1 Bone and Mineral Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia.
2 Present address: The Simpson Centre, University of New South Wales, Liverpool Hospital, Liverpool, New South Wales, Australia.
3 Present address: Department of Rheumatology, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
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ABSTRACT |
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aged; bone density; forearm; fractures; humeral fractures; humerus; osteoporosis; prospective studies
Abbreviations: BMD, bone mineral density; CI, confidence interval
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INTRODUCTION |
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In contrast to the intensive research into risk factors for hip fractures, little is known about risk factors for humerus, forearm, and wrist fractures. Case-control and cross-sectional studies have shown that women who suffer forearm fractures have slightly lower bone mineral density (BMD) in the forearm than controls do (46
). However, the difference could be due to bone loss after the fracture. Low BMD and neuromuscular impairment are independent predictors of fracture risk in women (7
). Those women in the lowest quintile of BMD have a fourfold and sevenfold increased incidence of distal forearm and proximal humerus fractures, respectively (8
). The incidence and determinants of upper limb fractures in men have not been studied systematically.
The present study addressed two specific issues: 1) what are common and independent risk factors for humerus, forearm, and wrist fractures in men and women; and 2) how much of this fracture risk can be attributed to these factors?
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MATERIALS AND METHODS |
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The Dubbo Osteoporosis Epidemiology Study is an ongoing investigation; by December 1997, 868 men and 1,383 women had participated. The present analysis was limited to men and women in the study sample who had had a proximal humerus, forearm, or wrist fracture and for whom clinical data, including BMD and fall-related measurements, were complete prior to the fracture event. Also included were those persons in the sample who had not had any fracture. On the basis of these criteria, 739 men and 1,105 women were included in the analysis. For these subjects, the total length of follow-up was 6,194 person-years for men and 8,026 person-years for women. The median duration of follow-up for men and women was 7.3 and 7.8 years, respectively. The study was approved by the St. Vincent's Hospital Committee (Sydney), and all subjects gave written informed consent.
Assessment of risk factors
After informed consent was obtained, subjects were interviewed by a nurse coordinator. The coordinator administered a structured questionnaire to collect data such as age and anthropometric variables, including current height and weight. Height loss was estimated as the difference between current height and peak height (lifetime maximum height). Lifestyle factors such as past and present tobacco use (assessed as pack-years) and alcohol consumption were elicited. Dietary assessment was based on a frequency questionnaire for calcium intake, which has been validated previously (12). Physical activity was assessed by using a questionnaire similar to that for the Framingham Heart Study (13
), in which each subject estimated the number of hours per day spent on five levels of physical activity: basal activity, sedentary, light, moderate, and heavy. A weighting or intensity factor (13
) based on the approximate oxygen consumption needed for each level of activity was multiplied by the number of hours engaged in each level of activity. The weighting factors were as follows: 1, basal activity; 1.1, sedentary; 1.5, light; 2.4, moderate; and 5, heavy. The resulting products for all activities were then summed to yield an index of total physical activity. A high index corresponds to a physically active lifestyle, and low levels correspond to habitual inactivity.
Subjects were asked to recall the number and cause of falls in the last 12 months. Falls caused by external forces (e.g., being struck by a moving vehicle) were excluded from the analysis. Various tests of postural stability were performed on each subject at baseline, as described previously (14). Quadriceps strength (maximum isometric contraction) was measured in the sitting position in the subject's dominant (stronger) leg by using a horizontal spring gauge calibrated to as much as 50 kg of force. Body sway, assessed by using a simple swaymeter that measured displacement of the body at waist level in 30-second periods, was measured under four test conditions: 1) eyes open, firm surface (wooden floor); 2) eyes closed, firm surface; 3) eyes open, compliant surface (15 cm deep, high-density foam); and 4) eyes closed, compliant surface. Full descriptions of the apparatus and procedures used, along with test-retest reliability scores (and confidence intervals) for the test measures, have been reported previously (14
).
Measurement of BMD
BMD (g/cm2) was evaluated in the lumbar spine and femoral neck by dual energy x-ray absorptiometry using a LUNAR DPX-L densitometer (LUNAR Corporation, Madison, Wisconsin). The radiation dose with this method is <0.1 µGy. The coefficients of reliability of BMD measurements at St. Vincent's Hospital were 0.98, 0.95, and 0.96 in the lumbar spine, femoral neck, and total body, respectively (15).
Ascertainment of fractures
Symptomatic humerus, forearm, and wrist fractures occurring during the study period were identified in residents of the Dubbo local government area by using radiologists' reports from the only two centers providing radiography services, as described previously (11). Fractures were included only if the report of fracture was definite and, on interview, the fracture was reported to have occurred with minimum or no trauma, including a fall from a standing height or lower. Fractures clearly due to major trauma such as motor vehicle accidents were excluded from the analysis.
Preliminary analyses indicated that many of the clinical characteristics of forearm and wrist fractures, such as BMD, quadriceps strength, body sway, and age, are common. Therefore, these fractures were combined into a single fracture group.
Statistical methods
Differences in the baseline characteristics of fracture and nonfracture subjects were tested by using the t test or the likelihood ratio chi-square test, as appropriate. Incidence rates of fractures, calculated for males and females separately as the number of fractures occurring during the study period divided by the number of person-years over the same period, were expressed per 10,000 person-years. A 95 percent confidence interval around the incidence was constructed by using the Poisson distribution. The study period was defined as the interval between the baseline and follow-up (December 1997) visits or, in the case of death, between baseline and the date of death.
To identify potential predictors of fracture risk, a Cox proportional hazards model (16) was used. In this model, time to fracture (dependent variable) was expressed as an exponential function of several risk factors. Final models were constructed by using stepwise and backward elimination algorithms (17
). The significance of parameter estimates derived from the Cox proportional hazards model was tested with the likelihood ratio statistic (18
). Before the model was constructed, a relatively high p value (0.15) was used for the immediate steps to include the effects of any potentially important variables that might be statistically nonsignificant because of the size (and resulting power) of the study. The assumption of proportional hazards for the levels of each risk factor was evaluated in relation to the linearity of plots of log(log(S(ti)j), where S(ti)j describes the jth survival time for the ith level (i = 1, 2) of each risk factor.
Further analyses were based on factors identified in the "final" Cox regression model. Each factor was dichotomized into two classes to represent high and low risk categories. For example, in terms of BMD, a subject was classified as osteoporotic if his or her BMD was 2.5 standard deviations or more below the young normal level or as normal. The "young normal" BMD was obtained from a sample of 52 Australian men and women aged 2032 years. Men and women were classified as osteoporotic if their BMD was <0.74 and <0.7 g/cm2, respectively. Those with a femoral neck BMD of more than 1 standard deviation below but less than 2.5 standard deviations below the young normal mean were classified as osteopenic (men, 0.740.92 g/cm2; women, 0.700.88 g/cm2). The relative risk for the class of each risk factor was estimated by using the Cox proportional hazards model. All database management and statistical analyses were performed via the SAS Statistical Analysis System (19).
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RESULTS |
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In the two fracture groups, women with a humerus fracture were older and had a significantly lower BMD and weight than those with forearm and wrist fractures. As was true for women, men with humerus fractures were also older and had a lower BMD than those with forearm and wrist fractures (table 1).
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Shorter current height was a significant risk factor for forearm and wrist fractures but not for humerus fracture. However, height loss (calculated as the difference between current height and peak height at age 30 years) was a common predictor of humerus, forearm, and wrist fractures in both men and women. Lower weight was a significant risk factor for humerus fracture in women but not in men.
Approximately 20 percent of men and 33 percent of women reported that they had fallen in the last 12 months before entering the study. Of these women, 22 percent had fallen once, as had 14 percent of men. About one third of both men and women who had fallen had done so multiple times (6 percent of men, 11 percent of women). History of falls was also a significant predictor of humerus fracture (in both men and women) and forearm and wrist fractures (in women only). While quadriceps weakness was a significant predictor of humerus fracture in men, body sway was a significant predictor of humerus fracture in women.
While the incidence of fractures in smokers was not significantly different from that in nonsmokers, alcohol drinkers had a significantly higher risk of humerus fracture than nondrinkers did. Lower dietary calcium intake was also a significant risk factor for forearm and wrist fractures in women but not in men (table 2).
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DISCUSSION |
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The finding that femoral neck BMD is one of the best predictors of humerus, forearm, and wrist fractures is consistent with a previous study of women (7). In fact, the strength of the association for women, assessed in terms of relative risk, was somewhat lower than that of hip fracture (20
). Nevertheless, osteoporotic women (2.5 standard deviations below the young normal mean) had a 5.3- and 2.1-fold increase in the risk of humerus and of forearm and wrist fractures, respectively. The strength of the association was even higher for men: 6.3-fold for humerus and 5.6-fold for forearm and wrist fractures. Lumbar spine BMD was associated with fracture risk for both men and women; however, it was not independent of femoral neck BMD. This study did not measure forearm BMD, but the strength of the association between femoral neck BMD and fracture risk, as reported in this paper, is comparable to that reported in the literature (21
), suggesting that the discriminatory power of measuring BMD in the femoral neck is equivalent to that in the forearm. These findings also suggest that low-trauma upper-limb fractures are largely osteoporotic.
For both sexes, a history of height loss was an independent and common predictor of fracture risk. Height loss has been found to be associated with hip fracture in men (22) and women (23
). These results suggest that the greater height loss may reflect a more generalized state of bone loss or that height loss is a surrogate for vertebral deformity. Indeed, a study of 144 men found that vertebral deformity was associated with reduced vertebral and femoral neck BMD and that the number of vertebral deformities was negatively correlated with BMD (24
). Vertebral deformity has also been associated with subsequent nonvertebral fractures independent of BMD (25
).
Poor grip strength has also been noted as a risk factor for hip fracture (26). Since quadriceps weakness and postural instability are associated with falls (27
), their role in predicting fracture implies that the event of fracture is not only a function of BMD but also a result of fall-related mechanisms. Apart from BMD and height loss, the present study also indicated that falls were strongly predictive of the risk of forearm and wrist fractures, particularly in women. Indeed, risk of fracture among fallers was almost threefold higher than that among nonfallers. Falls were reported by one in three women and increased with advancing age to 40 percent among women aged 80 years or more. Those who fell once had a higher risk of recurrent falls. These observations are similar to those of Prudham and Evans (28
), who also found that falls were more common in women than in men (34 vs. 19 percent). Age, postural stability, and quadriceps strength were strongly associated with falls (27
); thus, it was expected that higher body sway and quadriceps weakness would be associated with fractures. When falling was factored into the proportional hazards model, both quadriceps strength and body sway became statistically nonsignificant.
In this study sample, higher dietary calcium intake was associated with higher BMD in both the spine and the hip (10), in agreement with Kelly et al. (29
). Also, dietary calcium intake was inversely related to age for men but not women. Thus, the finding that dietary calcium intake was an independent predictor of humerus fracture in men but not women may reflect other age-related factors, such as hyperparathyroidism, involved in the determination of the risk of fractures in men. It has been proposed that estrogen deficiency causes bone loss in women (both the early postmenopausal accelerated phase and the late postmenopausal slow phase) and elderly men. The loss of bone is associated with progressive secondary hyperparathyroidism, which may activate bone turnover and hence cause bone loss. The relation between bone loss and secondary hyperparathyroidism is mediated mainly by loss of estrogen action on extraskeletal calcium homeostasis, which results in net calcium wasting and in increases in the level of dietary calcium intake required to maintain bone balance. Recent data (30
) indicated that estrogen is at least as important as testosterone in determining bone mass in men. In addition, elderly men have low circulating levels of both bioavailable estrogen and bioavailable testosterone; thus, estrogen deficiency may also contribute substantially to the continuous bone loss and hence increase the risk of fracture in men.
The role of lifestyle factors as determinants of BMD and hence fracture risk has received considerable attention. Smoking has been implicated as a risk factor for spinal fracture in men (31) and in women (31
). In the present study, despite smoking being negatively associated with BMD (12
), which is consistent with findings from several cross-sectional studies of women (33
35
), this relation did not translate to a higher risk of fracture. Higher physical activity had a protective effect against fracture risk, consistent with previous observations regarding hip fractures, as reported by Lau et al. (36
) for Chinese men and by Cooper et al. (26
) for a British population. However, in the present study, the association between physical activity and fracture risk was not independent of femoral neck BMD.
Fractures of the humerus and forearm are a risk factor for subsequent hip fracture (37, 38
). In fact, it has been estimated that as many as 16 percent of women with hip fractures have had a previous distal radial fracture (39
). Findings from the present study tend to indicate that the relation between upper-limb and hip fractures in persons who fall, compared with the general population, may be mediated by their greater propensity to fall and to be characterized by more-severe osteoporosis.
The present findings should be interpreted conditional on a number of potential limitations. The study population was of Caucasian background; therefore, generalization may not be applicable to other racial populations. Measurements of postural sway, BMD, dietary calcium intake, and physical activity index at a single time point included three measurement errors and hence could have underestimated any true association between these factors and fracture risk. It is possible that selection bias was present in the analysis, in that subjects who participated in the study were healthier than those who did not. Center et al. observed that mortality was generally lower in the present study sample compared with the overall community (40). Finally, epidemiologic data on factors directly affecting hip fracture risk cannot be taken as definitive evidence of causal associations.
This study has important implications for the prevention of upper-limb fractures. More than 40 percent of the humerus, forearm, and wrist fractures occurred in men and women whose femoral neck BMD was less than 0.7 g/cm2 (the cutoff level for the definition of osteoporosis). This severity of osteoporosis occurred in 11 percent of the men and 27 percent of the women. A history of falls also emerged as an important risk factor. Taken together, these data indicate that screening strategies that focus on persons with low BMD and a high risk of falling are likely to be more effective than focusing on low BMD alone. Interventions directed at reducing falls might be effective in reducing the incidence of forearm and wrist fractures, particularly in the elderly whose BMD is already below the fracture threshold.
In summary, femoral neck BMD, falls, and height loss or dietary calcium intake are independent risk factors for humerus, forearm, and wrist fractures in community-dwelling men and women. It seems that measures to maintain BMD and prevent falls, adequate exercise, and dietary calcium intake could contribute to a reduction in the incidence of upper-limb fractures in elderly men and women.
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ACKNOWLEDGMENTS |
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The authors acknowledge the expert assistance of Janet Watters and Angela Ferguson in conducting interviews, collecting the data, and measuring bone densitometry and of Orana Radiology Services in conducting radiologic analyses. The authors also acknowledge the invaluable help of the Dubbo Base Hospital staff, particularly B. Luton, M. Russell, and B. Ayrton.
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NOTES |
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REFERENCES |
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