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American Journal of Epidemiology Advance Access originally published online on August 20, 2007
American Journal of Epidemiology 2007 166(10):1191-1197; doi:10.1093/aje/kwm206
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Is Radiographic Vertebral Fracture a Risk Factor for Mortality?

Daniel W. Trone1,2, Donna Kritz-Silverstein1, Denise G. von Mühlen1, Deborah L. Wingard1 and Elizabeth Barrett-Connor1

1 Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA
2 Graduate School of Public Health, San Diego State University, San Diego, CA

Correspondence to Dr. Donna Kritz-Silverstein, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, 0631C, La Jolla, CA 92093-0607 (e-mail: dsilverstein{at}ucsd.edu).

Received for publication March 7, 2007. Accepted for publication June 8, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Clinical fractures predict increased mortality risk, but few studies report mortality based on prevalent radiographically defined vertebral fracture. This study examined whether radiographically defined vertebral fracture is a risk factor for mortality in older adults. The 1,580 participants in California (631 men, 949 women) were aged ≥50 years in 1992–1996. Lateral spine radiographs, and information about medical history and behaviors, were obtained. Overall, 55 (8.7%) men and 123 (13%) women had at least one prevalent fracture at baseline; of these, 48 women and 14 men had two or more. Over 7.6 years, 460 participants died, 27.6% without and 41.0% with prevalent fractures (p < 0.001). Prevalent vertebral fracture was not associated with all-cause mortality in both sexes combined (adjusted hazard ratio = 1.09, 95% confidence interval: 0.84, 1.42) or sex-specific analyses (women: adjusted hazard ratio = 1.15, 95% confidence interval: 0.83, 1.59; men: adjusted hazard ratio = 0.89, 95% confidence interval: 0.55, 1.46). However, women with two or more prevalent fractures had increased risk of all-cause mortality (adjusted hazard ratio = 1.56, 95% confidence interval: 1.01, 2.40; p = 0.04). Women with any prevalent vertebral fractures also had increased mortality risk from "other" causes (adjusted hazard ratio = 1.59, 95% confidence interval: 1.03, 2.45; p = 0.04) but not cardiovascular disease or cancer. A single radiographic vertebral fracture is not a risk for mortality in older women; larger, longer studies of men and those with two or more radiographic vertebral fractures are needed.

cohort studies; fractures, bone; mortality; osteoporosis; radiography; spinal fracture


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Clinical vertebral fractures have been associated with increased morbidity and mortality in men and women (1–6). Sex differences have been found in the prevalence of clinically diagnosed vertebral fracture; in Caucasians, the lifetime risk is about 16 percent for women compared with 5 percent for men (1). The prevalence of clinically diagnosed vertebral fractures increases steadily with age, from 20 percent for postmenopausal women aged 50 years to 65 percent for women aged 90 years or older (2). However, as reviewed by Cummings and Melton (1), a majority of spine fractures are subclinical or unrecognized without radiographic examination. They differ from clinical spine fractures in that they may have occurred many years prior to diagnosis and may have a different underlying etiology or prognosis (4, 7).

The purpose of this study was to determine whether radiographically defined vertebral fracture is a risk factor for all-cause (nontraumatic) mortality or cause-specific mortality in either sex.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Participants
The Rancho Bernardo cohort was established in 1972–1974 when 82 percent of all adult residents of a mostly middle- and upper-middle-class Caucasian community in southern California participated in a cardiovascular risk factor survey (8). Between 1992 and 1996, about 80 percent of surviving community-dwelling women (n = 1,082) and men (n = 699) participated in a follow-up visit. Excluded from these analyses were 168 subjects who did not have a spine radiograph because of transportation or scheduling constraints, 19 who were less than 50 years of age, three whose deaths were due to trauma, and 11 who were lost to follow-up. The present study included 949 women and 631 men who were at least 50 years of age at the time of their 1992–1996 research clinic visit and who had lateral spine radiographs. The University of California, San Diego Institutional Review Board approved these protocols, and all participants gave written informed consent.

Procedure
The 1992–1996 visit included a standardized questionnaire regarding personal history of cigarette smoking (current/past/never), alcohol consumption (grams/week during the previous 2 weeks (9) and drinking of alcohol at least three times/week), current use of postmenopausal estrogen (yes/no), current use of thiazide diuretics (≥1 year) and thyroid hormones (≥1 year), and physical activity (exercise ≥3 times/week). Grip strength (kilograms of pressure) in the participant's dominant hand was measured as the better of two trials by using a handgrip dynamometer.

Vertebral bone mineral density defined as the mean of four vertebrae (L1–L4) was measured by using dual energy x-ray absorptiometry (Hologic QDR model 1000; Hologic Inc., Waltham, Massachusetts). The dual energy x-ray absorptiometry scan data include total body weight (kilograms), fat (kilograms), fat percentage, vertebral bone mineral density, and t score. Height and weight were measured with participants wearing light clothing and no shoes. Body mass index was calculated as weight (kilograms) divided by height (meters squared).

Lateral vertebral radiographs of the thoracic and lumbar spine (T7–L4) were obtained and were read by a single radiologist specializing in skeletal deformities (Dr. David Sartoris, University of California, San Diego, California) who defined fracture status by using the qualitative and semiquantitative grading scheme for vertebral deformity modified from the method described by Genant et al. (10). Each vertebral body was assessed as fractured, probably fractured, or not fractured and was grouped by vertebral fracture status. Several months after the first reading, 60 radiographs were reread by the same radiologist without knowledge of his first reading, with only two disagreements (kappa = 0.82; proportion agreement = 96 percent).

Vital status, determined annually, was known for all 1,580 participants through May 2004. Follow-up time was calculated in months by subtracting the participants' date of last follow-up or date from their visit date. Participants were followed for a median of 7.6 years (range, 10 days–11.1 years). Death certificates were obtained for 90 percent (414 of 460) of decedents by May 2004. Date of death for decedents for whom death certificates were not available was obtained from a family member or published obituary. A certified nosologist used the International Classification of Diseases, Ninth Revision, manual to code underlying cause of death; by May 2004, cause of death was coded for 340 (73.9 percent) of 460 decedents. Cause-specific deaths were coded as cancer (codes 140–239), cardiovascular disease including ischemic heart disease (codes 401–414, 426–438, 440–448), other, and unknown/not coded. Other causes of death included infectious diseases, diabetes, mental disorders, nervous system disorders, respiratory illnesses, digestive system disorders, genitourinary disorders, musculoskeletal disorders, injuries, and ill-defined causes. These causes were combined into "other causes" because proportions of individuals who died from each were too small for meaningful separate analysis.

Statistical analysis
Osteoporosis was defined by using two separate bone mineral density criteria: 1) the National Osteoporosis Foundation diagnosis of osteoporosis defined as a lumbar t score of less than –2.0 (2 standard deviations below the mean for young adults), and 2) the World Health Organization diagnosis defined as a lumbar t score of less than –2.5 (2.5 standard deviations below the mean for young adults).

Age and other characteristics were compared by fracture status with t tests for continuous variables and chi-square tests for categorical variables. Age and age-adjusted comparisons of characteristics by vital status within those who did not have a fracture and, separately, within those who did have a history of fracture were performed with analysis of covariance for continuous variables and chi-square tests for categorical variables. Adjusted Cox proportional hazards estimates (11) were used to examine the association of fracture status and risk factors (age, sex, body mass index, thiazide medication, thyroid medication, alcohol intake, exercise, current smoking, grip strength, and, in models including women only, estrogen use) with all-cause mortality expressed as a hazard ratio and 95 percent confidence interval, cardiovascular disease mortality, cancer mortality, and other-cause mortality. Separate exploratory multivariate models for women also included current use of estrogen therapy. Separate sex-specific analyses restricted to those with two or more fractures were also performed. For all Cox proportional hazards models, follow-up time was defined as the time between a participant's clinic visit and either date of death or May 2004, when those who had not died were censored. The proportional hazards assumption was checked; plotting the survival function versus the survival time resulted in a graph with curves that did not cross.

All statistics were performed with SPSS statistical software (version 12.0.2; SPSS, Inc., Chicago, Illinois). We agree with Rothman (12) that tests for multiple comparisons are inappropriate in an exploratory analysis and might actually conceal important associations. Therefore, no adjustment was made for multiple comparisons; in this paper, exact p values are shown instead.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The overall mean age of participants was 71.9 (standard deviation, 10.5) years, with an average of 71.6 (standard deviation, 10.2) years for men and 72.1 (standard deviation, 10.7 years) for women. The majority of these men and women (72 percent) were aged 65 years or older. In this sample of older persons, 123 (13 percent) of the women and 55 (8.7 percent) of the men had at least one radiographic vertebral fracture (rate ratio = 1.56, 95 percent confidence interval: 1.10, 2.21; p < 0.01) in 1992–1996. Of these individuals, 48 women and 14 men had two or more radiographic vertebral fractures. Table 1 compares characteristics assessed at the 1992–1996 clinic visit for persons with versus without a radiographic spine fracture. As shown, weight, grip strength, and lumbar spine bone mineral density were significantly higher among those with no fracture, whereas age and osteoporosis, defined by either National Osteoporosis Foundation or World Health Organization criteria, were significantly higher among those with radiographic spine fracture. Additionally, significantly more women reported current use of estrogen therapy in the "no fracture" group (odds ratio = 2.43, 95 percent confidence interval: 1.57, 3.78; p < 0.001).


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  		TABLE 1. Comparison of characteristics, by vertebral fracture, of adults aged ≥50 years, Rancho Bernardo, California, 1992–1996

 
During the 7.6-year follow-up, 29.1 percent (n = 460) of the cohort died; the mortality rate was 27.6 percent among those without prevalent vertebral fracture and 41.0 percent among those with one or more prevalent vertebral fractures in 1992–1996 ({chi}2 = 13.12, p < 0.001). In the subgroup of 48 women and 14 men with two or more prevalent radiographic fractures, 20 women and five men had died, yielding mortality rates of 41.7 percent and 35.7 percent, respectively. Table 2 shows sex- and age-adjusted comparisons by vital status separately within those who did and did not have at least one radiographically confirmed prevalent vertebral fracture. As shown for those with no prevalent vertebral fracture, participants who died had lower weight and body fat, consumed less alcohol (grams/week) and drank less frequently, had lower grip strength, exercised less, and were more likely to smoke than participants who survived, but there were no significant differences by mortality status in body mass index, lumbar spine bone mineral density, estrogen (among women), thyroid or thiazide medication use, or osteoporosis status defined by either National Osteoporosis Foundation or World Health Organization criteria (table 2). Among participants with prevalent vertebral fracture in 1992–1996, those who died had significantly lower body fat and grip strength and more often reported thiazide medication use compared with those who survived. However, there were no significant differences by mortality status in weight, body mass index, weekly alcohol consumption or frequency, lumbar spine bone mineral density, estrogen (women only) or thyroid medication use, current smoking status, exercise frequency, or osteoporosis based on either the National Osteoporosis Foundation or the World Health Organization definition (table 2).


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  		TABLE 2. Sex- and age-adjusted comparison* of characteristics, by vital status, of adults aged ≥50 years with and without vertebral fracture, Rancho Bernardo, California, 1992–1996

 
Prevalent vertebral fracture was not associated with all-cause mortality in a Cox model adjusted for covariates (adjusted hazard ratio = 1.09, 95 percent confidence interval: 0.84, 1.42; p = 0.53) (table 3). In this model, age, sex, total body fat, current smoking and exercise, grip strength, and alcohol consumption were each significantly and independently associated with mortality risk. In models stratified by sex and adjusted for covariates, prevalent vertebral fracture was not a significant risk factor for all-cause mortality for either women (adjusted hazard ratio = 1.15, 95 percent confidence interval: 0.83, 1.59; p = 0.40) or men (adjusted hazard ratio = 0.89, 95 percent confidence interval: 0.55, 1.46; p = 0.65). Analyses within women stratified by estrogen use also showed no significant associations between prevalent vertebral fracture and risk of all-cause mortality (data not shown). Low spine bone mineral density is a risk factor for vertebral fracture; analyses performed after adjustment for spine bone mineral density yielded similar associations between prevalent vertebral fracture and mortality risk (data not shown).


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  		TABLE 3. Adjusted* Cox proportional hazards estimates (and 95% confidence intervals) for all-cause mortality, Rancho Bernardo, California, 1992–2004

 
Cause of death was available for 340 (73.9 percent) of the 460 decedents. Overall, 73 deaths were due to cancer, 124 were due to cardiovascular disease including ischemic heart disease, and 143 were due to other causes. Other Cox models showed no evidence that vertebral fracture was associated with the risk of cancer or cardiovascular death, either overall or separately by sex. Among women (but not men) who died of causes other than cardiovascular disease and cancer, prevalent vertebral fracture was associated with increased mortality risk (adjusted hazard ratio = 1.59, 95 percent confidence interval: 1.03, 2.45; p = 0.04).

Because a single spine fracture defined by the classic methods of morphometry cannot always distinguish between a congenital anomaly and a fracture but two or more morphometric fractures are more likely to be osteoporotic fractures (13), we examined the association of two or more radiographically defined vertebral fractures with risk of all-cause mortality. Among the participants with prevalent vertebral fracture, a subsample of 14 men and 48 women had two or more radiographically defined vertebral fractures. Women, but not men, with two or more prevalent vertebral fractures had a significantly increased risk of all-cause mortality (hazard ratio = 1.56, 95 percent confidence interval: 1.01, 2.40; p = 0.04). Because it was possible that radiographic fractures were only a marker for subclinical fractures, we examined the proportion with spine fractures and nonspine fractures. Of those with radiographic fractures in our sample, 10.7 percent reported a history of spine fracture and 18.6 percent reported a history of nonspine fracture. It is therefore unlikely that radiographic fractures are only a marker for clinical fractures.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Increasing longevity is expected to escalate the public health burden of osteoporotic fractures (2, 3, 14). However, the effect of fractures on survival depends on the type of fracture (1). Hip fractures are the most consequential; 10–20 percent more women than expected for age die within the first year of a hip fracture, and this excess mortality is greater than that for men (1, 15). The risk of death is greatest in the months immediately after hip fracture and decreases with time (15). The effect of osteoporotic spine fracture on mortality in old age is less clear, with previous studies showing that death after a clinical spine fracture extends well beyond the first 6 months (5) to at least 1 year after the fracture (1, 4).

In this older community-dwelling cohort, the majority of men and women in this study had only one prevalent vertebral fracture, and the presence of one radiographically confirmed prevalent vertebral fracture was not a risk factor for all-cause or cause-specific mortality in either men or women during a 7.6-year follow-up. However, both men and women with two or more prevalent, radiographic vertebral fractures had relatively high mortality rates over the follow-up period. Although small numbers in men precluded further analyses, women who had two or more prevalent radiographic vertebral fractures at baseline were at greater risk for all-cause mortality than those without fracture, suggesting that the presence of multiple subclinical fractures may be a better marker than a single fracture (1, 4) and that the predictive utility of a single, subclinical vertebral fracture as a risk factor for death in old age may be eclipsed by the presence of other powerful comorbid conditions. The finding that women with one or more prevalent vertebral fractures were at increased risk of mortality due to causes other than cardiovascular disease and cancer is also in accord with those of Kado et al. (4) from an 8.3-year follow-up study of women, 20 percent of whom had had a vertebral fracture at baseline. Furthermore, the absent association for a single spine fracture is not surprising because a single spine fracture defined by the classic methods of morphometry cannot always distinguish between a congenital anomaly and a fracture, but two or more morphometric fractures are more likely to be osteoporotic fractures (13).

In this sample, as expected, women lived longer than men, and nonsmokers lived longer than smokers. In addition, as body fat, exercise frequency, grip strength, and alcohol consumption increased, so did survival. Others have reported that increased body fat is associated with reduced death rates in older populations (1, 16, 17), probably reflecting disease-associated weight loss. However, adjustment for body fat and these other covariates did not alter the results. Results of the present study are similar to those of a study of 9,704 women aged 65 years or older reporting that the association between bone mineral density and all-cause mortality was no longer significant in a model that included measures of self-reported health status, weight, muscle strength, cigarette smoking, and current physical activity (18).

Other population-based studies report increasing prevalence of radiographic vertebral fracture with increasing age in women aged 50 years or older around the world (1): Europe, 11.5 percent in those aged 50–54 years, gradually increasing to 34.8 percent in women aged 80–84 years; Minnesota, 4.7–50.8 percent; Hawaii, 0–26.3 percent; Hiroshima, Japan, 5.4–42.9 percent; Taiwan, 4.5–29.7 percent; and Beijing, China, 4.9–36.6 percent. Rates for men have generally been reported to be lower than for women (1–3, 14, 16, 18, 19). In the present study, prevalent vertebral fractures in women aged 50 years or older were similar to those reported in previous studies and significantly greater than those found in men (p < 0.01).

There appears to be an etiologic difference between clinically diagnosed vertebral fracture and radiographically confirmed prevalent vertebral fracture. In a review of 36 vertebral fracture studies, Haczynski and Jakimiuk (2) concluded that the relative risk of death is almost nine times higher for women who suffer a clinically diagnosed spine fracture and have symptoms severe enough to seek physician assistance. Information on history of symptoms compatible with a spine fracture was not available in the present study. Subclinical or unrecognized vertebral fracture first recognized by radiography is about three times more common than symptomatic fracture (1, 2). Studies of clinical and subclinical vertebral fractures are also difficult to compare because there is no universally accepted radiographic definition of vertebral fracture (1). The fact that, in the present study, those with vertebral fractures also had lower bone mineral density provides indirect evidence that the spine fractures were osteoporotic. In the European Prospective Osteoporosis Study, rates of radiographic vertebral fracture in women were two times greater than those in men (20). In accord, the present study found a rate of vertebral fracture in women more than 1.5 times higher than the rate for men, supporting the validity of the diagnosis of radiographically defined prevalent vertebral fracture.

Results of the present study disagree with those of Cooper et al. (5), who reported that in a Rochester, Minnesota, population, the ratio of observed-to-expected 5-year relative survival after clinically diagnosed vertebral fracture was lower in men than women regardless of age. However, this lack of accord may be due to differences in methodology. Cooper et al. (5) estimated survival by the product-limit method (Kaplan-Meier estimate), which compares an observed population with an expected sex-specific age-standardized estimate of the outcome, rather than a within-population comparison, and does not adjust for covariates as in the present study.

Comparisons with data from large, randomized controlled clinical trials of antiresorptive agents (19, 21–25) are not straightforward because those studies typically select subjects at increased fracture risk who nevertheless tend to be healthier than the general population, intervene with a treatment to prevent fracture, and are usually conducted among women only. Published baseline data show a 20.2 percent rate of prevalent vertebral fracture among the 13,372 women enrolled in the FIT-1 trial (25) and a 21.4 percent rate among the 6,828 women enrolled in the MORE trial (21), both of which are higher than the 13.0 percent found in the present study.

Although this study is strengthened by the use of radiographically confirmed vertebral fracture, the assessment of which had high reliability, several limitations were also considered. Post hoc sex-specific power calculations showed that, given the sample sizes, the power to detect an association between vertebral fracture and mortality was greater than 80 percent among women but less than 60 percent among men. Thus, the lack of association observed among men may have been due to a lack of statistical power. Prevalent vertebral fractures could have occurred years earlier and had a traumatic onset not associated with aging or osteoporosis. However, vertebral fractures after severe trauma are more common in men than in women and usually occur when men are younger (5). This study may have been biased by its use of survey recall data to establish health habits and by presuming that subjects' lifestyle activities did not change during the 7-year follow-up period, a limitation shared by most other studies of prevalent fracture and mortality. Rancho Bernardo study participants are White, are middle class, and reside in southern California, where vitamin D deficiency is uncommon (26); thus, we cannot exclude the possibility that these results may not be generalizable to others. In the present study, we measured grip strength and not quadriceps strength at this visit, the latter being a stronger risk factor for fracture.

In conclusion, in this sample of relatively healthy, ambulatory, community-dwelling older adults, a single radiographically prevalent vertebral fracture was not a risk factor for all-cause or cause-specific mortality. However, having two or more radiographically prevalent vertebral fractures may be a risk factor for mortality. Sporadic associations of vertebral fracture with causes other than cancer and cardiovascular disease in women may reflect a true association or one due to chance. The overall lack of significant association may reflect the unknown and varying underlying etiology of a single prevalent vertebral fracture. The National Osteoporosis Foundation and other bone organizations have determined that a spine fracture, with or without symptoms, predicts an increased risk of future clinical fractures at the spine and other sites, with the resulting morbidity and mortality. Thus, this observation in our study has public health implications. The development of new dual energy x-ray absorptiometry attachments for vertebral fracture assessment may make the diagnosis of subclinical fractures possible without spine radiography and expand this application for older adults (27, 28).


   ACKNOWLEDGMENTS
 
This research was supported by National Institute on Aging grant AG07181.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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