What Is the Missing Hormonal Factor Controlling Menopausal Bone Resorption?

Abstract

Estrogen is critical for maintaining normal bone remodeling in women and also in men (1). Postmenopausal osteoporosis is characterized by an imbalance between increasedosteoclastactivityanddecreasedosteoblast function, resulting in increased bone remodeling, bone microarchitecturaldeterioration, andskeletal fragility.Estrogendeficiency may be responsible for both the accelerated phase of bone loss at the menopause and the slower phase of age-related bone loss later in life. Recently, this dogma has been challenged by the assertion that the concomitant increase in serum FSH levels at the time of the menopause may be the principal cause of the increase in bone resorption and accelerated bone loss occurring during the menopause transition. The identification of women with rapid perimenopausal bone loss is important to target aggressive early intervention. The diagnosis of osteoporosis based on T-scores alone or through stratification for a high fracture risk by the WHO FractureRiskAssessmentTool (FRAX)orother fracturerisk calculator tools will exclude these women who are rapidly losing bone. Because all antiosteoporosis therapies, in particular the bisphosphonates, reduce bone loss, some experts propose aggressive, short-term therapy with a goal to reduce bone loss, stabilize bone density, and prevent microarchitectural deterioration for these women with rapid perimenopausal bone loss (2). The finding that perimenopausal bone loss begins when serum estradiol concentrations are still in the normal range launched the search for a missing hormonal factor controlling menopausal bone resorption. Several potential endocrine contributors to this perimenopausal bone loss have been proposed over the years. They include alterations to the luteal phase of ovarian function resulting in low progesterone levels (3), reductions in circulating androgen levels (4), and decreases in serum inhibin (A and B) concentrations (5). Inhibin, which is present in ovarian follicular fluid (6), was originally identified because of its ability to suppress pituitary FSH secretion. Two isoforms have subsequently been identified, inhibin B and inhibin A. Inhibin B and inhibin A are heterodimeric proteins in the TGF superfamily comprising B and A subunits, respectively, and decreases in both have been associated with increases in bone turnover markers (5). However, currently more data have been gathered in favor of FSH having a likely role as a mediator of perimenopausal bone turnover. We previously demonstrated a stronger association between FSH levels and bone resorption markers in late premenopausal women than for serum estradiol, the latter of which remained within the normal range (7). Using an older RIA that did not differentiate between inhibin isoforms, we could not detect differences in serum inhibin levels in the same late premenopausal women, but we did demonstrate decreases in inhibin in both postmenopausal women and women on hormone therapy. Subsequently, other investigators have shown that a selective decrease in ovarian secretion of the inhibin B isoform is associated with this early rise in FSH in the late premenopause (8). Similar to our study, longitudinal data from the U.S. Study of Women’s Health Across the Nation (SWAN) showed that bone loss from the spine and hip was related both to the initial FSH concentrations and to changes in FSH levels, but to neither estradiol nor androgens (9). This could, however, be explained by FSH acting as a better integrated measure of ovarian estradiol production than a single measurement of serum estradiol, rather than being due to a direct effect of FSH on bone remodeling.