Experimental Study Of Therapeutic Effects Of Amylin On Glucocorticoid-induced Osteoporosis In Rats

Background and Objective: Glucocorticoid-induced bone loss is the most predictable and debilitating complication of prolonged administration of systemic corticosteroids. It has been shown that patients treated with glucocorticoids have an increased risk of osteoporotic fractures, resulting in marked morbidity, particularly in elderly individuals. Calcium, Calcitriol, calcitonin and fluoride may have roles as therapies but documentation of their efficacy is less satisfactory. It is incumbent on all physicians supervising long-term glucocorticoid therapy to ensure that a skeletal assessment is carried out and that the effective prevention and treatment of glucocorticoid-induced osteoporosis(GIO) are instituted, where appropriate.Amylin is a 37-amino acid peptide hormone cosecreted with insulin from the β-cells of the pancreatic islets. It is structurally related to calcitonin, calcitonin gene-related peptide(CGRP), and adrenomedullin (sequence identities 15%, 46% and 20%, respectively). Amylin has previously been shown to stimulate proliferation of osteoblasts and to inhibit osteoclastic bone resorption, both in vitro and in vivo. The effects result in substantial increase in bone mass when the peptide is administered either locally or systemically to sexually mature mice. These findings suggest that it could contribute to the regulation of bone mass and that it is a potential therapy for osteoporosis. It is particularly attractive in the latter role because of its effects on both formation and resorption, a combination not shared by any other osteoporosis treatment. However, the therapeutic effects on osteoporosis of its systemic administration are uncertain. The present experiment was performed to study the effects ofamylin on glucocorticoid-induced bone loss in rats.Methods: Four groups of female Wistar rats (3 months old) were treated for 12 weeks as follows: Ⅰ Normal Control; Ⅱ DXM; Ⅲ DXM+AMY; Ⅳ DXM+Vitamin D3. By intramuscular injection of desamethasone(DXM) 1mg/kg twice a week during the first 8 weeks, the animal model of glucocorticoid-induced osteopoprosis was made. During the last 4 weeks, the rats of group Ⅲ and group Ⅳ were given AMY 30ug/kg/d s.c. and Vitamin D3 60ku/kg im two weeks a time, respectively. BMD of the lumbar vertebrae and the femur were measured by DEXA. Bone biomechanics, bone morphology and the bone markers of serum and urine were also determined.Results: The following results were acquired from these studies:1. After the treatment with AMY, Bone mineral density (BMD) significantly increased by 35% at the lumbar spine and by 17% at the femur. (vs. DXM group) The BMD of the lumbar vertebrae was also higher in DXM+VitD than in DXM rats, but it was not different at the femur between these two groups.2. Compared with DXM group, the biomechanical properties markedly increased in DXM+AMY group. The peak load was increased from 55.5N in DXM to 68.1N in DXM+AMY, suggesting that the bones of the AMY treated rats were stronger.3. The highest plasma osteocalcin concentration was measured in DEX+AMY rats. Simultaneously, urinary HOP/Cr,uCa/Cr and uP/Cr were lower in DXM+AMY than in DXM rats. The levels of uCa/Cr and uP/Cr were remarkably lower in DXM+VitD than in DXM rats. No significant difference in plasma osteocalcin or urinary HOP excretion was observed between DXM and DXM+VitD rats.4. Histological analysis showed that the trabecular volume was significantly increased in DXM+AMY, compared with DXM group. Theincrease in trabecular volume was contributed to by increases in trabecular thickness and trabecular number and from a decline in trabecular separation. The same changes were also observed in DXM+VitD group.Conclusion: These results indicate that in GIO rats, AMY treatment inhibited bone loss both by inhibiting resorption and by stimulating osteoblastic activity. Thus, Amylin appears as an attractive candidate as a therapeutic agent for osteoporosis...