A systematic review of intervention thresholds based on FRAX : A report prepared for the National Osteoporosis Guideline Group and the International Osteoporosis Foundation

Abstract

This systematic review identified assessment guidelines for osteoporosis that incorporate FRAX. The rationale for intervention thresholds is given in a minority of papers. Intervention thresholds (fixed or age-dependent) need to be country-specific.

Introduction: In most assessment guidelines, treatment for osteoporosis is recommended in individuals with prior fragility fractures, especially fractures at spine and hip. However, for those without prior fractures, the intervention thresholds can be derived using different methods. The aim of this report was to undertake a systematic review of the available information on the use of FRAX® in assessment guidelines, in particular the setting of thresholds and their validation.

Methods: We identified 120 guidelines or academic papers that incorporated FRAX of which 38 provided no clear statement on how the fracture probabilities derived are to be used in decision-making in clinical practice. The remainder recommended a fixed intervention threshold (n = 58), most commonly as a component of more complex guidance (e.g. bone mineral density (BMD) thresholds) or an age-dependent threshold (n = 22). Two guidelines have adopted both age-dependent and fixed thresholds.

Results: Fixed probability thresholds have ranged from 4 to 20 % for a major fracture and 1.3-5 % for hip fracture. More than one half (39) of the 58 publications identified utilised a threshold probability of 20 % for a major osteoporotic fracture, many of which also mention a hip fracture probability of 3 % as an alternative intervention threshold. In nearly all instances, no rationale is provided other than that this was the threshold used by the National Osteoporosis Foundation of the USA. Where undertaken, fixed probability thresholds have been determined from tests of discrimination (Hong Kong), health economic assessment (USA, Switzerland), to match the prevalence of osteoporosis (China) or to align with pre-existing guidelines or reimbursement criteria (Japan, Poland). Age-dependent intervention thresholds, first developed by the National Osteoporosis Guideline Group (NOGG), are based on the rationale that if a woman with a prior fragility fracture is eligible for treatment, then, at any given age, a man or woman with the same fracture probability but in the absence of a previous fracture (i.e. at the 'fracture threshold') should also be eligible. Under current NOGG guidelines, based on age-dependent probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold using a hybrid model reduces this disparity.

Conclusion: The use of FRAX (fixed or age-dependent thresholds) as the gateway to assessment identifies individuals at high risk more effectively than the use of BMD. However, the setting of intervention thresholds needs to be country-specific.

Keywords: Assessment guidelines; Calibration; Discrimination; FRAX; Intervention threshold.

Figure 1

Flow diagram demonstrating study identification and selection.

Figure 2

Flow chart for the assessment of osteoporosis in Japan.

Figure 3

Summary of assessment algorithm in the SIGN guidance

Figure 4

Algorithm for the assessment of fracture risk in men and postmenopausal women from Taiwan [138]. CRFs, clinical risk factors. MOF, major osteoporotic fracture. ^a Prior fragility from the age of 50 years ^b Postmenopausal women age 50-65 years ^c Low FRAX risk; probability of MOF or hip fracture <10 % and <1.5 %, respectively ^d Moderate FRAX risk; hip fracture probability ≥1.5 % and <3 % or MOF probability >10 % and <20 % ^e High FRAX risk; hip fracture probability ≥3 % or MOF probability ≥20 %

Figure 5

The 10-year probability (%) of a major osteoporotic fracture by age in women with a prior fracture and no other clinical risk factors in the five major EU countries (weighted average of Spain, France, Germany, Italy and UK) as determined with FRAX (version 3.5). Body mass index was set to 24 kg/m² without BMD. The line dividing the red and green zones represents the age-dependent intervention threshold or ‘fracture threshold’. (Extracted from [28] with kind permission from Springer Science and Business Media.

Figure 6

Management algorithm for the assessment of individuals at risk of fracture [140], with kind permission from Springer Science and Business Media.

Figure 7

Assessment and treatment thresholds in the absence of a BMD test (left) and with a BMD test to compute fracture probability (right) for men and women. Redrawn from [141]

Figure 8

NOGG web page plotting the results of a FRAX measurement (Female age 75 years with a BMD T-score of -2.0 SD and a parental history of hip fracture). In the example, treatment is recommended since the hip fracture probability exceeds the intervention threshold (www.shef.ac.uk/NOGG ).

Figure 9

The 10-year probability of a major osteoporotic fracture by age in women with a prior fracture and no other clinical risk factors in the five major EU countries as determined with FRAX (version 3.5). Body mass index was set to 24 kg/m² without BMD [3], with kind permission from Springer Science and Business Media.

Figure 10

Ten-year probability of osteoporotic (hip, clinical spine, humerus or forearm) and hip fracture based on women at the threshold for the diagnosis of osteoporosis using the criteria of the Japanese Bone Mineral Metabolism Association. From [135] with kind permission from Springer Science and Business Media.

Figure 11

Intervention thresholds in Lebanon that use a fixed threshold up to the age of 70 years and thereafter an age-dependent threshold.

Figure 12

Graph of intervention and assessment thresholds showing the alternative thresholds in the hybrid model. The dotted line represents the intervention threshold and the assessment thresholds enclose the amber area. From [109] with kind permission from Springer Science and Business Media.

Figure 13

Mean probability of major osteoporotic fracture (MOF, %) in patients age 70 years or more identified for consideration of treatment under the current thresholds (light bars) and the alternative thresholds (shaded bars). Data extracted from [109].

Figure 14

Mean probability of hip fracture (HF, %) in patients age 70 years or more identified for consideration of treatment under the current thresholds (light bars) and the alternative thresholds (shaded bars). Data extracted from [109].

Figure 15

Correlation between the probability of a major osteoporotic fracture and cost-effectiveness of generic alendronate at the age of 50 years in women from the UK (BMI set to 26 kg/m²). The line indicates the willingness to pay set at £20,000/QALY gained. Each point represents a particular combination of BMD and clinical risk factors. Taken from [140] with kind permission from Springer Science and Business Media.

Figure 16

Fracture probabilities at which treatment with alendronate becomes cost-effective in men and women from Switzerland. The dotted line denotes the fracture probability at the fracture threshold (i.e. the probability equivalent to a woman with a prior fracture by age). Adapted from [105].

Figure 17

Relation between the 10-year probability of a major osteoporotic fracture and the 10-year probability of a hip fracture in women aged 50 years from the UK. Each point represents a particular combination of BMD and clinical risk factors. From [140] with kind permission from Springer Science and Business Media.

Figure 18

Comparison of the distribution of FRAX and QFracture (QF) model output by decile of risk in women for hip fracture (left panel) and major fracture (right panel). The diagonal line shows the line of identity. From [13] with kind permission from Springer Science and Business Media.

Figure 19

10-year fracture probability for a major fracture derived from the Canadian FRAX tool with and without BMD versus observed 10 year fracture rates (95 % confidence interval) by risk category (low, less than 10 %; moderate, 10-20 %; high, greater than 20 %) with BMD (solid line) and without BMD (dashed line). The dashed line depicts the line of identity. Redrawn from [195].

Figure 20

The various ways in which FRAX has been used to set thresholds.

Figure 21

The probability of a major osteoporotic fracture (MOF) in men and women from the UK by age. The horizontal line depicts an arbitrary intervention threshold set at 15 %. The left panel gives probabilities in the presence of a prior fracture and the right panel, probabilities with a T-score of -2.5 SD (BMI set to 23 kg/m², no other clinical risk factors). [http://www.shef.ac.uk/FRAX]

Figure 22

The impact of a fixed treatment threshold in postmenopausal women in the UK according to threshold values for the probability of a major osteoporotic fracture. The left hand panel shows the proportion of the postmenopausal population exceeding the threshold shown at each age. The right hand panel shows the proportion of the total postmenopausal population that exceed a given threshold. From [3] with kind permission from Springer Science and Business Media.

Figure 23

Proportion of men and women (%) aged 50–89 years with a 10-year probability of a major fracture that is more than 20 % in different countries of the European Union. Those marked with an asterisk utilise a 20 % intervention threshold for a major osteoporotic fracture. Adapted from [3].

Figure 24

T-scores in selected countries that are equivalent to a 20% 10-year probability of a major fracture (women aged 65 years, prior fracture and a BMI of 24kg/m²) From [216] with permission from John Wiley and Sons.

Figure 25

Mean BMD at the femoral neck (with 95 % confidence intervals) in randomly selected women aged 75 years or more according to their 10-year probability of a major fracture calculated without BMD. Figure derived from data in [142].

Figure 26

FRAX 10-year probability (%) of a major osteoporotic fracture (MOF) in women between the ages of 65 and 70 years from the European Union with a previous fracture (no other clinical risk factors, BMI of 24 kg/m² and without BMD) representing the age-specific intervention threshold under the NOGG approach. Note that FRAX models were not available for Bulgaria, Cyprus, Estonia, Latvia, Luxembourg and Slovenia (labelled above with an asterisk). For these countries surrogate FRAX models were used. Extracted from [2].