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Reduction in Blood Glucose through SGLT-2 Therapy Does Not Prevent Diabetic Bone Disease

Apr 16, 2016

Take bone density, history of osteoporosis into consideration when prescribing.

Type 1 and 2 diabetes patients are at increased risk for bone fractures. It is believed that the cause is the chronic hyperglycemia state that leads to a decrease in bone density, which in turn puts diabetes patients at risk for osteopenia and osteoporosis.  Therefore, bone microarchitecture and strength could be potentially amplified by down-regulating patients’ blood glucose levels.

One of the effective options for lowering blood glucose levels is using sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors), a popular group of oral medications that lower A1C levels by 0.7 to 1.0%.  They work by blocking sodium-glucose cotransporter 2 in the proximal tubules of the kidneys and reducing the reabsorption of filtered glucose from the tubular lumen, which lowers glucose levels in the blood. The added benefit of this group of medications is a slight weight loss. Paradoxically, previous studies indicated that treatment with the SGLT-2 inhibitor canagliflozin could actually worsen the bone structure and increase the risk for bone fractures by 30%. Kathryn Thraikill and colleagues attempted to re-examine these findings in their own designed study on how canagliflozin (CANA) could affect patients’ glucose levels and the strength of their bones.

In a ten-week study, they used DB/2J male strain mice that were treated with streptozotocin (STZ)—40 mg/kg/day for 5 days—or with vehicle (VEH) of 100mM of citrate in order to induce diabetes.  After 2-3 weeks, when animals had confirmed diabetes, they were randomly assigned to either a group that was fed chow containing STZ and CANA 50ppm (n=19) or a group that was fed STZ and VEH (n=18). The control group consisted of mice that were fed chow with CANA 65ppm (n=20) or chow with VEH (n=20). They checked the animals’ blood glucose levels at 3 and 10 weeks.  They also looked at the strength of axial skeletal by performing scans, biomechanical testing, bone biomarkers analysis, and quantitative RT-PCR.

Researchers found that CANA did reduce blood glucose levels in diabetic mice from 520.94mg/dL (+/-84.69mg/dL) to 358.84mg/dL (+/-72.3mg/dL)  at three weeks and from 525.18mg/dL (+/-53.64mg/dL) to 338.89mg/dL (+/-131.45mg/dL) at ten weeks (mean+/- SD; p<0.0001). Despite a significant decrease in blood glucose levels, CANA did not provide an increase in bone strength in the intervention group. Bending strength, toughness, peak moment, rigidity, and force were negatively affected in diabetic mice that were using CANA as compared to the control group mice that were taking CANA.   Moreover, both groups that were using CANA had increased RatLAPS biomarker (C-terminal telopeptides of type 1 collagen), which indicates increased bone resorption.  Control group using CANA also had calcium loss and destructive metaphyseal changes that were compensated by hyperparathyroidism.

Findings of the study definitely bring more information about the SGLT-2 inhibitors group medication. They suggest an association between the increased risk for bone fractures and using medications like canagliflozin, and caution in using them in a group of patient at high risk for bone fracture. The authors offered a two-component explanation for their findings. As canagliflozin causes the increase of sodium in tubular lumen, the ion is being reabsorbed by the sodium-potassium transporter, which in turn increases the level of potassium. Secondarily, it increases the growth of parathyroid hormone and fibroblast factor 23, which causes phosphaturia and returns to normal phosphate level.  Also, SGLT-2 inhibitors can contribute to hypercalciuria caused by osmotic diuresis.

Despite the importance of these findings, we cannot dismiss the fact that the study was conducted on only 77 mice for a short period of time — ten weeks. We definitely need more studies that involve human participants who would challenge these findings. The significance of the results may increase since, currently, SGLT-2 inhibitors are approved by the FDA only for type 2 diabetes patients, but it may change as new studies are being conducted on type 1 patients.

Practice Pearls:

  • SGLT-2 inhibitors can contribute to increased risk of bone fractures in diabetes patients.
  • In diabetes patients with a history of multiple bone fractures or osteoporosis, it may be wise to stay away from SGLT-2 inhibitors and try other groups of medications first.
  • Healthcare providers are encouraged to report any known incidents of sudden unexpected worsening of bone density in patients who recently got started on SGLT-2 inhibitor therapy.

Thrailkill, Kathryn M., et al. “SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice.” Bone 82 (2016): 101-107.

Researched and prepared by Renata Kulawik Doctor of Pharmacy Candidate LECOLM College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE