Osteoporosis: Social and Economic Impact

O s t e o p o ro s i s : So c i a l a n d Ec o n o m i c Im p a c t Juliet Compston, MD, FRCPath, FRCP, FMedSci KEYWORDS

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased bone fragility and increased fracture risk.1 These fractures are a major health problem in the elderly population, leading to significant morbidity, mortality, and cost to health care services. One in two women and one in five men over the age of 50 years will suffer a fracture due to osteoporosis during their remaining lifetime.2 Demographic changes over the next few decades will result in at least a doubling in the number of these fractures. Worldwide, it is estimated that there are around 9 million osteoporotic fractures each year and that over half of these occur in Europe and the Americas. A classification of osteoporosis based on bone mineral density (BMD) and fracture was proposed by the World Health Organization in 1994.3 According to this definition, osteoporosis is defined a BMD T-score less than or equal to -2.5 (ie, 2.5 or more standard deviations [SD] below the mean value in healthy young adults), osteopenia as a T-score between -1 and -2.5 and normal BMD as a T-score higher than -1. Established osteoporosis is defined as a T-score less than or equal to -2.5 and the presence of a fragility fracture. Based on these criteria, osteoporosis is present in 30% of all postmenopausal Caucasian women and 70% of those aged 80 years.4

EPIDEMIOLOGY The incidence of osteoporotic fractures increases markedly with age; in women, the median age for Colles fractures is around 65 years and for hip fracture, 80 years. The age at which vertebral fracture incidence reaches a peak is less well defined

but in women is thought to be between 65 and 80 years. In men, no age-related increase in forearm fractures is seen, but hip fracture incidence rises exponentially after the age of 75 years. The prevalence of vertebral fractures rises with age in men, although less steeply than in women.5 During the latter part of the 20th century, increases in the age-adjusted incidence of osteoporotic fractures, mainly hip fracture, were reported in Europe and the United States.6,7 This change was attributed to factors such as reduced physical activity, increased risk of falling, and possibly also changes in hip geometry such as longer hip axis length. Over the past decade, however, stabilization or a decrease in the ageadjusted incidence of osteoporotic fractures has been reported in some countries in the western world (for example Switzerland, Denmark and the United States),8–10 although others have reported an increase (for example Germany and Japan).11,12 These data mainly relate to hip fractures, since the incidence of other fracture types is not documented accurately in most countries. Notwithstanding secular changes in fracture incidence, the number of fractures will continue to rise as the population ages, and in Asia and Latin America, a five-fold increase in fractures is predicted during the next 40 to 50 years. Worldwide, it is estimated that the number of hip fractures will rise from 1.66 million in 1990 to 6.26 million in 2050.13 Geographical variations in the incidence of hip fractures have been reported in Caucasian women, with higher incidence rates in Scandinavia than in other parts of Europe or the United States.14 Within Europe alone, there is a more than tenfold variation in incidence rates for

Department of Medicine, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Box 157, Cambridge CB2 0QQ, UK E-mail address: [email protected] Radiol Clin N Am 48 (2010) 477–482 doi:10.1016/j.rcl.2010.02.010 0033-8389/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

radiologic.theclinics.com

 osteoporosis  Fracture  Bone mineral density  Economic cost  Fracture risk assessment

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Compston reasons that have yet to be clarified.15 Smaller differences in vertebral fractures incidence were noted within Europe in the European Vertebral Osteoporosis Study (EVOS).16 Overall, fracture incidence is higher in white than in black men and women, possibly because of lower BMD, smaller bone size, and greater rates of bone loss in the former. Fracture is a major risk factor for further fractures, an effect that is partially independent of BMD.17 Thus the presence of a prevalent vertebral fracture is associated with a seven- to tenfold increase in the risk of subsequent vertebral fracture,18 and the risk of a new vertebral fracture approaches 20% in the first 12 months after an incident vertebral fracture.19 A fragility fracture at any site is a risk factor for subsequent fracture at the same or other sites; for example, the risk of a hip fracture is increased 1.4-and 2.7-fold in women and men respectively following a distal forearm fracture,20 and the risk of hip fracture increases four- to fivefold in women with a vertebral fracture.21 These observations emphasize the importance of prompt intervention in patients presenting with a fracture to prevent further fractures.

ECONOMIC COSTS The economic costs of osteoporotic fractures include direct costs of hospitalization and aftercare and indirect costs attributable to the impact of fracture on daily life activities including working days. Together, these costs impose a huge financial burden on health care and social services. In the United States, the direct costs of osteoporotic fractures are estimated at around $18 billion annually,22 while in Europe the corresponding figure is around V36 billion.23 In the absence of a significant treatment impact on the global burden of fractures, these costs are set to increase twofold or more by 2050.

HIP FRACTURE The incidence of hip fractures increases exponentially with age in both women and men,24,25 with a female/male ratio of 2:1 to 3:1. Of all osteoporotic fractures, hip fractures have the greatest morbidity and mortality.26,27 They almost always follow a fall, usually backwards or to the side, and require surgical treatment. Because hip fractures characteristically affect frail elderly people, postoperative morbidity and mortality are high. At 6 months after fracture, mortality rates of 12% to 20% have been reported, and only a minority of surviving patients with hip fracture regain their former level of independence, with up to one-third requiring institutionalized care.28 Mortality after hip

fracture is higher in men than in women and increases with increasing age.29,30 The risk of death is highest immediately after the fracture has occurred and decreases gradually thereafter. Most deaths are related to existing comorbidities rather than a direct result of the fracture, reflecting the frailty of this population.

VERTEBRAL FRACTURE Vertebral fractures are the most common of all osteoporotic fractures. The diagnosis of vertebral fracture is based on changes in vertebral shape on standard radiographs or images obtained by dual energy X-ray absorptiometry (DXA). There are several different approaches to the definition of vertebral fracture (see the article by Guglielmi and colleagues elsewhere in this issue for further exploration of this topic), but at present there is no universally adopted gold standard for their diagnosis. Estimates of prevalence and incidence are complicated further by the low proportion of vertebral fractures that come to medical attention (20% to 30%).31 Data from EVOS have demonstrated that the age standardized prevalence in the European population is 12.0% for women and 12.2% for men aged 50 to 79 years.16 The similar prevalence in men and women likely reflects the higher risk of traumatic fractures in younger men; the gradient of increased prevalence with age is steeper in women than in men, with rates of 24% and 18% at age 75 to 79 years, respectively. Prospective data in a US population have shown an overall age-standardized incidence of 10.7 per 1000 person–years in women and 5.7 per person–years in men.32 Vertebral fractures may occur spontaneously or as a result of normal activities such as lifting, bending, and coughing. A minority of vertebral fractures (possibly around one third) present with acute and severe pain at the site of the fracture, often radiating around the thorax or abdomen. The natural history of this pain is variable; in general, there is a tendency for improvement with time, but resolution is often incomplete. Multiple vertebral fractures result in spinal deformity (kyphosis), height loss, and corresponding alterations in body shape with protuberance of the abdomen and loss of normal body contours. These changes commonly are associated with loss of self-confidence and self-esteem, difficulty with daily activities, and increased social isolation.33–36 The clinical impact of vertebral fractures is thus substantial, although often underestimated. Like hip fracture, vertebral fractures are associated with excess mortality mainly as a result of comorbidities. In contrast to hip fracture, however,

Osteoporosis: Social and Economic Impact mortality after vertebral fracture increases with increasing time from fracture. In a study of data from the UK General Practice Research Database, survival in women 12 months after vertebral fracture was 86.5% versus the expected 93.6%, with corresponding figures of 56.5% and 69.9% at 5 years.37

WRIST FRACTURE Fractures of the distal forearm are four times more common in women than in men and show distinct differences in age-related changes in incidence in the two sexes, increasing linearly from age 40 to 65 years and then stabilizing in women and remaining constant in men between ages 20 and 80 years.38 Wrist fractures typically occur after a fall forwards onto the outstretched hand. They cause considerable inconvenience, usually requiring 4 to 6 weeks in plaster, and long-term adverse sequelae occur in up to one third of patients. These include pain, sympathetic algodystrophy, deformity, and functional impairment. Only a minority requires hospitalization.

OTHER NONVERTEBRAL FRACTURES Fractures other than those at the spine, hip, and wrist make an important contribution to the overall morbidity associated with osteoporosis. These include fractures of the humerus, pelvis, ribs, clavicle, and lower leg.

PATHOGENESIS Bone mass increases through childhood and adolescence, due mainly to increases in bone size. Peak bone mass is attained in the third decade of life, and age-related bone loss is believed to start in both men and women around the beginning of the fifth decade; thereafter bone loss continues throughout life.39,40 In women, there is an acceleration of the rate of bone loss around the time of the menopause, the duration of which is poorly characterized but may be 5 to 10 years. Because women have a lower peak bone mass than men, lose bone more rapidly during the menopause, and live longer, they are at higher risk of fractures than men. Bone mass in later life thus depends both on the peak bone mass achieved in early adulthood and on the rate of age-related bone loss. Genetic factors strongly influence peak bone mass, accounting for up to 70% to 80% of its variance.41 Several genes are likely to be involved; these include the collagen type IA1 gene, a polymorphism of which is associated both with low BMD and fracture risk. Other genes that have been associated with increased

risk of osteoporosis and fracture include the osteoprotegerin (OPG) and low-density lipoprotein receptor 5-related (LRP-5) genes.42 Sex hormone status, nutrition, and physical activity also influence peak bone mass. In postmenopausal women, estrogen deficiency is the main cause of menopausal bone loss. In older men, estrogen status also is significantly related to BMD levels, whereas the relationship between age-related bone loss and declining testosterone levels is less prominent.43–45 In elderly patients, vitamin D insufficiency and secondary hyperparathyroidism are common and contribute to agerelated bone loss, particularly in cortical bone.46 Other potential pathogenetic factors include declining levels of physical activity and reduced serum levels of insulin-like growth factor.

ASSESSMENT OF FRACTURE RISK The use of BMD measurements to predict future fracture risk has a high specificity but a low sensitivity, and most postmenopausal women presenting with a fragility fracture have a BMD T-score higher than -2.5.47–51 Recently, the importance of clinical risk factors that affect fracture risk independently of BMD has been recognized. These are shown in Table 1 and are used in the World Health Organization (WHO)-supported FRAX risk algorithm, with or without femoral neck BMD.52,53 FRAX expresses fracture risk as the 10-year probability of hip fracture and of major osteoporotic fracture (hip, wrist, spine, or humerus), from which intervention thresholds can be derived. Countryspecific versions of FRAX are available for several countries. It should be noted that FRAX is designed only for postmenopausal women and men over the age of 40 who have not previously received bone-protective therapy. It uses only ‘‘yes’’ or ‘‘no’’ responses, and so does not take account of dose–responses for several risk factors including previous fracture, glucocorticoid therapy, and smoking. The weighting given to any previous fragility fracture is the same, and prior clinical vertebral fractures, which carry a higher risk than other previous fractures, are not considered separately. Falls are not included in the algorithm. For all these reasons, it is important to exercise clinical judgment when using FRAX to assess fracture risk in clinical practice. Other risk factors for fracture are mediated predominantly through reduction of BMD. These include untreated hypogonadism in men and in women (including aromatase inhibitor and androgen deprivation therapy),54,55 gastrointestinal disease, chronic liver disease, hyperthyroidism,

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Table 1 Risk factors for osteoporosis BMD-independent

BMD-dependent

Age Previous fragility fracture Maternal history of hip fracture Oral glucocorticoid therapy Current smoking Alcohol intake R3 units/day Rheumatoid arthritis BMI %19 kg/m2

Untreated hypogonadism Gastrointestinal disease Endocrine disease Chronic renal disease Chronic liver disease Chronic obstructive pulmonary disease Immobility Drugs (eg, aromatase inhibitors, androgen deprivation therapy, proton pump inhibitors, selective serotonin reuptake inhibitors, thiazolidenediones)

Falls Abbreviations: BMD, bone mineral density; BMI, body mass index.

hyperparathyroidism, immobilization, chronic pulmonary disease, and chronic renal disease. Increased fracture risk also has been reported in association with several medications, including proton pump inhibitors, selective serotonin reuptake inhibitors, and thiazolidenediones.56–60

4. 5. 6.

SUMMARY Osteoporotic fractures are a major cause of morbidity and mortality in older people and impose a huge economic burden on health services. Agerelated bone loss is a universal phenomenon and is related closely to estrogen deficiency, both in men and women; other pathogenetic factors include vitamin D insufficiency and reduced physical activity. Prediction of fracture risk using BMD measurements has high specificity but low sensitivity. Clinical risk factors for fracture that are to some extent independent of BMD enhance fracture risk prediction and are used with or without BMD in the WHO-supported fracture risk algorithm, FRAX, to generate 10-year probabilities of major osteoporotic and hip fractures.

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