Perspective on Fracture Risk and Phalangeal Bone Mineral Density

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1 Perspective Article Perspective on Fracture Risk and Phalangeal Bone Mineral Density Richard D. Wasnich, MD, FACP Clinical Professor of Medicine, Hawaii Osteoporosis Center, Honolulu, HI Abstract Current bone mineral density (BMD) represents the composite, cumulative effect of many past and present risk factors, including both genetic and lifestyle influences. Reduced BMD, increasing age, and the presence of pre-existing fractures independently increase the risk of osteoporotic fracture. BMD is the most clinically useful of these indicators. Assessment of phalangeal BMD by dual-energy X-ray absorptiometry (DXA) or radiographic absorptiometry (RA) has been shown to provide long-term value in predicting the risk of both hip and spine fracture. Data from phalangeal BMD measurements may be most valuable to the patient if they are used to compute the patient s remaining lifetime fracture probability (RLFP). Key Words: Absorptiometry; bone density; phalanges; bone mineral content; fracture risk; osteoporosis. Address correspondence to Dr. Richard D. Wasnich, Hawaii Osteoporosis Center, 401 Kamakee Street, Honolulu, HI rdw@medsurf.com Journal of Clinical Densitometry, vol.1, no. 3, , Fall 1998 Copyright 1998 by Humana Press Inc. All rights of any nature whatsoever reserved /98/1: /$10.50 Introduction Osteoporosis is a metabolic bone disease characterized by reduced bone density, increased skeletal fragility, and fracture. Osteoporotic fractures affect the spine, leading to loss of height, kyphosis, chronic back pain, the distal radius (Colles fracture), and the hip. However, as bone density declines, fractures can occur at many skeletal sites. Assessing fracture risk is a major concern in patients with osteoporosis because of the significant morbidity and mortality associated with these fractures. In the US, about 1.5 million fractures are attributable to osteoporosis each year (1). Expenditures for hip fractures alone are estimated at nearly $9 billion each year (2,3). In fact, hip fractures account for more than half of all osteoporosis-related hospital admissions among women 45 yr and older (4). Quantification of bone mineral density (BMD) at both axial and appendicular sites is useful not only to establish the risk of osteoporosis, but also to monitor bone loss rates as a means of determining treatment efficacy. The Consensus Conference on Prophylaxis and Treatment of Osteoporosis concluded that BMD measurement at any skeletal site was useful in estimating an individual s risk of fracture (5). Because of their ease of access and relative lack of surrounding soft tissue that sometimes can complicate BMD measurements, the phalanges may be an especially valuable skeletal site for assessing a patient s BMD. In patients with osteoporosis, the incidence of both hip fracture and vertebral fracture increases exponentially with age. The lifetime risk of a clinically diagnosed hip and vertebral fracture has been estimated to be as high as 17.5% and 15.6%, respectively, in 50-yr-old white women (Table 1) (6). Between the ages of 60 and 90 yr, the apparent incidence of hip frac- 259

2 260 Journal of Clinical Densitometry Volume 1, Number 3 Fall 1998 Table 1. Estimated Lifetime Fracture Risk in 50-Yr- Old White Women a Fracture risk (%) Hip fracture 17.5 Vertebral fracture b 15.6 Distal forearm fracture 16.0 Any of the three 39.7 a Adapted from: Melton et al.(6) b Clinically diagnosed vertebral fracture only. ture increases 50-fold, and that of vertebral fracture roughly 20-fold (7). Major technological advances in BMD measurement have occurred over the past few decades, culminating in current stateof-the-art absorptiometric techniques, such as quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA). QCT measures trabecular bone exclusively, mainly in the axial skeleton; DXA is used for axial and peripheral sites. Axial techniques require more time and typically result in a higher level of radiation exposure than do peripheral site techniques. They are also expensive, and this expense may be a barrier to widespread use in broad-based testing (8). Since peripheral sites are easier to measure and do not require exposing major internal organs to radiation, measurement at these sites may be more feasible for broad based testing (7). Computed digital absorptiometry (CDA) has been shown, in tests with cadavers, to predict bone mineral content accurately and precisely of the middle phalanx. After further clinical testing, CDA may become a new tool that is convenient to use in clinical settings for obtaining rapid, on-site BMD measurements to help assess a patient s risk of osteoporotic fracture (9). However, in order to assess fracture risk accurately, BMD measurements of the phalanges or any other site must be considered in combination with a variety of other factors. Bone Density and the Risk of Fracture Osteoporotic bone is characterized by excessive loss of mineral content with reduction in density per unit volume of bone, and is asymptomatic unless it results in a fracture. Additional structural alterations occur that reduce the mechanical strength of osteoporotic bone and increase the risk of fracture. Vertebral fractures can occur with minimal stress, such as sneezing, bending, or lifting a light object. Patients with multiple vertebral fractures can experience chronic back pain that is made worse by standing. Such patients tend to lose height, and they may develop the characteristic dorsal kyphosis and cervical lordosis known as dowager s hump. Hip fractures are among the most devastating sequelae of osteoporosis. They are often associated with falls. Secondary complications of hip fractures, such as pulmonary thromboembolism or nosocomial infections, may be a source of significant mortality in elderly persons. The age at which bone loss starts is uncertain, but it is generally believed to be during the 30s in both sexes. After reaching peak (adult) bone density, men sustain a small annual loss of bone density that roughly corresponds to the loss of other functions with age (e.g., loss of muscle mass). In fact, age-related decreases in bone mineral content disappear when BMD is adjusted for lean body mass (10,11). The rate of bone density loss in men is low (approx 3 5% decade), which partly explains the relatively low incidence of osteoporotic fractures in men (10). In premenopausal women, the rate of loss of bone is low and probably parallels that in men. Around the time of menopause, however, bone loss accelerates, averaging approx 2% yr over the next 5 to 10 yr. Loss is greatest in the early postmenopausal years and levels off

3 Phalangeal Bone Mineral Density 261 Fig. 1. Schematic representation of the changes in bone mass occurring over a lifetime Adapted with permission from Wasnich (12). Copyright 1997 by Exerpta Medica Inc. thereafter. However, continuing bone loss can still be demonstrated in the eighth and ninth decades. The accelerated postmenopausal bone loss and relatively lower peak bone density partially explain why osteoporosis is much more common in women than in men (10). The changes in bone density that occur over a lifetime suggest several different phases during which bone density measurements have potential utility (Fig. 1) (12). For example, BMD has been shown to be predictive of future fracture risk (13 19). When osteoporosis is suspected, BMD measurement is the single best diagnostic tool, because it helps the clinician estimate fracture risk and identify patients who are candidates for pharmacotherapeutic intervention. The results of prospective studies (17 19) of bone density and fractures indicate a significant, inverse relationship. This relationship, which is independent of age, exists regardless of the measurement method used for all fracture sites, including hip, spine, wrist, and various nonspine sites, including the phalanges. Mussolino et al. found that phalangeal BMD, as measured by photodensitometry (PD) or radiographic absorptiometry (RA), is a significant predictor of future hip fracture risk, and is as useful for predicting hip fracture as BMD measured at the wrist or other appendicular sites with other absorptiometric techniques (8). Assessment of risk factors for osteoporosis helps to elucidate the etiology of the disease and identify individuals at greatest risk of future fractures, who would most benefit from intervention. Increasing age increases fracture risk (with an approximate 50% increase in risk/decade). Age-related phenomena that may contribute to fracture susceptibility include diminished collagen elasticity, quantitative architectural changes in bone, reduced repair of microfractures, and reduced muscle strength (12). Mildto-moderate trauma also contributes to fracture risk (20,21). Current bone den-

4 262 Journal of Clinical Densitometry Volume 1, Number 3 Fall 1998 Fig. 2. Exponential relationship between decreasing bone mass (mean ± SD; mean age, 63.7 yr) and increasing incidence of vertebral fractures. Adapted from Wasnich (18). sity represents the composite, cumulative effect of many risk factors, both past and present, including genetic and lifestyle influences. This may partly explain why certain etiologic risk factors, such as body size, diet, and physical activity, are not strong enough to identify individual patients with either low bone density or high future fracture probability (22). Relative vs Absolute Fracture Risk BMD measurements can help to establish the presence of osteoporosis even in the absence of fractures. Fracture risk increases approx times for every 1.0 standard deviations (SD) an individual s bone density is below the mean peak bone density of healthy 25- to 35-yr-old individuals (13,18). Furthermore, the relationship between decreasing bone density and increasing fracture risk is exponential (Fig. 2) (18). For each 10% decrease in BMD, the fracture risk roughly doubles (10). The World Health Organization (WHO) has established diagnostic criteria for osteoporosis based on BMD measurements for women who have not sustained fragility fractures (10). According to these criteria, the diagnosis of osteoporosis and, consequently, the threshold for therapy, are established by a spinal bone density of more than 2.5 SD below the young adult mean value; in the US, the National Osteoporosis Foundation sets the diagnostic criterion at 2.0 SD. The proportion of patients with a BMD measurement below 2.5 SD of the young adult mean increases exponentially with age (23). Most bone densitometry reports designate relative fracture risk in the form of SD from the normal young adult mean in the form of T-scores. Diagnostic criteria are commonly stated as T-scores, because fracture risk is derived from epidemiologic studies that use this designation as a reference. A danger of the T-score approach is that the patient and/or physician may accept T-scores as being diagnostic of osteoporosis. Clearly, low BMD also can be a secondary manifestation of other conditions, such as hyperparathyroidism and renal hypercalciuria. These disease processes must be excluded by appropriate laboratory tests. The hazards of treating bone density levels rather than the underlying disease processes are apparent. Therapeutic efficacy and cost-effectiveness have not been definitively

5 Phalangeal Bone Mineral Density 263 Fig. 3. Gradient-risk chart showing current relative risk and RLFP on the basis of bone density (T-score) and age. Each age and BMD level are associated with a fracture incidence rate. The cumulative total of these rates represents cumulative fracture incidence (RLFP). Reprinted with permission from Wasnich (25). linked to specific levels of BMD. However, it is important to identify individuals with lesser reductions in bone density, because they also have a greater risk of fracture than individuals with normal bone density (24). A young adult does not have the same current fracture risk as an elderly individual, despite equal levels of reduced BMD, because of the independent effect of age on increasing fracture risk (20). However, because a younger individual s years of exposure to low and declining bone density will be longer than that of an elderly patient, the remaining lifetime fracture probability (RLFP), or absolute risk, is greater in the younger patient with no intervention (25). The RLFP is based on the patient s age and current bone density, and is dependent on variable rates of bone loss and life expectancy. A gradient-risk chart (Fig. 3), showing current and lifetime fracture risk based on age, bone density, and duration of exposure to low bone density, is useful for estimating the expected benefit of therapeutic interventions in terms of fracture reduction (24,25). A diagnosis of osteoporosis that is based on a single risk factor at a single point in time is tenuous. For example, consider a 49-yr-old woman with a T-score of 0.95, which is normal. With many years of future bone loss ahead of her, her RLFP, on average, may be more than 300% (i.e., three fractures). Prevention of bone loss in this individual will be beneficial and may reduce her RLFP by fivefold. Now consider an 80-yr-old woman with a similar T-score, 1.05, which is slightly below the arbitrary threshold for osteopenia. Despite her osteopenic label, this woman is actually in fairly good bone health and has a much lower RLFP of 50%. Our data have shown that the relationship of bone density to absolute fracture risk among men is virtually identical to that in women (26). Therefore, in order to have the same meaning in terms of absolute fracture risk, female reference values would have to be used to calculate male T-scores. An alternative to the use of T-scores would be an estimate of absolute fracture rate, which can be derived directly from the bone density value (Fig. 4). It is also apparent that when the desired outcome is absolute fracture incidence rate, it makes no difference which skeletal site is employed, provided the nature of the BMD/fracture relationship has been established. Phalangeal BMD BMD measurements help clinicians to assess a patient s risk of osteoporotic fracture and determine the appropriate therapeutic approach to prevent such fracture. The phalanges are readily accessible sites for BMD measurements whose accuracy

6 264 Journal of Clinical Densitometry Volume 1, Number 3 Fall 1998 Fig. 4. Vertebral fracture incidence vs BMD levels at three skeletal sites. Correct interpretation of the BMD results renders all BMD measurement sites equal. A vertebral fracture rate of 30/1000 patient yr corresponds to slightly different relative BMD levels (as expressed by T-scores), but all BMD sites yield the same information (e.g., absolute fracture incidence rates). It is incorrect to consecrate one BMD T-score as the gold standard, and to criticize the other sites because they yield different T-scores. is comparable with that obtained from measurements taken at other sites (Fig. 5). Emerging technologies may offer clinicians new diagnostic tools that are convenient to use for obtaining phalangeal BMD measurements rapidly and allow bone density results to be obtained immediately after the test (9). Measurements of phalangeal BMD have been shown in two recent studies (8,27) to provide long-term value in predicting the risk of both hip and spine fracture. The first study is a prospective study of 1579 white women >45 yr of age without previous hip fracture who participated in the first National Health and Nutrition Examination Survey (NHANES I) (7). The study used radiographic absorptiometry, a technique to measure bone density of the phalanges from hand X-ray films. It determines BMD based on the opacity of a bone image and the opacity of an aluminum reference wedge that is also imaged on the X-ray film. Baseline hand radiographs (including an aluminum wedge standard) were available for all women in the study. A total of 49 osteoporotic hip fractures were identified among subjects followed for a mean of 14 yr through The age-adjusted relative risk for hip fracture was 1.6 (95% CI, ) for RA of the second phalanx in the fifth digit of the left hand, and it was 1.7 (95% CI, ) for RA of the radius. This strong predictive association is comparable to that obtained with other forms of BMD measurement. The second study compared the degree of association between several BMD measurement techniques and recent vertebral fracture in a cohort of Japanese-American women (27,28). All bone measurements, from the phalanges and other sites, were significantly associated with vertebral deformation, and the association of RA with recent vertebral fracture compared favorably with the association of DXA and single-energy X-ray absorptiometry (SXA) measurements and recent vertebral fracture (Table 2). To validate the observation that measurement of the phalanges by RA correlates well with measurements of BMD by DXA and SXA at a variety of skeletal sites, a comparative study was performed in a random subgroup of 308 women from the multicenter Early Postmenopausal Interventional Cohort (EPIC) study (29). In this analysis, BMD measurements obtained from the phalanges by RA were compared to those obtained from SXA of the distal forearm and DXA of the lumbar spine, proximal femur, and distal forearm. The precision error was 1.5% for RA of the phalanges and in the range % for SXA and DXA. BMD measurements of the phalanges by RA correlated highly with those obtained by SXA and DXA (0.45 < r < 0.72, p < 0.001).

7 Phalangeal Bone Mineral Density 265 Table 2. Associations of Current Bone Density Measurements with Recent Vertebral Deformities a Measurement Odds ratio b per SD change (95% confidence interval) Radiographic absorptiometry Phalanges 1.69 (1.12, 2.54) Metacarpal 1.86 (1.40, 2.49) SXA Distal radius BMC 1.52 (1.18, 1.95) Distal radius BMD 1.49 (1.15, 1.92) Proximal radius BMC 1.54 (1.20, 1.99) Proximal radius BMD 1.40 (1.10, 1.78) Calcaneus 1.95 (1.54, 2.49) DXA Spine BMD 1.53 (1.16, 2.01) BUA Calcaneus 1.82 (1.45, 2.44) a Adapted from Ross et al.(27). b Odds ratios are based on a bone measurement decrease of 1 SD, and provide values that approximate the relative risk. For example, an odds ratio of 1.50 indicates that the vertebral deformation probability increases approx 1.5-fold for each 1.0-SD increase in bone density. SD = standard deviation; SXA = single-energy X-ray absorptiometry; BMC = bone mineral content (g/cm); BMD = bone mineral density (g/cm 2 ); DXA = dual-energy X-ray absorptiometry; BUA = broad-band ultrasound attenuation. Phalangeal BMD assessment techniques have been found to be significantly correlated with bone strength, an important risk factor for osteoporotic fracture (30). Oyster and Smith (30) used noninvasive methods commonly used for assessment of osteoporosis to examine prosected vertebrae and phalanges from 32 cadavers. Bone measures were then compared with a strength variable obtained by mechanically crushing or breaking the bones. The study determined that bone strength of the vertebrae was significantly correlated to that of the fingers. In addition, phalangeal measurement techniques appear to be comparable. A recent study (9) correlated CDA with other hand and forearm bone densitometry methods, using 26 cadaveric forearms. The study also determined the accuracy and short-term precision of CDA. BMD assessed by CDA correlated strongly with BMD of the hand and forearm regions as assessed by other bone densitometric methods (DXA, SXA, and RA) r = ). The short-term precision error was very small, with a coefficient of variation of 0.70% for BMD. This precision error is similar to those reported previously for RA measurements in cadaveric specimens and in duplicate or triplicate hand radiographs in patients (31 33). Clinical Applications Phalangeal measurement of BMD is clinically useful because it is a strong risk factor for osteoporotic fractures. The greatest potential application of BMD measurement is in patients without fractures, but who are at risk for fractures. Since such patients have no symptoms, and since there are usually no signs or other risk factors that can successfully identify individual patients who are at risk, there is a great clinical need for a practical way in which to identify such patients. Identification of patients at risk is essential so that pharmacologic agents, such as antiresorptive drugs and estrogen, can be selectively prescribed for those with the greatest need. Risk factors are of use in searching for disease etiology and in clinically identifying individuals at greatest risk of disease. However, it has not always been clear how to apply fracture risk data to clinical practice. A variety of interpretations may be applied to a given BMD measurement. SD criteria established by the WHO (10), which provide a useful cross-sectional description of BMD values, may be insufficient for clinical decision making, because they ignore age (and therefore future years of bone loss and risk exposure). T-scores fail to provide a mechanism to incorporate other important risk factors. To address

8 266 Journal of Clinical Densitometry Volume 1, Number 3 Fall 1998 Fig. 5. Sites of radiographic absorptiometry measurements. these deficiencies, a consensus panel of international experts adopted the concept of RLFP (29). RLFP addresses the need for a cumulative estimate of absolute fracture risk. Many risk factors for osteoporotic fracture appear to be mediated via bone density. Falls, previous fractures, and probably age are independently associated with fracture risk. Nevertheless, bone density is the most clinically useful of these indicators, for several reasons. Although falls in the elderly are associated with fracture, independent of BMD, most fractures still occur in patients with low BMD. Also, the decision to preserve bone density should occur at much earlier ages, when the tendency to fall is not yet apparent. Finally, preservation of bone density is likely to prevent many fractures even if falls cannot be completely eliminated. Summary In terms of accuracy and precision, the phalanges are as clinically useful as any other body site for assessing a patient s BMD. In terms of ease of access, from the perspective of both the patient and the physician, they are superior or at least equal to other sites. BMD measurements of the phalanges also have the virtue of sparing the patient s major organs from exposure to radiation. Among the currently available techniques for measuring the bone density of the phalanges, RA and CDA appear comparable to other techniques in terms of precision, accuracy, and predictive value for fracture. Furthermore, both have the potential to facilitate greatly widespread screening, since as they are relatively inexpensive compared to other BMD assessment techniques, do not require sophisticated equipment, and do not result in high levels of radiation exposure for patients or health care personnel. CDA may have an added benefit of providing immediate measurements on site. However determination of fracture risk based on BMD measurements of the phalanges (or any body site) alone may underestimate actual risk, because bone loss is a cumulative process, and many women live for many years beyond menopause. One approach to estimating cumulative risk of future fractures is to calculate RLFP. This approach also permits estimation of potential treatment effects on fracture probability. Acknowledgment This article was supported by an unrestricted educational grant from Merck, Inc. References 1. Riggs BL Overview of osteoporosis. West J Med 154: Riggs BL, Melton LJ III Involutional osteoporosis. N Engl J Med 314: Melton LJ III Epidemiology of hip fractures: implications of the exponential increase with age. Bone 18(Suppl):121S 125S.

9 Phalangeal Bone Mineral Density Phillips S, Fox N, Jacobs J, Wright WE The direct medical costs of osteoporosis for American women aged 45 and older, Bone 9: Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis Am J Med 94: Melton LJ III, Chrischilles EA, Cooper C, et al Perspective. How many women have osteoporosis? J Bone Miner Res 7: Kanis JA, McCloskey EV Epidemiology of vertebral osteoporosis. Bone. 13(Suppl): S1 S Mussolino ME, Looker AC, Madans JH, et al Phalangeal bone density and hip fracture risk Arch Intern Med 157: Bouxsein ML, Michaeli DA, Plass DB, et al Precision and accuracy of computed digital absorptiometry for assessment of bone density of the hand. Osteoporosis Int 7: World Health Organization Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. Report of a WHO Study Group. Geneva, Switzerland, WHO Technical Report Series 843, pp Thomsen K, Gotfredsen A, Christiansen C Is postmenopausal bone loss an agerelated phenomenon? Calcified Tissue Int 39: Wasnich RD Bone mass measurements in diagnosis and assessment of therapy. Am J Med 91(Suppl):54S 58S. 13. Cummings SR, Black DM, Nevitt MC, et al Bone density at various sites for prediction of hip fractures: the study of osteoporotic fractures. Lancet 341: Jergas M, Genant HK Current methods and recent advances in the diagnosis of osteoporosis. Arthritis Rheum 36: Melton LJ III, Atkinson EJ, O Fallon WM, Wahner HW, Riggs BL Long-term fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res. 8: Hui SL, Slemenda CW, Johnston CC Jr Baseline measurement of bone mass predicts fracture in white women. Ann Intern Med 111: Wasnich RD, Ross PD, Heilbrun LK, Vogel JM Prediction of postmenopausal fracture risk with bone mineral measurements. Am J Obstet Gynecol 153: Wasnich RD, Ross PD, MacLean CJ, et al A comparison of single versus multisite BMC measurements for assessment of spine fracture probability. J Nucleic Med 30: Cummings SR, Black DM, Nevitt MC, et al Appendicular bone density and age predict hip fracture in women. JAMA 263: Cummings SR, Nevitt MC, Browner WS, et al Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332: Wasnich RD Bone mass measurement: prediction of risk. Am J Med 95(Suppl): 6S 10S. 22. Cooper C, Atkinson EJ, O Fallon WM, Melton LJ III Incidence of clinically diagnosed vertebral fractures: a populationbased study in Rochester, Minnesota, J Bone Miner Res 7: Hodgson SF, Johnston CC Jr AACE clinical practice guidelines for the prevention and treatment of postmenopausal osteoporosis. Endocr Pract 2: Miller PD, Bonnick SL, Rosen CJ Clinical utility of bone mass measurements in adults: consensus of an international panel. Semin Arthritis Rheum 25: Wasnich RD A new, standardized approach to fracture risk interpretation. Hawaii Med J. 55: Ross PD, Kim S, Wasnich RD Bone density predicts vertebral fracture risk in both men and women: a prospective study. J Bone Miner Res 11(Suppl):S127 (Abstract). 27. Ross P, Huang C, Davis J Predicting vertebral deformity using bone densitometry at various skeletal sites and calcaneus ultrasound. Bone 16: Ross PD, Huang C, Davis JW, Wasnich Vertebral dimension measurements improve prediction of vertebral fracture incidence. Bone 16(Suppl):257S 262S. 29. Ravn P, Overgaard K, Huang C, Ross PD, Green D McClung M. Comparison of bone densitometry of the phalanges, distal forearm and axial skeleton in early postmenopausal women participating in the EPIC study. Osteoporos Int 6: Osyter N, Smith FW A postmortem correlation of four techniques of assessment of osteoporosis with force of bone compression Calcif Tissue Int 43:77 82.

10 268 Journal of Clinical Densitometry Volume 1, Number 3 Fall Yang S-O, Hagiwari S, Engelke K, Khillon MS, Guglielmi G, Bendavid EJ, et al Radiographic absorptiometry for bone mineral measurements of the phalanges: precision and accuracy study. Radiology 192: Yates AJ, Ross PD, Lydick E, Epstein RS Radiographic absorptiometry in the diagnosis of osteoporosis. Am J Med 98(Suppl): 41S 47S. 33. Matsumoro C, Kushida K, Yamazaki K, Imose K, Inoue T Metacarpal bone mass in normal and osteoporotic Japanese women using computed x-ray densitometry. Calcif Tissue Int 55: