Supplementary Online Content

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1 Supplementary Online Content Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. Published online January 4, doi: /jamainternmed etable 1. Effect of Treatment on Reaction Time, Grip Strength and Muscle Mass eappendix. Effect of Treatment on Intact Parathyroid Hormone Levels (ipth) etable 2. Prevention of Functional Decline and Falls by Achieved Quartile of 25(OH)D Status at 12 Month Follow-up (Quartile 1 Is Now the Reference) etable 3. Safety Laboratory etable 4. Individuals With Normal Serum Calcium, Mild Hypercalcemia and Hypercalcemia at Baseline, 2 Weeks, 6 and 12 Month Follow-up This supplementary material has been provided by the authors to give readers additional information about their work American Medical Association. All rights reserved. 1

2 etable 1. Effect of Treatment on Reaction Time, Grip Strength and Muscle Mass Treatment per month D IU vitamind3/month D IU vitamind3/month D3 +calcifediol IU vitamin D3 /month plus 300 µg calcifediol /month Difference between treatments in changes over time reaction time in sec (5 repeated chair stands) / / / Adjusted 6 month change a a (-1.44; -0.60) (-0.86; -0.02) (-1.53; -0.66) Adjusted 12 month change (-1.64; -0.67) (-1.45; -0.46) (-1.39; -0.40) grip strength dominant hand in bar / / / Adjusted 6 month change (+1.63; ) (+0.02; ) (+0.04; +3.25) Adjusted 12 month change (-0.49; +5.20) (-1.28; +4.51) -1.97; +3.80) muscle mass arms in grams / / / Adjusted 12 month change (-63.62, ) ( , ) (-94.12, ) muscle mass legs in grams / / / Adjusted 12 month change ( ,+8.09) ( , ) ( ,-36.71) p = 0.04* p = 0.93* p = 0.25* p = 0.63* etable 1 is an extension of Table 2 with additional endpoints related to muscle health. These findings support the main findings qualitatively. Changes over time for mean reaction time assessed with sit-to-stand performance and for grip strength, were compared between the 3 study arms using a repeated measures linear regression. *P-values are from the interaction between treatment group and time from a repeated measures linear regression, adjusted for baseline, age, gender, and bmi. The outcome measures in each model are 6 month change and 12 month change, except for leg and arm lean mass where only 12 month change was collected. Simpler linear 2015 American Medical Association. All rights reserved. 2

3 regression models were used to compare changes in arm lean mass from 12- to baseline (and leg mean mass) between the 3 arms. a Significant pairwise difference from D3. There were no significant pairwise differences between D3 and D3+calcifediol. For upper extremity strength, we measured grip strength at the dominant hand by the Martin Vigorimeter, which we validated in an earlier trial[39]. Appendicular muscle mass at the arms and legs was measured by dual-energy x-ray absorptiometry with use of an IDXA scanner (Lunar IDXA, GE Healthcare; scanner software encore 2010 Version 13.50). The coefficient of variation for the muscle mass measurements was 0.5% American Medical Association. All rights reserved. 3

4 eappendix. Effect of Treatment on Intact Parathyroid Hormone Levels (ipth) One of the goals of vitamin D treatment is to improve calcium metabolism. Therefore one of the benefits we anticipated with D3/24 000D3+calcifediol was increased PTH suppression. However, in the adjusted analyses, what we found was almost equal reductions in intact parathyroid hormone (ipth) between treatment arms (p =0.35). With D3, ipth decreased by pg/ml (-14.3; - 8.7) at 6 month, and by -8. pg/ml (- 11.1; -5.8) at 12. With D3, ipth decreased by pg/ml (-14.5; -9.0) at 6 month, and by pg/ml (-13.6; -8.3) at 12. With D3+calcifediol, ipth decreased by pg/ml (-13.6; -7.9) at 6 month, and by pg/ml (-12.9; - 7.5) at American Medical Association. All rights reserved. 4

5 etable 2. Prevention of Functional Decline and Falls by Achieved Quartile of 25(OH)D Status at 12 Month Follow-up (Quartile 1 Is Now the Reference) Variables Quartile ng/ml ng/ml Quartile ng/ml ng/ml Quartile ng/ml ng/ml Quartile 4 (--ref--) 50.2 ng/ml ng/ml Primary endpoint: prevention of functional decline SPPB score Adjusted 12 month change Number of fallers at 0-12 at ref (- 0.78,+ 0.18) p = (-0.61, +0.36) p = 0.63 Secondary endpoint: prevention of falls Odds of being a faller --ref (1.47, 8.78) (0.74,4.02) p = p = 0.21 Number of falls over time -- ref (0.46,1.22) 1.10 (0.71,1.48) p = (0.68,1.44) p = (-0.47, +0.55) p = (2.10,14.50) p = (1.19,2.00) p = 0.01 For etable 2, we divided the study cohort according to the quartile of achieved with the highest quartile as the reference category. For each of the outcomes we ran a linear regression model (logistic regression for incidence of being a faller) with the 12-month change in outcome as the dependent variable, indicator variables for the 4 quartiles of achieved 25(OH)D as the primary predictors, and the baseline measure, age, gender and BMI as covariates American Medical Association. All rights reserved. 5

6 etable 3. Safety Laboratory By treatment group at baseline, 2 weeks 6 and 12 Treatment Baseline (N = 199) 2 weeks (N = 199) 6 (N = 195) 12 (N = 190) p * p * p p Serum total calcium (mmol/l) D (0.08) (0.11) (0.12) D3+calcifediol 2.31 (0.08) (0.10) D (0.08) 2.33 Serum creatinine (μmol/l) D (18.81) (22.53) (17.80) (17.87) D3+calcifediol (16.67) (21.30) (19.64) (16.70) D (17.34) (17.23) (15.19) (13.84) Urine calcium / creatinine ratio D (0.21) D3+calcifediol 0.24 (0.15) 0.35 (0.28) 0.30 (0.21) D (0.22) 0.42 (0.37) 0.28 (0.23) 0.28 (0.22) * Based on one-way ANOVA and compares the 3 treatment groups at each time point 2015 American Medical Association. All rights reserved. 6

7 etable 4. Individuals With Normal Serum Calcium, Mild Hypercalcemia and Hypercalcemia at Baseline, 2 Weeks, 6 and 12 Month Follow-up Serum calcium level Treatment Baseline (N = 199) D D3+calcifediol D3 < 2.6 mmol/l 67 (100%) 66 (100%) 66 (100%) mmol/l 0 (0%) 0 (0%) 0 (0%) 2 weeks (N = 199) < 2.6 mmol/l 65 (97%) 66 (100%) 65 (98.5%) mmol/l 2 (3%) 0 (0%) 1 (1.5%) 6 (N = 195) < 2.6 mmol/l 66 (100%) 63 (98.4%) 65 (100%) mmol/l 0 (0%) 1 (1.6%) 0 (0%) 12 (N = 190) < 2.6 mmol/l 63 (96.9%) 62 (100%) 63 (100%) mmol/l 2 (3.1%) 0 (0%) 0 (0%) All together, we documented only 6 cases of mild hypercalcemia: at 2 weeks follow-up, there were 3 cases of mild hypercalcemia, 2 in the D3 group and 1 in the D3 group (all with serum calcium at 2.65 nmol/l); at 6 month follow-up, there was 1 case of mild hypercalcemia in the D3 group (2.60 mmol/l); at 12 month followup, there were 2 cases of mild hypercalcemia in the D3 group (2.63 and 2.64 mmol/l) American Medical Association. All rights reserved. 7