Investigation and management of osteoporosis

Juliet Compston

Professor of Bone Medicine, University of Cambridge School of Clinical Medicine

Summer School 11-14 July 2006
The Møller Centre, Storeys Way, Cambridge, UK

The addition of clinical risk factors that are, at least in part, independent of bone mineral density, to improve fracture risk prediction has recently been established in a large collection of prospective, population-based cohort studies. These risk factors include previous fracture, glucocorticoid therapy, a family history of hip fracture, tobacco use, alcohol abuse and rheumatoid arthritis. Using this approach, 10-year fracture probabilities can be estimated and, based on cost-effectiveness analyses, appropriate intervention thresholds defined. This will provide a more rational basis for treatment decisions and should widen the impact of therapy on the global burden imposed by osteoporosis.

Over the past two decades major advances have been made in the management of this disease and a number of pharmacological agents have been approved for the reduction of fracture risk in postmenopausal women with osteoporosis. These include the bisphosphonates, alendronate, etidronate, ibandronate and risedronate, raloxifene, strontium ranelate and teriparatide. The bisphosphonates and raloxifene act predominantly as inhibitors of bone resorption, whereas teriparatide is an anabolic agent that stimulates bone formation and leads to large increases in bone mass. The mode of action of strontium ranelate has not been clearly established, although it has a weak anti-resorptive effect and may also stimulate bone formation.

In clinical practice, the choice of treatment depends on several factors. Although available interventions appear to be similar in terms of the magnitude of reduction in vertebral fracture, not all of them have also been shown to reduce fracture risk at non-vertebral sites, particularly the hip. This is important since any fragility fracture is an independent risk factor for further fractures at any site. Evidence for reduction of both vertebral and hip fractures in postmenopausal women with osteoporosis is available only for alendronate, risedronate and strontium ranelate; hormone replacement therapy has also been shown to reduce clinical vertebral and hip fractures, albeit in healthy postmenopausal women. In contrast, reduction in fracture risk with raloxifene and ibandronate has only been demonstrated at vertebral sites and whilst teriparatide was shown to reduce both vertebral and non-vertebral fractures, specific evidence for hip fracture reduction is not available. Thus bisphosphonates and strontium ranelate are generally considered first-line options.

Safety and tolerability are major considerations in choosing treatment, particularly because intervention with these agents is long-term, does not produce symptomatic improvement and may be associated with side-effects. The introduction of once weekly dosing regimens for alendronate and risedronate has proved very popular with patients and has improved compliance and persistence, although the dosing instructions are difficult to follow for some, particularly the frail elderly. Similarly, the once monthly dosing regimen for ibandronate is likely to be preferred by some women. The most common side-effects of bisphosphonates are upper gastro-intestinal symptoms, which are more likely to occur if the instructions for the dosing regimen are not followed closely. Strontium ranelate is taken as granules dissolved in water at bedtime; it may be associated with diarrhoea, nausea and headache, particularly in the first few months and there is a small increase in the risk of venous thromboembolism. Raloxifene is taken as a once daily dose with no specific dosing instructions. It may exacerbate vasomotor menopausal symptoms in some women and is also associated with increased risk of thromboembolic disease, but the significant protection against breast cancer, which is maintained up to 8 years of treatment, is an important benefit for some women. The risk benefit balance of HRT is complex but generally unfavourable, except in women with menopausal symptoms. Finally, teriparatide is administered as a daily subcutaneous injection; it is generally well tolerated but may be associated with dizziness, headache and nausea.

Cost-effectiveness of treatment is an increasingly important consideration and is the basis on which the National Institute of Clinical Excellence (NICE) have produced their recent guidance on the secondary prevention of osteoporotic fractures. The costs of alendronate, risedronate, ibandronate, raloxifene and strontium ranelate are broadly similar (around £350 per year) although the recent introduction of generic alendronate should reduce the price of this drug. In contrast, teriparatide is more expensive (£3,500 per year), and its use is restricted to women with severe osteoporosis in whom other treatments appear ineffective or cannot be tolerated. Current NICE guidance recommends the use of bisphosphonates (etidronate, alendronate or risedronate) in postmenopausal women with fragility fractures, bone densitometry being required to demonstrate the presence of osteoporosis in women under the age of 75 years.

Since most of the clinical trials of osteoporosis therapy were conducted in women who were also supplemented with calcium and vitamin D, these supplements should be used as an adjunct to therapy unless there is evidence of a good dietary calcium intake and adequate vitamin D status. In addition appropriate levels of physical activity should be encouraged and falls risk assessment and advice offered where indicated. Physiotherapy has a major role in the management of pain, reduced mobility and lack of confidence in individuals with osteoporotic fracture and a 6-8 week course of calcitonin is also often effective in the acute management of pain following vertebral fracture.

The optimal duration of therapy has not been established. For many of the interventions, resumption of bone loss has been shown in the first one to two years after withdrawal of therapy although it is not certain whether this occurs at the normal rate for age-related bone loss or is accelerated. Whilst such data may indicate the need for continued treatment, there are potential concerns about long-term suppression of bone turnover particularly with the more potent bisphosphonates.

A number of other approaches to treatment are currently being developed. These include the use of intravenous bisphosphonates with dosing intervals from three monthly to once yearly, subcutaneous injections of an antibody to the osteoclastogenic cytokine RANKL (receptor activator of NFkB ligand), administered at six monthly intervals, new selective oestrogen receptor modulators and oral formulations of parathyroid hormone.

Key references

Sambrook P, Cooper C. Osteoporosis. Lancet 2006;367:2010-18.

Cummings S, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761-7.

Kanis J, Borgstrom F, De Laet C et al. Assessment of fracture risk. Osteoporosis International 2005;16:581-9.

Cranney A, Guyatt G, Griffith L et al. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:570-8.

Compston JE. Prevention of vertebral fractures by strontium ranelate in postmenopausal women with osteoporosis. Osteoporosis International 2005;16(suppl): S4-6.

Compston JE. Recombinant parathyroid hormone in the management of osteoporosis. Calcified Tissue International 2005;77:65-71.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 30-Oct-2006