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Keywords:

  • EPIDEMIOLOGY;
  • POPULATION STUDY;
  • VITAMIN D;
  • OSTEOPOROSIS;
  • FRACTURE

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Results from previous prospective studies linking serum 25-hydroxyvitamin D (25OHD) with fracture risk have been inconsistent. The present study examined the relationship between serum 25OHD and risk of incident major osteoporotic fracture (hip, spine, radius, and humerus) in older U.S. adults. The study used a pooled cohort of 4749 men and women ages 65 years and older from the third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) and NHANES 2000–2004. Incident fractures were identified using linked mortality and Medicare records that were obtained for participants from both surveys. Serum 25OHD values were measured by radioimmunoassay in both surveys. Cox proportional hazards models were used to estimate the relative risk (RR) of fracture by serum 25OHD level. There were 525 incident major osteoporotic fractures (287 hip fractures) in the sample. Serum 25OHD was a significant linear predictor of major osteoporotic fracture and significant quadratic predictor of hip fracture in the total sample and among those with less than 10 years of follow-up, but it was not related to risk of either fracture type among those with ≥10 years of follow-up. Major osteoporotic fracture risk was increased by 26% to 27% for each SD decrease in serum 25OHD among those with less than 10 years of follow-up. Serum 25OHD was significantly related to risk of major osteoporotic fractures as a group and to hip fracture alone in this cohort of older U.S. adults from NHANES III and NHANES 2000–2004. However, the predictive utility of serum 25OHD diminished after 10 years. In addition, the relationship appeared to be linear when major osteoporotic fracture risk was considered but quadratic when hip fracture risk was assessed. © 2013 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Vitamin D is known to be important for skeletal health, but several aspects of its relationship with fracture risk remain unclear. Several prospective studies have examined the relationship between fracture risk and serum 25-hydroxyvitamin D (25OHD), the preferred indicator of vitamin D.1–16 Slightly more than one-half of the studies published to date have reported a significant relationship between 25OHD and fracture risk for at least one of the skeletal sites studied,2–10, 16 but several others have found no significant relationship.3, 11–15 These studies have varied in terms of the skeletal sites and race/ethnic groups considered, and most have been limited to a single sex.2–4, 6, 8, 9, 12–14 Only one has reported results separately by race/ethnicity.4

A significant relationship between serum 25OHD and hip fracture was observed in a previous analysis of linked Medicare and mortality data from respondents in the third National Health and Nutrition Examination Survey (NHANES III).10 That study was limited to hip fracture risk in whites and analyses were performed for both sexes combined. Since completion of that study, an additional 7 years of follow-up of respondents from NHANES III have been obtained and from follow-up of respondents from NHANES 1999–2004 has been conducted. The present study expands the NHANES analysis by pooling all available mortality and Medicare-linked data for these two NHANES surveys; similar pooling of data for cohorts based on NHANES or other nationally representative health surveys has been successfully employed in other studies.17, 18 In addition, the present study expands the fracture outcomes to include major osteoporotic fracture, as defined by the fracture risk assessment tool (FRAX) model (eg, hip, medically-diagnosed vertebral, humerus, or radius fracture).19 The relationship between serum 25OHD and major osteoporotic fracture as a group and for hip fracture alone is examined by age, sex, and race/ethnicity, and also by recently recommended thresholds for serum 25OHD.1, 20

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Sample

The baseline data for this study came from NHANES III and NHANES 2000–2004, which were conducted by the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention, to assess the health and nutritional status of a large representative sample of the non-institutionalized, civilian population of the United States. In NHANES III, a nationally representative sample was obtained in two 3-year cycles between 1988 and 1994. The NHANES became a continuous survey starting in 1999, and from that date data were collected from a nationally representative sample every year. Although a representative sample is collected annually, data are released in 2-year periods starting with 1999 to protect confidentiality and increase statistical reliability. The present study is based on data from the continuous NHANES for the years 2000–2004 because serum 25OHD data were not collected in 1999. All procedures in each NHANES were approved by the NCHS Institutional Review Board, and written informed consent was obtained from all subjects.21, 22

In each NHANES, data were collected via household interviews and direct standardized physical examinations conducted in specially equipped mobile examination centers.21, 22

NHANES III and NHANES 2000–2004 were designed to provide reliable estimates for three race/ethnic groups: non-Hispanic whites (NHW), non-Hispanic blacks (NHB), and Mexican Americans (MA). Race and ethnicity were self-reported in both surveys.

Both surveys were linked with data from the mortality files created for each survey by NCHS and with Medicare enrollment and claims records in order to provide a longitudinal component to the survey. Vital status of study participants through 2006 was determined from the NHANES III and NHANES 2000–2004 Linked Mortality Files.23 These files contain mortality follow-up data based on a probabilistic match between the eligible NHANES III and NHANES 2000–2004 samples and the National Death Index (NDI). Vital status data are available for individuals from the date of their participation in the NHANES III and NHANES 2000–2004 surveys through December 31, 2006. In addition to data on vital status, information on underlying and multiple causes of death are available in this file. Vital status for the year 2007 was based on status from the Medicare Denominator file.24

Medicare enrollment and utilization data were available for NHANES respondents who agreed to provide personal identification.24 Of those who were age 65 years and older at the time of the Medicare linkage, 97% (n = 8024) of the 8303 eligible respondents from NHANES III and 98% (n = 4103) of the 4189 eligible respondents from NHANES 2000–2004 were successfully validated and matched with Medicare administrative records. Medicare claims data were provided from respondents who participated in fee-for-service care from 1991 through 2007 for NHANES III and for 1999 through 2007 for NHANES 2000–2004. Claims data were not available for those who enrolled in Medicare managed care plans. In the present study, claims data from the following files were used: Medicare Provider Analysis and Review (MEDPAR) Inpatient Hospital Stay File/Skilled Nursing Facility (SNF) File, Carrier Standard Analytic File, and Outpatient Standard Analytic File. The Medicare Denominator files were used to restrict the analytic sample to those who were successfully matched to the Medicare claims data, to obtain information about enrollment in managed care plans and to provide vital status for the year 2007.

The analytic sample in this study was restricted to individuals ages 65 years and older at the time of their NHANES interview at baseline, because Medicare provides comprehensive health care for roughly 98% of the U.S. population in this age range.25 In the Supplementary Appendix 1, Table A shows the number of persons excluded from the analytic sample and reason for exclusion for each survey. After excluding a total of 1146 individuals, 2946 (71%) of the original 4092 eligible interviewed and examined individuals from NHANES III were included in the final analytic sample. After excluding a total of 1562 individuals, 1803 (53%) of the original 3365 eligible interviewed and examined individuals from NHANES 2000–2004 were included in the final analytic sample. Approximately 16% of the eligible interviewed and examined sample from both surveys was excluded as a result of prior fracture at baseline. A relatively large number of respondents in NHANES 2000–2004 also had to be excluded because they were either ineligible for linkage to the Medicare denominator file or were enrolled in a health maintenance organization (HMO) at the time of their baseline examination. Descriptive characteristics and risk factors were compared between respondents who were retained versus excluded from the analytic sample in order to assess the potential for nonresponse bias in our results. The excluded respondents were older, more likely to be women, have blood drawn between November and April, have shorter height, and reported smoking, having poorer health and less activity than respondents who were included. Serum 25OHD levels were slightly, albeit not significantly, lower in excluded respondents.

Fracture case identification

Major osteoporotic fracture cases were identified using an approach based on methods developed by Ray and colleagues,26 Taylor and colleagues,27 and Curtis and colleagues.28 Cases were defined using relevant International Classification of Disease (ICD), Healthcare Common Procedure Coding System (HCPCS), or Current Procedural Terminology (CPT) codes for the years 1991–2007.29, 30 Cases identified from the MedPAR Hospital Inpatient/Skilled Nursing Facility files were based on ICD-9 diagnosis codes (primary diagnosis only for spine; any of 10 discharge diagnoses for hip, radius, or humerus). Cases identified from the Carrier file were based on ICD-9 diagnosis codes (principal diagnosis only for spine; any of five diagnoses for hip, radius, or humerus) and a concurrent relevant HCPCS/CPT procedure code. Cases identified from the Outpatient File were based on ICD diagnosis codes (principal only for spine; any of 11 diagnoses for hip, radius, or humerus) or ICD-9 surgical procedure code (hip, radius, humerus) and a concurrent relevant HCPCS/CPT code for any of 45 procedure variables. Respondents with codes indicating care of previous fracture or other bone diseases, neoplasm, or hip arthroplasty for arthritis were excluded from the analyses. Details regarding the definition of cases from Medicare records, including specific codes, are provided in Supplementary Appendix 2.

Cause of death information from the NHANES III and NHANES 2000-2004 Linked Mortality Files were also used to identify hip fracture. Persons with an ICD-9 code 820 or ICD-10 code S72.0–S72.2 listed as an underlying or multiple cause of death on their death certificate were also considered to be hip fracture cases (n = 47 from NHANES III; n = 8 from NHANES 2000–2004).

A total of 525 major osteoporotic fracture cases were identified in the analytic sample used in the present study. These cases consisted of 287 hip fractures (55%), 105 radius fractures (20%), 83 medically diagnosed (clinical) spine fractures (16%), and 50 humerus fractures (10%). This pattern of fractures in adults over age 65 years is similar to that seen in other studies of fracture based on Medicare data from older adults.27, 31 The majority of fracture cases (n = 328, or 62% of major osteoporotic cases; n = 221, or 77% of hip fracture cases) in the analytic sample had diagnoses consistent with fracture on records from more than one source (eg, inpatient hospital/SNF, carrier, outpatient, and/or death records). Of the 274 hip fracture cases that were identified via inpatient hospital records, 89% also had relevant surgical codes for hip fracture.

Variables

Serum 25OHD was assayed with a radioimmunoassay (RIA) kit (DiaSorin, Stillwater MN, USA) at the National Center for Environmental Health (CDC, Atlanta, GA, USA) in both surveys. Based on quality control pools that passed specification limits, the interassay coefficient of variation (CV) was 15% to 25% for lower values (20–62 nmol/L) and 14% to 18% for higher values (86–143 nmol/L) during NHANES III, and 8.3% to 11% for lower values (24–58 nmol/L) and 10% for higher values (102–112 nmol/L) during NHANES 2000–2004. Long-term performance of this laboratory in the international Vitamin D External Quality Assessment Scheme (DEQAS) proficiency testing program was excellent. Details of the assay methods have been published elsewhere.32, 33 A previous study indicated that serum 25OHD values from NHANES III and NHANES 2000–2004 were not directly comparable even though the same assay had been used, so serum 25OHD from NHANES III was adjusted to be comparable to serum 25OHD from NHANES 2000–2004 using a previously published equation.34 Serum 25OHD was examined both as a continuous and categorical variable using thresholds that were recently recommended by the Institute of Medicine (IOM)1 and Endocrine Society.20

Several variables were used to make exclusions from the sample or were evaluated for use as confounders in multivariate models. Only variables that were measured comparably in the two surveys were used. For example, because bone mineral density was not measured at the same skeletal site in the two surveys, it could not be included as a co-variable. Variables that were measured during the physical examination included body weight and height, which were used to calculate body mass index (BMI, equal to body weight in kilograms, divided by height in meters squared).20 Variables obtained by interview at baseline included age, self-reported race-ethnicity, calcium from food (mg/d) from a 24-hour recall, self-reported hip, wrist, or spine fracture, smoking status (current, former, never), alcohol consumption (drinks per day), self-reported physical activity level compared to others of the same age and sex or compared to the respondent's activity level 10 years prior to baseline (same, higher, lower), self-rated health status (excellent/very good/good versus fair/poor), and maternal history of hip fracture. Because NHANES examinations are performed in southern latitudes during the winter and northern latitudes during the summer, season of blood collection (November–April versus May–October) was also evaluated as a potential confounder.

Finally, use of prescription drugs to treat osteoporosis was evaluated. In both surveys, respondents showed the containers for all current prescription medications to the interviewer, who recorded the name of the product. The December 2007 Multum Lexicon Drug Database (Cerner Multum Inc, Denver, CO, USA; http://www.multum.com/Lexicon.htm) was used to assign generic drug names and codes in both surveys. These medications included sex hormones (estrogen and testosterone), bisphosphonates, selective estrogen receptor modifiers (SERMs), teriparatide, calcitonin, calcitriol, ergocalciferol, sodium fluoride, calcium acetate, tibolone, and strontium ranelate.

Statistical analysis

All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA) and SUDAAN software35 for analysis of data from complex sample surveys. Descriptive characteristics and risk factors at baseline were compared between fracture cases and non-cases using linear regression models and chi-square analyses. To control for all risk factors simultaneously and to account for unequal length of follow-up, Cox proportional hazards models were used to model time to event and to calculate estimates of the relative risk (RR) of major osteoporotic fractures as a group and hip fracture alone by serum 25OHD. For cases, length of follow-up was calculated as the time from date of examination to date of diagnosis or procedure for the relevant fractures identified by Medicare records or date of death for hip fractures identified by death certificates. For non-cases, follow-up time was calculated as time from baseline exam to date of death for decedents, date of entry into managed care for those who enrolled in a Medicare managed care program after their baseline examination, or end of follow-up on December 31, 2007 for those who did not fall into the first two categories.

Analyses to assess the validity of pooling results for NHANES III and NHANES 2000–2004 supported the combination of the analytic sample from the two surveys. Specifically, after adjusting for age, sex, and race/ethnicity, the RR per SD decline (1 SD = 21.1 nmol/L) in serum 25OHD did not differ significantly between surveys for major osteoporotic fracture (RR = 1.2 and 1.3 for NHANES III and NHANES 2000–2004, respectively; p > 0.05) or hip fracture alone (RR = 1.8 and 1.2 for NHANES III and NHANES 2000–2004, respectively; p > 0.05). In addition, the survey × serum 25OHD interaction term included in the Cox model applied to the pooled sample from the two surveys was not statistically significant for either major osteoporotic fracture (p = 0.55) or hip fracture (p = 0.10), which indicates that the relationship between serum 25OHD and fracture risk did not differ in the two surveys.

The proportional hazard assumption was tested by examining the consistency of the RR for major osteoporotic fracture and hip fracture across follow-up time for the pooled sample and separately by survey, because the two surveys differed in the amount of follow-up time. The risk of major osteoporotic fracture as a group and hip fracture alone differed significantly with increasing follow-up time in the pooled sample when based on the entire follow-up period (p < 0.001) but not when follow-up time was divided into <10 years versus ≥10 years. Results were similar when analyzed separately by survey. As a result, results for major osteoporotic fracture and hip fracture were analyzed by these follow-up time categories as well as for the combined follow-up period.

The best fitting model to describe the relationship between serum 25OHD and fracture risk was assessed by using an approach suggested by Korn and Graubard,36 in which a series of Cox models were calculated that successively included linear, quadratic, and cubic terms for serum 25OHD in addition to adjusting for age, sex, race/ethnicity, and survey period. The best model was chosen based on the statistical significance of the linear, quadratic, or cubic term for serum 25OHD. The predicted relative risk per 1 nmol/L change in serum 25OHD was calculated based on the best-fitting model and a smoothed plot was created using locally weighted regression (PROC LOESS) after truncating the serum distribution at 135 nmol/L in order to avoid extrapolation of fracture risk for serum 25OHD in a range where no cases were observed. Truncating the serum 25OHD distribution at 135 nmol/L for this graph resulted in excluding seven individuals, or less than 0.5% of the study population.

Cox regression models were also used to explore the relationship between serum 25OHD and risk of major osteoporotic fracture and hip fracture in more detail after grouping serum 25OHD into categories that reflected recently recommended thresholds (eg, 30 nmol/L, 50 nmol/L, 75 nmol/L). RR estimates were calculated after adjusting for age, sex, race/ethnicity, and survey period. Finally, Cox models were used to compare the relationship between serum 25OHD and major osteoporosis fracture risk by age (65–79 years versus 80+ years), sex, and race/ethnicity. The analyses by age, sex, and race/ethnicity were limited to major osteoporotic fracture because there were insufficient hip fracture cases in some of the subgroups to permit calculation of reliable statistical estimates.

Secondary analyses were performed to assess the potential impact of lack of Medicare data prior to 1991 by estimating the number of major osteoporotic fracture cases that might have occurred among adults ages 65 years and older in the NHANES III sample examined in 1988 to 1990 using age-adjusted mortality rates for the U.S. population for these years and age-adjusted incidence of these fractures from Medicare in the late 1980s.31, 37, 38

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Baseline characteristics of major osteoporotic and hip fracture cases versus non-cases are compared for the pooled analytic sample in Table 1. Results were similar when fractures were grouped as major osteoporotic fracture status and when hip fracture status was considered alone. Fracture cases were older, weighed less, were shorter, and had a lower BMI than non-cases. Hip fracture cases consumed less calcium than non-cases but calcium intake did not differ between major osteoporotic cases and non-cases. Conversely serum 25OHD levels were significantly lower among major osteoporotic cases than non-cases, but did not differ by hip fracture status. Both major osteoporotic and hip fracture were more common in women and in non-Hispanic whites. Both major osteoporotic and hip fracture cases were less likely to report using prescription osteoporosis drugs but more likely to report having excellent, very good, or good health status than non-cases. Respondents with major osteoporotic fracture were also more likely to smoke and to be less physically active than non-cases, whereas hip fracture cases were more likely to drink milk than non-cases. None of the other variables tested differed significantly by fracture status at baseline. Mean follow-up time was 7 years (range, 0.01–19.1 years). Mean age at fracture was 81.7 years for major osteoporotic fracture and 83.3 years for hip fracture.

Table 1. Pooled NHANES III and NHANES 2000–2004 Cohort Aged 65 Years and Older: Selected Baseline Characteristics of Analytic Sample by Fracture Status
 Major osteoporotic fracturepHip fracturep
YesNoYesNo
nMean or %nMean or %nMean or %nMean or %
  • NHANES = National Health and Nutrition Examination Survey.

  • a

    May be statistically unreliable, relative standard error (SE/percent) is 30% to 39%.

  • b

    Not shown, relative standard error (SE/percent) is ≥40%.

Age (years)52575.2422373.3<0.00128775.9446373.4<0.001
Body mass index (kg/m2)50926.3411127.40.00127625.5434427.3<0.001
Body weight (kg)51869.6415875.0<0.00128368.4439374.8<0.001
Height (cm)509162.54130165.3<0.001276163.44363165.10.03
Dietary calcium from food (mg)494710.34026738.00.24269671.64251738.60.05
Serum 25-hydroxy vitamin D (nmol/L)52557.5422360.10.0228757.6446160.00.12
Sex    <0.001    0.002
 Men17325.7225946.9 12034.4231245.0 
 Women35274.3196453.1 16765.6214955.0 
Race/ethnicity    <0.001    0.001
 Non-Hispanic white40792.5258184.5 23291.7275685.0 
 Non-Hispanic black453.77538.1 274.27717.8 
 Mexican American641.77462.6 221.1a7882.6 
 Other92.1a1434.9 6b1464.7 
Season of blood draw    0.11    0.43
 November–April20028.6192433.9 10529.7201933.6 
 May–October32571.4229966.1 18270.3244266.4 
Alcohol intake ≥3 drinks per day    0.85    0.83
 Yes306.42976.6 166.2a3116.6 
 No44993.6342993.4 24493.8363593.4 
Prescription osteoporosis drug use
 Yes265.02679.60.002103.4a2839.40.005
 No49995.0395690.4 27796.9417890.6 
Mother had hip fracture    0.92    0.47
 Yes4410.834410.5 2612.936210.4 
 No45989.2370089.5 24587.1391489.6 
Drink milk    0.30    0.01
 Yes43283.1336580.8 24486.8355380.7 
 No9316.984419.2 4313.289419.3 
Health status    0.005    0.003
 Excellent/very good31362.6223255.5 18365.0236255.8 
 Good17029.7145131.4 8629.0153531.3 
 Fair/poor417.853413.1 186.0a55712.9 
Smoking status    0.02    0.28
 Current5613.049010.5 3313.751310.6 
 Former18533.6170641.6 10235.9178941.0 
 Never28453.4202447.9 15250.4215648.4 
Physical activity compared to others    0.12    0.09
 More23345.4187048.1 12442.9197948.1 
 Less6711.164413.7 3010.868113.6 
 About the same20843.5159438.1 12446.3167838.3 
Physical activity compared to 10 years ago    0.02    0.76
 More254.62656.3 176.8a2736.1 
 Less35163.6293368.6 19465.2309068.2 
 About the same14831.8102025.1 7528.1109325.7 

Results of the analysis to assess whether serum 25OHD was related to fracture risk in a linear or nonlinear fashion are shown in Table 2 for the entire follow-up period and by follow-up time category (<10 years versus ≥10 years). Serum 25OHD was significantly related to both major osteoporotic and hip fracture in the total sample and in those with <10 years of follow-up, but not in those with 10 years of follow-up or more. The relationship between serum 25OHD and risk of major osteoporotic fracture was linear (since neither the quadratic or cubic regression coefficients were significant), whereas the relationship between serum 25OHD and hip fracture risk appeared to be quadratic (because the linear and quadratic coefficients were significant but the cubic coefficient was not). These relationships are illustrated graphically in Fig. 1, which shows the smoothed risk of fracture by serum 25OHD truncated at 135 nmol/L as predicted by these models for respondents with less than 10 years of follow-up after adjusting for age, sex, race/ethnicity, and survey. Results in Fig. 1 for hip fracture suggest a possible small increase in risk for serum 25OHD values ≥110 nmol/L, but these results are based on very sparse data: only 1.8% of the total sample, including five hip fracture cases, had serum 25OHD values between 110 and 135 nmol/L.

Table 2. Pooled NHANES III and NHANES 2000–2004 Cohort Aged 65 Years and Older: Cox Proportional Hazard Model Regression Coefficients for Different Models of the Relationship Between Serum 25OHD and Fracture Risk
Fracture typeAll follow-up years<10 years follow-up≥10 years follow-up
BetapBetapBetap
  1. All models were adjusted for age, sex, race, and survey. The quadratic model included serum 25OHD; the cubic model included serum 25OHD and serum 25OHD2.

  2. NHANES = National Health and Nutrition Examination Survey.

Major osteoporotic fracture cases (n)525 418 107 
Model
 Linear (serum 25OHD)−0.00820.004−0.01010.0010.00040.97
 Quadratic (serum 25OHD2)0.0000270.690.0000180.82−0.0001800.25
 Cubic (serum 25OHD3)−0.0000040.11−0.000010.330.0000030.18
Hip fracture cases (n)287 220 67 
Model
 Linear (serum 25OHD)−0.00950.03−0.0175<0.0010.00730.36
 Quadratic (serum 25OHD2)0.0001900.010.0001740.050.0000530.71
 Cubic (serum 25OHD3)−0.0000030.29−0.0000020.30−0.0000020.45
thumbnail image

Figure 1. Smoothed relative risk of major osteoporotic fracture or hip fracture by serum 25OHD value among persons with less than 10 years of follow-up, adjusted for age, sex, race/ethnicity, and survey

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Additional detail about the relationship between serum 25OHD and risk of major osteoporotic fracture or hip fracture was analyzed using categories based on recently recommended thresholds by the IOM1 and Endocrine Society39 from respondents with <10 years of follow-up. After adjusting for age, sex, race/ethnicity, and survey, fracture risk was significantly increased among respondents with serum 25OHD <30 nmol/L (major osteoporotic fracture RR = 2.09, 95% confidence interval [CI] = 1.32–3.32; hip fracture RR = 2.63, 95% CI = 1.60–4.32) when compared to respondents with serum 25OHD ≥30 nmol/L. Use of finer categories of serum 25OHD for values >30 nmol/L (as shown in Fig. 2) resulted in a significant downward linear trend overall (p < 0.009 for major osteoporotic fracture; p < 0.002 for hip fracture). Risk was significantly elevated among those with serum 25OHD <30 nmol/L for both fracture outcomes (eg, the 95% CIs for the RR did not include 1.00). However, risk for either fracture outcome among those with serum 25OHD in the two categories between 30 and 74 nmol/L did not differ from that seen in those with serum 25OHD ≥75 nmol/L, because the RRs for these categories had 95% CIs that included 1.00.

thumbnail image

Figure 2. Relative risk of major osteoporotic fracture (A) or hip fracture (B) by serum 25OHD category among persons with less than 10 years of follow-up, adjusted for age, sex, race/ethnicity, and survey. Note: the reference category for hip fracture analyses was defined as serum 25OHD between 75-110 nmol/L in light of the possible increase in hip fracture risk above this serum 25OHD value.

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Differences in the relationship between serum 25OHD and risk of major osteoporotic fracture by age group, sex, and race/ethnicity among those with <10 years of follow-up are presented in Table 3. Overall, major osteoporotic fracture risk was increased by 26% to 27% for each SD decrease in serum 25OHD. These RRs are only slightly lower than those observed for other important risk factors, such as age (RR = 1.5 per 5 years), BMI (RR = 1.4 per SD decrease), or femur neck BMD when predicting all fractures (RR = 1.6 per SD decrease).19, 40 The RR point estimates varied by age (RR80+y > RR65-79y), sex (RRmen > RRwomen), and race/ethnicity (RRNHB < RRNHW < RRMA), but when tests for interactions between these demographic variables and serum 25OHD were calculated, only the sex × serum 25OHD interaction was significant (p < 0.05).

Table 3. Pooled NHANES III and NHANES 2000–2004 Cohort Aged 65 Years and Older: Relative Risk of Major Osteoporotic Fracture per 1 SDa Unit Decline in Serum 25OHD by Age, Sex, or Race and Ethnicity Among Those With <10 Years of Follow-Up
 Base modelbFull modelc
Cases (n)RRLLULCases (n)RRLLUL
  • NHANES = National Health and Nutrition Examination Survey; RR = relative risk; LL = lower limit; UL = upper limit; BMI = body mass index.

  • a

    1 SD = 21.1 nmol/L.

  • b

    Adjusted for age, survey, race/ethnicity, and sex.

  • c

    Adjusted for BMI, height, smoking, health status, prescription osteoporosis drug use, current physical activity compared to activity 10 years ago, and milk intake in addition to variables used in the base model.

Total4181.261.111.434001.271.121.44
Age (years)
 65–792181.181.011.382121.140.971.34
 ≥802001.321.081.621881.401.131.74
Sex
 Male1351.441.131.831291.451.111.89
 Female2831.171.021.352711.161.011.33
Race/ethnicity
 Non-Hispanic white3191.241.081.423081.221.071.39
 Non-Hispanic black350.810.561.17320.910.611.35
 Mexican American561.621.142.32531.280.931.78

Results of secondary analyses to estimate the number of major osteoporotic fractures that were potentially classified as non-cases due to lack of Medicare records for NHANES III respondents prior to 1991 indicated that 38 major osteoporotic fracture (18 hip, 12 radius, 6 humerus, and 2 spine fractures) may have occurred in the analytic sample prior to 1991.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Results from this study based on a pooled cohort from NHANES III and NHANES 2000–2004 add to previous findings from NHANES regarding the relationship between serum 25OHD and hip fracture risk in older white U.S. adults10 by examining risk for major osteoporotic fracture, expanding the sample to include older adults of all races, and examining fracture risk by amount of follow-up time. Serum 25OHD was significantly related to risk of major osteoporotic fracture in a linear fashion, and, as previously seen, significantly related to hip fracture in a nonlinear, quadratic fashion. Results when stratified by amount of follow-up time suggested that serum 25OHD may lose predictive utility once an extended period of time has elapsed since its measurement. Specifically, both major osteoporotic fracture risk and hip fracture risk were significantly related to serum 25OHD among respondents with less than 10 years of follow-up time, but not for those with ≥10 years of follow-up time.

Previous studies of serum 25OHD and fracture have either been limited to less than 10 years of follow-up or have not reported predictive utility by follow-up time. Results of studies that have examined tracking of serum 25OHD over time are consistent with the possibility of attenuation in predictive utility with increasing time. For example, Platz and colleagues41 found that the correlation between serum 25OHD values measured on the same individuals after three years had elapsed was 0.7, whereas studies that have re-measured serum 25OHD after either 11 or 18 years found correlations that ranged from 0.42 to 0.52.9, 42 Other biochemical measurements, such as serum insulin or blood glucose, have been found to lose predictive utility for cardiovascular events over time.43 However, the present study may also have been underpowered to detect a relationship between serum 25OHD and fracture risk in the subsample with 10 or more years of follow-up, because less than 25% of the total sample were followed this long and the number of fracture cases among these respondents was small.

The shape of the best-fitting model also differed for hip fracture and major osteoporotic fracture. Major osteoporotic fracture risk by serum 25OHD has not been reported previously, but previous research regarding the shape of the relationship between serum 25OHD and hip fracture risk has conflicted. In addition to earlier results from NHANES III,10 Barbour and colleagues11 also reported a nonlinear relationship between serum 25OH and hip fracture risk in their analysis of the Health ABC cohort. However, a linear relationship between serum 25OHD and hip fracture risk has been reported in other studies2, 3, 7 Barbour and colleagues11 hypothesized that variability in the relationship between serum 25OHD and fracture risk at different skeletal sites could stem from differences in the relationship between serum 25OHD and bone type (cortical versus trabecular) because the proportion of these bone types varies at different skeletal sites.44–46 It is also possible that serum 25OHD may affect fracture risk via its relationship with other risk factors, such as muscle strength or falls,20 which in turn may differ in their relationship with fracture risk at different skeletal sites.

The shape of the quadratic relationship observed between hip fracture risk and serum 25OHD was suggestive of a possible increase in risk at the high end of the serum 25OHD distribution. Increased fracture risk among those with high serum 25OHD, at least in some groups, has been observed in a small number of other prospective studies.4, 47 However, caution is needed when interpreting the results observed in the present study, because the data in the range where risk appeared to show a slight increase (approximately 110–135 nmol/L) was very sparse: only 1.8% of the total sample and 5 fracture cases had values in this range.

Results from the present study can add to the discussion about appropriate serum 25OHD thresholds, which remains a controversial topic.48, 49 Risks of both fracture outcomes considered in the present study were significantly elevated among those with serum 25OHD <30 nmol/L, which is consistent with the definition of deficiency proposed by the IOM.1 However, risk was not significantly elevated for those with serum 25OHD in the two categories between 30 and 74 nmol/L when compared to serum 25OHD ≥75 nmol/L for either fracture outcome. These results are consistent with the IOM committee's observation of a plateau in effect for serum 25OHD levels between 30 and 40 nmol/L.49 However, it is important to note that recent recommendations from both the IOM and the Endocrine Society were based on consideration of data for more than one skeletal health indicator.1, 20 In addition, results from observational cohort studies have been viewed as offering only supportive and/or confirmatory input to data from randomized clinical trials.1 Thus, although the present study offers relevant data, it cannot resolve the issue of serum 25OHD thresholds in light of its observational cohort study design and focus on a single skeletal outcome.

Clear differences in the relationship between serum 25OHD and major osteoporotic fracture risk by sex or age were not detected in the present study. There was inconsistent evidence for a sex difference in the relationship: the sex × serum 25OHD interaction term was statistically significant, but the 95% CIs for the RR overlapped between sexes. Several other prospective studies have also found a similar relationship in both sexes.5, 7, 11, 15 Results from the present study did not support risk differences by age, as the 95% CIs overlapped between the two age categories studied and the age × serum 25OHD interaction term was not significant. Van Schoor and colleagues5 reported a significant interaction between age and serum 25OHD for risk of fracture at any skeletal site in Dutch men and women, but two other prospective studies performed in older U.S. adults found no significant interaction with age when examining the serum 25OHD–fracture relationship.2, 11

There was also inconsistent evidence to support the possibility of race/ethnic differences in the relationship between serum 25OHD and major osteoporotic fracture risk in the present study. Specifically, the RR point estimates for major osteoporotic fracture in NHW and MA's indicated a significant increase in fracture risk with decreasing serum 25OHD, whereas the RR point estimate for NHB fell below 1.00 and was not statistically significant. These results suggest that the serum 25OHD–fracture relationship may differ by race/ethnicity, because serum 25OHD appeared to be unrelated to fracture risk in blacks. However, firm conclusions are not possible in light of the nonsignificant race/ethnicity × serum 25OHD interaction term and the fact that the 95% CIs for the RR in blacks overlapped with the 95% CIs in the other two race/ethnic groups. The wide 95% CIs and failure to find a significant interaction term may stem from limited power in the present study to detect differences due to the small number of fracture cases among blacks (n = 798 blacks with 35 fractures). Two other prospective studies in older U.S. adults also found no significant interaction in the relationship between serum 25OHD and fracture risk by race,7, 11 but, similar to the present study, they were based on a small number of blacks. In contrast, Cauley and colleagues4 found that risk of clinical fractures was increased in black women compared to white women who participated in the observational study portion of the Women's Health Initiative, which had a much larger sample of blacks (n = 7639 blacks with 379 fractures).4 More studies with larger samples of nonwhites are needed to determine whether the serum 25OHD–fracture relationship differs between race/ethnic groups.

Comparing results between prospective studies that have examined the relationship between serum 25OHD and fracture risk is complicated by methodological differences between the studies. For example, use of different assays in the different studies could hamper comparisons because of the lack of assay standardization.50 Even the same assay can change over time, as noted for measurements from NHANES III compared with NHANES 2000–2004.34 Use of fractures at different skeletal sites may also complicate comparison of results from different studies. The present study examined risk of major osteoporotic fractures as a group and of hip fracture alone, whereas outcomes used in other studies have included fracture at any skeletal site, any fracture other than hand/finger or foot/toe, any nonspine fracture, hip fracture alone, or vertebral fracture alone.

Advantages of the current study include use of a pooled cohort that was derived from representative samples of the U.S. population, expansion of fracture outcomes to include major osteoporotic fractures as a group, and the ability to explore the relationship between serum 25OHD and fracture risk separately by age, sex, and race/ethnicity within the same cohort. Limitations of the present study include fracture cases that were identified using administrative medical records without confirmation by X-ray. In their validation study, Ray and colleagues26 found that the positive predictive values for hip, radius/ulna, and humerus fractures were ≥95% when based on Medicare records, which suggests that most fractures at those skeletal sites were likely correctly identified in the present study. The majority of fracture cases in the present study also had codes consistent with fracture on multiple medical records, which further supports the likelihood that identified cases suffered a fracture. However, vertebral fracture cases were limited to those which come to medical attention, which, although consistent with the approach used in the FRAX model, is an undercount of all vertebral fractures.51 In addition, the positive predictive value for incident vertebral fractures identified with the algorithm used in the present study was only 61%.28 Finally, some fracture cases may have been mistakenly classified as non-cases because Medicare records prior to 1991 were not available. This number is likely to be small: an estimated 38 undetected major osteoporotic fracture cases were projected to have occurred in the sample during 1988–1990. Furthermore, misclassification of cases as non-cases would likely tend to attenuate the relative risk estimates observed between fracture risk and serum 25OHD.

Results from the present study also apply only to the segment of the population ages 65 years and older that was not institutionalized at baseline and participated in Medicare fee-for-service programs because medical records for respondents who received care from managed care programs or in Veterans Administration facilities were not available. Furthermore, exclusions for missing data or loss to follow-up were also made. The respondents who were excluded from the analytic sample were more likely to have several characteristics that are associated with greater fracture risk (older, female, poorer health, and less activity) than respondents who were included. Thus, although based on a cohort that was derived from nationally representative samples of the civilian, noninstitutionalized population at baseline, results from the present study cannot be generalized to the entire adult population over age 65 years.

In conclusion, serum 25OHD was significantly related to risk of both major osteoporotic fractures as a group and hip fracture alone in this cohort of older adults, but the shape of the relationship differed (linear for major osteoporotic fracture, quadratic for hip fracture). For both major osteoporotic and hip fracture, serum 25OHD was a significant predictor of risk for up to 10 years after measurement, but was no longer significant after more than 10 years had elapsed. Clear differences in the relationship between serum 25OHD and fracture risk by age, sex, and race/ethnicity were not detected, although RR point estimates varied by these characteristics. The study may have been underpowered to assess long-term predictive utility or to detect a significant relationship by demographic characteristics, so replication of these results in other cohorts with larger numbers of fracture cases would be desirable.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Author's role: Study design, study conduct, data analysis, drafting, revising and approving content of final manuscript: ACL. ACL takes responsibility for the integrity of the data analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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jbmr_1828_sm_SupplAppendix.doc58KSupplementary Appendix
jbmr_1828_sm_chinese_translation.pdf621KSupporting Information

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