Osteoporosis is the most common bone disease in humans, and osteoporotic fracture is a major health problem. In the absence of fracture, however, osteoporosis is asymptomatic and often remains undiagnosed. There is no universally accepted policy for population screening in Europe to identify patients with osteoporosis or those at high risk of fracture. Most countries adopt a case-finding strategy where individuals with clinical risk factors are identified for further assessment. This strategy does not seem to work as intended, however, as osteoporosis remains underdiagnosed and undertreated in Denmark, and probably also elsewhere. New strategies are thus needed to reduce the large number of osteoporotic fractures expected in the future due to the aging of the world’s population. Targeting individuals with increased risk of osteoporotic fracture is an important challenge, and risk assessment tools may contribute to health care decision-making by identifying individuals at highest risk of osteoporotic fracture.
The primary aim of this thesis was to investigate the potential use of risk assessment tools in the clinical management of osteoporosis to identify women in highest risk of fracture. Specific objectives were addressed in four separate papers. In paper I, we evaluated whether the WHO fracture risk assessment tool (FRAX®) without BMD was applicable to Danish women. In paper II, we examined the prevalence of risk factors for fractures and the use of DXA scans in Danish women in relation to age, risk factors, distance to DXA-clinics and socio-economic factors. In paper III, we compared the power of FRAX® and simpler screenings tool to predict fractures. In the systematic review described in paper IV, we compared the power of valid and reliable risk assessment tools to identify women at highest risk of fractures.
For the purpose of this thesis, we developed and validated a questionnaire on risk factors for osteoporosis based that was based on and included the FRAX® risk factors. The thesis uses data collected using this questionnaire as well as data from Danish national registers and the published literature on osteoporosis fractures and osteoporosis risk assessment tools. The four studies conducted were prospective, crosssectional and population-based, and used different statistical analyses as appropriate for their aims and designs: chi²-test, various regression analyses, survival analyses, ROC and Harrell´s C. The systematic review followed the guidelines established by the PRISMA Group for reporting systematic reviews and metaanalyses and applied the QUADAS checklist to assess the methodological quality of included papers.
The self-administered questionnaire was mailed to 5,000 women aged 40-90 years and living in the Region of Southern Denmark, randomly selected from the Danish civil Registration system. A total of 4,194 (84%) responded and 3,860 (77%) completed the questionnaire. Fracture risk was calculated using different screening tools, e.g. FRAX®.
FRAX® without BMD appeared well calibrated for Danish women as regards hip fracture risk, as the predicted 10-year hip fracture risk calculated by FRAX® (without BMD) and the observed fracture risk from age-specific hip fracture rates from the National Patient Register and survival tables from Statistics Denmark were nearly identical; 7.9% and 7.6%, respectively (paper I).
When evaluating the prevalence of risk factors (paper II), we found that 37.4% of the women had no risk factors and 62.6% had one or more risk factors. However, 10.3% of women without risk factors had a history of DXA, while only 36.3% of women with three or more risk factors had a history of DXA. The study thus showed a relatively high use of DXA in low-risk women and a relatively low coverage in women with multiple risk factors, suggesting that the case-finding strategy does not work as intended. The study further showed that distance to the DXA clinic, patient age and a number of other socio-economic factors were associated with the use of DXA.
During the three years of follow-up (through the Danish National Register), we found that 4% of the women experienced a new osteoporotic fracture (paper III). Comparing the discriminatory power to predict future fractures, no difference was found between FRAX® and simpler tools such as OST¹, ORAI², OSIRIS³, SCORE⁴ or age alone with regards to the area under the curve (AUC) values, which were between 0.703 and 0.722 (p=0.86).
In paper IV, we identified 48 risk assessment tools for prediction of osteoporotic fractures, but only 20 of them were externally validated. Eight tools were developed to identify individuals at risk of low BMD and 12 tools were developed to identify individuals with increased risk of fractures. Only six of these tools had been tested more than once in a population-based setting with acceptable methodological quality. None of the tools performed consistently better than the others, and simple tools (i.e. OST, ORAI and Garvan) often did as well or better than more complex tools (i.e. SCORE, FRAX® and Qfracture). No studies had determined the effectiveness of tools in selecting patients for therapy and thus improving fracture outcomes.
In conclusion, the results presented in this thesis suggest that risk assessment tools could be potentially useful in the clinical management of osteoporosis by identifying women at highest risk of fracture, as a replacement for the case-finding strategies used in Denmark and elsewhere. FRAX® is the only tool incorporated in national guidelines, but in this thesis FRAX® did not perform better than simpler tools in predicting fractures. Simpler tools with fewer risk factors, which would be easier to use in clinical practice by the general practitioner or the patient herself, may be just as effective as FRAX® in the clinical management of osteoporosis. These simpler tools have not yet been validated in prospective randomized studies, however. Future research could thus focus on the validation of simpler tools (e.g. Garvan) in high quality, randomized studies with population-based samples or patient cohorts with different case mixes.