(January 11, 2011—Toronto, ON) Researchers at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital have shown in an animal model that use of sitagliptin (Januvia®), a relatively new treatment for type 2 diabetes, does not adversely affect bone quality and would not be expected to increase the risk of fractures—a risk seen with some other commonly used type 2 diabetes drugs, such as pioglitazone or rosiglitazone.
The study was published online last month in the leading medical journal Endocrinology.
People with type 2 diabetes have an increased risk of fracture that can be worsened by treatment with thiazolidinediones—a commonly used class of drugs that includes rosiglitazone (Avandia®) and pioglitazone (Actos®). Thiazolidinediones have been widely used, and help the body better use insulin and reduce the development of diabetes in at-risk patients. However, this therapeutic benefit has also been associated with significant adverse effects including reduced bone mineral density and increased risk of fracture, especially in women.
“Our findings contrasting the different actions of anti-diabetic agents such as sitagliptin versus pioglitazone on bone quality in an animal model provide new information about how different anti-diabetic agents affect the skeleton,” said clinician-scientist Dr. Daniel Drucker, Lunenfeld Senior Investigator and Director of the Banting & Best Diabetes Centre at the University of Toronto.
“We would predict that if these findings are confirmed in human studies, sitagliptin is much less likely to have adverse effects on bone than thiazolidinediones such as pioglitazone.”
“We know from related studies that organ systems don’t function in isolation,” said Dr. Marc Grynpas, Lunenfeld Senior Investigator and a leading expert in osteoporosis. “They interact with each other. For example, bone cells have insulin receptors and can be susceptible to the effects of anti-diabetic agents. So this was part of the rationale for this study.”
In 2008, sitagliptin was approved in Canada for the treatment of type 2 diabetes. The drug belongs to a class of agents called DPP-4 inhibitors that inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down specific gastrointestinal hormones that are released in response to a meal, promoting the release of insulin and driving blood glucose levels toward normal.
However until now, the effects of sitagliptin on bone quality, and hence risk of fracture, was unknown.
Using what is termed a two-armed experimental design, Drs. Drucker and Grynpas compared the effects of pioglitazone and sitagliptin on bone quality in preclinical models of diabetes and insulin resistance, mimicking the clinical scenario under which anti-diabetic agents are commonly used. The researchers also assessed bone quality in a model in which the molecular target of sitagliptin (DPP-4) had been genetically inactivated.
The study also examined the effects of pioglitazone and sitagliptin in females who had been ovariectomized (i.e., their ovaries were surgically removed). This condition produces estrogen deficiency and serves as a model for evaluating drug action in a hormonal setting—similar to that which occurs in postmenopausal women. (Most of the limb fractures seen in diabetic patients after treatment with thiazolidinediones were in post-menopausal women.)
By comparing the effects of both medications in animals in which DPP-4 was either chemically inhibited (i.e., using sitagliptin) or genetically ablated (i.e., in the DPP-4 ‘knock-out’ animal model), Drs. Drucker and Grynpas could obtain complementary lines of evidence about the consequences of reducing or eliminating DPP-4 activity on bone quality.
“We believe this was the most interesting aspect of the study,” said Dr. Grynpas. “In knock-out animals, you can often only assess the impact on bone quality when you ovariectomize. So the genetic ablation was a novel component of the study complementing the use of the DPP-4 inhibitor in normal animals.”
Results showed that sitagliptin had no negative effects on bone (as measured by bone mineral density and content, mechanical testing, and bone progenitor cell numbers). In contrast, deleterious effects on bone quality were seen in animals treated with pioglitazone, including the presence of ‘fatty’ bone marrow, reductions in vertebral bone strength, as well as reduced vertebral bone mineral density and a slowed rate of bone deposition (the latter effects were seen in males only). No significant adverse effects on bone were seen in animals that carried an inactivated DPP-4 gene.
Drs. Drucker and Grynpas noted that clinical studies will be required to fully understand the effects of sitagliptin on bone quality and risk of fracture in people with diabetes.
Diabetes has reached epidemic proportions worldwide and is a leading cause of heart disease, stroke, blindness, kidney failure and limb amputation. Several studies have shown that lifestyle changes and appropriate pharmacologic therapy can significantly reduce the development of type 2 diabetes in people at risk of the disease.
The study was supported by grants from the Canadian Diabetes Association, the Canadian Institutes of Health Research, and Merck Frosst Canada.