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Abstract and Introduction
Abstract
This is a review article designed to address the effects of soy isoflavones on bone metabolism in postmenopausal women and their place in the prevention and treatment of postmenopausal osteoporosis. Soy isoflavones are natural products that could be used as an alternative to menopausal hormone therapy because they are structurally and functionally related to 17β-estradiol. In vitro and animal studies have shown that they act in multiple ways to exert their bone-supporting effects. They act on both osteoblasts and osteoclasts through genomic and nongenomic pathways. Epidemiological studies and clinical trials suggest that soy isoflavones have beneficial effects on bone mineral density, bone turnover markers, and bone mechanical strength in postmenopausal women. However, there are conflicting results related to differences in study design, estrogen status of the body, metabolism of isoflavones among individuals, and other dietary factors. The long-term safety of soy isoflavone supplements remains to be demonstrated.
Introduction
Osteoporosis is a progressive systemic skeletal disorder characterized by reduced bone mass and poor bone quality leading to increased bone fragility and fracture risk. Because of increasing life expectancy and consequently the proportion of older individuals in the general population, the prevalence of osteoporosis is expected to increase as well, and it is considered to be a worldwide major health problem with increasing treatment costs. Osteoporosis-related fractures are one of the major causes of morbidity and mortality in postmenopausal women. The mortality of older men and women with hip fractures has increased by 15% to 20%. For white women, lifetime risks of hip, vertebral, and distal radius fractures are 19%, 15.6%, and 16%, respectively, and for women older than 50 years of age, the lifetime fracture risk for any skeletal region is 40%. In addition, there are other dire consequences to fractures, including adverse effects on quality of life for many years after the fracture.
Risk factors for osteoporosis include female gender, advanced age, family history of osteoporosis, thin body frame, postmenopausal estrogen deficiency, testosterone deficiency in men, cigarette smoking, excessive alcohol consumption, diet low in calcium, sedentary lifestyle, long-term use of drugs such as glucocorticoids and anticonvulsants, anorexia nervosa or bulimia, and white race. Bone loss occurs most rapidly during the years after menopause. Women may lose up to 20% of their bone mass in 5 years after menopause. However, this may be an overestimate as recent studies report a 5.6% bone loss in the 4 years after menopause. Therapies for the prevention and treatment of postmenopausal osteoporosis include agents that inhibit bone resorption (menopausal hormone therapy [MHT] with estrogen alone or a combination of estrogen and progestins, bisphosphonates, raloxifene, and calcitonin) and agents that stimulate bone formation (only teriparatide to date).
Before the publication of Women's Health Initiative (WHI) trial findings, the combination of estrogen with or without progestin therapy was a first-line therapy for the prevention of early postmenopausal bone loss and for the treatment of osteoporosis. The WHI study did not directly address early postmenopausal bone loss. The WHI trial demonstrated a 24% decreased risk of fractures and a 37% decreased risk of colon cancer, but a 26% increased risk of breast cancer and 22% increased risk of total cardiovascular outcomes after an average 5.2 years of use of the estrogen and progestin combination. The trial with an estrogen-alone arm in hysterectomized women demonstrated an increased risk of cerebrovascular events. Even before the WHI trial, compliance to MHT by many women was very low due to the concerns about the risks of therapy. The results of WHI trial only added more uncertainty for both postmenopausal women and their physicians. Therefore, research has begun to focus on pharmaceutical and natural alternatives to MHT that could provide the beneficial effects of estrogen on bone, cognitive function, and menopausal symptoms without adverse effects on the breast, uterus, and cardiovascular system.
Selective estrogen-receptor modulators (SERMs) were developed for this reason, and raloxifene has been approved in many countries as the first SERM for the prevention and treatment of postmenopausal osteoporosis. However, raloxifene treatment is not without risk. Besides having as much risk of thromboembolic events as estrogen, it may exacerbate menopausal symptoms. Therefore, both women and physicians remain concerned about the adverse effects of estrogen and are looking to natural products that have the beneficial effects of estrogen. Recent reports suggest that soy phytoestrogens (plant estrogens), namely isoflavones, act like natural SERMs. This review focuses on soy isoflavones, their effects on bone, and their place in the prevention and treatment of postmenopausal osteoporosis. The aim of this review is to explore the mechanism of action of soy isoflavones as reported in in vitro and animal studies, to discuss the results and controversies of observational and interventional studies, and to discuss the place of soy isoflavones in the management of postmenopausal osteoporosis. No attempt has been made to rate the quality of studies. A formal systematic review or meta-analysis was not performed because of the many differences in study populations, design, duration, route and dose of administration of soy proteins and/or isoflavones, and outcome variables ( Table 1 , Table 2 , and Table 3 ). In this review, we have included relevant reports published in the English literature listed in PubMed. After briefly reviewing the food sources of isoflavones and their structure and metabolism, we review preclinical (in vitro and animal) and human (observational and interventional) studies under separate headings. We also list the observational ( Table 1 ) and interventional studies in separate tables ( Table 2 and Table 3 ).
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