1 Division of Epidemiology, Stanford University School of Medicine, Stanford, CA.
2 Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, MA.
3 Kaiser Permanente Division of Research, Oakland, CA.
Received for publication June 30, 2003; accepted for publication March 16, 2004.
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ABSTRACT |
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accidental falls; estrogen replacement therapy; fractures; humerus; laterality; motor activity; pharmaceutical preparations
Abbreviations: Abbreviation: BMI, body mass index.
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INTRODUCTION |
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Risk factors for proximal humerus fracture suggested by the small number of studies previously undertaken include low bone mass (35) and factors associated with low bone mass such as height loss since age 25 years (5), personal history of fractures (5), maternal history of hip fracture (5), low level of physical activity (3, 5), and low body mass index (BMI) (4, 5), although another study (3) did not find an association with low BMI. In addition, menopausal hormone therapy has been found to protect against proximal humerus fracture (3). Previously suggested risk factors associated with falls include a history of falls (3, 5), poor vision (3, 5), insulin-dependent diabetes (3, 6), and alcohol consumption (4). Suggested risk factors associated with frailty include poor health (3), poor neuromuscular function (3, 5), and, again, a low physical activity level (3, 5). In addition, studies have shown that incidence rates increase with age (2), that females are at greater risk than males (2), and that Whites are at greater risk than Blacks (7, 8).
The purpose of the present research was to identify additional risk factors for proximal humerus fractures as well as to reevaluate previously suggested factors. Previous papers from this study have reported an increased risk associated with left-handedness (9) and a decreased risk with recent use of menopausal hormone therapy (10).
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MATERIALS AND METHODS |
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Cases
Incident proximal humerus fracture cases aged 45 years or older were identified weekly through computerized radiology reports and in- and outpatient records. For each case, the fracture diagnosis was confirmed by radiography, bone scan, or magnetic resonance imaging. Uncertain fractures were excluded. Proximal humerus fractures were defined as those that occurred at the level of or proximal to the surgical neck of the humerus. Pathologic fractures that resulted from certain diseases (e.g., Pagets disease, metastatic cancer) were excluded. If a case had simultaneous fractures at more than one site, only the first-listed fracture at the five sites considered in this study was included. Cases with previous fractures of the proximal humerus since age 45 years were excluded from the analyses presented in this paper. The analysis was conducted by both including and excluding cases that resulted from motor vehicle or recreational accidents. The point estimates changed very little, and all cases were included in the analyses presented here.
To increase the proportions of racial/ethnic minorities, all proximal humerus cases identified as minority in Kaiser Permanente medical records and those without recorded race/ethnicity information were included, while 50 percent of those recorded as being White were randomly sampled. Of all eligible cases, 71 percent agreed to participate.
Controls
Controls were sampled from the Kaiser Permanente membership of the same five medical centers over the same period of time. Control selection was carried out to obtain approximately the desired number of controls in each age and sex group for the study as a whole. Every 3 months, 25 percent of the Kaiser Permanente members aged 45 years or older from the five centers were randomly sampled from the membership lists. These members were subsequently stratified by 5-year age group and gender. These groups were randomly ordered, and the first 34 females and seven males in each age group were selected. From these 34 females and seven males in each age group, all minorities and persons of unknown race/ethnicity, and a random sample of 39 percent of White females and 78 percent of White males, were included as controls. Of all selected eligible controls, 65 percent agreed to participate. Controls with a previous fracture of the proximal humerus were excluded from the analyses presented here.
Data collection and summarization
Information regarding potential risk factors was obtained from a standardized questionnaire administered in English or Spanish by trained interviewers. For all variables, the questionnaire referred to the time period preceding the fracture for cases and to the period prior to the interview for controls. The questionnaire asked about the following areas: demographic characteristics, medical history, family history of osteoporotic fractures, anthropometric measures, medication history, certain surgeries, menopausal hormone therapy use, leisure-time physical activity in the past year and during adolescence, use of visual and hearing aids, physical functioning (use of mobility aids, physical and mental activities of daily living), smoking and alcohol consumption, dietary calcium intake, home environment, and history of falls. Medical history included history of foot problems, neuromuscular function, and selected medical conditions reported to have been diagnosed by a practitioner: diabetes; angina, heart attack, or heart failure; stroke or blood clot in the brain; epilepsy, seizures, convulsions, or fits; kidney disease; cataracts; glaucoma; Parkinsons disease; arthritis; and depression.
Neuromuscular function was measured roughly by asking subjects whether, during the previous year or the year before their fracture, they had had the following symptoms: pain, numbness or weakness in the feet or legs, problems with balance, limping, tremors and shakes, and dizziness and lightheadedness. Subjects were asked whether they had difficulty walking in dim light. Medication history queried the use of selected medications, including thiazides, water pills, calcium carbonate tablets, calcium supplements, multivitamin supplements, vitamin D/cod liver oil, melatonin, steroid pills, seizure medications, anxiety medications, and psychotropic medications.
A summary physical activity variable, metabolic equivalent hours per month, was created by assigning standard metabolic equivalents (12) to each type of leisure-time physical activity that a subject reported in the past year, multiplying these by the number of hours per month of participation in each activity, and summing the metabolic equivalent hours per month over all reported activities. Activities queried were brisk walking/hiking, gardening/yard work, exercise class, water exercises/swimming, bicycle riding, tennis, calisthenics, social dancing, running/jogging, golfing/bowling, stretching exercises/yoga, tai chi, and heavy housework. Those subjects with nonzero values for metabolic equivalent hours were divided into increasing activity tertiles by using tertile boundaries of the control group. Subjects were also asked how physically active they were at age 16, 30, and 50 years compared with other men or women of that age. Additionally, subjects were asked how often they performed selected physical activities at the age of 16 years (13).
Dietary calcium intake (milligrams/day) was assessed by using a calcium-validated food frequency questionnaire (14) and was divided into quartiles for analysis; the quartile boundaries of the control group were used. Use of calcium supplements, including calcium carbonate tablets, was queried separately in the medication portion of the questionnaire. BMI was divided into quartiles for analysis by using the quartile boundaries of the control group. Ten percent of the participants agreed to complete an abbreviated questionnaire that did not include questions on dietary calcium intake, physical activity, and cigarette smoking. Because of the reduction in sample size for these variables, they are not included in the multivariate analysis presented in the Results section.
During the first 3 years of the study, most interviews were conducted in person. Beginning on November 15, 2000, interviews were mainly conducted over the telephone to increase participation rates and the number of subjects interviewed. Type of interview was not an effect modifier and was included as a covariate in the analysis.
Questionnaires obtained for 110 subjects by proxy-respondent interviews were excluded because of missing data and because their numbers were too small to allow adequate evaluation of effect modification by respondent status for most variables. One participant was excluded because the interviewer considered the quality of the interview unsatisfactory.
Statistical analysis
The associations of proximal humerus fracture with potential risk factors were examined by using unconditional logistic regression with SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina) to compute adjusted odds ratios. All odds ratios controlled for 5-year age group, gender, and race/ethnicity as indicated by Kaiser Permanente records and for type of interview to account for the method by which subjects were sampled or interviewed. Self-reported race/ethnicity and age as a continuous variable were included to adjust more tightly for these variables. Self-reported race/ethnicity was categorized into the following groups based on similarity of odds ratios for fractures: 1) White, Native American, and other; 2) Black; 3) Chinese, Filipino, Japanese, Pacific Islander, and other Asians; and 4) Hispanic. Subjects who indicated more than one race/ethnicity group were placed in one of these four groups on the basis of their answers to immigration and acculturation questions. The multivariate model presented here used a backward stepwise elimination algorithm for variable selection from the variables generated in the initial analysis.
Estimates of age-adjusted odds ratios for proximal humerus fracture by self-reported race/ethnicity relative to Whites were computed taking into account the sampling of cases and controls. Because of previously identified inconsistencies between Kaiser Permanente-reported and self-reported race/ethnicity, especially for Hispanics (15), and because self-reported race/ethnicity is generally preferred, estimates were made according to self-reported race/ethnicity. All cases recorded as non-White or whose race/ethnicity was unrecorded on Kaiser Permanente records were subdivided according to self-reported race/ethnicity and were given a weight of 1.0 because all were included. All cases recorded on Kaiser Permanente records as White were classified according to self-reported race/ethnicity and were given a weight of 2.0 because one half were sampled throughout the study.
To estimate the odds of controls being in a specific racial/ethnic subgroup, we used data from the 1999 Northern California Kaiser Permanente membership survey. This survey was sent to a random sample of 40,000 members aged 20 years or older. It included questions on race/ethnicity similar to those used in our questionnaire and had a response rate (61.5 percent for members aged 45 years or older) similar to that for the controls in our study (65 percent). The distribution of self-reported race/ethnicity in each 5-year age group and facility in the membership survey was applied to the controls in our study to estimate what the control distribution would have been if random rather than weighted sampling had been used. Unconditional logistic regression controlling for 5-year age group was then used to compute the odds ratios for the association of race/ethnicity and proximal humerus fracture. In this paper, we present our best estimates of the odds ratios, but, because several assumptions were made in these computations, we do not give 95 percent confidence intervals.
Possible effect modification of proximal humerus fracture by self-reported race/ethnicity, age, and gender was assessed by visual examination and by logistic regression (16). Little evidence of effect modification was detected, and this issue is not discussed further here.
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RESULTS |
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Odds ratios for proximal humerus fracture adjusted for age, gender, race/ethnicity, and type of interview, as well as multivariate-adjusted odds ratios, are presented in table 2 for a variety of factors. Potential risk factors are grouped into those thought to be associated with low bone mass, falls, and frailty.
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Number of falls to the ground in the past year; practitioner-diagnosed diabetes mellitus, depression, and epilepsy; difficulty walking in dim light; seizure medication use; hearing aid use; and left-handedness were associated with elevated risks of proximal humerus fracture. Greater height, which could increase the risk of a fracture in the event of a fall, and alcohol consumption did not show much association with risk. Because epilepsy and use of seizure medication were highly correlated, only seizure medication use was included in the multivariate model.
Report of at least some leisure-time physical activity was associated with a reduction in proximal humerus fracture risk. Physical activity at age 16, 30, or 50 years (for those over the age of 50 years) was not associated with fracture risk (data not shown). Although needing help with activities of daily living showed trends toward an elevated risk of proximal humerus fracture, these associations were somewhat weakened when other variables were taken into account. Limping was associated with a decreased risk. Most indicators of neuromuscular function, use of medical aids to assist mobility (canes, walkers, wheelchairs, artificial legs, and leg braces), and physical functioning were not associated with risk (data not shown).
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DISCUSSION |
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The reduced risks of proximal humerus fracture in males compared with females and in Blacks compared with Whites agree with results from other studies (7, 8). While past studies have reported Asians and Hispanics to be at lower risk of hip fracture than Whites are (17, 18), we are not aware of any that consider the risk of proximal humerus fracture in these groups. Our findings for Asians are similar to those for hip fracture, but not for Hispanic females, who had a risk similar to Whites in this study.
Variables thought to be associated with low bone mass
Low bone mass is known to be an important predictor of proximal humerus fracture (3, 19). We found previous fractures since age 45 years and low dietary calcium to be associated with increased risks and recent use of menopausal hormone therapy and use of calcium carbonate supplements to be associated with decreased risks. The result regarding previous fractures is consistent with that of Lee et al. (5), and the apparent protective effect of menopausal hormone therapy is consistent with previous findings for the hip (2022), all nonspine fracture sites (23), and the proximal humerus (3). In contrast to our results, others have found no beneficial effect of recent dietary calcium intake on proximal humerus fracture (3, 4, 24), and the Study of Osteoporotic Fractures found an increased risk associated with use of calcium carbonate tablets (24). We have no explanation for these discrepant results. Unexpectedly in our study, the highest quartile of BMI, when compared with the lowest, was associated with a slightly increased risk of proximal humerus fracture. Other studies have shown either no increase in risk (3) or a decreased risk (4, 5) with higher BMI. Thus, no conclusions can be reached at this time, except that any association is unlikely to be strong.
Variables thought to be associated with falls
Prior studies of older persons have found that 9097 percent of proximal humerus fractures result from a fall (25, 26), consistent with our estimate of 92 percent. Two cohort studies have found that risk factors for falls (5), as well as a history of falls (3, 5), were associated with an increased risk of proximal humerus fracture, consistent with our finding that proximal humerus fracture risk increased 9 percent with each additional fall in the previous year.
Among specific diseases, diabetes, epilepsy, and depression were associated with proximal humerus fracture. The Study of Osteoporotic Fractures also found an association between diabetes in women aged 65 years or older and proximal humerus fracture (6). In that study, women with diabetes were in worse health and had poor balance, poor gait, peripheral neuropathy, and poor vision. These characteristics, in addition to other comorbidities associated with diabetes, are thought to put diabetics at a higher risk of falling and thereby of fracture (6). Epilepsy, apparently not considered in previous studies, is thought to increase a persons risk of fracture because of falls caused by seizures (27). Use of seizure medication, also not previously reported to our knowledge, may also increase risk. Side effects resulting from the use of seizure medication include nausea, dizziness, and sleepiness, all of which could lead to falls. In addition, osteomalacia has been associated with seizure medications (28). Another potential new risk factor, depression, has been linked to falls (29) and may be associated with fracture either because antidepressive medications reduce awareness or because depression itself reduces awareness. Depression has been linked to osteoporosis by causing an increase in interleukin-6 levels, which stimulate osteoclast precursors, leading to increased bone loss (30).
Difficulty walking in dim light, a measure of visual acuity, was associated with an increased risk of fracture. In a previous study, various categories of poor vision were associated with recurrent falls and fractures at any site (31). The authors stated that these associations might be related, in part, to existing medical conditions. When the present study adjusted for diabetes, a disease that can result in vision loss, the odds ratio for difficulty walking in dim light was only slightly reduced.
Another potential fall-related variable associated with proximal humerus fracture and, to our knowledge, not reported in previous studies was use of a hearing aid. Balance is highly dependent on a healthy inner ear. Previous studies of factors associated with Colles fracture reported that those who fractured had greater hearing loss (32) and that hearing problems were associated with recurrent falling (33). These associations were attributed to osteoporosis in the auditory ossicles. Age-related accumulation of calciferous granules can lead to saccular degeneration, further reducing a persons ability to moderate spatial orientation at movement and at rest (34).
Left-handedness is potentially another new risk factor. Compared with right-handedness, it was associated with more than double the risk of proximal humerus fracture. Results regarding the association between handedness and fractures at all sites considered in this study have been described elsewhere (9). The Health Professionals Follow-up Study reported a relative risk of 1.56 for distal forearm fractures in left-handed men compared with right-handed men (35). Reasons for the increased susceptibility to fracture in left-handed persons are not known, but it has been hypothesized that left-handedness is a marker for other biologically innate risk factors for falls or that subsequent fractures are the consequence of an environment developed mainly for right-handed people (35).
Variables thought to be associated with frailty
Our results to some extent support the findings of two cohort studies (3, 5) showing that those who fracture their proximal humerus are less active and more frail. Poor health and frailty are thought to be associated with proximal humerus fracture because frail people are more likely to fall and, in the course of a fall, less likely to put out a hand quickly enough to break the impact (3). Needing help with activities of daily living was slightly associated with higher risk, while difficulty with physical functioning was not associated. At least some leisure-time physical activity in the previous year was associated with a lower risk. Physical activity may have a beneficial effect on bone mass (36), or the most physically inactive may be in ill health and therefore at greater risk of falling.
The Epidémiologie de lOstéoporose Study (EPIDOS) (5) found that women practicing at least one form of physical activity were at a greater risk of proximal humerus fracture than those who did not practice a form of physical activity. The contradictory results may have occurred because this study used a cohort aged 75 years or older, while our study used a much younger cohort. The present study did not find much association with most indicators of neuromuscular function queried, perhaps because the measures of neuromuscular function in this study were based on responses to a questionnaire rather than on performance-based measures. Limping was associated with a decreased risk. This finding may be attributable to chance, but perhaps the decreased risk is the result of the use of walking aids or more careful movement by those who limp, knowing they are at risk of falls.
We have presented risk factors for proximal humerus fracture in the framework of their probable associations with low bone mass, falls, and frailty. However, it is important to note that many of the risk factors presented can be allocated to more than one of these categories.
One strength of this study is that it has a much larger number of cases of proximal humerus fracture than previous studies did. Cases were interviewed soon after the incident fracture occurred so that more accurate and detailed information could be obtained. This study was also the first known to include men and women of four different racial/ethnic groups. Because no effect modification was found by either of these factors, risk factors determined in this study can be generalized across sex and the four racial/ethnic groups studied. On the other hand, this study used a case-control design with incomplete participation and with the potential for error in ascertaining information on past events and exposures. Thus, selection bias cannot be ruled out, and it is possible that cases and controls remembered and reported past events differently.
In conclusion, proximal humerus fractures result primarily from low bone mass and falls. These fractures appear to be associated with fracture and fall history; medical conditions such as epilepsy, depression, and diabetes; use of seizure medication; and left-handedness. Factors associated with a decreased risk include leisure-time physical activity in the past year, recent use of menopausal hormone therapy, and use of calcium carbonate tablets at least once a week for 1 year or longer. Future recommendations for those at risk of proximal humerus fracture may include moderate levels of physical activity, use of calcium carbonate tablets as a calcium supplement, other measures to reduce loss of bone mass and prevent falls, and maintaining a high dietary calcium intake.
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ACKNOWLEDGMENTS |
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The authors thank Beverly Peters and Luisa Hamilton for project management, Michael Sorel for computing and database management, and Carolyn Salazar for medical record abstraction.
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NOTES |
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REFERENCES |
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