Physiology of bone loss

Abstract

The physiology of bone loss in aging women and men is largely explained by the effects of gonadal sex steroid deficiency on the skeleton. In women, estrogen deficiency is the main cause of early rapid postmenopausal bone loss, whereas hyperparathyroidism and vitamin D deficiency are thought to explain age-related bone loss later in life. Surprisingly, estrogen deficiency also plays a dominant role in the physiology of bone loss in aging men. Many other factors contribute to bone loss in aging women and men, including defective bone formation by aging osteoblasts, impairment of the growth hormone/insulin-like growth factor axis, reduced peak bone mass, age-associated sarcopenia, leptin secreted by adipocytes, serotonin secreted by the intestine, and a long list of sporadic secondary causes. Further elucidation of the relative importance of each of these factors will lead to improved preventive and therapeutic approaches for osteoporosis.

Figure 1

Patterns of are-related bone loss in women and men. Dashed lines represent trabecular bone and solid lines, cortical bone. The figure is based on multiple cross-sectional and longitudinal studies using DXA. (Reproduced from Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin N Am 2005;34(4):1017; with permission.)

Figure 2

(A) Values for vBMD (mg/cm³) of the total vertebral body 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 cortical vBMD at the distal radius in the same cohort, with color code as in (A). All changes with age were significant (P < .05). (Reproduced from Riggs BL, Melton LJ 3^rd, Robb RA, et al. A population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res 2004;19(12):1950; with permission.)

Figure 3

Age-specific incidence rates for proximal femur (hip), vertebral (spine), and distal forearm (wrist) fractures in Rochester, Minnesota, women (A) and men (B). (Adapted from Cooper C, Melton LJ. Epidemiology of osteoporosis. Trends Endocrinol Metab 1992;3(6):225; with permission.)

Figure 4

Summary of stimulatory and inhibitory factors involved in osteoclast development and apoptosis. (Reproduced from Quinn JMW, Saleh H. Modulation of osteoclast function in bone by the immune system. Mol Cell Endocrinol 2009;310(1–2):42; with permission.)

Figure 5

Rate of change in mid-radius BMD (A) and mid-ulna BMD (B) as a function of bioavailable estradiol levels in elderly men. Model R² values were 0.20 and 0.25 for the radius and ulna, respectively, both less than 0.001 for comparison with a one-slope model. Solid circles correspond to subjects with bioavailable estradiol levels below 40 pmol/L (11 pg/mL) and open circles those with values above 40 pmol/L. (Reproduced from Khosla S, Melton LJ 3^rd, Atkinson EJ, et al. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 2001;86(8);3558; with permission.)

Figure 6

Percent changes in (A) bone resorption markers (urinary deoxypyridinoline [Dpd] and N-telopeptide of type I collagen [NTx] and (B) bone formation markers (serum osteocalcin and N-terminal extension peptide of type I collagen [P1NP]) in a group of elderly men (mean age 68 years) made acutely hypogonadal and treated with an aromatase inhibitor (Group A), treated with estrogen alone (group B), treated with testosterone alone (Group C), or both (Group D). Significance for change from baseline: * P < .05; ** P < .01; *** P < .001. (Adapted from Falahati-Nini A, Riggs BL, Atkinson EJ, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000;106(12);1556–7; with permission.)