Abstract
Fracture risk in type 2 diabetes is increased despite normal or high bone mineral density, implicating poor bone quality as a risk factor. Raloxifene improves bone material and mechanical properties independent of bone mineral density. This study aimed to determine if raloxifene prevents the negative effects of diabetes on skeletal fragility in diabetes-prone rats. Adult Zucker Diabetic Sprague-Dawley (ZDSD) female rats (20-week-old, n = 24) were fed a diabetogenic high-fat diet and were randomized to receive daily subcutaneous injections of raloxifene or vehicle for 12 weeks. Blood glucose was measured weekly and glycated hemoglobin was measured at baseline and 12 weeks. At sacrifice, femora and lumbar vertebrae were harvested for imaging and mechanical testing. Raloxifene-treated rats had a lower incidence of type 2 diabetes compared with vehicle-treated rats. In addition, raloxifene-treated rats had blood glucose levels significantly lower than both diabetic vehicle-treated rats as well as vehicle-treated rats that did not become diabetic. Femoral toughness was greater in raloxifene-treated rats compared with both diabetic and non-diabetic vehicle-treated ZDSD rats, due to greater energy absorption in the post-yield region of the stress-strain curve. Similar differences between groups were observed for the structural (extrinsic) mechanical properties of energy-to-failure, post-yield energy-to-failure, and post-yield displacement. These results show that raloxifene is beneficial in preventing the onset of diabetes and improving bone material properties in the diabetes-prone ZDSD rat. This presents unique therapeutic potential for raloxifene in preserving bone quality in diabetes as well as in diabetes prevention, if these results can be supported by future experimental and clinical studies.
Highlights
People with type 2 diabetes mellitus have a greater risk for bone fragility fractures compared with healthy adults, despite normal or higher bone mineral density [1,2,3,4,5]
At the time of sacrifice, vehicle-treated non-diabetic (VEH-ND) rats weighed more than both vehicle-treated diabetic (VEH-D) (p,0.0001) and raloxifene-treated (RAL) (p,0.0001) rats (Table 1).vehicletreated diabetic rats (VEH-D) rats had higher blood glucose over the course of the study, as determined by area-under-the-curve (AUC) compared with RAL or VEH-ND rats (p,0.0001) (Fig. 1b,c)
This study showed that raloxifene treatment in female Zucker Diabetic Sprague-Dawley (ZDSD) rats improved blood glucose levels and showed a trend for prevention of type 2 diabetes while imparting a beneficial effect on bone material properties
Summary
People with type 2 diabetes mellitus have a greater risk for bone fragility fractures compared with healthy adults, despite normal or higher bone mineral density [1,2,3,4,5]. This suggests that bone quality, not quantity, is responsible for the increase in fracture risk in diabetes. In post-menopausal women, raloxifene decreases risk of fracture with little effect on bone mineral density [8,9,10]. This indicates that raloxifene improves bone resistance to fracture by affecting bone quality, and may be an agent with potential to improve bone properties in diabetes where fracture risk is higher apparently due to reduced bone quality rather than reduced bone mass
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