Osteopenia

Abstract: Osteoporosis is a complex disease that affects >10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease. In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high–bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted β-propeller module of the low-density lipoprotein receptor–related protein 5 (LRP5), that results in the HBM phenotype. During analysis of >1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.

Abstract: The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.

Abstract: ContextLarge segments of the population at risk for osteoporosis and fracture have not been evaluated, and the usefulness of peripheral measurements for short-term prediction of fracture risk is uncertain.ObjectivesTo describe the occurrence of low bone mineral density (BMD) in postmenopausal women, its risk factors, and fracture incidence during short-term follow-up.DesignThe National Osteoporosis Risk Assessment, a longitudinal observational study initiated September 1997 to March 1999, with approximately 12 months of subsequent follow-up.Setting and ParticipantsA total of 200 160 ambulatory postmenopausal women aged 50 years or older with no previous osteoporosis diagnosis, derived from 4236 primary care practices in 34 states.Main Outcome MeasuresBaseline BMD T scores, obtained from peripheral bone densitometry performed at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire responses; and clinical fracture rates at 12-month follow-up.ResultsUsing World Health Organization criteria, 39.6% had osteopenia (T score of –1 to –2.49) and 7.2% had osteoporosis (T score ≤−2.5). Age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use were associated with significantly increased likelihood of osteoporosis; higher body mass index, African American heritage, estrogen or diuretic use, exercise, and alcohol consumption significantly decreased the likelihood. Among the 163 979 participants with follow-up information, osteoporosis was associated with a fracture rate approximately 4 times that of normal BMD (rate ratio, 4.03; 95% confidence interval [CI], 3.59-4.53) and osteopenia was associated with a 1.8-fold higher rate (95% CI, 1.49-2.18).ConclusionsAlmost half of this population had previously undetected low BMD, including 7% with osteoporosis. Peripheral BMD results were highly predictive of fracture risk. Given the economic and social costs of osteoporotic fractures, strategies to identify and manage osteoporosis in the primary care setting need to be established and implemented.