Pharmacological interventions for post-menopausal osteoporosis: an evidence-based approach

J. E. Compston

Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

Fragility fracture is the hallmark of osteoporosis and its only significant clinical manifestation. The primary aim of intervention is therefore to reduce the risk of fracture, and demonstration of this effect is required before efficacy can be regarded as proven. Increases in bone mineral density cannot be used as a surrogate for fracture reduction because the relationship between these two outcomes is not always predictable either in direction or magnitude. The evidence-based approach thus requires proof of efficacy from adequately powered randomized controlled trials in which fracture is the primary end-point.

In recent years there have been significant advansces in the management of post-menopausal osteoporosis and a range of pharmacological options are now available. Largely for historical reasons, the level of evidence on which the registration of these agents is based varies widely. For hormone replacement therapy, evidence for anti-fracture efficacy is based mainly on observational data; because of the better health status of women who choose to take hormone replacement therapy compared with those who do not, such studies are likely to overestimate any benefit, or might even produce spurious results. In contrast, there is robust evidence from randomized controlled trials for the anti-fracture efficacy of an increasing number of interventions, including alendronate [1, 2], risedronate [3, 4], raloxifene [5] and combined calcium and vitamin D [6]. For other agents, such as calcitriol and calcitonin, evidence of efficacy from randomized controlled trials is less robust or, in the case of calcitriol, inconsistent [79].

For regulatory purposes, a distinction is drawn between the prevention and treatment of osteoporosis, the former being defined as the prevention of bone loss in women with osteopenia or normal bone mineral density and the latter as reduction in the risk of fracture in women with osteoporosis. These definitions are neither useful nor relevant in clinical practice, since all interventions currently in use act fundamentally in the same manner, namely by the inhibition of bone resorption, and there are therefore no theoretical grounds for distinguishing between prevention and treatment on the basis of the intervention. Furthermore, there is increasing evidence that relatively short-term treatment with these agents in women with established osteoporosis can achieve significant reductions in the fracture rate [3, 6, 10]. It is thus more appropriate to regard the indication for treatment as the prevention of osteoporotic fracture, regardless of whether a fragility fracture has already occurred.

Because of differences in the design of different clinical trials, in particular with respect to the patient population studied and variations in the criteria used to define vertebral deformity, it is not possible to compare anti-fracture efficacy directly between different interventions. Nevertheless, reductions in vertebral fracture of between 30 and 50% have been reported for alendronate, risedronate, raloxifene and calcitonin after 3-5 yr of treatment, those interventions which produce greater increases in spinal bone mineral density generally being associated with the greatest fracture reduction [11]. In the case of hormone replacement therapy, the magnitude of fracture reduction cannot be deduced accurately from the three small prospective studies so far reported [1214].

Fragility fracture at any one site is an important and independent risk factor for fracture elsewhere and thus an intervention should ideally be effective at all major fracture sites, particularly the spine and hip. In the majority of clinical trials, vertebral fracture has been the primary end-point and demonstration of a reduction in non-vertebral fractures, particularly hip fractures, has not been invariable (Table 1Go). Nevertheless, for alendronate and risedronate, the reduction in the risk of non-vertebral and hip fracture has been established with reasonable certainty in prospective studies [1, 3, 15], whilst in the case of cyclic etidronate, observational data from the General Practice Research Database indicate similar benefits [16]. Evidence for the anti-fracture efficacy of hormone replacement therapy at the hip is based exclusively on observational data [20], but a recent randomized controlled trial has provided evidence for efficacy against non-vertebral fractures in post-menopausal women [21]. In contrast, no evidence for non-vertebral fracture reduction was observed in a large randomized controlled trial of raloxifene, a selective oestrogen receptor modulator, in post-menopausal women with osteoporosis [5]. Similarly, in the recent randomized controlled trial of intranasal calcitonin, no effect on non-vertebral fractures was seen [22]. The reasons for the observed lack of anti-fracture efficacy of these two interventions at non-vertebral sites have not been established clearly, but may be related to their lower anti-resorptive potency when compared with oestrogen and the bisphosphonates.


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TABLE 1. Anti-fracture efficacy of pharmacological interventions based on data from randomized controlled trials

 
Safety and tolerability have become increasingly important issues in the positioning of different interventions as the number of options available increases. Bisphosphonates are generally well tolerated, but because of their poor intestinal absorption and the potential, in the case of aminobisphosphonates such as alendronate and risedronate, for upper gastrointestinal side-effects, the recommended dosing regimens may be problematic for some women. The issue of whether alendronate and risedronate are similar with respect to upper gastrointestinal safety has not been resolved; adverse oesophageal effects of alendronate were not seen in clinical trials and emerged only during post-marketing surveillance [23], and thus the absence of these effects in clinical trials with risedronate cannot be taken as conclusive evidence of safety. Symptoms such as nausea, flushing and paraesthesiae may be associated with the parenteral administration of calcitonin; when taken intranasally, the only documented side-effect is a small increase in the frequency of rhinitis. Calcitriol therapy may result in hypercalcaemia and hypercalciuria, and regular monitoring of serum calcium levels is required. The doses of calcium and vitamin D that are prescribed (generally between 500 and 1000 mg and 400–800 IU daily, respectively) are safe and, although gastrointestinal intolerance to calcium supplements may occur, other side-effects are rare.

Evaluation of the safety and tolerability of hormone replacement therapy and raloxifene is complex because of the potential but largely unproven extraskeletal risks and benefits of these interventions. With respect to short-term effects, the tolerability of hormone replacement therapy varies widely; on the one hand, it is enhanced by the alleviation of vasomotor and genitourinary symptoms in perimenopausal women, but it may be reduced by the occurrence of vaginal bleeding and other symptoms, such as breast pain. In the case of raloxifene, there is no alleviation (there may be exacerbation) of vasomotor menopausal symptoms, but it does not induce vaginal bleeding or breast pain. For many women taking long-term hormone replacement therapy, the increase in the risk of breast cancer is a major concern [24] and an important reason for non-compliance; in contrast, the risk of breast cancer is significantly reduced by raloxifene, at least for up to 4 yr of treatment [25], although the effects of longer treatment duration have not been established, nor is it known how risk is affected after the withdrawal of treatment. The most important potential benefit of both interventions concerns cardiovascular disease. However, in spite of the evidence from observational studies for a protective effect of hormone replacement therapy on heart disease [26], a recent randomized controlled trial of the effects of hormone replacement in the secondary prevention of coronary heart disease showed no beneficial effect, but rather an excess of coronary heart disease events and deaths during the first year or two of the study [27]. Furthermore, an interim report from another randomized controlled trial of hormone replacement therapy, the Womens' Health Initiative Study, has confirmed a small excess of cases of coronary heart disease and stroke during the first 2 yr of the study [28]. The effects of raloxifene on cardiovascular disease risk are unknown. Similarly, the effects of hormone replacement and of raloxifene on cognitive function remain to be established definitively. Both interventions are associated with an approximately threefold increase in the relative risk of venous thromboembolism [25, 2931].

Even when the rigorous approach of evidence-based medicine is adopted, difficulties in defining efficacy arise. For example, data may sometimes be inconsistent for the same agent between studies, as in the cases of calcitriol [7, 8] and native vitamin D [32, 33]. Extrapolation of trial data to other populations may be insecure; for example, the reduction in hip fracture associated with calcium and vitamin D supplementation in very elderly women living in sheltered accommodation [6] may not occur in free-living elderly women, in whom vitamin D deficiency and secondary hyperparathyroidism are less prevalent. There may also be apparent inconsistencies within a study, as recently reported in a randomized controlled trial of the effects of intranasal calcitonin, in which a significant reduction in vertebral fracture was seen in post-menopausal women with osteoporosis taking 200 IU daily, but not in those randomized to either a lower (100 IU) or higher (400 IU) daily dose [22].

In clinical practice, the choice of treatment will depend on a number of factors, including age, coexisting morbidity, safety and tolerability and the individual preferences and prejudices of the patient (and probably also the doctor). Interventions which reduce the risk of fracture do not improve existing symptoms and may even make the patient feel worse because of side-effects; it is therefore important to tailor the therapy to the individual woman, especially since the minimum duration of treatment is generally between 3 and 5 yr. The criteria on which selection for treatment should be based remain a matter of debate, but the recognition that the benefits of treatment are not maintained after the withdrawal of therapy and that significant reductions in the fracture rate can be achieved after only 1 yr of treatment in women with established osteoporosis has generated a move away from long-term preventive strategies towards shorter-term intervention in high-risk individuals. The optimal timing and duration of therapy, however, remain to be established and are important issues for future investigation

Notes

Correspondence to: Department of Medicine, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. Back

References

  1. Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet1996; 348:1535–41.[ISI][Medline]
  2. 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. J Am Med Assoc1998; 280:2077–82.[Abstract/Free Full Text]
  3. 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. J Am Med Assoc1999;282:1344–52.[Abstract/Free Full Text]
  4. 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 Int2000;11:83–91.[ISI][Medline]
  5. 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. J Am Med Assoc1999; 282:637–45.[Abstract/Free Full Text]
  6. Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 and calcium to prevent hip fracture in elderly women. N Engl J Med1992;327:1637–42.[Abstract]
  7. Tilyard MW, Spears GFS, Thomson J et al. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med1992;326:357–62.[Abstract]
  8. Ott S, Chesnut CH. Calcitriol is not effective in postmenopausal osteoporosis. Ann Intern Med1989; 110:267–74.[ISI][Medline]
  9. Stock JL, Avioli LV, Baylink DJ et al. Calcitonin-salmon nasal spray reduces the incidence of new vertebral fractures in postmenopausal women: three-year interim results of the PROOF study. J Bone Miner Res1997;12(Suppl. 1): S149.
  10. Pols HAP, Felsenberg D, Hanley DA et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporosis Int1999;9:461–8.[ISI][Medline]
  11. Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk. J Bone Miner Res2000; 15:183–7.[ISI][Medline]
  12. Lindsay R, Hart DM, Forrest C et al. Prevention of spinal osteoporosis in oophorectomised women. Lancet1980; ii:1151–3.
  13. Nachtigall LE, Nachtigall RH, Nachtigall RD et al. Estrogen replacement therapy 1: a 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol1979;53:277–81.[Abstract]
  14. Lufkin EG, Wahner HW, O'Fallon WM et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med1992;117:1–9.[ISI][Medline]
  15. Geusens P, Adami S, Bensen W et al. Risedronate reduces risk of hip fracture in elderly women with osteoporosis [abstract]. Calcif Tissue Int2000;66:S67.
  16. Van Staa TP, Abenhaim L, Cooper C. Use of cyclical etidronate and prevention of non-vertebral fractures. Br J Rheumatol1998;37:87–94.[ISI][Medline]
  17. Hutchinson A, Polansky SM, Feinstein AR. Postmenopausal estrogens protect against fractures of the hip and distal radius: a case control study. Lancet1979;ii:705–9.
  18. Weiss NS, Ure CL, Ballard JH et al. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogens. N Engl J Med1980;303:1195–8.[Abstract]
  19. Paganini-Hill A, Ross RK, Gerkins VR et al. Menopausal estrogen therapy and hip fractures. Ann Intern Med1981;95:28–31.[ISI][Medline]
  20. Michaëlsson K, Baron JA, Farahmand BY et al. Hormone replacement therapy and risk of hip fracture: population based case–control study. Br Med J1998; 316:1858–63.[Abstract/Free Full Text]
  21. 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. Maturitas1998;31:45–54.[ISI][Medline]
  22. Silverman SL, Chesnut C, Andriano K et al. Salmon calcitonin nasal spray (NS-CT) reduces risk of vertebral fracture(s) (VF) in established osteoporosis and has continuous efficacy with prolonged treatment: accrued 5 year worldwide data of the PROOF study. Bone1998; 23(Suppl.):S174.
  23. de Groen PC, Lubbe DF, Hirsch LJ et al. Esophagitis associated with the use of alendronate. N Engl J Med1996;335:1016–21.[Abstract/Free Full Text]
  24. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet1997; 350:1047–59.[ISI][Medline]
  25. Cummings SR, Eckert S, Krueger KA et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. J Am Med Assoc1999;261:2189–97.
  26. Grodstein F, Stampfer MJ, Manson JE et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med1996;335:453–61.[Abstract/Free Full Text]
  27. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc1998;280:605–13.[Abstract/Free Full Text]
  28. Larkin M. Ups and downs for HRT and heart disease. Lancet2000;355:1338.
  29. Jick H, Derby LE, Myers MW et al. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet1996;348:981–3.[ISI][Medline]
  30. Daly E, Vessey MP, Hawkins MM et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet1996;348:977–80.[ISI][Medline]
  31. Gutthann SP, Garcia-Rodriguez LA, Castellsague J et al. Hormone replacement therapy and risk of thromboembolism: population based case-control study. Br Med J1997;314:796–800.[Abstract/Free Full Text]
  32. Heikinheimo RJ, Inkovaara JA, Harju EJ. Annual injection of vitamin D and fracture of aged bones. Calcif Tissue Int1992;51:105–10.[ISI][Medline]
  33. Lips P, Graafmans WC, Ooms ME et al. Vitamin D supplementation and fracture incidence in elderly persons: a randomized, placebo-controlled clinical trial. Ann Intern Med1996;124:400–6.[Abstract/Free Full Text]