Role of genetic factors in the pathogenesis of osteoporosis

Abstract

Osteoporosis is a common disease with a strong genetic component characterised by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density and other determinants of osteoporotic fracture risk, such as ultrasound properties of bone, skeletal geometry and bone turnover. Osteoporosis is a polygenic disorder, determined by the effects of several genes, each with relatively modest effects on bone mass and other determinants of fracture risk. It is only on rare occasions that osteoporosis occurs as the result of mutations in a single gene. Linkage studies in man and experimental animals have defined multiple loci which regulate bone mass but the genes responsible for these effects remain to be defined. Population-based studies and case-control studies have similarly identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor, oestrogen receptor and collagen type I I gene. The individual contribution of these genes to the pathogenesis of osteoporosis is small however, reflected by the fact that the relationship between individual candidate genes and osteoporosis has been inconsistent in different studies. An important aim of future work will be to define how the genes which regulate bone mass, bone turnover and other aspects of bone metabolism interact with each other and with environmental variables to cause osteoporosis in individual patients. If that aim can be achieved then there is every prospect that preventative therapy could be targeted to those at greatest risk of the osteoporosis, before fractures have occurred.

Estrogen receptor alpha gene polymorphisms Pvu II and Xba I influence association between leptin receptor gene polymorphism (Gln223Arg) and bone mineral density in young men

“…Although evidence shows such an association, it has been shown to be dependent on the site of measurement, age, and ethnicity of the study population. Thus, no consensus has been made on the role of ERa polymorphism on female BMD (6). ERa polymorphism may be of interest in men as well in view of the evidence supporting the importance of estrogen on the male skeleton (3), but only a few reports have studied its role in association with male BMD (18,35).…”

“…Although environmental factors such as nutrition and physical activity may affect the peak bone mass, genetic factors are the deciding determinants (5). Several genes, such as the vitamin D receptor, estrogen receptor a (ERa), type 1 collagen, and transforming growth factor-b genes, have been studied for an association between their genetic polymorphisms and bone mass (6). In most of these studies, however, the study populations have been postmenopausal women, in whom accretion of bone mass has ceased and bone loss has begun.…”

LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density

“…The BMD, a good scale to predict the risk of subsequent fractures, is regulated by both polygenes and environmental factors. Although both twin and family studies have shown that 50-80% of age-related variance of BMD are genetically determined (Eisman 1999;Stewart and Ralston 2000), genetic susceptibility to osteoporosis has not fully been understood. Previous studies demonstrated that BMD is associated with several genes/proteins.…”

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

“…1 Positive family history is one of the major risk factors for osteoporosis, and epidemiological studies indicate that genetic factors contribute substantially to susceptibility to osteoporosis. 2 In 1998 we first reported a whole-genome scan of osteoporosis-related traits, based on the analysis of a small sample of extended Caucasian pedigrees of Canadian origin that had been selected through a proband with low bone mineral density (BMD). 3 Our study focused on quantitative trait linkage analysis of lumbar spine (LS) and femoral neck (FN) BMD and identified three regions with lod-scores X2.2 on chromosomes 1p, 2p, and 4q.…”