SGLT2 Inhibitors and Fracture Risk: A Review of What We Know

Data from clinical trials suggests increased frequency of bone fractures with SGLT2 inhibitor use.(1) Risk of fractures increases over time. Most patients on SGLT2 inhibitors do not have fractures. Patients with type 2 diabetes may have coexisting bone disease (postmenopausal osteoporosis, renal osteodystrophy, and diabetes-associated bone fragility), making them more susceptible to adverse effects of drugs on bone. Consider: Treatment with rosiglitazone (a thiazolidinedione) over 4 years may also increase the risk of bone fractures.(2)

Fracture risk does not increase during the first year of treatment, but does increase during the second.(3) A pooled analysis of eight clinical trials (mean duration 68 weeks), revealed a 30% increase in bone fractures in patients on canagliflozin. (3) Over 104 weeks, 4% of elderly on canagliflozin 300 mg had fractures, as did 3% on canagliflozin 100mg.(4)

Canagliflozin has been reported to increase bone turnover.(1) After 52 weeks of therapy, decreased bone mineral density in the lumbar spine and total hip was found with canagliflozin 300 mg.(3) Over 104 weeks, significant decreases in bone mineral density of the hip occurred with canagliflozin but not placebo in elderly treated with canagliflozin.(4)

In patients with moderate renal impairment: 9.4% on dapagliflozin 10 mg and 6.0% on 5 mg dapagliflozin had bone fractures at 104 weeks, compared to none in placebo.(5) Not reported to affect bone mineral density or bone turnover in patients with normal to mild renal impairment.(1) Difference between canagliflozin and dapagliflozin may be related to dosage. 300 mg canagliflozin maximally inhibits SGLT2, 10 mg dapagliflozin submaximally inhibits SGLT2. Still unclear whether the bone effects are drug-specific, or related to the SGLT2 inhibitor mechanism Head to head trials are needed.

SGLT2Is increase serum phosphate concentration , most likely due to increased tubular reabsorption of phosphate.(1) Increased serum phosphate increases concentrations of parathyroid hormone (PTH). Sustained increases in PTH increase bone resorption, increasing the risk of fractures.

Increased phosphate either directly increases fibroblast growth factor 23 (FGF23), or decreases. FGF23 perhaps via parathyroid hormone (PTH) (mechanism unknown). FGF23 regulates plasma phosphate concentration. Increased concentrations of FGF23 have been linked to bone disease. Research suggests that SGLT2-Is decrease mean 1,25-dihydroxyvitamin D ( 1,25-(OH)2 vitamin D).(3) Low levels of 1,25-(OH)2 vitamin D could decrease Ca2+ absorption from the gut, impairing bone calcification

Increased serum phosphate increases FGF23 and PTH, leading to phosphaturia. So increases in mean serum phosphate could be transient or small. Even small changes could affect bone health over time. Studies may not have been long enough to capture the effect of SGLT2 inhibitors on bone. Cardiovascular studies required by the FDA are underway and will be long enough to capture data on fracture risk.