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Osteoporosis is "a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture" (World Health Organisation 2002) In Ireland currently there are 2,800 hip fractures per year and is expected to exceed 5,700 by the year 2026. Inpatient cost of treating a hip fracture is â‚¬15,000, including rehabilitation and is expected to rise to â‚¬26,000. The Irish government now spends â‚¬420m a year on fractures and by the year 2030 this is estimated to exceed â‚¬2 billion. The most common clinical outcomes of osteoporosis are fracture of the spine, hip, and wrist. Therefore osteoporosis is a relatively common disease and is ever growing, and so warrants research into the multiple factors, which cause it. Fracture usually occurs in adults however some factors causing it manifest and develop from a younger age.
The disease is defined to exist when bone mineral density values as estimated by dual energy X-ray absorptiometry fall for more than 2.5 standard deviations below the young adult mean (Kansis et al. 1994). Bone mineral density (BMD) is the ratio between bone mineral content and bone area scanned (g/cm²). Osteoporosis therapies can be divided into drug therapies and lifestyle modifications. These include diet, exercise and also oestrogen and other drug therapies. Bone health is measured by analysing bone density and bone quality
The factors relating to osteoporosis are complex, involving a broad spectrum of endogenous and environmental factors. The determinants of bone health include 2 groups:
Unmodifiable- Genetics, Medical History, Age, Sex
Modifiable- Calcium Intake, Vitamin D, Smoking, Alcohol Consumption, BMI, Physical Activity
In this essay I will look at the evidence pertaining to genetic factors and smoking, and the risk of osteoporosis. I will discus the limitations associated with the evidence presented and conclude on both factors.
From twin and family studies, 46-80% of variance in BMD is genetically determined. Relatives of osteoporosis patients have reduced BMD and higher bone remodelling rates. Twin studies have shown that genetic factors contribute to osteoporosis by influencing BMD and other determinants of fracture risk such as, skeletal geometry and bone turnover. In the normal population, many different genes contribute to the regulation of these phenotypes in their interaction with environmental factors such as exercise and diet. There are two basic strategies for identifying genes that influence BMD or other complex traits [Nguyen et al. 2000]:
The candidate gene approach, in which individual genes are examined directly for a possible role in determination of the trait of interest.
The genome-wide screening approach, in which all genes are examined systematically with panels of micro-satellite DNA markers uniformly distributed throughout the genome. In each of these approaches, susceptibility genes or loci are identified by demonstration of a significant linkage or association [Nguyen et al. 2000].
The results of whole-genome linkage analysis, partial-genome linkage analysis, and linkage analysis of candidate loci or genes for BMD or osteoporosis are summarized in Table 1 [Johnson et al. 1997; Devoto et al. 1998; Devoto et al. 2001; Duncan et al. 1999; Ota et al. 1999, 2000; Raymond et al. 1999] Polymorphisms of a variety of candidate genes have been associated with BMD or with genetic susceptibility to osteoporosis/osteoporotic fracture. (Table 2) Polymorphisms in some of those genes contribute to regulation of bone in the normal population. The most frequently investigated candidate gene for osteoporosis is the VDR gene (Table 1)
The VDR gene
The role of vitamin D and its receptor (VDR), on skeletal metabolism is well known and mutations in the VDR gene cause 1, 25-dihydroxyvitamin D resistant rickets (Malloy et al, 1994). The first indication of a significant effect of a common allelic variant on bone homeostasis comes from common polymorphisms in the VDR gene, which is associated with the level of osteocalcin a specific marker of bone turnover and BMD in a cohort of 91 normal British-Australian Caucasians. (Morrisson et al, 1992),
Studies in different populations have subsequently reported contradictory findings: some supported an association between VDR genotype and BMD (Spector et al 1995, Riggs et al, 1995), while others did not, (Alahari et al, 1997, Looney et al, 1995) or found an inverse relationship (Uitterlinden et al 1995, Houston et al, 1996). The controversy between VDR genotype and BMD and the risk of osteoporosis has been debated in some critical reviews and a meta-analysis with contradictory results (Cooper et al, 1996). Large studies in more populations are needed before we can clarify if, and how, VDR polymorphisms are major determinants of the risk of osteoporosis.
An explanation for discrepancies between studies is that the majority of studies published so far investigated small samples sizes (< 250 women) and may have had insufficient power to detect weak associations, as seen in Graph 1 (Cooper et al, 1996). This may explain why some groups were unable to confirm the associations reported by others (Risch et al, 1996). It is possible that variation in BMD and the risk of osteoporosis are due to interactions between the VDR gene and other genes and with environmental factors like gynaecological and reproductive history, diet and exercise and drug exposure (Giguire et al, 2000). The meta-analysis involving Cooper et al, on 16 studies showed that common VDR allelic variants were possibly associated with BMD but only weakly, and that about 1.7-2.5% of BMD variance is attributable to polymorphisms at the VDR. Therefore is it worthwhile investing so much time and money into VDR gene analysis?
By being able to identify the major genes contributable to osteoporosis it will allow the identification of at risk individuals with unfavourable genetics and also the interactions between those genes and environmental factors like diet and exercise.
This will lead to more specific and better-adapted treatment, and monitoring specific genes through the use of drugs.
Smoking is known to inhibit osteoblasts, which suppress bone formation and increase bone resorption. Insufficient calcium absorption into the bone from smoking may have a link with osteoporosis. This may lead to decreased BMD and increased fracture risk. As it is a modifiable factor, reducing or even ceasing smoking, can have positive implications in terms of bone mineral density, as described below.
In this older, population-based cohort followed prospectively, cigarette smoking reported 16 to 18 years earlier significantly predicted lower bone mineral density at the hip in both men and women as seen in Graph 2. (Hollenbach et al, 1993) Longitudinal study showed that low bone mineral density at the femoral neck is a potential predictor of increased mortality in elderly women in Japan. (Suzuki et al, 2009)
In women, a relationship between number of cigarettes smoked and bone mineral density (dose response) was observed at all hip sites, supporting a causal association. These findings of significant dose response relationships are simular to those reported by other investigators. A case-control study identified a dose-response risk of hip fracture in women by both duration of years smoking and number of cigarettes smoked. (La Vecchia et al. 1991) Ex-smokers have bone densities between those of current and never smokers therefore showing that cessation has potential benefits in terms of future bone health. (Rundgren and Mellstrom, 1984)
To date, too few studies of smoking and bone density of the proximal femur have been published to conclude whether the elderly hip is particularly vulnerable to the effects of cigarette smoking. This would be an important finding, given the impact of hip fracture on public health in an aging society. Since cigarette smokers typically are leaner and exercise less than non-smokers, some protection in non-smokers could be mediated by greater body mass or bone strength. (Hollenbach et al, 1993) Only one of three short-term prospective studies of smoking and bone density has found bone loss to be related to cigarette smoking independent of obesity (Krall et al 1991, Slemenda et al, 1989, La Vecchia et al 1991). Many studies have found that women who smoke cigarettes often become postmenopausal 1 to 2 years earlier than women who have never smoked. (Baron et al, 1990) From reading it is clear that postmenopausal oestrogen deficiency is an important cause of osteoporosis in women, but this factor seems unlikely to explain the same decrease in bone density observed in men.
Studies investigating the association between cigarette smoking and osteoporosis have reported conflicting results. Potential reasons for these differences include variations in bone sites examined, end points of interest, age and menopausal status of subjects, methods of bone density measurement, source of subjects, and adjustment for contradictory variables. The validity, reliability and sensitivity of results are therefore questionable. However the link between smoking and increased osteoporotic risk seems plausible based on the research completed. Since smoking might influence fracture risk through several mechanisms unrelated to osteoporosis, studies of bone density theoretically provide less true measure of the overall effect of cigarette smoking on osteoporosis.
To conclude osteoporosis is a multifactorial disease with both modifiable and non-modifiable factors. From a genetic standpoint future research should allow those with unfavourable genes to be treated and improved. Genetics of osteoporosis is determined by multiple genes assembling together, which individually have small individual effects (<5% genetic variance), it follows that their utility in diagnosis or prognostication will be small. If future a large proportion of the genetic variance must be captured to make the study worthwhile (See Table 4).
Smoking and its link has conflicting results due to variations of methodologies and measurement sites etc. Therefore future research into this area is needed to clarify the results discussed above. All factors are interlinked with lifestyle factors like diet and exercise linked with genetics, smoking and other factors. Therefore it is difficult to treat and treatment strategies from various parameters (lifestyle and drug therapy) should be incorporated.
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