So far, the gold standard for the diagnosis of osteoporosis has been based on the use of dual energy X-ray absorptiometry (DXA). However, one of the main pitfalls of DXA is the considerable overlap between DXA values in patients with and without fractures. In recent years, many efforts have been made to develop novel tools to allow the identification of high-risk patients, thus leading to better prevention strategies. The purpose of this review is to summarize novel DXA-derived tools, clinical strategies, imaging techniques, and biochemical markers that were developed recently in order to improve fracture risk prediction.
DUAL ENERGY X-RAY ABSORPTIOMETRY
DXA is accepted as the best screening method for osteoporosis: bone mineral density (BMD) less than 2.5 SDs below the young adult mean (T-score of ≤2.5) is the WHO's definition of osteoporosis. Meta-analyses have confirmed that the BMD predicts low-trauma fractures . The relative risk of subsequent fracture was more than 1.5 to 3-fold for all levels of BMD for each SD decrease in BMD. Reports have found that the rate of BMD loss estimated from two BMD tests (less than 5 years) did not predict fracture risk for major osteoporotic fractures independently of current BMD results [2,3▪]. The most likely explanation is the large measurement errors . Within the constraints of currently available technologies, the rate of BMD loss is unlikely to be helpful for refining fracture risk; however, rapid bone loss was found to be an independent predictor of postfracture mortality risk in both women and men .
FRACTURE RISK PREDICTION TOOLS
Half of fragility fractures occur in individuals with nonosteoporotic BMD. The use of these clinical FRTs has been shown to enhance prediction of hip fracture and other major osteoporotic fractures over the use of BMD alone. There are several FRPTs currently available to assess a patient's 10-year possibility of having a fracture, which have been critically reviewed [6–7]. Fracture risk prediction (FRP) continues to be optimized for different cohort and country-specific populations. A large number of studies are recently available on fracture risk assessment tool (FRAX).
Fracture risk assessment tool
In 2008, the WHO Collaborating Centre released the FRAX for estimation of individualized 10-year probability of hip and major osteoporotic fracture (composite of hip, clinical spine, distal forearm, and proximal humerus) , in addition to age, sex, and BMI, additional prior fragility fracture, parental history of hip fracture (HP), prolonged use of glucocorticoids, rheumatoid arthritis, current cigarette smoking, alcohol intake of three or more units per day and secondary osteoporosis and (optionally) femoral neck BMD.
Fracture risk assessment tool limitations
FRAX without BMD overestimates fracture risk compared to calculations of FRAX with BMD. In individual patients, differences between FRAX with and without BMD were important, which may influence both physicians’ and patients’ attitudes to treatment needs . BMD is primarily measured at the lumbar spine, total hip, and femoral neck. When multiple sites measurement and femoral neck were compared, the multiple sites increased the prevalence of osteoporosis but was not superior to femoral neck BMD for FRP. However, BMD discordance between different sites has been identified as a FRP: greater discordance is associated with higher fracture risk in the Manitoba cohort . In postmenopausal Korean women, BMD discordance was considerably high. The different rates of BMD decrease across sites causes this discordance. Using a modified BMD adjusted for the number of osteoporotic sites (factor reflecting discordance) may offer more accurate FRPT . In 10 prospective cohorts from America, Europe, Asia, and Australia [12▪], the absolute differences in lumbar spine and femoral neck was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21% of women. Each 1 SD decrease in Δ lumbar spine–femoral neck was associated with a 9% increase in fracture risk (low BMD at the lumbar spine, relative to that at the femoral neck, is a predictor of increased fracture risk). It is important to note that adjustment of FRAX for these discrepancies impacts only a relatively small number of individuals (2.3–3.2%). FRAX, as other FRPT, calculates the 10-year probability of fracture. The FRP more than 20 years is poorly documented. In the French cohort OFELY , low BMD in women and parental history of hip fracture are significantly associated with an increased fracture risk more than 20 years, whereas the association between clinical risk factors and incident fractures declined after 10 years. FRAX is limited for predicting according to type, age, or recurrence of fracture. In a Danish study , a patient suffering a fracture (especially hip fracture) has a high risk of subsequent fractures, especially at a more proximal location in the same limb in case of appendicular fracture. In an Australian study , male patients who sustained a fracture before 51 years of age had a higher risk of sustaining subsequent fractures than those who did not. Women with prior fracture had an increased fracture risk in older adult life. A Canadian cohort  suggested that the FRAX (without BMD) underestimates the risk of recurrent fragility fracture in patients younger than 65 years and without previous fragility fracture.
Change in FRAX
As change in BMD is inadequate to predict fractures, changes in FRAX score could independently predict fracture risk. In the Manitoba cohort [17▪], the change in FRAX score more than 4 years did not independently predict incident fracture, suggesting that FRAX with BMD is a poor surrogate measure for treatment response and is not sensitive enough to be used as a target for goal-directed treatment. It is necessary to consider as treatment failures those patients who lose BMD or have recurrent fractures, and to continue successful treatment for the safest duration of time known for the therapy being used.
Fracture risk prediction tools and screening strategy
None of the screening strategies was substantially better than chance alone in discriminating women aged 50–64 years in the Women's Health Initiative (WHI) study who did and did not experience incident fracture during a follow-up period of 10 years . The US Preventive Services Task Force (USPSTF) recommends BMD testing for women who have at least 9.3% FRAX (without BMD) of major osteoporotic fracture; the osteoporosis Self-Assessment Tool (OST) is based on weight and age; the Simple Calculated Osteoporosis Risk Estimation Tool (SCORE) is based on race, rheumatoid arthritis, history of nontraumatic fracture, age, prior estrogen therapy, and weight. Among women aged 50–64 years, the USPTF strategy was modestly better than chance alone, and inferior to SCORE and OST strategies in discriminating between women with and without femoral neck BMD T-score −2.5 or less . These suggest that fracture prediction in younger postmenopausal women may require new assessment of fracture risk. It is possible that the lack of inclusion of an indicator of trabecular bone quality, such as lumbar spine BMD, may contribute to the suboptimal fracture prediction in younger women, because menopause is known to be associated with accelerated trabecular bone loss. In a study of Australian women  aged 40–65 years, very few women referred for DXA screening were found to have osteoporosis (only 6.9% at the lumbar spine and 3.6% in femoral neck). Three predictors of osteoporosis, which were the menopause, the nonuse of hormonal therapy, and BMI were identified and incorporated into the fracture risk score. This score may detect 70% of women with osteoporosis at the lumbar spine or femoral neck and excluded 60% of patients for DXA screening. In particular, the WHI women with baseline moderate or severe vasomotor symptoms have lower BMD in femoral neck and lumbar spine during follow-up and increased hip fracture rates during an average of 8.2 years of follow-up after adjustment . A systematic review and meta-analysis of the performance of clinical risk assessment instrument for screening for DXA for osteoporosis or low bone density shows that commonly evaluated instruments of OST, SCORE, ORAI (Osteoporosis Risk Assessment Instrument), OSTA (Osteoporosis Self-Assessment Tool for Asians), and body weight criteria each demonstrate high sensitivity approaching or exceeding 90% for identifying individuals with DXA–determined osteoporosis or low BMD but low specificity. These tools are a viable screening option for individuals who are not able to easily access DXA testing [22▪].
OTHER SPECIFIC CLINICAL FRACTURE RISK
In specific populations
Falls is an important fracture risk not included in FRAX, mainly because falls data are not available from all cohorts. In an Australian cohort , there was an association between FRAX and falls scores. However, this was likely explained by the inclusion of age and sex in the FRAX. For the authors, inclusion of falls in FRPT should be further explored. Frailty can be characterized as a state of diminished reserves (energy, physical ability, cognition, health) that gives rise to vulnerability. In the Canadian Multicenter Osteoporosis Study , a 30-item Frailty Index was associated with incident fractures, irrespective of age and low BMD. Over the 10-year study period, the risk of a hip fracture increased by 18% for each 0.10 increase in baseline Frailty Index score. Weight gain, weight loss, and intentional weight loss are associated with increased incidence of fracture .
A Canadian study  has shown that the fracture risk for men increased linearly with every decrease in income quintile. These associations were attenuated in women.
Low socioeconomic status in Australia does not appear to have an interaction with FRAX with and without BMD in women with previous fracture. However, it does appear to exist for those without previous fracture . Sick leave duration in working-aged women and men is a predictor of hip fracture in elderly patients .
TOOLS IN DUAL ENERGY X-RAY ABSORPTIOMETRY
DXA instruments can also measure other parameters.
Hip geometry measures
Hip axis length (HAL), distance from the base of greater trochanter to the inner pelvic rim, remained a robust predictor of hip fracture in all models including those that used BMD, height, and other geometry measures. In white women, HAL was found  to robustly predict hip fracture, when adjusted for covariates including FRAX with BMD, with a modest but significant improvement in net reclassification (15%). The effect of HAL was particularly strong among younger (<70 years) non-osteoporotic women.
Trabecular bone score
In recent years, the trabecular bone score (TBS) has emerged as a novel tool for fracture risk. TBS is a textural index that evaluates pixel gray-level variations in the lumbar spine DXA image, providing an indirect index of trabecular microarchitecture [30▪]. TBS is not a direct physical measurement of bone microarchitecture, but an overall score computed by the projection of the three-dimensional structure onto a two-dimensional plane . As reviewed by Silva et al. [30▪], TBS has been shown, both in cross-sectional and prospective studies, to discriminate between fractured and nonfractured postmenopausal women [32–39]. Recent data regarding TBS in FRPT mainly concern the added value of TBS in FRAX and its applicability to discriminate fractures in men and in postmenopausal women [40–42]. The main added value of TBS is that it may indicate bone fragility in patients in whom DXA does not indicate osteoporosis. The performance of TBS to detect patients with vertebral fractures as determined by the area under the curve (AUC) was higher than the AUC of lumbar spine BMD but not of hip BMD . In an analysis from the population-based cohort study of 33 352 women from the Canadian province of Manitoba, lumbar spine TBS was found to be an age and BMD-independent risk factor for incident major osteoporotic fractures . In a study of 180 male patients (mean age 63.3 ± 12.6 years), men with fractures had significantly lower TBS compared to control patients . In a study of 3620 men aged greater than 50 years from the Province of Manitoba, TBS predicted major osteoporotic fractures independently of the clinical FRAX but not after adjustment for hip or lumbar spine BMD, and hip fracture independently of FRAX and BMD . A recent study in elderly Japanese men (FORMEN cohort study) suggests that TBS improves FRAX prediction in men . This validity of TBS was observed after adjustment for FRAX with femoral neck BMD. This is consistent with another recent analysis of the Manitoba cohort, in which the predictive ability of TBS was found to be independent of FRAX clinical risk factors and femoral neck BMD . Converging data suggest that TBS is also associated with fracture risk in patients with conditions related to bone quality in secondary osteoporosis [30▪,46▪,47]. Altogether, lumbar spine TBS is an easily available technology with potential applications in detecting fracture risk in patients that are not detected by DXA.
Vertebral fracture assessment
Vertebral fracture assessment (VFA) is a thoraco-lumbar spine imaging based on DXA technology, with much lower radiation than traditional radiology. People with vertebral fracture have been shown to respond well to standard medications for osteoporosis even in those without WHO-defined osteoporosis on DXA scan. VFA is also routinely being used in fracture liaison services . VFA appears to be cost-effective in routine practice [49▪] in two situations: women attending DXA after a low trauma fracture, and older women from primary care (respectively vertebral fracture 9.8 and 13.9% and T-score <−2.5 16.2 and 24.7%) and based on FRAX treatment thresholds (20% of major fracture, 3% of HP). Asymptomatic women from Marocco showed evidence of moderate/severe vertebral fracture in 19.7% of cases and FRAX for major fracture without BMD had better discriminative capacity in identifying women with prevalent vertebral fracture than lumbar spine and femoral neck T-scores .
Other tools in dual energy X-ray absorptiometry
FRAX was not affected by variation in body composition . Finite element models of the proximal femur estimate femoral strength. These models make use of the geometry and bone density distribution information embedded in medical images of the hip acquired by DXA. In a study of osteoporotic fractures (SOF) , finite element analysis of DXA scans is an independent predictor and performs at least as well as femoral neck BMD in predicting incident hip fracture.
OTHER TECHNICAL TOOLS
In an individual-level analysis in nine prospective cohorts (46 124 men and women) from Asia, Europe, and North America [53▪], quantitative ultrasound (QUS) was found to be an independent predictor of fracture in men and women, particularly at low QUS values. However, QUS is a weaker predictor than femoral neck BMD for hip fracture and its predictive value decreases over time with important implications for the incorporation of QUS into FRPT such as FRAX.
Reference point indentation
In the first report evaluating microindentation in vivo, indentation distance  with bone material strength (BMS) is measured after local anesthesia, is inserted in the skin of the midshaft of the right tibia until it reaches the bone surface, which is indented upon activation of the instrument. Patients with fracture  have altered material properties of bone which are not captured by BMD. Reference point indentation has been shown to detect altered bone tissue properties. The measure was comparable in patients with a fragility fracture whether they had osteopenia or osteoporosis.
In particular, high-resolution MRI offers new perspectives for trabecular bone architecture characterization by noninvasive nonionizing methods. Fractal lacunary analysis is a promising approach to quantify morphofunctional changes in both aging and pathologic bone . MRI shows the potential to study cortical bone, which has been recognized as a modulator of fracture susceptibility. It is necessary to obtain large scale trials with bone MRI.
Computed tomography peripheral quantitative computed tomography
Peripheral quantitative computed tomography (pQCT) is a method for assessing volumetric BMD in peripheral sites, which estimates trabecular and cortical compartments, which has been shown to be associated fracture risk in men . A UK cohort  demonstrates a relationship between pQCT and incident fractures but this relation was attenuated after adjustment for BMD. As pQCT is not widely available, a Norwegian study  assessed the ability of subtrochanteric cortical porosity measured with a standard femoral CT to detect nonvertebral fractures. Porosity identified 26% additional women with fracture not identified by T-score less than −2.5 and 21% not identified by a FRAX with BMD threshold more than 20%.
MAY THE MEASUREMENT OF BIOLOGICAL PARAMETERS HELP IN PREDICTING FRACTURE RISK?
An attractive aspect of biological markers in general is that blood or urine samples are easily collected. Serum markers of bone turnover (BTMs) are those which primarily come to mind when evoking the FRP. A joint working group of the International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine has proposed serum P1NP and CTX as the reference BTMs to evaluate bone formation and bone resorption, respectively . The same joint group recently published a meta-analysis of studies that evaluated the relationship between these two BTMs and the fracture risk in different populations [61▪]. On the basis of 10 separate studies, they concluded that there is a moderate but significant association between these BTMs and the risk of future fracture, including hip fracture (HR per SD increase in BTM concentration ranging from 1.18 to 1.23). However, they were not able to determine firmly whether this association was independent of BMD, a point that would be interesting and could lead to include BTMs to the FRAX. In addition, the established BTMs (i.e., P1NP, and CTX), assays for new BTMs became available recently. High serum concentrations of sclerostin, a well identified inhibitor of bone formation, were significantly and positively associated with fracture risk in postmenopausal women in the prospective CEOR study  but not in the OFELY study . Surprisingly, high sclerostin levels were associated with a lower fracture risk in men participating in the MINOS study  In another study of 569 elderly women, serum sclerostin concentration was associated with fracture risk in those with no history of nonvertebral fracture (NVF) . However, the relationship was not linear and the increased fracture risk was only found in those in the second quartile of sclerostin concentration. These discrepant results make that measuring sclerostin for FRP is premature to-date. The serum concentration of periostin, a mediator of the effects of mechanical factors and parathyroid hormone (PTH) on cortical BMD that downregulates sclerostin expression, has also been recently studied as a predictor of fractures. In the OFELY cohort, serum periostin in the highest quartile was associated with fracture risk over a 7-year period (Q4 vs. Q1 age-adjusted OR: 1.9; CI, 1.1–3.2) . This was found to be independent of BMD as those with both a periostin level within the high quartile and a hip BMD less than −2.5 T-score were at greater fracture risk (age-adjusted OR: 7.2; CI, 2.4–21.8). Many studies have evaluated the association between the blood level of calciotropic hormones and the fracture risk. The 25-hydroxyvitamin D (25OHD) serum concentration was significantly and negatively associated with the risk of NVF in many cohorts as confirmed in four recent studies in women across the menopausal transition , in an elderly population , and in Japanese  and Chinese  postmenopausal women. Similarly, high or normal-high serum PTH levels have been associated with an increased fracture risk in the presence of low 25OHD levels [71,72]. It is important to note that low 25OHD, either isolated or associated to a high PTH, is a condition that can be easily corrected with an appropriate vitamin D supplementation. Furthermore, this supplementation is specially important as it has been shown that vitamin D supplementation decreases the risk of NVF in patients more than 65 years old , and that osteoporosis treatments seem less effective in terms of reducing the fracture risk when administered to vitamin D deficient patients . Biological markers that are not directly related to bone or mineral metabolism have also been tested as predictors of fracture risk. Increased serum urate levels have been shown to be correlated with the risk of hip fracture in men participating in the Cardiovascular Health Study , and with the risk of NVF in men participating in the MrOs study . Similarly, high levels of the inflammatory markers IL-6 and type 1 soluble receptor for tumor necrosis factor, were significantly associated with an increased risk of hip fracture in women included in the SOF . Hyponatremia has also been linked to fractures in several studies . Recently, it was shown that men older than 65 years with serum sodium less than 135 mg/l had an increased risk of incident vertebral fracture (HR: 3.53; CI, 1.35–9.19), but not NVF . The way hyponatremia causes fractures, and if correction of hyponatremia decreases fractures deserve further studies. Finally, with the evidence for heritability of osteoporotic fractures, especially nonspine fractures, and considering the improvement in genetic testing, the clinical usefulness of genetic scores derived from genomewide association studies for the prediction of BMD, BMD changes, and fractures has been studied. Results are conflicting as one study found that such scores improved FRP  whereas another study reported limited clinical utility .
DXA and clinical fracture risk prediction tools including FRAX are easily applicable in daily practice (Fig. 1). Clinical fracture risk prediction alone might be used if DXA facilities are unavailable. Other tools including TBS, QUS, and BTM, seem promising in predicting fracture risk, but are not yet applicable and their future use in routine practice requires further studies to determine bone fragility and treatment thresholds. Factors such as falls, HAL, and VFA could be used in specific populations. This may significantly improve the clinical decision-making, particularly with probabilities close to an intervention threshold.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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