Pathophysiology of osteoporosis: unresolved problems and new insights.

Optimal bone mass depends on sufficient sex hormones, building materials, and loading. Sex hormones add to bone mass the amount that is needed for reproduction. Healthy males keep their testosterone until death, but the female sex loses estrogens at menopause, connected with high bone turnover and bone loss. It is not known why and which women lose more bone than others and develop osteoporosis. One factor could be latent hypoandrogenism. Even in men the levels of bioavailable plasma testosterone correlate with bone mineral density. With respect to nutrition, calcium and vitamin D are most important contributors to bone mass. Osteoporotics absorb less calcium from the gut than controls, perhaps because of unfavorable gene alleles for the vitamin D receptor. Furthermore, the general supply with calcium and vitamin D in the normal population could be of greater significance than assumed. The combination of a receptor defect and a latent deficiency could be deleterious. Finally, bones need loading. Mechanoreceptors that transform physical stress into biochemical signals are postulated to exist and to be upregulated by the sex hormones. As a result, bone mass increases more after exercise when it has been exposed to sex hormones. The amount of bone mass due to spontaneous activity is likely to be genetically determined. Current efforts are devoted to the better identification of risk factors and behavior that impair bone mass and density. The discovery of genetic risks and their early diagnosis in humans would greatly facilitate a preventive regimen.