Fracture risk assessment in postmenopausal women
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- Hamdy, R.C. Rev Endocr Metab Disord (2010) 11: 229. doi:10.1007/s11154-009-9118-4
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Patients with osteoporosis have an increased risk of sustaining fractures because of the low bone mineral density (BMD) and altered bone micro-architecture which are characteristic features of the disease. Although a good correlation exists between BMD and fracture risks, many other factors influence this relationship. While there is consensus that patients with osteoporosis should be investigated and treated, the issue is much less clear for patients with osteopenia. Because osteopenia is so prevalent, it would be unrealistic to treat all patients with this condition. Therefore, there is a need to identify those patients who are at risk of sustaining a fracture and would benefit most from the available therapy. Providing treatment to the appropriate risk group would not only reduce the number of fractures, but could also reduce the adverse effects associated with treatment, as treating patients earlier could shorten the treatment time. The availability of tools to select patients at risk of fracture should change the impact of the disease.
KeywordsFracture risk assessmentFRAX®OsteoporosisTreatment guidelines
Osteoporosis is a silent disease defined as “a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the interaction of two main features: bone density and bone quality .” The diagnosis of osteoporosis can be made either by bone densitometry or by documenting the presence of a low-energy or fragility fracture, i.e., a fracture occurring after a fall from a height not exceeding the body height or after sustaining minimal or no trauma.
Bone densitometry, as determined by Dual Energy X-ray Absorptiometry (DXA), is at present the gold standard for the diagnosis of osteoporosis. During this test, the surface area and the mineral content of the bones scanned are determined. The bone mineral density (BMD) is then calculated by dividing the latter by the former and is compared to 2 reference populations: young healthy adults of the same gender to derive the T-score; and an age- and sex-matched population to derive the Z-score. Some reference bases are also matched for the patient’s ethnic group. The T-scores and Z-scores represent the number of standard deviations of the subject’s BMD from that of the reference population.
The World Health Organization (WHO) guidelines for the diagnosis of osteoporosis are universally accepted: a T-score of −1.0 or higher is normal; a T-score of −2.5 or lower is osteoporosis; and those with T-scores between these two values have osteopenia . This classification is valid only for the BMD of the lumbar vertebrae (PA), femoral neck, total hip, and distal one-third (or 33%) radius by Dual X-ray Absorptiometry (DXA), but cannot be applied to the BMD of peripheral bones such as the phalanges or the calcaneus.
2 BMD and fracture risk
A good correlation exists between BMD and fracture risk. The relationship is exponential, and there are no thresholds. There is very little difference between the fracture risk of a patient with a T-score of −2.4 and another with a T-score of −2.5, even though the former has osteopenia and the latter has osteoporosis. Similarly, the fracture risk of a patient with a T-score of −1.1 is much lower than one with a T-score of −2.4, even they both have osteopenia according to their densitometric diagnostic category. Although there is consensus that patients with osteoporosis should be investigated and treated , the issue is much less clear for patients with osteopenia.
2.1 Why assess the fracture risk?
Osteopenia is so prevalent that it would be unrealistic to treat all patients with this condition . Additionally, such treatment may unnecessarily expose patients to the potential adverse effects of medications, especially if they are treated for prolonged periods. Furthermore, many patients with osteopenia, or even osteoporosis, do not sustain fractures . The risk factors for fractures and for a low bone mass are not the same. There is consequently a need to identify those patients who are at risk of sustaining a fracture and would benefit most from the available therapy .
Estimating the fracture risk and understanding the impact of fractures can help patients, clinicians, and caregivers better understand the severity and significance of the underlying disease. It may also improve the patient’s compliance with the long-term intake of a medication, even though the disease is asymptomatic and no immediate effect will be noticed if a few doses are missed. Targeting these patients for treatment would also ensure better utilization of resources. A number of risk factor assessment tools and algorithms have been developed to estimate the fracture risk [7–14].
2.2 The impact of osteoporotic fractures
Fractures are associated with a significant increase in mortality and morbidity [15–23]. Functional recovery occurs in less than half of the women who sustain an osteoporotic hip fracture; and one year after sustaining the hip fracture, about 25% of the patients reside in long-term care institutions . The outcome is even worse in men [21–23]. Although osteoporotic vertebral fractures are often asymptomatic, and therefore appear to be benign, they too significantly increase the risk of further fractures and are associated with an increased mortality [13, 19]. Once a fragility fracture is sustained, the relative risk of sustaining subsequent fractures also increases significantly [9, 20, 24]. It is therefore important to prevent fractures from occurring. This prevention is now possible with the availability of a number of safe and effective medications that can significantly reduce the risk of fractures.
3 Predicting the fracture risk
3.1 BMD as a predicting factor
The BMD of any bone can be used to predict the fracture risk of another bone. For each standard deviation below the mean (T-score) of any bone, the risk of fracture of any bone is significantly increased [8, 25, 26]. The best predictor of a fracture, however, is the BMD of that bone. For instance the BMD of the hip is the best predictor of the fracture risk of the hip, and the BMD of the vertebrae is the best predictor of vertebral fracture. Based on a formula developed after examining 11 prospective cohort studies which included over 90,000 person-years observation and more than 2,000 fractures; the risk of vertebral fracture can be calculated as: 2.3 T-score of the lumbar vertebrae. For instance, if a patient has a T-score of −2.0 in the lumbar vertebrae, the relative fracture risk for a vertebral fracture is 2.32, or 5.29. Similarly the relative risk of a hip fracture can be calculated as: 2.6 T-score of the hip; and the fracture risk of the radius is calculated as: 1.8 T-score of the radius. These fracture risks are relative risks compared to a population with a normal T-score.
This, however, raises an important question: when calculating the fracture risk, should the patient’s BMD be compared to that of a young healthy adult population, or to an age- and sex-matched population? In other words, should the T-score or the Z-score be used to calculate the relative risk of fracture? Although the T-score is used to establish the patient’s diagnosis; using it to calculate the relative fracture risk compares the patient’s risk to that of a younger population—a proposition that can be difficult to justify. On the other hand, when calculating the relative fracture risk using the Z-score, the patient’s fracture risk is compared to that of an age- and sex-matched population, which can be problematic. Although this may seem a more appropriate comparison, it raises the issue of what constitutes normal aging: does the fact that many older people fall and fracture their hip make repeated falls and fractures part of the normal aging process? Surely not. Perhaps, then, comparing the patient’s BMD to that of a healthy young population using the T-score, rather than comparing the patient’s BMD to an age-matched population using the Z-score, is more appropriate in the permutation of the fracture risk.
Many patients with a low BMD, however, do not sustain fractures : only about 44% of women and 21% of men who have sustained a non-vertebral fracture had densitometric evidence of osteoporosis . Clearly the BMD is not the only factor predisposing to fractures; it takes into account neither the bone architecture nor bone quality. Data from studies with fluoride, for instance, show that the BMD can be significantly increased while the bones simultaneously become more fragile. There is also little correlation between medication-induced increases in BMD and reductions in fracture risk . Several other factors, then, independent of the BMD, affect the overall fracture risk. In order to maximize the benefits of treatment and minimize the potential adverse effects and cost, there is therefore a need to identify patients who are at risk of fractures.
3.2 Other factors affecting the fracture risk
The presence of a previous fracture
A patient who has sustained a fragility fracture, including asymptomatic vertebral deformities, is more likely to sustain further fractures [5, 12, 24, 28–32]. For instance, once a patient has sustained a vertebral fragility fracture, the subsequent risk of another vertebral fracture is increased by a factor of 4.4; that of a hip fracture is increased by a factor of 2.3; and that of a wrist fracture by a factor of 1.4. Similarly, a fragility hip fracture increases the risk of vertebral or hip fracture by factors of 2.5 and 2.3 respectively . Given this increased risk, it is unfortunate that many patients who present with an osteoporotic fracture are not treated for osteoporosis [33, 34], especially as medications are available to reduce the morbidity and mortality associated with osteoporotic fractures [35, 36]. The magnitude of this problem is such that the American Orthopaedic Association has developed the “Own the Bone” initiative to specifically address this issue .
Bone architecture, bone geometry, and bone turnover
Bone architecture is an important determinant of bone strength. The mechanical strength of a vertical rod can be greatly increased by the presence of horizontal supports, and conversely, deprived of such supports, the vertical rod becomes mechanically weaker. Bone trabeculae act in a similar way.
The bone geometry also affects the bone strength . For any given density, a longer hip axis is more likely to fracture than a shorter hip axis. (Fig. 1) Similarly, the more acute the femoral neck angle is, the more efficient it is at dissipating the mechanical impact of the trauma sustained after falling, and subsequently, the less likely it is to fracture. (Fig. 2)
The higher the rate of bone turnover, the more likely the bone is to fracture. For each standard deviation above the normal levels, the risk of fracture is about doubled [5, 12, 39–41]. The impact of bone turnover on fractures is at least of the same magnitude as a decrease in BMD.
Aging is associated with an increased fracture risk independently of the BMD . The aging process itself is associated with a reduction in BMD; in addition, at any given BMD, older individuals are more likely to sustain a fracture than younger individuals [4, 5]. For instance, two postmenopausal women may have exactly the same BMD and T-score, and thus the same relative risk of fracture; yet their absolute fracture risks are totally different because one is 54 years old, whereas the other is 74 years old. Aging is likely to be associated with an altered bone architecture which in turn has a negative impact on the bone strength and increases the risk of fracture.
Several other factors, independently of bone mineral density and architecture, increase the risk of fracture as individuals age. Aging is associated with a reduced muscle mass, a less sensitive sense of equilibrium, impaired postural reflexes, increased sway, and an increased propensity to fall. Furthermore, because of the reduced muscle and fat mass, the mechanical trauma from the fall cannot dissipate to adjacent structures, and the risk of fracture is increased accordingly. Finally, older people are often on a number of medications that may reduce stability, impair postural reflexes, increase sway, cloud the sensorium, and increase the risk of falls and subsequent fractures.
Women tend to have smaller skeletons than men and consequently are more at risk of sustaining fractures than men. The accelerated bone loss that many women experience in the first few years after menopause further increases their fracture risk. And yet, at any given BMD there is no significant gender difference between the fracture risks [42, 43] This has prompted some researchers to postulate that when calculating the T-scores of men, their BMD should be compared to that of a female rather than that of a male reference population. The present ISCD position nevertheless is that when calculating the T-scores, the reference population should be of the same gender as the patient.
Black people tend to have larger skeletons than Caucasians, and as a result their fracture risk is less than that of Caucasians . Hispanics and Caucasians tend to have a similar fracture risk. Although Asians tend to have a smaller bone mass than Caucasians, their fracture risk appears to be less. This is possibly related to differences in the skeletal geometry, such as the hip axis length and the femoral neck angle. It is also possible that different lifestyles affect stability and sway as well as pelvic girdle muscle mass and strength.
Parental history of fragility hip fractures
Body Mass Index (BMI)
A low BMI increases the risk of fractures. For instance, when compared to a BMI of 25 kg/m2, a BMI of 20 kg/m2 almost doubles the risk of hip fracture, and a BMI of 30 kg/m2 reduces the risk of fractures by about 17% . The lower the body weight, the less the bone mass, and the more fragile the skeleton [7, 13, 46, 48, 49].
Cigarette smoking is associated with a reduced bone mass [7, 50, 51]. In addition, cigarette smokers tend to be less active physically than non-smokers, and their dietary intake may not be adequate, especially as far as calcium and vitamin D are concerned. It is also possible that cigarette smoking increases the metabolic degradation of vitamin D. Cigarette smoking during childhood and adolescence may prevent the individual from reaching her peak bone mass, and consequently, when bone loss occurs, the likelihood of the smoker reaching a BMD in the osteoporotic range is increased.
Whereas alcohol intake in moderation, i.e. 2 drinks a day for men and one a day for women, may be associated with an increase in BMD; alcohol abuse is associated with a reduced BMD and an increased risk of fractures [7, 49]. Alcohol may also interact with a number of medications that may cloud the sensorium and dull the patient’s cognitive functions and sense of equilibrium, thus increasing the risk of falls. Those who abuse alcohol are also likely to have repeated falls, which may further increase the risk of fractures.
A number of medications reduce the BMD and increase the risk of fracture [13, 52] some by acting directly on the bones. Others increase fracture risk by acting on bone-regulating factors, like glucocorticoids, which decrease the rate of gastro-intestinal absorption of calcium, increase the rate of renal calcium excretion, stimulate the osteoclasts, inhibit the osteoblasts, and interfere with the hypothalamic-pituitary-gonadal axis, leading to hypogonadism. Some anticonvulsants affect bone metabolism by increasing the rate of hepatic metabolic degradation of vitamin D ; loop diuretics increase the renal calcium ; and an excessive amount of thyroid replacement in patients with hypothyroidism may also lead to a low BMD. A number of other medications are associated with a reduced bone mass.
Many diseases are associated with a reduced BMD . Gastro-intestinal diseases associated with malabsorption may reduce the absorption of calcium or vitamin D, detrimentally affecting the BMD. Similarly, diseases associated with an increased urinary calcium loss may lead to a negative calcium balance and detrimentally affect the BMD. A number of endocrinal diseases are associated with an increased rate of bone resorption, including Cushing’s disease, hyperparathyroidism, and thyroid dysfunction. Other diseases may increase the risk of fracture by increasing the risk of falling, like orthostatic hypotension, diabetes mellitus, transient ischemic attacks, epilepsy, and heart failure.
Impaired perception of the environment
Several factors may impair the patient’s accurate perception of the environment and may increase the risk of fracture by increasing the risk of falls. Impaired vision, including refraction errors, cataract, glaucoma, and macular degeneration, may increase the risk of falls and therefore fractures. Bi-focal eyeglasses also pose a problem, as the area around the feet is perceived through the lower lens, which is meant for reading, and the ground may appear distorted as a result, increasing fall and fracture risk.
Factors extraneous to the patient
A number of factors extraneous to the patient may increase the risk of falls and therefore fractures, including poor or inadequate lighting, excessive glare, trailing electric wires, or other obstacles such as loose carpets, small rugs, and low decorative furniture.
Patients who experience repeated falls are at a higher risk of sustaining fractures than those who do not .
4 Expressing the patient’s fracture risk
The patient’s fracture risk can be calculated for a particular bone (site-specific fracture risk), or for any bone (global fracture risk). The fracture risk can be expressed in different ways.
4.1 Absolute fracture risk
The absolute fracture risk represents the risk of sustaining fractures in a defined population over a defined period of time. For instance, the study conducted by DeLaet and colleagues has shown that in a 65-year old woman with a femoral neck BMD of 0.600 g/cm2, the one-year absolute risk of sustaining a hip fracture is 0.5% . It must be emphasized that in this permutation only two factors are taken into account: the patient’s age and the BMD. Other factors such as other concomitant diseases, medications, or even previous fractures are not taken into account. Hence, the term “absolute” is in a sense misleading, as it is absolute only as far as the age and BMD are concerned, but does not include other risk factors.
4.2 Relative fracture risk
The relative risk is the ratio of the patient’s absolute risk of sustaining a fracture to that of a reference population. The question that arises, however, is which reference population to use. Should that population be a healthy young adult population (such as the one used to calculate the T-score) or should it be an age- and sex-matched population such as the Z-score? The calculation of the relative fracture risk based on the formula derived from the work of Marshall et al has been described earlier in this article .
4.3 Lifetime fracture risk
The lifetime fracture risk estimates the odds of the patient sustaining a fracture during her lifetime; in addition to the BMD and patient’s age, it takes into account the patient’s life expectancy and projected rate of bone loss. Clearly, however, other diseases that may afflict the patient at a future time and thus affect the risk of fractures cannot be included in the permutation, such as strokes which may interfere with the patient’s stability and increase the risk of falls and therefore fractures. In this sense, then, the “lifetime fracture risk” is misleading as it assumes the patient’s condition does not change over her lifetime, a scarcely realistic proposition.
4.4 The fracture risk assessment tool (FRAX®)
On February 21, 2008, the World Health Organization unveiled its FRAX® and made it available free of charge through the internet to all interested parties at www.shef.ac.uk/FRAX. This tool calculates the 10-year probability of sustaining a fracture of the hip or other major osteoporotic fractures. The databases used to develop the FRAX® tool included 59,232 subjects (74% women) and 249,898 person years. There were 957 hip and 3,495 osteoporotic fractures .
Inclusion of the BMD in the FRAX® permutation is optional . This is a cause for concern because it may be tempting to use the FRAX® tool in lieu of DXA scans to preselect those patients who will be investigated or treated. Because of this, some patients who need treatment may be missed, and some patients who do not need treatment may be offered treatment .
At the time of writing this manuscript, the FRAX® permutation is specific for certain countries: Austria, China, France, Germany, Italy, Japan, Spain, Sweden, Switzerland, Turkey, the United Kingdom and the United States . It is likely that as more data become available, other country-specific permutations will be developed. In these days of increased population mobility, however, problems may arise when someone is born and raised in one country but lives in another one. When used for a US population, a different permutation is used for each of the following ethnic groups: Caucasians, African-Americans, Hispanics, and Asians. Again, problems are likely to arise with patients of Native American origin, of mixed ethnic heritage, and those who have been adopted. The FRAX® permutation can be used for both genders, and the age range extends from 40 to 90 years.
A number of limitations of the FRAX® tool have been identified, including the fact that the femoral neck BMD (or total hip in women) is taken into consideration, rather than the lumbar vertebrae BMD; the answers to most risk factors are binary (yes/no); and many other factors predisposing to fractures are not taken into account, such as bone turnover rate; propensity for falling; low daily calcium intake; and medications, apart from corticosteroids . The inability of using the FRAX® tool to follow patients up is also unfortunate .
The FRAX® tool, however, represents a major step forward in the estimation of the fracture risk because in addition to the patient’s BMD, age, and gender, it takes into account a number of other risk factors including: the patient’s ethnic group; body weight; body height; parental history of fragility fractures; personal history of fragility fractures; current cigarette smoking; intake of glucocorticoids; diagnosis of rheumatoid arthritis; alcohol abuse; and secondary osteoporosis. The FRAX® is a work in evolution and is expected to be fine tuned as more data become available.
Based on the FRAX® permutations and cost effectiveness of therapy , the National Osteoporosis Foundation issued guidelines that recommend initiating treatment in patients with osteopenia if the 10-year probability of sustaining a hip fracture or a major osteoporotic fracture meets or exceeds 3% and 20% respectively [3, 58, 59]. The 2003 recommendations to treat patients with osteoporosis have not changed.
The main goal of treating osteoporosis and osteopenia is to reduce the risk of fractures. The prognosis of fractures is so dismal that preventing fractures is of paramount importance. We now have at our disposal medications that can significantly reduce the risk of fractures and reduce mortality. Indeed, it is currently cost effective to treat patients with osteoporosis in order to reduce fractures.
The cost of the medication is affordable, especially as generic preparations are available, and more will be available soon; yet when considering the macro-economics, the treatment of large populations may become prohibitive. Furthermore, although the safety profile of most of medications for osteoporosis is acceptable, no medication is without adverse effects, especially if it has to be given over a very long period of time. The cost and adverse effect profile of the available medications must be balanced against the potential benefits. For this reason, there is a pressing need to identify as early as possible those patients who are particularly at risk of sustaining a fracture and would benefit most from treatment. The earlier this detection occurs, the better the outlook, as it may be possible to prevent a fracture rather than treat one. It also may be possible to administer the medication for shorter periods if treatment is instituted early, thus reducing the overall cost of treatment and at the same time reducing the potential for adverse effects. Unfortunately, as the disease is silent until a fracture occurs, most patients who fracture have not been diagnosed with osteoporosis before the fracture occurs. The availability of tools to select patients at risk of fracture should change the impact of the disease.
I would like to thank Ms. Lindy Russell for her editorial assistance.