Strontium Ranelate Combined with Insulin Is as Beneficial as Insulin Alone in Treatment of Fracture Healing in Ovariectomized Diabetic Rats

Abstract

BackgroundType 2 diabetes mellitus (T2DM) and estrogen deficiency both predispose fracture patients to increased risk of delayed union or nonunion. The present study investigated the effects of strontium ranelate (SR) on fracture healing in ovariectomized (OVX) diabetic rats.Material/MethodsA mid-shaft fracture was established in female normal control (CF), diabetic (DF), and OVX diabetic (DOF) rats. Treated DOF rats received either insulin alone (DOFI) or combined with SR (DOFIS). All rats were euthanized at 2 or 3 weeks after fracture. Fracture healing was evaluated using radiological, histological, immunohistochemical, and micro-computed tomography analyses.ResultsAt 3 weeks after fracture, radiological and histological evaluations demonstrated delayed fracture healing in the DF group compared with the CF group, which was exacerbated by OVX, as indicated by the significantly lower X-ray score, BMD, BV/TV, and Md.Ar/Ps.Cl.Ar, and the markedly decreased OCN and Col I expression in the DOF group. All these changes were prevented by insulin alone or combined with SR treatment. In comparison with the DOFI group, DOFIS rats displayed markedly higher OCN expression at 2 weeks after fracture and Col I expression at 2 and 3 weeks after fracture.ConclusionsThese results demonstrated delayed fracture healing with preexisting estrogen deficiency and T2DM. While insulin alone and combined with SR were both effective in promoting bone fracture healing in this model, their combined treatment showed significant improvement in promoting osteogenic marker expression, but not of the radiological appearance, compared with insulin alone.

The effect of osteoporosis and its treatment on fracture healing a systematic review of animal and clinical studies

“…In rats, several studies showed that in the osteoporotic group the total callus, there was less bony callus and newly formed bone [11] as well as the bone mineral content and bone mineral density was reduced at the fracture site 12 , 13 , 14 , 15 , 16 . Other studies showed that the presence of osteoporosis had a negative impact on the quality and quantity of callus during early fracture healing 12 , 17 and biomechanical testing 11 , 12 , 13 , 16 , 18 , 19 , 20 , 21 , 22 .…”

“…Osteoporotic animal models – Administration of strontium ranelate in several fracture or osteotomy animal models resulted in increased bone formation 22 , 69 , bone mineral density 22 , 69 , 70 , higher mechanical strength 22 , 69 , 71 and fracture stiffness [71] , improved callus formation 69 , 70 , 71 . However, one study showed that administration of strontium ranelate with insulin compared to only insulin in ovariectomized diabetic rats did not display a significant advantage regarding fracture healing [14] .…”

“…The effect of osteoporosis on fracture healing in animal models was primarily investigated in rats and mice. The majority of the results suggested a negative biomechanical or histopathological influence of osteoporosis on fracture healing 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 21 , 23 , 24 , 26 , whereas only three studies found radiological evidence of delayed union 12 , 16 , 18 . This may suggest that local signs of impaired or lagging fracture healing cannot always be radiologically objectivated, which has to be taken into mind while interpret the results.…”

“…All studies used ovariectomized animals to create an animal osteoporosis model, except for one study, which used a genetically induced osteoporosis model. [10] In six studies complementary diet was used after ovariectomy 13 , 14 , 15 , 22 , 24 , 26 . Since this is not a natural process in animals, interference with fracture healing could occur.…”