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Osteoporotic fracture is associated with considerable morbidity and mortality in women throughout the world. However, significant variation in hip fracture rates among women from different nations have been observed, and are likely to represent a combination of real and apparent differences due to ascertainment bias. Higher rates are observed in Caucasian women, with lowest rates observed in black women and intermediate rates among Asian women. These differences are likely to represent a combination of genetic and environmental differences; for example, among European women, the highest fracture rates are observed in Scandinavian women where vitamin D insufficiency is common. In all groups, an expansion in absolute fracture numbers is anticipated due to demographic changes.
Osteoporosis is a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in the fragility of bone . It represents a major public health problem through its association with low trauma fractures. These fractures increase dramatically with aging and are more frequent in women than men. The most common fracture sites are hip, spine and distal forearm. These fractures are the serious and important outcomes of the condition and lead to severe morbidity and mortality, a significant burden on society in general and a huge impact economically. Osteoporotic fractures alone cost the United States around $17.9 billion per annum and the United Kingdom around £1.7 billion .
This review aims to explore the geographic variation and secular trends of fragility fractures (with a particular emphasis on hip fracture) in postmenopausal women, within the methodological limits of comparing data drawn from different countries, where fracture ascertainment may be influenced by for example ICD coding, or data-bases used. The studies included in this review were identified through a PubMed search that included the key words: osteoporosis, fracture, geographic, variation, women, and epidemiology.
Traditionally, osteoporosis has been defined as a bone mineral density (BMD) value in women of more than 2.5 standard deviations (SD) below the young normal mean , with osteopenia being defined as BMD levels between 1 and 2.5 SD below the young normal mean. However, this definition does not consider any of the micro-architectural changes that may weaken bone independently of any effect on BMD . More recently, in a move to incorporate the strongest risk factors for fracture and to make results more intuitive for patients and clinicians, BMD results can now be incorporated into an assessment of individualized 10-year absolute fracture risk through the WHO FRAX tool . This has the advantage of including risk factors that are partly independent of BMD, such as age and previous fracture, to more accurately predict outcome.
Osteoporosis related fractures are a great healthcare burden, as highlighted by the United States (US) Surgeon General 2004 report . An estimated 10 million Americans over 50 years old have osteoporosis and another 34 million are at risk of the disorder. This is likely to increase to over 14 million in 2020. There are an estimated 1.5 million fragility fractures each year. The lifetime risks for osteoporotic fracture for women aged 50 years and over are 17.5% for hip fracture, 15.6% for clinically diagnosed vertebral fracture and 16% for distal forearm fracture.
The United Kingdom (UK) population fracture risk, based on data from the General Practice Research Database in the United Kingdom , is similar to that in the US. Half of women will have an osteoporotic fracture in their lifetime. The majority of these will be hip, vertebral or wrist fractures. The lifetime risk for hip fracture is 14% for women and rates of radiographic vertebral fracture are somewhere between a quarter and a third. Finally, one in 8 women will suffer a wrist fracture at some point in their life.
Peak bone mass is generally achieved by age 30 years. Thereafter, bone density progressively falls with age and consequently the prevalence of osteoporosis thus increases. While most white women under the age of 50years have normal bone density, by the age of 80 years 27% are osteopenic and 70% are osteoporotic at the hip, lumbar spine or forearm .
Fracture incidence is bimodal. There are peaks in childhood and in the elderly. In young people fractures may follow significant trauma and predominantly affect long bones. In the elderly, in contrast, fractures are typically due to minor or moderate trauma. They usually occur following falls from the standing position, but have been known to occur spontaneously. The incidence of fractures of the hip, vertebrae and wrist is greater in elderly women than in elderly men . Figure 1 shows rates of hip, clinical vertebral, radiographic vertebral and wrist fractures increasing with age.
Hip fracture incidence increases exponentially with age, with about 90% affecting people over 50 years . Worldwide it is estimated that 1.66 million hip fractures occurred in 1990 and includes 1,197,000 fractures in females. The total figure is predicted rise to 6.3 million by 2050 due to an increasing number of elderly people in the population . Above 50 years of age, there is a female to male incidence ratio of around two to one . In the UK, the 10 year risk of hip fracture is 0.3% for a 50 year old woman and 8.7% at the age of 80 years . In addition to increased skeletal fragility observed with aging, the risk of falling also rises with advancing age. The direction of falling is important; a fall laterally onto the hip has a greater likelihood of resulting in a hip fracture than falling forwards . In women aged 40-49, approximately 20% will fall each year. This figure rises to half of women over 85 years, highlighting falls prevention as one important component of fracture prevention .
Most vertebral fractures are asymptomatic. Only about a third of all vertebral deformities noted on radiographs come to medical attention. As a result, in studies using radiographic screening of populations, the incidence of all vertebral deformities has been found to be even higher than that for hip fracture [15,16].
A study carried out in Rochester, MN, showed that the age-adjusted incidence of clinical vertebral fractures in women is almost twice that in men . Data from the EPIDOS study also shows an increased prevalence of vertebral fractures in women with age with figures rising from 19% among women aged 75-79 years to 41.4% among those aged 85 years and older . In the European Vertebral Osteoporosis Study (EVOS), vertebral deformities were noted in around 1 in 20 women aged 50-54 years. While far fewer data are available describing geographic variation in vertebral than hip fracture, findings from the EVOS study will be described later in this review.
Wrist fractures show a pattern of occurrence which differs from that of hip and vertebral fractures. There is an increase in incidence in white women between the ages of 45 and 60 years, followed by a plateau (Figure 1). The plateau with age in women may be explained by mode of falls, which changes with age. Later in life a woman is more likely to fall onto a hip than an outstretched hand as her neuromuscular co-ordination deteriorates.
Proximal humerus, pelvis, proximal tibia and distal femur fracture incidences rise with age, and are linked with low bone density . The incidence of proximal tibia fractures is bimodal with peaks in the young and in the elderly . Very few data are available describing geographic variation in wrist fracture.
Many of those, who sustain a fragility fracture, are left with long term impairment: in the United States about 7% of survivors of all types of fragility fractures have a degree of permanent disability and 8% end up requiring long term nursing home care. Overall, after any type of fracture, a 50 year old US white woman has a 13% chance of experiencing attributable functional decline .
Following a hip fracture patients are at risk of acute complications. These include urinary tract infections, pressure sorts and bronchopneumonia. The degree of functional recovery after hip fracture is age-dependent. Fourteen percent of 50-55 year old patients require nursing home care following discharge from hospital and this figure is more than 50% in those over the age of 90 years . Pre-morbid status is also a strong predictor of outcome. In the US 25% of formerly independent people became at least partially dependent, 50% of those who were dependent pre-fracture were admitted to nursing homes, and those who were already in nursing homes remained there .
Despite only a minority of vertebral fractures coming to clinical attention, they account for around 52,000 hospital admissions in the US and 2,188 in England and Wales each year in patients aged 45 years or over. The major clinical consequences of vertebral fracture are back pain, kyphosis, and height loss . This can be associated with functional loss and lead to depression, loss of self-esteem and social isolation. Participants in the European Prospective Osteoporosis Study (EPOS) with radiologically identified vertebral fracture at baseline had repeat radiographs performed 3 years later. Women who had suffered a further fracture during this period experienced substantial levels of disability with impairment in key physical functions of independent living .
Wrist fractures may impact on some activities such as writing, washing and dressing. Overall few patients are completely disabled, but, after 6 months, half of patients still report poor function. In addition, complications such as reflex sympathetic dystrophy, neuropathies and post-traumatic arthritis are not infrequently seen . There is a shortage of epidemiological studies reporting long term outcome after these fractures, with most studies reporting outcome after different orthopedic procedures to reduce and stabilize fractures.
People who sustained hip or vertebral fractures have increased mortality rates compared to those without fractures. Survival rates 5 years after a hip or vertebral fracture, in Rochester, MN, were found to be approximately 80% of those expected for women of similar age without fractures .
Hip fracture mortality increases with age, and is greater for those with poor pre-fracture functional status and coexisting illnesses . In the US, around 3% of women aged over 50 years die during the initial admission. Mortality rates after hip fracture continue to rise over the subsequent months and peak at one year with a rate of 21% . Studies from the UK show similar rates . The risk of death is greatest immediately after the fracture and decreases gradually over time. The elevated risk has been shown to persist for up to 10 years . In only 25% does the cause of death occur directly due to the fracture itself or resulting complications such as infection, thrombo-embolic disease or surgery ; in the remaining majority it is attributable to coexisting morbidity due to underlying diseases.
The excess mortality after vertebral fracture persists for up to 5 years [25,28]. In the UK General Practice Research Database (GPRD) study, survival at 1 and 5 years post vertebral fracture were 86.5% and 56.5% respectively. These were markedly lower than the expected levels of 93.6% and 69.9% respectively .
The remainder of this review will focus on what is known regarding geographic variation in hip fracture rates among women, and how secular changes in fracture rate vary by region. It is well known that there are considerable variations in fracture rates depending on geographic area and race with lower rates observed in black than in Caucasian or Asian populations. In general people who live in latitudes further from the equator seem to have a higher incidence of fracture. The highest rates of hip fracture are seen in Caucasians living in northern Europe, especially Scandinavians. The rates are intermediate in Asians , China , and Kuwait  and lowest in black populations . Generally, when hip fracture risk is high, there is a propensity for this to be reflected by high levels of other fragility fractures in the same area [34, 35].
Kanis et al  determined the 10-year probability of hip fracture standardized for gender and age in twenty nine separate countries. There were found to be large differences in the 10-year probability of hip fracture between countries. Figure 2 graphically shows the marked variations in hip fracture rates worldwide . There was a greater than 10-fold variation in hip fracture risk between countries, with high rates in Scandanavia and low rates in Africa and South America. The variation is sufficiently large that it cannot be explained by error in case ascertainment or the catchment population .
Variations between estimates of incidence trends throughout the world are summarized in Figure 3 . Incidence rates may vary widely even within the same country and within populations of a given sex and race; geographic variations in fracture rates within countries suggest that environmental factors are important in the pathogenesis of fracture. Typically, however, these differences have not been explained by variation in activity levels, smoking, obesity, alcohol consumption, or migration status . They are likely to represent a combination of genetic and environmental factors that affect peak bone mass, rate of bone loss and propensity to fall. A detailed description of hip fracture rates by region follows.
The US has some of the highest fracture rates in the world. Age standardized incidence of hip fracture has been reported to range from 511 to 553 per 100,000 person-years in women . These rates have plateaued over the last twenty years and in some areas have been observed to decrease. Data from Rochester, MN, suggest that age-adjusted hip fracture incidence rates initially began stabilizing from around 1955  and were falling between 1980 and 2006 . Also in those over 65 years, Bauer et al noted a change in trend in the age adjusted hip fracture incidence over decades . It increased by 9% from 1986 to 1995 and subsequently significantly declined by 24% from 1995 to 2005. The decline corresponded to an increase in bisphosphonate use among participants. The annual mean number of hip fractures per 100,000 person years in this age group was 957.3 for women . When the age-adjusted incidence of hip fractures among white women aged over 65 years, according to their county of residence in the United States, were calculated, rates were found to be higher in the south than the north and in those counties with a larger proportion of the over 65 population below the poverty line .
The difference in hip fracture rates among ethnic minorities in US has also been studied. Zingmond et al reported that in those over 55 years, between 1983 and 2000 the age standardized hip fracture incidence fell by 0.6% per year in non-Hispanic white women . In contrast, in women of Hispanic ethnicity these figures rose by 4.9%. No significant change was reported among black or Asian women. While these observations might be explained by differences in physical activity and risk of nutritional deficits between the populations, an alternative explanation relates to variations in environment during growth and development.
It has been suggested that a birth cohort effect may also be operating in the Framingham Study, a population based cohort studied from 1948 to 1996 . Researchers demonstrated rates of hip fracture 20% and 40% higher among women born from 1901-1910 and from 1911-1920, respectively, compared to those born by 1900. Such an effect has also been reported in European studies and points to etiological factors acting early in the lifecourse [47, 48].
Between 1945 and 1994, age-adjusted incidence rates of distal forearm fracture increased by, on average, 0.5% per year in Rochester, MN . In women, the age-adjusted rate peaked in 1975 and declined thereafter. This is similar to the trends shown for hip fracture in the same population. In contrast to hip and distal forearm fracture, there was no overall increase in clinically ascertained vertebral fracture incidence rates, when evaluated between 1950 and 1989 .
In Canada hip fracture rates are significantly lower than observed in the US. In a population based study in Canada the age standardized incidence of hip fracture per 100,000 person years was 86.4 in women . Overall fracture rates were almost 30% lower in Canadians then in Americans more than 80 years old. Despite the marked differences mentioned above between Canada and the US, trends in hip fracture incidence are similar. Age- and sex-adjusted rates tended to be stable throughout the 80s and early 90s with a gradually increasing decline subsequently [52, 53].
A Mexican study in 2005 estimated the annual rate of hip fracture at 169 per 100,000 person years among women . These rates of hip fracture are lower than US, similar to southern countries in Europe, but significantly higher than in Canada. In contrast to US and Canada, data from Mexico shows an age adjusted incidence increasing by around 1% per year between 2000 and 2006 .
Limited data is available from South American countries. Reira-Espinoza reviewed data from Latin America and reported hip fracture incidence per 100,000 persons that ranged between 263-304 in community studies and 40-362 in hospital based studies .
In Argentina, age and sex standardized incidence of hip fracture per 100,000 person-years among women has been reported to range from 259.6 to 405 [56, 57, 58, 59]. Of environmental factors that may contribute to the differences in hip fracture incidence observed, climate differences between regions, which may lead to differences observed in vitamin D levels of their populations, may be important . Plasma vitamin D levels in the elderly are increased by sun exposure  and vitamin D insufficiency raised fracture risk . Thus lower vitamin D levels in those further from the equator may play a role, as may physical activity; a lower incidence of hip fracture observed in the study among women from a predominantly rural area may represent a more physically active lifestyle. Such an effect was also reported in European studies [63, 64].
In Chile, the incidence of hip fracture at the age of 80 years was one of the lowest reported in the world. The annual mean number of hip fractures per 100,000 person years in this age group was 119 for women. In contrast, in Venezuela this rate was 381 per 100,000 years; and in Argentina 1432 per 100,000 years) . It is important to consider the possibility of ascertainment bias when interpreting fracture rates between countries measured in different studies, where different health reporting systems operate.
There have been a large number of studies looking at incidence rates of hip fracture in Europe. The incidence rates vary in southern and northern Europe, with the highest rates observed in Sweden and Norway and the lowest in France and Switzerland. Figure 4 shows the variation in hip fracture incidence throughout Europe .
Scandinavia has the highest reported hip fracture incidence worldwide. In Oslo, Norway, the reported age standardized annual incidence rate of hip fracture was 1180 per 100,000 in women in 1996-1997 . In those over 80 years, these rates steeply rise to 1665 . Studies from Norway and Sweden have shown a lower bone mass among Scandinavian women compared with other European populations , but this difference does not fully explain the greater fracture rates in these countries. Within central Norway significant differences between rates in rural and urban settings have also been identified .
Epidemiological data from Scandinavian countries indicate that in early studies, dating from the1950’s, there was an increasing hip fracture incidence; these rates appear to have fallen in the last two decades. Studies from Sweden reported an increase in age and sex adjusted incidence of hip fracture between 1965 and1980 and 1950 and 1985 [69, 70]. In Malmo, Sweden between 1992 and 1995 these figures plateaued . Giversen also reported a steep increase in the incidence rate of hip fracture in Viborg county, Denmark, observed between 1987 and 1997 . Similar trends were observed in Finland where the age adjusted hip fracture rate per 100,000 increased from 292 to 467 in women between 1970 and 1997 .
In general, hip fracture rates in southern Europe are lower than in the rest of the continent. In Sienna, Italy, the incidence of hip fracture overall between 1980 and 1991 was 157 per 100,000 persons . In Spain between 1988 and 2002, there were no significant changes in age-adjusted incidence rates among women . Some of the lowest incidence rates in Europe are found in Switzerland and France, with the former having age standardized annual incidence rates of hip fracture per 100,000 of only 346 in women.
In Hungary the reported rates of hip fracture between 1999 and 2003 were 430 per 100,000 in women . During the period studied above rates remained stable. Interestingly in neighboring Austria these figures were higher and rose from 637 to 759 . In the Netherlands, the age-adjusted incidence of hip fracture increased in a linear fashion between 1972 and 1987 . Rates then stabilized and begin to drop . In Germany in women between 40 – 74 years old there was a similar period of stabilization before the rates began to decrease . In those above 75 years however rates continue to increase. The increase was significantly higher in Eastern compared to Western Germany. The potential explanation for the high incidence rate of hip fractures in the oldest age groups might be the lack of a structured nationwide osteoporosis prevention approach in this country.
The incidence of hip fractures in the UK is shown in detail in Figure 5 . A four-fold variation in hip fracture incidence is demonstrated across the region, and although rates tend to be higher in urban areas than rural ones, rates are also low in London. The trends observed in the studies from the UK have shown age-specific rates increasing steadily to a plateau in the 1980s and 1990s [47, 82, 83].
Some data is also available for geographic variation in vertebral fractures among Europeans; the EVOS study showed a 3-fold difference in prevalence of vertebral deformities between countries, with the highest rates again in Scandinavia. The prevalence range between centers was 6.2-20.7% for women. Some of these variations could be explained by body mass index and physical activity levels .
Hip fracture data are available from several areas in Asia and demonstrate considerable variability, with the highest rates observed in Singapore and Hong-Kong and the lowest in central China. Figure 6 shows the variation in hip fracture incidence throughout Asia 
In Singapore, in those above 50 years, age standardized incidence of hip fracture rates between 1991 and 1998 were 402 in women . When these values were compared to those derived in 1965 an increase in age adjusted hip fracture rate of around 1–1.5% per year was reported. Interestingly, there were statistically significant racial differences with the highest rates among Chinese, intermediate in Indians and the lowest in Malays; mean rates of fracture for these women when above 50 years were 410, 361, and 264 per 100.000 person years respectively. Time trends varied between different ethnic groups; an increase in hip fracture rates have been seen in Chinese and Malays, while rates in Indians appear to have decreased. Factors which may be responsible for these racial differences include body weight, physical activity, cigarette smoking, alcohol consumption and nutrition.
In Tottori prefecture, Japan the hip fracture incidence rate per 100,000 person years after the age of 35 was 368 in women . There is limited data available from the Middle East. In Iran, studies using the Iranian Multicenter Study on Accidental Injuries report age-standardized hip fracture incidence rates per 100,000 person years of 164.6 in women . In Kuwait age-standardized rates per 100,000 for hip fractures were 295 among Kuwaiti women, and 374 per 100,000 among expatriates, who predominantly originate from Southeast Asian and Arab countries .
There is a dearth of data from Africa, but those studies available suggest that fragility fracture rates are low. In Cameroon the annual incidence of hip fracture, per 100,000 persons, in women above 35 years was 4.1 . Similar low fractures rates have been reported from Morocco in 2005 . It appears that fracture rates in African counties are much lower than the western population. It is possible that the low rates of fracture documented are due to under-reporting due to a lack of the necessary infrastructure.
In both New Zealand and Australia the fracture incidence rates are comparable to those seen in Europe and North America. In New South Wales, Australia between 1990 and 2000 the age-adjusted rate of hip fractures was reported at around 390 per 100,000 in women . During the period studied the overall rates of fracture remained unchanged. Pelvic fracture data, however, from the same region, showed an increased age-standardized hospitalization rate by around 50% from1988 to 2000 . Another Australian study, analyzing fracture rates in a suburban area to the north west of Sydney between 1989 and 2000 showed that age-adjusted rates of hip fracture were declining . Recent work using the Geelong Osteoporosis Study to examine possible reasons for a falling hip fracture rate among Australian women aged >75 years suggested that increasing adiposity and consequent rise in bone mineral density, and increased uptake of bone-active agents may be possible explanations . Researchers working with the Geelong Osteoporosis Study have also recently demonstrated lower hip fracture rates in rural communities, when compared with urban areas, that could not be accounted for by fracture ascertainment bias . In New Zealand age-adjusted rates for hip fracture increased significantly between 1950 and 1987  before subsequently stabilizing. These overall trends are similar to those in Europe and North America.
Currently about half of all hip fractures among elderly people occur in populations living in Europe and North America; however, hip fractures rates are falling in these populations, with observed decreases much too large to be explained by the use of anti-osteoporotic medication . In Sweden, where traditionally fracture rates have been high, the age-standardised hip fracture incidence has decreased since 1996, more than counteracting the effects of the aging population and resulting in a decline in the annual number of hip fractures during the period 1999-2002 . Current projections suggest that this proportion of hip fractures seen in Europe and North America will fall to around one quarter in 2050, when rapid increases in hip fractures rates will be seen in Asia and Latin America, due to a combination of an aging population and secular trends in fracture rate. Several recent reports have highlighted the observation that the greatest increase in the number of osteoporotic fractures is likely to be in the Middle East, Asia, and Latin America, where life expectancy will increase most over in the coming decades. Variation in fracture rate across nations represents a combination of genetic and environmental factors, many of which remain poorly elucidated. The association between socioeconomic status and fracture, if any, is unclear, but a recent systematic review has suggested that educational attainment was positively associated with bone mineral density among women; further work is clearly needed in this area .
Over the next 5 years, we will see an increase in the knowledge of global epidemiology of osteoporotic fracture; it is to be hoped that much of the new data will come from areas of the world where few studies have been currently performed, including healthcare costs attributable to fracture in these populations; in a recent analysis, patients with osteoporosis-related fractures were found to incur nearly US $10,000 in estimated direct healthcare costs in the 6 months post-fracture, compared with patients with no fracture, in a population identified from a commercially insured population with integrated medical and pharmacy claims . From this research, an accurate picture of the size of the problem affecting all ethnic groups can be obtained, and strategies developed to counteract this for the future.