Pathogenesis of age-related bone loss in humans

Abstract

Background: Although data from rodent systems are extremely useful in providing insights into possible mechanisms of age-related bone loss, concepts evolving from animal models need to ultimately be tested in humans.

Methods: This review provides an update on mechanisms of age-related bone loss in humans based on the author's knowledge of the field and focused literature reviews.

Results: Novel imaging, experimental models, biomarkers, and analytic techniques applied directly to human studies are providing new insights into the patterns of bone mass acquisition and loss as well as the role of sex steroids, in particular estrogen, on bone metabolism and bone loss with aging in women and men. These studies have identified the onset of trabecular bone loss at multiple sites that begins in young adulthood and remains unexplained, at least based on current paradigms of the mechanisms of bone loss. In addition, estrogen appears to be a major regulator of bone metabolism not only in women but also in men. Studies assessing mechanisms of estrogen action on bone in humans have identified effects of estrogen on RANKL expression by several different cell types in the bone microenvironment, a role for TNF-α and IL-1β in mediating effects of estrogen deficiency on bone, and possible regulation of the Wnt inhibitor, sclerostin, by estrogen.

Conclusions: There have been considerable advances in our understanding of age-related bone loss in humans. However, there are also significant gaps in knowledge, particularly in defining cell autonomous changes in bone in human studies to test or validate concepts emerging from studies in rodents. Decision Editor: Luigi Ferrucci, MD, PhD.

Keywords: Aging.; Bone; Estrogen; Osteoporosis.

Figure 1.

(A) Values for vBMD (mg/cm³) of cortical bone at the distal radius in a population sample of Rochester, Minnesota women and men between the ages of 20 and 97 years. Individual values and smoother lines are given for premenopausal women in red, for postmenopausal women in blue, and for men in black. (B) Values for vBMD of the total vertebral body in the same cohort. Color code is as in Panel (A). All changes with age were significant (p < .05). Reproduced from Riggs and coworkers (7), with permission.

Figure 2.

Representative cross-sectional images from HRpQCT scans from younger and older women (top panels) and younger and older men (bottom panels) with similar UD radius vBMD values (within 3% of each other) but marked differences in cortical porosity. Reproduced from Nicks and coworkers (11), with permission.

Figure 3.

Proportional change (%) in serum C-telopeptide of type I collagen in postmenopausal women treated for 60 days with transdermal estradiol, made acutely estrogen deficient, and treated with saline (control), an IL-1 blocker (anakinra), or a TNF blocker (etanercept). From Charatcharoenwitthaya and coworkers (26), with permission.

Figure 4.

Intrinsic mechanisms that are involved in osteoblast senescence and resulting in decreased bone formation and bone loss associated with aging. Reproduced from Kassem and coworkers (54), with permission.

Figure 5.

Serum sclerostin levels versus age in (A) women and (B) men. Correlation coefficients are as noted. Reproduced from Mödder and coworkers (57), with permission.