The effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on fracture healing

Renin- Angiotensin System (RAS) is an important indicator of regulation of blood pressure and fluid electrolyte modulation. Previous studies had shown that this system, by means of specific receptors in various parts of the body, increases blood pressure by inducing arterial vasoconstriction and renal reabsorption of water, promotes cell proliferation, differentiation and regeneration, increases inflammatory response, induces apoptosis and neovascularization. After demonstration of RAS receptors on bone tissue, potential effects of RAS on osseous cellularity and mineralization became an area of interest. There is insufficient data available regarding the effects of RAS on fracture healing. On the other hand, prevalence of hypertension in the community is increasing and drugs inhibiting RAS or preventing its action by blocking the receptors of the system are prescribed more frequently. Thus, it was hypothesised that bone metabolism may be affected by the use of these drugs, which in turn may alter healing mechanisms of fractures in hypertensive patients. The aim of this study is to investigate the effects of Angiotensin- Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARB) on fracture healing in an animal model; if there is any effect, to determine the stage of fracture healing affected by these medications by objective criteria and to obtain clues about the influence of antihypertensive treatment protocol on healing patterns in patients using these drugs. In this study, 108 male Wistar-Albino rats were equally divided into three groups as; Control, ARB group and ACE group. Under general anesthesia, a transverse fracture was surgically made on middle thirds of diaphysis of left femur, followed by intramedullary K-wire fixation to all rats. Afterwards the rats were left to their natural environment and 10 mg/kg Losartan was administered to ARB group and 10mg/kg Enalapril was administered to ACE group by adding the drugs into their drinking water. Rats were sacrificed at 2nd and 5th weeks for radiological and histopathological evaluation. Radiological evaluation was performed using the methods described by Lane-Sandhu. Radiological scores at 2nd week were found to be; 1.80 ± 0.63 in ACE group, 1.90 ± 0.73 in ARB group and 0.80 ± 0.42 in Control group. There was significant difference among scores of groups at 2nd week (p=0.001). The score of Control group was found to be significantly lower than both ACE (p=0.003) and ARB (p=0.003) groups. Radiological scores at 5th week were determined to be; 2.89 ± 0.60 in ACE group, 1.89 ± 0.60 in ARB group and 1.67 ± 0.50 in Control group. There was also significant difference among groups at 5th week (p=0.001). The score of Control group was found to be significantly lower than both ACE (p=0.001) and ARB (p=0.001) groups. Histologic scores at 2nd week were, 2.13 ± 0.83 in ACE group, 2.63 ± 0.51 in ARB group and 1.38 ± 0.74 in control group. There was significant difference among histologic scores of groups at 2nd week (p=0.015). The score of Control group was found to be significantly lower than ARB (p=0.007). The scores at 5th week were 7.70 ± 0.48 in ACE group, 5.88 ± 1.64 in ARB group and 5.00 ± 0.75 in Control group. There was significant difference among histological results of groups at 5th week (p=0.001). ACE group showed significantly higher mean scores than both control (p<0.001) and ARB (p=0.016) groups. Results of this preliminary experimental study revealed that ACE inhibitors improved the process of fracture healing. It was also observed that, Angiotensin receptor blockers had also some favorable effects on fracture healing but at the eventual outcome no difference could be demonstrated. Keywords: Fracture healing, Angiotensin Converting Enzyme Inhibitor, Angiotensin Receptor Blocker, Hypertension, Rat femur