Seeking genetic causes of "osteoporosis:" insights of the Utah paradigm of skeletal physiology.

This article investigates: (1) the criteria used to select cohorts of patients for study when seeking genetic causes of "osteoporosis;" (2) the possibilities, genetic and otherwise, that might cause or help to cause this disorder; and (3) how one should define this disorder and bone health. Patients selected for such a study because current World Health Organization (WHO) absorptiometric criteria diagnosed them with "osteoporosis," or because they had extremity bone fractures, could possibly include people with biologically different disorders, in addition to those with healthy or diseased bones. Seeking a common genetic cause of "osteoporosis" in such inhomogeneous cohorts may be like seeking a common genetic cause of "anemia" in a cohort that contained iron deficiency and pernicious anemias, thalassemia, sickle-cell disease, anemias due to blood loss, malnutrition, malaria, metastatic disease, etc. The Utah paradigm's insights suggest how to select more homogeneous cohorts for such studies. This would require defining bone health in a way that acknowledges the main purpose of load-bearing bones, which the WHO criteria do not do. The present understanding of bone physiology indicates that many biologic mechanisms and features could cause or help to cause an osteopenia or osteoporosis. This study identifies 30 such mechanisms, some osseous and some extraosseous, and even this number seems conservative. Because each such mechanism could depend on any number of genes, when a strong genetic association with some kind of osteopenia or osteoporosis is found it could be difficult to determine which mechanism(s) it perturbed. This article summarizes the evidence and ideas on which these suggestions depend.