Fractures are the only important clinical manifestation of osteoporosis. Clinicians should be interested in osteoporosis because these fractures are so common that the majority of their patients will be affected sooner or later. Indeed, the lifetime risk of a hip, spine or forearm fracture has been estimated at 40% in white women aged 50 years and more in the United States and 13% in white men in this age group.57 Most fractures in elderly women are partly caused by low bone mass;90 the lifetime risk of any fracture was recently estimated at 75%.25 It is increasingly recognized that osteoporosis is an important public health problem because of the large size of the affected population and because of the devastating impact of osteoporotic fractures on morbidity and mortality and on social costs. Policy makers also worry that all aspects of the problem will increase with the growing elderly population. There is, however, a growing armamentarium of diagnostic tests and therapeutic options that the informed clinician might employ to reduce the impact of osteoporosis. This review describes the epidemiology of low bone mineral density (BMD) in the population as well as the epidemiology of osteoporotic fractures, which may involve risk factors besides low bone density. The focus here is on differences between osteoporosis of the spine and low bone mass at other skeletal sites and between vertebral fractures and other types of osteoporotic fractures. This background will provide a context for the articles that follow, which describe the diagnosis and treatment of osteoporosis in greater detail.
Using the suggested World Health Organization definition of osteoporosis, a BMD more than 2.5 standard deviations below the mean in young, normal people47 approximately 30% of postmenopausal white women in the United States have osteoporosis of the hip, spine, or forearm according to extrapolation of data from an age-stratified sample of women in Rochester, Minnesota.60 Prevalence rates are lower when bone density is assessed at a single skeletal site; therefore, 16% of postmenopausal women in the sample had osteoporosis of the lumbar spine and a comparable 16% had osteoporosis of the proximal femur. This compares with an estimated prevalence of hip osteoporosis in white women of 21% from the third National Health and Nutrition Examination Survey.54 In data from that study, the prevalence of osteoporosis in the proximal femur was 16% in Hispanic women and only 10% in African-American women in the United States. As shown in Table 1, however, the age-specific prevalence of osteoporosis of the hip or wrist rises more than 10-fold between 50 and 59 years of age and 80 years of age and more, compared with a 4-fold increase in osteoporosis of the spine over this age group. This is because the prevalence of spinal osteoporosis is relatively high soon after menopause because of exponential bone loss from the axial skeleton at menopause.30 In addition, bone loss from the vertebral bodies later in life may be masked by age-related increases in aortic calcification29,100 or, more important, hypertrophic changes in the spine.23,45,56,69,76,80,101
What determines the likelihood that osteoporosis will develop? The risk factors relate to inadequate accumulation of bone mass during growth and development (peak bone mass) and to excessive bone loss thereafter. Peak bone mass is the product of linear growth, which is completed by age 20 years, as well as a period of "consolidation" that may span another 5 to 15 years when mineral accretion continues without appreciable change in skeletal size.79 The risk factors for low peak bone mass are not well quantified, but it is recognized that skeletal size is inherited, accounting in part for the race and gender differences in osteoporosis risk.96 Although there is considerable controversy about the particular genes involved, heritability appears to account for up to 80% of the variation in bone density at a variety of skeletal sites.26,71 However, environmental factors must also play a role, in that it has been shown that increased calcium intake and exercise can augment bone mass in children,44,94 whereas hypogonadism reduces it.17,28 Most of the other risk factors that have been identified during this period of life, including pregnancy, lactation, and oral contraceptive use, have weak or inconsistent effects.58,96,98 In addition to the accelerated phase of bone loss associated with menopause in women, bone loss also results from age-related factors that affect both sexes: decreased renal 1α-hydroxylase activity, reduced calcium absorption from the gut, and secondary hyperparathyroidism.8 Finally, certain medical and surgical conditions produce "secondary" osteoporosis in particular patients.78 These latter factors (e.g., corticosteroid excess, hyperthyroidism, and multiple myeloma) may have particular impact on the spine.50 For example, prolonged steroid therapy at a dose equivalent to 7.5 mg prednisolone per day appears to cause accelerated loss of bone from the axial skeleton, particularly in the first year, and doubles the risk of fracture.24
In the most comprehensive study sampled from four communities in the United States, the determinants of bone density at various skeletal sites were assessed in a large number of white and Asian-American women 65 years of age or more of risk factors in the Study of Osteoporotic Fractures (Table 2). Later age at menopause, estrogen or thiazide use, non-insulin-dependent diabetes, and greater height, weight, strength, and dietary calcium intake were all positively associated with bone mass at the distal radius, whereas advanced age, cigarette smoking, caffeine intake, prior gastric surgery, and maternal history of fracture were all negatively associated.2 Despite the large number of potential risk factors that were assessed, models incorporating all of the independent predictors explained only 20-34% of the variance in bone density at the radius or calcaneus. The determinants of lumbar spine and femoral BMD were recently reported, using this same population.70 In multivariate analyses, greater height and weight, older age at menopause, a history of arthritis, more physical activity, use of alcoholic beverages, diuretic treatment and current estrogen replacement therapy were associated with higher spinal BMD, whereas later age at menarche and a maternal history of fracture were associated with lower levels.70 Increasing age was positively correlated with spinal BMD in these elderly women-again, probably because of hypertrophic changes in the spine.45 The BMD in the femoral neck was positively associated with most of the same protective factors, along with stronger quadriceps, higher calcium intake, and a history of non-insulin-dependent diabetes.70 A maternal history of fracture and a personal history of wrist fracture were associated with low BMD in the femoral neck. Higher age was a risk factor for low BMD in the femoral neck, as it was for low BMD of the radius and calcaneus. In aggregate, these factors accounted for 21% of the variance in BMD in the femoral neck and for 25% of that in the lumbar spine.
Although risk factors can be identified in populations of patients, it is difficult to apply this information in the treatment of individual patients. Slemenda et al identified predictors of bone density at various skeletal sites and then compared predicted values with the results actually observed among 124 perimenopausal women in Indiana.93 The best predictor of BMD in the femoral neck model was 0.79 + (0.001 × height) + (0.0041 × weight) − (0.00018 × cigarette pack-years) − (0.00023 × urinary calcium-creatinine) + (0.00005 × dietary calcium). However, this model correctly classified only 65% of the women whose bone density was in the lowest tertile. The same risk factors were weighted somewhat differently: 0.69 + (0.00099 × height) + (0.0043 × weight) − (0.00046 × cigarette pack-years) − (0.0002 × urinary calcium-creatinine) + (0.00002 × dietary calcium), in a model that correctly identified 61% of the women with low BMD in the lumbar spine (Figure 1). The weightings were different yet again, −1.1 + (0.0075 × height) + (0.0022 × weight) − (0.00044 × cigarette pack-years) + (0.12 × wrist width) − (0.00016 × urinary calcium-creatinine) + (0.00004 × dietary calcium), in a model that correctly classified 68% of women with low bone mineral content at the midradius.93 None of these models accounted for more than 50% of the variance in bone mass, and none are adequate for making clinical decisions about interventions in individual patients, because bone density can be measured directly with less misclassification error.89
Risk of fractures increases with age. Incidence rates for proximal femur fractures increase exponentially with aging in both sexes (Figure 2), reaching approximately 3% per year among white women aged 85 years and over.61 Hip fracture incidence rates in white men at any age are approximately 50% of those in women in data recorded in most studies but, because women live longer, the life-time risk of a hip fracture is approximately 17% in white women from 50 years of age onward compared with only 6% in white men.57 Hip fractures are considerably less frequent among African-Americans, with less difference in age-adjusted rates between African-American men and women compared with their white counterparts; incidence rates among those of Asian ancestry lie between those of whites and blacks.61,92 There is also a substantial excess in women of distal forearm fractures, but the steep rise in incidence begins earlier in life and levels off after approximately age 60 (Figure 2). Consequently, rates in the elderly are less than those of hip fractures. Nonetheless, the lifetime risk of a distal forearm fracture is 16% in white women but only slightly more than 2% in white men.57 Whereas forearm fractures seem to be less frequent in African-American and Asian populations,34,35 the epidemiologic picture is similar.
The incidence of vertebral fractures in white women and white men has a pattern similar to that of hip fractures (Figure 2), but the number of affected people depends on who is counted. Results of a study of clinically diagnosed vertebral fractures in Rochester, Minnesota, showed rapidly rising incidence rates with aging in both sexes.15 Rates rose from less than 0.2 per 1,000 per year in men and women less than 45 years of age to annual rates of 1.3 per 1,000 men and 1.2 per 1,000 women aged 85 years and more. Based on these data, the lifetime risk of a clinically evident vertebral fracture is approximately 16% in white women and 5% in white men.57 The figure in women is comparable with the combined risk in women of breast, ovarian, or endometrial cancer. Because a substantial proportion of vertebral fractures are asymptomatic and never diagnosed,15 these are undoubtedly low estimates. Even so, the overall age- and sex-adjusted annual incidence of vertebral fractures in Rochester-117 per 100,000-was an order of magnitude greater than that documented in results of other similar studies.22 That the true frequency is higher is evidenced by the high prevalence of vertebral fractures recorded in the results of most studies. A radiographic survey of women in Rochester, for example, revealed a rapid rise in prevalence of vertebral fracture with age, affecting more than 50% of the women aged 85 years and over.59 Altogether, 25% of women in Rochester 50 years old and older had one or more vertebral fractures, counting crushed, wedged, or ballooned vertebrae. This rate is consistent with the 20% reported in an Australian population,46 the 21% reported in a random sample of 70-year-old Danish women,42 the 24% documented among elderly white women from the Study of Osteoporotic Fractures27 and the 19% and 26% reported, respectively, in women in Western Europe and Scandinavia from the European Vertebral Osteoporosis Study.67 However, there are substantial differences in the prevalence of vertebral fracture from one country to another.67
The estimated prevalence of vertebral fractures depends entirely on the criteria for diagnosis. Using a morphometric approach,1 Black et al showed that prevalence of fractures in elderly women from the study of osteoporotic fractures varied from a high of 63% when the ratio of vertebral heights (e.g., anterior height divided by posterior height to define a wedge fracture) was more than 2 standard deviations below the mean, down to 25% when a cut-off of 3 standard deviations was used and down to only 12% when the height ratio was 0.8 or less (Figure 3).6 In addition, this approach is sensitive to the normal values that are used, and there is increasing evidence that these may vary from one population to another.51,66,82 Additional variation is introduced by the particular algorithm that is chosen to define a vertebral fracture.7,87 Thus, the prevalence of vertebral fractures in a population of middle-aged English women was only 2% when one method was used, compared with the 10% expected on the basis of prevalence rates reported for Rochester women.97 When the Rochester methods were used to define a vertebral fracture, however, the English rate was a comparable 9%. Methods that yield comparable prevalence rates produce similar correlations between vertebral fracture prevalence and BMD in the lumbar spine, height loss, and chronic back symptoms.7 Semiquantitative readings by a radiologist may produce vertebral fracture prevalence rates that are higher or lower than morphometric readings, depending on the definition of vertebral fracture severity (Grade 1 vs. Grade 2, for example) but there is substantial disagreement between the results of the two approaches when used in individual patients.31
It has long been held that vertebral fractures are uncommon in men so that the female:male ratio greatly exceeds that seen with other osteoporotic fractures. However, results documented in recent population-based studies show an unexpectedly high frequency of vertebral fractures in men.3,15,43,46,52,67,86 For example, the overall female:male ratio of age-adjusted vertebral fracture incidence rates in the Rochester results was only 2:1.15 The sex ratio was 4:1 in the age-group 55 to 64 years, probably accounting for the 4:1 ratio reported among women and men with vertebral fractures referred to metabolic bone disease clinics.77 In the most comprehensive study, the prevalence rate of vertebral fracture prevalence, in European men and women was an identical 20.2% in each group.67 In Rotterdam, the prevalence of Grade 1 vertebral deformities was similar in women and men (7% vs. 8%, respectively) but Grade 2 deformities were more frequent in women than in men (8% vs. 4%, respectively).9 In the European Vertebral Osteoporosis Study, prevalence rates in women were 2% to 7% higher than those in men in Scandinavia, Eastern Europe, and the Mediterranean region but 7% lower in Western Europe.67 In Australia, prevalence of vertebral fracture was approximately 25% higher in men than women.46 Prevalence rates were also higher in men in two surveys of clinic outpatients in North Dakota, ranging from approximately 20% in men 45 to 54 years old to nearly 50% in men 65 years old and older.5 The higher prevalence of vertebral fractures in young and middle-aged men compared with that in women of the same age20,67 may be a reflection of occupationally related vertebral fractures. Farming was the primary occupation of the men from rural North Dakota.
The influence of race is also poorly documented thus far. The prevalence of vertebral fractures among Asians seems to be as high as that in whites,51,85 despite their lower hip fracture rates. For example, hip fracture incidence rates are lower among Japanese women than among Japanese-Americans, whose rates in turn are lower than those of whites.83 In contrast, vertebral fracture prevalence rates were almost twice as high among women in Hiroshima compared with those in Hawaiian women of Japanese descent, but they were 20% to 80% higher than even the rates for white women in Rochester.85 Few data are available for other ethnic groups. There appear to be no studies assessing the influence of other races on vertebral fracture prevalence in unselected people from the general community. Smith and Rizek95 found vertebral fractures in approximately 5% of selected white women 45 years old and older but none in the 137 black women volunteers who were studied in Michigan. More recently, it was shown that hospital discharge rates for vertebral fractures in the United States are approximately four times higher among elderly whites than in African-American men and women.40 Within each race and gender, the age-specific pattern of hospitalization for vertebral fracture was similar to that for hip fracture (Figure 4). Likewise, the prevalence of vertebral fractures is lower among Mexican-American than in non-Hispanic white women,3 as is the risk of hip fracture.61 The sex ratio for Hispanic women and men is approximately 1:1.
Many studies have been conducted in an attempt to identify the factors most closely linked to an increased risk of hip, spine, and forearm fractures, but the results can be best described as inconsistent. It seems clear that falls are more important in the cause of hip and forearm fractures than in spine fractures,62 but the falls that lead to hip and forearm fractures differ.63 In the most comprehensive report, an exhaustive set of potential risk factors on hip fractures, was evaluated in a prospective study of 9516 white and Asian-American women in the United States.19 The independent predictors of hip fracture risk in a multivariate analysis adjusting for age and BMD in the calcaneus included maternal history of hip fracture, weight gain since age 25 (protective), greater height, poorer self-rated health status, history of hyperthyroidism, use of long-acting benzodiazepines, current caffeine intake, more hours of standing each day, inability to rise from a chair, impaired depth perception or contrast sensitivity, and resting heart rate of more than 80 beats/min. Incidence of hip fracture was 17 times higher among 15% of the women who had five or more risk factors in the United States, exclusive of bone density, compared with the women who had two risk factors or less (47% of the total).19 However, women with five or more risk factors had an even higher risk of hip fracture if their bone density z score was in the lowest tertile. In results of a comparable analysis, only low bone density in the distal radius, increased distance walked each week, and earlier age at menopause were independent risk factors for distal forearm fractures in the study of osteoporotic disease.49
Preliminary results from the European Vertebral Osteoporosis Study indicate that age, history of fracture, history of osteoporosis, decreased height and physical activity were associated with vertebral fractures in men and women.41 However, three of these (history of osteoporosis, fracture, loss of height) are manifestations of vertebral osteoporosis per se, and it is known that the presence of a vertebral fracture is a powerful predictor of additional vertebral fractures in the future.81 In results of other studies in men, cigarette smoking, use of alcoholic beverages, and secondary osteoporosis (particularly corticosteroid use, gastrectomy, and hypogonadism) were risk factors for vertebral fracture, whereas obesity was protective.91 In still other results, age, cigarette smoking; and a history of trauma, tuberculosis, or peptic ulcer were associated with fractures of the thoracic spine in men.86 In the European Vertebral Osteoporosis Study, late menarche, early menopause and a corresponding short duration of fertility, low consumption of cheese and yogurt, low physical activity, and family history of hip fracture were additional predictors of vertebral fractures in women.41 Data from more detailed analyses in this study confirmed the increased risk associated with late menarche and early menopause, whereas oral contraceptive use and alcohol consumption reduced the risk of vertebral fractures.21,68 Risk factors of this sort did not predict vertebral fractures among a group of 704 Japanese-American women (Table 3); the lack of specificity was demonstrated by the fact that all of the women had at least two risk factors and 91% had four or more of them.102 Results of a more recent analysis from this group indicate that chronological age, weight, and age at menopause were correlated with spinal BMD (R2 = 0.18); and that after adjusting for BMD, age, and length of the fertile period (years between menarche and menopause), these factors were independent predictors of vertebral fracture.39 However, a risk factor score did not identify vertebral fractures among 1012 women in the United Kingdom.13 A cut-off score selected to assure high sensitivity (91%) had a specificity of only 23%, and most of this modest predictive power was contributed by a history of vertebral fracture.13
The adverse outcomes of osteoporotic fractures encompass mortality, morbidity, and cost. It has been estimated that fractures of the hip, spine, and forearm will result in 2 million person-years of functional impairment among postmenopausal white women in the United States during the next 10 years, along with $45.2 billion in direct medical costs.11 Hip fractures are most important in each adverse outcome. Up to 20% of patients die in the year after hip fracture, representing a 5% to 20% reduction from the survival expected.72 The excess deaths are mainly attributable to serious underlying diseases,55,73 and they diminish with time so that survival does not differ from expected rates 6 to 12 months after the fracture (Figure 5). Only approximately 33% of survivors regain the level of function that they had before the hip fracture.99 It has been estimated that 10% of women who sustain a hip fracture become functionally dependent in the activities of daily living, taking prefracture functional status into account, and that 19% require long-term nursing home care because of the fracture.10 Less than 1% of forearm fracture patients become dependent as a result of the fracture,10 but nearly 50% report only fair or poor functional outcomes at 6 months.48 There is no increased risk of death after distal forearm fractures.16
Although the majority of vertebral fractures are not medically attended but are found incidentally on a radiograph taken for some other purpose,15 acute fractures may be quite painful.64,84 In addition, vertebral fractures in patients aged 65 years or older account for 150,000 hospital admissions in the United States each year,40 along with 161,000 physician office visits and more than 5 million restricted-activity days for those 45 years old and older.37 These fractures may lead to progressive loss of height, kyphosis, postural changes, and persistent pain that interfere with the activities of daily living; but these difficulties are mostly confined to those with severe or multiple vertebral deformities.4,27,38 Thus, among only 10% of elderly women in the Study of Osteoporotic Fractures who had severe vertebral deformities (of 4 standard deviations) was the likelihood of these chronic problems higher than expected.27 Nevertheless, the adverse impact of vertebral fractures on most of the activities of daily living is approximately as great as that seen with hip fractures33 (Table 4). Only 4% of patients with a vertebral fracture become completely dependent because of the fracture,10 but the negative emotional impact of vertebral fractures may be an even more important determinant of reduced quality of life.12,32 There is no early excess of vertebral fracture deaths similar to that seen with hip fractures. Instead, survival appears to worsen with the passage of time (Figure 5), probably as the result of underlying diseases that increase the risk of vertebral fracture and of death.16
Because of the large number of people affected and the expensive and protracted care often required, the total cost of fractures may be as much as $20 billion per year in the United States.74 Direct medical expenditures for osteoporotic fractures alone were estimated at $13.8 billion in 1995.75 As shown in Table 5, the highest expenses were for inpatient and outpatient medical services and nursing home care. Vertebral fractures accounted for just 5% of the total expenditures, whereas care for hip fractures consumed 63%. These costs are likely to rise in the future as the number of elderly people increases. In the United States, the number of people 65 years old and older is expected to rise from 32 million in 1990 to 69 million in 2050, whereas the number 85 years old and older will grow from 3 to 15 million. Because hip fracture incidence rates rise exponentially with aging, the number of hip fractures and their associated costs could double or triple by 2040.18,88 In addition, there is evidence that the incidence of distal forearm fractures, ankle fractures, proximal humerus fractures, proximal tibia fractures, and possibly vertebral fractures is also increasing.4,65 In the United States, hospital discharges for vertebral fractures rose 40% between 1970 and 1980,53 but the relation of this finding to actual secular changes in the incidence of vertebral fracture is unclear, because relatively few patients are hospitalized for such fractures. Results of detailed studies have shown no evidence of an increase in vertebral fracture incidence in more recent years.14,36 Nonetheless, any increase in fracture incidence, other than that attributable to population aging, will increase the number of future fractures still further.
A wealth of new data show that a variety of pathophysiologic mechanisms contribute to the age-related decline in bone density, which leads to an increased likelihood of fracture, the main clinical manifestation of osteoporosis. Although osteoporosis is widely viewed as a major public health concern, the exact magnitude of the problem depends on how the condition is defined. Whether assessed on the basis of the widespread prevalence of low bone mass or the high incidence of age-related fractures, osteoporosis is very common. Therefore, large numbers of people experience the pain, expense, disability, and decreased quality of life caused by osteoporotic fractures. Because of the growing number of elderly people in the population, there will be a dramatic increase in the number of these fractures in coming years. If the high costs associated with osteoporotic fractures are to be reduced, increased attention must be given to the design and implementation of effective control programs.
The author thanks Mary Roberts for help in preparing the manuscript.
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