Dr Juliet Compston weighs up the evidence for different osteoporosis treatments and explains how to tailor treatment to the individual patient


   

Although osteoporosis is widely recognised by GPs as a significant health problem and one in which they play a primary role, a recent survey suggests that many remain unaware of national guidelines for the management of the disease.1 This may reflect to some extent the relatively low representation of osteoporosis in Health Improvement Programmes (HImPs) and the absence in many PCGs or trusts of locally agreed guidelines.

These findings emphasise the need to ensure that the evidence-based approach provided by the Update to the Royal College of Physicians' guidelines on the management of osteoporosis2 is actively promoted in primary care and used to improve the clinical management of individuals with osteoporosis.

The updated guidelines summarise recent evidence for the efficacy of new and existing pharmacological agents (see Tables 1, 2 and 3, below). They also provide a management algorithm in which a number of treatment options are listed.

Table 1: Grading of evidence base*

Grade A
  • Meta-analysis of randomised controlled trials (RCTs) or from at least one RCT
Grade B
  • From at least one well-designed controlled study without randomisation
  • From at least one other type of well-designed quasi-experimental study
  • From well-designed non-experimental descriptive studies, e.g. comparative studies, correlation studies, case-control studies
Grade C
  • From expert committee reports/opinions and/or clinical experience of authorities

 

Table 2: Effect of interventions on the prevention/reduction of
postmenopausal bone loss: grade of recommendations*

Alendronate A
Calcitonin A
Calcitriol A
Calcium A
Cessation of smoking B
Cyclic etidronate A
Hormone replacement therapy A
Physical exercise A
Raloxifene A
Reduced alcohol consumption C
Risedronate A
Tibolone A
Vitamin D + calcium A

 

Table 3. Anti-fracture efficacy of interventions in
postmenopausal osteoporotic women: grade of recommendations*

 
Spine
Non-vertebral
Hip
Alendronate
A
A
A
Calcitonin
A
B
B
Calcitriol
A
A
nd
Calcium
A
B
B
Calcium + vitamin D
nd
A
A
Cyclic etidronate
A
B
B
Hip protectors
A
Hormone replacement therapy
A
A
B
Physical exercise
nd
B
B
Raloxifene
A
nd
nd
Risedronate
A
A
A
Tibolone
nd
nd
nd
Vitamin D
nd
B
B
nd = not demonstrated

* Tables 1, 2 & 3 are reproduced from: Royal College of Physicians and Bone and Tooth Society of Great Britain. Osteoporosis: Clinical Guidelines for Prevention and Treatment. Update on pharmacological intereventions and an algorithm for management. London: RCP, 2000, pp 3 & 4, by kind permission of the Royal College of Physicians.

Largely for historical reasons, the level of evidence on which the registration of these pharmacological agents is based varies considerably, and adequately powered, randomised controlled trials (RCTs) with fracture as the primary end-point have not been)conducted for all licensed treatments.

In addition, the majority of trials have focused on vertebral fractures, and evidence for anti-fracture efficacy at non-vertebral sites, particularly the hip, is by no means universal.

Together with safety, tolerability and cost, the above factors may affect decision making in the individual patient.

Hormone replacement therapy

No longer the 'gold standard'

Evidence for the anti-fracture efficacy of hormone replacement therapy (HRT) is based almost exclusively on observational data, in which fracture rates in women who chose to take HRT at the menopause are compared with those in non-users.3

These studies are subject to bias, since women who take HRT are healthier in a number of respects than those who do not; any benefits of HRT emerging from such studies are thus likely to be overestimated or might even be spurious.

Nonetheless, a few small RCTs have demonstrated a reduction in vertebral fractures in women taking HRT and, more recently, in wrist fractures.4 There is increasing evidence for attenuation of the beneficial effects of HRT after therapy is withdrawn,5 jmphasising the need for life-long therapy after the menopause to maintain protection against fracture.

Bisphosphonates and raloxifene

More robust RCT evidence

Large RCTs have demonstrated a reduction of around 50% in vertebral fracture risk in postmenopausal women with osteoporosis treated with alendronate or risedronate.6-9 These studies have also shown a similar reduction in non-vertebral fracture, including hip fracture, in treated women.

Treatment with these agents produces a rapid response in women with established osteoporosis, significant reductions in fracture being demonstrated after only one year's treatment. The best response is seen in women with established osteoporosis;10 the number needed to treat rises steeply in those without fracture and with less severely reduced bone mineral density.

In the case of cyclic etidronate, favourable trends were observed towards reduced vertebral fracture risk in clinical trials, although these were not adequately powered to produce unequivocal evidence of decreased fracture risk.11,12 Observational data from the General Practice Research Database support the contention that cyclic etidronate therapy also protects against non-vertebral fractures.13

Raloxifene is the first selective oestrogen receptor modulator to be licensed for the prevention of osteoporotic fractures.

In a large RCT in postmenopausal women with osteoporosis, a significant reduction (30-50%) in vertebral fracture risk was demonstrated after 3 years' treatment.14 However, despite the large number of women in the study, no significant reduction was seen after 3 years' treatment in non-vertebral fractures, including hip fracture.

The reason for this apparent lack of effect is uncertain, but the weaker anti-resorptive potency of raloxifene, as opposed to the bisphosphonates, may be responsible. As with alendronate and risedronate, there is evidence of reduced vertebral fracture risk after only one year's treatment with raloxifene.

Calcitonin

Less certainty about the evidence

In a recent large RCT of the effects of three doses of intranasal calcitonin in postmenopausal women with osteoporosis, a significant 39% reduction in vertebral fracture was observed in women receiving 200 units daily, but not in those taking a lower (100 units) or higher (400 units) daily dose.15

This apparent lack of any dose-response effect, together with a very high drop-out rate from the trial, raises some concerns about the interpretation of the results; in this study a significant reduction was seen in non-vertebral fracture in the 100 unit treatment group only.

A recent systematic review concluded that calcitonin may protect against both vertebral and non-vertebral fractures;16 nevertheless, there remainsusome uncertainty about the anti-fracture efficacy of calcitonin, and it should be regarded as a second-line option.

Calcitriol

Inconsistent evidence

Although one RCT demonstrated a significant reduction in both vertebral and non-vertebral fractures (70% and 50% respectively) in postmenopausal women with osteoporosis,17 this finding has not been universal.

The efficacy of this agent cannot therefore be regarded as firmly established and, like calcitonin, it should be regarded as a second-line option in postmenopausal women with osteoporosis.

Combined calcium and vitamin D

Strong evidence for reduced non-vertebral fractures in the elderly

An RCT in elderly women (mean age 84 years) living in sheltered accommodation in France demonstrated a significant reduction in non-vertebral fractures, including hip fracture, in women taking a combination of 800 units vitamin D and 1.2g calcium daily.18

There is also evidence that similar doses of calcium and vitamin D protect against non-vertebral fracture in older men and women (over 65 years) living independently.19

However, it is unclear whether the benefits observed in these studies were due to vitamin D, calcium or the combination of both, and the important question of whether vitamin D alone protects against hip fracture remains unanswered at present.

Safety and tolerability

With the range of options now available, safety and tolerability assume increasing importance.

HRT provides effective relief from menopausal symptoms but withdrawal bleeding and fears about an increased risk of breast cancer significantly limit uptake and compliance.

There is also an increased risk of thromboembolism; although this is small in terms of absolute risk, HRT should generally be avoided in women with a history of or predisposition towards thromboembolic disorders.

Raloxifene, in contrast to HRT, does not stimulate the endometrium and its use is associated with a decreased risk of breast cancer.20 However, it does not alleviate and may exacerbate menopausal vasomotor symptoms and it is therefore not suitable for symptomatic perimenopausal women.

Raloxifene use is also associated with an increased risk of thromboembolism, of a similar magnitude to that seen with HRT.

The long-term effects of HRT and raloxifene on heart disease and cognitive function remain to be accurately characterised and quantified. Although observational data indicate that HRT protects against heart disease, emerging evidence from prospective studies has questioned this benefit, particularly in women who already have coronary heart disease.

Similarly, the effects of both HRT and raloxifene on cognitive function and risk of dementia require further investigation.

Bisphosphonates are very poorly absorbed from the gastrointestinal tract and must therefore be taken some time away from meals. In addition, because of the potential for nitrogen-containing bisphosphonates to cause irritation of the upper gastrointestinal tract, the tablet should be swallowed whole with a full glass of water and the patient is advised to stand or sit upright for the next 30 minutes.

This dosing regimen can be restrictive for those with busy lifestyles and may be difficult for frail elderly individuals. Side-effects other than those related to the gastrointestinal tract only occur rarely with the bisphosphonates.

Side-effects with intranasal calcitonin are rare although the frequency of rhinitis is increased.

Calcitriol therapy is associated with an increased risk of hypercalcaemia and hypercalciuria, and regular monitoring is therefore required.

Choice of therapy for the individual patient

In clinical practice, the choice of treatment will be influenced by a number of factors, including age, existing co-morbidity, and the individual preferences and prejudices of the patient.

In younger women with vasomotor symptoms HRT is often the preferred therapy, whereas for older women who are some years past the menopause, raloxifene or a bisphosphonate may be more appropriate.

Where there is evidence of non-vertebral osteoporosis, raloxifene should be regarded as a second-line option because of the lack of evidence of anti-fracture efficacy at these sites.

Calcium and vitamin D should be considered in the frail elderly and are also used as an adjunct to other treatments where evidence of reduced intake or synthesis exists.

Putting evidence into practice

The production and dissemination of guidelines does not, per se, guarantee their implementation in clinical practice.21 Nevertheless, a number of steps can be taken to optimise the uptake of guidelines, including the use of relatively simple and 'user-friendly' algorithms, appropriate dissemination, and continuing education of health professionals and the public.

With the current shift towards primary care, it is particularly important that primary care groups and trusts develop appropriate strategies for osteoporosis. In this respect the involvement of osteoporosis in HImPs and National Service Frameworks should raise the profile of the disease and encourage more widespread use of guidelines.

Finally, the increasing use of audit and appraisal as part of the clinical governance agenda will be a powerful tool to assess the uptake of evidence-based guidelines and to ensure that they are used appropriately in clinical practice.

References

  1. Omnimed. Management of Osteoporosis by General Practitioners – A Survey. Taylor Nelson Sofres. March 2000.
  2. Writing Group for the Royal College of Physicians and the Bone and Tooth Society of Great Britain. Osteoporosis: Clinical guidelines for Prevention and Treatment. Update on Pharmacological Interventions and an Algorithm for Management. London: Royal College of Physicians, 2000.
  3. Compston JE. Prevention and management of osteoporosis: current trends and future prospects. Drugs 1997b; 53: 727-35.
  4. Komulainen MH, Kroger H, Tuppurainen MT et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5-year randomized trial. Maturitas 1998; 31: 45-54.
  5. Micha"lsson K, Baron JA, Farahmand BY et al. Hormone replacement therapy and risk of hip fracture: population-based case-control study. Br Med J 1998; 316: 1858-63.
  6. Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535-41.
  7. Harris ST, Watts NB, Genant HK et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. A randomized controlled trial. JAMA 1999; 282: 1344-52.
  8. Reginster J-Y, Minne HW, Sorensen OH et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporosis Int 2000; 11: 83-91.
  9. Geusens P, Adami S, Bensen W et al. Risedronate reduces risk of hip fracture in elderly women with osteoporosis. Calcif Tissue Int 2000; 66: S67 (Abstract).
  10. Cummings SR, Black DM, Thompson DE et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures – results from the Fracture Intervention Trial. JAMA 1998; 280: 2077-82.
  11. Storm T, Thamsborg G, Steiniche T, Genant HK, SËrensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265-71.
  12. Watts NB, Harris ST, Genant HK et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 72-9.
  13. Van Staa TP, Abenhaim L, Cooper C. Use of cyclical etidronate and prevention of non-vertebral fractures. Br J Rheumatol 1998; 37: 87-94.
  14. Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999; 282: 637-45.
  15. Chesnut CH, Silverman S, Andriano K et al. A randomised trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 2000; 109: 267-76.
  16. Kanis JA, McCloskey EV. Effect of calcitonin on vertebral and other fractures. Q J Med 1999; 92: 143-9.
  17. Tilyard MW, Spears GFS, Thomson J, Dovey A. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992; 326: 357-62.
  18. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Br Med J 1994; 308: 1081-2.
  19. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age and older. N Engl J Med 1997; 337: 670-6.
  20. Cummings SR, Eckert S, Krueger KA et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 261: 2189-97.
  21. Davis DA, Thomson MA, Oxman A, D, Haynes RB. Changing physician performance: a systematic review of continuing medical edutation. JAMA 1995; 274: 700-5.

Guidelines in Practice, January 2001, Volume 4(1)
© 2001 MGP Ltd
further information | subscribe