ORIGINAL ARTICLE Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate Naglaa F. Khedr a *, Nahla E. El-Ashmawy a , Hoda A. El-Bahrawy a , Ali A. Haggag a and Eman E. El-Abd b a Department of Biochemistry, Faculty of Pharmacy, Tanta University, Gharbia, 31527, Egypt b Medical Research Center, Alexandria University, Alexandria, Egypt Keywords BMD, cathepsin-K, orchidectomy, osteocalcin, raloxifene, risedronate Received 14 November 2011; revised 15 April 2012; accepted 11 May 2012 *Correspondence and reprints: naglaa_khedr2000@yahoo.com ABSTRACT Osteoporosis is a reduction in bone mineral density (BMD). It develops less often in men than in women. This study aimed to evaluate the bone protective effects of raloxifene (RAL), risedronate (RIS), and their combination on osteoporotic male rats. Forty male Wister rats (12 weeks) were randomly divided into five groups: sham- operated group (n = 8), orchidectomized (ORX) group (n = 7), RAL group (n = 9), RIS group (n = 7) and RAL + RIS group (n = 7). RAL was orally administered at 3 mg/kg three times/week, and RIS was given subcutaneously at 5 lg/kg, twice weekly. After 6 weeks of treatment, serum cathepsin-K, alkaline (ALP) and acid phosphatase activities, serum osteocalcin, serum Ca 2+ , and Pi were determined. Uri- nary Ca 2+ and deoxypyridinoline levels, BMD, and Ca 2+ content of femur ash were estimated. Histochemical localization of ALP activity of tibia and histomorphometry was examined. As compared to sham, ORX rats showed a significant increase in bone turnover markers, and histochemical activity of ALP was increased markedly in proximal tibia of ORX rats, whereas BMD and Ca 2+ content of femur ash were reduced after ORX. These changes were modulated after treatment with RAL and RIS or both to ORX rats; BMD of femur was improved by each treatment, and bone turnover markers were reduced as compared to ORX vehicle group. We concluded that orchidectomy induced osteoporosis and increased bone turnover in male rats because of withdrawal of sex hormones. Both RAL and RIS could treat osteoporosis in ORX rats; they reduced bone turnover markers and maintained BMD. INTRODUCTION Osteoporosis is a chronic progressive disease character- ized by low bone mass, bone deterioration, and decreased bone strength, resulting in bone fragility and increased fracture risk. Osteoporosis develops less often in men than in women because men have larger skeletons, their bone loss starts later and progresses more slowly [1]. Androgen deficiency may be associated with an increase in bone resorption in elderly men and so with remodeling imbalance and fracture risk. It is firmly established that androgen withdrawal induced by orchidectomy (ORX) results in decreased bone mass in animal models especially in rodents [2]. Many factors contribute to the development and maintenance of skeletal mass. Bone remodeling is char- acterized by a balance between osteoclast bone resorp- tion and osteoblast bone formation. During development and growth, bone formation exceeds bone resorption, with a net gain in bone mass. In aging individuals, osteoclast dysfunction is believed to play a pivotal role in reducing bone mass in osteoporosis [3]. Testosterone has direct and indirect inhibitory effects on human osteoclast formation and bone resorption, ª 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 1 doi: 10.1111/j.1472-8206.2012.01047.x Fundamental & Clinical Pharmacology