Clinical Review

Osteoporosis and its management

¹ Addenbrooke's Hospital, Cambridge CB2 2QQ

Correspondence to: J E Compston jec1001@cam.ac.uk

Fractures caused by osteoporosis affect one in two women and one in five men over the age of 50, resulting in an estimated annual cost to the health services of around ?1.8bn (2.7bn; $3.5bn) in the United Kingdom and 30bn in all of Europe.^{1 2} Most patients with osteoporosis are managed in primary care, but a minority will benefit from referral to specialised centres. In recent years considerable advances have been made both in the identification of people at high risk of fracture and in therapeutic options to reduce the risk of fracture. This review focuses on these areas and also on the partnership that is required between primary and secondary care to optimise the management of patients with osteoporosis.

What is osteoporosis?

Osteoporosis results from reduced bone mass and disruption of the micro-architecture of bone (fig 1), giving decreased bone strength and increased risk of fracture, particularly of the spine, hip, wrist, humerus, and pelvis. The risk of fractures increases steeply with age (fig 2) and most of those affected are over 75.^{1 2} Globally, osteoporotic fractures caused an estimated 5.8 million disability adjusted life years in the year 2000^w1 and are also associated with increased mortality. Hip fractures (fig 3) result in loss of independence for at least a third of people with osteoporosis, and vertebral fractures (fig 4) cause height loss, chronic pain, and difficulty with normal daily activities.

Fig 1 Scanning electron micrographs to show the structure of L3 vertebra in a 31 year old woman (top) and in a 70 year old woman (bottom). Note that many of the plate-like structures have become converted to thin rods

Fig 2 Epidemiology of osteoporotic fractures in men and women. Reprinted with permission28

Fig 3 Fracture of the femoral neck

Fig 4 Vertebral fracture

Age related bone loss starts in the fourth or fifth decade of life (fig 5). It occurs as a result of increased bone breakdown by osteoclasts (fig 6) and decreased bone formation by osteoblasts.³ The role of oestrogen deficiency in menopausal and age related bone loss in women is well documented, and bone mass in elderly men is also positively related to oestrogen levels. Vitamin D insufficiency and secondary hyperparathyroidism are common in elderly people and may contribute. Other possible factors are reduced physical activity with ageing and decreased production of insulin-like growth factors.

Fig 5 Age related changes in bone mass throughout life in women and men. Peak bone mass is attained in the third decade of life and age related bone loss probably starts around the age of 40 in both men and women. In women, bone loss accelerates around the time of the menopause

Fig 6 Scanning electron micrograph of an osteoclast resorbing bone

Although low bone mass has a major role in the pathogenesis of fracture, factors related to falling?risk of falling, protective response, and energy absorption? make an important contribution. In addition, aspects of bone composition and structure that may not be captured by bone mineral density measurements, such as bone size and geometry, and bone structure and material, contribute to increased bone fragility.

Who is at risk of osteoporosis?

Lower peak bone mass, increased bone loss at the menopause, and greater longevity all confer a greater risk of osteoporosis in women than in men, and the disease is most commonly seen in postmenopausal women. Some of the risk factors for osteoporosis (box 1) are at least partially independent of bone mineral density,^w2-w6 whereas the effect of others on fracture risk is mediated solely through reduced bone mineral density. Oral glucocorticoids, which are taken by about 1% of the population and 2.5% of those aged over 75, are a common cause of osteoporosis, and there are specific national guidelines for the prevention and management of glucocorticoid induced osteoporosis (see additional educational resources box).

How does osteoporosis present?

Osteoporosis often presents as a clinically evident fracture. A low trauma fracture (following a fall from standing height or less) in someone aged over 45 should trigger the suspicion of osteoporosis. In other cases, osteoporosis may present as backache, height loss, spinal deformity, or radiological osteopenia.

Although most fractures due to osteoporosis present clinically, vertebral fractures may be asymptomatic in as many as two thirds of patients.⁴ It is important to detect these fractures since they carry a high risk of further fractures in the spine and elsewhere.⁵ Lateral x rays of the spine should be considered in patients with height loss or spinal deformity.

Who should be treated?

The World Health Organization's definition of osteoporosis is based on bone mineral density in the spine and proximal femur measured with dual energy x ray absorptiometry (DXA). Osteoporosis is classified as a bone mineral density 2.5 or more standard deviations below normal peak bone mass?that is, a T score ?2.5.⁶ Other techniques?for example, ultrasound of the calcaneus and peripheral DXA measurements?cannot be used in the same way to diagnose osteoporosis but are useful as a preliminary assessment of risk where access to axial DXA is inadequate.

Although osteoporosis indicates a high likelihood of fracture, many fragility fractures occur in people with bone density values above the defined level.⁷ Fractures can be better predicted by adding clinical risk factors that contribute to fracture risk independently of bone mineral density (fig 7; box 1).⁸ This approach is being developed under the auspices of the WHO and will be delivered in the form of an algorithm that enables the probability of a fracture to be calculated from clinical risk factors with or without bone mineral density values. Intervention thresholds based on cost effectiveness^w7 can be used to make a decision about treatment.⁹

Fig 7 Age affects fracture risk independently of bone mineral density. For any given bone density, the fracture probability increases with age. For example, at a T score of ?2, the 10 year hip fracture probability at the age of 50 is around 5% but at the age of 80 it is around 30%29

Management of osteoporosis

Non-pharmacological measures
Falls have an important role in the pathogenesis of fragility fractures, particularly in frail and elderly people. Multiple medical and environmental factors increase the risk of falling and many of these are modifiable. Multifaceted interventions have been shown to reduce the frequency of falling but not fractures.¹⁰

Lifestyle measures to improve bone health include maintaining adequate dietary calcium intake and normal vitamin D status.^{w8 w9} Appropriate levels of exercise should be recommended and smoking and alcohol abuse discouraged.¹¹ Physiotherapy and pain relief are important in managing fractures.

Pharmacological interventions
Therapeutic options for osteoporosis have increased considerably over recent years. Although most patients with osteoporosis can be managed in primary care, some patients benefit from specialist assessment: younger men and women, patients who continue to fracture despite treatment, and those who require assessment for anabolic treatments. Anabolic and intravenous treatments are generally instigated by hospital specialists; thereafter, shared care between primary and secondary organisations is appropriate.

Currently licensed treatments (table) include the bisphosphonates, raloxifene and hormone replacement therapy (which prevent bone resorption), strontium ranelate (uncertain mechanism of action), and parathyroid hormone peptides (anabolic). Without head to head comparison trials with fracture end points, the efficacy of these drugs cannot be directly compared. Some, but not all, have proved efficacy against vertebral and non-vertebral fractures, including hip fractures,^w10 and this is an important factor influencing choice. Safety, tolerability, and cost are important considerations, and NICE (the National Institute for Health and Clinical Excellence) is currently assessing the cost effectiveness of different interventions in the primary and secondary prevention of osteoporotic fractures.^w11

Bisphosphonates
Alendronate, etidronate, ibandronate, and risedronate are approved for treating postmenopausal osteoporosis. Alendronate, etidronate, and risedronate are approved for glucocorticoid induced osteoporosis, and alendronate is approved for osteoporosis in men. Because alendronate and risedronate have been shown to reduce vertebral and non-vertebral fractures, including hip fractures,^{12 13 14 15 w12 w13} they are considered first line options for preventing postmenopausal osteoporosis. Oral bisphosphonates must be taken fasting, with a full glass of water, and the individual must be upright and stay sitting or standing without taking food or drink for the next 30-60 minutes. Bisphosphonates are generally well tolerated but may be associated with upper gastrointestinal side effects, particularly if the dosing regimen is not adhered to.

An intravenous formulation of ibandronate is approved for postmenopausal osteoporosis. It is given as an injection over 15-30 seconds every three months. Antifracture efficacy has not been directly shown for this formulation or for the oral 150 mg once monthly regimen, but it is assumed from a bridging study based on changes in bone mineral density.^{16 17}

Strontium ranelate
Strontium ranelate (a sachet mixed with water and taken daily) reduces vertebral and non-vertebral (including hip) fractures in postmenopausal women with osteoporosis.^{18 19} Adverse events are generally mild and include diarrhoea and headache. The spectrum of anti-fracture efficacy of strontium ranelate makes it an alternative front line option to alendronate or risedronate,^w14 particularly in people for whom these drugs are contraindicated or are not tolerated.

Raloxifene
Raloxifene reduces the risk of vertebral fractures, but has not been shown to prevent fractures at other sites.^{20 w15} Side effects include hot flushes, leg cramps, and a threefold increase in the relative risk of venous thromboembolism. Raloxifene also protects against breast cancer.²¹ It can be regarded as a second line option in younger postmenopausal women with vertebral osteoporosis.

Parathyroid hormone peptides
Teriparatide (recombinant 1-34 parathyroid hormone), given as a subcutaneous daily injection of 20 ?g, reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis.^{22 w16} Preotact, the full 1-84 parathyroid hormone peptide, has recently been approved and is given in the same way in a daily dose of 100 ?g. Neither of these interventions has been shown to reduce hip fractures. Because they cost more than other options, they are reserved for patients with severe osteoporosis who are unable to tolerate or seem to be unresponsive to other treatments.

Hormone replacement therapy
Because the risk-benefit balance of hormone replacement therapy is generally unfavourable in older postmenopausal women, it is regarded as a second line treatment option.²³ It is an appropriate option in younger postmenopausal women at high risk of fracture, particularly those with vasomotor symptoms.

Calcium and vitamin D
The available evidence does not support a role for calcium and vitamin D alone in preventing osteoporotic fractures, except in institutionalised elderly people.^{24 25 w17} Calcium and vitamin D supplements should be prescribed with other treatments for osteoporosis since the evidence base for their efficacy in preventing fractures is derived from studies in which calcium and vitamin D were routinely administered.

Monitoring of treatment
Whether treatment response should be monitored and, if so, whether bone density measurements or biochemical markers should be used, is unclear. Compliance and persistence with osteoporosis treatments need to be improved²⁶; possible approaches include better patient education and the use of intermittent dosing regimens, such as once weekly or once monthly oral bisphosphonate therapy and three monthly intravenous ibandronate. Even longer dosing intervals are expected in the near future, with the likely approval of once yearly intravenous zoledronic acid.²⁷

References w1-w17 are on bmj.com

We thank T R Arnett, University College London, for the scanning electron micrographs (figures 1 and 6).

Competing interests: KESP has been reimbursed by the Alliance for Better Bone Health for attending a scientific conference. JEC has received payment for consultancy work and speaking engagements from Procter & Gamble, Eli Lilly, GSK/Roche, Amgen, Pfizer, Servier, Shire, Novartis and Nycomed and has been reimbursed for attending scientific conferences by Procter & Gamble, Eli Lilly, and Servier. She receives funding for a grant from Procter & Gamble and has acted as an expert witness in several cases of glucocorticoid-induced osteoporosis and in an alendronate patent dispute.

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