Effect of SGLT2 Inhibitor Use on Bone Health

September 15, 2015

In light of the recent FDA warning on increased fracture risk with canagliflozin, we report on a study exploring possible mechanisms for bone loss.

Results from a new study point to the need to monitor bone health during long-term use of SGLT2 inhibitors.1 The study was done in mice, and found that inhibiting SGLT2 receptors with canagliflozin lead to detrimental effects on bone.  Whether or not these results were due to direct drug effects, or subtherapeutic control of gylcemia is unclear.

Patients with type 1 diabetes and type 2 diabetes (T2DM) already have increased fracture risk. Chronic hyperglycemia, accumulation of advanced glycation end products (AGE), and secondary hyperparathyroidism may all play a role. 

Early clinical trials have also suggested about a 30% increase in bone fractures in patients with T2DM who have received canagliflozin.2 One possible mechanism is increased parathyroid hormone (PTH)  and fibroblast growth factor 23 (FGF23) due to increased reabsorption of sodium and higher serum phosphate levels following SGLT2 inhibition. Chronic glucosuria resulting from SGLT2 inhibition could also increase the amount of calcium lost through the urine.

In the study, researchers used a mouse model of diabetic bone disease. Male mice with or without streptozotocin-induced diabetes were given oral canagliflozin for 10 weeks (doses ranged from 14.2-20.6 mg/kg/day). After that, researchers measured serum bone markers, fracture resistance of cortical bone with micro-CT, a three-point bending test of the femur, and vertebral bone strength using compression testing. Canagliflozin-treated diabetic mice showed a 35% drop in blood glucose.

Results in diabetic mice showed:

• Deficits in trabecular bone microarchitecture in the femur metaphysis and L6 vertebra:

♦ Less resistance to compression testing (p<0.0001)

♦ Decreased trabecular bone volume fraction, number, thickness, and mineral density (p<0.0001)

♦ Increased trabecular spacing (p<0.0001)

♦ Changes in trabecular shape (p=0.002)

• Decreased cortical bone area, thickness, and minimal moment of inertia (p<0.0001 for all), and increased cortical porosity (p<0.0001)

• Decreased fracture resistance:

♦ Decreased material bending strength, toughness, structural strength, and rigidity (p<0.001 for all)

• Significantly increased PTH (p<0.0001), RatLAPS (a marker of bone resorption) (p=0.0002), and urine calcium concentration (p<0.0001)

Treatment with canagliflozin was associated with:

• Increased calciuria and FGF23

• Further increases in RatLAPS

• Lower bending strength, toughness, peak moment, rigidity, and force in canagliflozin-treated diabetic mice compared to canagliflozin-treated non-diabetic mice

• Deficits in trabecular bone microarchitecture in the metaphysis in nondiabetic mice treated with canagliflozin

The bone deficits with canagliflozin could be explained, the authors pointed out, by subtherapeutic improvement in glycemia, which was not sufficient to counteract the detrimental effects of diabetes on bone. Canagliflozin could also have direct effects on bone, they added, though studies have not found that bone osteoclasts and osteoblasts express SGLT2 receptors.

“In light of our findings which suggest possible drug-induced metaphyseal deficits in non-diabetic mice, it may become important to monitor the impact of longer-term SGLT2 inhibition on bone in all clinical conditions in which is it used…”  concluded first author Kathryn Thrailkill, MD, of the University of Kentucky, and colleagues,  “Our findings would suggest that as the clinical indications for SGLT2 inhibitor therapy expand, care should be taken to monitor skeletal health in persons receiving this class of drugs.”

Take Home Points

• Mice with experimentally induced diabetes develop deficits in cortical bone and trabecular bone, decreased fracture resistance, as well as increased PTH, urine calcium, and markers of bone resorption.

• Treatment with canagliflozin was associated with lower bending strength, toughness, peak moment, rigidity and force, and deficits in trabecular bone.

• Treatment with canagliflozin was associated with increased calciuria, FGF23, and markers of bone resorption.

• Bone health may need monitoring with long-term use of SGLT2 inhibitors.

The authors reported no conflicts of interest.  The study was supported by grants from the Arkansas Children’s Hospital Research Institute, the Arkansas Biosciences Institute, NIH, and the Department of Veterans Affairs.




1. Thrailkill KM, et al. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice. Bone. 2015 Jul 23.

2. Taylor SI, et al. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015 Jan;3(1):8-10.