Abstract
-
Background
Vertebral fractures identified by radiographic morphometry are associated with increased mortality risk. However, there is limited data regarding the association between vertebral fractures detected by lateral spine dual energy X-ray absorptiometry (DXA) scans and the risk of mortality.
-
Methods
The present study was based on data from participants aged 40 years and older in the 2013 to 2014 cycle of the National Health and Nutrition Examination Survey (NHANES). Vertebral fracture assessment (VFA) performed using lateral spine DXA scans was used to provide fracture information of the vertebrae from T4 to L4. Vertebral fracture severity was categorized according to Genant’s semiquantitative technique and the NHANES 2019 public-use linked mortality files were used to determine mortality status.
-
Results
Of 3,219 participants, the prevalence of vertebral fractures identified by VFA was 5.5% (95% confidence interval [CI], 4.7–6.5). During a median follow-up of 71.0 months, 277 participants died, 18.2% (95% CI, 12.2–26.3) with vertebral fractures and 6.3% (95% CI, 5.0–8.0) without fractures (P<0.0001). Cox regression analysis demonstrated that participants with moderate to severe vertebral fractures (>25% height loss) were 1.7 times more likely to die compared with their counterparts without (hazard ratio [HR], 1.79; 95% CI, 1.05–3.04). Notably, in a subgroup analysis, older adults (HR, 2.16; 95% CI, 1.41–3.30) and men with vertebral fractures (HR, 2.28; 95% CI, 1.49–3.47) had a 2-fold greater mortality risk compared to those without vertebral fractures.
-
Conclusions
Vertebral fracture severity identified by VFA was significantly associated with greater all-cause mortality risk. This association was also observed among men and older adults with any baseline vertebral fractures.
-
Key words: DXA scan · Mortality · Vertebral fractures · Vertebral fracture assessment
GRAPHICAL ABSTRACT
INTRODUCTION
Vertebral fractures, the most common type of osteoporotic fractures, are associated with considerable pain, functional limitations, and impaired quality of life. [
1,
2] Fractures detected by spinal radiographs also predict future vertebral and non-vertebral fractures, independent of bone mineral density (BMD).[
3,
4] In general, vertebral fractures are similarly distributed by gender, increase with age, and differ according to geographic regions.[
2,
5] Notably, vertebral fractures may be asymptomatic and frequently underreported on radiographs.[
6,
7] Several studies have previously demonstrated that vertebral fractures identified by radiographic morphometry are associated with mortality risk, particularly in older women with osteoporosis.[
8–
11]
Vertebral fracture assessment (VFA) with dual energy X-ray absorptiometry (DXA) has been proposed as an alternative approach for the identification of vertebral fractures owing to low-dose radiation exposure, high positive predictive value, significant agreement as compared with spinal radiographs, and simultaneous measurements of BMD. Moreover, the detection of vertebral fractures by VFA has important clinical implications regarding BMD monitoring and treatment of osteoporosis.[
2,
12,
13]
Despite these facts, there is scarce data with contradictory results regarding the association between vertebral fractures identified by VFA and mortality risk.[
14,
15] Schousboe et al. [
14] in a large cohort of older adults meeting criteria for VFA described a weak association between vertebral fractures and mortality risk. In contrast, participants in the Tromsø study with severe vertebral fractures or ≥3 vertebral fractures detected by VFA, and after a mean follow-up of 11.2 years, had 1.6- and 2.4-fold greater all-cause mortality risk than their counterparts without fractures, respectively.[
15] Thus, the present study aimed to examine the association between vertebral fractures identified by VFA and all-cause mortality risk, in a nationally representative sample of adults.
METHODS
1. Study population
The National Health and Nutrition Examination Survey (NHANES) is a continuous biannual study conducted by the National Center for Health Statistics (NCHS) to assess the health and nutritional status of adults in the United States. Data from participants aged 40 years and older in the NHANES cycle 2013 to 2014 were used for the present study. The NHANES protocol was approved by the NCHS Research Ethics Review Board (continuation of protocol # 2011-17) and informed consent was obtained from all participants. A detailed description of the methods and analytic guidelines used in the NHANES can be found at:
https://wwwn.cdc.gov/nchs/nhanes/analyticguidelines.aspx.
VFA was obtained using lateral spine DXA scans on Hologic Discovery model A densitometers (Hologic Inc., Bedford, MA, USA) and provided fracture information for vertebrae T4-L4. All scans were analyzed by Optasia Spinalizer software using Genant’s semiquantitative technique, which was categorized as normal, mild, 20% to 25% loss of height; moderate, 25% to 40% loss of height; and severe, >40% loss of height. VFA images were read by a single reader at the University of California, San Francisco, and scans of participants who were coded as having a vertebral deformity on any vertebrae were re-examined by Dr. Genant to confirm fracture status.[
16] For this analysis, participants with more than one fracture were classified by the most severe fracture.
The demographic characteristics of the participants were self-reported. Smoking status was categorized as never, former, or current smoker. Moderate alcohol consumption was defined if women reported up to 1 drink per day and men up to 2 drinks per day.[
17] Participants reported the time spent in moderate or intense recreational physical activity during the previous week. Then, the level of physical activity was classified according to the Physical Activity Guidelines for Americans.[
18] In the mobile examination center, body mass index (BMI) was determined by dividing weight in kilograms by height in meters squared. Diabetes mellitus was prevalent if participants reported a physician’s diagnosis of diabetes or had a hemoglobin A1c ≥6.5%. [
19] Hypertension was defined as a systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg based on the mean of three consecutive blood pressure readings or reporting the use of prescribed medications for hypertension.[
20] Participants were considered to have a prevalent cardiovascular disease if they responded positively to the question “Has a doctor ever told you that you had coronary heart disease, angina pectoris, heart attack, or stroke?” Total lumbar spine (L1–L4) and femur scans were performed with a Hologic QDR 4500A fan-beam densitometers (Hologic Inc.), using software version Apex 3.2. T-scores for the femoral neck were calculated using the mean BMD of non-Hispanic white females aged 20 to 29 years from NHANES III as the reference group. Participants with a femoral neck T-score of ≤-1 were defined as having low bone mass.[
21]
The public-use-linked mortality files provided mortality follow-up data from the date of survey participation through December 31, 2019. These data were obtained from the National Death Index. Time to death was calculated in months and the underlying cause of death was classified according to the International Classification of Diseases, Tenth Revision (ICD-10) codes.
5. Statistical analysis
The prevalence of vertebral fractures based on selected participant characteristics was compared using the χ2 test. Kaplan-Meier curves were used to estimate survival probability over time according to vertebral fracture prevalence (yes vs. none), number of fractures (0, 1, and ≥2 fractures), and severity of vertebral fractures (none, mild, and moderate/severe), which were compared using the log-rank test. Subsequently, Cox proportional hazard models were developed to assess the association between vertebral fractures and the mortality risk. Model 1 was adjusted for age, gender, race/ethnicity, education, and BMI (kg/m2). Model 2 was further adjusted for smoking status, moderate alcohol use, physical activity, diabetes, hypertension, self-reported cardiovascular disease, and total lumbar spine and femoral neck BMD. Similarly, in a subgroup analysis, the association between prevalent vertebral fractures and all-cause mortality was examined by age groups, sex, and femoral neck T-scores. Results are presented as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Stata version 18 (Stata Corp., College Station, TX, USA) survey data analysis command was used to incorporate NHANES examination sampled weights and to adjust for non-response and oversampling of certain populations. A P-value less than 0.05 was considered statistically significant.
RESULTS
The study sample comprised 3,219 participants with a mean age of 57.2 years (standard error, 0.2). Overall, the prevalence of vertebral fractures identified by VFA was 5.5% (95% CI, 4.7–6.5) among adults aged 40 years and older. In addition, the prevalence of moderate to severe vertebral fractures and ≥2 fractures occurred in 3.2% (95% CI, 2.4–4.3) and 1.8% (95% CI, 1.2–2.6) of participants, respectively.
As shown in
Table 1, the prevalence of vertebral fractures was significantly increased among older adults, non-Hispanic whites, former smokers, subjects with hypertension, and particularly those with osteoporosis. During a median follow-up of 71.0 months, 277 participants died. Of those, 18.2% (95% CI, 12.2–26.3) with vertebral fractures and 6.3% (95% CI, 5.0–8.0) without fractures (
P<0.0001). In general, malignant neoplasms and diseases of the heart were reported as the leading underlying causes of death in 27.6% (95% CI, 21.4–34.7) and 23.3% (95% CI, 17.3–30.5) of the decedents, respectively.
Kaplan-Meier curves showed a decrease in survival probability among participants with prevalent vertebral fractures (
Fig. 1). Also, shorter survival occurred in subjects with ≥2 vertebral fractures and particularly among those with moderate to severe vertebral fractures, which appear to diverge about 40 months into the study period (
Fig. 2,
3).
As shown in
Table 2, Cox regression analysis demonstrated that participants with baseline prevalent vertebral fractures and those with ≥2 vertebral fractures had 40% and 49% greater all-cause mortality risk compared with their counterparts without fractures, respectively. However, these associations did not reach statistical significance. In contrast, after adjusting for potential confounders including lumbar spine and femoral neck BMD, participants with moderate to severe vertebral fractures (≥25% height loss) were 1.7 times more likely to die than those without fractures (HR, 1.79; 95% CI, 1.05–3.04).
In a subgroup analysis, older adults with any vertebral fracture had 2-fold greater all-cause mortality risk than those without (HR, 2.16; 95% CI, 1.41–3.30). Similarly, men with prevalent vertebral fractures were 2.2 times more likely to die than their counterparts without (HR, 2.28; 95% CI, 1.49–3.47). In contrast, a baseline vertebral fracture identified by VFA did not significantly increase the risk of mortality among younger participants, women, or according to BMD status (
Table 3).
DISCUSSION
In a nationally representative sample, adults with baseline moderate to severe vertebral fractures identified by VFA, and during a median follow-up of 71 months, were 1.7 times more likely to die than their counterparts without vertebral fractures. Likewise, participants with any vertebral fracture had 1.5-fold higher risk of dying. However, after adjusting for behavioral characteristics, comorbidities, and BMD, this association was attenuated and did not reach statistical significance. Notably, in a subgroup analysis, older adults and men with any prevalent vertebral fracture had 2-fold greater mortality risk than those who did not.
In agreement with the present results, participants in the Tromsø study with severe vertebral fractures identified by VFA, and after a mean follow-up time of 12.2 years, had 1.6-fold higher mortality risk than those without fractures. However, in that study, the prevalence of any vertebral fracture did not significantly increase the risk of mortality. [
15] A large cohort study among older adults with a T-score of ≤ −1.5 and meeting criteria for VFA also reported a weak association between prevalent vertebral fractures and all-cause mortality risk.[
14] Prior studies using radiographic morphometry have demonstrated a non-significant association between prevalent vertebral fractures and mortality risk.[
10,
11,
22] Possible explanations for differences in study results might be related to the characteristics of participants, methods used to define vertebral fractures, and follow-up time.
Although a small number of participants had ≥2 vertebral fractures identified by VFA, the mortality rate was significantly higher than those without fractures. However, after adjusting for possible confounders, the HR did not reach statistical significance. The present findings differed from those in the Tromsø study in which participants with ≥3 vertebral fractures had 2.4-fold greater mortality risk than their counterparts without fractures, even after adjusting for total hip BMD.[
15] Likewise, in the Study of Osteoporotic Fractures, women with multiple vertebral fractures or severe fractures had the greatest increase in mortality risk over time, regardless of whether they were aware of their fractures.[
8,
9] Moreover, in the Rancho Bernardo study, women with ≥2 vertebral fractures had a 56% increased risk of all-cause mortality.[
22]
Of relevance, in a subgroup analysis, men with any baseline prevalent vertebral fracture had 2-fold higher risk of all-cause mortality than those who did not. Similarly, Son et al. [
23] using data from a cohort study in South Korea reported that older men with prevalent vertebral fractures, and after a mean follow-up period of 5.8 years, were 1.8 times more likely to die as compared with women. Previously, Edidin et al. [
24] described among Medicare beneficiaries that mortality risk was higher in men than in women for operated and non-operated vertebral compression fractures, even after controlling for comorbidities, which is consistent with the present study results.
The association between vertebral fractures and mortality risk has not been completely elucidated. Nevertheless, excess mortality does not appear to be exclusively explained by poor health status.[
8] In fact, in a large cohort of patients hospitalized for vertebral fractures only 28% of the deaths were attributed to the vertebral fracture itself.[
25] Schousboe [
26] postulated that increased mortality risk may be linked to loss of functional capacity and physical performance following vertebral fractures, which may subsequently reduce the physiological reserve to withstand the stress of comorbidities. Kado et al. [
27] also reported that older women with incident vertebral fractures may have an increased risk of mortality that may be explained by weight loss and physical frailty. Notably, in the Dubbo Osteoporosis Epidemiology Study, among participants with vertebral fractures, those with quadriceps muscle weakness had a greater mortality risk than their counterparts who did not. [
28] Similarly, in the MrOs cohort study, older men with fractures who were unable to complete physical performance measurements had a greater risk of post-fracture mortality than those who did not.[
29] Although prevalent vertebral fractures are associated with greater thoracic kyphosis, women with prevalent vertebral fractures and increased kyphosis are at greater risk of mortality than those without fractures.[
30,
31] More recently, severe kyphosis in older men was also reported to increase mortality risk, independent of prior vertebral fractures.[
32] This association has been explained by impaired pulmonary function, poor physical function, incident fractures and falls, which may subsequently increase the risk for mortality.[
31]
Although the cause-specific mortality associated with vertebral fractures has not been consistently described across studies, older women with vertebral fractures were 2 to 3 times more likely to die of pulmonary causes.[
9] Likewise, a long-term population-based study in Finland demonstrated that men and women with vertebral fractures of the thoracic spine had 3- and 8-fold higher risk of dying from respiratory diseases and injuries than their counterparts without fractures, respectively.[
10] Choi et al. [
33] using data from the Korean National Health Insurance Service similarly described higher mortality rates for diseases of the musculoskeletal, digestive, and respiratory systems among subjects with vertebral fractures.
Clinically relevant, pharmacological treatments and minimally invasive surgery for vertebral fractures have been shown to potentially decrease the risk of mortality. Iida et al. [
34] reported that among older Japanese hospitalized for vertebral fractures, the use bisphosphonates improved survival by 41%. Likewise, a secondary data analysis of the Taiwanese Health Insurance also demonstrated that older adults with vertebral fractures who received treatment for osteoporosis had 26% greater survival than those who did not. Furthermore, survival rate improved by 66% among those treated ≥3 years.[
35] Despite this evidence, the use of osteoporosis medication in U.S. postmenopausal women has decreased over time and it is suboptimal even in women with osteoporosis.[
36] Among Medicare beneficiaries diagnosed with vertebral fractures identified from inpatient and outpatient claims, and after a follow-up period of 4 years, patients who underwent vertebroplasty or kyphoplasty were 37% less likely to die than non-operated vertebral fracture patients, which was attributed to improvement in their pulmonary function.[
24]
The present study has several limitations that should be mentioned. First, as an observational study, the causality of the association between vertebral fractures and all-cause mortality risk may not be established. Second, the mortality risk was limited to baseline vertebral fractures identified by VFA. Thus, comorbidities or events leading to mortality during the follow-up period could not be determined. Third, the present study has limited power to examine the association between vertebral fractures and cause-specific mortality. Despite these limitations, the present findings may be generalized to U.S. middle-aged and older adults.
In conclusion, vertebral fracture severity identified by VFA was significantly associated with greater all-cause mortality risk. This association was also demonstrated among older adults, including men, with any baseline vertebral fractures. These findings underscore the importance of broader implementation of VFA during routine DXA scans and highlight the need for further research to elucidate the sequence of events leading to increased mortality risk following vertebral fractures.
DECLARATIONS
-
Funding
The authors received no financial support for this article.
-
Ethics approval and consent to participate
The NHANES protocol was approved by the NCHS Research Ethics Review Board (continuation of protocol # 2011-17) and informed consent was obtained from all participants.
-
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Fig. 1Prevalence of vertebral fractures and all-cause mortality.
Fig. 2Number of vertebral fractures and all-cause mortality.
Fig. 3Vertebral fracture severity and mortality risk.
Table 1Prevalence of vertebral fractures according to characteristics of participants, National Health and Nutrition Examination Survey 2013–2014
Table 1
|
Variables |
No. |
% (SE)a)
|
P-value |
|
Age-group (yr) |
|
|
<0.0001 |
|
40–59 |
1,732 |
3.2 (0.4) |
|
|
≥60 |
1,487 |
9.1 (0.8) |
|
|
|
Gender |
|
|
0.142 |
|
Male |
1,558 |
6.4 (0.7) |
|
|
Female |
1,661 |
4.8 (0.5) |
|
|
|
Race/ethnicity |
|
|
<0.05 |
|
Hispanic |
716 |
2.8 (0.5) |
|
|
Non-Hispanic white |
1,422 |
6.5 (0.4) |
|
|
Non-Hispanic black |
647 |
2.6 (0.4) |
|
|
Multiracial |
434 |
4.6 (1.8) |
|
|
|
Education |
|
|
0.894 |
|
≤11th grade |
746 |
5.0 (1.3) |
|
|
High school graduate |
720 |
6.0 (0.9) |
|
|
Some college |
913 |
5.7 (1.0) |
|
|
College graduate |
838 |
5.3 (0.7) |
|
|
|
BMI (kg/m2) |
|
|
0.088 |
|
Normal |
864 |
7.4 (1.1) |
|
|
Overweight |
1,151 |
5.3 (0.6) |
|
|
Obesity |
1,204 |
4.6 (0.7) |
|
|
|
Smoking |
|
|
<0.05 |
|
Never |
1,719 |
4.6 (0.4) |
|
|
Former |
900 |
8.0 (1.0) |
|
|
Current |
600 |
4.5 (1.0) |
|
|
|
Moderate alcohol useb)
|
|
|
0.135 |
|
Yes |
1,929 |
4.8 (0.5) |
|
|
No |
1,290 |
7.1 (1.2) |
|
|
|
Physical activity |
|
|
0.155 |
|
Yes |
945 |
4.4 (0.7) |
|
|
No |
2,274 |
6.1 (0.6) |
|
|
|
Diabetes |
|
|
0.739 |
|
Yes |
686 |
5.2 (1.2) |
|
|
No |
2,533 |
5.6 (0.3) |
|
|
|
Hypertension |
|
|
<0.05 |
|
Yes |
1,981 |
6.9 (0.5) |
|
|
No |
1,238 |
3.6 (0.6) |
|
|
|
Cardiovascular disease |
|
|
0.248 |
|
Yes |
376 |
7.0 (1.3) |
|
|
No |
2,828 |
5.4 (0.4) |
|
|
|
BMDc)
|
|
|
<0.0001 |
|
Osteoporosis |
152 |
20.4 (3.2) |
|
|
Osteopenia |
1,101 |
6.9 (1.1) |
|
|
Normal |
1,966 |
3.7 (0.4) |
|
Table 2The association between vertebral fractures identified by vertebral fracture assessment and mortality risk in adults
Table 2
|
Variables |
No. |
Time at riska)
|
Rateb)
|
HR (95% CI)c)
|
HR (95% CI)d)
|
|
Vertebral fracture |
|
No |
3,033 |
211,229 |
1.10 |
1.00 |
1.00 |
|
Yes |
186 |
12,151 |
3.53 |
1.59 (1.00–2.51)
|
1.40 (0.88–2.25) |
|
|
Number of fractures |
|
None |
3,033 |
211,229 |
1.10 |
1.00 |
1.00 |
|
1 |
125 |
8,267 |
3.38 |
1.66 (1.00–2.76) |
1.36 (0.80–2.31) |
|
≥2 |
61 |
3,888 |
3.86 |
1.46 (0.74–2.88) |
1.49 (0.76–2.90) |
|
|
Fracture severity |
|
None |
3,033 |
211,229 |
1.10 |
1.00 |
1.00 |
|
Mild |
72 |
5,016 |
1.59 |
0.69 (0.27–1.77) |
0.69 (0.26–1.82) |
|
Moderate/severe |
114 |
7,135 |
4.90 |
2.15 (1.26–3.65)
|
1.79 (1.05–3.04)
|
Table 3Baseline prevalence of vertebral fractures and mortality risk according to age, gender, and bone mineral density
Table 3
|
Variables |
No. |
Time at riska)
|
Rateb)
|
HR (95% CI)c)
|
HR (95% CI)d)
|
|
Aged 40–59 yr |
|
No |
1,686 |
119,866 |
0.40 |
1.00 |
1.00 |
|
Yes |
46 |
3,288 |
0.91 |
0.83 (0.19–3.54) |
0.45 (0.06–3.00) |
|
|
Aged ≥60 yr |
|
No |
1,347 |
91,363 |
2.02 |
1.00 |
1.00 |
|
Yes |
140 |
8,863 |
4.51 |
2.37 (1.46–3.85)
|
2.16 (1.41–3.30)
|
|
|
Male |
|
No |
1,453 |
100,675 |
1.15 |
1.00 |
1.00 |
|
Yes |
105 |
6,755 |
4.14 |
2.29 (1.48–3.54)
|
2.28 (1.49–3.47)
|
|
|
Female |
|
No |
1,580 |
110,554 |
1.06 |
1.00 |
1.00 |
|
Yes |
81 |
5,396 |
2.77 |
1.05 (0.48–2.30) |
0.89 (0.41–1.93) |
|
|
Normal BMD |
|
No |
1,893 |
132,358 |
0.88 |
1.00 |
1.00 |
|
Yes |
73 |
4,997 |
2.60 |
1.62 (0.93–2.83) |
1.79 (0.99–3.22) |
|
|
Low BMDe)
|
|
No |
1,140 |
78,871 |
1.48 |
1.00 |
1.00 |
|
Yes |
113 |
7,154 |
4.19 |
1.50 (0.89–2.55) |
1.39 (0.81–2.39) |
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