Diabetes is a common condition with significant morbidities (1). The World Health Organization estimates that the number of diabetics increased from 85 million in 1985 to 217 million in 2005 and may reach 366 million by 2030. It is a major cause of cardiovascular, renal, neurologic and ophthalmologic diseases. In the United States the cost of diabetic care is projected to reach almost 200 billion dollars by 2020. Type 2 diabetes, which has in the past was called non-insulin dependent or adult onset, is the most prevalent form, comprising at least 90% of the cases. Because the incidence of both type 2 diabetes and osteoporosis increases with age, it is not unusual for both conditions to occur in the same patient. A variety of medications have been approved to treat type 2 diabetes and these are often taken for prolonged periods. However, it is now recognized that some of these have detrimental effects on bone health.
Meier et al recently published an excellent review of this topic (2). They point out that diabetes itself is a risk factor for osteoporosis despite the higher bone mineral density that is often seen in diabetic patients. The reasons for this are multifactorial and only partially understood. Among the drugs used to treat type 2 diabetes, the thiazolidinediones (TZD) have most clearly been shown to decrease bone mass and increase fracture incidence (3). The mechanism for the effects of TZD-induced bone loss centers on the action of these agents on the peroxisome proliferator-activated receptor gamma (PPARg). Activation of PPARg by TZD inhibits osteoblast differentiation while enhancing adipocyte and osteoclast differentiation. Interestingly, the effects of TZD on bone are similar to the effects of aging.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the most recent class of anti-diabetic drug to be approved. SGLT2 regulates renal glucose reabsorption in the kidney. The SGLT2 inhibitors block this action, increasing glucose excretion in the urine to improve glycemic control. However, the use in patients of two approved members of this medication class: dapagliflozin and canagliflozin, has been associated with an increased incidence of fractures (2). Because it received new data about fracture risk, the US Food and Drug Administration (FDA) recently updated the prescribing information for canagliflozin to include a strengthened warning (4). The FDA stated in its safety announcement about canagliflozin that it had “revised the drug label and added a new Warning and Precaution. The additional data confirm the finding that fractures occur more frequently with canagliflozin than placebo, which is an inactive treatment. Fractures can occur as early as 12 weeks after starting the drug. In the clinical trials, when trauma occurred prior to a fracture, it was usually minor, such as falling from no more than standing height.”
The FDA also added information about a two-year clinical trial that it required the manufacturer of canagliflozin to perform. This demonstrated a greater loss of bone mineral density at the hip and lower spine with canagliflozin than with placebo.
The FDA is continuing to evaluate the risk of fractures with other members of the SGLT2 inhibitor class to determine if additional label changes or studies are needed.
These new findings are of concern and demonstrate that patients at increased risk for osteoporosis who are prescribed these medications need to be carefully monitored or considered for treatment with other anti-diabetic agents.
Farmington, CT, USA
Diabetes Medications and Bone Health
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