Uncovering the Genetic Basis of Osteoporosis
Philip Dopp, BSc
The disturbing statistics with regard to the prevalence of osteoporosis among older women are well known. By 65 years of age, one in four women have experienced an osteoporotic fracture, and the rate of incidence rises to one in two by the age of 75. The incidence of hip fractures among women in the United States is 2 per 1000 patient years by the age of 65 and 30 per 1000 patient years by the age of 85.1 More importantly, hip fractures in the elderly are associated with a high mortality rate. Both men and women are between two and five times more likely to die during the first 12 months following a hip fracture when compared to age and sex matched controls without hip fractures. Given this and other serious consequences, there is much interest in discovering factors that can prevent or slow the rate of development of this disease.1
Pathophysiology of Osteoporosis
Osteoporosis is the generalized, progressive diminution in bone tissue mass per unit volume which causes skeletal weakness, even though the remaining bone is normal morphologically. It is well known that factors that decrease bone mineral density (BMD) and increase the risk of osteoporotic fractures include family history, white race, female gender, estrogen deficiency, low dietary levels of calcium and vitamin D, limited physical activity or immobility and medications such as corticosteroids.1,2 Currently, there has been an increased interest in determining the role that genetic factors play in the pathogenesis of osteoporosis.
A Genetic Basis for Osteoporosis?
Recent studies have suggested that between 50% and 80% of the variability in bone mass, may be genetically related.3-5 Numerous family and twin studies have demonstrated a strong genetic component in the development of osteoporosis. In an attempt to explain these findings, researchers have identified several genes that may play a role in the progression of osteoporosis.
Family studies have been used to demonstrate the effect of genetic factors on peak bone mass. Studies of mother-daughter pairs have revealed that the daughters of women with hip fractures have reduced proximal femoral bone density. Similarly, women with a maternal history of osteoporosis were found to have a 6-7% decrease in bone mineral content of the mid- and distal radius when compared to controls with no familial history of osteoporosis.4,6 Other studies have found heritability estimates, or the proportion of a population's phenotypic variation that is attributable to genetic factors, to be as high as 0.50-0.70 for bone mass/width and bone mass, when radial bone mass of mother and daughter were correlated.7 Finally, it has been found that there is a significant correlation in BMD in the lumbar and femoral areas in mother-daughter pairs.4
Several twin studies have shown strong genetic influences on BMD in both peripheral and axial bone. Interestingly, the largest genetic influence was noted in areas of high trabecular bone content, such as the spine and Ward's triangle in the proximal femur, rather than in areas of cortical bone.8,9 Given the influence of bone size and geometry (or structural arrangement), along with bone microarchitecture in determining skeletal strength, it is significant that twin studies have also found that genes are a strong determinant of bone geometry and of the capa-city of bone to respond to exercise.9 Additional twin studies have examined whether the rate of bone loss that occurs with aging is influenced by genetics. Though earlier data suggested that there might be no genetic influence on the rate of bone loss, more recent data have shown that the rate of change