy for Osteopenia/Osteoporosis in Patients With Chronic Kidney Disease: A Systematic Review and Individual Patient-Level Meta-Analysis of Placebo-Controlled Randomized Trials.

Abstract

Background: The efficacy and safety of bisphosphonate therapy for the treatment of osteoporosis and osteopenia in the setting of chronic kidney disease (CKD) is unclear.

Objective: To determine the effect of bisphosphonate therapy on fractures, bone mineral density (BMD), and adverse events in adults across the spectrum of CKD and dialysis.

Design: Systematic review and individual patient-level meta-analysis.

Setting: Searches of Ageline, CINAHL, the Cochrane Library, EMBASE, and Medline from inception to August 25, 2016, supplemented with manual screening and clinicalstudydatarequest.com. Authors were contacted for individual patient-level data.

Patients: Randomized, placebo-controlled trials with 100 or more participants that evaluated the treatment of primary osteoporosis/osteopenia in adult men and women with bisphosphonate therapy.

Measurements: Study characteristics, quality, and data were assessed independently by 2 reviewers. Outcome measures were fractures, BMD, and adverse events including decline in estimated glomerular filtration rate (eGFR) and hypocalcemia (calcium <2.00 mmol/L).

Methods: Single-stage individual patient-level meta-analysis.

Results: Of 39 eligible studies, individual patient-level data was available for 7 studies, all of which were studies of ibandronate. Of 7428 participants (5010 ibandronate, 2418 placebo), 100% were female, 98.6% were white, the mean body mass index was 25.7 kg/m² (SD 3.9), 18.9% were smokers and there were 740 fracture events. The mean eGFR was 69.1 mL/min/1.73 m² (SD 15.9) including 14.5%, 54.9%, 27.5%, 3.0%, and 0.2% stages G1, G2, G3A, G3B, and G4 CKD. Ibandronate increased hip and lumbar spine BMD and decreased the risk of fracture in the overall population (hazard ratio (HR) 0.871, 95% confidence interval (CI) 0.746, 1.018) but in patients with stage G3B CKD, it increased the risk of fracture (HR 3.862, 95% CI 1.156, 12.903). Ibandronate did not impact eGFR over 12 months but increased the risk of hypocalcemia (HR 1.324, 95% CI 1.056, 1.660) with no evidence of any effect modification by CKD stage (all tests of interaction p > 0.05).

Limitations: Clinically significant heterogeneity among studies, lack of long-term follow-up and bone biopsy results, limited representation of stage G4 and G5 CKD patients.

Conclusions: Chronic kidney disease potentially modifies the efficacy but not the safety of bisphosphonate therapy in osteopenia and osteoporosis.

Registration: PROSPERO CRD42020145613.