Therapeutic options for treatment of osteoporosis-related fractures in males; a novel strategy for treatment of osteoporosis using new selective androgen receptor modulators (SARMs)

骨质疏松症和骨质疏松相关骨折的发病率预计在未来几年将急剧增加。与男性骨质疏松症不同，绝经后女性骨质疏松症的诊断和治疗一直是研究的重点。尽管人们越来越认识到男性骨质疏松症的问题，但关于这种疾病及其治疗的知识仍然存在相当大的差距。男性骨质疏松症的治疗方法很少，有双磷酸盐、人甲状旁腺激素（PTH）、雷奈酸锶（SR）和地诺单抗。所有这些药物主要影响骨组织，对肌肉组织没有或很少影响。在第一次骨折发生之前，骨质疏松症在临床上是沉默的。骨质疏松症的诊断通常在骨折后进行。已批准的骨质疏松治疗在骨折愈合期间不开处方，因为有证据表明抗骨质疏松药物可能影响骨愈合过程。目前，非甾体选择性雄激素受体调节剂（SARMs）正处于开发阶段。研究两个化合物ostarine和BMS-564929。在受癌症恶病质影响的男女患者中，Ostarine增加瘦体重和身体表现。BMS-564929已开发用于治疗男性雄激素水平与年龄相关的下降症状。关于骨组织和骨折愈合的研究至今未见报道。在本研究中，我们将研究SARMs对完整骨和骨折愈合的影响。第一部分，我们将在去睾丸大鼠身上建立胫骨干骺端截骨联合t钢板成骨。sarm和睾酮将用于骨质疏松症的治疗或预防，以研究骨愈合和肌肉功能。雌激素和睾丸激素对预防男性骨质和肌肉流失很重要。然而，由于副作用，它们并没有被应用。由于雌激素和雄激素在骨骼和肌肉代谢中的相互作用，serm和SARMs可能具有协同作用。在第二部分中，我们将在大鼠中研究选择性受体调节剂（SERM或/和SARM）替代睾酮和雌激素的作用。切除睾丸的大鼠会出现骨质疏松症，然后在胫骨截骨前和骨愈合期间进行药物治疗。该结果将为男性骨质疏松症及其治疗提供新的知识。使用新的SARMs治疗骨质疏松症的新策略将在男性中进行评估。本研究结果可能为骨质疏松症及骨质疏松相关骨折的治疗提供新的视角。

The incidence of osteoporosis and osteoporosis-related fractures is predicted to be increased dramatically in the coming years. In contrast to the male osteoporosis, diagnosis and treatment of postmenopausal osteoporosis in women has been the main focus of the research. Despite increasing recognition of the problem of male osteoporosis, the considerable gap remains in the knowledge regarding this disorder and its treatment. There are few treatments of osteoporosis in men, bisphosphonates, human parathyroid hormone (PTH), strontium ranelate (SR) and denosumab. All these drugs affect predominantly bone tissue having no or little effect on muscle tissue. Until the onset of the first fractures, osteoporosis is clinically silent. Diagnosis of osteoporosis is often done after a fracture occurs. The approved treatments for osteoporosis are not prescribed during fracture healing because it is supported that anti-osteoporosis agents could affect bone healing processes. Currently, non-steroidal selective androgen receptor modulators (SARMs) are being developing. Two compounds ostarine and BMS-564929 will be studied. Ostarine increases the lean body mass and physical performance in patients of both sexes affected by cancer cachexia. BMS-564929 has been developed for the treatment of symptoms of age-related decline in androgen levels in men. Studies regarding bone tissue and fracture healing have been not reported so far.In the proposed study, the effect of SARMs on intact bone and fracture healing will be studiedIn the first part, the metaphyseal osteotomy of tibia with T-plate osteosynthesis will be created in orchiectomized rats. SARMs and testosterone will be applied as osteoporosis therapy or prophylaxis to study bone healing and muscle function.Estrogen and testosterone are important for the prevention of bone and muscle loss in men. However, they are not applied because of the negative side effects. Due to the interaction between estrogens and androgens in bone and muscle metabolism, synergistic effects of SERMs and SARMs could be possible. In Part 2, the replacement of testosterone and estrogen with selective receptor modulators (SERM or/and SARM) will be studied in rats. Orchiectomized rats will develop osteoporosis, and then will be treated with substances prior to the tibia osteotomy and during bone healing period. The results will provide a new knowledge regarding osteoporosis as well as its treatment in men. A novel strategy for the treatment of osteoporosis using new SARMs will be evaluated in males. The findings of the proposed studies may show up a new perspective for therapeutic treatment of osteoporosis and osteoporosis-related fractures.