SGLT2 Inhibitors and Skeletal Safety in Patients with Chronic Kidney Disease: Key Points from a Systematic Review

The systematic review indicates limited and inconsistent evidence regarding the effects of SGLT2 inhibitors on the skeleton of patients with CKD, with particularly sparse data in severe CKD populations. [1]

Study type: Systematic Review, Journal Article (category: Clinical guideline / high-quality systematic review) Published: Journal of nephrology, 2026-10-10 Source: PubMed public abstract

The systematic review indicates limited and inconsistent evidence regarding the effects of SGLT2 inhibitors on the skeleton of patients with CKD, with particularly sparse data in severe CKD populations. [1]

Why this study matters

Why this topic is of concern

SGLT2 inhibitors are important medications for treating chronic kidney disease (CKD), but there are clinical concerns about whether they affect bone metabolism, fracture risk, or risk of amputation. The systematic review collected randomized controlled trials and observational cohort studies to try to summarize existing evidence on bone-related events (such as osteoporosis, fractures, falls, amputations) and markers of bone metabolism, in order to assess skeletal safety when using SGLT2 inhibitors in patients with CKD. [1]

What the study actually found

Main findings (based on the systematic review abstract)

• Among included studies, one randomized controlled trial and one cohort study reported significantly increased risks of fractures and amputations, but most other subsequent cohort studies and randomized trials did not find significant differences; the results are inconsistent. [1]
• Reporting of bone-related outcomes in the literature was inconsistent, making direct aggregation and comparison difficult. [1]
• A substantial proportion of the evidence comes from studies focused on type 2 diabetes, and these studies mainly involved early-stage CKD populations, meaning data for moderate-to-advanced CKD are limited. [1]
• One study reported that SGLT2 inhibitors might be favorable for adjusting some biochemical markers of CKD-related mineral and bone disorder (CKD-MBD), reporting lower risks of hyperphosphatemia, hypocalcemia, elevated PTH, and low vitamin D; however, this is an observation from a single study and requires further validation. [1]
• The review mainly covered the drugs empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. [1]

Possible implications for patients with CKD, on dialysis, or with transplantation

Interpretation for patients and caregivers

• Current evidence leans toward “possibly reassuring skeletal safety,” but this is not a definitive conclusion; studies reporting increased risks of fractures or amputations exist, and results have not been consistently reproduced across studies. [1]
• In early-stage CKD populations, most studies did not show significant differences, but for patients with moderate-to-advanced CKD, evidence remains insufficient and safety cannot be assumed.
• The above are observational associations and cannot be directly interpreted as causal; results from a single study do not equal consensus in the medical community. [1]

Limitations of current research

Study and manuscript limitations

• Definitions and reporting of bone-related events varied across included studies, increasing uncertainty in the overall conclusions. [1]
• Much of the data derive from trials primarily focused on diabetes and involve early CKD stages, limiting generalizability to moderate-to-severe CKD. [1]
• Whether there is a class effect (differences between various SGLT2 inhibitors) is still unclear. [1]
• This article is based on a PubMed public abstract and the full texts were not reviewed; therefore details (such as individual study sample sizes, follow-up durations, and risk-of-bias assessments) could not be further verified or supplemented.

What remains uncertain

Unresolved questions (observed associations vs. unproven hypotheses)

• Fracture and amputation risk: some studies observed increased risk, but most did not replicate this, so the association is inconsistent and not an established causal relationship. [1]
• Safety in moderate-to-advanced CKD patients: evidence is insufficient to draw conclusions.
• Long-term skeletal outcomes (multi-year fracture rates, changes in bone mineral density) lack adequate prospective data.
• Whether there are differences between SGLT2 agents with respect to bone metabolism remains unproven.
• There are mechanistic hypotheses (e.g., effects on phosphate, calcium, PTH, vitamin D), but existing clinical human data do not establish direct impacts of these mechanisms on clinical outcomes. [1]

Questions to discuss with your clinical team

• I am taking an SGLT2 inhibitor—does it increase my risk of fractures or amputation? (Study results are inconsistent; discuss individual risk with your treating physician.)
• Is use of SGLT2 inhibitors safe for patients with moderate or advanced CKD? (Current evidence is limited; more dedicated studies are needed.)
• If I have osteoporosis or a history of fractures, should I stop my SGLT2 inhibitor? (This review cannot directly recommend stopping medication; discuss risks and benefits with your care team.)
• Are additional tests needed (such as bone density or serum calcium, phosphate, PTH, vitamin D)? (Assess individual circumstances with your physician to determine necessity.)
• Do different SGLT2 drugs have the same skeletal safety? (Current evidence does not clearly differentiate class effects.)
• Which future study results should alter clinical practice? (Prospective, long-term trials with skeletal outcomes as primary endpoints, especially in moderate-to-advanced CKD populations.)

How to read this study (our interpretation)

This section was written by the Beyond CKD editor — a kidney-transplant recipient with a health-management background, not a physician — using only the PubMed abstract. We have not read the full paper, and no clinician has reviewed this text. It is meant to help you understand the numbers, not to advise treatment.

What the study asked

SGLT2 inhibitors (empagliflozin, dapagliflozin and others) are now core CKD treatment, but early trials raised a signal of more fractures and amputations. This systematic review gathered randomised trials and cohort studies to ask how safe these drugs are for bone in people with CKD.

How to read the results

There is no single pooled number here; the result is directional. One randomised trial and one cohort study did find more fractures and amputations, but later trials and cohorts did not reproduce it and mostly showed no significant difference. One study even suggested SGLT2 inhibitors may improve markers of CKD mineral and bone disorder (lower risk of high phosphate, low calcium, high parathyroid hormone and low vitamin D). When reading evidence like this, the question is not whether any one study found harm but whether the body of evidence points the same way — and it currently leans reassuring, without being settled.

Limitations

Bone outcomes were reported inconsistently, and many studies were never designed to measure fractures. Most evidence comes from people with type 2 diabetes and early-stage CKD; data in moderate to advanced CKD (stages 4–5) are scarce. The review covered empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, and the abstract does not separate them even though the original signal came mainly from canagliflozin.

What it means for readers and people with kidney disease

If you take an SGLT2 inhibitor to protect your kidneys, the overall evidence does not support stopping it out of fear of fractures. If you have stage 4–5 CKD, osteoporosis or frequent falls, the data genuinely are thin and worth discussing. This review does not prove these drugs are good for bone — that was a single-study hint.

How to check further

Ask your doctor: Is my CKD stage within the range where this evidence is reasonably solid? Should I have a bone-density scan? Are my calcium, phosphate and parathyroid hormone levels stable?

Original abstract: PubMed 42301927 (https://pubmed.ncbi.nlm.nih.gov/42301927/). Interpretation last updated 2026-11-06.

References

[1] Cassani de Oliveira M, Rufino L, Mendes Lourenço AL, Corrêa EA, Mac-Way F, Pelepenko LE. Effects of gliflozins on bone health of patients with chronic kidney disease: a systematic review.. Journal of nephrology. 2026. DOI: 10.1093/joneph/aajag035. PMID: 42301927.

Medical disclaimer: This article is for general health education and information only. It does not constitute individual medical diagnosis, treatment advice, or a doctor–patient relationship. Medical research is continually updated, and study findings have their own scope and limitations. Every patient's condition, laboratory values, medications and treatment needs differ. Do not stop or adjust medication doses, change your diet or fluid intake, or alter dialysis or transplant treatment based on this article alone. For any medical questions, please consult your nephrologist or another qualified healthcare professional.

Article created: 2026-11-03 | Original study published: 2026-10-10 | Last checked: 2026-11-03 (source metadata verified with PubMed)