Postmenopausal Osteoporosis

About

Background Osteoporosis is a bone disease characterized by the accelerated loss of bone mineral density (BMD). Approximately 50% of postmenopausal women experience the disease. Hormone replacement therapy (HRT) used to be one of the best choices for the prevention and treatment of the disease. However, many women have discontinued its use because of the reported risk for cancer. Similar to HRT, most drugs currently available, such as bisphosphonates, raloxifene, and denosumab are antiresorptive, which target osteoclasts and decrease bone resorption. Withdrawal of these drugs often induces rapid bone turnover and bone loss. Drugs targeting osteoblasts and promoting bone formation are limited and, if any, two drugs, the recombinant human parathyroid hormone (PTH) and strontium ranelate, have a mode of action in bone formation. Women receiving the combined therapy of raloxifene and PTH had higher bone gain than women receiving either alone. The clinical benefits have made pharmaceutical industry actively searching for new ones stimulating bone formation.   Description of the Project Bone turnover rate is increased by 90% after menopause with bone resorption outpacing bone formation by a ratio of 2:1. Estrogen deficiency, due to cease of ovarian function, is the cause that increases bone turnover rate and resorption. Dr. Huang has found that, in addition to estrogen deficiency, a concurrent but inverse change occurs in iron level, which is caused by the cessation of menstruation (Figure 1). Data fromin vitro and in vivo experiments have shown that increased iron contributes to postmenopausal osteoporosis by slowing down bone formation, a mode of action that is different from estrogen. In vitro, an elevated level of iron inhibits osteoblast differentiation and maturation and has minimal effects on osteoclasts. In vivo, mice fed on an iron-rich diet display a significant decrease in BMD compared to control mice on a normal diet. Human body has many ways to absorb, transfer, and store iron but has no effective way to excrete it. Decreasing body iron levels in postmenopausal women hits the real target and presents a viable therapeutic solution to improve the bone. The principal regulator of iron homeostasis, hepcidin, can be administered to achieve this goal. Hepcidin is a peptide hormone that binds to the sole cellular exporter of iron, ferroportin, induces its internalization and, thus, blocks iron transport and uptake from the gut to the circulation. Therefore, hepcidin can be used to treat, prevent, or reduce the risk of osteoporosis in older women.   Applications: This novel finding shows that a high iron level in postmenopausal conditions is a critical factor in osteoporosis and can potentially be treated by hepcidin or a functional equivalent that will reduce iron levels. Figure 1. Concurrent but inverse changes in ferritin versus estrogen levels during menopausal transition. Estrogen deficiency promotes bone resorption and increased iron inhibits bone formation. Bone resorption outpacing bone formation is the real cause of postmenopausal osteoporosis.