ORIGINAL
ARTICLE
E n d o c r i n e
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Long-Term Dietary Vitamin D Intake and Risk of Fracture and Osteoporosis: A Longitudinal Cohort Study of Swedish Middle-aged and Elderly Women Greta Snellman, Liisa Byberg, Eva Warensjo¨ Lemming, Håkan Melhus, Rolf Gedeborg, Hans Mallmin, Alicja Wolk, and Karl Michaëlsson Department of Surgical Sciences (G.S., L.B., E.W.L., K.M., H.Ma.), Section of Orthopedics; Department of Medical Sciences (H.Me.), Section of Clinical Pharmacology; and Department of Surgical Sciences (R.G.), Section of Anesthesiology and Intensive Care, Uppsala University, SE-751 85 Uppsala, Sweden; and Department of Nutritional Epidemiology (A.W.), Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Context: The importance of dietary vitamin D for osteoporotic fracture prevention is uncertain. Objective: Our objective was to investigate associations between dietary vitamin D intake with risk of fracture and osteoporosis. Design and Participants: In the population-based Swedish Mammography Cohort (including 61 433 women followed for 19 years), diet was assessed by repeated food frequency questionnaires. Setting: The study was conducted in 2 municipalities in central Sweden. Main Outcome Measure: Incident fractures were identified from registry data. In a subcohort (n ⫽ 5022), bone mineral density was determined by dual-energy x-ray absorptiometry and serum 25-hydroxyvitamin D was measured using HPLC-tandem mass spectrometry. Results: A total of 14 738 women experienced any type of first fracture during follow-up, and 3871 had a hip fracture. Multivariable-adjusted hazard ratio (HR) for any first fracture was 0.96 (95% confidence interval, 0.92–1.01) for the lowest (mean, 3.1 g/d) and 1.02 (0.96 –1.07) for the highest (mean, 6.9 g/d) quintile compared with the third quintile of vitamin D intake. The corresponding HR for a first hip fracture was 1.02 (0.96 –1.08) for the lowest and 1.14 (1.03–1.26) for the highest quintile. Intakes ⬎10 g/d, compared with ⬍5 g/d, conferred an HR of 1.02 (0.92–1.13) for any fracture and an HR of 1.27 (1.03–1.57) for hip fracture. The intake of vitamin D did not affect the odds for osteoporosis, although higher levels were associated with higher bone mineral density (0.3%–2%, P ⬍ .0001). A positive association was observed between vitamin D intake and serum 25-hydroxyvitamin D. Conclusions: Dietary intakes of vitamin D seem of minor importance for the occurrence of fractures and osteoporosis in community-dwelling Swedish women. (J Clin Endocrinol Metab 99: 781–790, 2014)
A
large proportion of women and men will have 1 or more osteoporotic fractures during their lifetime (1). Moreover, the worldwide incidence of hip fractures is expected to increase almost 4-fold by 2050 (2). Therefore,
fracture prevention is essential. Vitamin D is imperative for bone mineralization in that it enables absorption of dietary calcium and has a negative feedback on PTH secretion. Vitamin D insufficiency may therefore contribute
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 23, 2013. Accepted December 3, 2013.
Abbreviations: BMD, bone mineral density; BMI, body mass index; CI, confidence interval; FFQ, food frequency and lifestyle questionnaire; HR, hazard ratio; NHS, Nurses Health Study; OR, odds ratio; S-25(OH)D, 25-hydroxyvitamin D; SMC, Swedish Mammography Cohort; SMCC, SMC Clinical.
doi: 10.1210/jc.2013-1738
J Clin Endocrinol Metab, March 2014, 99(3):781–790
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to calcium loss from bone with osteoporosis and fractures as a final consequence (3). Vitamin D status is primarily determined by genetic constitution and UV-B radiation, although the dietary intake of vitamin D also contributes to circulating vitamin D levels, but the influence seems to be of modest importance (4 – 6). Therefore, weak associations between dietary vitamin D intakes and future fracture risk are to be expected. The significance and optimal level of dietary vitamin D intake for the prevention of osteoporosis and fractures have, nevertheless, been much debated and remain unclear (7, 8). This uncertainty is reflected by the wide range of official and nonofficial intake recommendations for middle-aged and older individuals: from 5 g vitamin D/d to 50 g/d (9 –11). Recommendations regarding vitamin D intake based on the results from clinical trials and previous cohort studies are challenging. Meta-analyses of randomized trials have found that supplemental vitamin D alone in doses of 10 to 20 g/d provides no reduction in fracture rate (12, 13). Randomized controlled trials on fracture prevention with vitamin D in combination with calcium supplementation in community-dwelling women found no certain beneficial effects, although there is evidence that the combination can prevent fractures in old, frail women (8, 14). To what extent long-term dietary vitamin D intake promotes bone health is not well understood. Prospective observational studies are few, and those that have been done have yielded conflicting results (15–17). Against this background, we aimed to investigate associations between long-term dietary intake of vitamin D with risk of fracture of any type, with hip fractures, with osteoporosis, and finally with serum 25-hydroxyvitamin D (S-25(OH)D) levels in a large population-based prospective study of Swedish middle-aged and elderly women.
J Clin Endocrinol Metab, March 2014, 99(3):781–790
Baseline invitees (n=90 303)
FFQ1, 1987-1990
Non-responders (n=23 652) Responders (n=66 651)
Exclusions* (n=5218) Baseline sample (n=66 433) 1997 invitees (n=56 030)
FFQ2, 1997
Non-responders (n=16 803) Responders (n=39 227) xcluded if energy intake was implausible (n=243) 1997 sample (n=38 984) hort FFQ3, 2003-2009 (n=5 022)
Figure 1. Flow chart of the participants in the SMC. *, Excluded were persons with an erroneous personal identification number, date of moving out of the study area, or death, questionnaires not properly dated, implausible energy intake (⫾3 SD from the mean value of the log-transformed energy intake), and a cancer diagnosis (except nonmelanoma skin cancer) before baseline.
Fracture identification Fracture events were collated through linkage with the Swedish National Patient Registry. Data on outpatient-treated fractures were identified from outpatient registers. A complete deterministic record linkage was achieved by use of the unique personal identification number assigned to all Swedish permanent residents. Any first fracture event after cohort entry was defined as a hospital admission or an outpatient visit with an International Classification of Diseases (ICD-10) diagnosis code of S12, S22, S32, S42, S52, S62, S72, S82, or S92. Hip fracture cases were defined by the codes S720, S721, and S722. Incident fracture admissions were separated from readmissions from a previous fracture event by the use of a validated method (19). Repeated fractures were also assessed.
The SMC Clinical (SMCC)
Subjects and Methods The Swedish Mammography Cohort The Swedish Mammography Cohort (SMC) is a populationbased cohort in central Sweden (latitude, 60° N). All women born between 1914 and 1948 living in Uppsala County (n ⫽ 48 517) and all women born between 1917 and 1948 living in Västmanland County (n ⫽ 41 786) were asked to respond to a comprehensive 6-page food frequency and lifestyle questionnaire (FFQ) when invited to a mammography screening (March 1987 to December 1990). Completed questionnaires were obtained from 66 651 (74%) women in the source population. After exclusions, 61 433 women remained in the cohort (18). In 1997, a second expanded questionnaire was sent to all participants who still lived in the study area (n ⫽ 56 030). Of these, 38 984 (70%) returned the second questionnaire (Figure 1).
In the period 2003 to 2009, a randomly selected subgroup from the SMC was invited to participate in a physical examination, and 5022 women (65%) accepted to participate. A third FFQ was answered 1 to 3 months before the clinical examination. Fasting blood samples were collected at the research visit. Bone mineral density (BMD) at the hip, the lumbar spine (L1– L4), and of the total body was also measured using dual-energy x-ray absorptiometry (Lunar Prodigy; Lunar Corp). Osteoporosis was defined as a BMD of 2.5 SD or more below the mean of U.S. white female reference populations, aged 20 to 40 years (20). The short-term precision measurement error, based on duplicate measurements with repositioning according to recommendations from the International Society for Clinical Densitometry, varied between 0.8% and 1.5% depending on the site. The long-term coefficient of variation was ⬍1% for a spine phantom (21).
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doi: 10.1210/jc.2013-1738
Determination of S-25(OH)D with HPLC-atmospheric pressure chemical ionization (APCI)-tandem mass spectrometry In 2012, determination of 25(OH)D2, 3-epi-25(OH)D3 and 25(OH)D3 in plasma with HPLC-APCI-MS/MS was done at Vitas, Oslo, Norway (www.vitas.no). Samples from 5019 of 5022 women in the SMC Clinical (SMCC) were analyzed. The samples had been stored at ⫺80°C protected from light and were not thawed before analysis. The coefficient of variation for 25(OH)D was 9.7% (36.94nM) and 10.2% (48.08nM) using plasma quality control samples at 2 levels analyzed in series with study samples.
Description of the FFQ Nutrient intake was estimated by multiplying the frequency of consumption of each food item by the nutrient content of age-specific portion sizes and by use of data from the Swedish National Food Administration database. All nutrients were adjusted for total energy intake (mean 1700 kcal in the study population) using the residual method (22). In the second and third FFQ (the 1997 expanded questionnaire and the questionnaire completed by the SMCC subcohort), the lifetime use of dietary supplements was reported. Total vitamin D intake included supplemental vitamin D. Reported frequency of supplement use within the cohort during the first years of follow-up was ⬍5% (23). Low-fat dairy products and margarine are fortified with vitamin D and, together with fatty fish, they constitute the major food sources of vitamin D in Sweden. Validation of vitamin D intake from the FFQ was carried out with four 7-day food records every third month in 104 of the women (r ⫽ 0.72). There are only small systematic errors related to intake level between the methods with an average difference of only 0.11 g higher vitamin D values with the food records (95% confidence interval (CI), ⫺0.15 to 0.38), an indication of good accuracy for the FFQ.
Additional information The questionnaires provided lifestyle information, including use of postmenopausal estrogen therapy, menopausal status, parity information, medication use, weight and height, smoking habits, and leisure-time physical activity during the past year (with 5 predefined levels ranging from 1 h/wk to ⬎5 h/wk). Physical activity collected in the 1997 questionnaire is valid when compared with activity records and accelerometer data (24). The educational level was categorized as ⱕ9 years, 10 to 12 years, ⬎12 years, and other education (such as vocational). ICD diagnosis codes were collated from the Swedish National Patient Registry to calculate Charlson’s comorbidity index (25).
Statistical analyses The present study was made up of 2 study samples: the SMC with the primary outcomes any first fracture and first hip fracture and the SMCC with the secondary outcomes osteoporosis, BMD, and S-25(OH)D levels. For each woman in the SMC, person-years of follow-up were calculated from the date they entered the cohort until the date of fracture, date of death, the date of emigration, or the end of the follow-up period (December 31, 2008), whichever occurred first. We estimated age-adjusted and multivariable-adjusted hazard ratios (HRs) of fracture by Cox proportional hazard regression and odds ratios (ORs) of osteoporosis by logistic regression.
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To better account for changes in diet during follow-up and to better represent long-term dietary intake, vitamin D intake and the covariates were treated as time-updated variables in the Cox models and as cumulative average intakes in the logistic regression models (26). The proportional hazard assumptions in the Cox models were confirmed graphically by comparing NelsonAalen plots and by Schoenfeld’s test. We estimated associations for dietary and for total vitamin D intake, including both diet and supplement use. In addition, we examined the relation between quintiles of vitamin D intake and risk of fracture and osteoporosis. To facilitate comparisons of the estimates, the same quintile cutoffs were used in the SMCC as in the entire cohort. We further analyzed the rate of fracture after stratification by calcium intake (⬍800 mg/d vs ⱖ800 mg/d). To obtain a clearer view of the shape of the association between vitamin D intake and fracture risk, we used restricted cubic spline models, with 4 knots located at percentiles 5, 35, 65, and 95 of vitamin D intake. This approach allowed us to obtain a smoothed dose-risk curve with 95% CI. In addition, we contrasted women who consistently reported lowest quintile of vitamin D intake to women who reported a constant intake within the highest quintile for all outcomes. Finally, we broadened our categorical exposure range into 4 vitamin D intake categories (⬍5.0, 5.0 –7.5, 7.5–10, and ⬎10 g/d), which reflects different current dietary recommendations, and also into 5 categories (⬍3.5, 3.5– 6, 6 –9, 9 –12.5, and ⬎12.5 g/d) as previously described (15). In the multivariable model, we included age; total energy intake; alcohol, retinol, protein, potassium, and calcium intake; body mass index (BMI); height (all continuous); education level (ⱕ9, 12, ⬎12 years, and other); nulliparity (yes or no); vitamin D supplement use (yes or no); calcium supplements (yes or no); physical activity (5 categories); smoking status (never, former, or current); previous fracture before study start (yes or no); and Charlson’s comorbidity index (continuous, 1–16). In the analysis of SMCC, we also included estrogen, bisphosphonate, and cortisone use as separate marker variables in the multivariable model. Covariates not assessed in the baseline FFQ (such as smoking habits and physical activity) were imputed by the Markov chain Monte Carlo multiple imputation procedure. Sensitivity analysis with restriction to nonmissing data did not alter our interpretation of the results. Given that both low and high vitamin D intake might be related to prevalent disease and mortality, we compared cumulative incidence curves with Kaplan-Meier failure curves to address the potential competing risk problem from mortality (27). The curves indicated that our results would not be compromised by competing risk from mortality (Supplemental Figure 1, published on The Endocrine Society’s Journals Online website at http://jcem.endojournals.org). The association between total S-25(OH)D (the sum of S-25(OH)D2 and S-25(OH)D3 although not including 3-epi25(OH)D3) and vitamin D intake from diet and supplements was analyzed by linear regression analyses, adjusting for age, weight, height, and season). The statistical analyses were performed with STATA version 11 (StataCorp).
Ethical approval The study was approved by the regional ethical review board in Stockholm, Sweden, and all participants gave their informed consent.
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Results The basic characteristics of the study participants by quintiles of dietary vitamin D intake are presented in Table 1. With increasing intake of vitamin D, the average age and BMI of the women as well as intake of calcium and retinol were higher, whereas the intake of alcohol was lower. However,
Table 1. Intakea
J Clin Endocrinol Metab, March 2014, 99(3):781–790
level of education, physical activity, and smoking status were similar across categories of vitamin D intake. The women were followed for a median time of 19.2 years, which contributed to 996 800 person-years at risk. During this time, 14 738 women suffered any type of first fracture, of which 5043 had had 1 or more additional fractures during follow-up. In addition, 3871 of the
Characteristics of the Total Cohort (SMC) and the Subcohort (SMCC) by Quintiles of Dietary Vitamin D Quintile
Number of participants Vitamin D intake, g/d SMC Age at entry, y BMI at entry, kg/m2) Dietary vitamin D intake, g/d Total vitamin D intake,b g/d Vitamin D supplement use n (%)c,d Dietary calcium intake, mg/d Total calcium intake,b mg/d Energy intake, kcal/d Dietary retinol intake, g/d Alcohol intake, g/d Nulliparity, n (%) Leisure time PA level, n (%)d 1 (lowest) 2 3 4 5 (highest) Smoking status, n (%)d Current Former Never Education level, n (%)e ⱕ9 y 9 –12 y ⬎12 y Other SMCC Age at DXA investigation, y BMI, kg/m2 Energy intake, kcal/d Vitamin D intake, g/d Vitamin D supplement use, n (%)c,d Total vitamin D intake,b g/d Calcium intake, mg/d Supplemental calcium intake, mg/d (n ⫽ 610) Total calcium intake,b mg/d Retinol intake, g/d Alcohol intake, g/d
Q1
Q2
Q3
Q4
Q5
12 286 ⬍3.3
12 287 3.3– 4.0
12 287 4.0 – 4.7
12 282 4.7–5.4
12 291 ⬎5.4
56.1 (10.2) 24.4 (4.3) 2.6 (0.5) 3.1 (1.7) 1622 (13) 919 (275) 969 (413) 1642 (531) 267 (467) 3.4 (5.2) 2245 (11)
55.9 (10.2) 24.6 (4.2) 3.7 (0.2) 4.1 (1.8) 1828 (15) 907 (255) 956 (394) 1661 (485) 319 (531) 3.4 (4.5) 2061 (10)
56.5 (10.3) 24.7 (3.8) 4.3 (0.2) 4.8 (1.6) 1730 (14) 927 (260) 974 (390) 1646 (475) 362 (601) 3.3 (4.3) 2006 (10)
57.2 (10.3) 25.1 (4.1) 5.0 (0.2) 5.4 (1.5) 1816 (15) 983 (259) 1025 (364) 1640 (470) 359 (648) 2.9 (3.8) 1914 (10)
59.0 (10.7) 25.7 (4.6) 6.5 (1.5) 6.9 (2.2) 1604 (13) 1067 (320) 1109 (417) 1609 (614) 421 (752) 2.6 (3.8) 2239 (11)
392 (20) 4806 (24) 6336 (32) 2773 (14) 1971 (10)
3844 (19) 5128 (26) 6483 (32) 2698 (13) 1893 (10)
3837 (19) 5209 (25) 667 (33) 2728 (13) 2012 (10)
362 (19) 4952 (26) 6326 (33) 2637 (14) 1831 (8)
4072 (20) 5115 (25) 6646 (32) 2845 (14) 2065 (9)
4245 (21) 5425 (27) 10 136 (51)
4113 (21) 5593 (28) 1034 (52)
4178 (20) 5583 (27) 10 695 (52)
3902 (20) 5131 (26) 10 333 (53)
4590 (22) 5674 (27) 10 479 (51)
14 976 (76) 1579 (8) 2267 (11) 984 (5)
15 232 (76) 1589 (8) 2195 (11) 103 (5)
15 808 (77) 155 (8) 2095 (10) 1003 (5)
15 215 (79) 1400 (7) 1722 (9) 1029 (5)
16 657 (80) 1328 (6) 1737 (8) 1021 (5)
66.5 (6.4) 23.6 (3.2) 1698 (442) 2.8 (0.5) 112 (13.7) 4.9 (2.2) 976 (209) 348 (187) 1033 (233) 409 (265) 6.0 (5.7)
66.5 (6.5) 24.0 (3.5) 1735 (398) 3.7 (0.2) 68 (13.9) 4.0 (2.6) 991 (188) 360 (185) 1028 (248) 449 (262) 5.4 (4.7)
67.0 (6.5) 24.3 (3.2) 1714 (385) 4.3 (0.2) 164 (14.2) 5.6 (2.3) 982 (184) 362 (185) 1028 (228) 482 (239) 5.5 (4.8)
67.6 (6.7) 24.9 (3.4) 1722 (388) 5.0 (0.2) 228 (16.9) 6.3 (3.0) 1028 (204) 382 (180) 1068 (244) 539 (252) 5.1 (4.4)
69.5 (7.1) 25.4 (3.8) 1692 (377) 6.2 (0.8) 201 (16.6) 7.4 (2.4) 1064 (223) 381 (179) 1108 (262) 590 (342) 4.8 (4.7)
Abbreviations: DXA, dual-energy x-ray absorptiometry; PA, physical activity. a
Data are shown as mean ⫾ SD or as otherwise indicated. Intake per day refers to the energy adjusted intake in the subcohort (SMCC).
b
Total intake is the sum of dietary and supplemental intakes.
c
Supplemental vitamin D alone in combination with calcium or as multivitamins.
d
Information only available in the 1997 questionnaire and in the DXA questionnaire.
e
Educational level: ’Other’ refers to vocational or other education.
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doi: 10.1210/jc.2013-1738
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Table 2. HRs With 95% CIs for the First of Any Type of Fracture and Hip Fracture by Quintiles of Vitamin D Intake and ORs With 95% CIs for Osteoporosis in the Subcohort SMCC by Quintiles of Vitamin Da Vitamin D intake, g/d First event any fracture Dietary intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Total intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b First event of hip fracture Dietary intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Total intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Osteoporosis Dietary intake of vitamin D Number of women (%) Women without osteoporosis n (%) Women with osteoporosis, n (%) Age-adjusted OR (95% CI) Multivariable-adjusted OR (95% CI)c Total intake of vitamin D Number of women (%) Women without osteoporosis n (%) Women with osteoporosis n (%) Age-adjusted OR (95% CI) Multivariable-adjusted OR (95% CI)c a
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
⬍3.3
3.3– 4.0
4.0 – 4.7
4.7–5.4
⬎5.4
2884 212 880 13.5 (13.1–14.1) 1.01 (0.96 –1.07) 0.96 (0.92–1.01)
2813 212 240 13.3 (12.8 –13.8) 0.99 (0.94 –1.05) 0.98 (0.93–1.03)
2952 213 360 13.8 (13.3–14.3) 1 (reference) 1 (reference)
2855 202 290 14.1 (13.6 –14.6) 1.01 (0.96 –1.06) 1.01 (0.96 –1.07)
3234 210 510 15.4 (14.8 –15.9) 1.00 (0.95–1.05) 1.02 (0.96 –1.07)
2630 197 560 13.3 (12.8 –13.8) 1.02 (0.97–1.08) 0.97 (0.92–1.03)
2528 197 120 12.8 (12.3–13.3) 0.99 (0.93–1.04) 0.97 (0.92–1.02)
2652 197 700 13.4 (12.9 –13.9) 1 (reference) 1 (reference)
2598 189 800 13.7 (13.2–14.2) 1.00 (0.95–1.06) 1.01 (0.95–1.06)
4330 269 100 16.1 (15.6 –16.6) 0.94 (0.90 – 0.99) 1.01 (0.96 –1.07)
734 228 580 3.2 (3.0 –3.5) 1.10 (0.99 –1.21) 1.02 (0.96 –1.08)
686 227 490 3.0 (2.8 –3.2) 1.03 (0.93–1.14) 0.94 (0.93– 0.96)
723 230 000 3.1 (2.9 –3.4) 1 (reference) 1 (reference)
774 217 700 3.6 (3.3–3.8) 1.09 (0.98 –1.20) 1.10 (0.99 –1.21)
954 227 830 4.2 (3.9 – 4.5) 1.07 (0.97–1.18) 1.14 (1.03–1.26)
682 211 440 3.2 (3.0 –3.5) 1.06 (0.96 –1.18) 0.94 (0.84 –1.04)
631 210 240 3.0 (2.8 –3.2) 0.99 (0.89 –1.10) 0.93 (0.84 –1.04)
685 212 240 3.2 (3.0 –3.5) 1 (reference) 1 (reference)
718 203 590 3.5 (3.3–3.8) 1.04 (0.94 –1.15) 1.06 (0.95–1.18)
1155 294 090 3.9 (3.7– 4.2) 0.85 (0.77– 0.93) 1.09 (0.99 –1.21)
395 (7.9) 308 (78.0) 87 (22.0) 1.27 (0.95–1.69) 1.15 (0.85–1.55)
819 (16.3) 641 (78.3) 178 (21.7) 1.24 (0.99 –1.55) 1.13 (0.89 –1.44)
1277 (25.4) 1033 (80.9) 244 (19.1) 1 (reference) 1 (reference)
1421 (28.3) 1146 (80.7) 275 (19.4) 0.96 (0.79 –1.17) 1.10 (0.89 –1.35)
1110 (22.1) 882 (79.5) 228 (20.5) 0.87 (0.70 –1.07) 1.08 (0.85–1.37)
280 (5.6) 213 (76.1) 67 (23.9) 1.37 (0.98 –1.90) 1.20 (0.85–1.71)
568 (11.3) 437 (76.9) 131 (23.1) 1.36 (1.04 –1.76) 1.21 (0.92–1.60)
929 (18.5) 754 (81.2) 175 (18.8) 1 (reference) 1 (reference)
1105 (22.0) 902 (81.6) 203 (18.4) 0.94 (0.75–1.19) 1.03 (0.81–1.32)
2140 (42.6) 1704 (79.6) 436 (20.4) 0.95 (0.78 –1.16) 0.99 (0.78 –1.25)
Energy-adjusted mean nutrient data were estimated with data from the baseline and the 1997 questionnaire.
b
The multivariable-adjusted HRs were adjusted for age; BMI; height; total energy intake; retinol, potassium, protein, alcohol, and calcium intake; calcium and vitamin D supplementation; nulliparity; educational and physical activity level; smoking status; previous fracture of any type before baseline; and Charlson’s comorbidity index. c Osteoporosis was defined in subjects when the T-score, determined at the total hip, femoral neck, or lumbar spine, was ⱕ⫺2.5 SD below the mean of a young adult reference range. The multivariable-adjusted HRs were adjusted for age; BMI; height; total energy intake; retinol, potassium, protein, alcohol, and calcium intake; calcium and vitamin D supplementation; nulliparity; educational and physical activity level; smoking status; previous fracture of any type before baseline; Charlson’s comorbidity index; estrogen replacement therapy; and cortisone and bisphosphonate use.
women had a first hip fracture during follow-up and 1368 experienced multiple hip fractures. In the SMCC subcohort, 20% (n ⫽ 1012) of the women were classified as osteoporotic. Vitamin D intake and fractures The HRs for a first fracture by quintiles of dietary and total vitamin D intake are presented in Table 2. Despite a more than 2-fold difference in median vitamin D intake between lowest and highest quintiles, the rate of fracture was not higher among women with the lowest intake levels. On the contrary, a somewhat higher rate for a first hip fracture was discerned within the highest dietary quintile of vitamin D intake (HR, 1.14; 95% CI, 1.03–1.26), an
observation confirmed when analyzing multiple hip fracture events (Supplemental Table 1). The risks with more extreme intakes of vitamin D are displayed by the spline curves illustrated in Figure 2, A and B, and by the categories shown in Supplemental Tables 2 and 3. In comparison with a vitamin D intake below 5 g/d, women with an intake higher than 10 g/d did not have a lower rate of fracture of any type (HR 1.02; 0.92–1.13), and they even had a higher rate of hip fracture (HR, 1.27; 1.03–1.57). Even more extreme intakes (⬍3.5 vs ⬎12.5 g) did not alter our results (Figure 3 and Supplemental Table 3). Calcium intake (higher or less than 800 mg daily, Supplemental Table 4) did not modify the association between
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Hazard ratio of any first fracture (adjusted)
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J Clin Endocrinol Metab, March 2014, 99(3):781–790
Dietary vitamin D intake (>10 µg vs 10 µg vs 12.5 µg vs
ARTICLE
E n d o c r i n e
C a r e
Long-Term Dietary Vitamin D Intake and Risk of Fracture and Osteoporosis: A Longitudinal Cohort Study of Swedish Middle-aged and Elderly Women Greta Snellman, Liisa Byberg, Eva Warensjo¨ Lemming, Håkan Melhus, Rolf Gedeborg, Hans Mallmin, Alicja Wolk, and Karl Michaëlsson Department of Surgical Sciences (G.S., L.B., E.W.L., K.M., H.Ma.), Section of Orthopedics; Department of Medical Sciences (H.Me.), Section of Clinical Pharmacology; and Department of Surgical Sciences (R.G.), Section of Anesthesiology and Intensive Care, Uppsala University, SE-751 85 Uppsala, Sweden; and Department of Nutritional Epidemiology (A.W.), Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Context: The importance of dietary vitamin D for osteoporotic fracture prevention is uncertain. Objective: Our objective was to investigate associations between dietary vitamin D intake with risk of fracture and osteoporosis. Design and Participants: In the population-based Swedish Mammography Cohort (including 61 433 women followed for 19 years), diet was assessed by repeated food frequency questionnaires. Setting: The study was conducted in 2 municipalities in central Sweden. Main Outcome Measure: Incident fractures were identified from registry data. In a subcohort (n ⫽ 5022), bone mineral density was determined by dual-energy x-ray absorptiometry and serum 25-hydroxyvitamin D was measured using HPLC-tandem mass spectrometry. Results: A total of 14 738 women experienced any type of first fracture during follow-up, and 3871 had a hip fracture. Multivariable-adjusted hazard ratio (HR) for any first fracture was 0.96 (95% confidence interval, 0.92–1.01) for the lowest (mean, 3.1 g/d) and 1.02 (0.96 –1.07) for the highest (mean, 6.9 g/d) quintile compared with the third quintile of vitamin D intake. The corresponding HR for a first hip fracture was 1.02 (0.96 –1.08) for the lowest and 1.14 (1.03–1.26) for the highest quintile. Intakes ⬎10 g/d, compared with ⬍5 g/d, conferred an HR of 1.02 (0.92–1.13) for any fracture and an HR of 1.27 (1.03–1.57) for hip fracture. The intake of vitamin D did not affect the odds for osteoporosis, although higher levels were associated with higher bone mineral density (0.3%–2%, P ⬍ .0001). A positive association was observed between vitamin D intake and serum 25-hydroxyvitamin D. Conclusions: Dietary intakes of vitamin D seem of minor importance for the occurrence of fractures and osteoporosis in community-dwelling Swedish women. (J Clin Endocrinol Metab 99: 781–790, 2014)
A
large proportion of women and men will have 1 or more osteoporotic fractures during their lifetime (1). Moreover, the worldwide incidence of hip fractures is expected to increase almost 4-fold by 2050 (2). Therefore,
fracture prevention is essential. Vitamin D is imperative for bone mineralization in that it enables absorption of dietary calcium and has a negative feedback on PTH secretion. Vitamin D insufficiency may therefore contribute
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received March 23, 2013. Accepted December 3, 2013.
Abbreviations: BMD, bone mineral density; BMI, body mass index; CI, confidence interval; FFQ, food frequency and lifestyle questionnaire; HR, hazard ratio; NHS, Nurses Health Study; OR, odds ratio; S-25(OH)D, 25-hydroxyvitamin D; SMC, Swedish Mammography Cohort; SMCC, SMC Clinical.
doi: 10.1210/jc.2013-1738
J Clin Endocrinol Metab, March 2014, 99(3):781–790
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to calcium loss from bone with osteoporosis and fractures as a final consequence (3). Vitamin D status is primarily determined by genetic constitution and UV-B radiation, although the dietary intake of vitamin D also contributes to circulating vitamin D levels, but the influence seems to be of modest importance (4 – 6). Therefore, weak associations between dietary vitamin D intakes and future fracture risk are to be expected. The significance and optimal level of dietary vitamin D intake for the prevention of osteoporosis and fractures have, nevertheless, been much debated and remain unclear (7, 8). This uncertainty is reflected by the wide range of official and nonofficial intake recommendations for middle-aged and older individuals: from 5 g vitamin D/d to 50 g/d (9 –11). Recommendations regarding vitamin D intake based on the results from clinical trials and previous cohort studies are challenging. Meta-analyses of randomized trials have found that supplemental vitamin D alone in doses of 10 to 20 g/d provides no reduction in fracture rate (12, 13). Randomized controlled trials on fracture prevention with vitamin D in combination with calcium supplementation in community-dwelling women found no certain beneficial effects, although there is evidence that the combination can prevent fractures in old, frail women (8, 14). To what extent long-term dietary vitamin D intake promotes bone health is not well understood. Prospective observational studies are few, and those that have been done have yielded conflicting results (15–17). Against this background, we aimed to investigate associations between long-term dietary intake of vitamin D with risk of fracture of any type, with hip fractures, with osteoporosis, and finally with serum 25-hydroxyvitamin D (S-25(OH)D) levels in a large population-based prospective study of Swedish middle-aged and elderly women.
J Clin Endocrinol Metab, March 2014, 99(3):781–790
Baseline invitees (n=90 303)
FFQ1, 1987-1990
Non-responders (n=23 652) Responders (n=66 651)
Exclusions* (n=5218) Baseline sample (n=66 433) 1997 invitees (n=56 030)
FFQ2, 1997
Non-responders (n=16 803) Responders (n=39 227) xcluded if energy intake was implausible (n=243) 1997 sample (n=38 984) hort FFQ3, 2003-2009 (n=5 022)
Figure 1. Flow chart of the participants in the SMC. *, Excluded were persons with an erroneous personal identification number, date of moving out of the study area, or death, questionnaires not properly dated, implausible energy intake (⫾3 SD from the mean value of the log-transformed energy intake), and a cancer diagnosis (except nonmelanoma skin cancer) before baseline.
Fracture identification Fracture events were collated through linkage with the Swedish National Patient Registry. Data on outpatient-treated fractures were identified from outpatient registers. A complete deterministic record linkage was achieved by use of the unique personal identification number assigned to all Swedish permanent residents. Any first fracture event after cohort entry was defined as a hospital admission or an outpatient visit with an International Classification of Diseases (ICD-10) diagnosis code of S12, S22, S32, S42, S52, S62, S72, S82, or S92. Hip fracture cases were defined by the codes S720, S721, and S722. Incident fracture admissions were separated from readmissions from a previous fracture event by the use of a validated method (19). Repeated fractures were also assessed.
The SMC Clinical (SMCC)
Subjects and Methods The Swedish Mammography Cohort The Swedish Mammography Cohort (SMC) is a populationbased cohort in central Sweden (latitude, 60° N). All women born between 1914 and 1948 living in Uppsala County (n ⫽ 48 517) and all women born between 1917 and 1948 living in Västmanland County (n ⫽ 41 786) were asked to respond to a comprehensive 6-page food frequency and lifestyle questionnaire (FFQ) when invited to a mammography screening (March 1987 to December 1990). Completed questionnaires were obtained from 66 651 (74%) women in the source population. After exclusions, 61 433 women remained in the cohort (18). In 1997, a second expanded questionnaire was sent to all participants who still lived in the study area (n ⫽ 56 030). Of these, 38 984 (70%) returned the second questionnaire (Figure 1).
In the period 2003 to 2009, a randomly selected subgroup from the SMC was invited to participate in a physical examination, and 5022 women (65%) accepted to participate. A third FFQ was answered 1 to 3 months before the clinical examination. Fasting blood samples were collected at the research visit. Bone mineral density (BMD) at the hip, the lumbar spine (L1– L4), and of the total body was also measured using dual-energy x-ray absorptiometry (Lunar Prodigy; Lunar Corp). Osteoporosis was defined as a BMD of 2.5 SD or more below the mean of U.S. white female reference populations, aged 20 to 40 years (20). The short-term precision measurement error, based on duplicate measurements with repositioning according to recommendations from the International Society for Clinical Densitometry, varied between 0.8% and 1.5% depending on the site. The long-term coefficient of variation was ⬍1% for a spine phantom (21).
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doi: 10.1210/jc.2013-1738
Determination of S-25(OH)D with HPLC-atmospheric pressure chemical ionization (APCI)-tandem mass spectrometry In 2012, determination of 25(OH)D2, 3-epi-25(OH)D3 and 25(OH)D3 in plasma with HPLC-APCI-MS/MS was done at Vitas, Oslo, Norway (www.vitas.no). Samples from 5019 of 5022 women in the SMC Clinical (SMCC) were analyzed. The samples had been stored at ⫺80°C protected from light and were not thawed before analysis. The coefficient of variation for 25(OH)D was 9.7% (36.94nM) and 10.2% (48.08nM) using plasma quality control samples at 2 levels analyzed in series with study samples.
Description of the FFQ Nutrient intake was estimated by multiplying the frequency of consumption of each food item by the nutrient content of age-specific portion sizes and by use of data from the Swedish National Food Administration database. All nutrients were adjusted for total energy intake (mean 1700 kcal in the study population) using the residual method (22). In the second and third FFQ (the 1997 expanded questionnaire and the questionnaire completed by the SMCC subcohort), the lifetime use of dietary supplements was reported. Total vitamin D intake included supplemental vitamin D. Reported frequency of supplement use within the cohort during the first years of follow-up was ⬍5% (23). Low-fat dairy products and margarine are fortified with vitamin D and, together with fatty fish, they constitute the major food sources of vitamin D in Sweden. Validation of vitamin D intake from the FFQ was carried out with four 7-day food records every third month in 104 of the women (r ⫽ 0.72). There are only small systematic errors related to intake level between the methods with an average difference of only 0.11 g higher vitamin D values with the food records (95% confidence interval (CI), ⫺0.15 to 0.38), an indication of good accuracy for the FFQ.
Additional information The questionnaires provided lifestyle information, including use of postmenopausal estrogen therapy, menopausal status, parity information, medication use, weight and height, smoking habits, and leisure-time physical activity during the past year (with 5 predefined levels ranging from 1 h/wk to ⬎5 h/wk). Physical activity collected in the 1997 questionnaire is valid when compared with activity records and accelerometer data (24). The educational level was categorized as ⱕ9 years, 10 to 12 years, ⬎12 years, and other education (such as vocational). ICD diagnosis codes were collated from the Swedish National Patient Registry to calculate Charlson’s comorbidity index (25).
Statistical analyses The present study was made up of 2 study samples: the SMC with the primary outcomes any first fracture and first hip fracture and the SMCC with the secondary outcomes osteoporosis, BMD, and S-25(OH)D levels. For each woman in the SMC, person-years of follow-up were calculated from the date they entered the cohort until the date of fracture, date of death, the date of emigration, or the end of the follow-up period (December 31, 2008), whichever occurred first. We estimated age-adjusted and multivariable-adjusted hazard ratios (HRs) of fracture by Cox proportional hazard regression and odds ratios (ORs) of osteoporosis by logistic regression.
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To better account for changes in diet during follow-up and to better represent long-term dietary intake, vitamin D intake and the covariates were treated as time-updated variables in the Cox models and as cumulative average intakes in the logistic regression models (26). The proportional hazard assumptions in the Cox models were confirmed graphically by comparing NelsonAalen plots and by Schoenfeld’s test. We estimated associations for dietary and for total vitamin D intake, including both diet and supplement use. In addition, we examined the relation between quintiles of vitamin D intake and risk of fracture and osteoporosis. To facilitate comparisons of the estimates, the same quintile cutoffs were used in the SMCC as in the entire cohort. We further analyzed the rate of fracture after stratification by calcium intake (⬍800 mg/d vs ⱖ800 mg/d). To obtain a clearer view of the shape of the association between vitamin D intake and fracture risk, we used restricted cubic spline models, with 4 knots located at percentiles 5, 35, 65, and 95 of vitamin D intake. This approach allowed us to obtain a smoothed dose-risk curve with 95% CI. In addition, we contrasted women who consistently reported lowest quintile of vitamin D intake to women who reported a constant intake within the highest quintile for all outcomes. Finally, we broadened our categorical exposure range into 4 vitamin D intake categories (⬍5.0, 5.0 –7.5, 7.5–10, and ⬎10 g/d), which reflects different current dietary recommendations, and also into 5 categories (⬍3.5, 3.5– 6, 6 –9, 9 –12.5, and ⬎12.5 g/d) as previously described (15). In the multivariable model, we included age; total energy intake; alcohol, retinol, protein, potassium, and calcium intake; body mass index (BMI); height (all continuous); education level (ⱕ9, 12, ⬎12 years, and other); nulliparity (yes or no); vitamin D supplement use (yes or no); calcium supplements (yes or no); physical activity (5 categories); smoking status (never, former, or current); previous fracture before study start (yes or no); and Charlson’s comorbidity index (continuous, 1–16). In the analysis of SMCC, we also included estrogen, bisphosphonate, and cortisone use as separate marker variables in the multivariable model. Covariates not assessed in the baseline FFQ (such as smoking habits and physical activity) were imputed by the Markov chain Monte Carlo multiple imputation procedure. Sensitivity analysis with restriction to nonmissing data did not alter our interpretation of the results. Given that both low and high vitamin D intake might be related to prevalent disease and mortality, we compared cumulative incidence curves with Kaplan-Meier failure curves to address the potential competing risk problem from mortality (27). The curves indicated that our results would not be compromised by competing risk from mortality (Supplemental Figure 1, published on The Endocrine Society’s Journals Online website at http://jcem.endojournals.org). The association between total S-25(OH)D (the sum of S-25(OH)D2 and S-25(OH)D3 although not including 3-epi25(OH)D3) and vitamin D intake from diet and supplements was analyzed by linear regression analyses, adjusting for age, weight, height, and season). The statistical analyses were performed with STATA version 11 (StataCorp).
Ethical approval The study was approved by the regional ethical review board in Stockholm, Sweden, and all participants gave their informed consent.
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Results The basic characteristics of the study participants by quintiles of dietary vitamin D intake are presented in Table 1. With increasing intake of vitamin D, the average age and BMI of the women as well as intake of calcium and retinol were higher, whereas the intake of alcohol was lower. However,
Table 1. Intakea
J Clin Endocrinol Metab, March 2014, 99(3):781–790
level of education, physical activity, and smoking status were similar across categories of vitamin D intake. The women were followed for a median time of 19.2 years, which contributed to 996 800 person-years at risk. During this time, 14 738 women suffered any type of first fracture, of which 5043 had had 1 or more additional fractures during follow-up. In addition, 3871 of the
Characteristics of the Total Cohort (SMC) and the Subcohort (SMCC) by Quintiles of Dietary Vitamin D Quintile
Number of participants Vitamin D intake, g/d SMC Age at entry, y BMI at entry, kg/m2) Dietary vitamin D intake, g/d Total vitamin D intake,b g/d Vitamin D supplement use n (%)c,d Dietary calcium intake, mg/d Total calcium intake,b mg/d Energy intake, kcal/d Dietary retinol intake, g/d Alcohol intake, g/d Nulliparity, n (%) Leisure time PA level, n (%)d 1 (lowest) 2 3 4 5 (highest) Smoking status, n (%)d Current Former Never Education level, n (%)e ⱕ9 y 9 –12 y ⬎12 y Other SMCC Age at DXA investigation, y BMI, kg/m2 Energy intake, kcal/d Vitamin D intake, g/d Vitamin D supplement use, n (%)c,d Total vitamin D intake,b g/d Calcium intake, mg/d Supplemental calcium intake, mg/d (n ⫽ 610) Total calcium intake,b mg/d Retinol intake, g/d Alcohol intake, g/d
Q1
Q2
Q3
Q4
Q5
12 286 ⬍3.3
12 287 3.3– 4.0
12 287 4.0 – 4.7
12 282 4.7–5.4
12 291 ⬎5.4
56.1 (10.2) 24.4 (4.3) 2.6 (0.5) 3.1 (1.7) 1622 (13) 919 (275) 969 (413) 1642 (531) 267 (467) 3.4 (5.2) 2245 (11)
55.9 (10.2) 24.6 (4.2) 3.7 (0.2) 4.1 (1.8) 1828 (15) 907 (255) 956 (394) 1661 (485) 319 (531) 3.4 (4.5) 2061 (10)
56.5 (10.3) 24.7 (3.8) 4.3 (0.2) 4.8 (1.6) 1730 (14) 927 (260) 974 (390) 1646 (475) 362 (601) 3.3 (4.3) 2006 (10)
57.2 (10.3) 25.1 (4.1) 5.0 (0.2) 5.4 (1.5) 1816 (15) 983 (259) 1025 (364) 1640 (470) 359 (648) 2.9 (3.8) 1914 (10)
59.0 (10.7) 25.7 (4.6) 6.5 (1.5) 6.9 (2.2) 1604 (13) 1067 (320) 1109 (417) 1609 (614) 421 (752) 2.6 (3.8) 2239 (11)
392 (20) 4806 (24) 6336 (32) 2773 (14) 1971 (10)
3844 (19) 5128 (26) 6483 (32) 2698 (13) 1893 (10)
3837 (19) 5209 (25) 667 (33) 2728 (13) 2012 (10)
362 (19) 4952 (26) 6326 (33) 2637 (14) 1831 (8)
4072 (20) 5115 (25) 6646 (32) 2845 (14) 2065 (9)
4245 (21) 5425 (27) 10 136 (51)
4113 (21) 5593 (28) 1034 (52)
4178 (20) 5583 (27) 10 695 (52)
3902 (20) 5131 (26) 10 333 (53)
4590 (22) 5674 (27) 10 479 (51)
14 976 (76) 1579 (8) 2267 (11) 984 (5)
15 232 (76) 1589 (8) 2195 (11) 103 (5)
15 808 (77) 155 (8) 2095 (10) 1003 (5)
15 215 (79) 1400 (7) 1722 (9) 1029 (5)
16 657 (80) 1328 (6) 1737 (8) 1021 (5)
66.5 (6.4) 23.6 (3.2) 1698 (442) 2.8 (0.5) 112 (13.7) 4.9 (2.2) 976 (209) 348 (187) 1033 (233) 409 (265) 6.0 (5.7)
66.5 (6.5) 24.0 (3.5) 1735 (398) 3.7 (0.2) 68 (13.9) 4.0 (2.6) 991 (188) 360 (185) 1028 (248) 449 (262) 5.4 (4.7)
67.0 (6.5) 24.3 (3.2) 1714 (385) 4.3 (0.2) 164 (14.2) 5.6 (2.3) 982 (184) 362 (185) 1028 (228) 482 (239) 5.5 (4.8)
67.6 (6.7) 24.9 (3.4) 1722 (388) 5.0 (0.2) 228 (16.9) 6.3 (3.0) 1028 (204) 382 (180) 1068 (244) 539 (252) 5.1 (4.4)
69.5 (7.1) 25.4 (3.8) 1692 (377) 6.2 (0.8) 201 (16.6) 7.4 (2.4) 1064 (223) 381 (179) 1108 (262) 590 (342) 4.8 (4.7)
Abbreviations: DXA, dual-energy x-ray absorptiometry; PA, physical activity. a
Data are shown as mean ⫾ SD or as otherwise indicated. Intake per day refers to the energy adjusted intake in the subcohort (SMCC).
b
Total intake is the sum of dietary and supplemental intakes.
c
Supplemental vitamin D alone in combination with calcium or as multivitamins.
d
Information only available in the 1997 questionnaire and in the DXA questionnaire.
e
Educational level: ’Other’ refers to vocational or other education.
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doi: 10.1210/jc.2013-1738
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Table 2. HRs With 95% CIs for the First of Any Type of Fracture and Hip Fracture by Quintiles of Vitamin D Intake and ORs With 95% CIs for Osteoporosis in the Subcohort SMCC by Quintiles of Vitamin Da Vitamin D intake, g/d First event any fracture Dietary intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Total intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b First event of hip fracture Dietary intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Total intake of vitamin D Number of fractures Person-years at risk Rate per 1000 person years Age-adjusted HR (95% CI) Multivariable-adjusted HR (95% CI)b Osteoporosis Dietary intake of vitamin D Number of women (%) Women without osteoporosis n (%) Women with osteoporosis, n (%) Age-adjusted OR (95% CI) Multivariable-adjusted OR (95% CI)c Total intake of vitamin D Number of women (%) Women without osteoporosis n (%) Women with osteoporosis n (%) Age-adjusted OR (95% CI) Multivariable-adjusted OR (95% CI)c a
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
⬍3.3
3.3– 4.0
4.0 – 4.7
4.7–5.4
⬎5.4
2884 212 880 13.5 (13.1–14.1) 1.01 (0.96 –1.07) 0.96 (0.92–1.01)
2813 212 240 13.3 (12.8 –13.8) 0.99 (0.94 –1.05) 0.98 (0.93–1.03)
2952 213 360 13.8 (13.3–14.3) 1 (reference) 1 (reference)
2855 202 290 14.1 (13.6 –14.6) 1.01 (0.96 –1.06) 1.01 (0.96 –1.07)
3234 210 510 15.4 (14.8 –15.9) 1.00 (0.95–1.05) 1.02 (0.96 –1.07)
2630 197 560 13.3 (12.8 –13.8) 1.02 (0.97–1.08) 0.97 (0.92–1.03)
2528 197 120 12.8 (12.3–13.3) 0.99 (0.93–1.04) 0.97 (0.92–1.02)
2652 197 700 13.4 (12.9 –13.9) 1 (reference) 1 (reference)
2598 189 800 13.7 (13.2–14.2) 1.00 (0.95–1.06) 1.01 (0.95–1.06)
4330 269 100 16.1 (15.6 –16.6) 0.94 (0.90 – 0.99) 1.01 (0.96 –1.07)
734 228 580 3.2 (3.0 –3.5) 1.10 (0.99 –1.21) 1.02 (0.96 –1.08)
686 227 490 3.0 (2.8 –3.2) 1.03 (0.93–1.14) 0.94 (0.93– 0.96)
723 230 000 3.1 (2.9 –3.4) 1 (reference) 1 (reference)
774 217 700 3.6 (3.3–3.8) 1.09 (0.98 –1.20) 1.10 (0.99 –1.21)
954 227 830 4.2 (3.9 – 4.5) 1.07 (0.97–1.18) 1.14 (1.03–1.26)
682 211 440 3.2 (3.0 –3.5) 1.06 (0.96 –1.18) 0.94 (0.84 –1.04)
631 210 240 3.0 (2.8 –3.2) 0.99 (0.89 –1.10) 0.93 (0.84 –1.04)
685 212 240 3.2 (3.0 –3.5) 1 (reference) 1 (reference)
718 203 590 3.5 (3.3–3.8) 1.04 (0.94 –1.15) 1.06 (0.95–1.18)
1155 294 090 3.9 (3.7– 4.2) 0.85 (0.77– 0.93) 1.09 (0.99 –1.21)
395 (7.9) 308 (78.0) 87 (22.0) 1.27 (0.95–1.69) 1.15 (0.85–1.55)
819 (16.3) 641 (78.3) 178 (21.7) 1.24 (0.99 –1.55) 1.13 (0.89 –1.44)
1277 (25.4) 1033 (80.9) 244 (19.1) 1 (reference) 1 (reference)
1421 (28.3) 1146 (80.7) 275 (19.4) 0.96 (0.79 –1.17) 1.10 (0.89 –1.35)
1110 (22.1) 882 (79.5) 228 (20.5) 0.87 (0.70 –1.07) 1.08 (0.85–1.37)
280 (5.6) 213 (76.1) 67 (23.9) 1.37 (0.98 –1.90) 1.20 (0.85–1.71)
568 (11.3) 437 (76.9) 131 (23.1) 1.36 (1.04 –1.76) 1.21 (0.92–1.60)
929 (18.5) 754 (81.2) 175 (18.8) 1 (reference) 1 (reference)
1105 (22.0) 902 (81.6) 203 (18.4) 0.94 (0.75–1.19) 1.03 (0.81–1.32)
2140 (42.6) 1704 (79.6) 436 (20.4) 0.95 (0.78 –1.16) 0.99 (0.78 –1.25)
Energy-adjusted mean nutrient data were estimated with data from the baseline and the 1997 questionnaire.
b
The multivariable-adjusted HRs were adjusted for age; BMI; height; total energy intake; retinol, potassium, protein, alcohol, and calcium intake; calcium and vitamin D supplementation; nulliparity; educational and physical activity level; smoking status; previous fracture of any type before baseline; and Charlson’s comorbidity index. c Osteoporosis was defined in subjects when the T-score, determined at the total hip, femoral neck, or lumbar spine, was ⱕ⫺2.5 SD below the mean of a young adult reference range. The multivariable-adjusted HRs were adjusted for age; BMI; height; total energy intake; retinol, potassium, protein, alcohol, and calcium intake; calcium and vitamin D supplementation; nulliparity; educational and physical activity level; smoking status; previous fracture of any type before baseline; Charlson’s comorbidity index; estrogen replacement therapy; and cortisone and bisphosphonate use.
women had a first hip fracture during follow-up and 1368 experienced multiple hip fractures. In the SMCC subcohort, 20% (n ⫽ 1012) of the women were classified as osteoporotic. Vitamin D intake and fractures The HRs for a first fracture by quintiles of dietary and total vitamin D intake are presented in Table 2. Despite a more than 2-fold difference in median vitamin D intake between lowest and highest quintiles, the rate of fracture was not higher among women with the lowest intake levels. On the contrary, a somewhat higher rate for a first hip fracture was discerned within the highest dietary quintile of vitamin D intake (HR, 1.14; 95% CI, 1.03–1.26), an
observation confirmed when analyzing multiple hip fracture events (Supplemental Table 1). The risks with more extreme intakes of vitamin D are displayed by the spline curves illustrated in Figure 2, A and B, and by the categories shown in Supplemental Tables 2 and 3. In comparison with a vitamin D intake below 5 g/d, women with an intake higher than 10 g/d did not have a lower rate of fracture of any type (HR 1.02; 0.92–1.13), and they even had a higher rate of hip fracture (HR, 1.27; 1.03–1.57). Even more extreme intakes (⬍3.5 vs ⬎12.5 g) did not alter our results (Figure 3 and Supplemental Table 3). Calcium intake (higher or less than 800 mg daily, Supplemental Table 4) did not modify the association between
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Hazard ratio of any first fracture (adjusted)
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Dietary vitamin D intake (>10 µg vs 10 µg vs 12.5 µg vs
