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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 3 1030-1035
Copyright © 2002 by The Endocrine Society

Endocrine Care

Serum Leptin Level Is a Predictor of Bone Mineral Density in Postmenopausal Women

Hubert Blain, Anne Vuillemin, Francis Guillemin, Richard Durant, Bernadette Hanesse, Nicole de Talance, Brigitte Doucet and Claude Jeandel

The University of Montpellier (H.B., R.D., C.J.), Department of Internal Medicine and Geriatrics, Montpellier 34295 Cedex 5, France; 1124 (A.V., F.G.), Public Health School, Henri Poincaré University, 54000 Nancy, France; Department of Internal Medicine and Geriatrics (B.H.), Nancy University Hospital, and Metabolic Research and Chemistry Unit (N.T., B.D.), Central Hospital, 54000 Nancy, France

Address all correspondence and requests for reprints to: Claude Jeandel, M.D., Service de Médecine Interne-Gériatrie, Centre de Prévention et de Traitement des Maladies du Vieillissement, 39 avenue Charles Flahault, 34295 Montpellier Cedex 5, France. E-mail: . c-jeandel{at}chu-montpellier.fr

Abstract

To assess whether leptin is an independent predictor of bone mineral density (BMD) in postmenopausal women, we studied the relationships of BMD to serum leptin, 25(OH)D, 1,25(OH)2D, PTH, E2, dehydroepiandrosterone sulfate, GH, IGF-I, creatinine clearance, calcium intake, fat mass, and lean mass in 107 women aged 50–90 yr. We also related serum leptin to markers of bone formation [serum bone alkaline phosphatase and osteocalcin (OC)] and resorption (urine C-telopeptide of type I collagen). In stepwise multiple linear regression, lean mass explained 28.5%, age 10.3%, and leptin 7.2% of the whole body BMD variance. Age explained 21.1%, lean mass 12.8%, and leptin 3.7% of the femoral neck BMD variance. After adjustment for fat mass and creatinine clearance, correlations between leptin and bone alkaline phosphatase (positive) and OC (negative) disappeared but, remained significant with urine C-telopeptide of type I collagen (r = -0.27, P < 0.01). Markers of bone formation and resorption were strongly intercorrelated. These data demonstrate that leptin is an independent predictor of whole body and femoral neck BMD in postmenopausal women. Although the relationships between leptin and markers of bone formation appear complex, leptin may exert a protective effect on bone by limiting the excessive bone resorption coupled to bone formation associated with bone loss after menopause.

OSTEOPOROSIS IS A major public health problem in postmenopausal women because of the association between low bone mineral density (BMD) and vertebral and hip fractures (1). A number of cross-sectional studies have established the strong relationship between BMD and fat mass in women (2), especially after menopause (3). These studies suggested that this association may be the result of mechanical and hormonal factors. Indeed, fat mass may act as a peripheral site for the conversion of androgens to estrogens (2, 4), and serum estrogens are thought to be associated with BMD and the risk of fracture in elderly women (5, 6, 7).

Leptin, the soluble 16-kDa protein product of the adipose-specific obese (ob) gene in adipocytes (8), might be another mediator between body fat and bone because circulating levels of leptin correlate positively with fat mass in healthy persons (9, 10, 11). In accordance with this hypothesis, recent in vitro studies have shown that leptin is expressed in and secreted from primary cultures of human osteoblasts during the mineralization period (12) and that it may enhance osteogenic activity in human bone marrow (13). Moreover, leptin may be implicated in fetal and growing bone metabolism (14, 15, 16) and may reduce ovariectomy-induced bone loss in rats (17), suggesting its potential bone anabolic effect in both the first and last stages of life.

The exact relationship between leptin and BMD, however, has not yet been elucidated. Some of the cross-sectional studies that adjusted for fat mass or body mass index (BMI) observed no correlation between circulating leptin and bone mineral content at several sites in women (18, 19, 20, 21) or between leptin and markers of bone turnover (18, 19, 20). Others found a significant correlation between circulating leptin and BMD in postmenopausal women only (22) or in pre- and postmenopausal women (23).

Unfortunately, none of these studies measured levels of the main factors involved in bone metabolism, including lean mass (24, 25, 26), calcium intake (27), 25(OH)D and 1,25(OH)2D, or of other factors both involved in bone metabolism and associated with leptin and/or body composition in women, including E2 (28, 29), creatinine clearance (30), PTH(29, 31, 32), GH (32, 33, 34, 35, 36), IGF-I (33, 35), and dehydroepiandrosterone sulfate (DHEA) (36, 37). It therefore remains to be determined whether leptin is a significant and independent predictor of BMD in older women.

The purpose of this study was to examine the respective influence of serum leptin and these hormonal and nonhormonal factors on bone mineral density and the relationships between leptin and turnover markers in nonobese postmenopausal women.

Subjects and Methods

Subjects

The study took place in a university hospital center (Centre Hospitalier Universitaire Nancy-Brabois). Subjects were from a large age-stratified sample of healthy women recruited consecutively in 1996–1997, from two main sources: members of cultural associations and individuals attending a preventive medicine center (38). Included in this study were postmenopausal Caucasian women in apparent good health after physical examination. Menopause was defined as 1 yr without flow (39). Of the 155 postmenopausal women eligible to participate in the study, 107 nonobese women (BMI < 30.0) (40), aged 50–90 yr, were ultimately involved in the study after signing an informed consent form. These women had not been exposed to ovarian hormonal therapy because menopause and had neither prostheses nor pacemakers. They had no established endocrinologic diseases (e.g. hyperthyroidism, Cushing’s disease, diabetes mellitus) or rheumatologic pathologies (e.g. rheumatoid arthritis, ankylosing spondylitis), and were receiving no treatment (e.g. fluoride, calcium, corticosteroids, vitamin D, calcitonin, bisphosphonates, anti-vitamin K, or diuretics) that could influence BMD. The study was approved by the Ethics Committee of Lorraine County.

Protocol

Blood and urine samples were obtained from all volunteers. The subjects reported to the laboratory at 0900 h after an overnight fast. Blood samples were collected after a 30-min rest in the supine position. The blood samples were allowed to clot and were then centrifuged; aliquots were stored at -80 C until analyzed. Information on dietary calcium intake was taken and blood and urine collection, measures of BMD, and anthropometry were performed on the same day. Height and weight measurements to the nearest 0.5 cm and 0.1 kg were used to calculate the BMI (kg/m2).

Assays

Serum leptin concentration was determined by RIA using standard techniques (Linco Research, Inc., St. Charles, MO) with an intraassay variation of 3.9% and an interassay variation of 4.7%. Serum concentrations of DHEA (Immunotech S.A., Marseille, France) (intraassay variation of 4.5%, interassay variation of 7.2%), IGF-I (Immunotech) (intraassay variation 7.1%, interassay variation 11.9%), GH (Immunotech S.A.) (intraassay variation 0.6%, interassay variation of 13.5%) and E2 (Immunotech S.A.) (intraassay variation 6.3%, interassay variation 6.1%) were also determined. Serum intact PTH was determined by radioimmunometric assay (CIS-Bio International, Gif-sur-Yvette, France) with an intraassay variation of 4.2% and an interassay variation of 3.4%.

Circulating osteocalcin (bone-gla-protein) level was determined by radioimmunometric assay (CIS-Bio International) with an intraassay variation of 3.9% and an interassay variation of 6.2%, as was bone alkaline phosphatase (BAP) (tandem-R Ostase; Hybritech, Beckman Coulter, Inc. S.A., Paris, France) with an intraassay variation of 6.7% and an interassay variation of 8.1%. Urine C-telopeptide of type I collagen (CTx) levels were determined by immunoenzymatic measurement (Cross-laps EIA, CIS-Bio International) with an intraassay variation of 5.4% and an interassay variation of 8.6%.

A standard colorimetric dry chemistry assay was used to measure serum creatinine (Synchron Automate CX3, Beckman Coulter, Inc.). Creatinine clearance was calculated according to the Cockcroft and Gault formula (41). Serum levels of 25(OH)D and 1,25(OH)2D were determined by immunoradiometric assay [25(OH)D and 1,25(OH)2D (INCSTAR Corp., DiaSorin, Inc., Paris, France)] with a coefficient of variation of less than 10%.

Bone densitometry

Whole body BMD (in g/cm2) and BMD at the lumbar spine (L2-L4) and femoral neck were determined on each subject by use of dual-energy x-ray absorptiometry (DEXA; Norland XR-26, software version 2.5.2). The coefficient of variation for our instrument during measurement on a standard phantom was less than 1%. BMD was measured twice in eight postmenopausal women of various ages with repositioning between scans, providing a short-term in vivo coefficient of variation of less than 3% for whole body, lumbar spine and femoral neck BMD.

Statistics

Standard statistical methods were used to calculate means and SD. The Kolmogorov-Smirnov test was used to test for normal distribution of all data. Associations are given as Pearson’s correlation coefficients. To account for the influence of age on BMD, all correlation coefficients with BMD were recalculated after adjustment for years since menopause. To further assess the individual contributions of the factors significantly associated with BMD at different sites (P < 0.1), these variables were included in a stepwise multiple linear regression with BMD taken as dependent variable. Final models retained variables at P < 0.05. The validity of the models was expressed by the multiple R2 coefficient, which represents the part of the variance of the dependent variable explained by the covariates entered in the model. All statistical analyses were performed using the BMDP statistical package (BMDP Statistical Software, BMDP/Dynamic release 7.0).

Results

Characteristics of the study population and assessments in all 107 subjects of BMD, body composition, biological parameters, and calcium intake are presented in Table 1Go.


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  		Table 1. Characteristics of the study population

 
Whole body (r = -0.49, P < 0.001), femoral neck (r = -0.55, P < 0.001) and lumbar spine BMD (r = -0.33, P < 0.001) were inversely correlated with years since menopause, as were weight (r = -0.25, P = 0.01), BMI (r = -0.2, P = 0.043), fat mass (r = -0.2, P = 0.04), creatinine clearance (r = -0.35, P < 0.001), and levels of IGF-I (r = -0.28, P = 0.003), GH (r = -0.27, P < 0.01), and DHEA (r = -0.35, P < 0.001). Lean mass and levels of leptin, E2, 25(OH)D, 1,25(OH)2D, and PTH were not correlated with years since menopause.

Correlation coefficients with BMD are shown in Table 2Go. Whole body, femoral neck, and lumbar spine BMD were positively correlated with weight, lean mass, fat mass, BMI, and levels of leptin. Whole body BMD was positively correlated with DHEA, IGF-I and calcium intake. Femoral neck BMD was positively correlated with levels of DHEA and IGF-I. Although not always significant, negative correlations were found between BMD and all markers of bone formation and resorption.


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  		Table 2. Correlations with BMD

 
After adjustment for years since menopause, whole body, femoral neck and lumbar spine BMD remained positively correlated with weight (r = 0.59, r = 0.50, r = 0.51, respectively; P < 0.001), lean mass (r = 0.52, r = 0.40, r = 0.42, respectively; P < 0.001), fat mass (r = 0.36, r = 0.29, r = 0.37, respectively; P < 0.001) and BMI (r = 0.55, r = 0.47, r = 0.46, respectively; P < 0.001), and inversely correlated with osteocalcin (r = -0.26, P < 0.01; r = -0.35, P < 0.001; r = -0.24, P < 0.05). The positive association remained between whole body BMD and leptin (r = 0.34, P < 0.001) and between femoral neck BMD and leptin (r = 0.23, P < 0.05) and IGF-I (r = 0.2, P < 0.05).

Bone turnover markers were positively intercorrelated [urine CTx and osteocalcin (r = 0.43, P < 0.001), osteocalcin and BAP (r = 0.40, P < 0.001), and urine CTx and BAP (r = 0.17, P = 0.08)].

Correlation coefficients with leptin are shown in Table 3Go. Leptin level was positively correlated with weight, fat mass, BMI, E2, creatinine clearance, and BAP level and inversely correlated with urine CTx. The negative correlation between leptin and osteocalcin was of borderline significance. After adjustment for fat mass and creatinine clearance, the relationship of leptin remained significant with urine CTx (r = -0.27, P < 0.01) and of borderline significance with BAP (r = 0.18, P = 0.06).


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  		Table 3. Correlations with serum leptin

 
Table 4Go presents the stepwise multiple linear regression model fitted to data for whole body, femoral neck, and lumbar spine BMD. Variables associated with BMD in the univariate analysis (P < 0.1), including years since menopause, lean mass, fat mass, creatinine clearance, E2, leptin, DHEA, IGF-I, and calcium intake were entered in this analysis. Lean mass explained 28.5%, years since menopause explained 10.3% and leptin explained 7.2% of whole body BMD variance. Years since menopause explained 21.1%, lean mass 12.8% and leptin 3.7% of femoral neck BMD variance. Lean mass explained 20.2%, fat mass 6.2%, and years since menopause 4.1% of the lumbar spine BMD variance.


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  		Table 4. Parameters identified as significant and independent predictors of BMD

 
Discussion

The main result of the present study is that leptin is significantly associated with whole body and femoral neck BMD, this association being independent of the influence on BMD of years since menopause, fat mass, lean mass, creatinine clearance, calcium intake, and other hormonal factors studied. This finding thus supports the hypothesis that leptin may play a significant role in regulating bone mass in postmenopausal women.

The present study found an expected age-related decline in bone density consistent with a continuous loss of skeletal integrity after menopause (42, 43, 44). Age was associated with significant decreases in weight, BMI, fat mass (45, 46), creatinine clearance (41), IGF-I (47), and DHEA levels (37, 47), factors that were also significantly associated with bone density (30, 35, 36, 43, 44, 45, 46). Thus, leptin (17, 22) and lean mass (4) were also strongly associated with BMD, but not with aging (45, 48, 49, 50). After adjustment for age or years since menopause, the correlations with BMD fell or were nonsignificant for DHEA and IGF-I, suggesting that their role in bone loss might be explained by their age-related decline (47). In contrast, body weight, fat, and lean mass continued to be significantly correlated with BMD (4, 26, 44), as did leptin levels with whole body and femoral neck BMD (18, 22, 23).

E2 levels were significantly correlated with fat mass and weight but not with years since menopause (6). The correlation of E2 levels was not significant with femoral and lumbar spine BMD and was of borderline significance with whole body BMD. However, it is well documented that postmenopausal women with undetectable E2 levels (<5 pg/ml) have lower BMD and a higher prevalence of hip or vertebral fracture than women whose serum E2 levels are between 5–25 pg/ml (5, 6, 7, 23, 51, 52). These apparently conflicting results are likely explained by the fact that 10% of the women had residual levels below 5 pg/ml and 20% below 10 pg/ml in the present study, whereas 20–50% of the postmenopausal women had undetectable concentrations of E2 or estrone in these previous studies. Taken together, our results confirm the high heterogeneity of residual E2 in postmenopausal women and suggest that the relationship between E2 and BMD may be nonlinear and less marked in women whose serum E2 levels are over 5 or 10 pg/ml.

A key role in the concept of age-related osteoporosis has been attributed to reduced dietary calcium intake and to vitamin D deficiency-related secondary hyperparathyroidism (53). However, in this study and others, current calcium intake was not significantly associated with bone density (43, 46). Thus, no significant relationships were observed between vitamin D status, BMD, and PTH, before or after age adjustment (36, 54). These data support the hypothesis that, contrary to the findings in vitamin D-deficient women (55), significant relationships between vitamin D status, PTH, and bone mass are not apparent in vitamin D-replete healthy women (29, 54, 56).

As in most of the earlier studies, we found that leptin was strongly correlated with weight, BMI, and fat mass (18, 22, 35, 48, 57, 58). Leptin was also significantly associated with E2 (23) and creatinine clearance (59), both factors that were strongly associated with body weight (P < 0.001). After adjustment for body weight, the associations between leptin and both E2 and creatinine clearance disappeared, suggesting that leptin levels are not directly influenced by creatinine clearance and E2 levels in women without renal failure (23, 60).

Although leptin is needed for normal spontaneous secretion of GH (33), we were unable to demonstrate a significant relationship between the levels of GH and IGF-I and those of leptin. This result supports the hypothesis that the influence of leptin on bone metabolism through the central nervous system is in most part, independent of the effects of IGF-I and GH (61).

Pasco and colleagues were the first to show an association between serum leptin levels and both whole body and femoral (Ward’s triangle and trochanter) bone mineral content and lateral spine BMD after adjustment for age and fat mass in women (22). Thomas and colleagues further showed that the strength of the association between fat mass and BMD was reduced after adjustment for leptin and not influenced by the level of bioavailable E2 in women (23). In contrast, another recent study observed no correlation between leptin and the BMD of postmenopausal women after adjustment for BMI (21). However, leptin is produced in adipocytes and is exponentially correlated to fat mass and not to lean mass in nonobese women (10). BMI is calculated from both weight, which takes into account lean mass, and height, which shows change with aging (62). Therefore, controlling the association between leptin and BMD for BMI is very likely less accurate than controlling for fat mass (49, 57, 58, 63) and may have altered the association between leptin and BMD in this study. Accordingly, the correlation between BMD and leptin was significant after adjustment for body fat mass in the present study, but disappeared after adjustment for BMI. The inclusion of obese women, who display a possible leptin resistance (32, 64) and a wide range of serum leptin concentrations, may explain the lack of significant correlation between leptin and BMD in another study (18).

The present study found that leptin was a significant and independent predictor of BMD, explaining about 7% of the variance of whole body BMD and about 4% of the variance of femoral neck BMD. This supports the hypothesis that leptin may exert a positive effect on the skeleton (22) and that this effect is independent of that of E2 (23). For the first time to our knowledge, this study also shows that this protecting effect on bone is also independent of kidney function and levels of GH, IGF-I, DHEA and PTH.

We also found inverse correlations between BMD and urine CTx, a marker of bone resorption, and osteocalcin and BAP, two markers of bone formation. These findings support the widely accepted hypothesis that the bone loss that occurs during menopause is characterized by an increased bone turnover, with excessive bone resorption relative to bone formation (65, 66).

In the present study, the association of leptin was negative with urine CTx, a marker of bone resorption (67), positive with BAP, a marker of bone formation, and negative and of borderline significance with osteocalcin, a marker of bone formation and turnover (66, 68). After adjustment for fat mass and creatinine clearance, the negative correlation remained only between leptin and urine CTx, and disappeared with markers of bone formation, suggesting an inhibiting effect of leptin on bone resorption. Recent studies showed that leptin influenced bone metabolism by acting on differentiated osteoblasts, whereas it had no direct effect on the osteoclast (69). Because markers of bone turnover were highly intercorrelated in the present study and in others (70), the negative association between leptin levels and urine CTx observed in our study and others (19, 20, 23) may be due to the coupling between bone formation and resorption. Therefore, our results suggest that leptin might exert its protective effect on bone by limiting the excessive bone resorption coupled with bone formation that is associated with bone loss after menopause. The dissociated relationship between leptin and both osteocalcin and BAP in the present study and others (18, 20, 31), may illustrate the complex influence of leptin on bone formation because leptin has been shown both to inhibit bone formation by acting on its receptor in hypothalamic nuclei (61) and to enhance osteoblastic differentiation (13) and bone mineralization (12).

In summary, our results show that leptin is a significant and independent predictor of BMD in postmenopausal women, and they support the suggestion that circulating leptin exerts its protective effect on bone through limiting the excessive bone resorption coupled with bone formation that is associated with bone loss after menopause.

Acknowledgments

We are grateful to B. Martin, R.N., for assistance in collecting data, Professor P. Jouanny and A. M. Dupuy for their technical advice, and we acknowledge Lynn Salhi, Ph.D., and Catherine Scott-Carmeni for editorial assistance.

Footnotes

Funding for this research was provided by the French Ministry of Health (Projet Hospitalier de Recherche Clinique).

Abbreviations: BAP, Bone alkaline phosphatase; BMD, bone mineral density; BMI, body mass index; CTx, C-telopeptide of type I collagen; DHEA, dehydroepiandrosterone sulfate; OC, osteocalcin.

Received June 29, 2001.

Accepted December 4, 2001.

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