Dr Pam Brown discusses Technology Appraisal 160 on the primary prevention of post-menopausal osteoporotic fragility fractures


Osteoporosis is a preventable and treatable chronic skeletal disease, which is important because it increases the risk of fragility fractures resulting in higher mortality and morbidity, and loss of mobility. In October 2008, NICE published two technology appraisals on the primary and secondary prevention of osteoporotic fragility fractures in post-menopausal women.1,2 This article will discuss the delays to the publication of these documents and then focus on Technology Appraisal (TA) 160 on Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women.1 An article on TA161 on the secondary prevention of osteoporotic fragility fractures will be featured in the February issue of Guidelines in Practice.

Development of the technology appraisals

The scope for the NICE guideline on drug treatments for the prevention of osteoporotic fragility fractures in post-menopausal women was originally agreed in August 2002 and included both primary and secondary prevention; a decision was then made in 2004 to develop two separate appraisals.

Technology Appraisal 87 on treatments for the secondary prevention of osteoporotic fragility fractures in post-menopausal women was published in December 2005,3 and then superseded by TA161 in October 2008.2

The development of the primary prevention guidance was more complicated: it progressed through three further appraisal consultation documents (ACDs) before a final appraisal document (FAD) was published in June 2007. Following an appeal, treatments other than alendronate were added back into the guidance, and a further ACD and FAD were published in March and July 2008, respectively. Technology Appraisal 160 was finally published in October 2008.1 Thus, this guidance took 6 years to develop and many women who would have qualified for treatment have been denied it during this period, while clinicians awaited guidance.

TA160—primary prevention of osteoporotic fragility fractures

Technology Appraisal 160 applies only to post-menopausal women who have not had a fragility fracture and are not committed to taking corticosteroids for ?3 months.1 The NICE guidance recommends that clinicians ascertain whether women are calcium and vitamin D replete before starting treatment with a bone-sparing agent.1 In practice it is very difficult to ensure women are consuming adequate dietary calcium, and most laboratories are not willing to measure vitamin D levels on all women starting therapy, so the majority of patients will need adjuvant calcium (of at least 1000 mg/day) and vitamin D (800 IU/day) supplements.4

Implementing the recommendations from TA160 will be challenging as age, bone mineral density (BMD) T-score, and a variety of independent clinical risk factors (see Box 1) for fracture and indicators of low BMD must be taken into account to determine whether a woman qualifies for treatment. In addition, different combinations of BMD and risk factors are needed to qualify for different treatment options—this could result in some women who are intolerant to alendronate, requiring lower BMD or evidence of deterioration to qualify for alternative treatments. As dual-energy X-ray absorptiometry (DXA) scanning is only recommended at 18–24 month intervals,5 many will suffer a delay in access to alternative therapy.

First-line treatment

Alendronate is recommended as the first-line treatment in women who are:1

  • aged ?70 years, who have a T-score of ?-2.5 standard deviations (SD) (i.e. confirmed to have osteoporosis) and have one independent clinical risk factor for fracture or indicator of low BMD (see Box 1). Depending on the discretion of the treating clinician, DXA may not be required in women who are ?75 years and have two or more independent risk factors for fracture or indicators of low BMD
  • aged 65–69 years with a T-score of ?-2.5 SD who have an independent clinical risk factor for fracture
  • aged <65 years and post-menopausal who have a T-score of ?-2.5 SD, an independent clinical risk factor for fracture and at least one indicator of low BMD.

The use of combinations of different numbers of independent clinical risk factors for fracture and indicators of low BMD for the different age ranges, without allowing these to be collated in a calculator, makes this guidance difficult to implement in a clinical setting.

Once the decision has been made to treat with alendronate, the NICE technology appraisal recommends the use of the most cost-effective preparation (i.e. generic alendronate). Few women will have an independent clinical risk factor. Therefore, in practice, most women under 70 years of age will not qualify for bone-sparing treatment until they suffer their first fragility fracture and can then be assessed under the secondary prevention guidance.

Alternative treatment options

Risedronate or etidronate can be prescribed for women provided they fulfil the more stringent criteria for age, risk factors, and T-score as shown in Table 1 and if:1

  • they are unable to comply with dosing instructions for alendronate (these are similar for alendronate and risedronate so it is unlikely any women will be in this group)
  • they are intolerant of alendronate (intolerance is defined as persistent upper gastrointestinal disturbance that warrants discontinuation of treatment despite complying fully with the instructions for administration)
  • alendronate is contraindicated.

The NICE appraisal encourages clinicians to use judgement when choosing between risedronate and etidronate. There is no randomised control trial evidence for hip-fracture reduction with etidronate, so it would seem inappropriate to prescribe this therapy when there is supporting evidence for risedronate.

Strontium ranelate is recommended for use in women who are unable to comply with dosing instructions, or who are intolerant of alendronate and either risedronate or etidronate, or where these are contraindicated. Patients should have osteoporosis and meet the additional criteria shown in Table 2.1

Despite the evidence for vertebral fracture reduction, and reduction in
the risk of oestrogen-positive breast cancer with raloxifene, NICE does not recommend raloxifene use for the primary prevention of osteoporotic fractures. This denies younger post-menopausal women with a strong family history of breast cancer a useful interim treatment while they are at low risk of hip fracture.

Every GP will have post-menopausal women who are currently on bone-sparing treatment for the primary prevention of osteoporosis on their list of patients. Many of these patients will not qualify for therapy under this new guidance—although treatment in this group of patients is recommended by the guidelines from the Royal College of Physicians6,7 and the recent guideline from the National Osteoporosis Guideline Group (NOGG).4 Fortunately NICE stresses that women currently receiving treatment who would no longer qualify under the recommendations in TA160 should be allowed to continue until they and their clinicians consider it appropriate to stop.1 This will avoid any difficult conversations occurring with women who were previously diagnosed with osteoporosis and advised of the importance of adhering to therapy.

Box 1: 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
  • Medical conditions including ankylosing spondylitis, Crohn's disease
  • Conditions that result in prolonged immobility
  • Untreated premature menopause
  • Rheumatoid arthritis
 
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 patients are unable to take alendronate1

Age (years)Number of independent clinical risk factors for fracture
  0 1 2
65–69 Not recommended -3.5 -3.0
70–74 -3.5 -3.0 -2.5
?75 -3.0 -3.0 -2.5*
*Women ?75 years with two or more independent 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) TA160. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE. Available from www.nice.org.uk/TA160 Reproduced with permission.

Table 2: T-scores in standard deviations at (or below) which strontium ranelate is recommended when patients are unable to take alendronate and either etidronate or risedronate1

Age (years)Number of independent clinical risk factors for fracture
  0 1 2
65–69 Not recommended

-4.5

-4.0

70–74

-4.5

-4.0

-3.5

?75

-4.0

-4.0

-3.0

National Institute for Health and Care Excellence (NICE) (2008) TA160. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. London: NICE. Available from www.nice.org.uk/TA160 Reproduced with permission.

Fracture risk assessment

The absolute 10-year fracture risk assessment for men and women over 50 years of age and those on corticosteroids can be calculated using the World Health Organization online fracture risk assessment tool (FRAX®) (BMD measurement is not required initially): available at www.shef.ac.uk/FRAX/. Once fracture risk has been assessed, a link to the NOGG website (www.shef.ac.uk/NOGG/) provides guidance on whether to treat or reassure the patient or refer them for a DXA scan. This calculator will be incorporated into GP computer software systems in the near future.

Conclusion

Audits have demonstrated that the previous NICE guidance3 on the secondary prevention of osteoporosis has not been implemented widely in primary care, with only 10–12% of those at highest risk of fracture receiving appropriate bone-sparing therapy.8 Hopefully, primary care teams will be motivated to implement the new NICE guidance on the primary and secondary prevention of osteoporosis, or if this proves too complicated they can use the FRAX® calculator and NOGG guideline to reduce the burden of fragility fracture in their practices.

  1. National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 160. London: NICE, 2008.
  2. National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal 161. London: NICE, 2008.
  3. 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.
  4. 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.
  5. Blake G, Fogelman I. The radiological diagnosis of osteoporosis. In: Arden N, editor. Osteoporosis. Oxford: Remedica, 2006.
  6. Royal College of Physicians. Osteoporosis: clinical guidelines for prevention and treatment. London: RCP, 1999.
  7. Royal College of Physicians and Bone and Tooth Society of Great Britain. Osteoporosis—clinical guidelines for prevention and treatment; update on pharmacological interventions and an algorithm for management. London: RCP, 2000.
  8. 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.G