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Randomized Controlled Trial
. 2025 May 24;40(5):591-602.
doi: 10.1093/jbmr/zjaf030.

Effects of cocoa extract supplementation and multivitamin/multimineral supplements on self-reported fractures in the Cocoa Supplement and Multivitamins Outcomes Study randomized clinical trial

Carolyn J Crandall  1 , Sharon Chou  2   3 , Eunjung Kim  4 , Dana Ratnarajah  2 , Nancy R Cook  3   4   5 , Allison Clar  4 , Howard D Sesso  3   4   5 , JoAnn E Manson  3   4   5 , Meryl S LeBoff  2   3
Affiliations
Randomized Controlled Trial

Effects of cocoa extract supplementation and multivitamin/multimineral supplements on self-reported fractures in the Cocoa Supplement and Multivitamins Outcomes Study randomized clinical trial

Carolyn J Crandall et al. J Bone Miner Res. .

Abstract

Osteoporosis is a major public health problem among older adults. Forty percent of older US adults take multivitamin/multimineral (MVM) supplementation. The effects of MVM supplementation on fractures are unclear. Preclinical and observational studies suggest that MVM and flavanols may have beneficial effects on bone. We conducted an ancillary study to Cocoa Supplement and Multivitamin Outcomes Study (COSMOS; NCT05232669) designed to investigate incident fracture and injurious falls in 21 442 COSMOS participants (12 666 females aged ≥65 yr and 8776 males aged ≥60 yr) randomized in a 2 × 2 factorial design to 1 of 4 intervention groups: cocoa extract + MVM, cocoa extract + MVM placebo, cocoa extract placebo + MVM, or double placebo. The daily cocoa extract supplement contained 500 mg/d flavanols and 80 mg/d (-)-epicatechin (Mars Edge); the daily MVM supplement was Centrum Silver (Haleon). The median (interquartile range) duration of the intervention was 3.6 (3.2-4.2) yr. Annually, participants self-reported incident fractures. In intention-to-treat analyses, we examined the effects of cocoa extract and MVM on the primary outcomes of total clinical fracture (hip, upper leg, forearm/wrist, pelvis, upper arm/shoulder, spine, knee, or other), hip fracture, and nonvertebral fracture, and secondary outcomes of clinical spine, forearm/wrist, major osteoporotic, and pelvic fracture using Cox proportional hazards models. During the intervention period, 2083 incident clinical fractures occurred. Compared with placebo, cocoa extract was not significantly associated with lower risk of incident clinical fracture (adjusted hazard ratio [aHR] 1.03, 95% CI 0.95-1.12) or nonvertebral fracture (aHR 1.05, 95% CI 0.96-1.14). MVM supplementation was not associated with lower risk of total clinical fracture (aHR 1.09, 95% CI 1.00-1.19), hip fracture (aHR 1.06, 95% CI 0.80-1.42), or nonvertebral fracture (aHR 1.10, 95% CI 1.00-1.20). These findings do not support the use of cocoa extract or MVM to decrease fracture risk in older individuals not selected for pre-existing osteoporosis.

Keywords: clinical trial; cocoa; cosmos; flavanol; fracture; multivitamin; osteoporosis.

Plain language summary

Osteoporosis is a major public health problem among older adults. Some studies suggest that flavanols, which are present in large quantities in cocoa, may have beneficial effects on bone. Multivitamin/multimineral (MVM) supplementation, taken by 40% of the US population, may also have beneficial effects on bone. We conducted an ancillary study to the COSMOS clinical trial. The COSMOS trial assigned 21 442 participants (12 666 females aged ≥65 yr and 8776 males aged ≥60 yr) to receive 2 of 4 study pills: cocoa extract + MVM, cocoa extract + MVM placebo, cocoa extract placebo + MVM, or double placebo. After accounting for age, race/ethnicity, and sex, compared with placebo, cocoa extract supplementation was not significantly associated with the risk of clinical fractures. MVM supplementation also did not reduce risk of total clinical, hip, or nonvertebral fracture. In this large study of older men and women, cocoa extract compared with placebo supplementation given for an average of 3.6 yr did not significantly affect the risk of fractures. Similarly, MVM supplement (vs placebo) did not reduce the risk of clinical fracture in older community-dwelling persons. MVM may have other health benefits, including helping to ensure adequate intake of calcium and vitamin D.

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Conflict of interest statement

None declared: C.J.C., D.R., E.K., A.C., N.C., S.C., B.H. C.J.C. reports grants from the National Institutes of Health during the conduct of this study. HDS Dr. Sesso reports receiving investigator-initiated grants from Mars Edge, a segment of Mars Incorporated dedicated to nutrition research and products, for infrastructure support and donation of COSMOS study pills and packaging, and Pfizer Consumer Healthcare (now Haleon) for donation of COSMOS study pills and packaging during the conduct of the study. Dr. Sesso additionally reports receiving investigator-initiated grants from Pure Encapsulations and Pfizer Inc. and honoraria and/or travel for lectures from the Council for Responsible Nutrition, BASF, NIH, and American Society of Nutrition during the conduct of the study. J.E.M.: Dr. Manson receives funding from Mars Edge and support from Pfizer Consumer Healthcare (now Haleon) for donation of COSMOS study pills and packaging during the conduct of the study. M.S.L. reports grants from the National Institutes of Health during the conduct of this study and Amgen stock ownership unrelated to this study.

Figures

Figure 1
Figure 1
Kaplan–Meier curves displaying incident clinical fractures with cocoa extract vs placebo over time.
Figure 2
Figure 2
Kaplan–Meier curves displaying incident clinical fractures with multivitamin vs placebo over time.
See this image and copyright information in PMC

Comment in

References

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