Prescribing Review - Drugs used for Osteoporosis

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Drugs used for Osteoporosis

The National Osteoporosis Society estimates that osteoporosis affects 3 million postmenopausal women in the UK.¹ 1.14 million postmenopausal women in England and Wales have a confirmed diagnosis of osteoporosis after a dual-energy x-ray absorptiometry (DXA) scan.¹ It is estimated that annually there are 180,000 osteoporosis-related symptomatic fractures in England and Wales. The most common of these is a hip fracture (70,000).² Hip fractures are associated with a high level of disability such as being unable to walk independently or perform other activities of daily living. Fifty per cent of hip fracture patients are no longer able to live independently and 20% die within 6 months.³

Diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD) with reference to the number of standard deviations from the BMD in an average 25-year old woman (T-score). Osteoporosis is diagnosed where the T-score is -2.5 or below, severe osteoporosis is where the T-score is -2.5 or below and there has been one or more associated fractures. The gold standard for diagnosis is measurement at the femoral neck (hip), other techniques and sites for DXA measurement are useful for risk assessment rather than diagnosis.⁴ Using BMD alone is not ideal for predicting fracture risk. One-third of the female population over 70 years, and half of those over 80 years will have a T-score of -2.5 or below. A woman of 80 years with a T-score of -2.5 has a 10-year probability of hip fracture of more than 10% compared to a woman of 50 years with the same T-score where the probability is less than 2%. The predictive value of BMD could be enhanced by evaluation of clinical risk factors for fracture.⁴

Prescribing and spending on drugs for the prevention and treatment of osteoporosis have increased three-fold in the last five years (charts 1 and 2). Alendronic acid accounts for half of the current spending in this area and almost one-third of prescription items. A recent systematic review stated that approximately 480,000 women are prescribed medication for osteoporosis in the UK.⁵

Risk factors

Although many risk factors have been identified for osteoporosis, risk factor scores show poor specificity and sensitivity for predicting either BMD or fracture risk.⁴ Patients who have suffered one or more previous fragility fractures should be priority targets for investigation and treatment of osteoporosis.³ Non-modifiable risk factors include: age, sex, ethnicity, early menopause and family history of osteoporosis. Prevalence of osteoporosis increases markedly with age in both sexes. After the menopause when bone loss is accelerated, prevalence rises from 2% at 50 years to over 25% at 80 years.² Afro-Caribbean women have a higher BMD than Caucasian women at all ages.³ Modifiable risk factors include: weight loss and/or low body mass index, smoking, exercise and diet. BMD is affected positively by current physical activity and activity undertaken in adolescence.³ Past dietary intake of milk in premenopausal women (45-49 years) is associated positively with BMD.³ However evidence of association between current calcium intake and low BMD is inconsistent. People taking corticosteroid therapy can develop osteoporosis; this appears to be dose and duration dependent. There is no strong evidence to recommend minimum doses of corticosteroids below which there is no osteoporosis risk. The consensus view suggests that prednisolone doses of greater than 7.5mg per day continued over 6 months or more may result in significant bone loss.⁶

Prevention of osteoporosis

Postmenopausal women should take regular exercise and increase their daily intake of calcium to 1,000 milligrams, either from dietary intake or calcium supplements to help prevent osteoporosis.³ Women over 65 years should aim to take 10 micrograms of vitamin D per day, in most cases this is only achieved by taking a supplement.³ Calcium and vitamin D supplementation has been shown to significantly decrease the risk of hip fractures in elderly women living in nursing homes. A recent study of the effect of supplementation for secondary prevention of low-trauma fractures in elderly people did not confirm this benefit, however, the population were younger and most were living in the community.⁷

Hormone Replacement Therapy (HRT) should no longer be used as first-line therapy to prevent osteoporosis.⁸ Women who experience premature menopause can receive HRT but this should be reviewed when they reach 50 years. Individual patients may benefit from HRT if they are intolerant of other osteoporosis therapies or there are contra-indications (e.g. chronic renal failure) or there is evidence of treatment failure or unsatisfactory response, but the individual risks and benefits should be assessed.⁸

Prevention of fractures

Individuals at risk of falling should be offered advice about measures to prevent further falls. Older people reporting a fall should have their gait and balance assessed to see if there would be any benefit from interventions such as strength and balance training, vision assessment and medication review.⁹ Previous trial data suggested that hip protectors significantly reduced the incidence of hip fractures, however, subsequent trials have found them to be ineffective for those living at home and their effectiveness for people in institutions is also uncertain.¹⁰

NICE has published its guidance on prevention of osteoporotic fragility fractures in post menopausal women with previous fracture (secondary prevention). Where women do not have adequate levels of calcium or vitamin D, supplements should be prescribed for one or both if necessary.¹¹ NICE recommends bisphosphonates (alendronate, etidronate and risedronate) as treatment options:

• in women aged 75 years and over, without the need for DXA scanning
• in women aged 65-74 years if osteoporosis is confirmed by DXA scanning
• in postmenopausal women younger than 65 if they have a T-score of approximately -3 or below established by DXA scan, or if they have confirmed osteoporosis and one or more additional clinical risk factors.¹¹

Strontium ranelate is an alternative where: bisphosphonates are contraindicated; patients are unable to comply with the special instructions for their administration; patients are intolerant of bisphosphonates and where women have had an unsatisfactory response to a bisphosphonate. An unsatisfactory response is considered to be when a woman has suffered another fragility fracture despite full adherence to treatment for one year and there is evidence of decline in BMD below pre-treatment baseline.¹¹ Raloxifene is a suitable alternative if women have an unsatisfactory response to strontium ranelate or are intolerant of it, or it is contraindicated.¹¹ Teriparatide is a suitable option for women who are 65 years or over and who have had an unsatisfactory response to bisphosphonates or intolerance to bisphosphonates where they have:

• an extremely low BMD (with a T-score of approximately -4 or below)
• a very low BMD (with a T-score of approximately -3 or below) plus multiple fractures (more than two), plus one or more additional clinical risk factors.¹¹

Ibandronic acid has been recently marketed as a once-monthly bisphosphonate licensed to treat postmenopausal osteoporosis, in order to reduce the risk of vertebral fractures. Efficacy on femoral neck fractures has not been established and NICE has not yet reviewed ibandronic acid.

NICE's preliminary recommendations for primary prevention of osteoporotic fragility fractures in postmenopausal women are that bisphosphonates (alendronate, etidronate and risedronate) are suitable treatment options only in women aged 70 years or older if they meet specific requirements with regard to clinical risk factors and T-scores. NICE include the following as clinical risk factors: parental history of hip fracture; low body mass index (less than 19kg/m²); and medical conditions independently associated with bone loss, such as rheumatoid arthritis.² However after considering the responses received from consultees and commentators, the Appraisal Committee has decided that some reanalysis of the evidence is required.

Assessment of BMD by DXA is a prerequisite for targeting treatment in most cases. The exception is patients who have had at least two vertebral fractures and are known not to have underlying metastatic tumours, myeloma or other destructive disease.³ Targeting treatment to reduce fracture risk on the basis of clinical risk factors for falling (without measurement of BMD) has been shown to be ineffective as a means of reducing the incidence of fractures.³ In some areas the availability of DXA scans may be problematic.

Prescribing Data

There is almost 2-fold variation in spending on drugs used for prevention and treatment of osteoporosis across strategic health authorities (Chart 3). Alendronic acid (including the combination with Vitamin D) accounts for 64% of all prescribing of drugs used for osteoporosis within BNF 6.6.2 (bisphosphonates and other drugs affecting bone metabolism). In the quarter to December 2005 there were 796,000 alendronic acid items, costing £23.7 million and 379,000 risedronate sodium items, costing £9.5 million. Disodium etidronate items have fallen by 72% in the last 5 years to 40,000 per quarter, while its cost has decreased by 81% to £1.1 million per quarter. There were 6,000 items for ibandronic acid (£0.25 million), quarter to December 2005.

Prescribing of strontium ranelate and raloxifene accounted for 18,000 items and 45,000 items, costing £0.5 million and £1.4 million respectively. There is low prescribing of calcitonin in general practice, almost 2,000 items costing £90,000 per quarter.

Calcium is usually prescribed with vitamin D or a vitamin D analogue. In the quarter to December 2005 there were 570,000 items for Adcal D3® costing £2.5 million; 5 years ago there were only 16,000 items costing £84,000. Calcichew D3 Forte® items have increased over 4-fold in the last 5 years to 504,000 per quarter, while spending has more than tripled to £2.4 million. Calcichew D3® items have increased by 40% to 157,000, costing £1.6 million per quarter. Generic calcium and vitamin D items have remained constant over the last 5 years at 74,000 per quarter, costing £0.3 million. Generic calcium carbonate items have increased by 23% to 119,000 (costing £945,000) per quarter. Prescribing and spending on Sandocal® has fallen over the last 5 years by over a third to 16,000 items (costing £133,000) per quarter.

REFERENCES

1. National Osteoporosis Society. Osteoporosis facts and figures v1.1. January 2006 www.nos.org.uk
2. NICE. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Appraisal Consultation Document, September 2005 www.nice.org.uk/page.aspx?o=273457#
3. Scottish Intercollegiate Guidelines Network. Management of Osteoporosis. June 2003 www.sign.ac.uk/pdf/sign71.pdf
4. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929-1936
5. Stevenson M, Lloyd JM, De Nigris E et al. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene, teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technology Assessment 2005; 9: 1-160 www.hta.ac.uk/fullmono/mon922.pdf
6. Arthritis Research Campaign. Corticosteroid-induced osteoporosis - Prevention and Treatment. No. 5, May 2001 www.arc.org.uk/about_arth/med_reports/series4/ip/6505/6505.pdf
7. Grant A, Avenell A, Campbell M, McDonald A, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005; 365: 1621-1628
8. Duff G. Further advice on safety of HRT: Risk:Benefit unfavourable for first-line use in prevention of osteoporosis. Message from Professor Gordon Duff, Chairman, Committee on Safety of Medicines. December 2003
9. NICE. Falls. The assessment and prevention of falls in older people. Clinical guideline 21. November 2004. www.nice.org.uk/pdf/CG021NICEguideline.pdf
10. Parker M, Gillespie W, Gillespie L. Effectiveness of hip protectors for preventing hip fractures in elderly people: systematic review. BMJ 2006; 332: 571-574
11. NICE. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Appraisal Consultation Document, September 2005. www.nice.org.uk/page.aspx?o=273698

SUMMARY

• Patients should be encouraged to address lifestyle measures such as stopping smoking, diet and taking regular exercise to reduce their osteoporosis risk.
• Bisphosphonates are suitable treatments for secondary prevention of osteoporosis; bisphosphonate choice should be made based on individual patient factors taking account of the effectiveness of the drug versus the adverse effect profile.
• Strontium ranelate is a suitable alternative in secondary prevention of osteoporosis where bisphosphonates are unsuitable.
• Hormone replacement therapy should no longer be used as first-line therapy to prevent osteoporosis. HRT can be used in women who experience premature menopause but this should be reviewed when they reach 50 years.