The relationship between weight loss, weight regain, and bone health is complex, especially for individuals with type 2 diabetes. This article examines the impact of different weight change patterns following intentional weight loss on fracture risk and bone mineral density (BMD) in overweight and obese adults with type 2 diabetes.
Background
Osteoporotic fracture is a serious and costly clinical problem associated with type 2 diabetes. Overweight or obese individuals with diabetes are often prescribed weight loss to improve glycemic control, yet weight loss may further augment fracture risk. Indeed, recent results from the Look AHEAD study suggest 6% to 9% weight loss achieved and maintained over nearly a decade is associated with significantly reduced bone mineral density (BMD) and increased risk of hip, pelvis, and upper arm fracture. Data also suggest that bone mass is not recovered when lost weight is regained, raising concern about the long‐term impact of repeated weight loss attempts on bone health. Given the well‐known recidivism of obesity, surprisingly little is known about the effect of weight regain or weight cycling on incident fracture risk. Limited observational data do link weight variability and self‐reported weight cycling with higher fracture incidence; however, the long‐term impact of objectively measured patterns of weight change on fracture risk following a structured weight loss program has not been assessed.
The Look AHEAD Study
Data collected in the Look AHEAD (Action for Health in Diabetes) study provide a unique opportunity to address this question. The Look AHEAD Study was a multicenter, randomized controlled trial designed to determine whether intentional weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The study was approved by local Institutional Review Boards and all participants provided informed consent.
Participants
A total of 1885 individuals with type 2 diabetes (baseline age: 58.5 ± 6.7 years, 58% women, body mass index: 35.7 ± 6.0 kg/m2) who participated in the Look AHEAD study and lost any weight 1 year after being randomized to an intensive lifestyle intervention were assessed.
Methods
Body weight was measured annually and participants were categorized as weight regainers, weight cyclers, or continued losers/maintainers based on a ±3% annual change in weight from year 1 to year 4. Adjudicated overall fracture incidence was captured from years 4 through 13 (median follow‐up duration 11.5 years). Hip and spine BMD was assessed in a subset of participants at baseline, year 4 (n = 468), and year 8 (n = 354), using dual‐energy X‐ray absorptiometry. Cox proportional hazards and linear regression models, adjusted for relevant covariates, were performed for fracture and BMD outcomes, respectively. Self‐reported characteristics (ie, age, gender, race/ethnicity, smoking status, and alcohol consumption) and medical history were assessed using standardized questionnaires. Height was measured in duplicate using a stadiometer and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Participants brought current prescription medications to update medication records, with bone negative medications defined as: loop diuretics, selective serotonin reuptake inhibitors (SSRIs), thyroid hormones, oral steroids such as prednisone, tricyclic antidepressants, and thiazolidinedione (TZDs); and bone positive medications defined as: androgens (anabolic steroids), calcium, antacids containing calcium, and antiresorptive agents such as bisphosphonates, calcitonin nasal spray, estrogens, and selective estrogen receptor modulators (SERMs). Fasting blood specimens were analyzed by the Central Biochemistry Laboratory (Northwest Lipid Research Laboratories, University of Washington, Seattle, WA, USA) using standardized laboratory procedures for measuring glycated hemoglobin (HbA1c). Descriptive statistics were calculated overall and by weight pattern classification at baseline. Cox proportional hazards models, both unadjusted and adjusted for relevant baseline covariates (including: age category, gender, race, BMI category, bone‐positive medication use, and bone‐negative medication use, history of arthritis, HbA1c, smoking status, alcohol consumption, diabetes duration, and BDI score) were performed for incident overall and hip, pelvis, or upper arm fracture outcomes. Because fracture risk is elevated in older women, a formal test of interaction between age, gender, and weight pattern category was conducted to inform whether stratified analyses should be performed. Differences in hip, femoral neck, and lumbar spine BMD at years 4 and 8 were assessed in a subset of participants using linear regression models, adjusting for the same covariates described above plus baseline value of the outcome, and presented as least square means and standard errors.
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Weight Change Patterns
Fifty‐eight percent, 22%, and 20% of participants were classified as weight regainers, weight cyclers, and continued losers/maintainers, respectively; and 217 fractures (men n = 63; women n = 154) were recorded during the follow‐up period. On average, by the year 4 visit, regainers gained 8.3 ± 5.5 kg, weight cyclers gained 1.1 ± 7.0 kg, and continued losers/maintainers lost 2.9 ± 6.0 kg from the year 1 weight. Weight cyclers were more likely to be between the ages of 50 and 59 years, female, Hispanic, and using bone‐positive medications, than other categories (all p ≤ 0.02).
Fracture Incidence
There were no statistically significant differences in total incident fracture rates for weight regainers (HR [95% CI]: 1.01 [95% CI, 0.71 to 1.44]) or weight cyclers (HR [95% CI]: 1.02 [95% CI, 0.68 to 1.53]) when compared to continued losers/maintainers (p = 0.99). Similar results were observed for incident hip, pelvis, or upper arm fracture.
Bone Mineral Density
As with incident fracture, no significant associations were observed between weight pattern classification and year 4 and year 8 regional BMD at any site. Trends for lower BMD at the femoral neck and total hip were observed in continued losers/maintainers and weight cyclers compared with weight regainers, yet they did not attain statistical significance. Specifically, by year 8, femoral neck BMD was reduced from baseline by −0.050 ± 0.012 g/cm2 (−4.5%), −0.055 ± 0.012 g/cm2 (−3.9%), and −0.039 ± 0.010 g/cm2 (−3.0%) in continued losers/maintainers, weight cyclers, and weight regainers, respectively (p = 0.11). Likewise, by year 8, total hip BMD was reduced by −0.046 ± 0.012 g/cm2 (−3.9%), −0.042 ± 0.012 g/cm2 (−3.3%), and −0.032 ± 0.011 g/cm2 (−1.9%) from baseline values in continued losers/maintainers, weight cyclers, and weight regainers, respectively (p = 0.21).
Comparison with Existing Research
There is increasing interest in understanding the skeletal effects of obesity and diabetes, particularly in the context of weight loss. We are aware of only four studies examining the effect of weight variability or cycling on fracture risk to date, all of which report positive associations. The earliest reports, examining weight variability (defined using the root mean square error) and incident hip fracture, suggest a 50% to 270% increased risk for those in the highest quartile of weight variability, compared to the lowest. More recent studies led by Søgaard and colleagues extend these findings to weight cycling, demonstrating increased risk of forearm fracture in men and nonvertebral fracture in women who self‐reported multiple weight loss episodes. In contrast, relative to continued weight loss or weight loss maintenance, we did not observe an association between a single bout of weight regain or weight cycling on fracture incidence, thereby adding equipoise to a limited evidence base.
To our knowledge, our study is the first to assess the effect of weight patterns dynamics following intentional weight loss on incident fracture; although the effect of weight change following voluntary weight loss on BMD has been assessed in a handful of studies. Some, but not all, studies suggest that the well‐described 2% decline in BMD with 10% weight loss continues progressively despite weight loss maintenance, and does not return with weight regain. Trends observed in our BMD data are in general agreement with prior reports, although results were nonsignificant.
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Strengths and Limitations
Strengths of this study include use of objectively measured weights to assess changing weight dynamics following intentional weight loss, as well as adjustment for multiple, relevant covariates. Despite these design strengths, Look AHEAD was not designed to detect differences in incident fracture rates between weight pattern classifications; thus, our analyses may have been underpowered. Certainly, DXA data, which were only available in a subset, are meant to be hypothesis generating, rather than confirmatory. A general limitation in this field of research is the lack of an operational definition for weight cycling. Although we used patterns previously employed in the Look AHEAD study and a clinically meaningful ±3% weight change threshold, conclusions may differ by weight pattern category definition used.
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