SGLT2 Inhibitors and Fracture Risk: A Review of What We Know
It's probably too early to pass judgment but data from clinical trials point to decreased bone mineral density and increased treatment-emergent fractures in patients taking the new antidiabetes drugs.
The sodium glucose co-transporter 2 inhibitors lower A1c in a non-insulin dependent manner, are associated with modest weight loss, and have a mild effect on hypertension. Analysis of clinical trial data, however, has found evidence of decreased bone mineral density and of increased bone turnover in patients taking both canagliflozin and dapagliflozin.It remains unclear whether persons with diabetes have coexisting bone disease that may make them more susceptible to adverse effects of the drugs on bone or if the SGLT2 inhibitor mechanism itself underlies the observed changes.  This short slide show summarizes the current literature.Â
References:
1. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. Published online December 16, 2014. http://dx.doi.org/10.1016/S2213-8587(14)70227-X
2. Kahn SE, Zinman B, Lachin JM, et al Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008;31:845-51. doi: 10.2337/dc07-2270. Epub 2008 Jan 25. http://www.ncbi.nlm.nih.gov/pubmed/?term=10.2337%2Fdc07-2270
3. Kwon H. CANA: clinical efficacy and safety. Endocrinology and Metabolic Drugs Advisory Committee Meeting, 2013. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336234.pdf
4. Bode B, Stenlof K, Harris S. Long-term efficacy and safety of CANA over 104 weeks in patients aged 55 to 80 years with type 2 diabetes. Diabetes Obes Metab. 2014 Dec 13. doi: 10.1111/dom.12428. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1111%2Fdom.12428
5. Kohan DE, Fioretto P2, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that DAPA reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014 Apr;85(4):962-71. doi: 10.1038/ki.2013.356. Epub 2013 Sep 25. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973038/
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.
