The effects of vitamin D supplementation on frailty in older adults at risk for falls

Yurun Cai, Amal A Wanigatunga, Christine M Mitchell, Jacek K Urbanek, Edgar R Miller 3rd, Stephen P Juraschek, Erin D Michos, Rita R Kalyani, David L Roth, Lawrence J Appel, Jennifer A Schrack, Yurun Cai, Amal A Wanigatunga, Christine M Mitchell, Jacek K Urbanek, Edgar R Miller 3rd, Stephen P Juraschek, Erin D Michos, Rita R Kalyani, David L Roth, Lawrence J Appel, Jennifer A Schrack

Abstract

Background: Low serum 25-hydroxyvitamin D [25(OH)D] level is associated with a greater risk of frailty, but the effects of daily vitamin D supplementation on frailty are uncertain. This secondary analysis aimed to examine the effects of vitamin D supplementation on frailty using data from the Study To Understand Fall Reduction and Vitamin D in You (STURDY).

Methods: The STURDY trial, a two-stage Bayesian, response-adaptive, randomized controlled trial, enrolled 688 community-dwelling adults aged ≥ 70 years with a low serum 25(OH)D level (10-29 ng/mL) and elevated fall risk. Participants were initially randomized to 200 IU/d (control dose; n = 339) or a higher dose (1000 IU/d, 2000 IU/d, or 4000 IU/d; n = 349) of vitamin D3. Once the 1000 IU/d was selected as the best higher dose, other higher dose groups were reassigned to the 1000 IU/d group and new enrollees were randomized 1:1 to 1000 IU/d or control group. Data were collected at baseline, 3, 12, and 24 months. Frailty phenotype was based on number of the following conditions: unintentional weight loss, exhaustion, slowness, low activity, and weakness (≥ 3 conditions as frail, 1 or 2 as pre-frail, and 0 as robust). Cox proportional hazard models estimated the risk of developing frailty, or improving or worsening frailty status at follow-up. All models were adjusted for demographics, health conditions, and further stratified by baseline serum 25(OH)D level (insufficiency (20-29 ng/mL) vs. deficiency (10-19 ng/mL)).

Results: Among 687 participants (mean age 77.1 ± 5.4, 44% women) with frailty assessment at baseline, 208 (30%) were robust, 402 (59%) were pre-frail, and 77 (11%) were frail. Overall, there was no significant difference in risk of frailty outcomes comparing the pooled higher doses (PHD; ≥ 1000 IU/d) vs. 200 IU/d. When comparing each higher dose vs. 200 IU/d, the 2000 IU/d group had nearly double the risk of worsening frailty status (HR = 1.89, 95% CI: 1.13-3.16), while the 4000 IU/d group had a lower risk of developing frailty (HR = 0.22, 95% CI: 0.05-0.97). There were no significant associations between vitamin D doses and frailty status in the analyses stratified by baseline serum 25(OH)D level.

Conclusions: High dose vitamin D supplementation did not prevent frailty. Significant subgroup findings might be the results of type 1 error.

Trial registration: ClinicalTrials.gov: NCT02166333 .

Keywords: Frailty; Nutrition supplementation; Randomized controlled trial; Vitamin D3.

Conflict of interest statement

The authors do not have completing interests to declare.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Percentage of participants with each frailty status at baseline and follow-up visits. A Pooled higher dose (PHD) vs. 200 IU/d. B Pure 1000 IU/d vs. 200 IU/d. PHD = Pooled higher doses (combined 1000 IU/d, 2000 IU/d, and 4000 IU/d). IU/d = International units per day
Fig. 2
Fig. 2
Hazard ratios (HRs) of developing frailty, improving frailty status, and worsening frailty status by vitamin D treatment groups in the confirmatory stage and dose-finding stage. The two sets of analyses comparing PHD vs. 200 IU/d and pure 1000 IU/d vs. 200 IU/d were conducted from the confirmatory stage. The four vitamin D treatment groups were compared among participants in the burn-in cohort from the dose-finding stage. This is an unbiased population for comparison of each higher dose versus control because these participants were randomized prior to the first adaptation of the randomization probabilities. PHD = pooled higher doses (combined 1000 IU/d, 2000 IU/d, and 4000 IU/d). IU/d = international units per day

References

    1. Fried LP, Cohen AA, Xue Q-L, Walston J, Bandeen-Roche K, Varadhan R. The physical frailty syndrome as a transition from homeostatic symphony to cacophony. Nat Aging. 2021;1(1):36–46. doi: 10.1038/s43587-020-00017-z.
    1. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. Journals Gerontol Ser A-Biological Sci Med Sci. 2001;56A(3):M146–M156. doi: 10.1093/gerona/56.3.M146.
    1. Bandeen-Roche K, Seplaki CL, Huang J, et al. Frailty in older adults: a nationally representative profile in the United States. Journals Gerontol - Ser A Biol Sci Med Sci. 2015;70(11):1427–1434. doi: 10.1093/gerona/glv133.
    1. Gregorevic KJ, Hubbard RE, Lim WK, Katz B. The clinical frailty scale predicts functional decline and mortality when used by junior medical staff: a prospective cohort study. BMC Geriatr. 2016;16:117. doi: 10.1186/s12877-016-0292-4.
    1. Ensrud KE, Ewing SK, Taylor BC, et al. Frailty and risk of falls, fracture, and mortality in older women: the Study of Osteoporotic Fractures. Journals Gerontol Ser A. 2007;62(7):744–751. doi: 10.1093/gerona/62.7.744.
    1. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL. Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int. 2011;22(3):859–871. doi: 10.1007/s00198-010-1407-y.
    1. Rosendahl-Riise H, Spielau U, Ranhoff AH, Gudbrandsen OA, Dierkes J. Vitamin D supplementation and its influence on muscle strength and mobility in community-dwelling older persons: a systematic review and meta-analysis. J Hum Nutr Diet. 2017;30(1):3–15. doi: 10.1111/jhn.12394.
    1. Muir SW, Montero-Odasso M. Effect of Vitamin D Supplementation on Muscle Strength, Gait and Balance in Older Adults: A Systematic Review and Meta-Analysis. J Am Geriatr Soc. 2011;59(12):2291–2300. doi: 10.1111/j.1532-5415.2011.03733.x.
    1. Beaudart C, Buckinx F, Rabenda V, et al. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2014;99(11):4336–4345. doi: 10.1210/jc.2014-1742.
    1. Zhu K, Austin N, Devine A, Bruce D, Prince RL. A randomized controlled trial of the effects of vitamin D on muscle strength and mobility in older women with vitamin D insufficiency. J Am Geriatr Soc. 2010;58(11):2063–2068. doi: 10.1111/j.1532-5415.2010.03142.x.
    1. Ensrud KE, Blackwell TL, Cauley JA, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the Osteoporotic Fractures in Men study. J Am Geriatr Soc. 2011;59(1):101–106. doi: 10.1111/j.1532-5415.2010.03201.x.
    1. Ju SY, Lee JY, Kim DH. Low 25-hydroxyvitamin D levels and the risk of frailty syndrome: a systematic review and dose-response meta-analysis. BMC Geriatr. 2018;18(1):1–11. doi: 10.1186/s12877-018-0904-2.
    1. Buta B, Choudhury PP, Xue Q-L, et al. The association of vitamin D deficiency and incident frailty in older women: the role of cardiometabolic diseases. J Am Geriatr Soc. 2017;65(3):619–624. doi: 10.1111/jgs.14677.
    1. Wong YYE, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older men: the Health in Men Study. J Clin Endocrinol Metab. 2013;98(9):3821–3828. doi: 10.1210/jc.2013-1702.
    1. Bolzetta F, Stubbs B, Noale M, et al. Low-dose vitamin D supplementation and incident frailty in older people: an eight year longitudinal study. Exp Gerontol. 2017;2018(101):1–6. doi: 10.1016/j.exger.2017.11.007.
    1. Appel LJ, Michos ED, Mitchell CM, et al. The effects of four doses of vitamin D supplements on falls in older adults. Ann Intern Med. 2020;174(2):145–156. doi: 10.7326/M20-3812.
    1. Michos ED, Mitchell CM, Miller ER, III, et al. Rationale and design of the Study To Understand Fall Reduction and Vitamin D in You (STURDY): A randomized clinical trial of Vitamin D supplement doses for the prevention of falls in older adults. Contemp Clin Trials. 2018;73:111–122. doi: 10.1016/j.cct.2018.08.004.
    1. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–M156. doi: 10.1093/gerona/56.3.m146.
    1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281. doi: 10.1056/NEJMra070553.
    1. Wilhelm-Leen ER, Hall YN, DeBoer IH, Chertow GM. Vitamin D deficiency and frailty in older Americans. J Intern Med. 2010;268(2):171–180. doi: 10.1111/j.1365-2796.2010.02248.x.
    1. Vaes AMM, Brouwer-Brolsma EM, Toussaint N, et al. The association between 25-hydroxyvitamin D concentration, physical performance and frailty status in older adults. Eur J Nutr. 2019;58(3):1173–1181. doi: 10.1007/s00394-018-1634-0.
    1. Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle function. Osteoporos Int. 2002;13(3):187–194. doi: 10.1007/s001980200012.
    1. Rejnmark L. Effects of vitamin D on muscle function and performance: a review of evidence from randomized controlled trials. Ther Adv Chronic Dis. 2010;2(1):25–37. doi: 10.1177/2040622310381934.
    1. Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2009;20(2):315–322. doi: 10.1007/s00198-008-0662-7.
    1. Gowda U, Mutowo MP, Smith BJ, Wluka AE, Renzaho AMN. Vitamin D supplementation to reduce depression in adults: Meta-analysis of randomized controlled trials. Nutrition. 2015;31(3):421–429. doi: 10.1016/j.nut.2014.06.017.
    1. Shaffer JA, Edmondson D, Wasson LT, et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014;76(3):190–196. doi: 10.1097/PSY.0000000000000044.
    1. Havdahl A, Mitchell R, Paternoster L, Davey SG. Investigating causality in the association between vitamin D status and self-reported tiredness. Sci Rep. 2019;9(1):2880. doi: 10.1038/s41598-019-39359-z.
    1. Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue: a double-blind randomized placebo-controlled trial. Medicine. 2016;95(52). .
    1. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. doi: 10.1210/jc.2011-0385.
    1. Wanigatunga AA, Sternberg AL, Blackford AL, et al. The effects of vitamin D supplementation on types of falls. J Am Geriatr Soc. 2021;n/a(n/a). 10.1111/jgs.17290
    1. Grant WB, Karras SN, Bischoff-Ferrari HA, et al. Do studies reporting ’U’-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects? Dermatoendocrinol. 2016;8(1):e1187349–e1187349. doi: 10.1080/19381980.2016.1187349.
    1. Davis CD. Vitamin D and health: can too much be harmful? Am J Lifestyle Med. 2009;3(5):407–408. doi: 10.1177/1559827609338154.
    1. Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629–1637. doi: 10.1001/archinte.168.15.1629.
    1. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117(4):503–511. doi: 10.1161/CIRCULATIONAHA.107.706127.
    1. Bislev LS, Langagergaard Rødbro L, Rolighed L, Sikjaer T, Rejnmark L. Effects of vitamin D3 supplementation on muscle strength, mass, and physical performance in women with vitamin D insufficiency: a randomized placebo-controlled trial. Calcif Tissue Int. 2018;103(5):483–493. doi: 10.1007/s00223-018-0443-z.
    1. Zhou J, Huang P, Liu P, et al. Association of vitamin D deficiency and frailty: a systematic review and meta-analysis. Maturitas. 2016;94:70–76. doi: 10.1016/j.maturitas.2016.09.003.
    1. Houston DK, Cesari M, Ferrucci L, et al. Association between vitamin D status and physical performance: the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2007;62(4):440–446. doi: 10.1093/gerona/62.4.440.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe