Online Publications : Working Party Reports

Osteoporosis

Clinical guidelines for prevention and treatment

Update on pharmacological interventions and an algorithm for management

Royal College of Physicians
Bone and Tooth Society of Great Britain

Writing Group
1 Background
2 Diagnosis and risk assessment
3 Update on pharmacological interventions
4 Osteoporosis in premenopausal women and in men
Algorithm for medical management of men and women aged over 45 years who have or are at risk of ostreoporosis
References

Writing Group

Bone and Tooth Society of Great Britain: Dr Juliet Compston (Chairman), Department of Medicine, University of Cambridge
Professor Richard Eastell, Clinical Sciences Centre, University of Sheffield
Dr Roger Francis, Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne
Dr Eugene McCloskey, WHO Collaborating Centre for Metabolic Bone Diseases, Sheffield
Professor David Reid, Department of Medicine and Therapeutics, University of Aberdeen
Dr Jon Tobias, Division of Medicine, University of Bristol
Royal College of Physicians Guideline Development Group: Professor David Barlow, Nuffield Department of Obstetrics and Gynaecology, University of Oxford
Professor Cyrus Cooper, MRC Environmental Epidemiology Unit, University of Southampton
Professor John Kanis, WHO Collaborating Centre for Metabolic Bone Diseases, Sheffield
Mr Malcolm Whitehead, Department of Obstetrics and Gynaecology, King's College Hospital, London
with contributions from: Professor Stuart Ralston, Department of Medicine and Therapeutics, University of Aberdeen
Dr Peter Selby, Department of Medicine, Manchester Royal Infirmary
Dr Colin Waine, Director of Health Programmes and Primary Care, Sunderland Health Authority

1 Background

U1.1 Osteoporosis is defined as a progressive systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the UK, the disorder results in over 200,000 fractures each year, causing severe pain and disability to individual patients at an annual cost to the National Health Service of over £940 million. More than one-third of adult women will sustain one or more osteoporotic fractures in their lifetime. Lifetime risk among men is less, but still substantial.

U1.2 In 1999, guidelines on the prevention and treatment of osteoporosis were prepared under the auspices of the Royal College of Physicians, sponsored by the Department of Health. The scope of these guidelines was to review the assessment and diagnosis of osteoporosis, the therapeutic agents available, and the manner in which these could be used to develop management strategies for both prevention and treatment. The guidelines were prepared by a writing group convened by the Royal College of Physicians, and reviewed at a consensus workshop meeting after which a final version of the document was prepared. The workshop comprised a range of relevant specialists and representatives of Royal Colleges, professional societies and relevant patient organisations (Amarant Trust, National Osteoporosis Society, Osteoporosis Dorset, Osteoporosis 2000 and Womens Health Concern). Following guidelines audit, the document was endorsed by the Department of Health and the Primary Care Synopsis was launched by the Minister of Public Health.

U1.3 The guidelines reviewed the position of bone density measurement in clinical practice and distinguished between the diagnostic use of bone densitometry and the role of measurement in providing information on future risk of fracture. The balance of evidence supporting the World Health Organisation (WHO) definition of osteoporosis (as a threshold value of 2.5 standard deviation (SD) or more below the young adult mean) was summarised. Evaluation of the prognostic role of bone density measurement confirmed that the most widely evaluated technique (dual energy X-ray absorptiometry) has been shown to predict future fracture with high specificity, but low sensitivity. The working group recommended the use of this test in the context of a case-finding strategy, rather than for population screening. This Update addresses recent developments in both the diagnostic and prognostic functions of bone mass measurement and biochemical markers of bone turnover.

U1.4 Approaches to the prevention and treatment of osteoporosis include population-based strategies and those targeted to people at the highest risk. Possible measures to reduce fracture risk in the general population include increasing the level of physical activity undertaken at all ages, reducing the prevalence of smoking, and increasing dietary calcium intake. Epidemiological studies have shown, with varying degrees of certainty, that these risk factors are associated with osteoporosis, but there is little evidence about their effect on fracture risk from randomised controlled trials. The guidelines therefore made no recommendations concerning such population-based strategies. Among high risk strategies, there was no clear evidence that population-wide screening using any modality (risk factors, biochemical markers of bone turnover, or bone densitometry) was effective in reducing fracture incidence. For these reasons, the report recommended that the major thrust of prevention should be directed towards selective case finding. Assessments were then made of the level of evidence supporting the use of various lifestyle and therapeutic interventions in the prevention of bone loss, and reduction in the incidence of vertebral or hip fracture. In this context, the terms 'prevention' and 'treatment' referred to prevention and treatment of osteoporosis itself, rather than of fracture (see below). Finally, a list of recommendations was provided for health authorities and other commissioners of health care for the establishment of osteoporosis services.

U1.5 The aim of the guidelines was not to provide a working document for clinical practice, but rather to produce a framework from which local management protocols could be developed. When they were released, the results of some important randomised controlled trials had been published. However, the ensuing 18 months have seen these supplemented by new clinical trial data both for existing and new pharmacological interventions. Although a comprehensive revision of the Royal College of Physicians Osteoporosis Guidelines will not be due for several years, the College has endorsed this Update which has been prepared by the original Guidelines Writing Group in collaboration with the Bone and Tooth Society to address two purposes. Firstly, the Update supplements the evidence-based account of therapeutic interventions in the light of newly published trials. Secondly, an algorithm has been distilled for the management of individual patients based on the evidence-based synthesis of the different pharmacological interventions. Such an algorithm meets a need expressed by many practicing clinicians. By this means the Update seeks to maintain and extend the usefulness of the Osteoporosis Guidelines to clinicians, consistent with their spirit and methodology.

Prevention and treatment of osteoporosis

U1.6 For regulatory purposes, specific definitions of prevention and treatment are used in the context of osteoporosis. The term 'prevention' is used to denote the prevention of bone loss in postmenopausal women with osteopenia (bone mineral density T score between -1 and -2.5) and increased risk of fracture, whereas 'treatment' is defined as reduction in fracture risk in postmenopausal women with osteoporosis (bone mineral density T score below -2.5, with or without a previous or prevalent fracture). Prevention studies are usually performed in early postmenopausal women with osteopenia or normal bone mineral density, in whom the absolute risk of fragility fracture is low and thus, within the relatively short time frame of these studies (usually one to two years), anti-fracture efficacy cannot be tested. In contrast, the much higher risk of fragility fracture in treatment populations as defined above enables assessment of anti-fracture efficacy. Regulatory authorities thus require demonstration of reduction in fracture risk in treatment populations before the prevention indication for an agent is granted.

U1.7 In clinical practice this distinction between prevention and treatment is less appropriate, since all agents currently in use act fundamentally in the same manner, ie by inhibition of bone resorption. Furthermore, with the increasing evidence for a relatively rapid rate of treatment onset and offset for these interventions, there has been a move away from long-term preventive strategies towards the use of shorter-term therapy in high risk individuals. The latter approach is supported by the demonstration of significant reductions in vertebral and non-vertebral fracture rate in postmenopausal women with established osteoporosis after one years treatment (Pols et al 1999; Harris et al 1999; Ensrud et al 1997). In addition, there is some evidence that the greatest fracture reduction may be achieved in women with lower bone mineral density (Cummings et al 1998). It is therefore most useful to consider the indication for intervention as prevention of osteoporotic fracture, whether or not a fragility fracture has already occurred.

U1.8 Tables 2 and 3 provide guideline recommendations on the evidence for efficacy of different interventions in the prevention of postmenopausal bone loss (Table 2) and fracture reduction (Table 3). These gradings refer solely to the level of evidence of efficacy, regardless of effect size; it should also be noted that for some agents there are inconsistencies between studies. Evidence for reduction in vertebral and all non-vertebral fractures and hip fractures is considered separately in view of the lack (or differing levels) of evidence, for some interventions, of efficacy at all three sites. The grading of evidence base is shown in Table 1.

Table 1 Grading of evidence base
Grade	Evidence
Grade A:	> meta-analysis of RCTs or from at least one RCT
	> from at least one well designed controlled study without randomisation
Grade B:	> from at least one other type of well designed quasi-experimental study
	> from well-designed non-experimental descriptive studies, eg comparative studies, correlation studies, case-control studies
Grade C:	> from expert committee reports/opinions and/or clinical experience of authorities
RCT: randomised controlled trial

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
HRT	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
Grade	Spine	Non-vertebral	Hip
Alendronate	A	A	A
Calcitonin	A	B	B
Calcitriol	A	A	nd
Calcium	A	B	B
Calcium + vit D	nd	A	A
Cyclic etidronate	A	B	B
Hip protectors	-	-	A
HRT	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

2 Diagnosis and risk assessment

U2.1 A variety of bone mass measurement techniques is predictive of fracture, including dual energy X-ray absorptiometry (DXA) and quantitative ultrasound. Site-specific measurements are more predictive (relative risk of 2.0-2.8 for one SD reduction in bone mineral density) than assessments at other sites (relative risk of 1.5-2.2 for one SD reduction in bone mineral density). Measurements undertaken at different sites or at the same site with different technologies in the same individual are not well correlated, both as a result of errors of measurement accuracy and of biological variability in the composition of bone, and onset and rate of bone loss with age. Accordingly, a universal T-score cut-off for the diagnosis of osteoporosis is inappropriate, since the proportion of individuals classified as having osteoporosis (a T score below -2.5) will vary substantially depending on the site and method of measurement.

U2.2 In order to avoid these variations in disease classification, it has been suggested that a gold standard should be adopted for diagnostic purposes in terms of the site and method of measurement (Kanis & GlŸer 2000). The most appropriate candidate is total hip bone mineral density measured by DXA, since this measurement is predictive of both cervical and trochanteric fractures, which collectively cause the highest morbidity, mortality and cost of all osteoporotic fractures. Furthermore, the precision error of measurements at this site is low and adequate reference data are available for Caucasian men and women.

U2.3 Assessment of the risk of fracture in an individual should ideally be expressed as absolute rather than relative risk and be related to a relevant time interval, for example 10 years; this approach is likely to be increasingly used in the future to determine interventional, as opposed to diagnostic, thresholds. A variety of bone mass measurements at sites other than the hip and using different technologies is useful in risk assessment, including peripheral and spinal DXA measurements and ultrasound of the os calcis. Further improvement of fracture prediction can be achieved by the addition of risk factors for fracture which are independent of bone mineral density, for example previous fragility fracture, maternal history of hip fracture, risk factors for falling and increased levels of bone resorption markers.

U2.4 Bone mineral density measurements may be used to monitor responses to treatment, the spine being the preferred site. In postmenopausal women with osteoporosis significant treatment benefits can often be detected after two years treatment with an anti-resorptive agent. Biochemical markers of bone turnover may have a place in monitoring the response to treatment; however, further research is recommended to evaluate their utility in clinical practice.

3 Update on pharmacological interventions

Bisphosphonates

U3.1 Three bisphosphonates are now licensed for use in both postmenopausal and glucocorticoid-induced osteoporosis, namely cyclic etidronate, alendronate and risedronate. Etidronate is given cyclically and intermittently with calcium, and alendronate and risedronate are given as a single daily dose without calcium included in the formulation. The optimal duration of bisphosphonate therapy has not been established.

Cyclic etidronate

U3.2 Cyclic etidronate is licensed for the prevention and treatment of osteoporosis in postmenopausal women and for the prevention and treatment of glucocorticoid-induced osteoporosis. Etidronate in a dose of 400 mg daily is given for 14 days followed by 500 mg calcium daily for 76 days. This cycle is then repeated for the duration of treatment.

U3.3 In addition to the evidence that cyclic etidronate reduces vertebral fracture rate in postmenopausal women with established osteoporosis, reviewed in the 1999 Royal College of Physicians Osteoporosis Guidelines, observational data support a protective effect against non-vertebral fractures. Using information from the General Practice Research Database in 7,977 patients taking cyclic etidronate and 7,977 age- and sex-matched controls, van Staa et al (1998) reported that the risk of non-vertebral fracture was reduced by 20% and of hip fracture by 34% relative to osteoporosis control patients. The relative risk of hip fracture was 0.66 (95% CI 0.51-0.85) and that of wrist fracture 0.81 (95% CI 0.58-1.14).

Alendronate

U3.4 Alendronate is licensed for the prevention and treatment of postmenopausal osteoporosis (recommended daily dose 5 mg and 10 mg respectively) and for the prevention and treatment of glucocorticoid-induced osteoporosis. For the latter indication, the recommended daily dose is 5 mg for all categories of patients except postmenopausal women not receiving hormone replacement therapy, in whom the recommended daily dose is 10 mg.

U3.5 Subsequent to the demonstration of anti-fracture efficacy in the Fracture Intervention Trial (FIT) in postmenopausal women with established osteoporosis (Black et al 1996), the results of the second arm of this study have been published (Cummings et al 1998). The study included 4,432 postmenopausal women with a low femoral neck bone mineral density but no vertebral fracture at baseline who were randomised to placebo or alendronate. The daily dose of alendronate was 5 mg for 2 two years and 10 mg for the remainder of the four-year trial. All women reporting calcium intakes of 1,000 mg/day or less were given a daily supplement of 500 mg calcium and 250 IU vitamin D. Significant treatment benefits in bone mineral density were seen in alendronate treated women at the femoral neck when compared to the placebo group (mean 4.6%, p<0.001), total hip (mean 5.0%, p<0.001) and lumbar spine (mean 6.6%; p<0.001). There was a non-significant reduction in all clinical fractures [relative hazard 0.86 (95% CI 0.73-1.01)]. In the subgroup of women who had a baseline femoral neck bone mineral density T score below -2.5, the reduction in clinical fractures was statistically significant [relative hazard 0.64 (95% CI 0.50-0.82)]. Overall, alendronate reduced the risk of radiographic vertebral fractures by 44% [relative risk 0.56 (95% CI 0.39-0.80)].

U3.6 In another study (Pols et al 1999), the effects of alendronate therapy were studied in 1908 postmenopausal women with low bone mass (spine bone mineral density T score below -2SD) in a multicentre randomised controlled trial. After 12 months treatment, a significant reduction in non-vertebral fractures was demonstrated in alendronate-treated women [relative risk 0.53 (95% CI 0.30-0.90)].

U3.7 There is evidence from a recent study that the efficacy of intermittent oral administration of alendronate is similar to that of daily oral administration, at least with respect to effects on bone mineral density. In a one-year randomised controlled trial, the effects of alendronate 70 mg once weekly, alendronate 35 mg twice weekly and alendronate 10 mg daily were compared in 1,200 postmenopausal women with osteoporosis (Schnitzer et al 2000). Changes in bone mineral density and biochemical markers of bone turnover were equivalent across all treatment groups.

Risedronate

U3.8 Risedronate is a pyridinyl bisphosphonate which has recently been licensed for the treatment and prevention of osteoporosis in postmenopausal women and for prevention and treatment of glucocorticoid-induced osteoporosis in postmenopausal women (recommended dose for both indications 5 mg daily).

U3.9 Two randomised controlled trials of the effects of risedronate on vertebral and non- vertebral fracture rate in postmenopausal women with established osteoporosis (at least one vertebral fracture at baseline) have recently been published. In a study from North America 2,458 women with established osteoporosis were treated with risedronate 2.5 or 5 mg daily or placebo (Harris et al 1999). All subjects received calcium 1,000 mg daily and those with low baseline serum 25-hydroxyvitamin D levels were also given a vitamin D supplement of 500 IU daily. The 2.5 mg arm of the trial was discontinued after one year. Treatment with risedronate 5 mg daily was associated with a relative risk of new vertebral fracture of 0.35 (95% CI 0.19-0.62) after one year and 0.59 (95% CI 0.43-0.82) after three years. At three years there was also a significant reduction in non-vertebral fracture [relative risk 0.6 (95% CI 0.39-0.94)]. Significant increases in bone mineral density compared with placebo were seen at the lumbar spine (mean 4.3%), femoral neck (mean 2.8%) and trochanter (mean 4.0%).

U3.10 In a second randomised controlled trial performed in Europe and Australia (Reginster et al 2000), the effects of risedronate were studied in 1,226 postmenopausal women with established osteoporosis (at least two prevalent vertebral fractures at baseline). In this study the 2.5 mg arm of the trial was discontinued after two years and calcium and vitamin D supplementation were given according to the same protocol as the North American study. A significant reduction in vertebral fractures was seen in the 5 mg daily group at one year with a relative risk of 0.39 (95% CI 0.22-0.68) and at three years [0.51 (95% CI 0.36-0.73)]. There was also a non-significant reduction in non-vertebral fracture [relative risk 0.67; (95% CI 0.44-1.04)]. Significant treatment benefits were observed on bone mineral density in the lumbar spine (mean 5.9%), femoral trochanter (mean 6.4%), femoral neck (mean 3.1%) and midshaft radius (mean 2.1%), when compared to placebo.

U3.11 The overall incidence of adverse events was similar in treatment and placebo groups in both these trials. In particular, the incidence of upper gastrointestinal tract adverse events was similar across groups. Previous or active gastrointestinal disease or concomitant use of non-steroidal anti-inflammatory drugs or aspirin were not exclusion criteria for entry to these two studies.

U3.12 The results of a large study to investigate the efficacy of risedronate, 5 mg daily, in prevention of hip fracture have recently been published in abstract form (Geusens et al 2000). Over 9,300 patients were enrolled into one of two groups. In Group 1 (n = 5,445) patients were aged less than 80 years old and had a femoral neck bone mineral density T score below -3 plus at least one additional risk factor for hip fracture. In Group 2 (n = 3,886) the only entry criterion was at least one risk factor for hip fracture. In risedronate-treated women with low femoral neck bone mineral density, there was a 39% reduction in hip fracture (p = 0.02) and in women with both low femoral neck bone mineral density and a prevalent vertebral fracture the reduction in hip fracture was 58% (p = 0.004) after three years treatment. No significant reduction in hip fracture was demonstrated in Group 2.

Calcitonin

U3.13 Currently only parenteral calcitonin is licensed for use in postmenopausal osteoporosis, in the form of salcatonin. The recommended dose is 100 IU daily and co-administration of calcium and vitamin D is recommended in daily doses of 600 mg and 400 IU respectively.

U3.14 The results of a five-year double-blind randomised placebo-controlled study of 1,255 postmenopausal women with established osteoporosis randomised to placebo, or 100, 200, or 400 IU intranasal calcitonin daily have been published in abstract form (Silverman et al 1998). Lumbar spine bone mineral density showed mean increments from baseline of 0.7%, 1.2%, 1.2%, and 1.6% respectively for placebo, 100 IU, 200 IU and 400 IU dose categories. These increases were statistically significant over baseline in the active treatment groups, but not in the placebo group who, in common with all treatment groups, were prescribed 1 g calcium and 400 IU vitamin D daily. No significant treatment differences in bone mineral density were observed at the femoral neck.

U3.15 Over the five-year period of the study, there was a 39% reduction in the risk of new and/or worsening vertebral deformities defined by radiographic morphometry (p = 0.03) in the 200 IU dose category when compared with the placebo group. Consistent with this was the observation of a 42% reduction in the deterioration of spinal deformity index in this category when compared with placebo (p = 0.015). The 100 IU and 400 IU dose categories showed improvements in the above fracture indices, but these did not attain statistical significance. No significant reduction in non-vertebral fractures was observed. No serious adverse events have emerged from clinical trials with intranasal calcitonin although the frequency of rhinitis is increased.

U3.16 Data on the effects of calcitonin on fracture rates have recently been summarised in a systematic review (Kanis & McCloskey, 1999) in which 14 randomised trials, including 1,309 men and women, were identified. All but one of these studies used synthetic salmon calcitonin and the route of administration varied. The relative risk of any fracture for individuals taking calcitonin, when compared to those not taking the drug, was 0.43 (95% CI 0.38-0.50). The effect was apparent for both vertebral fracture (relative risk = 0.45; 95% CI 0.39-0.53) and non-vertebral fractures (relative risk = 0.34; 95% CI 0.17-0.68). When studies identifying patients with fracture, rather than numbers of fractures, were pooled, the magnitude of effect was somewhat less (relative risk = 0.74; 95% CI 0.60-0.93), and the separate effects on vertebral and non-vertebral fractures became non-significant. These data suggested that calcitonin treatment was associated with a significant decrease in the number of vertebral and non-vertebral fractures, but that these benefits might be lower than those observed in trials of bisphosphonates.

Hormone replacement therapy

U3.17 A number of oral and transdermal hormone replacement preparations are licensed for the prevention of postmenopausal osteoporosis. These are discussed in detail in the 1999 Royal College of Physicians Osteoporosis Guidelines.

U3.18 The majority of evidence for anti-fracture efficacy of hormone replacement therapy is derived from observational data, which are likely to overestimate its beneficial effects because of the better health status of women who choose to take hormone replacement at the menopause as opposed to those who do not. Recently, a randomised controlled trial of the effects of hormone replacement therapy on non-vertebral fractures in postmenopausal women has been reported (Komulainen et al 1998). In this four-year study, 464 early postmenopausal women were randomised to hormone replacement therapy (sequential combined oestradiol valerate 2 mg and 1 mg cyproterone acetate), vitamin D (300 IU daily for the first four years and 100 IU daily for the fifth year), hormone replacement therapy and vitamin D or placebo. There was a significant decrease in non-vertebral fractures in women treated with hormone replacement therapy alone (p = 0.048) and in the pooled hormone replacement therapy groups (p = 0.042), but not in those receiving vitamin D alone. The estimated relative risk of new non-vertebral fracture in women treated with hormone replacement therapy alone was 0.29 (95% CI 0.10-0.90), with vitamin D 0.47 (95% CI 0.20-1.14) and with combined hormone replacement and vitamin D 0.44 (95% CI 0.17-1.15) after adjustment for femoral bone mineral density and previous fractures.

U3.19 Data from observational studies have provided evidence for attenuation of the beneficial skeletal effects of hormone replacement therapy after its withdrawal (Cauley et al 1995; Weiss et al 1980). Micha'lsson et al (1998) have recently reported the results of a population based case-control study of 1,327 women aged 50-81 years with hip fracture. The odds ratio of hip fracture in current hormone users was 0.35 (95% CI 0.24-0.53) as opposed to 0.76 (95% CI 0.57-1.01) in former users. These data thus provide further support for the contention that continued hormone replacement therapy is required after the menopause to maintain protection against fracture.

Raloxifene

U3.20 Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In early postmenopausal women, raloxifene prevents bone loss in the lumbar spine, proximal femur and total body, the mean differences in bone mineral density between treatment and control groups being between 2% and 3% (Delmas et al 1997). In a randomised controlled trial of 7,705 postmenopausal women with osteoporosis, three years treatment with raloxifene 60 mg daily was associated with a significant reduction in risk of vertebral fracture (relative risk 0.7; 95% CI 0.5-0.8), the reduction being similar in women with or without one or more prevalent vertebral fractures at baseline. Significant treatment benefits were also seen for bone mineral density in both the spine and proximal femur, with mean differences between the treatment and control group of between 2% and 3% (Ettinger et al 1999). There was no difference in the risk of all non-vertebral fractures or hip fracture between treatment and control groups. In this trial all women received calcium (500 mg daily) and vitamin D (400-600 IU daily).

U3.21 The relative risk of breast cancer in these women after a median follow-up period of 40 months was significantly reduced (relative risk 0.24; 95% CI 0.13-0.44), this benefit being seen only for oestrogen receptor positive tumours with no effect on oestrogen receptor negative tumours (Cummings et al 1999). There was no increase in the incidence of vaginal bleeding in raloxifene treated women when compared to the control group or in the risk of endometrial cancer (relative risk 0.8; 95% CI 0.2-2.7). Raloxifene use is associated with a small increase in the frequency of hot flushes, leg cramps and peripheral oedema. There is also an increase in the risk of venous thromboembolism, similar to that seen with hormone replacement therapy and tamoxifen (relative risk 3.1; 95% CI 1.5-6.2). The effects of raloxifene on coronary heart disease morbidity and mortality have not been established; however, raloxifene use is associated with favourable effects on biochemical markers of cardiovascular risk (Walsh et al 1998).

Calcium and Vitamin D

U3.22 Evidence for the efficacy of vitamin D and calcium supplementation in the prevention of hip and non-vertebral fractures was reviewed in the 1999 Royal College of Physicians Osteoporosis Guidelines and no large trials have been reported subsequently. It is unclear if the benefits of treatment seen in these studies are due to vitamin D, calcium or the combination of both. Although it appears reasonable to use combined calcium and vitamin D supplements in the management of frail elderly individuals, there is little information on the effect on vertebral fracture incidence or definite evidence of benefit in patients who already have fractures.

Calcitriol

U3.23 Calcitriol is licensed for the treatment of postmenopausal osteoporosis. The recommended dose is 0.25 µg twice daily by mouth. Studies of the effect of calcitriol on bone loss and fractures have produced conflicting results. The largest study compared calcitriol 0.25 µg twice daily with calcium 1 g daily in 622 women (mean age 64 years) with vertebral fractures (Tilyard et al 1992). This showed a 70% reduction in new vertebral fractures with calcitriol, although this was due mainly to an increase in fracture rate with calcium, rather than a reduction with calcitriol. There was also a 50% decrease in non-vertebral fractures with calcitriol compared with calcium supplements.

Reducing the incidence of falls

U3.24 A number of randomised controlled trials have assessed the effect of modifying risk factors for falling, although the results have not all been consistent. In an American study of 301 elderly patients with an apparent risk factor for falling, the intervention group underwent geriatric assessment, with modification of risk factors for falling, whereas the control group had the usual health care and social visits (Tinetti et al 1994). Over the 12 months, 35% of the intervention group had falls compared to 47% in the control group. A more recent British study examined the effectiveness of a detailed medical and occupational therapy assessment in 397 older patients presenting to an accident and emergency department with a fall (Close et al 1999). There was a significant 61% reduction in the risk of falls in the intervention group over 12 months, compared with the control group. Although both studies showed a significant decrease in falls, neither had the statistical power to detect a meaningful reduction in fracture incidence.

Reducing the impact of falls

U3.25 An alternative approach to fracture prevention is to decrease the impact of falls using external hip protectors, which are incorporated into specially designed underwear. A Danish study block randomised 665 elderly residents of nursing homes to receive external hip protectors or to serve as controls (Lauritzen et al 1993). Over the 12 month study there was a reduction in hip fracture risk of over 50% in those using the hip protectors. In the group randomised to receive hip protectors, the only patients who fractured were not using hip protectors at the time. Although this is potentially one of the most promising interventions for the prevention of hip fractures, external hip protectors are generally bulky and uncomfortable, so may be unacceptable to many older people at risk of hip fracture.

4 Osteoporosis in premenopausal women and in men

Premenopausal women

U4.1 In the absence of any established treatment for premenopausal women with osteoporosis, such patients should be referred to specialist centres, for investigation of possible underlying causes and advice on further management.

Osteoporosis in men

U4.2 Up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men. The WHO has defined osteoporosis as a bone mineral density 2.5 standard deviations or more below the mean value for young adults (T score below -2.5), but this has only been established for women. Nevertheless, there is a similar relationship between absolute bone density values and fracture risk in both sexes (De Laet et al 1997; Cheng et al 1997). Furthermore, work from the US shows the prevalence of osteoporosis at the hip, spine or forearm, using the definition of a T score below -2.5 (derived from female and male reference data respectively), is 35% in women over the age of 50 years, compared with 19% in men (Melton et al 1998). These figures are broadly comparable to those reported for the lifetime risk of fractures at these sites in 50-year-old women (39.7%) and men (13.1%).

U4.3 There are two approaches to the definition, using WHO criteria, of osteoporosis in men. The first uses a threshold bone mineral density T score of 2.5 below the young normal male mean value while the second uses a T score of 2.5 below the young normal female mean value. The optimal approach is not clear at present but adoption of the former option provides a more conservative estimate of the prevalence of the disease in men.

U4.4 Any underlying cause of secondary osteoporosis should, if possible, be treated as specific treatment of conditions such as hypogonadism increases bone density by up to 15% (Behre et al 1999). There is as yet no established treatment for idiopathic osteoporosis in men, but there is little to suggest that men and women with osteoporosis respond differently to therapeutic intervention. Observational studies in men with idiopathic and secondary osteoporosis suggest that intermittent cyclic etidronate therapy increases bone density at the lumbar spine by 5-10%, with smaller increases at the hip (Francis 1998). It would therefore appear that cyclical etidronate has comparable effects on bone density in men and women, but the effect on fracture incidence in men has not been established. A recent non-randomised but controlled study showed similar increases in spine bone density in men and women with primary and secondary osteoporosis treated with alendronate for one year (Ho et al 2000). A two-year randomised controlled trial in 241 men with osteoporosis aged between 31 and 87 years, 36% of whom were hypogonadal, showed significant increases in lumbar spine and femoral neck bone density, a reduction in morphometric vertebral fractures and decreased height loss with alendronate (Orwoll et al 1999).

U4.5 As there is no established treatment for osteoporosis in men, consideration should be given to referral to a specialist centre, for investigation of underlying causes and advice on further management. This is particularly the case in younger men (age <65 years).

Medical management of men and women aged over 45 years who have or are at risk of osteoporosis

Major risk factors [other than previous fragility fracture] include the following:

Untreated hypogonadism [premature menopause, 2° amenorrhoea, 1° hypogonadism in women; 1° or 2°¡ hypogonadism in men]
Glucocorticoids [7.5 mg per day prednisolone for 6 months or more]#
Disease associated with increased prevalence of osteoporosis
[eg gastrointestinal disease, chronic liver disease, hyperparathyroidism, hyperthyroidism]
Radiological osteopenia

Other risk factors in national and international guidelines include family history, low body weight, cigarette smoking, height loss, or low bone mass as assessed by other techniques.

Lifestyle advice

Adequate nutrition especially with calcium and vitamin D
Regular weight bearing exercise
Avoidance of tobacco use and alcohol abuse

For men aged less than 65 years, specialist referral should be considered.
*Recommended daily dose 0.5-1 g and 800 IU respectively.
#Refer to previously published guidelines.
**Treatments listed in alphabetical order. Vitamin D and calcium are generally regarded as adjuncts to treatment. HRT: oestrogen in women, testosterone in hypogonadal men.
BMD: bone mineral density
DXA: dual energy x-ray absorptiometry
HRT: hormone replacement therapy

Previous fragility fracture
Defined as a fracture from standing height or less and includes prevalent vertebral deformity. A previous fragility fracture is a strong independent risk for further fracture and may be regarded as an indication for treatment without the need for BMD measurement when the clinical history is unequivocal.

Investigations

FBC, ESR
Bone and liver function tests [Ca, P, alk phos, albumin, AST/gGT]
Serum creatinine
Serum TSH

If indicated

Lateral thoracic and lumbar spine X-rays
Serum paraproteins and urine Bence Jones protein
Isotope bone scan
Serum FSH if hormonal status unclear [women]
Serum testosterone, LH and SHBG [men]

References

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This page last updated on January 5, 2001