Osteoporosis is a heterogeneous disorder that is caused by multiple pathogenetic mechanisms. The clinical manifestation of osteoporosis is fracture, and the mechanisms that lead to fracture are multifactorial and include factors that result in low peak bone mass, bone loss after menopause, and factors involved in falls (see Plate 3-26).

Age and Sex Factors. The development of osteoporosis in postmenopausal women is linked to a number of factors, the most important being estrogen deficiency. Before menopause, bone formation and resorption are balanced. At menopause, the rate of bone turnover increases with the rate of bone resorption increasing more than formation. Biochemical markers of bone resorption are increased. Estrogen plays a central role in regulating RANK ligand (RANKL), a molecule that is critical for osteoclast formation and activity. As estrogen declines, RANKL is unregulated and osteoclast activity is increased. Because men do not undergo the abrupt hormonal equivalent of menopause, they experience a slower rate of decline in bone mass and fewer fractures. Other risk factors include low peak bone mass, reduced levels of 1,25(OH)₂D, a calciumdeficient diet, and reduced calcium absorption from the intestine (characteristic of elderly persons).

Genetic Factors. Studies of monozygotic and dizygotic twins show a high heritability, between 60% and 80%, of bone mass. The heritability of fracture risk is less because environmental factors such as exercise, diet, and fall risk have a significant effect with aging. Genetic factors are likely to be important in the development of peak bone mass. Candidate genes for low bone mass include those responsible for receptors or proteins involved in bone biology such as lipoprotein receptor 5 (LRP5) and sclerostin (involved in Wnt signaling), vitamin D receptor, estrogen receptor, and type I collagen among others. Polymorphisms in candidate genes have a small effect size, indicating that osteoporosis is multifactorial with many genes involved.

Endocrine Abnormalities. Endocrine-mediated osteoporosis should be suspected in any young or middle-aged person with osteopenia. In the elderly person, endocrine-mediated osteoporosis can occur in conjunction with postmenopausal or age-related osteoporosis.

Hypogonadism causes bone loss in both men and women. In postmenopausal women estrogen deficiency plays a key role in increasing osteoclast activity and bone resorption. Other hypogonadal conditions that lead to bone loss are panhypopituitarism, Klinefelter syndrome, Turner syndrome, and idiopathic hypogonadotropic hypogonadism. Medications that lower the level of estrogens, such as medroxyprogesterone (inhibits pituitary gonadotropin release) and aromatase inhibitors (inhibit enzymatic androgen conversion to estrogen), increase the rate of bone loss in women. Medications that lower the level of androgens, such as bicalutamide (binds and inhibits androgen receptors) and leuprolide (inhibits gonadotropin release suppressing ovarian and testicular steroidogenesis) increase the rate of bone loss in men.

Thyrotoxicosis, caused by glandular hyperactivity or by excessive replacement of thyroid hormone, increases bone turnover and bone resorption. Older postmenopausal women with TSH levels below 0.1 have been shown to have a significant increase in hip, vertebral, and nonvertebral fracture risk compared with women with levels between 0.5 and 5.5.