Dr Pam Brown reviews the recommendations made by NICE in Technology Appraisal 161 and discusses their implementation

Post-menopausal women with a previous fragility fracture have been identified as being in the highest risk group for further fracture.1 They need prompt, effective treatment that is tailored to their individual needs. The recent NICE Technology Appraisal (TA) 161 on Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women,1 published in October 2008, offers guidance on managing this group of post-menopausal women with some of the available therapies,1 and supersedes NICE TA87, which was published in 2005.2

Sadly, this long awaited guidance is highly complex and therefore challenging to implement in its current format. It is also unethical since it recommends that high-risk women with osteoporosis and previous fracture who cannot tolerate alendronate therapy must wait until they have deteriorated further before they can receive other fracture prevention therapies. This is not acceptable to clinicians.

There is evidence that future fracture rates can be reduced by 30–50% over 3 years in this high-risk group if the women comply with their treatment regimen.3 However, there is a very real danger that the complex instructions in TA161 for identifying who qualifies for treatment will result in doctors being uncertain of whom to treat. Also, women who are intolerant of alendronate may fail to qualify for alternative treatments; thus many women at very high risk of fracture will be denied effective treatment and will continue to be at risk of further fractures.

Summary of the guidance from Technology Appraisal 161

The treatment recommendations from TA161 are summarised with additional guidance on which patients qualify for treatments other than alendronate outlined in Box 2, Table 1, and Table 2. These highlight the challenging complexity of this guidance. The inclusion of etidronate has been challenged as there is only evidence for hip fracture from a study using the General Practice Research Database and no RCT evidence.1,4 Likewise, RCTs have failed to demonstrate hip fracture reduction with raloxifene.1,5

An unsatisfactory response to treatment is defined as ‘when a woman has another fragility fracture despite adhering fully to treatment for 1 year, and there is evidence of a decline in bone mineral density (BMD) below her pre-treatment levels’.1 The results of a dual energy X-ray absorptiometry (DXA) scan are reported as T-scores, which compare the patient’s BMD to that of a young healthy adult. A T-score of -1 represents a value of 1 standard deviation (SD) from the mean for a young healthy adult.

The NICE guideline indicates that women aged ?75 years can be treated without performing a DXA scan, so in this group, a decline below baseline BMD will be impossible to identify. Therefore, this would mean that the GP has to either begin conducting DXA scans on women aged ?75 years, or accept that they will never be able to prove that these patients have had an unsatisfactory response to treatment.

Box 1: Treatment for the secondary prevention of osteoporotic fragility fractures in post-menopausal women

  • Alendronate
    • BMD T-score ?-2.5 SD (those aged ?75 years may not need a DXA scan)
  • Risedronate and etidronate
    • unable to comply with dosing instructions for alendronate or contraindicated or intolerant
    • BMD ?-2.5 to -3.0 SD depending on age and number of independent
      clinical risk factors for fracture (see Table 1 and Box 2)
      (those aged ?75 years may not need a DXA scan)
  • Strontium ranelate and raloxifene
    • unable to comply with dosing for bisphosphonates or contraindicated or intolerant
    • BMD ?-2.5 to -4 SD depending on age and number of independent clinical risk factors for fracture (see Table 2 and Box 2)
    • aged ?75 years with one or more independent clinical risk factors for fracture or indicators of low BMD (a DXA scan may not be needed)
  • Teriparatide
    • unable to comply with dosing for bisphosphonates, or contraindicated or intolerant to alendronate and either risedronate or etidronate or strontium ranelate, OR unsatisfactory response to bisphosphonates AND
    • aged ?65 years with T-score ?-4.0 SD, OR T-score ?-3.5 SD plus two or more
      fractures, OR aged 55–64 years and T-score ?-4 SD plus two or more fractures
BMD=bone mineral density; SD=standard deviation; DXA=dual X-ray absorptiometry

Box 2: Clinical risk factors for fracture and indicators of low BMD1

  • Independent clinical risk factors for fracture
    • Parental history of hip fracture
    • Alcohol intake ?4 units per day
    • Rheumatoid arthritis
  • Indicators of low BMD
    • BMI <22 kg/m2
    • Untreated premature menopause
    • Conditions that result in prolonged immobility
    • Ankylosing spondylitis, Crohn’s disease
BMD=bone mineral density; BMI=body mass index

Table 1: T-scores in standard deviations at (or below) which risedronate or etidronate is recommended when alendronate cannot be taken1

Age (years) Number of independent clinical risk factors for fracture
  0 1 2

50–54

Not recommended

-3.0

-2.5

55–59

-3.0

-3.0

-2.5

60–64

-3.0

-3.0

-2.5

65–69

-3.0

-2.5

-2.5

?70

-2.5

-2.5

-2.5

National Institute for Health and Care Excellence (NICE) (2008) TA161. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE. Available from www.nice.org.uk/TA161 Reproduced with permission.

Table 2: T-scores in standard deviations at (or below) which strontium ranelate or raloxifene is recommended when alendronate and either

risedronate or etidronate cannot be taken1

Age (years) Number of independent clinical risk factors for fracture
  0 1 2

50–54

Not recommended

-3.5

-3.5

55–59

-4.0

-3.5

-3.5

60–64

-4.0

-3.5

-3.5

65–69

-4.0

-3.5

-3.0

70–74

-3.0

-3.0

-2.5

?75*

-3.0

-2.5

-2.5

*Women ?75 years with one or more independent clinical risk factors or indicators of low bone mineral density can be treated without dual-energy X-ray absorptiometry at the discretion of their clinician.

National Institute for Health and Care Excellence (NICE) (2008) TA161. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE. Available from www.nice.org.uk/TA161 Reproduced with permission.

Differences from Technology Appraisal 87

In 2005, NICE TA87 provided guidance on the use of bisphosphonates, selective oestrogen receptor modulators (raloxifene) and teriparatide.2 The new TA161 includes guidance on these therapies and also strontium ranelate. In TA87, the three bisphosphonates (alendronate, risedronate, and etidronate) were ranked equally as first-line therapy, with raloxifene as second-line therapy, and teriparatide reserved for those with severe osteoporosis who were intolerant of bisphosphonates or had an unsatisfactory response.2 In TA161, alendronate is the first-choice therapy, with risedronate and etidronate as possible first alternatives, and strontium ranelate as the second alternative in those who are intolerant of alendronate, where it is contraindicated, or where the patient is unable to comply with dosing instructions.1

Teriparatide retains its positioning for severe disease, but can now be used in women aged ?55 years provided they have a very low BMD (T-score ?-4 SD) and more than two fractures. Older women (?65 years of age) qualify for teriparatide treatment if they have a T-score ?-4 SD, or ?-3.5 SD and two or more fractures.1

Although intravenous zoledronate and ibandronate are not covered by the NICE TA161, most secondary care centres consider these therapies in preference to teriparatide for women who are intolerant to, or are not benefiting from oral treatments. Annual zoledronate, delivered by intravenous infusion, is easier to administer and cheaper than teriparatide. It also has robust clinical data for hip fracture reduction and mortality reduction post hip fracture.6

Intolerance to bisphosphonates was previously defined by endoscopic criteria,2 (i.e. oesophageal ulceration, erosion, or stricture) whereas it is now defined as ‘persistent upper gastrointestinal (GI) disturbance sufficiently severe to warrant discontinuation of treatment, and that occurs even though the instructions for administration have been followed correctly.’1 This more pragmatic approach reflects current practice, which sees few patients referred for endoscopy, and also highlights the importance of compliance with dosing instructions to minimise upper GI side-effects.

Implementation of secondary prevention guidance

Unfortunately, TA87 was poorly implemented despite being more straightforward than TA161. An audit of 525 practices (covering approximately 3.4 million patients) undertaken by Hippisley-Cox et al7 demonstrated that only an average of 25% (individual practice range 0–86%) of women aged ?75 years who were coded with a fragility fracture were receiving treatment. Of those with fragility fractures who were aged 65–74 years, only 10% (range 0–75%) had a DXA scan to assess their treatment needs, as recommended in TA87.2,6

On average, 34% of women aged ?75 years who had been coded with fracture, were receiving treatment, and 21% of those aged 65–74 years with coded fractures had been referred for DXA scanning. These treatment levels are likely to be overestimates as coded fracture rates are lower than anticipated, suggesting uncoded fractures and poor data quality.

Results from a study, which I undertook across 32 general practices in Swansea, demonstrated a similar low level of implementation: on average, 34% of women aged ?75 years were coded with fracture receiving therapy, and 21% of 65–74-year-olds were coded with fractures referred for DXA scanning. Some practices had no fractures or DXA referrals coded; this suggests that they have chosen not to code these, and may not be making use of the direct access to DXA services available locally.

Unfortunately, the complexity of TA161 makes it highly unlikely that it will encourage primary care teams to become more active in the identification and management of post-menopausal women with previous fragility fractures. However, it is hoped that the Directed Enhanced Services (DES) in England and Northern Ireland, and the Local Enhanced Services (LES) in parts of Wales will help motivate teams to treat those with new fragility fractures, and that eventual inclusion in the quality and outcomes framework (QOF) in 2010 will provide continued motivation.

The way forward

The guideline published by the National Osteoporosis Guideline Group (NOGG) (www.shef.ac.uk/NOGG/) recognises that post-menopausal women and men aged over 50 years with a previous fragility fracture are at high risk of recurrence.8 Younger post-menopausal women should undergo a DXA scan and the results used to inform treatment decisions.

It is stressed in TA161 that post-menopausal women who have already had a fracture and are receiving treatment can continue therapy until they or their physician feels it is appropriate for them to stop, even if
they do not meet the new treatment criteria. This is good news, allowing women who were previously managed according to TA87 to continue with treatment.1

In reality, if NICE wants primary care teams to implement TA161 and manage the post-menopausal women who are at the highest risk of future fracture, then an easy to use risk calculator, similar to the World Health Organisation online fracture risk assessment (FRAX) calculator (www.shef.ac.uk/NOGG/) that is used in conjunction with the NOGG guideline, is urgently needed. In addition, primary care education and inclusion of osteoporosis in the QOF from 2010 are vital.

In the meantime, doctors can encourage women who are already on treatment to continue taking their medication. If in doubt about whether new patients qualify for treatment, primary care trusts or local health board pharmaceutical advisers should be able to provide guidance as trusts and these organisations are responsible for implementing TA161 within 90 days of its publication, which takes them up to the end of January 2009.

  1. National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 161. London: NICE, 2008.www.nice.org.uk/Guidance/TA161
  2. National Institute for Clinical Excellence. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 87. London: NICE, 2005.
  3. Kanis J, Adams J, Borgstrom F et al. The cost effectiveness of alendronate in the management of osteoporosis. Bone 2008; 42 (1): 14–15.
  4. van Staa T, Abenheim L, Cooper C. Use of cyclical etidronate and prevention of non-vertebral fractures. British Journal of Rheumatology 1998; 37 (1): 87–94.
  5. Cranney A, Tugwell P, Zytaruk N et al. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev 2002; 23 (4): 524–528.
  6. Lyles K, Colon-Emeric C, Magaziner J et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357 (18): 1799–1809.
  7. Hippisley-Cox J, Bayly J, Potter J et al. Evaluation of standards of care for osteoporosis and falls in primary care. London: QRESEARCH, The Information Centre for Health and Social Care, 2007.
  8. National Osteoporosis Guideline Group on behalf of the Bone Research Society, British Geriatrics Society, British Orthopaedic Association, British Society of Rheumatology, National Osteoporosis Society, Osteoporosis 2000, Osteoporosis Dorset, Primary Care Rheumatology Society, and Society for Endocrinology. Osteoporosis—clinical guideline for prevention and treatment. London: NOGG, 2008. www.shef.ac.uk/NOGG/G