Review Articles

The two national guidelines (NICE and NOF) cited earlier were developed from general literature review by opinion leaders. The international validity of candidate risk factors and the extent to which they can identify a reversible risk is amenable to an evidenced-based approach. There are well-established methods for evaluating the quality of evidence of different approaches (Khan K, 2003). The lowest level of evidence is provided by expert committees or clinical experience i.e. level V11 evidence. Systematic reviews and meta- analysis represent the gold standards because they constitute level I evidence and provide more robust evidence than general literature reviews.

The publication by Brownbill and colleagues identified some indices of hip geometry as predictors of hip fractures in females (HAL, FNW and NSA). It was suggested that the different incidence rates in hip fracture in females may be explainable by these but it is not known if these measurements also predict other fractures. While these measurements may be useful in a subset of the population, further studies are needed to assess their usefulness as predictors of fragility fractures.

129 2.5.2 Meta-analyses

2.5.2.1 Meta-analysis of How Well Measures of Bone Mineral Density Predict Occurrence of Osteoporotic Fractures

The aim of the meta-analysis to determine the ability of measurements of bone density in women to predict later fractures; a combination of prospective cohort and case-control studies were used. The main outcome measure was the relative risk of fracture for a decrease in BMD of one standard deviation below age adjusted mean. The results were similar in the two groups, therefore the authors concluded that measurement of BMD can predict fracture risk but cannot identify individuals who will have a fracture.

The study had some strengths; first the design (meta-analysis) of the study. Meta-analysis of high quality randomised controlled studies that show consistent effects is the gold standard in evidence based intervention and the inclusion of an internal control is important for the highest level of evidence (Khan K, 2003). But the demonstration of a significant risk for 1SD decrease of BMD in postmenopausal women would not provide enough evidence for a similar degree of risk in males because a sample frame that does not capture the population in which the test would be applied results in a lower level of evidence (level II studies and below).

The results of the group analyses were similar; the different designs (prospective cohort and case-control) indicate consistency of the relative risk of fracture for fractures in women. However, case-control studies are efficient only for studies aimed at finding the independent predictors of an outcome out of a larger set, not for developing a prediction model. This is because this design does not allow for estimation of absolute risks because the correct baseline risk or hazard cannot be retrieved from the data except by using a nested case-control or case- control design (Moons, 2010, Biesheuvel et al., 2008).

130 This meta-analysis had limitations: the restriction of the search language to English may have omitted some publications. It compared BMD with a group of Swedish women but mortality and fracture rates vary between populations which may underestimate or overestimate risk. Also, the studies were conducted in the developed countries (USA, Sweden, UK, Finland, and Australia) which suggest that the findings may not be applicable to other geographical settings.

The ethnic composition of the participants was not stated; ethnic composition is important because of the known differences in fracture risk. Also, the results may not be applicable to males as only females were included. Therefore, from a clinical perspective, the participants are not representative of those who will receive the test in practice. In addition, different techniques were used in the baseline assessment of the BMD; BMD measurements between techniques are not transferable and comparable because the correlation coefficients between skeletal sites are too low for predictive purposes and population variances differ as do apparent rates of bone loss.

Although BMD is the gold standard for the diagnosis of osteoporosis, the technique of estimation has some limitations; DEXA provides a two-dimensional projection of a three- dimensional structure, therefore it cannot capture bone geometry or microarchitecture. Consequently, the BMD values obtained with DEXA do not represent the true volumetric bone mineral density but rather a projected areal bone mineral density, DEXA estimation is confounded by bone size because it cannot distinguish between increased BMD values arising from thicker bones (geometric change) and those arising from increased tissue mineral density (material change). DEXA estimates can be distorted by aortic calcification, soft-tissue calcification, and other artefacts in an older individual who are at greater risk of fracture. DEXA does not distinguish the contributions from trabecular and cortical bones.

131 DEXA provides static information and may not detect any differences for several years after osteoporosis treatment (Bonnick, Shulman, 2006, Delmas, 2000, Roux et al., 2005) and the assessment is not pragmatic for care home residents who will be required to disrobe. DEXA scans are expensive, their availability is restricted to major hospitals and the cost of examination is substantial. The labour force required is also immense (Eastell, 1998). In some countries, it is predominantly a research tool. DEXA machines range in cost from $25,000 to $85,000. DEXA machines are not portable unlike quantitative ultrasound (QUS). Given these limitations, BMD is not recommended as a sole predictor for fracture assessment.

It is unclear whether uninterpretable tests and withdrawals were reported in the studies which were analysed. The analyses were based on relative risk but this approach does not include the background risk of the individual patient beyond age and gender-adjustments, therefore it is an imperfect estimate of the absolute risk for an individual over a given period. This researcher`s quality assessment score on QUADAS was 6.

2.5.2.2. Body Mass Index as a Predictor of Fracture Risk

The findings were convincing that low BMI is associated with a substantial increase in fracture risk of similar magnitude in men and women whereas high BMI is protective. The risk associated with low BMI was present at most ages for all types of fractures but was strongest for hip fracture. At BMI of 30 kg/m² and 35 kg/m², BMD appears to have less influence on hip fractures given the RRs reported. It is plausible that the impact of the force of impact may be more important at these values of BMI because the bigger the mass, the greater the gravitational force.

The strength of the study was that it was an international prospective cohort study with prolonged periods of follow-up. The limitations were: cohorts in Middle East, South America

132 and Africa were not included therefore it is not known how the findings apply to people in these continents. BMD assessments were done by different methods which may also affect the estimates. Lastly fracture assessment was sometimes by self-report which may have introduced some bias if these were not verified by X-ray reports.