Osteoporosis: strategies for prevention and management

Best Practice & Research Clinical Rheumatology Vol. 21, No. 1, pp. 109e122, 2007 doi:10.1016/j.berh.2006.10.004 available online at http://www.sciencedirect.com

7 Osteoporosis: strategies for prevention and management Richard Keen*

BSc, PhD, MRCP

Consultant Rheumatologist and Honorary Senior Lecturer in Metabolic Bone Disease Institute of Orthopaedics and Musculoskeletal Sciences, The Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK

Osteoporosis is a serious public health issue, affecting up to 1 in 2 women and 1 in 5 men over the age of 50 years. The common osteoporotic fractures occur at the spine, wrist and hip. For the patient affected by osteoporosis, these fractures are associated with significant morbidity and, in the case of hip and spine fractures, an excess mortality. The treatment of osteoporotic fractures is also associated with a significant healthcare cost for society. Currently, measurement of bone mineral density using dual energy X-ray absorptiometry is the gold standard for the diagnosis of osteoporosis. In the future, however, assessment of fracture risk will be based on algorithms incorporating clinical risk factors and bone density measurements, where appropriate. The goal of treatment is to reduce the risk of future fracture. Patients at high risk for fracture should be assessed and screened to exclude secondary causes for osteoporosis. Bisphosphonates (alendronate, etidronate, ibandronate, risedronate) are the first-line therapy for the majority of patients and these treatments can be given either orally or intravenously. Alternative treatment options include strontium ranelate and raloxifene. Anabolic therapy with parathyroid hormone can be considered for patients with severe disease. These patients will often require referral for specialist assessment and monitoring. All patients at risk of developing osteoporosis should be given lifestyle advice regarding dietary intake of calcium and vitamin D and regular weight-bearing exercise. Key words: osteoporosis; management; fracture; bisphosphonates.

Osteoporosis is a skeletal disease characterised by low bone mass and microarchitectural deterioration, with a resulting increase in bone fragility and hence susceptibility to fracture.1 Fractures of the hip, vertebral body and distal forearm have long been regarded as the classical osteoporotic fractures. Osteoporosis is, however, a systemic * Tel.: þ44 20 8090 5289; Fax: þ44 20 8420 7487. E-mail address: [email protected] 1521-6942/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

110 R. Keen

disease and prospective studies have demonstrated an increase in risk for almost all fractures in individuals with low bone mass.2 WHAT IS THE SIZE OF THE PROBLEM The incidence of osteoporosis is best measured as the incidence of fractures that are the consequences of osteoporosis (Figure 1). In Western populations, hip fracture incidence rates increase exponentially with age. Above 50 years of age there is a female to male incidence ratio of approximately 3:1. Overall about 98% of hip fractures occur among people aged 65 years or older and 80% occur in women due to the fact that there are more elderly women than men. Worldwide, elderly people represent the fastest growing age group and with an ageing population the incidence of hip fractures is likely to rise substantially. It is predicted that the estimated number of hip fractures worldwide will rise from 1.7 million in 1990 to 6.3 million in 2050.3 This estimate assumes that fracture rates remain the same over this time period, although there is evidence that age-adjusted hip fracture rates may indeed be increasing. Under these circumstances, even assuming only a rise of 1% per year in the age-adjusted rate, the estimated number of hip fractures could be as high as 8.2 million by 2050. Incidence rates for morphometric vertebral deformities have been obtained through the European Prospective Osteoporosis study (EPOS).4 The incidence of new vertebral deformities was estimated from radiographs at baseline and at 4 year follow-up in these subjects. Overall, age and sex-adjusted incidence rates were 1% per year among women and 0.6% per year among men. Only about a third of all radiographically identified fractures come to specialist attention and fewer than 10% result in hospital admission. Distal forearm fractures display a different pattern of incidence rates. Studies from northern USA around 10 years ago suggested that rates increased linearly among women between the ages of 40 and 65 years; thereafter rates appeared to plateau.5 Among men,

Figure 1. Incidence of osteoporotic fractures in women.

Osteoporosis: prevention and management 111

incidence rates remained constant between the ages of 20 and 80 years. As a consequence, most distal forearm fractures occur in women, 50% of whom are older than 65 years. Burden of the disease Overall, the remaining lifetime risk for a 50 year old woman sustaining an osteoporoticrelated fracture is estimated at 50%.6 For a man, this lifetime risk is estimated at 20% (Table 1). Hip fractures are the most devastating result of osteoporosis leading to emergency hospitalisation, surgery and subsequent rehabilitation. These fractures are associated with an excess mortality and significant morbidity. Up to 20% of patients admitted with an acute fracture will die within 6 months.7 Of those that survive, up to one third become totally dependent and some permanently disabled, necessitating institutionalisation.8 Vertebral fractures are also associated with excess mortality, although this appears to be related to comorbid conditions rather than being directly attributable to the fracture. Spine fractures cause significant disability due to pain and thoracic kyphosis. This morbidity varies with the frequency and site of the fractures. Multiple fractures typically cause the most pain and disability and fractures in the thoracic spine appear more symptomatic and disabling than those in the lumbar spine.9 Quality of life studies have shown an increasing impact on quality of life with an increasing number of vertebral fractures.10 Although it is recognised that osteoporotic fractures represent a significant burden of morbidity for patients, the economic burden to society is equally high. Studies in various countries have shown that the costs of osteoporosis are very substantial. It has recently been estimated that the combined cost of all osteoporotic fractures is $20 billion in the USA and about $30 billion in the European Union.11 Acute care following hip fracture contributes significantly to these costs, although substantial costs are also incurred for rehabilitation and social care. In Europe, the total costs of caring for people in the first year after a hip fracture is estimated at V14.7 billion12 and the scale of costs is similar in the USA.13

ASSESSMENT OF FRACTURE RISK Assessment of bone mineral density (BMD) has been critical for the diagnosis of osteoporosis, as proposed by the World Health Organisation (WHO) in 1994. BMD is

Table 1. The lifetime and 10 year probability of a future fracture for men and women at different ages. Current age (years)

50

60

70

80

Lifetime risk of any fractures (%)

Men Women

20.7 53.2

14.7 45.5

11.4 36.9

9.6 28.6

10 year risk of any fractures (%)

Men Women

7.1 9.8

5.7 13.3

6.2 17.0

8.0 21.7

Source: Adapted from van Staa et al (2001).6

112 R. Keen

able to predict fracture risk as good as, if not better, than the ability to predict heart disease risk from blood cholesterol concentrations and to predict stroke risk from blood pressure measurement values.14 Low bone density itself does not, however, mean that an individual will fracture and it has become clear that there are additional clinical risk factors that are able to predict fracture risk independent of BMD. The WHO has identified the following risk factors15:       

History of fragility fracture Use of glucocorticoids Parental history of fracture Associated medical diseases (i.e. rheumatoid arthritis) Cigarette smoking Excessive alcohol intake Low body weight (body mass index < 19 kg/m2)

The combined use of these risk factors together with age and BMD enables the prediction of 10-year probabilities for hip and other fractures. Intervention thresholds for various agents can then be derived using health economic modelling.

POPULATIONS TO TARGET When considering the individuals at whom intervention should be targeted, the following groups can be identified within a population: Normal: The whole population at all ages At risk: As detailed above using WHO risk factors Osteoporosis: Men and women with a BMD T score at the spine and/or hip of e2.5 or lower Established osteoporosis: Men and women with one or more fragility fractures  BMD T score below 2.5. Most strategies will be targeted to those at risk, or to those with disease (with or without a history of fracture). Improving the skeletal health of the whole population appears attractive from a public health perspective, although data that this strategy would be effective in reducing fracture incidence is not available.

EVIDENCE-BASE FOR INTERVENTIONS Non-pharmacological therapy General life style measurements should be adopted in all subjects at risk of osteoporosis. Many of these interventions are based on epidemiological data linking either deficiency or excess of a particular factor with an increased risk of fracture (Table 2). It is less clear, however, whether modification of the epidemiological factors will result in a reduced fracture risk.

Osteoporosis: prevention and management 113

Table 2. Risk factors for bone loss, development of osteoporosis and fracture. Ageing Female sex Previous fracture after low energy trauma Radiographic evidence of osteopaenia or vertebral deformity, or both Loss of height and thoracic kyphosis (after radiographic confirmation of vertebral deformities) Low body weight (body mass index <19 kg/m2) History of corticosteroid use Maternal family history of hip fracture Reduced lifetime exposure to oestrogen (primary or secondary amenorrhoea or early natural or surgical menopause (<45 years))

Various disorders associated with osteoporosis: Previous low body weight Rheumatoid arthritis Malabsorption syndromes, including chronic liver disease and inflammatory bowel disease Primary hyperparathyroidism Long-term immobilisation

Behavioural risk factors: Low calcium intake (<500e850 mg/day) Physical inactivity Vitamin D deficiency Smoking (current) Excessive alcohol consumption

Diet An optimal diet for the management of osteoporosis includes an adequate intake of calories (to avoid malnutrition), calcium and vitamin D. A dietary survey has shown that adolescents and the elderly are most at risk of vitamin D insufficiency and deficiency.16,17 Most of the elderly surveyed had low dietary intakes of vitamin D and 10% of community dwelling and 37% of institutionalised elderly had low serum levels of vitamin D.17 In general, most guidelines recommend that people aged 70 years and under should take 400 IU (10 mg) per day of vitamin D. Older people and patients with osteoporosis may, however, require higher doses of up to 600e800 IU (15e20 mg) per day. In addition, adults with osteoporosis require a dietary intake of calcium of 1000e1500 mg/day and this can be achieved either through the diet or with a formal supplement. The Framingham Osteoporosis Study and other population-based studies have linked high intakes of potassium, magnesium and vitamin K from fruit and vegetables with improved BMD and reduced hip fracture risk in the elderly.18e20 Excess caffeine intake has also been associated with an increase in hip fracture risk, although a recent study has identified spinal bone loss in those with high caffeine intakes and low calcium intakes.21 Excess alcohol consumption also appears to have a negative effect on bone health, both directly and also by indirectly increasing the risk of falls. The WHO has identified a daily intake of more than 2 units as being associated with a significant increase in fracture risk.15 Smoking Cigarette smoking is associated with reduced bone mass and an increased risk of fracture.22 Subjects concerned about their skeletal health should be strongly encouraged to stop smoking as this increase in risk reduces 5 years after cessation of smoking in men, although not in women.

114 R. Keen

Exercise Regular weight-bearing exercise is encouraged to improve BMD. Any fracture reduction associated with exercise is probably as a result of improved muscle strength and a lower risk of falling, particularly in the elderly.23 Excessive exercise in premenopausal women may actually have detrimental effects on bone due to weight loss and secondary amenorrhoea. Hip protectors Controlled studies conducted in care homes have demonstrated that a structured education programme and the provision of hip protectors can reduce the number of hip fractures.24 Compliance with hip protectors is often poor and a recent meta-analysis suggested that the beneficial effect is limited to the elderly in residential care rather than those living in the community.25 Pharmacological agents Calcium and vitamin D Adequate calcium nutrition is essential for the development and maintenance of a normal skeleton. At present, calcium supplements are often administered as a combined therapy with other agents for the treatment of osteoporosis. Vitamin D acts to increase calcium absorption in the gastrointestinal tract and thereby inhibits parathyroid hormone (PTH)-mediated bone resorption. The recommended daily requirement for calcium intake in postmenopausal women is 1000e1500 mg/day and for vitamin D it is 400e800 IU/day. These values may, however, vary depending on age, ethnic group, nutrition status and skeletal size. Calcium appears to have little effect if given within the first 5 years of the menopause when bone loss is predominantly due to oestrogen withdrawal.26 Calcium supplements have been shown to reduce ageing-associated bone loss in prospective controlled trials by up to 50%.26,27 In the frail elderly, supplementation with 1.2 gm/day of elemental calcium and 800 IU/day of cholecalciferol has been shown to reduce the risk of hip fracture and other non-vertebral fractures.28 More recent studies have, however, failed to demonstrate any significant effect of calcium and vitamin D on fracture risk.29,30 Hormone replacement therapy (HRT) The association between osteoporosis and oestrogen deficiency was first described by Fuller Albright in 1941, when he noted that 40 out of 42 women with osteoporotic fractures were postmenopausal.31 For many years oestrogen (plus progestogen in those with an intact uterus) replacement was considered the ‘first-line’ therapy for women, as both a prevention and a treatment for osteoporosis. Although HRT was known to reduce menopause-related bone loss, evidence for its fracture efficacy was limited. Data from meta-analyses has recently demonstrated that HRT can reduce the risk of both vertebral and non-vertebral fractures.32,33 These results have also been confirmed following the publication of the Women’s Health Initiative (WHI), where treatment with HRT reduced clinical fractures in postmenopausal women.34,35 In one arm of the study 16,608 postmenopausal women with an intact uterus and aged > 50 years, were randomised to conjugated equine oestrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily or placebo.34 This study was stopped 3 years early after 5.2 years because of unfavourable outcomes. In the other

Osteoporosis: prevention and management 115

arm, 10,739 postmenopausal women 50e79 years of age with hysterectomy were randomised to CEE 0.625 mg daily or placebo and followed for an average 7.1 years.35 These studies demonstrated that HRT use was associated with a significant reduction in risk of clinical vertebral fracture and non-vertebral fractures, including hip. Despite these beneficial effects on osteoporosis, treatment with CEE plus progestagen was associated with an increased risk of breast cancer, myocardial infarction, stroke and venous thromboembolic events, and CEE use alone with an increased risk of stroke. Although the risks to an individual are small, HRT is no longer recommended as a first-choice therapy in postmenopausal women for management of osteoporosis. It is currently recommended that HRT be considered for short-term use in the management of menopausal symptoms and that alternative agents are considered for the treatment of osteoporosis. Extended use of HRT may occur where individuals find that cessation of treatment causes a return of menopausal vasomotor symptoms and a poor quality of life. Such individuals should be counselled about the risks and benefits of treatment and alternative options explored. They should undergo regular screening for breast cancer and appropriate management of concurrent risk factors for vascular events would also be prudent. Selective oestrogen receptor modulators (SERMs) SERMs are designed to have tissue-specific effects, acting as either an oestrogen agonist or antagonist. Currently raloxifene is the only SERM licensed for the management of osteoporosis, although agents such as lasofoxifene are undergoing phase III clinical trials. Raloxifene is a benzothiophene that acts as an agonist in bone and lipid metabolism but as an antagonist in the breast and endometrium. In the Multiple Outcome of Raloxifene Evaluation (MORE) study, 7705 women with osteoporosis received raloxifene.36 There was a significant reduction in vertebral fracture risk in both those with pre-existing vertebral fractures (reduction of 50%) and in those without pre-existing vertebral fractures (reduction of 30%), although no effect was seen on non-vertebral fractures. In an extension of the phase III study for an additional 4 years in 4011 women, non-vertebral fracture was a secondary endpoint, but there was still no significant difference in overall non-vertebral fracture rates.37 These data therefore suggest that raloxifene should not be used in patients at high risk of hip fracture. It may be more suitable for women aged < 70 years, although in the early postmenopausal years the incidence of menopausal vasomotor symptoms may be induced. The MORE study also demonstrated that the frequency of breast cancer was lowered by 70% and this additional non-skeletal benefit may be important in aiding a decision on treatment. Bisphosphonates Bisphosphonates are synthetic analogues of pyrophosphate that bind to hydroxyapatite at sites of active bone remodelling. By inhibiting the action of osteoclasts they reduce bone resorption. They contain a non-hydrolyzable P-C-P bond and have two side chains, one that participates in binding to bone and one that determines the pharmacological properties of the drug. Absorption of an oral dose is less than 5% and subsequent uptake by bone is 30e40%, with the remainder undergoing renal excretion. Bisphosphonates have a short plasma half-life but elimination from the skeleton is slow with a half-life in bone of several years. Etidronate was the first bisphosphonate to be developed and licensed for the management of osteoporosis. Treatment is given intermittently (400 mg/day for 2 weeks,

116 R. Keen

repeated every 13 weeks). Etidronate has been shown to increase spinal bone density by 4e5% during the first 2 years of treatment in two placebo-controlled studies.38,39 Despite certain limitations regarding the power of these two studies, the combined results suggest that this intermittent regimen of etidronate therapy is effective in reducing further vertebral fractures in patients with severe osteoporosis and possibly accelerated bone loss. Findings from a meta-analysis of controlled trials of etidronate over 1e4 years suggest a reduction in vertebral fracture risk with a relative risk (RR) of 0.63 (95% confidence interval (CI) ¼ 0.44e0.92), but no effect was seen for nonvertebral fractures.40 Alendronate, ibandronate and risedronate are more potent inhibitors of bone resorption than etidronate. Alendronate and risedronate have been shown to reduce fracture risk at all the clinically important sites, including the hip, whereas ibandronate has only been shown to reduce the risk of vertebral fractures. In women with osteoporosis (as defined by a BMD T-score below 2.5) and/or presence of at least one vertebral fracture, treatment with alendronate was associated with a 50% reduction in fracture risk at spine, wrist and hip when compared to placebo.41 Risedronate has also been shown to reduce the risk of vertebral42 and non-vertebral fracture.43 Ibandronate has been shown to reduce the risk of vertebral fractures in women with low BMD and one or more baseline fractures.44 The optimal treatment duration is not yet known. Most clinical studies have been conducted over a 3 year duration, but data is available for alendronate up to 10 years.45 The results of further studies with long term data on BMD, facture rates, bone turnover and bone histology are needed to aid in management decisions. Compliance with therapy has been aided by once weekly dosing, which is available for both risedronate (35 mg/week) and alendronate (70 mg/week). Monthly dosing in also available for ibandronate (150 mg/month). Oral bisphosphonates are generally well tolerated. However, in those with gastrointestinal intolerance or poor long term compliance intravenous treatment offers an alternative. Pamidronate infused every 3 months increases BMD at the spine and hip.46 There is, however, no data on fractures with this intermittent dosing regimen. Intravenous ibandronate is licensed for the treatment of postmenopausal osteoporosis, given as 3 mg every 3 months. Zoledronic acid is a cyclic nitrogen containing a third generation bisphosphonate that is the most potent of the available bisphosphonates. A single 4 mg infusion of zoledronate has been shown to have effects on bone turnover for up to 12 months, with increases in BMD similar to those achieved with currently available oral bisphosphonates.47 Phase III studies are examining the role for zoledronic acid in the treatment of postmenopausal osteoporosis and also in the immediate post-operative period following hip fracture in the elderly. Bisphosphonates are now regarded as the treatment of choice for postmenopausal osteoporosis due to proven efficacy and a good safety profile.48 Strontium ranelate Strontium ranelate has been approved by the European Union for the treatment of postmenopausal osteoporosis. Its mode of action is unclear, although it appears to have a modest effect on inhibiting bone resorption with no negative effect on bone formation. Results from a phase II trial in 1649 postmenopausal women demonstrated that strontium ranelate reduced the risk of vertebral fractures by 49% by 1 year and by 41% over 3 years.49 Results from a second study in older women, showed that strontium ranelate reduced the risk of non-vertebral fracture by a modest 16%50, with a reduction in the risk of hip fracture in those aged > 74 years with a low BMD (T-score below 3).

Osteoporosis: prevention and management 117

In general treatment with strontium ranelate was well tolerated apart from a low rate of gastro-intestinal side-effects and an unexplained increased risk of venous thrombosis. Strontium ranelate can be considered as an alternative to bisphosphonate therapy in the management of postmenopausal osteoporosis. Parathyroid hormone (PTH) Intermittent doses of human PTH given as daily subcutaneous injections have been shown to exert an anabolic effect leading to increased osteoblast number and increases in bone formation. This contrasts with continuous exposure to PTH, which leads to increased bone resorption and a net decrease in trabecular bone volume. Currently teriparatide (recombinant human PTH [1-34]) is the only formulation of PTH available for the management of osteoporosis. It is anticipated, however, that the full-length recombinant molecule (hPTH 1-84) will also soon be available. In a phase III trial in 1637 postmenopausal women, treatment with teriparatide was shown to reduce the risk of vertebral fractures by 65% and non-vertebral fractures overall by 53%.51 The study was not powered to detect treatment effects at individual skeletal sites and, therefore, there is no data on hip fracture reduction. In Europe teriparatide has recently been approved for a treatment duration of 18 months in postmenopausal women, whereas in the US treatment is licensed for 24 months and it is also available for use in men. Calcitonin Calcitonin is an endogenous peptide of 32 amino acids that possesses anti-osteoclastic activity. It interacts with the osteoclast via specific receptors resulting in a flattening of the cell brush border and an alteration of its cytoplasm. Calcitonin is also thought to interfere with the differentiation of pre-osteoclasts thereby reducing the lifespan and number of mature osteoclasts. In clinical practice, four calcitonins (human, pig, salmon, eel) have been used in studies of osteoporosis. Parenteral administration of calcitonin is given either by intramuscular injection, suppository or nasal spray. Data for an effect of calcitonin on fracture risk is limited and comes mainly from the Prevent Recurrence Of Osteoporotic Fractures (PROOF) study.52 This was a Table 3. Effect of lifestyle interventions on key outcomes in osteoporosis. Lifestyle interventions

Aim of intervention Function and structure Tissue damage

Diet e calcium Weight e maintenance of a normal body mass index Exercise e weight bearing Avoiding smoking Avoiding alcohol abuse

Activity and participation

Symptom

BMD

Fracture

Iaþ IIIþ

IIIþ IIIþ

IE IE

IE IE

Iaþ IIIþ IVþ

IIIþ IIIþ IVþ

IE IE IE

IE IE IE

Ia e IV, grading of evidence. Nature of effect: þ, positive; 0, evidence of no effect; , negative effect; #, inconsistent findings; IE, inadequate evidence.

118 R. Keen

Table 4. Effect of therapeutic interventions on outcomes in postmenopausal osteoporosis. Pharmacological interventions

Aim of intervention Function and structure Tissue damage BMD

Fracture Vert

Analgesics Anti-inflammatories/analgesics Calcitonin (short-term) HRT Raloxifene Calcium þ vitamin D Vitamin D Etidronate Alendronate Risedronate Ibandronate Zoledronate Calcitonin PTH 1-34 peptide Strontium ranelate

Symptom pain

Activity and participation

Non Vert

Hip IVþ IVþ Ibþ (vert fract)

Iaþ Ibþ Ibþ Ibþ Iaþ Iaþ Iaþ Ibþ Ibþ Iaþ Ibþ 1bþ

Ibþ Ibþ

Ibþ

Ibþ

Ibþ Ibþ

Iaþ Iaþ Iaþ Ibþ

Ibþa IIaþ IIIþ Iaþ Iaþ# Ibþb

Ibþa IIIþ# IIIþ Iaþ Ibþ

Iaþ# Ibþ Ibþ

Iaþ# Ibþ Ibþ

IIIþ

Ibþ

Ibþb

Ibþ

Ibþ

Ibþ

Ibþ

Ia e IV, grading of evidence. Nature of effect: þ, positive; #, inconsistent findings. a Evidence only applies to very elderly women living in sheltered accommodation, not the whole elderly population. b Post-hoc analysis.

5 year prospective double blind, randomised, placebo-controlled study of 1255 postmenopausal women with osteoporosis. Data from that study demonstrated a reduction of vertebral fractures by 30% in individuals taking 200 IU of intranasal salmon calcitonin. There was, however, no effect on peripheral fractures. The study has subsequently been criticised for the following reasons: 60% of subjects in the study were lost to follow-up, doses of 100 IU and 400 IU had no effect on vertebral fracture risk and there was no consistent effect on BMD and biochemical markers of bone turnover. Although rarely used as a first-line treatment to prevent fractures, calcitonin has been shown to have analgesic properties which make it suitable for use in those with pain secondary to vertebral collapse, particularly in the acute state. The physiological mechanisms underlying this action are poorly understood. TARGETS FOR INTERVENTION Targets that are most important in the prevention or management of osteoporosis and low trauma fractures are to:  Maximise bone mass  Maximise peak bone mass  Reduce age-related bone loss

Osteoporosis: prevention and management 119

   

Prevent falls Avoid other risk factors for osteoporosis and fracture Reduce pain Reduce disability These can be further grouped into the following categories: Symptoms: Pain Tissue damage: BMD, fracture Activity and participation: Quality of life measurements (disease-specific or generic).

Table 3 summarises the level of evidence for lifestyle interventions on the target outcomes. Table 4 summarises the evidence for therapeutic interventions. CONCLUSIONS General lifestyle advice regarding bone health should be offered to all. This should include advice on ensuring an adequate dietary intake of calcium and vitamin D, regular weight-bearing exercise, avoidance of smoking and excess alcohol, and maintenance of an optimal body weight. A case-finding strategy is proposed to identify those at increased risk of fracture. This currently utilises clinical risk factors and measurement of bone mineral density (BMD), although biochemical markers of bone turnover may also be utilised in the future. Bisphosphonates are the mainstay of therapy, but additional treatments such as strontium ranelate and raloxifene may be considered as alternatives. For patients with severe disease or in those who continue to fracture despite anti-resorptive therapy, treatment with an anabolic agent should be considered.

Practice points  All patients should be encouraged to ensure an adequate dietary intake of calcium (1000e1500 mg/day) and vitamin D (400e800 IU/day) and take regular weight-bearing exercise.  Other lifestyle advice should be given regarding avoidance of smoking and excess alcohol consumption, and maintenance of an optimal body weight (BMI > 19 kg/m2).  Patients with clinical risk factors should be offered an osteoporosis assessment.  If dual energy X-ray absorptiometry (DEXA) is available, measurement of BMD at the spine and hip should be undertaken to aid in risk assessment.  Patients deemed to be at high risk for future fracture should be offered appropriate treatment. Currently bisphosphonate therapy would be the first-line treatment for the majority of patients.  In patients intolerant to bisphosphonates or in those with contra-indications to bisphosphonates, strontium ranelate or raloxifene can be considered as alternatives. Intravenous bisphosphonates will offer advantages in those with gastrointestinal disease or poor tolerability to oral medication.

120 R. Keen

 Unless clinicians are confident that a patient has an adequate dietary intake of calcium and is vitamin D replete, calcium and vitamin D should be given as adjunctive therapy.  In patients with severe disease, or in those not responding to standard treatment, an anabolic agent such as teriparatide should be considered. These patients should be referred for specialist assessment.  Patients should be offered follow-up to monitor compliance with therapy and to reassess the clinical situation. In most instances, the initial treatment duration with a bisphosphonate would be for 5 years.

Research agenda  Strategies need to be developed to identify patients with asymptomatic vertebral fractures.  The role for biochemical markers of bone turnover to aid in patient management, which would include the baseline assessment of fracture risk and evaluating the response to therapy, needs to be further studied.  More studies are needed to evaluate treatment efficacy in patients with secondary osteoporosis.  The optimal treatment duration for bisphosphonate therapy needs to be established.  Further studies are required to determine the optimal treatment duration for parathyroid hormone and whether previous treatment with bisphosphonate therapy may blunt the anabolic response.  Research to evaluate the role of combination and sequential therapy is needed.  The impact of therapeutic interventions on quality of life and activity needs to be assessed.  Further work is needed to link the management of osteoporosis fracture risk with falls prevention programmes.

REFERENCES 1. World Health Organization Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series No. 843. Geneva: World Health Organization, 1994. 2. Kanis JA, Johnell O, De Laet C et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004; 29: 517e522. *3. Sambrook P & Cooper C. Osteoporosis. Lancet 2006; 367: 2010e2018. 4. Roy DK, O’Neill TW, Finn JD et al. Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporosis International 2003; 14(1): 19e26. 5. O’Neill TW, Cooper C, Finn JD et al. Incidence of distal forearm fracture in British men and women. Osteoporosis International 2001; 12: 555e558. 6. van Staa TP, Dennison EM, Leufkens HG & Cooper C. Epidemiology of fractures in England and Wales. Bone 2001; 29(6): 517e522. 7. Sexson SB & Lehner JT. Factors affecting hip fracture mortality. Journal of Orthopaedic Trauma 1987; 1(4): 298e305.

Osteoporosis: prevention and management 121 8. Bonar SK, Tinetti ME, Speechley M & Cooney LM. Factors associated with short-versus longterm skilled nursing facility placement among community-living hip fracture patients. Journal of the American Geriatrics Society 1990; 38(10): 1139e1144. 9. Pluijm SM, Tromp AM, Smit JH et al. Consequences of vertebral deformities in older men and women. Journal of Bone and Mineral Research 2000; 15(8): 1564e1572. 10. Oleksik A, Lips P, Dawson A et al. Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures. Journal of Bone and Mineral Research 2000; 15(7): 1384e1392. 11. Cummings SR & Melton LJ. Epidemiology and outcomes of osteoporotic fracture. Lancet 2002; 359: 1761e1767. 12. European Commission. Report on Osteoporosis in the European Community: Action for Prevention. Luxembourg: European Commission, 1998. 13. Ray NF, Chan JK, Thamer M & Melton III LJ. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. Journal of Bone and Mineral Research 1997; 12(1): 24e35. *14. Marshall D, Johnell O & Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal 1996; 312: 1254e1259. *15. Kanis J, Borgsrom F, De Lart C et al. Assessment of fracture risk. Osteoporosis International 2005; 16: 581e589. 16. Gregory L, Lowe C, Bates C et al. National Diet and Nutrition Survey: Young People aged 4 to 18 Years. Volume 1: Report of the Diet and Nutrition Survey. London: The Stationery Office, 1998. 17. Finch S, Doyle W, Lowe C et al. National Diet and Nutrition Survey: People aged 65 Years or Over. Volume 1: Report of the Diet and Nutrition Survey. London: The Stationery Office, 1998. 18. New SA, Robins SP, Campbell MK et al. Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health. American Journal of Clinical Nutrition 2000; 71: 142e151. 19. Tucker KL, Hannan MT, Chen H et al. Potassium, magnesium, and fruit and vegetable intake are associated with greater bone mineral density in elderly men and women. American Journal of Clinical Nutrition 1999; 69: 727e736. 20. Booth SL, Tucker KL, Chen H et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. American Journal of Clinical Nutrition 2000; 71: 2504e2512. 21. Harris SS & Dawson-Hughes B. Caffeine and bone loss in healthy menopausal women. American Journal of Clinical Nutrition 1994; 60: 573e578. 22. Law MR & Hackshaw AK. A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. British Medical Journal 1997; 315: 841e846. 23. Feder G, Cryer C, Donovan S et al. Guidelines for the prevention of falls in people over 65. British Medical Journal 2000; 321: 1007e1011. 24. Van Schoor NM, Deville WL, Bouter LM et al. Acceptance and compliance with external hip protectors: a systemic review of the literature. Osteoporosis International 2002; 13: 917e924. 25. Sawka AM, Boulos P, Beattie K et al. Do hip protectors decrease the risk of hip fracture in institutional and community-dwelling elderly? A systematic review and meta-analysis of randomized controlled trials. Osteoporosis International 2005; 16: 1461e1474. 26. Dawson-Hughes B, Dallal GE, Krall EA et al. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. The New England Journal of Medicine 1990; 323: 878e883. 27. Reid IA, Ames RW, Evans MC et al. Effect of calcium supplementation on bone loss in postmenopausal women. The New England Journal of Medicine 1993; 328: 460e464. *28. Chapuy MC, Arlot ME, Delmas PD & Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fracture in elderly women. British Medical Journal 1994; 308: 1081e1082. *29. Grant AM, Avenell A, Campbell MK 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: 1621e1628. 30. Jackson RD, LaCroix AZ, Gass M et al. Calcium plus vitamin D supplementation and the risk of fractures. The New England Journal of Medicine 2006; 354: 669e683. 31. Albright F, Smith PH & Richardson AM. Postmenopausal osteoporosis. Journal of the American Medical Association 1941; 116: 2465e2474.

122 R. Keen 32. Torgerson DJ & Bell-Seyer SE. Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomized trials. BMC Musculoskeletal Disorders 2001; 2: 7. 33. Torgerson DJ & Bell-Seyer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. Journal of the American Medical Association 2001; 285: 2891e2897. 34. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association 2002; 288: 321e333. 35. Jackson RD, Wactawski-Wende J, LaCroix AZ et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. Journal of Bone and Mineral Research 2006; 21: 817e828. 36. 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. Journal of the American Medical Association 1999; 282: 637e645. 37. Siris E, Harris ST, Eastell R et al. Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) Study. Journal of Bone and Mineral Research 2005; 20: 1514e1524. 38. Storm T, Thamsborg G, Steiniche Tet al. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. The New England Journal of Medicine 1990; 322: 1265e1271. 39. Harris ST, Watts NB, Jackson RD et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. American Journal of Medicine 1993; 95: 557e567. 40. Cranney A, Guyatt G, Krolicki N et al. A meta-analysis of etidronate for the treatment of postmenopausal osteoporosis. Osteoporosis International 2001; 12: 140e151. *41. Black DM, Thompson DE, Bauer DC et al. Fracture risk reduction with aledronate in women with osteoporosis: the fracture intervention trial. The Journal of Clinical Endocrinology and Metabolism 2000; 85: 4118e4124. 42. Harris ST, Watts NB, Genat HK et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Journal of the American Medical Association 1999; 282: 1344e1352. *43. McClung MR, Geusens P, Miller PD et al. Effect of risedronate on the risk of hip fracture in elderly women. The New England Journal of Medicine 2001; 344: 333e340. 44. Chesnut 3rd CH, Skag A, Christiansen C et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Journal of Bone and Mineral Research 2004; 19: 1241e1249. 45. Bone HG, Hosking D, Devogelaer JP et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. The New England Journal of Medicine 2004; 350: 1189e1199. 46. Reid IR, Wattie DJ, Evans MC et al. Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. The Journal of Clinical Endrocrinology and Metabolism 1994; 79: 1595e1599. 47. Reid IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. The New England Journal of Medicine 2002; 346: 653e661. *48. National Institute for Clinical Excellence. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Health Technology Appraisal 87. London: NICE, 2005. Available at: http://www.nice.org.uk/TA087guidance. 49. Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. The New England Journal of Medicine 2004; 350: 459e468. *50. Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. The Journal of Clinical Endocrinology and Metabolism 2005; 90: 2816e2822. *51. Neer RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. The New England Journal of Medicine 2001; 344: 1434e1441. 52. Chesnut 3rd CH, Silvermann S, Andriano K et al. A randomised trial of nasal spray salmon calcitonin in postmenopausal osteoporosis: the prevent recurrence of osteoporotic fracture study. American Journal of Medicine 2000; 109: 267e276.