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Third Department of Internal Medicine, Gifu University School of Medicine (M.S., N.T., H.S., K.T., A.S., S.K., K.Yo., K.Ya.), and Department of Internal Medicine, Matsunami General Hospital (R.T., M.H.), Gifu 500-8705, Japan
Address all correspondence and requests for reprints to: Noriyuki Takeda, M.D., Third Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. E-mail: ntkd{at}cc.gifu-u.ac.jp
Abstract
Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (±SD) age and body mass index of 52.1 ± 8.7 yr and 23.6 ± 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans.
LEPTIN, THE PRODUCT of the ob gene, is secreted primarily by the adipocytes and plays an important role in the regulation of food intake and energy expenditure (1). In addition to its adipostatic function, the hormone regulates multiple hypothalamic-pituitary axes and may have a role in hemopoiesis and fetoplacental function (2). Recently, Ducy et al. (3) discovered a noble action of leptin on bone formation in mice. It is generally thought that obesity protects against osteoporosis (4). As serum leptin concentrations are elevated in obesity (5), except in rare individuals with leptin gene mutation (6), a favorable effect of leptin on bone mineral density (BMD) can be anticipated. In favor of this view, leptin has been shown to enhance the differentiation of immortalized bone marrow stromal cell to osteoblast (7). However, the study by Ducy et al. (3) demonstrated the contrary. They found a massive increase in bone mass in ob/ob and db/db obese mice, which are deficient in leptin or its receptor. Prevention of obesity by diet did not affect the high bone mass phenotype. Intracerebroventricular administration of leptin in ob/ob mice reversed the high bone mass. The effect of leptin was also seen in wild mice. Leptin inhibited bone formation, but had no effect on bone resorption. In vitro there was no direct effect of leptin on osteoblastic function. Therefore, they proposed that leptin inhibits bone formation in mice via a hypothalamic mechanism. As osteoporosis is a very common disease, and obesity is a growing problem worldwide, whether leptin has any role in human bone physiology is an important problem. To address this, we studied a correlation between serum leptin concentration and BMD, and biochemical markers of bone turnover in adult men.
Subjects and Methods
The study subjects (Table 1
) were 221 Japanese men with a
mean age of 52.1 ± 8.7(SD) yr (range, 21–73 yr) and
a mean body mass index (weight in kilograms divided by the square of
height in meters) of 23.6 ± 2.8 kg/m2 (range, 17.0–31.2).
They were recruited between September 1996 and May 1997 from
participants of a periodic health examination program at Matsunami
General Hospital, which is situated in an urban area of Gifu, Japan.
There were several courses in the health check program. Participants of
the most intensive course were invited to participate in the study.
More than 95% of them gave informed consent and entered the study.
Most of our study subjects were workers. The study was approved by the
ethics committees of Matsunami General Hospital and Gifu University
School of Medicine. BMD (in milligrams per cm2)
was measured by single photon absorptiometry. The right calcaneus was
scanned using an Osteoanalyzer SXA 2000 (8) (McCue Plc.,
Compton, UK). The coefficient of variation for the SXA2000 calcaneal
BMD measurement was 1.3% (8). A blood sample was taken
between 0800–0830 h after an overnight fast. The serum leptin
concentration was measured by RIA using a commercially available kit
(Linco Research, Inc., St. Charles, MO) with a detection
limit of 0.5 ng/ml. Intra- and interassay coefficients of variation in
our hands were 5.2% and 6.3%, respectively. The serum concentration
of carboxyterminal propeptide of type 1 procollagen (PICP) as a
maker of bone formation was measured with an RIA kit (Orion
Diagnostica, Espoo, Finland). The intra- and interassay coefficients of
variation were 5.7% and 5.1% at a PICP concentration of approximately
200 ng/ml. As a marker of bone resorption, cross-linked
carboxyterminal teleopeptide of type 1 collagen (ICTP) was measured
with an RIA kit (Orion Diagnostica) with intra- and interassay
coefficients of variation of 6.9% and 7.7%, respectively. Total body
fat mass was estimated by bioelectrical impedance analysis using a
TBF-102 BIA system (Tanita, Tokyo, Japan).
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Data are expressed as the mean ± SD unless otherwise stated. Statistical analyses were performed using Statistical Analysis System version 6.12 for Windows (SAS Institute, Inc., Cary, NC). Relations between variables were evaluated by Spearman’s rank correlation test. For multivariate analysis, confounders of the association between two variables were included in regression models as covariates, and partial correlation coefficients were calculated. Statistical significance was defined as P < 0.05.
Results
Similar to numerous previous studies, serum leptin concentrations in this study population were strongly correlated with body weight (rs = 0.481; P = 0.0001), body mass index (rs = 0.565; P = 0.0001), and total fat mass (rs = 0.604; P = 0.0001).
In unadjusted analyses (Table 2),
calcaneal BMD was correlated with height, body weight, and fat mass.
Age, serum leptin, and biochemical markers of bone turnover (PICP and
ICTP) were not associated with BMD. However, after adjustment for body
weight, BMD was inversely associated with serum leptin concentrations.
Notably, there was a negative correlation between BMD and total fat
mass after adjustment for body weight. Height and body mass index did
not retain significant correlations with BMD. Figure 1 shows calcaneal BMD according to fat
mass tertiles. The mean BMD for the low fat mass tertile was
significantly lower than that for the high fat mass tertile in
unadjusted analyses. On the contrary, after adjustment for body weight,
the mean BMD for the lowest fat mass tertile was higher than that for
the lowest fat mass tertile. BMD according to the tertiles of serum
leptin concentration is shown in Fig. 2.
There were no differences in the mean values of BMD for the three
tertiles of leptin in unadjusted analyses. After adjustment for body
weight, the mean BMDs for the low and the middle tertiles of leptin
were lower than that for the high tertile. As shown in Table 3, PICP, a marker of bone formation, was
inversely correlated with age and serum leptin. There was no
correlation of PICP with body weight or total fat mass. ICTP, a marker
of bone resorption, was correlated with body weight and serum leptin.
PICP retained a statistically significant inverse association with
leptin (rs = -0.1540; P =
0.0223) even after adjustment for age. On the other hand, adjustment
for body weight eliminated the association between ICTP and leptin.
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We found that BMD of the calcaneus was inversely associated with serum leptin concentrations after adjustment for body weight in adult men. In these subjects there was an inverse correlation between serum leptin concentrations and PICP, a biochemical marker of bone formation. These results suggest that an increase in serum leptin concentration may reduce bone formation and decrease BMD in adult men. Our study was in good accordance with a recent report by Ducy et al. (3) that demonstrated an inhibitory effect of leptin on bone formation in mice.
A number of investigators (9, 10, 11, 12, 13, 14, 15, 16, 17) have addressed the role of leptin in human bone physiology. Most of them have found leptin to have no effect. No association between serum leptin and BMD was found in pre- and postmenopausal woman (10, 11, 12, 16) and in female and male children (9). There are a few studies suggesting a possible role for leptin in the regulation of human BMD. Their results are contradictory to the findings of our study. Ogueh et al. (13) found an inverse association between fetal blood levels of leptin and ICTP, a marker of bone resorption. They concluded that leptin might decrease bone resorption with the overall effect of increasing bone mass in human fetus. A bone-maintaining effect of leptin was suggested in postmenopausal women with osteoporosis (12), premenopausal women (14), and female hemodialysis patients (15). In addition, Pasco et al. (17) very recently reported that in nonobese Australian women there was a positive correlation between bone mass and serum leptin levels independent of body weight and fat mass.
The explanation for the discrepancy between these and our study is not known. The size of the subject population in most of the previous studies except for the study by Pasco et al. (17) was much smaller than ours. The gender difference in study subjects may be important. Most of the previous studies included postmenopausal women. As we believed that rapid bone loss after menopause may mask the leptin-BMD relationship, we deliberately excluded women and studied adult men only. To our knowledge this is the first report on the association between serum leptin and BMD in healthy adult men.
Apart from our observation, there are several lines of evidence implying the role of leptin and a hypothalamic control in bone remodeling in humans (18). Patients with generalized lipodystrophy who are characterized by a nearly complete absence of adipocyte and low serum leptin have been shown to exhibit osteosclerosis (extremely increased bone formation) (19). Increased bone mass was noted in patients with a defect in hypothalamic melanocortin receptor 4, which plays a role in energy homeostasis (20).
Obese individuals generally have increased BMD compared with lean subject. Yet, they have increased serum leptin concentrations. The inhibitory effect of leptin on bone formation appears apparently contradictory to these facts. Ducy et al. (3) provided a plausible explanation. They proposed that obese individuals are resistant to the biological effects of leptin, and leptin resistance may be the mechanism of the protective effect of obesity on bone mass. Regarding the mechanism of protective effects of obesity against osteoporosis, whether obesity exerts any specific effect on BMD other than mechanical weight load is a matter of debate (21). The conversion of androgen to E in adipose tissue has been presumed to have a favorable effect on BMD. Unfavorable effects of adiposity on BMD also have been suggested. BMD in obese children was shown to be inadequately low for their body weight (22). This fits nicely with our demonstration that both leptin and fat mass were inversely associated with BMD after adjustment for body weight. In this context, it may be conceived that obesity exerts opposite influences on BMD. A positive mechanical effect of weight load and a negative effect mediated via leptin may serve a homeostatic function to keep bone density within normal range.
Our study was observational in nature. A causal relation between serum leptin and BMD cannot be determined. Further studies are needed to determine whether leptin has a regulatory role for bone formation and whether a hypothalamic control of bone formation operates in humans. Elucidation of such mechanism may lead to a novel therapeutic approach to osteoporosis. In conclusion, serum leptin concentrations were inversely associated with a marker of bone formation and BMD in healthy adult men.
Footnotes
1 M.S. and N.T. contributed equally to this work. 
Abbreviations: BMD, Bone mineral density; ICTP, cross-linked carboxyterminal teleopeptide of type 1 collagen; PICP, carboxyterminal propeptide of type 1 procollagen.
Received May 7, 2001.
Accepted August 7, 2001.
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