Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are an important therapeutic class in chronic kidney disease (CKD). Despite renal and cardiovascular benefits shown in many trials, concerns have been raised regarding possible adverse effects on bone metabolism and skeletal safety. This systematic review aimed to evaluate available randomized controlled trials (RCTs) and observational cohort studies addressing skeletal outcomes and mineral metabolism in patients with CKD.
The authors performed a systematic review that included RCTs and observational cohort studies. Extracted information encompassed study design, population characteristics, baseline kidney function, bone-related comorbidities, and outcomes relevant to bone health: osteoporosis diagnoses, fractures, falls, amputations, and bone mineral markers. Risk of bias was assessed according to the type of included study. The review synthesized reported results without pooling data into a meta-analysis in the abstracted summary.
The literature assessed in the review primarily reported data for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. A substantial portion of the evidence base derived from studies originally designed for patients with type 2 diabetes; many enrolled participants with early-stage CKD rather than moderate-to-advanced CKD. Details on the exact distribution of CKD stages across included studies were summarized by the authors but are not fully detailed in the abstract.
Across the included studies, outcomes pertinent to skeletal safety were variably reported. One randomized controlled trial and one cohort study identified a statistically significant increase in risk of bone fracture and amputation. However, this signal was not consistent: subsequent cohort studies and other randomized trials generally did not show significant differences in fracture or amputation rates between SGLT2i and comparator groups. Reporting practices for fractures, falls, and amputation events were inconsistent across the literature, limiting the ability to draw definitive conclusions about absolute or relative risk.
Among the reviewed literature, at least one study suggested that SGLT2i may have favorable effects on markers of CKD–mineral and bone disorder (CKD–MBD). That study reported reduced risks of hyperphosphatemia, hypocalcemia, elevated parathyroid hormone, and low vitamin D levels with SGLT2i exposure. The abstract does not provide numerical effect sizes or details about which SGLT2i produced these findings or the CKD stages of participants in that study.
The authors highlighted important limitations in the evidence base. Reporting of bone-related outcomes across trials and cohorts was inconsistent, which complicates synthesis. Much of the available evidence comes from trials enrolling patients with type 2 diabetes and earlier stages of CKD, so findings may not generalize to populations with moderate-to-advanced CKD. The inconsistent detection of fracture and amputation risk—significant in a small number of studies but absent in most others—underscores uncertainty. The review notes that long-term outcomes specifically and prospectively defined for skeletal safety are lacking.
The systematic review concludes that, overall, SGLT2i demonstrated a possibly reassuring skeletal safety profile in patients with CKD. Initial signals of increased fracture risk have not been consistently reproduced across the literature. Nonetheless, evidence remains limited for patients with moderate-to-advanced CKD, and the authors call for long-term, prospectively defined skeletal outcome studies to confirm safety and to clarify whether any class effects exist. Such studies should use consistent definitions and systematic ascertainment of fractures, falls, amputations, and mineral metabolism markers.
The authors declared no conflicts of interest related to this work.
Notes on evidence gaps
The abstract emphasizes that many included studies were not primarily designed to examine bone outcomes, and that inconsistent outcome reporting and limited representation of advanced CKD stages are important gaps. The review identifies a need for rigorously designed trials or prospective observational studies with standardized skeletal endpoints and extended follow-up in CKD populations to resolve remaining uncertainties about SGLT2i and bone health.