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Editorial |
Department of Family and Preventive Medicine (E.B.-C., C.A.S.) and Department of Medicine (C.A.S.), School of Medicine, University of California, San Diego, La Jolla, California 92093-0607
Address all correspondence and requests for reprints to: Elizabeth Barrett-Connor, M.D., Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0607, La Jolla, California 92093-0607. E-mail: ebarrettconnor{at}ucsd.edu.
The menopause transition is commonly associated with weight gain, an increase in low-density lipoprotein (LDL)-cholesterol, and bone loss; these unhealthy changes are attenuated by estrogen therapy (1). Results from the two Women’s Health Initiative clinical trials, published in 2002 (2) and 2004 (3) provided the first trial-based estimates of the risks and benefits of estrogen therapy with regard to clinical outcomes such as hip fracture and heart disease—in women who were unselected for osteoporosis or heart disease at baseline. The only consistent benefit of estrogen therapy in both Women’s Health Initiative trials was the more than 30% reduction in hip fracture (2, 3).
Unfortunately, short-term estrogen for the treatment of menopause symptoms in younger women, as is now recommended by the U.S. Food and Drug Administration (www.fda.gov), may not prevent fractures because bone loss increases rapidly when estrogen is discontinued. As reviewed elsewhere, most observational studies and several short clinical trials show that bone loss resumes after cessation of estrogen (4). The increased bone resorption increases bone fragility. In the large National Osteoporosis Risk Assessment cohort study, the risk of fracture increased during the first 5 yr after cessation of estrogen (5).
What else can women do if they want to prevent the weight gain, slow the accelerated bone loss, and avoid the unfavorable LDL changes that often appear during the menopause transition? This question was addressed in the Women’s Healthy Lifestyle Project, a landmark clinical trial conducted by Lewis Kuller and colleagues in the 1990s (6). Premenopausal women were randomly assigned to a control group or a lifestyle intervention. The latter targeted weight loss by calorie control and dietary changes, particularly reduced fat and saturated fat, along with increased physical activity. By 18 months, women in the lifestyle group had lost an average of 3.2 kg compared with women in the control group who gained an average of 0.42 kg, a difference of 3.6 kg or almost 8 pounds (6). Unfortunately, women in the intervention group also lost twice as much bone at the hip as the control group.
The Women’s Healthy Lifestyle Project paper published in 2001 described the 54-month end-of-trial results, with a focus on the superior weight control and better LDL cholesterol levels in the women randomized to diet and exercise (7). At 54 months the average weight gain in the control group was 2.6 kg; the intervention group did not gain weight with a 0.4 kg loss since baseline.
The new report from the Women’s Healthy Lifestyle Project, published in this issue of JCEM (8), provides more information on bone loss at trial end and adds results from two posttrial visits at 66 and 78 months. Bone loss was greatest in the lifestyle intervention group in the women who had passed through menopause without estrogen use. At trial end, women randomized to the lifestyle intervention had continued to experience greater rates of bone loss at the hip than women in the control group. During the 2-yr postintervention period, however, weight control diminished in the lifestyle intervention group, as did the difference in weight between the two groups; significant differences in bone loss between the lifestyle and control group disappeared.
The Women’s Healthy Lifestyle Project provides great news for women fighting midlife weight gain, but not good news for maintaining bone health. These results should not be surprising. Many observational prospective studies [reviewed by Shapses and Riedt in 2006 (9)] have reported that weight loss predicts increased bone loss in older women, but these epidemiologic studies could not exclude the possibility that illness-associated weight loss caused the bone loss (10). The Women’s Healthy Lifestyle Project is the first lifestyle trial to show that intentional weight loss in nonobese women accelerates bone loss during the menopause transition. The age of the cohort and the trial design make it unlikely that persons who were ill were the ones who lost both bone and weight.
Because weight control, healthy diet, and physical activity constitute the centerpiece of lifestyle prevention programs for healthy aging, the consistent association of weight loss with bone loss is disconcerting. Understanding the mechanism for this phenomenon might give clues to preventive strategies, whereby weight loss could be accomplished with little or no bone loss.
One possible mechanism is that women who lose weight have less weight to bear: weight bearing is essential for bone preservation but the usual 3 to 5% weight loss seems small to postulate such a large gravitational effect. If a biomechanical etiology is important, then weight-loss programs that include weight-bearing physical activity would be expected to minimize bone loss. In one cohort study there was less bone loss in women losing weight if they had good grip strength (11). In another cohort study, weight loss promoted bone loss, but regular stair climbing modified this effect in women (12). In a third cohort study, however, more physical activity was reported to increase bone loss in women who lost weight (13). The Women’s Healthy Lifestyle Project results (8) do not support a bone-sparing effect of physical activity in dieters, in that physical activity was said to explain most of the weight loss but did not prevent the associated bone loss. In a clinical trial conducted in obese premenopausal women, a 3-month very low-calorie diet was followed by a 9-month walking intervention; walking did not prevent weight regain or restore lost bone mineral density (14). Overall, there is too little information on the type or amount of exercise needed to balance the negative effects of weight loss on bone.
Another potentially modifiable cause of the weight loss-bone loss association is the content of the weight-loss diet. Calorie-restricted diets are often low in calcium because avoidance of calorie-dense dairy products is commonly recommended. In a small clinical trial, overweight postmenopausal women on a calorie-restricted diet lost less bone if they were assigned to high-calcium (1.7 g/d) supplements than women assigned to less calcium (1.0 g/d) (15). In a second trial, overweight premenopausal women (age 38 yr) did not lose bone during caloric restriction and weight loss whether assigned to 1.0 g/d or 1.8 g/d of calcium (16). These findings suggest that weight-loss-associated bone loss could be prevented in young premenopausal women with 1 g of daily calcium ingestion, although postmenopausal women (and probably perimenopausal women) require more calcium. These studies also suggest that heavier women may be more resistant to bone loss when losing weight than normal-weight women (as studied in the Women’s Healthy Lifestyle Project). The women in the Healthy Lifestyle Project reported taking 1 g of calcium per day at baseline.
In the Women’s Healthy Lifestyle Project, the main recommended dietary change for weight loss in the intensive lifestyle group was less fat, particularly less saturated fat, which in the United States translates to less animal protein. Prospective population-based observational studies such as the Rancho Bernardo Study (17) and the Framingham study (18) observed that low animal protein in the diet (based on a food-frequency questionnaire) was associated with low bone mineral density. A UK cohort study (12), however, found no evidence that meat intake (based on 7-d diaries) reduced bone loss. It is not clear whether these differences reflect different methods or different populations.
Reducing diets that are low in fat and refined sugar are typically high in dietary fiber. There is some limited evidence that a high-fiber diet is associated with bone loss (19). High-fiber, low-fat, reduced-calorie diets can acutely lower postmenopausal estradiol levels (20), one plausible mechanism for this association.
Endocrine changes associated with weight loss might contribute to diet-induced bone loss. In addition to decreases in estrogen in the peri- and postmenopausal population, decreases in leptin, glucagon-like peptide-2, GH, and IGF-1 along with increases in cortisol and PTH have each been postulated as possible mechanisms for bone loss (9). It is surprisingly unclear whether estrogen therapy prevents the bone loss associated with voluntary weight loss. Data from a large Finnish cohort study suggested that menopausal estrogen therapy prevented weight-loss-related bone loss (21), but in the Women’s Healthy Lifestyle Project more bone loss was experienced among the women who lost greater than 3% body weight despite starting estrogen during the trial. And, even if estrogen was protective during weight loss, most of the existing data suggest that the bone loss would resume as soon as estrogen was discontinued at the end of the weight-loss program.
It is clear that new clinical trials are necessary to determine which interventions, if any, can modify the bone loss and the increase in bone turnover markers associated with voluntary weight loss programs. A comparison of walking with resistance training would be of interest, as would a factorial design in which women placed on a weight loss intervention were then randomly assigned to placebo, estrogen therapy, calcium supplements, or both estrogen and calcium supplements. The trials would need to be long enough to accomplish a 5–7% weight loss, 6–12 months, but women in such trials should be followed for at least 2 yr after the intervention is completed (as was done in the Women’s Healthy Lifestyle Project) to quantify the bone effects of maintained weight loss or regained weight.
In the meantime, the best advice for middle-aged women now seeking to lose weight is to be mindful of the potential risk of bone loss with weight loss, and the probable need for additional weight-bearing activity and calcium supplements. If a woman also suffers from menopausal vasomotor symptoms, short-term low-dose estrogen therapy might temper bone loss, at least transiently.
In postmenopausal women with a history of sustained or cyclic weight loss, bone mineral density should be measured, and if necessary, therapies to prevent bone loss and reduce osteoporotic fracture risk should be considered according to current practice guidelines. As a further understanding of the mechanisms of weight-loss-induced bone loss emerges, other preventive strategies should be forthcoming.
Footnotes
This work was supported by National Institute on Aging Grant AG07181.
Abbreviation: LDL, Low-density lipoprotein.
Received August 15, 2007.
Accepted August 17, 2007.
References
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