Osteoporosis in the European Union: medical management, epidemiology and economic burden

Archives of Osteoporosis, Oct 2013

Summary This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). Introduction Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. Methods The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. Results Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Incident fractures represented 66 % of this cost, long-term fracture care 29 % and pharmacological prevention 5 %. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. Conclusions In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted.

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Osteoporosis in the European Union: medical management, epidemiology and economic burden

E. Hernlund 0 1 3 4 5 6 A. Svedbom 0 1 3 4 5 6 M. Ivergrd 0 1 3 4 5 6 J. Compston 0 1 3 4 5 6 C. Cooper 0 1 3 4 5 6 J. Stenmark 0 1 3 4 5 6 E. V. McCloskey 0 1 3 4 5 6 B. Jnsson 0 1 3 4 5 6 J. A. Kanis 0 1 3 4 5 6 0 C. Cooper MRC Lifecourse Epidemiology Unit, University of Southampton , Southampton, UK 1 J. Compston Department of Medicine, Addenbrooke's Hospital, Cambridge University , Cambridge, UK 2 ) WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School , Beech Hill Road, Sheffield S10 2RX, UK 3 B. Jnsson Stockholm School of Economics , Stockholm, Sweden 4 E. V. McCloskey Academic Unit of Bone Metabolism, Northern General Hospital, University of Sheffield , Sheffield, UK 5 J. Stenmark International Osteoporosis Foundation , Nyon, Switzerland 6 C. Cooper NIHR Musculoskeletal Biomedical Research Unit, Institute of Musculoskeletal Sciences, University of Oxford , Oxford, UK Summary This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). Introduction Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. Methods The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010. - Conclusions In spite of the high social and economic cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by the aging populations, the use of pharmacological interventions to prevent fractures has decreased in recent years, suggesting that a change in healthcare policy is warranted. Table of Contents 1. Introduction to osteoporosis Summary and key messages 1.1 Introduction and aims of the report 1.3 Defining osteoporosis 1.4 Prevalence of osteoporosis 1.5 Defining osteoporotic fracture 1.6 Common osteoporotic fractures 1.6.1 Hip fracture 1.6.2 Vertebral fracture 1.6.3 Distal forearm fracture 1.7 Fracture burden worldwide 1.8 The future burden References 2. Medical innovation and its clinical uptake in the management of osteoporosis Summary and key messages 2.1 Introduction 2.2 Use of BMD 2.2.1 Availability of DXA 2.3 Assessment of fracture risk 2.3.1 Assessment risk with BMD 2.3.2 Clinical risk factors (CRFs) 2.4 FRAX 2.4.1 Utilisation of FRAX 2.5 Treatment of osteoporosis and prevention fracture 2.5.1 General management 2.5.2 Major pharmacological interventions 2.5.3 Future developments in the treatment of osteoporosis 2.5.4 Vertebroplasty and balloon kyphoplasty 2.5.5 Fracture liaison services 2.6 Cost-effectiveness of pharmaceutical interventions 2.7 Adherence, compliance and persistence 2.7.1 Measurements of adherence 2.7.2 Adherence in a real world setting 2.7.3 Adherence and anti-fracture efficacy 2.7.4 Cost-effectiveness and adherence 2.8 National guidelines and reimbursement policies for the management of osteoporosis in the EU 2.8.1 Compliance with guidelines 2.8.2 Imperfect health care practice References Appendix A Literature review of recent adherence literature in the EU 1 Methods 2 Results 2.1 Study characteristics 2.2 Persistence 2.3 Compliance 2.4 Data synthesis 2.5 Determinants and outcomes of adherence in reported studies 3 Discussion References 3. Epidemiology of osteoporosis Summary and key messages 3.1 Epidemiology of osteoporosis and fracture 3.2 Population at risk 3.3 Prevalence of osteoporosis 3.4 Incidence of fractures 3.5 Incidence of hip fractures 3.6 Incidence of vertebral fractures 3.7 Incidence of forearm and other osteoporotic fractures 3.8 Number of incident fractures 3.9 Prior fractures 3.10 Mortality due to fracture 3.11 Deaths due to facture References 4. Burden of fractures Summary and key messages 4.4.5 Cost of osteoporosis up to 2025 excluding QALYs lost 4.4.6 Projection of QALYs lost due to osteoporosis up to 2025 4.4.7 Cost of osteoporosis up to 2025 including QALYs lost References 5. Uptake of osteoporosis treatments Summary and key messages 5.1 Uptake of osteoporosis treatment 5.2 Data and methods 5.3 Pharmacological treatment 5.4 Market shares 5.5 Population coverage 5.6 Uptake of individual treatments 5.6.1 Alendronate 5.6.2 Denosumab 5.6.3 Etidronate 5.6.4 Ibandronate 5.6.5 PTH (1-84) 5.6.6 Raloxifene 5.6.7 Risedronate 5.6.8 Strontium ranelate 5.6.9 Teriparatide 5.7 Patients eligible for treatments and treatment gap 5.8 Proportion of patients treated References List of abbreviations BMD POSSIBLE EU Foreword Osteoporosis, literally porous bone, is a disease characterized by weak bone. It is a major public health problem, affecting hundreds of millions of people worldwide, predominantly postmenopausal women. The main clinical consequence of the disease is bone fractures. It is estimated that one in three women and one in five men over the age of 50 worldwide will sustain an osteoporotic fracture. Hip and spine fractures are the two most serious fracture types, associated with substantial pain and suffering, disability, and even death. As a result, osteoporosis imposes a significant burden on both the individual and society. During the past two decades, a range of medications has become available for the treatment and prevention of osteoporosis. The primary aim of pharmacological therapy is to reduce the risk of osteoporotic fractures. The objective of this report is to review and describe the current burden of osteoporosis and highlight recent advances and ongoing challenges for treatment and prevention of the disease. The report encompasses both epidemiological and health economic aspects of osteoporosis and osteoporotic fractures with a geographic focus on EU27. Projections of the future prevalence of osteoporosis and fracture incidence, the direct and total societal burden of the disease, and the consequences of different intervention strategies receive special attention. The report may serve as a basis for the formulation of healthcare policy concerning osteoporosis in general and the treatment and prevention of osteoporosis in particular. It may also provide guidance regarding the overall healthcare priority of the disease. The report is divided into five chapters: 1. Introduction to osteoporosis This introductory chapter briefly reviews the way in which osteoporosis and the associated fractures are defined, describes the most common osteoporotic fractures, and the extent of the burden worldwide. 2. Medical innovation and its clinical uptake in the management of osteoporosis The second chapter reviews the measurement of bone mineral density, diagnosis of osteoporosis, methods for assessment of fracture risk, the development of interventions that reduce the risk of fractures, practice guidelines, and the cost-effectiveness of osteoporosis treatments. 3. Epidemiology of osteoporosis The third chapter reviews the epidemiology and consequences of osteoporosis and fractures, as well as different approaches for setting intervention thresholds (i.e. at what fracture risk it is appropriate to initiate treatment). 4. Burden of fractures The fourth chapter presents a model estimation of the burden of osteoporosis in the EU27 for 2010. The burden is described in terms of fractures, costs, and QALYs lost. Fracture burden is also projected to the year 2025 based on expected demographic changes. 5. Uptake of osteoporosis treatments The fifth chapter provides a description of the current uptake of osteoporosis treatments, that is, how many patients of those eligible for treatment that actually can be treated in the EU27. International sales data from 2001 and forward were used to analyse international variations in treatment uptake. 1. Introduction to osteoporosis Summary This introductory chapter briefly reviews the way in which osteoporosis and the associated fractures are defined, describes the most common osteoporotic fractures, and the extent of the burden worldwide. The key messages of this chapter are: Osteoporosis is characterized by reduced bone mass and disruption of bone microarchitecture, resulting in increased bone fragility and increased fracture risk. In 1994 and 2008, the WHO published diagnostic criteria for osteoporosis in postmenopausal women based on the T-score for bone mineral density (BMD). Osteoporosis is defined as a value for BMD 2.5 standard deviations (SD) or more below the young female adult mean (T-score less than or equal to 2.5 SD). Based on these diagnostic criteria, approximately 6 % of men and 21 % of women aged 5084 years have osteoporosis affecting 27.6 million men and women in the EU in 2010. The most common osteoporotic fractures are those at the hip, spine, forearm and humerus. At the age of 50 years, the remaining lifetime probability of one of these fractures is 22 % and 46 % in men and women, respectively. There are very large variations in the incidence of osteoporotic fractures between and within countries for reasons that are not known, but are partly associated with economic prosperity. Osteoporosis causes more than 8.9 million fractures annually worldwide and over one-third of all osteoporotic fractures occur in Europe. In Europe osteoporotic fractures account for 2 million disability adjusted life years (DALYs) annually, somewhat more than are accounted for by hypertensive heart disease or rheumatoid arthritis. The number of osteoporotic fractures is rising in many countries. Reasons for this relate in part to the increased longevity of the population. The age- and sex-specific incidence of fracture has also increased in some but not all countries. 1.1 Introduction and aims of the report Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased bone fragility and increased fracture risk [1]. The publication of a World Health Organization (WHO) report on the assessment of fracture risk and its application to screening for postmenopausal osteoporosis in 1994 provided diagnostic criteria for osteoporosis based on the measurement of bone mineral density (BMD) and recognized osteoporosis as an established and well-defined disease that affected more than 75 million people in the United States, Europe and Japan [2]. Osteoporosis represents a major non-communicable disease of today and is set to increase markedly in the future. There is underutilisation of the measures available to combat the disease and there is therefore a need for assessment of best practices in prevention and treatment, since the adoption of these across countries can potentially result in significant reductions in the burden of this disease. This report reviews country-specific information on the application of new technologies in osteoporosis, the epidemiology of fracture, future trends, and the uptake of treatments. The aim is to quantify the burden of osteoporosis in terms of prevalence, fractures, patients at risk, uptake of treatment, mortality and the societal costs in different countries using a common methodology. The countries reviewed comprise member states of the EU. An earlier report reviewed the larger populations of Europe (Spain, Italy, France, Germany and the UK) and Sweden [3]. The present review extends this outreach. The consequences of osteoporosis reside in the fractures that arise. This introduction covers briefly the way in which osteoporosis is defined, describes the most common osteoporotic fractures, and the extent of the burden worldwide shown in current literature. Parts of the introduction have been taken from the earlier report [3] that considered the burden of osteoporosis in the five major EU countries and Sweden where relevant to the context of the present report. 1.2 Measurement of BMD The description of osteoporosis captures the notion that low bone mass is an important component of the risk of fracture, but other abnormalities such as micro-architectural deterioration contribute to skeletal fragility. Ideally, clinical assessment of the skeleton should capture all these determinants of fracture risk, but at present the assessment of bone mass is the only aspect that can be readily measured in clinical practice, and forms the cornerstone for the general management of osteoporosis being used for diagnosis, risk prediction, and monitoring of patients on treatment [2, 4, 5]. BMD is the amount of bone mass per unit volume (volumetric density, g/cm3), or per unit area (areal density, g/cm2), and both can be measured in vivo by densitometric techniques. For the purpose of this report BMD refers to an areal BMD unless otherwise specified. A large variety of techniques is available [2] but the most widely used techniques by far are based on x-ray absorptiometry in bone, particularly dual energy x-ray absorptiometry (DXA). DXA is based on the absorption of x-rays which is very sensitive to the calcium content of tissue, of which bone is the most important fraction. DXA provides a two-dimensional areal value rather than a volumetric density and thus is influenced by bone size as well as true density. The most commonly measured sites are the lumbar spine (L1-L4) and the proximal femur. However, in older people the accuracy of measurements in the lumbar spine may be impaired by scoliosis, vertebral deformity, osteophytes and extraskeletal calcification and the proximal femur is the reference site for diagnosis [5, 6]. Lumbar spine measurements are most widely used to monitor treatment since they are sensitive to treatmentinduced changes. DXA techniques using the lateral view of the spine rather than in the customary postero-anterior projection are increasingly used to detect vertebral fractures [7, 8]. 1.3 Defining osteoporosis The diagnostic criterion for osteoporosis is based on the measurement of BMD [9]. BMD is most often described as a T-score or Zscore, both of which are units of SD. The Z-score describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex (Fig. 1). The T-score describes the number of SDs by which the BMD in an individual differs from the mean value expected in young healthy individuals. The operational definition of osteoporosis is based on the T-score for BMD in women [2, 9] and is defined as a value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to 2.5 SD) as shown in Figure 2. This threshold was originally developed for measurements of BMD at the spine, hip, or forearm. More recently, the operational definition of osteoporosis has been refined by WHO with the femoral neck as the standard measurement site and the use of an international reference standard for the Fig. 1 Schematic diagram showing the mean BMD with SD intervals in women by age and the derivation of Z-scores and T-scores from BMD Fig. 2 The distribution of BMD in young healthy women in SD units and threshold values for osteoporosis and low bone mass calculation of the T-score [6]. The reference population for both men and women is the mean and SD values in young women from the NHANES III study [10]. Thus the diagnostic criterion for men uses the same threshold for BMD as that for women. This arises fortuitously because for any age and BMD at the femoral neck, the risk of hip fracture or a major osteoporotic fracture is approximately the same in men and women [1113]. Note that the use of the T-score threshold is inappropriate in children or adolescents. For the purposes of this report, the term osteoporosis refers to the densitometric criterion outlined above. These considerations should not be taken, however, to infer that the use of other techniques or other sites do not have clinical utility for the management of patients where they have been shown to provide information on fracture risk. It is also relevant to make the distinction between the definition of osteoporosis based on BMD and a clinical diagnosis based on the occurrence of fragility fractures. Finally, it is important to recognise that the presence or absence of osteoporosis based on BMD is not synonymous with an intervention threshold which is more appropriately based on fracture risk rather than on BMD alone. 1.4 Prevalence of osteoporosis Because the distribution of BMD in the young healthy population is normally distributed [14] and bone loss occurs with advancing age, the prevalence of osteoporosis increases with age. The prevalence of osteoporosis in Sweden using the WHO criterion is shown for Swedish men and women in Table 1 [15]. Approximately 6 % of men and 21 % of women aged 5084 years are classified as having osteoporosis. The prevalence of osteoporosis in women over the age of 50 years is 34 times greater than in mencomparable to the difference in lifetime risk of an osteoporotic fracture in men and women. For the purposes of this report, it is assumed that the mean femoral neck BMD is similar across countries at the age of 50 years and so too is the rate of bone loss at the femoral neck with age. The same assumptions have been used elsewhere [3, 16, 17]. The assumptions are consistent with empirical observation in some [5, 1820] but not all studies [2124]. Although differences in the age-dependent BMD (and hence the prevalence of osteoporosis) have been reported between countries, the differences are relatively small [5, 22, 24] and most studies are on limited sample sizes, subject to selection bias, undertaken on a regional rather than national basis and cross-sectional in nature. It is notable that the variations in BMD between populations are substantially less than variations in fracture risk. Indeed, age- and sex-specific risks of hip fracture differ more than 10-fold, even within Europe [2528]. These differences are very much larger than can be accounted for by any differences in BMD between communities. With these caveats, the prevalence of densitometric osteoporosis varies somewhat between member states according to the demography of the population. In men over the age of 50 years the prevalence of osteoporosis varies from 5.9 % (Poland) to 7.2 % (Luxembourg). In women, the rates vary from 19.1 % (Cyprus) to 23.5 % (France). Further details on a country by country basis are given in Chapter 3 and the country-specific reports published as a compendium in this issue of Archives in Osteoporosis. The prevalence of osteoporosis in the EU is estimated at 27.6 million in 2010 (Fig. 3). The extension of this report from the 5 major countries (EU5) to the EU27 increases the proportion of men and women with osteoporosis by 35 %. Fig. 3 The prevalence distribution of osteoporosis in the EU and the 5 countries with the highest populations in 2010 1.5 Defining osteoporotic fracture Osteoporosis is manifested by fractures but the definition of an osteoporotic fracture is not straightforward. Opinions differ concerning the inclusion or exclusion of different sites of fracture in describing osteoporotic fractures. One approach is to consider all fractures from low energy trauma as being osteoporotic. Low energy may variously be defined as a fall from a standing height or less, or trauma that in a healthy individual would not give rise to fracture [29]. This characterization of low trauma indicates that the vast majority of hip and forearm fractures are low energy injuries or fragility fractures [30, 31]. The consideration of low energy has the merit of recognizing the multifactorial causation of fracture, but osteoporotic individuals are more likely to fracture than their normal counterparts following high energy injuries [31]. As might be expected, there is also an imperfect concordance between low energy fractures and those associated with reductions in BMD [32, 33]. The rising incidence of fractures with age does not provide direct evidence for osteoporosis, since a rising incidence of falls could also be a cause. By contrast, a lack of increasing incidence with age is reasonable presumptive evidence that a fracture type is unlikely to be osteoporosis-related. An indirect arbiter of an osteoporotic fracture is the finding of a strong association between the fracture and the risk of classical osteoporotic fractures at other sites. Vertebral fractures, for example, are a very strong risk factor for subsequent hip and vertebral fracture [3438], whereas forearm fractures predict future vertebral and hip fractures [39]. Due to the difficulties of knowing which fractures have been caused by low energy trauma, the approach used in this report and elsewhere is to characterize fracture sites as osteoporotic when they are associated with low bone mass and their incidence rises with age after the age of 50 years [40]. The most common fractures defined in this way are those at the hip, spine and forearm, and humerus but many other fractures after the age of 50 years are related at least in part to low BMD and should be regarded as osteoporotic [32, 4042]. These include fractures of the ribs, tibia (in women, but not including ankle fractures), pelvis and other femoral fractures (Fig. 4). Their neglect underestimates the burden of osteoporosis, particularly in younger individuals. Under this schema, the fracture sites that would be Fig. 4 Hazard ratio and 95 % confidence intervals for osteoporosis as judged by BMD at the hip according to fracture site in women from France [41] excluded are those at the ankle, hands and feet, digits, skull and face. 1.6 Common osteoporotic fractures The most common osteoporotic fractures comprise vertebral fractures, fractures of the forearm (particularly Colles fracture), hip fractures, and proximal humerus fractures [2]. In Sweden, the remaining lifetime risk at the age of 50 years of sustaining a hip fracture is 22.9 % in women and 10.7 % in men. The remaining lifetime risk of a major osteoporotic fracture (clinical spine, hip, forearm or humeral fracture) is 46.4 % in women and 22.4 % in men [43] (Table 2). The vast majority of osteoporotic fractures occur in elderly women [44]. Overall, women have about twice as high a risk of sustaining any fracture than men. However, there are variations between different fracture sites. For example women have about a 5 times higher risk of sustaining a forearm fracture than men but less than twice the risk of sustaining a spine fracture. The reasons for this relate in part to differences in bone density at maturity and in particular to the loss of bone that occurs after the menopause. In addition, women live longer than men and are exposed, therefore, for longer periods to a reduced bone density and other risk factors for osteoporosis or fracture. Men have higher rates of fracture-related mortality than women [45], possibly related to higher rates of comorbidity [46, 47]. Table 2 Remaining lifetime probability of fracture (%) in men and women from Sweden at the ages shown. The risk ratio refers to the female/male probabilities [43] The incidence of fragility fractures increases markedly with age, though the rate of rise with age differs for different fracture outcomes. For this reason, the proportion of fractures at any site also varies with age. This is most evident for forearm and hip fractures [48] (Fig. 5). Thus forearm fractures account for a greater proportion at younger ages than in the elderly. Conversely, hip fractures are rare at the age of 50 years but become the predominant osteoporosis fracture from the age of 75 years. In women, the median age for distal forearm fractures is around 65 years and for hip fracture, 80 years. Thus both the number of fractures and the type of fracture are critically dependent on the age of the populations at risk. Fig. 5 The site specific pattern of osteoporotic fractures between the ages of 5054 and 8589 years in women from Sweden [48] 1.6.1 Hip fracture Hip fracture is the most serious osteoporotic fracture. Most are caused by a fall from the standing position, although they sometimes occur spontaneously [49]. The risk of falling increases with age and is somewhat higher in elderly women than in elderly men. About one-third of elderly individuals fall annually, with the result that 5 % will sustain a fracture and 1 % will suffer a hip fracture [50]. Hip fracture is painful and nearly always necessitates hospitalisation. A hip fracture is a fracture of the proximal femur, either through the femoral cervix (sub-capital or trans-cervical: intra-capsular fracture) or more distally through the trochanteric region (intra-trochanteric: extra-capsular fracture). Trochanteric fractures are more characteristically osteoporotic, and the increase in age-specific and sex-specific risks for hip fracture is greater for trochanteric than for cervical fractures [51]. Trochanteric fractures are also more commonly associated with a prior fragility fracture. Displaced cervical fractures have a high incidence of malunion and osteonecrosis following internal fixation, and the prognosis is improved with hip replacement. Trochanteric hip fractures appear to heal normally after adequate surgical management. Complications may arise because of immobility. The outcome is much poorer where surgery is delayed for more than 2 days. Up to 20 % of patients die in the first year following hip fracture, mostly as a result of serious underlying medical conditions [52, 53] and less than half of survivors regain the level of function that they had prior to hip fracture [54]. Patients with hip fracture often have significant co-morbidities, so that not all deaths associated with hip fracture are due to the hip fracture event. It is estimated that approximately 30 % of deaths are causally related [55]. When this is taken into account, hip fracture causes more deaths than road traffic accidents in Sweden and about the same number as those caused by breast cancer (Table 3). Compared with other fractures, a great deal of information is available on the epidemiology of hip fracture. The reason is that nearly all patients with hip fracture are admitted to hospital and appear on discharge records. In most cases information is also available from surgical records. At most other sites of fracture, a minority of patients are admitted but may attend hospital on an outpatient basis. 1.6.2 Vertebral fracture The vast majority of vertebral fractures are a result of moderate or minimal trauma [56]. The incidence and morbidity of vertebral fractures are not well documented, in part related to the difficulties in defining vertebral fracture, and also because of the non-specific nature of the morbidity occasioned by the disorder (e.g., back pain). Thus, the diagnosis is made on a change in the shape of the vertebral body on x-rays. The deformities that result from osteoporotic fracture are usually classified as a crush fracture (involving compression of the entire vertebral body), a wedge fracture (in which there is anterior or posterior height loss), and biconcavity (where there is relative maintenance of the anterior and posterior heights with central compression of the end-plate regions). A number of morphometric approaches has been developed to quantify the shape of the vertebral body from radiographs of the lateral spine, and this has helped in defining the prevalence and incidence of vertebral fracture. A widely used clinical system is to classify vertebral fractures as mild (2025 % height loss), moderate (2540 % height loss), or severe (>40 % height loss) [57]. A further problem in describing the epidemiology of vertebral fracture is that not all fractures come to clinical attention [5861]. Estimates for the proportion of vertebral deformities that reach primary care attention vary, however, in different countries [58, 6062]. In register studies, the discharge rate for hospitalised vertebral fractures is closely correlated with the discharge rate for hip fracture [59]. In Sweden, approximately 23 % of vertebral deformities come to clinical attention in women, and a somewhat higher proportion in men [60]. A similar proportion has been observed in the placebo wing of multinational intervention studies [63]. For the purpose of this report that deals with the burden of disease, vertebral fractures are defined as those coming to clinical attention (clinical vertebral fractures). Vertebral fractures may give rise to pain, loss of height and progressive curvature of the spine (kyphosis). The consequences of kyphosis include difficulties in performing daily activities and a loss of self-esteem due to the change in body shape. Severe kyphosis also gives rise to respiratory and gastrointestinal disorders. Although vertebral fractures that come to clinical attention are less costly than hip fractures, the morbidity from an acute fracture in the first year is nearly as severe as that due to a hip fracture [64] and is associated with an increase in mortality [65]. Vertebral fractures are also a very strong risk factor for a further fracture at the spine and elsewhere [3436, 66]. 1.6.3 Distal forearm fracture The most common distal forearm fracture is a Colles fracture. This fracture lies within 2.5 cm of the wrist joint Table 3 Causes of death in men and women aged 45 years or more from Sweden [55] margin and is associated with dorsal angulation and displacement of the distal fragment of the radius. It may be accompanied by a fracture of the ulna styloid process. A Smith fracture resulting in ventral angulation usually follows a forcible flexion injury to the wrist and is relatively uncommon in the elderly. The cause of fracture is usually a fall on the outstretched hand [54]. Although fractures of the forearm cause less morbidity than hip fractures, are rarely fatal, and seldom require hospitalisation, the consequences are often underestimated. Fractures are painful and need 46 weeks in plaster. Approximately 1 % of patients with a forearm fracture become dependent as a result of the fracture [67], but nearly half report only fair or poor functional outcome at 6 months [68]. There is a high incidence of algodystrophya syndrome which gives rise to pain, tenderness, stiffness and swelling of the hand, and more rarely to frozen shoulder syndrome [69]. Moreover, the risk of other osteoporotic fractures in later life is also increased after Colles fracture [34, 35, 66]. 1.7 Fracture burden worldwide There is a marked difference in the incidence of hip fracture worldwide and probably in other osteoporotic fractures [28] (Fig. 6). Indeed, the difference in incidence between countries is much greater than the differences in incidence between sexes within a country [26, 27]. The EU comprises countries with some of the highest hip fracture rates which are considered in Chapter 3. Many risk factors for osteoporosis, and in particular for hip fracture have been identified which include a low body mass index (BMI), low calcium intake, reduced sunlight exposure and early menopause. These may have important effects within communities but do not explain differences in risk between communities. The factor which best predicts this is socio-economic prosperity that in turn may be related to low levels of physical activity [70] (Fig. 7). This is plausible, but only a hypothesis. It will be important to determine whether this and other factors are truly responsible for the heterogeneity of fracture risk. If such factors can be identified and are reversible, the primordial prevention of hip fracture in those communities with presently low rates might be feasible and, conversely, primary prevention of hip fracture in communities with high rates might be undertaken. Osteoporosis causes more than 8.9 million fractures annually worldwide (Table 4)approximately 1,000 per hour [48]. Fracture rates are higher in the western world than in other regions so that, despite the lower population, slightly more than one-third of all osteoporotic fractures occur in Europe. Fig. 6 Annual incidence of hip fracture in men and women from selected countries standardized to the world population for 2010 [28]. EU countries are highlighted Fig. 7 Correlation between age standardized incidence of hip fracture in women in different countries and gross domestic product (GDP) per capita [70] Table 4 Number of osteoporotic fractures by site, in men and women aged 50 years or more in 2000, by WHO region [48] aIncludes Australia, China, Japan, New Zealand and the Republic of Korea US, rates have stabilised or even slightly decreased [72, 73]. Reasons for an increase relate in part to the increased longevity of the population, which is occurring both in the developed and developing world. The global burden of osteoporosis can be quantified by DALYs [71]. This integrates the years of life lost due to a fracture and the disability in those that survive. A year lost due to premature mortality is equal to one DALY. If the quality of life is halved by a fracture (1 = death; 0 = perfect health), then a year of life disabled is equal to a DALY of 0.5. In the year 2000 there were an estimated 9 million osteoporotic fractures world-wide of which 1.6 million were at the hip, 1.7 million at the forearm and 1.4 million were clinical vertebral fractures. The total DALYs lost was 5.8 million accounting for 0.83 % of the global burden of non-communicable disease. In Europe osteoporotic fractures account for 2 million DALYs annually, somewhat more than accounted for by hypertensive heart disease and rheumatoid arthritis [48], but less than chronic obstructive pulmonary disease (Fig. 8). With the exception of lung cancer, fractures due to osteoporosis account for more combined deaths and morbidity than any cancer type (Fig. 9). Collectively, osteoporotic fractures account for approximately 1 % of the DALYs attributable to non-communicable diseases in Europe. 1.8 The future burden The frequency of osteoporotic fracture is rising in many countries. In some other countries such as the UK and Fig. 8 Burden of diseases estimated as DALYs in 2002 in Europe for the non-communicable diseases shown [48]. IHD: Ischemic heart disease, COPD: Chronic obstructive pulmonary disease, OA: Osteoarthritis, HD: heart disease, RA: Rheumatoid arthritis, BPH: Benign prostatic hyperplasia Fig. 9 Burden of diseases estimated as DALYs for osteoporosis and specific sites of cancer in 2002 in Europe [48] Improvements in socio-economic prosperity that in turn decrease everyday levels of physical activity may be a factor associated with increasing fracture rates. In Europe, the total population will not increase markedly over the next 25 years, but the proportion accounted for by the elderly will increase by 56 % in men and by 41 % in women. In the developing world, the total population as well as life expectancy of the elderly will increase by more than two-fold over the next 25 years, so that osteoporotic fractures will assume even greater significance for health care planning. For the very elderly, the size of the population aged 85 years or more will increase by 129 % in men and by 73 % in women. These projections are relatively robust in the sense that all individuals who will be elderly in 2035 are already born. There are important differences in demographic shifts between the EU countries. For example, the number of men and women aged 65 years or more will increase by 50.6 % in the EU but the increase ranges from 10.4 % in Bulgaria to 117.3 % in Ireland (Fig. 10). Moreover the economic burden will increase further in the sense that the productive segment of the population to sustain this increase will decrease in size. For example, in 2010 the population aged 2064 years was 307.3 million but will decrease by 9 % to 279.8 million in 2035 [74]. The number of hip fractures has been estimated to more than double over an interval of 50 years assuming no change in age-specific risk [73, 75] but would more than quadruple with rather conservative estimates of the secular trend [73] (Table 5). Fig. 10 Predicted increases in the population (men and women) aged 65 years or more in the EU by country [74] Table 5 Number of hip fractures estimated worldwide for the year 2000 and those projected by demographic changes alone and those assuming additional increases in age- and sex-specific risk [73] Melton LJ, III, Thamer M, Ray NF, Chan JK, Chesnut CH, III, Einhorn TA, Johnston CC, Raisz LG, Silverman SL, Siris ES (1997) Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation. J Bone Miner Res 12:1623 Mackey DC, Lui LY, Cawthon PM, Bauer DC, Nevitt MC, Cauley JA, Hillier TA, Lewis CE, Barrett-Connor E, Cummings SR (2007) High-trauma fractures and low bone mineral density in older women and men. JAMA 298:23812388 exclusion of high trauma fractures may underestimate the prevalence of bone fragility fractures in the community: the Geelong Osteoporosis Study. J Bone Miner Res 13:13371342 Michaelsson K, Weiderpass E, Farahmand BY, Baron JA, Persson PG, Ziden L, Zetterberg C, Ljunghall S (1999) Differences in risk factor patterns between cervical and trochanteric hip fractures. Swedish Hip Fracture Study Group. Osteoporos Int 10:487494 WHO (2003) The burden of musculoskeletal conditions at the start of the new millennium. World Health Organization Tech Rep Ser 919: i-218 (eds) The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge University Press, Cambridge, pp 201246 Cooper C, Cole ZA, Holroyd CR, Earl SC, Harvey NC, Dennison EM, Melton LJ, Cummings SR, Kanis JA (2011) Secular trends in the incidence of hip and other osteoporotic fractures. Osteoporos Int 22:12771288 Gullberg B, Johnell O, Kanis JA (1997) World-wide projections for hip fracture. Osteoporos Int 7:407413 United Nations Department of Economic and Social Affairs Population Division (2011)World Population Prospects test. Data accessed November, 2011. http://esa.un.org/unpd/wpp/unpp/ p2k0data.asp Cooper C, Campion G, Melton LJ, III (1992) Hip fractures in the elderly: a world-wide projection. Osteoporos Int 2:285289 2. Medical innovation and its clinical uptake in the management of osteoporosis In recent years, there has been a number of advances, particularly in the measurement of BMD, diagnosis of osteoporosis, the assessment of fracture risk, the development of interventions that reduce the risk of fractures and the production of practice guidelines. This chapter describes the current state of these aspects in the field of osteoporosis. Also, the costeffectiveness of osteoporosis treatments is addressed. The key messages of this chapter are: BMD forms a cornerstone for the general management of osteoporosis, being used for diagnosis, fracture risk assessment, selection of patients for treatment and monitoring of patients on treatment. There is marked heterogeneity in the availability of DXA in the EU, and most countries have insufficient resources to implement practice guidelines. There is an important distinction to be made between the use of BMD for diagnosis and for fracture risk assessment. Fracture risk assessment is improved by the concurrent consideration of risk factors that operate independently of BMD. FRAX models integrate the weight of clinical risk factors (CRFs) for fracture risk, with or without information on BMD and provide estimates of the probability of fracture. Models are available for 16 member states. Austria, Belgium Denmark, Finland, Hungary and the UK have the highest usage of FRAX. If Denmark is excluded because of exceptionally high uptake, this amounts to an average of 4,800 tests/million of the general population which is within the estimated service requirement for FRAX. The uptake of FRAX is sub-optimal in the majority of EU countries for which models are available. A p p ro v e d p h ar m ac o l o g i c a l i n t e r v e n t i o n s i n c l u d e bisphosphonates, strontium ranelate, raloxifene, denosumab and parathyroid hormone peptides (PTHs). These are widely available but their use is restricted by reimbursement policies. Full or near full reimbursement is available in a minority of member states. In other countries reimbursement is partial or restricted to individuals with a prior fracture or to women only. Some countries that provide reimbursement exclude PTH. Fracture prevention with generic alendronate in women aged 50 years and older at high risk of fracture is costeffective in most Western countries. Other treatments are cost-effective alternatives to no treatment, particularly in patients that cannot take alendronate. Compliance and persistence with treatment for osteoporosis are poor; approximately 50 % of patients do not follow their prescribed treatment regimen and/or discontinue treatment within 1 year. Measures to improve adherence will lead to more avoided fractures and are cost-effective complements to currently available treatments. In all national treatment guidelines a case-finding approach is suggested for patient identification. However, they vary in terms of which risk factors are acknowledged, how fracture risk should be assessed and how BMD measurements should be used. Notwithstanding the availability of guidelines, recommendations in national guidelines are not always implemented. 2.1 Introduction In recent years, there has been a number of advances, particularly in the measurement of BMD, the assessment of fracture risk, the development of interventions that reduce the risk of fractures and the production of practice guidelines. These advances have been extensively reviewed in an earlier report [1] but relevant sections are summarised in the present report to give the report appropriate context. A particular focus of the chapter is to describe the manner in which these advances have been applied in member states. 2.2 Use of BMD The assessment of bone mass forms a cornerstone for the general management of osteoporosis being used for diagnosis, risk prediction, selection of patients for treatment and monitoring of patients on treatment [2]. In addition to categorising individuals as having or not having osteoporosis (Chapter 1), a much more important use of bone mineral measurement is to provide prognostic information of future fracture risk [3, 4]. A further use is as a tool to monitor changes in bone mass in a treated or untreated patient, though this remains a somewhat contentious issue [57]. 2.2.1 Availability of DXA The requirement for assessing and monitoring the treatment of osteoporosis in accordance with practice guidelines has been estimated at 10.6 DXA units per million of the general population [8]. Several surveys have indicated marked heterogeneity in the availability of DXA in the EU [8, 9] and a recent survey, based on Fig. 11 DXA units/million of the general population in 2010 based on sales of DXA in the EU supplied by manufacturers (Kanis J.A. personal communication, 2011) manufacturer sales, confirms this finding (Kanis J.A. personal communication 2011). The survey indicated that about 50 % of countries in the EU had the recommended number of DXA machines for their population. It is important to note that the figures provided do not distinguish machines dedicated in part or in full to clinical research, or machines that lie idle or are underutilised because of lack of funding. It is likely, therefore, that a majority of countries are underresourced in the context of practice guidelines. A further consideration is the uneven geographical location of equipment, which is known to be problematic in Italy, Spain and the UK. This inequity results in long waiting times or long distances to travel or, in many cases, no practical access at all. A recent audit of the IOF [10] (an update of an earlier audit [9]) reported that the average waiting time among the EU countries is 29 days but ranges from 0 to 6 months in different countries. Within countries there may also be a large range in waiting times, in some instances up to 1 year. The median waiting times are shown in Fig. 12. There is no clear relationship between waiting times and the availability of DXA. For example, the average waiting time in Italy is reported to be 83 days, though the availability is high (18.6 machines/million of the general population). Conversely, there is no waiting time in Bulgaria where the provision of DXA is low. The latter observation presumably reflects the fact that the few machines available are only used to service specialised departments and that BMD assessments are unavailable to the vast majority of the population at risk. The disparity between the availability of equipment and waiting time identifies a high heterogeneity in the use of BMD to assess osteoporosis. Reimbursement for DXA scans varies widely between member states both in terms of the criteria required and level of reimbursement awarded but only a minority of countries (11/27) provided full reimbursement under any circumstances in 2008. Since then reimbursement policies have improved and 18 countries offered unconditional reimbursement in 2013 [10] (Table 6). In others, reimbursement or partial reimbursement is limited and usually dependent on physician referral for approved indications, sometimes restricted to criteria that do not satisfy the requirements of good clinical practice. An example is seen in Bulgaria (and incidentally in Switzerland) where reimbursement is only offered if the BMD test turns out to be positive (i.e. shows osteoporosis). The cost of DXA also varies widely (Table 6) and bears little relationship to the wealth of the nation or to the availability of DXA machines. Fig. 12 Average waiting time for a DXA assessment by EU country [10] Table 6 The number and provision of central DXA units available in the EU27 (Data on reimbursement and waiting time [10]) * average of range; adata; ddays 2.3 Assessment of fracture risk Although the diagnosis of the disease relies on the quantitative assessment of BMD, which is a major determinant of bone strength, the clinical significance of osteoporosis lies in the fractures that arise. In this respect, there are some analogies with other multifactorial chronic diseases. For example, hypertension is diagnosed on the basis of blood pressure, whereas an important clinical consequence of hypertension is stroke. Because a variety of non-skeletal factors contributes to fracture risk [4, 28], the diagnosis of osteoporosis by the use of BMD measurements is at the same time an assessment of a risk factor for the clinical outcome of fracture. For these reasons there is a distinction to be made between the use of BMD for diagnosis and for risk assessment. 2.3.1 Assessing risk with BMD The use of bone mass measurements for prognosis depends upon accuracy. Accuracy in this context is the ability of the measurement to predict fracture. As reviewed previously, many prospective population studies indicate that the risk for fracture increases by a factor of 1.5 to 3.0 for each SD decrease in BMD [29]. The ability of BMD to predict fracture is comparable to the use of blood pressure to predict stroke, and significantly better than serum cholesterol to predict myocardial infarction [3, 4]. The highest gradient of risk is found at the hip to predict hip fracture where the fracture risk increases 2.6 fold for each SD decrease in hip BMD. Despite these performance characteristics, it should be recognised that just because BMD is normal, there is no guarantee that a fracture will not occuronly that the risk is lower. Conversely, if BMD is in the osteoporotic range, then fractures are more likely, but not invariable. The principal difficulty is that BMD alone has high specificity but low sensitivity, so that the majority of osteoporotic fractures will occur in individuals with BMD values above the osteoporosis threshold [3034]. The low sensitivity is one of the reasons why widespread population-based screening is not recommended in women at the time of the menopause. factors that operate independently of BMD. A good example is age. The same T-score with the same technique at any one site has a different prognostic significance at different ages [35, 36], indicating that age contributes to risk independently of BMD (Fig. 13). Thus, the consideration of age and BMD together increases the range of risk that can be identified. There are, however, a large number of additional risk factors that provide information on fracture risk independently of both age and BMD. A caveat is that some risk factors may not identify a risk that is amenable to particular treatments, so that the relationship between absolute probability of fracture and reversibility of risk is important [37]. Liability to falls is an appropriate example where the risk of fracture is high, but treatment with agents affecting bone metabolism may have little effect [38]. Over the past few years a series of meta-analyses has been undertaken to identify internationally validated independent CRFs to be used in case finding strategies with or without the use of BMD. These are summarised in Table 7 [39] and form the input to compute fracture probability with FRAX. Detailed considerations of the CRFs used have been recently reviewed [1, 40]. 2.3.2 Clinical risk factors (CRFs) The performance characteristics of the test can, however, be improved by the concurrent consideration of risk Fig. 13 The relationship between BMD at the femoral neck expressed as a T-score and 10-year hip fracture probability in women from Sweden according to age. For any given T-score, the probability of fracture is higher with increasing age [36], with kind permission from Springer Science and Business Media The introduction of generic versions has, as expected, driven prices downwards, albeit by a different extent in different countries. The annual prices of generic alendronate and other medications indicated for osteoporosis are shown in Table 61. The prices differ markedly between the countries, e.g., the yearly price of generic alendronate ranges from 4 in the Netherlands to 327 in Cyprus, and generic risedronate from 19 in Belgium to 514 in Ireland. 5.4 Market shares Data on estimated population-adjusted total sales and market shares, presented as sales of DDDs and in Euros, are shown in Figs. 33 and 34 for the time period 2001 through 2011 (and related to the size of the population). In terms of value, sales increased rapidly from 2001 to 2005; grew at a slower pace until 2008 and thereafter decreased. Over the entire period, the value of sales in the EU27 increased from approximately 344/100 persons aged 50 or above in 2001 to 883 in 2011. In terms of volume (DDDs per 100 personyears aged 50 or above) sales increased almost linearly until 2010 decreased slightly in 2011. The discrepancy between the development of sales in terms of value and volume was predominately driven by the decreased price of generic alendronate. DDDs per 100 personTable 61 Yearly cost () of treatment with respective medications indicated for osteoporosis treatment years and value of sales for each drug and country are presented in the compendium of country specific summaries published concurrently with this report. Estimated sales per product in 2010 measured both as DDDs and in Euros along with market shares are shown in Table 62. A comparison of market shares measured as sales and volume shows a substantially higher market share in terms of volume than in sales for alendronate, reflecting the low price of generic alendronate. Conversely, the effect of high price is seen with PTH and teriparatide, which have higher market shares in sales than in volume. The estimated value of sales per region of the European Union (Northern, Western, Eastern and Southern Europe) for osteoporotic drugs is shown in Figs. 35 to 38. In Northern and Eastern Europe, sales per 100 persons aged 50 years or above were generally lower than the average for EU27, whilst the opposite was observed for countries from Western and Southern Europe. The average cost per DDD by region is presented in Figs. 39 to 42. Across all regions, the average cost per DDD remained stable from 2001 to 2005 and subsequently decreased year on year until 2011. If inflation during these years is taken into account, the decrease would be even more marked. The largest and smallest intra-region variation was observed in Eastern and Southern Europe, respectively. In Western Europe, cost per DDD was comparatively homogenous in 2001 but variation increased thereafter. A similar pattern, albeit less marked, was observed in Northern Europe. Much of the variation seen in the cost per DDD can be explained by the market penetration of generic alendronate. The most notable decrease in cost Years Fig. 35 Estimated annual sales in Northern Europe 20012011 (/100 persons aged 50 years or above) per DDD was observed in the UK (1.64 in 2001 to 0.24 in 2011). 5.5 Population coverage The population coverage estimations are calculated, as described in the Data and Methods section, using the DDDs sold per year adjusted by the proportion of the population over 50 years that could be treated. This estimate is subsequently adjusted for suboptimal compliance. For the European Union in total, there seems to be an increase up until 2008, followed by a subsequent plateau or even a decrease in population coverage. The uptake differs among the regions of the European Union, as is shown in Figs. 43 to 46. Generally, uptake is lower than the average for EU27 in Northern and Eastern Europe (exceptions being Ireland and to some extent Hungary), whilst Western Europe shows Table 62 Estimated sales in EU27 and market shares in 2010 based on IMS Health data Years Fig. 36 Estimated annual sales in Western Europe 20012011 (/100 persons aged 50 years or above) Year Fig. 39 Cost () per DDD in Northern Europe: average for all drugs Years Fig. 37 Estimated annual sales in Eastern Europe 20012011 (/100 persons aged 50 years or above) Year Fig. 40 Cost () per DDD in Western Europe: average for all drugs Cost ( ) per DDD Year Fig. 42 Cost () per DDD in Southern Europe: average for all drugs slightly higher population coverage. There is no country in Southern Europe that has a lower coverage than the EU27 average from 2010. In 2010, the proportion of persons, aged 50 years or more, potentially treated (assuming treatment for 73 % of the year) ranged from approximately 0.5 % in Bulgaria to 9.3 % in Spain. 5.6 Uptake of individual treatments The uptake, measured by DDDs per 100 of the population aged 50 years or more stratified by country, is shown in the figures below. The countries are grouped into four regions as discussed above. 5.6.1 Alendronate The general trend in the EU27 of the uptake of alendronate was an increase from 2001 to approximately 2008, followed by a plateau. A slight decrease was noted in 2011. This is in Year Fig. 44 Estimated proportion (%) of the population 50 years or older treated in Western Europe sharp contrast to statins, for example simvastatin, where after patent expiration the sales in volume more than doubled. In the UK, treatments for hypercholesterolaemia and osteoporosis have been available for a similar time period; simvastatin was introduced in 1989 and etidronate in 1992. Simvastatin and alendronate were the most prescribed products in their drug class prior to the introduction of cheap generic equivalents in 2003 and 2005, respectively. In 2007 there was, however, a 5-fold difference between peak annual drug spend on statins and osteoporosis drugs indicating significantly different levels of clinical activity in these two chronic diseases [24]. There may be several reasons for the observed development. One is that there are fewer incentives to market the product or that better alternatives are available. This seems unlikely given the continued dominance of alendronate in the market and the contraction of the general market. A possible factor may be that persistence has reduced over time, and there is some evidence that generic formulations are associated with a greater frequency of adverse effects and poorer persistence than proprietary formulations [25]. The factor that is likely to have affected the market, particularly the bisphosphonates, is the wide publicity given to rare side effects so that many doctors Year Fig. 46 Estimated proportion (%) of the population 50 years or older treated in Southern Europe and patients are more frightened of the side effects than they are of the disease. The three countries with the highest uptake of alendronate in 2010 were Hungary, Ireland and the UK with approximately 1.68, 1.17 and 1.14 million DDDs per 100 persons aged 50 years or above, respectively. The three countries with the lowest uptake in 2010 were Bulgaria, Lithuania and Slovakia (42, 74 and 75 DDDs per 100 persons aged 50 years or above, respectively). The difference between the country with the highest and the lowest uptake was thus 40-fold. However, it should be noted that sales from Hungary, for example, are not adjusted for parallel trade, which consequently could be a reason for the high numbers estimated for this country. In Northern Europe, Baltic countries were below the average for the EU27 (Fig. 47) whereas Denmark, Ireland and the UK were above the average. Finland showed a three-fold increase in uptake between 2001 and 2006, Year Fig. 48 Uptake of alendronate in Western Europe (DDDs per 100 persons aged 50 years or above) followed by a decrease over the next 5 years, resulting in a below average uptake in 2011. The highest increase in uptake was observed in Denmark. In Western Europe, except for Germany, most countries showed an above average uptake for most of the period (Fig. 48). Uptake in all countries decreased in recent years, so that in 2010, Germany, France and Luxemburg had a below average uptake in 2011. In Eastern Europe, all countries except Hungary had lower uptake than the EU27 average (Fig. 49). The converse was noted for Southern Europe where all countries showed higher uptake than the EU27 average (Fig. 50). Slovenia and Portugal showed a marked decrease in the last few years. 5.6.2 Denosumab The latest drug to be introduced for treatment of osteoporosis was denosumaba monoclonal antibody. It was Fig. 49 Uptake of alendronate in Eastern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 50 Uptake of alendronate in Southern Europe (DDDs/100 persons aged 50 years or above) introduced in 2010, and approved in nine EU countries the same year. In 2011, denosumab was sold in all countries except France, Greece and Portugal. The highest uptake in 2010 was observed in Denmark and Germany with uptakes of 8.4 and 6.4 DDD per 100 persons aged 50 years or above, respectively, and in 2011 in Slovakia (160 DDDs per 100 persons aged 50 years or above) (Fig. 51). 5.6.3 Etidronate In 2011, etidronate was marketed in 11 EU countries. Overall, the uptake decreased markedly from 76 DDDs in 2001 per 100 persons aged 50 years or above to 3 DDDs per 100 persons aged 50 years or above in 2011. The phenomenon likely reflects the availability of new bisphosphonates with more robust evidence for efficacy. Sweden had the highest uptake of the countries in Northern Europe, whilst there was Year Fig. 52 Uptake of etidronate in Northern Europe (DDDs per 100 persons aged 50 years or above) no uptake in Lithuania (Fig. 52). Of the countries in Western Europe, France followed the aggregated estimates for EU27, while there was higher uptake in Germany and the Netherlands and lower uptake than average in the other countries (Fig. 53). In Eastern Europe, etidronate was not marketed after 2005 (Fig. 54). Also in Southern Europe the uptake was low (Fig. 55). This decrease in uptake for etidronate may reflect the superior evidence that alendronate and other pharmacological therapies reduce fracture rates more than etidronate. 5.6.4 Ibandronate Since the first approval of ibandronate for treatment of osteoporosis in 2005, the uptake increased in all countries (except for Sweden where ibandronate is not available for the treatment of osteoporosis) (Figs. 56 59). The highest uptake in 2010 was seen in Spain, Greece and Slovenia (438, 426, and 407 DDDs per Year Fig. 54 Uptake of etidronate in Eastern Europe (DDDs per 100 persons aged 50 years or above) DDDs /100 person-years Year Fig. 57 Uptake of ibandronate in Western Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 55 Uptake of etidronate in Southern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 58 Uptake of ibandronate in Eastern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 60 Uptake of PTH in Northern Europe (DDDs per 100 persons aged 50 years or above) 100 persons aged 50 years or above, respectively). Apart from Sweden, Austria (2.2 DDDs per 100 persons aged 50 years or above), Hungary (15.1 DDDs per 100 persons aged 50 years or above) and Germany (30.6 DDDs per 100 persons aged 50 years or above) show the lowest uptake in 2010. When estimating the uptake of ibandronate, only prescriptions for osteoporosis and not cancer related treatment were considered. 5.6.5 PTH (184) The first sales of PTH were registered in 2006. PTH (184) is the recombinant full-length PTH protein (amino acids 184), in contrast to teriparatide, which comprises the first 34 amino acids of PTH. In 2011, PTH was sold in 16 out of 27 countries in the European Union. In 2010, the highest uptake was observed in Fig. 62 Uptake of PTH in Eastern Europe (DDDs per 100 persons aged 50 years or above) Greece, followed by Denmark and Slovakia (11.2, 4.8. and 4.4 DDDs/100 persons aged 50 years or above, respectively) (Figs. 6063). 5.6.6 Raloxifene In the European Union, the uptake of raloxifene increased from 2001 to 2005 and then decreased continuously. Raloxifene has been shown to increase the risk of venous thromboembolic events when compared to controls. On the other hand, beneficial effects on the risk of breast cancer were seen [26]. The uptake of raloxifene was highest in Spain throughout the time period studied, followed by France and Portugal (232, 202, and 167 DDDs per 100 persons aged 50 years or above, respectively, in 2010). Latvia and Estonia had virtually no uptake of this drug. By region, the uptake was highest in Southern Europe and lowest in Northern and Eastern Europe (Figs. 64 to 67). DDDs /100 person-years Year Fig. 64 Uptake of raloxifene in Northern Europe (DDDs per 100 persons aged 50 years or above) 5.6.7 Risedronate The uptake of risedronate increased rapidly between 2001 and 2006 but has not changed substantially between 2006 and 2010 when studied at the level of the European Union, although a slight downward trend is evident in later years (Figs. 6871). In individual countries, uptake is seen both to increase (e.g., in Slovakia, Spain and Greece) and decrease substantially (e.g., in Austria, Germany and Portugal) over the last 5 years. The highest uptake in 2010 was seen in Spain (715 DDDs per 100 persons aged 50 years or above), Slovakia (606 DDDs per 100 persons aged 50 years or above) and Greece (603 DDDs per 100 persons aged 50 years or above) whilst the lowest was seen in Poland (9.7 DDDs per 100 persons aged 50 years or above), Bulgaria (18.9 DDDs per 100 persons aged 50 years or above) and Denmark (21 DDDs per 100 persons aged 50 years or above). Year Fig. 66 Uptake of raloxifene in Eastern Europe (DDDs per 100 persons aged 50 years or above) 5.6.8 Strontium ranelate Strontium ranelate showed a progressive increase in uptake in the European Union since its introduction on the market in 2004. This was also the case for most individual countries (exceptions being Latvia, Lithuania and Poland). The uptake by region is shown in Figs. 72 to 75. Although there was a continuous increase, most countries showed modest absolute uptake of strontium ranelate. Portugal had the highest increase and level of uptake (263 DDDs per 100 persons aged 50 or above in 2010). In Northern, Eastern and Western Europe, all countries but three had an uptake below the average European uptake. In Southern Europe on the other hand, all countries had an uptake above the European average. 5.6.9 Teriparatide Teriparatide is the more commonly used of the two PTH peptides available for treatment of osteoporosis (i.e., DDDs /100 person-years Year Fig. 68 Uptake of risedronate (DDDs per 100 persons aged 50 years or above) in Northern Europe Year Fig. 71 Uptake of risedronate (DDDs (per 100 persons aged 50 years or above) in Southern Europe Year Fig. 69 Uptake of risedronate (DDDs per 100 persons aged 50 years or above) in Western Europe Year Fig. 72 Uptake of strontium ranelate in Northern Europe (DDDs per 100 persons aged 50 years or above) DDDs /100 person-years Year Fig. 74 Uptake of strontium ranelate in Eastern Europe (DDDs (per 100 persons aged 50 years or above) Fig. 77 Uptake of teriparatide in Western Europe (DDDs per 100 persons aged 50 years or above) DDDs /100 person-years Year Fig. 75 Uptake of strontium ranelate in Southern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 78 Uptake of teriparatide in Eastern Europe (DDDs per 100 persons aged 50 years or above) Fig. 76 Uptake of teriparatide in Northern Europe (DDDs per 100 persons aged 50 years or above) Fig. 79 Uptake of teriparatide in Southern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 80 Uptake of zoledronic acid in Northern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 83 Uptake of zoledronic acid in Southern Europe (DDDs per 100 persons aged 50 years or above) Year Fig. 81 Uptake of zoledronic acid in Western Europe (DDDs per 100 persons aged 50 years or above) teriparatide and PTH). It is sold in all countries of the European Union except in Bulgaria. Even though there has been a steady increase in uptake of teriparatide since its introduction on the market in 2003, the absolute numbers remain low. Up until 2011, sales were highest in Greece (peaking at 54 DDDs per 100 persons aged 50 or above in 2009). In 2011, sales were highest in Spain, estimated at 41 DDDs per 100, persons aged 50 years or above, in 2010. The uptake per region is shown in Figs. 76 to 79. Compared to other regions, Eastern Europe had a low uptake of teriparatide. 5.6.10 Zoledronic acid The uptake of zoledronic acid increased steeply since its approval for osteoporosis in 2005. Note that cancer-related use of zoledronic acid was not included in this analysis. Figures 80 to 83 show uptake of zoledronic acid in Northern, Western, Eastern and Southern Europe, respectively. The pattern of uptake was different with zoledronic acid compared to most other drugs, with highest uptake in Western and Eastern Europe and lowest in Northern and Southern Europe. The individual country with the highest uptake was Belgium, followed by Slovakia (196 and 156 DDDs per 100 persons aged 50 years or above in 2010, respectively). Luxembourg and Estonia had very low uptakes of zoledronic acid. 5.6.11 Summary Overall, these data indicate a decrease in the population coverage in the last 2 years (i.e., the proportion of the population treated at or above the age of 50 years). Also the pattern of drugs prescribed has changed over the 11 years studied (20012011). The population coverage varies substantially between countries. Ireland is the country where the highest proportion of the population over 50 years is treated, followed by Spain and Greece. The high numbers observed for Ireland and Greece could be a result of parallel trade, since the data from IMS Health were not corrected for this factor in these countries. The lowest proportions treated were found in Bulgaria, Romania and the Baltic States. In Bulgaria, 0.5 % of the population above 50 years is treated. This can be compared to population coverage of almost 9 % in Ireland. The uptake of etidronate and raloxifene was observed to decrease over the study period, whereas the uptake of all other treatments was generally observed to increase. As expected, the increase was highest for drugs approved within the study period. In all years of analysis, the drug with the highest uptake was alendronate. As mentioned in the Data and methods section however, all analyses should be interpreted with caution since the original sales data are imperfect. The most disturbing finding is the plateau and downward trend in the number of patients being treated. The Table 63 FRAX 10-year probability (%) of a major osteoporotic fracture in women with a previous fracture (no other clinical risk factors, BMI of 24 kg/m2 and without BMD) Table 64 The proportion (%) of the male population in each age category at or above a probability based fracture threshold *surrogate country used phenomenon is most marked in the case of the bisphosphonates (Fig. 84). As noted above, many doctors and patients are more frightened of the rare but serious side effects than they are of the disease. The substantial difference in prescribing for hypercholesterolaemia and osteoporosis may also arise because of inconsistent approaches to health technology assessment. For example, the 2008 NICE Technology Appraisals [27, 28] on osteoporosis treatments in the UK restricted access to more costly second-line agents other than generic alendronate until BMD was lower, the patient older or they developed more clinical risk factors. This was not the case for second-line statin therapies described in the relevant guidance (NICE TA 94). This inconsistency of recommendations in the two disease areas is surprising given the volume and costs incurred by the prescribing of non-generic statins by the NHS in England compared to that for bone remodelling agents. 5.7 Patients eligible for treatments and treatment gap To estimate the proportion of patients treated out of those eligible for treatment, it is necessary to define an intervention threshold. There are several approaches to estimate intervention thresholds; they have traditionally been estimated on the basis of T-score for BMD with little consideration of cost-effectiveness. This approach is still largely reflected in the guidance in several European countries. Efforts have also been made to develop intervention thresholds in osteoporosis treatment based on costeffectiveness. In Europe, several studies have described the hip fracture probability at or over which treatment becomes cost-effective [2932]. The advent of FRAX (www.shef.ac.uk/FRAX) in 2008 provided a clinical tool for the calculation of fracture probability which can be applied to the development of intervention thresholds [33]. Application of FRAX in Table 65 The proportion (%) of the female population in each age category at or above a probability based fracture threshold *surrogate country used clinical practice provides a tool for determination of the fracture probability at which to intervene. This can be done using two approaches: firstly to translate the current practice in the light of FRAX and justify the thresholds developed by cost-effectiveness analyses or secondly, to determine the fracture probability at which intervention becomes cost-effective. The second approach has been used in North America [34, 35] whereas the former has been favoured in Europe. The UK guidance for the identification of individuals at high fracture risk developed by the NOGG is an example of the translation of former guidance provided by the Royal College of Physicians (RCP) [36, 37] into probability based assessment [37]. The RCP guidance indicates that women with a prior fragility fracture may be considered for intervention without the necessity for a BMD test, and the management of women over the age of 50 years on this basis has been shown to be costeffective [38]. For this reason, the intervention threshold set by NOGG was at the 10-year fracture probability equivalent to women with a prior fragility fracture without knowledge of BMD [36]. Thus, the intervention threshold can be likened to a fracture threshold expressed in terms of fracture probability. The same intervention threshold was applied to men, since the effectiveness of intervention in men is broadly similar to that in women for equivalent risk. This translational approach from existing treatment guidelines is characterised by an intervention threshold that increases progressively with age. The major reason for this is that the source guidelines took little or no account of age. Since age is an important independent factor for fracture risk, the fracture probability of an individual with a prior fracture is higher at the age of 70 years than at the age of 50 years. This age-dependent increase in the intervention threshold is not found when intervention thresholds are derived from health economic analyses alone [37]. The NOGG guideline provides an opportunity to determine the burden of disease in terms of FRAX. In other words, to determine the number of individuals that have a 10-year fracture probability that is equivalent to or exceeds the fracture threshold (i.e., simulation based on the distribution of the risk-score among the cohorts used by WHO to develop FRAX and the epidemiology of fracture and death in each EU country. Tables 64 and 65 show the proportion of men and women with a probability of a major osteoporotic fracture exceeding that of a woman with a previous fracture and no other clinical risk factor, an average BMI and unknown BMD. This proportion, which in this report represents the proportion that could be eligible for treatment, varied between countries and by age and sex. The relative difference between countries was larger in men than in women. Greece and the UK appear to have the highest proportion of women falling above the fracture threshold, whilst the UK shows the lowest proportion of men. This variation across countries is caused by differences in fracture risk between women and men and differences in population prevalence of the risk factors used by FRAX. 0 100 200 300 400 500 600 Fig. 85 Number (in thousands) of men in each age group that have a 10-year probability for osteoporotic fracture above the probability threshold for fracture the age and country specific probability of fracture in a woman with a prior fragility fracture). The 10-year probability of a major osteoporotic fracture of women at the fracture threshold is provided for the countries of the European Union for different ages in Table 63. The fracture thresholds differ between countries due to the differences in fracture risk in the respective countries. For example, the fracture threshold at the age of 87 years ranged from a 10-year probability of 12 % (Bulgaria and Romania) to 46 % (Denmark). Note that FRAX models are not available for Bulgaria, Cyprus, Estonia, Latvia, Luxembourg and Slovenia. For these countries surrogate FRAX models were used (Romania, Malta, Lithuania, Lithuania, Belgium and Hungary, respectively). The surrogate countries were chosen on the likelihood that the fracture rate (and mortality) was similar to that of the index country. The proportion of men and women who exceed the probability threshold for fracture can be computed by Fig. 86 Number (in thousands) of women in each age group that have a 10-year probability for osteoporotic fracture above the probability threshold for fracture All of the countries in the European Union have higher estimates for women that should be treated than the estimates of patients actually treated. The lowest treatment gap is seen for Spain, where sales are high and fracture risks relatively low, with approximately 75 % of the women eligible for treatment potentially treated. Other countries with low treatment gaps are Ireland and Hungary. More detailed data for men and women are shown in Table 66 and Table 67, respectively. For men, the data indicate that the volume of sold osteoporosis drugs would be sufficient to cover treatment for more patients than the number that fall above the fracture threshold in Greece, Luxembourg and the UK. It should be noted, however, that the results from this analysis should be interpreted with some caution since it has been assumed that the distribution of drug use between genders observed in Sweden is valid for all countries. In addition, it is not known how well treatment is targeted to the high risk population. In total in the EU, 1.7 million men out of the 2.9 million men that exceed the risk level are not treated. Corresponding numbers for women are 10.6 million out of 18.4 million women exceeding the fracture threshold. 0 200 400 600 Fig. 87 Estimated number (in thousands) of men treated (blue) and patients eligible for treatment that are not treated (red) in 2010 Combined with UN data on population demography [39], the resulting number of persons with a fracture probability at or above the fracture threshold, and thus here regarded eligible for treatment, is shown for the countries of the European Union in Figs. 85 and 86. 5.8 Proportion of patients treated Figures 87 and 88 show the number of men and women that could be treated for the year 2010 given sales in 2010 and adjusted for suboptimal adherence, compared to the remaining number of persons eligible for treatment according to risks described in the section above. The proportion of patients estimated to be eligible for treatment but not receiving treatment can be viewed as an approximation of the treatment gap. The treatment gap varies between countries, in accordance with different sales of anti-osteoporotic treatments as well as differences in fracture risk between countries. The highest treatment gap for women is noted for Bulgaria and the Baltic states, where less than 15 % of the population eligible for treatment receives an osteoporotic drug. The same countries, with the addition of Romania, also show the highest treatment gap for men. Fig. 88 Estimated number (in thousands) of women treated (blue) and patients eligible for treatment that are not treated (red) in 2010 Table 66 Number of men eligible for treatment, treated and treatment gap in 2010 These analyses suggest that there is wide intercountry variation in the treatment penetration of women with higher risk for osteoporotic fractures. Large treatment gaps are identified in countries with populations of both high and low risks of fracture. The strength of the information based on IMS Health data is that information is available for nearly all EU member states. However, the pattern of use cannot be ascertained, so that it is not possible to determine whether treatment is targeted appropriately to high risk individuals. There are several indicators that suggest that the targeting of treatment is heterogeneous in the EU. Good evidence comes from the Global Longitudinal Study of Osteoporosis in Women (GLOW) which is a general practice based observational cohort study in women aged 55 years or more conducted in 10 countries, including several EU countries [40]. In the EU, there was heterogeneity of treatment uptake between countries with the lowest proportion of women aged 55 years or more treated in the Netherlands (7 %) and the highest in Spain (23 %) (Fig. 89). Although treatment uptake was higher in women at very high risk (a prior hip or spine fracture), a minority (45 %) was receiving treatment in these countries. Again, there was heterogeneity in treatment uptake with a range from 36 % in the Netherlands to 57 % in Italy. Moreover, some low risk women were targeted in all countries. These data demonstrate that a large number of women at high risk of fractures are not receiving treatment, that a substantial number of women at low risk are prescribed treatment and that there are important differences in the uptake of treatment between countries. The differences could not be explained by other clinical risk factors, and the regional difference in probability of treatment thus seems to have little correlation to existing evidence of best practice and cost-effectiveness. Comparing data for Sweden from IMS Health and the Swedish Drug Register and Sales Data To validate the data from IMS Health, a comparison of the data was made with data from the Swedish Prescribed Drug Register. Information on all filled prescriptions outside of the hospital setting are available from 2006 (available on the website of National Board of Health and Welfare [www.sos.se]). The database Table 67 Number of women eligible for treatment, treated and treatment gap in 2010 Proportion treated (%) Belgium France Italy Netherlands Spain UK Europe Fig. 89 Proportion of women, included in the GLOW study, receiving treatment in six EU member states according to category of risk. All women refer to women aged 55 years or more (n=24,249). Low risk comprises women aged less than 75 years with a T-score for BMD in the range of osteopenia, no prior fracture, no maternal hip fracture or osteoporosis (n=1166). High risk refers to women reported to have a BMD measurement in the range of osteoporosis (n=5258). Very high risk comprises women with a previous hip or spine fracture (n=913) [41] contains information on the number of patients filling a prescription, the number of prescriptions and the number of DDDs. Figure 90 shows the number of DDDs of alendronate sold as reported by the Swedish drug registry database and by IMS Health. These numbers correspond well with the data in this report, although IMS Health reports slightly higher numbers (23 %). Fig. 90 DDDs of alendronate sold in Sweden as reported by IMS Health and the Swedish Prescribed Drug Register Fig. 91 DDDs of teriparatide sold in Sweden as reported by IMS Health and the Swedish Prescribed Drug Register Comparison of bisphosphonates used in cancer treatment is not as easily undertaken since only data from IMS Health discriminates the two indications. The sales of teriparatide, on the other hand, show a greater discrepancy between the numbers from the Swedish Prescribed Drug Register and IMS Health, and the trend is reversed with IMS Health data being 1417 % lower than the numbers from the Swedish Prescribed Drug Register (Fig. 91). The reasons for these differences, however small, are not evident, since neither the data from IMS Health nor the Swedish registry data claim to take hospital use into account. Using Swedish data from the National Board of Health and Welfare, it appears that treatment variation could exist Fig. 93 Correlation of hip fracture and prescription rates on county level in women aged 50 years or above in Sweden 2011 within countries as well as between countries, suggesting a lack of evidence based treatment for osteoporosis on the national level: Among the 21 county councils in Sweden, the number of women aged over 50 years per 1,000 who filled at least on prescription of medications used to treat osteoporosis (ATC code M05B) in 2011 ranged from 36 to 63 (Fig. 92) with an average of 48. This variation in prescription rates among counties does not appear to be explained by differences in fracture risk given that there were no significant correlations (r = 0.3 p = 0.9) between prescription and hip fracture rates (ICD-10 code S72) (Fig. 93). Fig. 92 Number of women per (1,000) aged 50 years or above prescribed medication to treat osteoporosis (M05B) Acknowledgments This report has been sponsored by an unrestricted educational grant from the European Federation of Pharmaceutical Industry Associations (EFPIA) and the International Osteoporosis Foundation (IOF). We thank Judy Stenmark who provided the liaison between the two organizations, respectively. We acknowledge the assistance of Helena Johansson and Prof Anders Oden for their help in the calculations of fracture probability. We thank Oskar Strm and Fredrik Borgstrm who were prominent authors of an earlier report covering a similar topic in a sample of EU countries and provided the template for the present report. We also thank Dr Dominique Pierroz and Dr Fina Liu of the IOF for their help in editing the report. The report has been reviewed by the members of the IOF EU Osteoporosis Consultation Panel and the IOF European Parliament Osteoporosis Interest Group, and we are grateful for their local insights on the management of osteoporosis in each country. The report has been reviewed and endorsed by the Committee of Scientific Advisors of the IOF and benefitted from their feedback. Conflicts of interest All authors have received research funding from pharmaceutical companies involved in marketing products for treatment of osteoporosis. Competing interests have been lodged with IOF. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


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Osteoporosis in the European Union: medical management, epidemiology and economic burden, Archives of Osteoporosis, 2013, DOI: 10.1007/s11657-013-0136-1