Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications

Abstract

Bone is a multi-skilled tissue, protecting major organs, regulating calcium phosphate balance and producing hormones. Its development during childhood determines height and stature as well as resistance against fracture in advanced age. Estrogens are key regulators of bone turnover in both females and males. These hormones play a major role in longitudinal and width growth throughout puberty as well as in the regulation of bone turnover. In women, estrogen deficiency is one of the major causes of postmenopausal osteoporosis. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens not only in females but also in males, during different life stages. Effects of estrogens on bone involve either Estrogen Receptor (ER)α or ERβ depending on the type of bone (femur, vertebrae, tibia, mandible), the compartment (trabecular or cortical), cell types involved (osteoclasts, osteoblasts and osteocytes) and sex. Finally, we will discuss new ongoing strategies to increase the benefit/risk ratio of the hormonal treatment of menopause.

Keywords: ERαMISS; bone remodeling; estrogen receptor; estrogens; nuclear effects; sexual dimorphism.

Figure 1

Roles of estrogen in women and men throughout life. (E2: 17β-estradiol).

Figure 2

Regulation of bone metabolism by estrogen receptors, cellular and molecular aspects. Estrogen’s protective effects on trabecular and cortical bone are mainly mediated by Estrogen Receptor α (ERα) in both females and males, while ERβ only plays a minor role in female and none in male. ERα belongs to the nuclear receptor superfamily and exerts its transcriptional activity though two activating functions (AFs), AF1 and AF2. Both AF1 and AF2 functions are necessary to mediate estrogen effects, whereas, in the cortical compartment, only AF2 function is necessary in females and males. Genetic murine models have allowed the study of the role of ERα in bone cells (osteoclasts, osteoblasts and osteocytes). For each bone compartment and sex, the cell types involved in estrogen’s protective effects are indicated. A red box highlights essential ERα subfunctions in each cell type, whereas a red X indicates the dispensable ERα subfunction.