Further evidence that FSH causes bone loss independently of low estrogen

Abstract

IntroductionThe premise that menopause causes osteoporosis was firstproposed by Fuller Albright at the Massachusetts GeneralHospital [1]. His hypothesis linking the loss of sex steroidsto bone loss led to estrogen hormone replacement therapy(HRT) becoming the first successful treatment for osteo-porosis [2]. More recently, however, a finer re-examinationof menopausal bone loss has revealed that nearly half oflifetime loss occurs within the first 5 years [3, 4]. Bone lossaccelerates dramatically during the late peri-menopause,and can, in fact, be most rapid up to 3 years before the lastmenstrual period [3–5] (Fig. 1a). During this early phaseup to 5 years before the last menstrual period, estrogenlevels are relatively unperturbed, whereas follicle-stimu-lating hormone (FSH) levels are rising to compensate forfailing ovaries [6, 7] (Fig. 1b). These most rapid rates ofbone loss cannot conceivably be explained by low estro-gen; other pathophysiological mechanisms must play adominant role.In the early 2000s, we showed that pituitary hormonescan directly affect the skeleton by bypassing their usualendocrine targets. Thyroid-stimulating hormone (TSH) wasfirst documented to regulate bone remodeling directly byacting on both osteoclasts and osteoblasts [8]. Not only didthis study attribute the osteoporosis of hyperthyroidism, inpart, to low TSH levels, it set forth a new paradigm for theexistence of a pituitary-bone axis (Fig. 2). As part of thisparadigm shift, we later discovered that FSH directlystimulates bone resorption [9]; thus the idea that rising FSHlevels during the late peri-menopause could potentiallycontribute to the bone loss traditionally attributed solely tolow estrogen [10]. We are by no means limiting the provenimportance of low estrogen in causing bone loss. Instead,we suggest circumstances, such as the late peri-menopause,where FSH may play a dominant role.Several studies have confirmed direct effects of FSH onbone. Amenorrheic women with a higher mean serum FSH(*35 IU/L) have greater bone loss than those with lowerlevels (*8 IU/L) in the face of near-equal estrogen levels[11]. Likewise, in a recent study, patients with functionalhypothalamic amenorrhea, in whom both FSH and estrogenwere low, showed slight to moderate skeletal defects [12].Furthermore, women harboring an activating FSH receptor(FSHR) polymorphism, rs6166, have lower bone mass andhigher resorption markers [13]; this attests to a role forFSHRs in human physiology, and perhaps, even humanpathophysiology. Consistent with these human studies,exogenously administration of FSH to rats augmentedovariectomy-induced bone loss [14, 15]. Moreover, an FSHantagonist reduced bone loss post-ovariectomy, as well asthat induced by exogenous FSH [14, 15].Clinical correlations between bone loss and serum FSHlevels have been documented extensively. Most impressiveis the Study of Women’s Health across the Nations(SWAN), a longitudinal cohort of 2,375 peri-menopausalwomen. Not only was there a strong correlation betweenserum FSH levels and markers of bone resorption, a changein FSH levels over 4 years predicted decrements in bone