Soy phytoestrogens: impact on postmenopausal bone loss and mechanisms of action Raewyn C Poulsen and Marlena C Kruger Due to their ability to mimic the actions of mammalian estrogens, soy phytoestrogens have been proposed as potential therapeutic agents to aid in preventing postmenopausal bone loss. In vitro, phytoestrogens promote osteoblastogenesis and inhibit osteoclastogenesis. Although a relatively large number of intervention studies have been undertaken in animals and humans, the efficacy of phytoestrogens as bone-protective agents in vivo remains unclear. Differences in the bioactivities of individual phytoestrogens, differences in phytoestrogen metabolism and bioavailability within different study populations, and imprecise reporting of the dose of phytoestrogens administered in intervention studies may have contributed to the disparity in study findings. © 2008 International Life Sciences Institute INTRODUCTION Phytoestrogens are plant-derived compounds that exhibit similar, albeit weaker, effects than mammalian estrogens. Menopause in women results in reduced production of endogenous estrogens. Estrogens play a major role in the regulation of bone metabolism and some of the conse- quences of menopause are reductions in bone mass and increased risk of osteoporosis. There is interest in deter- mining the efficacy of phytoestrogens as a possible means of minimizing postmenopausal bone loss in women. In Western countries, approximately 30% of women over the age of 50 years have osteoporosis. 1 Osteoporosis is a debilitating disease characterized by decreased bone mass, microarchitectural deterioration of bone tissue, and increased risk of fracture. 2 It arises due to disruption of the normal process of bone remodeling. Bone remodeling occurs throughout the lifetime. It involves the sequential and coupled resorption of fatigued bone tissue and replacement with newly synthe- sized bone. Bone remodeling ensures the structural integ- rity of the skeleton is maintained. Three different types of bone cell – osteocytes, osteoclasts, and osteoblasts – are involved in the remodeling process. Osteocytes are cells that reside within bone. They sense mechanical stress and signal the need for remodeling at specific sites in bone. 3 In response to osteocyte signaling, osteoclasts resorb fatigued bone tissue. 4 New bone is then synthesized and laid down by osteoblasts. 5 Usually, osteoclast-mediated bone resorption is balanced completely by osteoblast- mediated bone formation. However, lifestyle factors, endocrine changes, such as those that occur with aging, or inflammation, which may arise as a result of illness, impact the regulation of bone remodeling. 6 A major factor contributing to the high incidence of osteoporosis in older women is the reduction in estrogen synthesis that occurs during menopause. Estrogen has wide-ranging effects on the regulation of bone remodeling. Through both direct and indirect effects, it influences calcium bioavailability, the activity of other endocrine factors involved in the regulation of bone remodeling, and the synthesis and activity of various inflammatory cytokines. In rats, surgical menopause (ovariectomy) leads to a selective reduction in the number of vitamin D receptors (VDR) in jejunal but not renal cells. 7 A reduction in the jejunal VDR number results in reduced responsiveness of intestinal cells to vitamin D signaling and, therefore, Affiliations: RC Poulsen and MC Kruger are with the Institute of Food Nutrition and Human Health, Massey University, Palmerston North, New Zealand. Correspondence: MC Kruger, Institute of Food Nutrition and Human Health, Massey University, Private Bag 11-222, Palmerston North, New Zealand. E-mail m.c.kruger@massey.ac.nz, Phone: +64-6-350-5905, Fax: +64-6-350-5446. Key words: daidzein, genistein, isoflavones, osteoblast, osteoclast, osteoporosis. Lead Article doi:10.1111/j.1753-4887.2008.00046.x Nutrition Reviews® Vol. 66(7):359–374 359