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The Effect of Intentional Weight Loss on Fracture Risk in Persons With Diabetes: Results From the Look AHEAD Randomized Clinical Trial
Open accessAbstract
Intentional weight loss is an important treatment option for overweight persons with type 2 diabetes mellitus (DM), but the effects on long-term fracture risk are not known. The purpose of this Look AHEAD analysis was to evaluate whether long-term intentional weight loss would increase fracture risk in overweight or obese persons with DM. Look AHEAD is a multicenter, randomized clinical trial. Recruitment began in August 2001 and follow-up continued for a median of 11.3 years at 16 academic centers. A total of 5145 persons aged 45 to 76 years with DM were randomized to either an intensive lifestyle intervention (ILI) with reduced calorie consumption and increased physical activity designed to achieve and maintain ≥7% weight loss or to diabetes support and education intervention (DSE). Incident fractures were ascertained every 6 months by self-report and confirmed with central adjudication of medical records. The baseline mean age of participants was 59 years, 60% were women, 63% were white, and the mean BMI was 36 kg/m2. Weight loss over the intervention period (median 9.6 years) was 6.0% in ILI and 3.5% in DSE. A total of 731 participants had a confirmed incident fracture (358 in DSE versus 373 in ILI). There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR 1.39; 95% CI, 1.02 to 1.89). An intensive lifestyle intervention resulting in long-term weight loss in overweight/obese adults with DM was not associated with an overall increased risk of incident fracture but may be associated with an increased risk of frailty fracture. When intentional weight loss is planned, consideration of bone preservation and fracture prevention is warranted. © 2017 American Society for Bone and Mineral Research.
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“However, 2017 data from the Look AHEAD trial showed that long-term intentional weight loss was associated with a 39% increased risk of fragility fractures325.”
From Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies (2018) · cites this paper as [325]
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“However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR = 1.39, 95% CI 1.02, 1.89). [32]”
From New drugs for the treatment of obesity: do we need approaches to preserve muscle mass? (2025) · cites this paper as [32]
In the citing paper
“Reduced LBM may be of additional clinical importance given its association with decreased bone mineral density and increased risk of fractures, as well as its relation to metabolic function (e.g., insulin sensitivity) and aerobic capacity [72, 73].”
From The Role of Lifestyle Modification with Second-Generation Anti-obesity Medications: Comparisons, Questions, and Clinical Opportunities (2023) · cites this paper as [72]
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Goodpaster, B. H., Park, S. W., Harris, T. B., Kritchevsky, S. B., Nevitt, M., Schwartz, A. V., Simonsick, E. M., Tylavsky, F. A., Visser, M., Newman, A. B., et al. (2006) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/61.10.1059 · Cited by 3,083 · cited 1×
“changes in body composition including a loss of lean body mass with a concomitant increase in fat mass.((28,29)) In the Look AHEAD DXA subgroup, lean body mass decreased more in the ILI than DSE between baseline and year 1 and remained lower through year 8.”
BackgroundSelf-citationCardiovascular effects of intensive lifestyle intervention in type 2 diabetes
The Look AHEAD Research Group (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1212914 · Cited by 2,908 · cited 1×
“However, despite these changes in lean body mass, the ILI group increased their physical activity resulting in improved fitness.(31) Further in the Look AHEAD trial, the weight loss and improved fitness have been shown to slow the decline in mobility in the ILI group compared to the DSE group.”
Dawson‐Hughes, B., Harris, S. S., Krall, E. A., & Dallal, G. E. (1997) · New England Journal of Medicine · doi:10.1056/nejm199709043371003 · Cited by 2,276
Kanis, J. А., Borgström, F., Laet, C. E. D. H. D., Johansson, H., Johnell, O., Jönsson, B., Odén, A., Zethraeus, N., Pfleger, B., & Khaltaev, N. (2004) · Osteoporosis International · doi:10.1007/s00198-004-1780-5 · Cited by 1,257
Prevention of falls and consequent injuries in elderly people
Kannus, P., Sievänen, H. T., Palvanen, M., Järvinen, T. L. N., & Parkkari, J. P. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67604-0 · Cited by 1,128
Weight loss, exercise, or both and physical function in obese older adults
Villareal, D. T., Chode, S., Parimi, N., Sinacore, D. R., Hilton, T., Armamento-Villareal, R., Napoli, N., Qualls, C., & Shah, K. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1008234 · Cited by 1,096
Smoking and fracture risk: a meta-analysis
Kanis, J. A., Johnell, O., Oden, A., Johansson, H., De Laet, C., Eisman, J. A., Fujiwara, S., Kroger, H., McCloskey, E. V., Mellstrom, D., et al. (2005) · Osteoporosis International · doi:10.1007/s00198-004-1640-3 · Cited by 999
An estimate of the worldwide prevalence, mortality and disability associated with hip fracture
Johnell, O., & Kanis, J. A. (2004) · Osteoporosis International · doi:10.1007/s00198-004-1627-0 · Cited by 962
The Look AHEAD Study: A Description of the Lifestyle Intervention and the Evidence Supporting It
The Look AHEAD Research Group (2006) · Obesity · doi:10.1038/oby.2006.84 · Cited by 873
Mortality after osteoporotic fractures
Johnell, O., Kanis, J. А., Odén, A., Sernbo, I., Redlund-Johnell, I., Petterson, C., Laet, C. E. D. H. D., & Jönsson, B. (2003) · Osteoporosis International · doi:10.1007/s00198-003-1490-4 · Cited by 852
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Why Do We Lose Bone During Weight Loss: Can It Be Prevented?
Shapses, S. A., & McGuire, B. D. (2026) · Current Osteoporosis Reports · doi:10.1007/s11914-026-00984-z
The incretin-bone axis: molecular mechanisms and clinical implications
Muscarà, A., Bellone, F., & Rossi, M. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1907875
Li, B., Liu, L., Luo, E., Liu, H., & Rosen, C. J. (2026) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2026.102208
赵翩翩, Sheng, Z., Xu, L., Li, P., Wenjin, X., Yuan, C., Zhanwei, X., Yang, M., Qian, Y., Jiadong, Z., et al. (2023) · medRxiv · doi:10.1101/2023.06.23.23291786
Metadata
- Authors
- Johnson, K. C., Bray, G. A., Cheskin, L. J., Clark, J. M., Egan, C. M., Foreyt, J. P., Garcia, K. R., Glasser, S., Greenway, F. L., Gregg, E. W., Hazuda, H. P., Hergenroeder, A., Hill, J. O., Horton, E. S., Jakicic, J. M., Jeffery, R. W., Kahn, S. E., Knowler, W. C., Lewis, C. E., Miller, M., Montez, M. G., Nathan, D. M., Patricio, J. L., Peters, A. L., Pi-Sunyer, X., Pownall, H. J., Reboussin, D., Redmon, J. B., Steinberg, H., Wadden, T. A., Wagenknecht, L. E., Wing, R. R., Womack, C. R., Yanovski, S. Z., Zhang, P., Schwartz, A. V., & for the Look AHEAD Study Group
- Affiliations
- University of Tennessee Health Science Center (US)
- Pennington Biomedical Research Center (US)
- Johns Hopkins University (US)
- Weight Control and Diabetes Research CenterProvidenceRIUSA
- Baylor College of Medicine (US)
- Wake Forest University Health Sciences (US)
- University of Alabama (US)
- Centers for Disease Control and Prevention (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Pittsburgh (US)
- University of Colorado Anschutz (US)
- Joslin Diabetes Center (US)
- University of Minnesota (US)
- University of Washington (US)
- Southwestern American Indian CenterPhoenixAZUSA
- Harvard University (US)
- St. Luke's-Roosevelt Hospital Center (US)
- University of Southern California (US)
- Columbia University Medical CenterNew YorkNYUSA
- Houston Methodist (US)
- University of Pennsylvania (US)
- Brown University (US)
- National Institutes of Health (US)
- Centers for Disease Control and PreventionAtlantaGAUSA
- University of California, San Francisco (US)
- Corresponding author
- Johnson, Karen C
- ORCID
- Johnson, Karen C
- Bray, George A
- Cheskin, Lawrence J
- Clark, Jeanne M
- Glasser, Stephen
- Greenway, Frank L
- Gregg, Edward W
- Hazuda, Helen P
- Hergenroeder, Andrea
- Hill, James O
- Horton, Edward S
- Jakicic, John M
- Kahn, Steven E
- Knowler, William C
- Lewis, Cora E
- Peters, Anne L
- Pownall, Henry J
- Reboussin, David
- Redmon, J Bruce
- Wadden, Thomas A
- Wagenknecht, Lynne E
- Wing, Rena R
- Schwartz, Ann V
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-05
- Volume
- 32
- Issue
- 11
- Pages
- 2278-2287
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- PMC
- PMC5685890
- OpenAlex
- W2727111851
- Cited by
- 104
- References
- 43
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 7 · 2019: 10 · 2018: 9
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Foundation for the National Institutes of Health (DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992, DK 046204)
- National Heart, Lung, and Blood Institute
- National Center on Minority Health and Health Disparities
- Office of Research on Women's Health
- Centers for Disease Control and Prevention
- National Institute of Diabetes and Digestive and Kidney Diseases
- Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719)
- Massachusetts General Hospital (M01RR01066)
- Harvard Catalyst (RR025758-04)
- University of Colorado (M01RR00051)
- Clinical Nutrition Research Unit (P30 DK48520)
- University of Tennessee (M01RR0021140)
- University of Pittsburgh (M01RR000056)
- Clinical Translational Research Center (CTRC) funded by the Clinical & Translational Science Award (UL1 RR 024153)
- U.S. Department of Veterans Affairs (M01RR01346)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- intentional weight loss, fracture risk, type 2 diabetes, intensive lifestyle intervention, diabetes support and education, hip fracture, obesity, overweight, Look AHEAD trial, bone preservation, fracture prevention
- MeSH terms
- Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Risk Factors, Weight Loss, Incidence, Proportional Hazards Models, Fractures, Bone
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