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American Journal of Epidemiology Copyright ª 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A. Vol. 164, No. 9 DOI: 10.1093/aje/kwj268 Advance Access publication August 3, 2006 Original Contribution What Is the Influence of Weight Change on Forearm Bone Mineral Density in Peri- and Postmenopausal Women? The Health Study of Nord-Trøndelag, Norway Siri Forsmo1, Jørn Aaen2, Berit Schei1, and Arnulf Langhammer1 1 2 Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway. Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Received for publication April 18, 2005; accepted for publication April 5, 2006. Weight loss in the elderly increases bone loss and the risk of fractures, especially at the hip and spine. The influence of weight change on non-weight-bearing parts of the skeleton is less well known. The purpose of this study was to investigate an association between weight change during the peri- and postmenopausal years and forearm bone mineral density (BMD). Among 8,856 women aged 45–60 years attending the first Health Study of Nord-Trøndelag, Norway (HUNT I, 1984–1986), a random sample of 2,795 women was invited to forearm densitometry (single x-ray absorptiometry technology) at HUNT II (1995–1997), after a mean period of 11.3 years. A total of 2,005 women (mean age: 65.1 years) were eligible. The mean weight had increased 3.4 kg; the gain was greater in the youngest women. A total of 382 women (19.1%) had lost and 1,331 women (66.3%) had gained weight. Weight change explained little of the BMD variance, 0.7% and 0.4% for weight loss and weight gain, respectively. Weight loss was an independent and statistically significant negative predictor of BMD, adjusted for body weight, age, age at menopause, smoking, and ovarian hormone treatment, particularly among women with a baseline body mass index greater than 25 kg/m2. No independent association between weight gain and forearm BMD was found. body weight changes; bone density; cohort studies; densitometry; forearm; menopause; women Abbreviations: BMD, bone mineral density; HUNT, the Health Study of Nord-Trøndelag, Norway. decrease the risk of forearm fractures in elderly women (5). In retrospective data, weight gain may even increase the forearm fracture risk (10). Other studies have found no association between weight change and wrist fractures (11). As a non-weight-bearing part of the skeleton, the distal radius is less influenced by changing mechanical strain due to weight gain or loss. Body weight is, however, a strong and positive predictor of forearm BMD in postmenopausal women (12, 13). Whether there is an effect of weight change on BMD, independent of body weight at baseline, or of weight at follow-up is not known. The distal forearm consists of both cortical and cancellous bone. At the ultradistal radius, cancellous bone makes up to 80 percent of the total (14). Cancellous bone has a higher metabolic activity than does cortical bone and is Bone mineral density (BMD) is positively associated with body weight, and low body weight is a risk factor of fractures. Weight loss has been shown to increase axillary bone loss in the elderly (1). Weight loss also increases the risk of fractures, especially at the hip (2–4). The bone effects of intentional weight loss do not seem to differ from unintentional weight loss (5). Among important risk factors for forearm fractures are low BMD, a history of falling, and previous fractures (6, 7). Very few lifestyle factors have been linked to increased risk of wrist fractures; one exception is physical activity that is positively associated with Colles’ fracture, possibly because of the greater risk of falling (8, 9). The influence of weight change on the risk of forearm fractures in women is not clear. Self-reported weight gain between the ages of 25 and 50 years has been found to Correspondence to Dr. Siri Forsmo, Department of Public Health and General Practice, Medisinsk-teknisk senter, N-7489 Trondheim, Norway (e-mail: [email protected]). 890 Am J Epidemiol 2006;164:890–897 Weight Change and Forearm Bone Density in Midlife Women 891 more influenced by factors such as menopause-related, reduced-estrogen availability. More cancellous than cortical bone mass is lost with aging (15, 16). Menopause is frequently associated with weight gain, although the physiologic causes are unclear. Weight gain is related partially to the decline in sex hormones, partially to normal aging, and partially to a more sedentary lifestyle (17–19). Menopause may also be associated with changes in body composition and fat distribution (20). The average body weight in general has increased over the last decades, especially in the United States, but also worldwide, with increasing weight-related morbidity (21, 22). Data from Norway also show the same pattern (23). On the other hand, weight loss is also associated with health hazards, especially in an elderly population (24). The purpose of this study was to investigate whether there is an association between weight change and forearm BMD during the peri- and postmenopausal years in a populationbased cohort of Norwegian women followed for more than 11 years. A more specific purpose was to explore whether the association between weight gain or weight loss and forearm BMD was independent of body weight, or if the BMD response to weight changes differed according to body size at baseline. Among all participants at HUNT I (baseline), a total of 8,856 women were aged 45–60 years, and their age-cohort participation rate was 95.3 percent. Forearm bone density was included at the physical examination in HUNT II for preplanned subsets of the female population: 35 percent of those aged 50–59 years, 5 percent of the age group 60–64 years, and 100 percent of the women aged 65 years or older. This involved 2,795 women from the baseline cohort, of whom 2,188 (78.3 percent) women attended and had forearm bone density measurements. All women in this study were menopausal at their examination in HUNT II, and menopause was defined as no menstrual bleeding within the last 12 months prior to the examination. The lifestyle and reproductive variables used for this study are based on the questionnaires used in HUNT II, because no reproductive data were collected at baseline. All women who reported treatment for hyper- or hypothyroidism, which totaled 174, were excluded from the analyses. Additional exclusions included the eight women for whom weight and height data from one or both of the examinations were missing. Finally, three women had no BMD data registered. These exclusions left 2,005 women whose mean age was 65.1 (range: 55–71) years as eligible for the analyses. No data were available with which to determine whether or not weight change between baseline and follow-up was intentional. MATERIALS AND METHODS Bone mineral density The Health Study of Nord-Trøndelag, Norway (HUNT), is a multipurpose health survey focusing on the total population in the rural county of Nord-Trøndelag in mid-Norway (25). The first data collection (HUNT I) took place between 1984 and 1986; the second observation (HUNT II) was during 1995–1997. On both occasions, all county citizens over the age of 19 years were invited to participate, and the total potential numbers included 85,100 and 92,936, respectively. The overall participation rate was 88.1 percent in 1984– 1986 and 71.2 percent in 1995–1997, with somewhat better rates for women than for men (26, 27). With the exception of body weight and height that were measured at both baseline and follow-up, all other variables used for this analysis are from the follow-up study (HUNT II). At both evaluations, data collection was carried out by practically identical protocols. A comprehensive health questionnaire was sent by mail along with an invitation for a general health examination (27). The questionnaire form included questions about general health and lifestyle, and the participants were requested to bring it to the physical examination. A second, more detailed questionnaire concerning illnesses, symptoms, medical treatment, socioeconomic factors, lifestyle and, for women, reproductive factors was distributed after the examination, to be completed at home and returned by mail. The physical examinations at both HUNT I and HUNT II involved measurements of blood pressure, height, weight, and blood glucose. Height (in centimeters) and weight (in kilograms) were measured without shoes and with participants wearing only light clothing. Forearm densitometry was included as part of one of several substudies, but only in HUNT II. BMD (in grams/centimeter squared, transformed to milligrams/centimeter squared for these analyses) was measured at the distal forearm and ultradistal radius of the nondominant arm by three different single energy x-ray bone densitometers (DTX 100; Osteometer Meditech A/S, Copenhagen, Denmark). Daily calibration of the densitometers was performed with equipment-specific phantoms. A cross-calibration study among the three devices was carried out and did not reveal significant differences. All sites for measurement were manually controlled and corrected. The densitometry procedure and quality assessments have been described in detail previously (13, 28). Am J Epidemiol 2006;164:890–897 Analysis Weight change was calculated as the difference in kilograms between body weight at follow-up (HUNT II) and at baseline (HUNT I). Negative values therefore indicated weight loss, and positive values meant weight gain. The choice to study change in body weight instead of change in body weight for height (body mass index) or relative weight change (percentage) was based on the fact that BMD is more strongly related to absolute weight than to other anthropometric measures. This was confirmed in preliminary analyses and is in accordance with other studies (12). A change in weight of 1-kg gain or loss was defined as stable body weight. For most purposes, weight change was stratified in weight loss, stable weight, and weight gain. For some of the bivariate analyses, however, weight change was categorized into five groups: weight loss; stable weight; and weight gain of 1.1–4.0, 4.1–7.0, and >7.0 kg. These 892 Forsmo et al. cutpoints were chosen because they provided weight change groups with adequate numbers for stratified analyses. Body mass index was calculated as body weight (kg)/height (m)2 , measured at baseline and in follow-up. Women’s age at follow-up was used in these analyses. The interval between baseline and follow-up was quantified in years to one decimal point. Other covariates from follow-up included smoking, history of cancer or diabetes, ovarian hormone treatment (estradiol with or without progesterone/progestin), and age at menopause. A total of 534 women (26.6 percent) did not answer the ovarian hormone treatment question. These women did not differ significantly in BMD or anthropometric data from those who reported no use of ovarian hormone treatment, but they were older than the women reporting ever ovarian hormone treatment use. It was assumed that nonresponse was because the question was irrelevant for these women; thus, for the multivariate analyses, the nonresponders were categorized as never users. The other ovarian hormone treatment categories were current and prior use. Smoking was calculated as pack-years, that is, (daily cigarettes 3 years of smoking)/20. The history of smoking was categorized as current, prior, and never smokers as reported at follow-up. Bivariate associations for continuous data were analyzed by independent and paired sample t tests. Odds ratios for dichotomous variables were calculated by logistic regression. In order to determine the separate associations of weight gain and weight loss with BMD, we used two multiple linear regression models, one for weight loss and the other for weight gain. The models included final weight, age, ovarian hormone treatment, pack-years of smoking, and age at menopause; all are variables with a linear association with BMD. The interval between baseline and follow-up was not a statistically significant predictor and was omitted from the models. Similar analyses were also performed, adjusting for baseline instead of final body weight and for medical conditions that could induce weight change, such as diabetes and cancer. The analyses documented an interaction between body weight and weight change. In order to assess whether the effect of weight loss or gain differed according to body mass index at baseline, we carried out multiple linear regression in stratified models of body mass index less than or equal to 25.0 kg/m2 and body mass index greater than 25.0 kg/m2. This cutoff represented the median baseline body mass index. All models were tested for collinearity and heteroscedasticity. The final multiple regression analyses were performed without residual outliers (3 standard deviations), at the maximum 21 cases (1 percent). The results are presented as regression coefficients (change in BMD (milligrams/centimeter squared) per unit change of the explanatory variable). All statistical tests were two sided, and the analyses were carried out with SPSS, version 13.0, software (29). Ethics The HUNT study was approved by the Regional Committee for Medical Research Ethics and by the Norwegian Data Inspectorate. RESULTS Selected characteristics of the prospective cohort of the 2,005 women who had forearm BMD measurements at follow-up are shown in table 1. The mean body weight in this population of midlife women had increased by 3.4 kg over the 11.3 years of follow-up, and 66.3 percent of the women had gained weight. A total of 382 women (19.1 percent) had lost more than 1 kg of body weight. These women were older at the BMD examination than were the women with stable or increased weight; the mean age was 67.1 years (95 percent confidence interval: 66.6, 67.5) for those who had lost weight and 65.5 years (95 percent confidence interval: 65.2, 65.7) for those with stable and increased weight (pooled together). However, the women who had lost weight had the highest mean body weight at baseline. Their mean weight loss was 5.2 kg that corresponded to an average relative loss of 7.3 percent of body weight. The mean forearm BMD was statistically significantly lower in women with a history of weight loss or stable weight than the BMD for women with weight gain (table 1). No difference in age at menopause between the weight-change categories was found with the differences in time since menopause being explained by the differences in age between these groups. Women with weight gain reported statistically significantly more ovarian hormone therapy use than did women with stable weight (p ¼ 0.003). However, compared with women with weight loss, women with weight gain were not statistically significantly more likely to use ovarian hormone treatment (p ¼ 0.07). Current smoking was more frequent in the groups of women with either weight loss or stable weight than in the women who had weight gain (table 1). In a logistic regression model adjusting for age, the odds ratio of weight loss among current smokers was 1.95 (95 percent confidence interval: 1.5, 2.5) compared with never smokers. A diagnosis of diabetes was more frequent in the women who had lost weight. No association was present between weight change and a history of cancer (table 1). Body weight at baseline and follow-up in two strata of baseline body mass index (25.0 and >25.0 kg/m2) and by categories of weight change is presented in table 2. The women with baseline body mass index greater than 25.0 kg/m2 had lost 2.1 kg more weight (95 percent confidence interval: 1.4, 2.8) than did the women with body mass index less than or equal to 25.0 kg/m2 at baseline. This explained the difference in total weight change between the two strata of baseline body mass index. Figure 1 shows the mean BMD at the distal forearm according to five categories of weight change, stratified by baseline body mass index (25.0 and >25.0 kg/m2). Women with baseline body mass index greater than 25.0 kg/m2 had on average higher BMD than did the women with baseline body mass index less than or equal to 25.0 kg/m2. Weight gain, however, seemed to be positively associated with BMD for both body mass index strata before controlling for other covariates. The most noticeable BMD difference between the two body mass index strata was found in women who had lost weight. Women in the lowest body mass index stratum had almost 10 percent lower BMD than did women with baseline body mass index greater than 25.0 kg/m2. It should, however, be noted that the Am J Epidemiol 2006;164:890–897 Weight Change and Forearm Bone Density in Midlife Women 893 TABLE 1. Characteristics of 2,005 women by category of body weight change between baseline at HUNT* I (1984–1986) and follow-up at HUNT II (1995–1997), an average period of 11.3 yearsy Category of weight change, from baseline to follow-up (11.3 years) Total (n ¼ 2,005) p valuez Weight loss§ (n ¼ 382) Stable weight§ (n ¼ 292) Weight gain§ (n ¼ 1,331) Continuous data, mean (SD*) 2 Distal BMD* (mg/cm ) 385.7 (68.9) 373.9 (68.7) 373.7 (67.0) 391.7 (68.6) Ultradistal BMD (mg/cm2) 287.9 (62.5) 277.4 (63.5) 277.0 (61.8) 293.4 (61.8) 0.001 Age at baseline (years) 54.5 (4.9) 55.6 (4.2) 55.4 (4.6) 53.9 (5.1) 0.001 Age at follow-up (years) 65.8 (5.1) 67.1 (4.5) 66.5 (4.7) 65.2 (5.3) 0.001 0.001 Duration of baseline follow-up (years) 11.3 (1.3) 11.5 (1.3) 11.2 (1.3) 11.3 (1.2) 0.003 Weight at baseline (kg) 68.0 (11.1) 70.4 (13.0) 66.7 (10.9) 67.6 (10.4) 0.001 Weight at follow-up (kg) 71.4 (12.2) 65.2 (12.0) 66.8 (11.0) 74.2 (11.5) 0.001 Weight change (kg) 3.4 (6.2) 5.2 (4.1) 0.1 (0.7) 6.6 (4.4) 0.001 2 BMI* at baseline (kg/m ) 25.7 (4.0) 26.6 (4.8) 25.3 (4.0) 25.5 (3.7) 0.001 BMI at follow-up (kg/m2) 27.4 (4.4) 25.2 (4.5) 25.8 (4.1) 28.3 (4.1) 0.001 BMI change (kg/m2) 1.7 (2.3) 1.4 (1.6) 0.5 (0.6) 2.9 (1.7) 0.001 Age at menopause (years) 49.3 (4.1) 49.1 (3.8) 49.4 (3.8) 49.3 (4.2) NS* Years since menopause (no.) 16.5 (6.5) 17.9 (5.9) 17.2 (5.6) 15.9 (6.8) 0.001 Smoking{ (pack-years) 9.8 (10.9) 11.3 (11.5) 9.7 (9.8) 9.4 (11.0) 0.04 Categorical data Current smokers (%) (n ¼ 453) 22.7 33.2 27.7 18.5 0.001 OHT* (current or prior)# (%) (n ¼ 292) 19.9 16.7 12.8 22.2 NS Diabetes mellitus (%) (n ¼ 92) 4.6 10.5 3.4 3.2 0.001 History of cancer (%) (n ¼ 146) 7.3 7.6 6.8 7.3 NS * HUNT, the Health Study of Nord-Trøndelag, Norway; SD, standard deviation; BMD, bone mineral density; BMI, body mass index; NS, not statistically significant (p > 0.05); OHT, ovarian hormone treatment. y Unless noted, all data were measured at HUNT II (follow-up). Bone mineral density was measured at the forearm. z Two samples of the t test or chi-square test of differences between the categories of weight loss and weight gain. § Categories of weight change: weight loss, >1-kg loss; stable weight, 1 kg; weight gain, >1-kg increase. { Smoking in pack-years among 946 current or previous smokers at follow-up. # History of ovarian hormone treatment among 1,471 women who answered the question. TABLE 2. Body weight at baseline (HUNT* I, 1984–1986) and follow-up (HUNT II, 1995–1997) and the magnitude of weight change with 95% confidence intervals in the categories of weight loss, stable weight, and weight gain between baseline and follow-up, an average period of 11.3 years, and by two strata of body mass index at baseline Baseline BMI* 25 kg/m2 Weight changey Weight loss Baseline BMI >25 kg/m2 Body weight at baseline and follow-up and weight change (kg) Body weight at baseline and follow-up and weight change (kg) No. No. 162 Baseline Follow-up Change 95% confidence interval 59.3 55.2 4.0 4.4, 3.6 220 Baseline Follow-up Change 95% confidence interval 78.6 72.5 6.1 6.8, 5.5 Stable weight 154 59.1 59.2 0.1 0.0, 0.2 138 75.1 75.2 0.1 0.0, 0.2 Weight gain 672 60.5 67.1 6.5 6.2, 6.8 659 74.8 81.6 6.7 6.4, 7.1 Total 988 60.1 63.9 3.8 3.4, 4.1 1,017 75.7 78.7 3.0 2.6, 3.5 * HUNT, the Health Study of Nord-Trøndelag, Norway; BMI, body mass index. y Categories of weight change: weight loss, >1-kg loss; stable weight, 1 kg; weight gain, >1-kg increase. Am J Epidemiol 2006;164:890–897 894 Forsmo et al. FIGURE 1. The curves show the mean distal-forearm bone mineral density by categories of weight change during the 11.3 years between baseline at HUNT I (1984–1986) and follow-up at HUNT II (1995–1997). (Vertical bars denote 95% confidence intervals). These data are stratified according to body mass index (BMI) at baseline. The solid curve represents the mean bone mineral density in 1,013 women with a baseline body mass index greater than 25 kg/m2, and the dashed line shows the mean bone mineral density in 992 women with a baseline body mass index less than or equal to 25 kg/m2. The light, dotted bars show the mean weight at baseline, and the dark, diagonally striped bars show the mean weight at follow-up in the categories of weight change, with 95% confidence intervals (vertical bars). HUNT, the Health Study of Nord-Trøndelag, Norway. difference in body weight at the time of densitometry was 17.2 kg between these two groups (table 2). The women with weight loss in the lower baseline body mass index group had statistically significantly lower BMD than did women with stable weight or weight gain within the same body mass index stratum. The same pattern was found for BMD measured at the ultradistal radius. In the multiple linear regression models shown in table 3 and table 4, there was an inverse association between BMD and both weight loss and weight gain, when adjustment was made for body weight at follow-up along with other covariates. Weight change explained less than 1 percent of the total BMD variance with contributions of 0.7 and 0.4 percent for weight loss and gain, respectively. When performing the same analysis but adjusting for baseline instead of follow-up body weight, we found that weight gain was positively associated with BMD, but the association was not statistically significant. For weight loss, the association remained inverse and statistically significant. This indicates that weight loss has a negative effect on forearm BMD, whereas the effect of weight gain is explained by the body weight at baseline. Because of the interaction between baseline weight and weight change (p ¼ 0.04), multiple linear regression was performed by use of models stratified for baseline body mass index (25.0 kg/m2 vs. >25.0 kg/m2). An independent and inverse association between weight loss and BMD was found in women with baseline body mass index greater than 25.0 (regression coefficient: 1.84, p ¼ 0.04). This association was not present for women with baseline body mass index less than or equal to 25.0 kg/m2. However, in the latter group of women, there was an inverse and statistically significant association between weight gain and BMD, but only when adjustment was made for body weight at follow-up. This observation is thus not independent of baseline weight. These results indicate that the negative effect of weight loss on forearm BMD can be demonstrated only in women who were overweight (body mass index >25 kg/m2) at baseline. A history of cancer was not a confounder in the multiple linear regression models, whereas a diagnosis of diabetes was a statistically significant positive predictor of BMD in women who had lost weight (data not shown). When eliminating the 92 women reporting diabetes from the multivariate analyses, we found that the inverse association between weight loss and BMD became stronger. DISCUSSION This population-based study shows that women’s weight loss through the peri- and postmenopausal years adversely affects forearm BMD. This was particularly the case for women with a relatively high body mass index at baseline. The apparent inverse association between weight gain and BMD was explained by a lower weight at baseline. In women having lost weight, however, the inverse association Am J Epidemiol 2006;164:890–897 Weight Change and Forearm Bone Density in Midlife Women TABLE 3. Multiple linear regression of bone mineral density measured at the distal forearm and ultradistal radius in a model of 382 women with weight loss greater than 1 kg during the 11.3 years between baseline (HUNT* I, 1984–1986) and follow-up (HUNT II, 1995–1997)y Predictors Distal forearm, R 2 ¼ 26.0% Weight loss (kg) Body weight at BMD (kg) Age at BMD (years) Age at menopause (years) Smoking (pack-years) OHT* (never/prior/ current) TABLE 4. Multiple linear regression of bone mineral density measured at the distal forearm and ultradistal radius in a model of 1,331 women with weight gain greater than 1 kg during 11.3 years between baseline (HUNT* I, 1984–1986) and follow-up (HUNT II, 1995–1997)y Predictors p value BMD (mg/cm2) 455.1 <0.001 368.9 <0.001 Constant 1.6 <0.033 1.5 <0.042 Weight gain (kg) 1.8 <0.001 1.6 <0.001 Body weight at BMD (kg) 4.7 <0.001 4.4 <0.001 Age at BMD (years) <0.003 Age at menopause (years) BMD* (mg/cm2) Constant Ultradistal radius, R 2 ¼ 22.3% 2.3 <0.003 0.6 <0.067 13.2 <0.039 2.2 p value NS* Smoking (pack-years) NS OHT* (never/prior/ current) * HUNT, the Health Study of Nord-Trøndelag, Norway; BMD, bone mineral density; NS, not statistically significant; OHT, ovarian hormone therapy. y The complete model is presented. between weight change and BMD was independent of body weight whether at baseline or at follow-up. Predicted BMD at a given body weight will thus be lower in women with a history of substantial weight loss than in women with a smaller loss, despite a higher mean weight in the former group. This indicates that weight loss is negative for BMD, even in non-weight-bearing bones. The strengths of this study are its population-based design and high participation rate. The women invited to densitometry, although a subset of the age-stratified population, were selected at random. They did not differ concerning anthropometric measures from other women of similar age who participated in HUNT. A study of nonresponders in HUNT II did not reveal any important selection biases except for a slightly higher prevalence of current smokers in those who did not attend (26, 27). In this study, smokers had lower body weight than did nonsmokers, and smoking was more prevalent among women with weight loss. However, smoking was included as a covariate in the multivariate analyses, and thus, we do not think that selection represented a major bias to the final result. This study involved only middle-aged and elderly women, and therefore the results cannot be generalized to the entire adult population. We have no information about the causes for weight loss, whether it was deliberate or due to medical conditions or treatment. The women with weight loss greater than 1 kg between baseline and follow-up had the highest mean weight at baseline, and women with a baseline body mass index greater than 25.0 kg/m2 had lost more than did those with a body mass index less than or equal to 25.0 kg/m2. This may indicate that weight loss was intentional for the majority of women losing weight, although the effect of regression toward the mean should not be ignored. A recent study rejected the hypothesis that intentional weight loss is Am J Epidemiol 2006;164:890–897 895 Distal forearm, R 2 ¼ 21.0% Ultradistal radius, R 2 ¼ 20.0% BMD* (mg/cm2) p value BMD (mg/cm2) p value 542.6 <0.001 411.6 <0.001 1.4 <0.001 1.0 <0.010 1.5 <0.001 1.3 <0.001 4.9 <0.001 4.2 <0.001 1.3 <0.001 1.2 <0.001 0.6 <0.001 0.6 <0.001 5.9 <0.030 7.3 <0.030 * HUNT, the Health Study of Nord-Trøndelag, Norway; BMD, bone mineral density; OHT, ovarian hormone therapy. y The complete model is presented. less detrimental than unintentional weight loss, at least in elderly women (5). The possibility remains, however, that during deliberate weight loss the women will increase physical activity and be more conscientious about nutrient intake than during unintentional weight loss and that these behavior changes could minimize the negative effect of weight loss on the skeleton. This was not explored in our study. Some medical conditions could explain weight change, and we excluded women reporting treatment for thyroid diseases from all analyses. The women with diabetes in this age span mainly have diabetes type 2 (30), and these women had slightly higher BMD as has been shown in other crosssectional studies (31). However, more rapid bone loss in diabetic women has recently been reported (32). Weight loss was more frequent in women with diabetes than in those without it. Elimination of the women reporting diabetes from the analyses increased the inverse effect of weight loss on BMD. Hence, the possibility remains that subclinical illness could explain both weight loss and low BMD, as has been discussed by Ensrud et al. (5). These authors also observed that hip fracture risk was unchanged over time when following a cohort of elderly women with a history of both intentional and unintentional weight loss (5). One would have expected the association between weight loss and fractures to diminish with time if subclinical pathology had provided the explanation for the weight loss. The interval between the two weight measurements in this study was rather large. With only these two points in time, we are not able to assess the influence of rapid weight loss compared with slower loss or the effects of weight cycling that seems to be associated with reduced BMD at the radius in obese premenopausal women (33). Weight loss has been shown to induce a higher rate of bone loss in premenopausal women (34, 35) and in the elderly (1, 36). In this study, BMD was not measured at 896 Forsmo et al. baseline, and the influence of weight change on bone loss could not be assessed. Body weight is a strong positive predictor of BMD and of peak bone mass (37). Further, women with low body mass index experience more rapid bone loss (36, 38). The results of this study indirectly suggest that weight loss increases bone loss. The rather unexpected result that the independent negative effect of weight loss on forearm BMD could be demonstrated only among women with relatively high body size at baseline may be explained by somewhat higher relative weight loss than in women of smaller size. It is also possible that the influence of weight loss on bone is more discernible in women with an increased BMD related to their higher body weight. These women, however, do still benefit from a relatively high body weight that explains that their forearm BMD values were significantly higher than for the more slender women with a history of weight loss. When considering these results, one should take into account that the impact of weight loss on BMD was rather small. For a predicted difference of 1 standard deviation in forearm BMD in women with baseline body mass index greater than 25 kg/m2, the difference in weight loss must be 33 kg, given the same body weight at follow-up. This would, however, increase the forearm fracture risk by 50 percent (7). Bauer et al. (12) found that each 10-kg weight loss was associated with 3.9 percent lower bone mass (12). This is comparable with our results that showed that a 10-kg loss was associated with 4.1 percent lower BMD. Mechanisms are unclear for the adverse effect of weight loss on the skeleton. Reduced mechanical strain due to reduced body weight is one hypothesis. This should, however, not count as much for the forearm as for the weight-bearing parts of the skeleton. Reduced conversion of circulating androgens to estrogen due to less adipose tissue is another explanation. Serum leptin could represent a plausible mediator between body fat and bone (39). There are, however, conflicting results about whether this mechanism relates to the mature skeleton and the distal radius (40, 41). Alternatively, weight loss could induce changes in insulin-like growth factors and sex-hormone binding globulin that would alter the bioavailability of estrogen (42, 43). About two thirds of the women in this cohort had gained weight, with the younger women gaining more than the older women. Although we found a positive crude association between weight gain and forearm BMD, there was no effect of weight gain independent of body weight. Trovas et al. (44) found a positive correlation between weight gain and lumbar spine BMD; however, these authors did not adjust for body weight or body mass index as either final weight or at baseline. When assessing the effect of weight change on BMD, we found it important to adjust for body weight. The positive crude association between weight gain and BMD found in this study was explained mainly by age, as the younger women, with more weight gain, had higher BMD than did older women. The negative association of weight gain with BMD that appeared when adjustment was made for current weight may indicate that BMD is associated with weight history throughout adult life. It is possible that the women with a history of midlife weight gain follow a different profile of bone change than do women whose weight remains stable in midlife. Their baseline BMD might have been lower, but bone loss was reduced because of weight gain, as has been found in other studies (1, 36). This was seen particularly in women whose baseline body mass index was less than or equal to 25 kg/m2. In summary, weight gain during the peri- and postmenopausal years was common in this cohort of 2,005 middleaged women followed over a period of more than 11 years. Weight loss had a small, but inverse and independent effect on forearm bone mineral density. This was found particularly in women with a body mass index greater than 25 kg/m2 at baseline. This study did not document an independent effect of weight gain on forearm BMD; the observed inverse association was explained by their lower body weight at baseline. ACKNOWLEDGMENTS The study was supported by grants from the Norwegian Women’s Public Health Association, the Norwegian Research Council, the Norwegian Osteoporosis Foundation, and the Association of Health and Rehabilitation. The authors are grateful to W. Dana Flanders and Jerilynn C. Prior who assisted with revisions of the manuscript. The Health Study of Nord-Trøndelag is a collaboration among the HUNT Research Centre, the Norwegian University of Science and Technology, the Norwegian Institute of Public Health, and the Nord-Trøndelag County Council. Conflict of interest: none declared. REFERENCES 1. 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