Low D3Cr muscle mass increases risk of hip and potentially other fractures

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Older men with lower amounts of muscle mass have significantly increased risk of hip and potentially other fractures, new research led by investigators at Sutter Health’s San Francisco Coordinating Center (SFCC) in San Francisco, CA has shown.

Results of a prospective study were published online earlier this month in the Journal of Bone and Mineral Research, the official journal of the American Society for Bone and Mineral Research.

“Previous findings from our research and other studies have shown that low DXA lean mass – a commonly used but inaccurate approximation of muscle – is unrelated to a higher risk of fracture. This has led some researchers to erroneously conclude that muscle is relatively unimportant for fracture risk,” says Peggy Cawthon, Ph.D., lead author of the study, principal investigator of the Osteoporotic Fractures in Men (MrOS) Study Research Group at SFCC and a professor in the department of epidemiology and biostatistics at the University of California, San Francisco.

“However, these new results suggest low muscle mass is in fact associated with increased risk of hip fractures in older men, even after accounting for factors such as age and bone mineral density that may influence muscle mass and fracture risk.”

Dr. Cawthon and colleagues at leading academic medical centers across the U.S. prospectively studied 1,363 men (mean age, 84.2 years). The risk of fracture by quartile of D3Cr muscle mass was determined, and the study authors also investigated the mediating influence of physical performance (walking speed, chair stands and grip strength) on the relationship between muscle mass and fracture.

Results showed D3Cr muscle mass weakly correlated with femoral BMD (r=0.10, p<.001). However, D3Cr muscle mass correlated strongly with fractures, especially hip fracture. Compared with men in the highest quartile, those in the lowest quartile of D3Cr muscle mass/weight were about twice as likely to have a clinical fracture, any non-spine fracture, and were about six times more likely to have a hip fracture after approximately four years of follow-up. Study authors believe the relationship between D3CR muscle mass and fracture may be mediated by poor physical performance.

D3Cr dilution assessment of muscle mass – currently available only in research settings and being tested by the MrOS Study and other researchers for clinical use – relies on several aspects of creatine biology to estimate muscle mass that do not rely on the same assumptions of compartment models (such as DXA), and may therefore represent a more accurate assessment of muscle mass.

“The clear association between muscle mass and hip fracture was striking. For example, men in the lowest quartile of muscle mass were almost six times more likely to have a fracture than men highest quartile,” says Steve Cummings, M.D., director of the SFCC and a principal investigator of MrOS at Sutter’s California Pacific Medical Center. “Our findings suggest muscle mass is an important contributor to fractures. Resistance exercise and even simple activities like climbing stairs may be important for maintaining muscle strength and preventing fractures, however more information from the best evidence – randomized controlled trials – is needed to confirm these findings and help guide clinical decision making.” Dr. Cawthon notes that a limitation of the study is its sole cohort was male, as the measure of muscle mass was added to an ongoing study about osteoporosis in men (MrOS). “It is important to determine if these associations are also true in women,” she says. “If so, then it will be critical to test whether interventions that improve muscle mass also lower fracture risk, and how the D3Cr dilution assessment of muscle mass may potentially be used in the clinic to measure health outcomes.”

About 36 million falls are reported among older adults each year – resulting in more than 32,000 deaths. Every year, about three million older adults are treated in emergency departments for a fall injury. One out of every five falls causes an injury, such as broken bones or a head injury. Each year at least 300,000 older people are hospitalized for hip fractures.


The current study demonstrates a clear relationship between muscle mass, measured by D3Cr, and physical function in community-dwelling postmenopausal women. Women with high muscle mass had higher scores on all domains of the SPPB (balance, gait speed, and chair stand) and were less likely to report any prevalent physical limitations (physical activity, climbing stairs, bending/kneeling, walking, bathing/dressing).

Associations of D3Cr with physical function were stronger than DXA-defined LBM or ALM, lending support to the hypothesis that D3Cr is a more accurate measure of muscle mass than measures from DXA. In a commentary on the use of the D3Cr method, Schaap succinctly describes one of the key benefits of this approach: “By isolating contractile muscle mass from non-contractile components including fat, the D3-creatine assessment is not only an accurate method to assess muscle mass but is less biased by obesity and aging than DXA appendicular lean mass” (17).

Our findings are broadly consistent with measures of D3Cr and physical performance in older men in the Osteoporotic Fractures in Men (MrOS) study (5). Cawthon and colleagues reported older men in MrOs with low D3Cr muscle mass had worse physical function, higher incident disability (ie, difficulty completing activities of daily living and instrumental activities of daily living and mobility disability), and mortality risk (5,14).

The MrOs results are similar to our results in postmenopausal women; both studies report strong and consistent associations between muscle mass, SPPB, and functional limitation and weaker associations were observed for the relation of DXA ALM and physical function (5). Women in this study had lower absolute values of D3Cr muscle mass than men in the MrOS study, as well as lower physical function scores than men (eg, grip strength, SPPB) (5). These results demonstrate that although the association between D3Cr functional outcomes is similar in older men and women, we observe notable sex differences.

These results echo previous results on body composition in older adults using DXA. The Copenhagen Sarcopenia Study highlighted differences in DXA total body lean mass in 1305 older men and women: total body lean mass was 57.6 kg in men aged 60–69, 53.6 kg in men aged 70–79, and 51.3 kg in men >80 years compared to 40.8 kg, 39.4 kg, and 36.9 kg among women in the same age groups (26). Given known differences in body composition in older men and women, there is a clear scientific need for further research examining muscle mass in a large sample of older women.

The D3Cr method presents a tremendous opportunity for researchers interested in aging and body composition. There are many potential future directions for research using the D3Cr method, including analyses comparing older men and women, exploration of the dynamic relationship between muscle mass and fat mass in older adults, and the relation of D3Cr with risk of incident disease and morbidity.

This study was designed as a pilot study to examine the use of D3Cr in older women and has limitations similar to most pilot studies. Given the small sample size, we may be underpowered to detect the main effects of interest. Additional research is needed in a larger group of women to confirm the relationships between muscle mass, physical function, and functional limitation. A larger sample size would also generate a more precise estimates of the association between D3Cr and physical function outcomes.

Given the local recruitment and predominantly White study participants, our findings might not be generalizable to a larger sample of women in the WHI or older women in the general U.S. population. Our results also demonstrated that all odds ratios adjusted for physical activity were attenuated, which may be due to physical activity being a mediator of the relationship between muscle mass and physical functioning (27).

Additional analyses, including a causal mediation analysis in a larger sample, would be valuable to disentangle the complex relationship between muscle mass and physical activity (28). Despite these limitations, this study represents an important step forward for our understanding of muscle mass in a community-dwelling sample of postmenopausal women.

At present, the largest study examining the relation of D3Cr muscle mass with outcomes includes older men only. The results of this pilot study make an important scientific and clinical contribution to our understanding of muscle mass in older women and clearly highlight the need for future research in a larger sample of older women.

Our study contributes to an emerging body of literature on the relation of D3Cr and age-related outcomes. This study presents preliminary cross-sectional data on muscle mass and functional outcomes in postmenopausal women. Longitudinal research is urgently needed in a large, diverse sample of older adults. As women age, the risk of falls, fractures, and frailty markedly increases (29,30).

Studying the relation between muscle mass and functional outcomes is an important first step toward developing intervention strategies to reduce morbidity in this high-risk age group.

reference link :https://academic.oup.com/biomedgerontology/article/76/9/1591/6105073?login=false#285660196


More information: Peggy M. Cawthon et al, Association Between Muscle Mass Determined by D3‐Creatine Dilution and Incident Fractures in a Prospective Cohort Study of Older Men, Journal of Bone and Mineral Research (2022). DOI: 10.1002/jbmr.4505

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