FRAX®

Since its launch in 2008, the web-based fracture risk assessment tool FRAX^® [1] has been evaluated thoroughly in additional validation studies and widely published in meta-analyses and clinical review papers. Furthermore, its predictive and discriminative powers have been compared with other osteoporotic fracture risk prediction tools [2]. Two recent papers elucidate different aspects of the tool, one assessing its diagnostic accuracy in women and men from five different non-US populations [3], the other one calculating the time to ‘clinically relevant’ risk scores in US postmenopausal women [4], and both using the 10-year intervention thresholds of 20% for major osteoporotic fractures (MOF) and 3% for hip fractures (HF), as suggested by the National Osteoporosis Foundation (NOF) [5].

In the first paper, a systematic review and meta-analysis of seven studies from New Zealand, Canada, the USA, France and Poland, which tested FRAX^® in populations other than the derivation cohorts, the tool ‘performed better in identifying patients who will not have a MOF or HF within 10 years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10 years of follow-up, were missed by the baseline FRAX^® assessment’, as stated by the authors in their conclusion.

For MOF prediction, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76–25.06%), 97.02% (91.17–99.03%) and 3.71 (2.73–5.05); for HF prediction 45.70% (24.88–68.13%), 84.70% (76.41–90.44%) and 4.66 (2.39–9.08), respectively, the latter one being less precise because of its larger confidence region.

FRAX^® is freely available and easy to use, not least because of its condensed and time-saving features. But this is at the expense of its sensitivity. Tools with a larger number of clinical risk factors, e.g. QFracture^®, may be more sensitive but less feasible [2]. Lowering the intervention threshold may also improve sensitivity but increase over-treatment [6].

The second paper estimates the timing of occurring ‘clinically relevant’ scores, i.e. treatment-level FRAX^® scores, according to 2014 National Osteoporosis Foundation guidelines [5], and screening-level FRAX^® scores, according to 2011 US Preventive Services Task Force (USPSTF) guidelines [7], in postmenopausal women of the Women’s Health Initiative (WHI) cohort.

The screening level was proposed by the USPSTF to identify postmenopausal women < 65 years of age as candidates for bone mineral density (BMD) testing by dual-energy X-ray absorptiometry (DXA) if their FRAX^® score was equal to or greater than that of a 65-year-old white woman who has no additional risk factors, i.e. a 10-year risk for MOF of ≥ 9.3%. The screening-level score had low predictive ability in postmenopausal women aged 50–64, as shown before with data of the same cohort and in comparison to other non-satisfying fracture risk tools [8], leading to the conclusion ‘… that fracture prediction in younger postmenopausal women requires assessment of risk factors not included in currently available strategies.’ The treatment-level score without BMD measurements occurred in 10% of women aged ≥ 65 after 3–5 years of baseline score (effective maximum length of follow-up 18.6 years), and the treatment-level score with BMD measurements after 5–7 years (maximum follow-up 11.2 years), respectively. Thus, scores calculated without BMD indicated higher risk than scores with BMD.

The authors conclude by confirming a familiar sounding message: ‘Postmenopausal women with sub-threshold fracture risk scores at baseline were unlikely to develop a treatment-level FRAX^® score between ages 50 and 64. After age 65, the increased incidence of treatment-level fracture risk scores …. supports more frequent consideration of FRAX^® and bone mineral density (BMD) testing.’

Nevertheless, we are confronted with a high prevalence of osteoporosis and fragility fractures in middle-aged women (< 65 years) [9,10] and badly need to improve our strategies of identifying women at risk as early as age 40 by including more clinical risk factors, e.g. detrimental gyneco-endocrinological conditions such as premature ovarian insufficiency, laboratory tests as bone turnover markers, and, last but not least, intensified interdisciplinary cooperation in preventive measures.

Author(s)

• Ewald P. Boschitsch
  Ambulatorium Klimax, Menopause and Osteoporosis Clinic, Vienna, Austria
• H. P. Dimai
  Department of Internal Medicine, Medical University of Graz, Graz, Austria

Citations

1. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19:385-97
   https://www.ncbi.nlm.nih.gov/pubmed/18292978
2. Marques A, Ferreira RJ, Santos E, Loza E, Carmona L, da Silva JA. The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis. Ann Rheum Dis 2015 Nov;74:1958-67
   https://www.ncbi.nlm.nih.gov/pubmed/26248637
3. Jiang X, Gruner M, Trémollieres F, et al. Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: A systematic review and meta-analysis. Bone 2017;99:20-5
   https://www.ncbi.nlm.nih.gov/pubmed/28274799
4. Gourlay ML, Overman RA, Fine JP, et al.; Women’s Health Initiative Investigators. Time to clinically relevant fracture risk scores in postmenopausal women. Am J Med 2017;130862
   https://www.ncbi.nlm.nih.gov/pubmed/28285070
5. Cosman F, de Beur SJ, LeBoff MS, et al.; National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int 2014;25:2359-81
   https://www.ncbi.nlm.nih.gov/pubmed/25182228
6. Bansal S, Pecina JL, Merry SP, et al. US Preventative Services Task Force FRAX threshold has a low sensitivity to detect osteoporosis in women ages 50-64 years. Osteoporos Int 2015;26:1429-33
   https://www.ncbi.nlm.nih.gov/pubmed/25614141
7. U.S. Preventive Services Task Force. Screening for osteoporosis: US preventive services task force recommendation statement. Ann Intern Med 2011;154:356-64
   https://www.ncbi.nlm.nih.gov/pubmed/21242341
8. Crandall CJ, Larson JC, Watts NB, et al. Comparison of fracture risk prediction by the US Preventive Services Task Force Strategy and two alternative strategies in women 50-64 years old in the Women’s Health Initiative. J Clin Endocrinol Metab 2014;99:4514-22
   https://www.ncbi.nlm.nih.gov/pubmed/25322268
9. Siris ES, Brenneman SK, Miller PD, et al. Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50–64 and 65 and older: results from the National Osteoporosis Risk Assessment (NORA). J Bone Miner Res 2004;19:1215-20
   https://www.ncbi.nlm.nih.gov/pubmed/15231007
10. Boschitsch EP, Durchschlag E, Dimai HP. Age-related prevalence of osteoporosis and fragility fractures: real-world data from an Austrian Menopause and Osteoporosis Clinic. Climacteric 2017;20:157-63
    https://www.ncbi.nlm.nih.gov/pubmed/28286986