Expert opinion: fracture risk assessment in osteoporosis

Identifying those at risk is central to managing osteoporosis. By Dr En C Fung and Professor Tim Spector

ABSTRACT

Until cost-effective screening is developed, the key to managing osteoporosis remains a case-finding approach, targeting those most at risk and most likely to benefit from intervention. New guidelines and the FRAX risk assessment tool emphasise a multifactorial approach. The recommendations will change with time and the NICE guidelines have been challenged, but this is an opportune moment to see what they suggest.

Key words
Osteoporosis, bone mineral density, fracture risk

New national guidelines1,2 and a worldwide fracture risk score (FRAX)3,4 will change the way clinicians assess fracture risk and influence the way osteoporosis is treated in the UK.

About two million women in the UK have osteoporosis.1 One in two women and one in five men over the age of 50 years will develop a fragility fracture in their lifetime.5 Mortality rate after a hip fracture is about 20 per cent within six months5 and 60 per cent of survivors will require help with mobility and activities of daily living,6 some needing long-term care. This significant health problem costs the NHS about £1.8 billion per year.

WHO defines osteoporosis as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.7 The most practical way to assess this is by measuring bone mineral density (BMD) using DXA scanning (the gold standard for diagnosing osteoporosis) and comparing the patient's result with that of a sex-matched 30-year-old, known as the T-score (see box 1).

BOX 1: T-SCORE CLASSIFICATION

Osteoporosis T-score ≤-2.5 standard deviations below the reference population mean

Osteopenia T-score -1.1 to -2.4 standard deviations below the reference population mean

Normal T-score ≥-1.0 standard deviation below the reference population mean

Bone density is, however, not the only indicator of fracture risk. In one study, just over half of women with postmenopausal hip fracture did not have BMD classified as osteoporosis (T-score >-2.5).8 Age, previous history of fragility fracture and family history are independent risk factors for future fractures.

There are other relevant risk factors but hitherto, there has been no consensus on which to include, resulting in variations in management. There is concern that young postmenopausal women with osteopenia but a low risk of fracture may be treated unnecessarily and conversely, that older patients who are borderline osteopenic/normal but have a high risk of fracture may not be treated on the basis of BMD alone.

Fracture risk assessment
Collaborative work between WHO and researchers in Sheffield has produced a model where nine clinical risk factors can be combined with BMD to assess the absolute risk of hip or any major osteoporotic fracture within 10 years (www.shef.ac.uk/FRAX).4 This is analogous to the Framingham 10-year risk assessment for cardiovascular disease.

The data were derived from epidemiological studies in Europe, the US, Australia and Asia and validated in these regions. The strongest risk factors are age, previous fragility fractures and BMD, followed by BMI, parental history of hip fracture, glucocorticoid use, alcohol use, rheumatoid arthritis, secondary osteoporosis and smoking (see box 2). This approach has shifted the focus from DXA scans, with implications in terms of logistics and cost. There will be some patients whose risk of fracture is so high, BMD measurement adds little to the decision to treat, and some at such low risk that BMD will not change their status, so they will fall below the threshold to treat.

BOX 2: CLINICAL RISK FACTORS (FROM FRAX)
  • Age
  • BMI
  • Prior fragility fracture
  • Parental history of hip fracture
  • Ever long-term use of oral glucocorticoid
  • Rheumatoid arthritis
  • Other causes of secondary osteoporosis
  • Current smoking
  • Alcohol intake ≥3 units daily

There is a middle zone, where BMD measurement is needed to decide whether the patient falls above or below the threshold. FRAX does not prescribe these thresholds, it merely provides a model that individual countries need to adapt to local resources and 'willingness to pay' per quality-adjusted life year.

The National Osteoporosis Guideline Group (NOGG) has adopted the FRAX model in the UK and recently published guidance to update the Royal College of Physicians guidelines. The FRAX score can be applied to men and non-Caucasian women, previously unaddressed groups. The rationale is that by considering the absolute fracture risk, better treatment outcomes can be achieved in those most at risk (see box 3, for NOGG treatment recommendations).

BOX 3: ANTIFRACTURE EFFICACY OF TREATMENT
Graded recommendations by NOGG2
DrugVertebralNon-vertebralHip
AlendronateAAA
EtidronateABNAE
IbandronateAA*NAE
RisedronateAAA
ZoledronateAAA
CalcitoninABB
CalcitriolABNAE
RaloxifeneANAENAE
Strontium ranelateAAA*
TeriparatideAANAE
Recombinant human
parathyroid hormone (1-84)
ANAENAE
HRTAAA
*Post-hoc analysis subset patients. NAE: not adequately evaluated

NICE has not stated who should have DXA screening. Each patient should be assessed individually, taking into account their risk factors (see box 4). The NOGG guidelines offer a practical solution for clinicians in terms of helping to standardise management.

BOX 4: RISK FACTORS FOR INCREASED FRACTURE RISK
Clinical risk factors
  • Parental hip fracture
  • Alcohol intake ≥4 units per day
  • Rheumatoid arthritis
Indicators of low bone mineral density
  • Low BMI (<22kg/m2)
  • Conditions such as ankylosing spondylitis, Crohn's disease
  • Periods of immobility
  • Untreated premature menopause
Source: NICE

Treatment of osteoporosis
NICE
continues to recommend alendronate as first-line therapy for the treatment of confirmed osteoporosis in postmenopausal women (figure 1), on the basis of the cost-effectiveness of the generic drug.1 Meta-analysis has shown a 44 per cent reduction in RR for vertebral fractures and a 38 per cent reduction in RR for hip fractures for alendronate compared with placebo.

Fig 1: NICE criteria for starting alendronate in primary prevention of fragility fracture in postmenopausal women1

Although this assumes a DXA scan has been performed to confirm osteoporosis, one subgroup of women, who sustained a fragility fracture after the age of 75, are deemed to have a high enough probability of osteoporosis for DXA to be unnecessary.

In the event that a patient is unable to continue alendronate (intolerant, unable to comply or contraindicated), which occurs in 20-40 per cent of cases, risedronate and etidronate are suggested as alternatives, followed by strontium ranelate. However, their increased costs are reflected in the higher BMD thresholds for these agents. For example, a 70-year-old woman with osteoporosis and one clinical risk factor requires a T-score of -2.5 (osteoporosis by definition) to qualify for alendronate. If she were intolerant and wanted to take risedronate or strontium ranelate, she would need a T-score of -3.0 and -4.0 respectively, which could take up to five years to change risk category. This two-tiered proposal is controversial; although it is based on cost analysis, it is totally impractical.

NICE has found that raloxifene is not as efficacious and cost-effective as alendronate in fracture prevention and does not recommend its use for primary prevention of fracture in postmenopausal women with confirmed osteoporosis, mainly because of its lack of effect on non-vertebral sites. All studies have ensured that both treatment and placebo arms are calcium and vitamin D replete, thus it follows that the reported relative reductions in fracture risk assume adequate levels of these. All guidelines have concluded that calcium and/or vitamin D supplementation should be given to all osteoporosis patients unless the patient is already known to have adequate intake.

However, NICE did not address recommendations for other subgroups, such as patients with osteopenia, glucocorticoid-induced osteoporosis and male osteoporosis. It did not consider ibandronate, IV zoledronate, calcitriol, drug holidays or switches from long-term alendronate in fracture prevention.

Conclusion
The management of osteoporosis is essentially the management of fracture risk. Although BMD is the best predictor of risk, other risk factors have been shown to be as significant.

The NICE recommendations focus on risk assessment in terms of absolute rather than relative risk. Using the NOGG guidelines with the FRAX score is the practical way forward, focusing attention on elderly, high-risk groups.

The NICE appraisal can be used as a framework, as long as the details and unworkable elements are ignored. A composite measurement of fracture risk in whatever form is desirable for all clinicians involved in the care of patients who are, or potentially will be, osteoporotic.

The NOGG guidelines have emphasised a multifactorial approach to osteoporosis not unlike the assessment of cardiovascular disease. They should help to identify those who are most at risk in the immediate future and most likely to benefit from treatment.

Dr En C Fung is honorary clinical fellow at the department of chemical pathology, St Thomas' Hospital, London; Professor Tim Spector is professor of genetic epidemiology at King's College London School of Medicine and consultant rheumatologist at Guy's and St Thomas' Hospitals, London

Competing interests: Professor Spector has past and current consultancies with MSD, P&G and Servier, and is an adviser to the National Osteoporosis Society

References
1. NICE. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. TA160. NICE, London, October 2008.
2. National Osteoporosis Guideline Group. Osteoporosis: clinical guideline for prevention and treatment. Executive Summary. University of Sheffield Press, Sheffield, 2008.
3. Kanis JA, Johnell O, Oden A et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008; 19: 385-97.
4. Kanis JA, Burlet N, Cooper C et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008; 19: 399-428.
5. Van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone 2001; 29: 517-22.
6. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med 1997; 103(2A): 12S-17S.
7. Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis. Am J Med 1993; 94: 646-50.
8. Wainwright SA, Marshall LM, Ensrud KE et al. Hip fracture in women without osteoporosis. J Clin Endocrinol Metab 2005; 90: 2787-93.
9. Kanis JA, McCloskey EV, Johansson H et al. Case finding for the management of osteoporosis with FRAX - assessment and intervention thresholds for the UK. Osteoporos Int 2008; 19: 1395-408.


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