Relationship between growth hormone–IGF-I–IGFBP-3 axis and serum leptin levels with bone mass and body composition in patients with rheumatoid arthritis

É. Toussirot, N. U. Nguyen1, G. Dumoulin1, F. Aubin2, J.-P. Cédoz and D. Wendling

Department of Rheumatology and 1 Department of Physiology, University Hospital Jean Minjoz, Bd Fleming, 25030 Besançon and 2 Department of Dermatology, St Jacques Hospital, Place St Jacques, 25030 Besançon, France.

Correspondence to: E. Toussirot, Department of Rheumatology, University Hospital Jean Minjoz, Bd Fleming, 25030 Besançon cedex, France. E-mail: eric.toussirot{at}ufc-chu.univ-fcomte.fr


    Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Objectives. Hormonal factors playing a role in bone mass and body composition have been rarely assessed in rheumatoid arthritis (RA). In this study, we aimed to evaluate the growth hormone (GH)–insulin-like growth factor-I (IGF-I)–insulin-like growth factor binding protein-3 (IGFPB-3) axis and serum leptin levels in patients with RA and to determine whether these hormonal/growth factors may influence bone mass and body composition in RA.

Methods. Serum GH, IGF-I, IGFPB-3 and leptin were evaluated in 38 corticosteroid-treated RA patients, 14 non-RA patients under corticosteroids (corticosteroid controls, CC) and 32 healthy controls (HC). Bone density was evaluated using dual X-ray absorptiometry (DEXA), and expressed as bone mineral density (BMD), and quantitative ultrasound (QUS). Body composition was assessed by DEXA.

Results. The three groups differed regarding femoral neck, total body BMD, lean mass and QUS parameters with lower values in the RA group (all P ≤ 0.05). Growth hormone was higher in RA patients (P = 0.0001) while IGF-I and IGFBP-3 did not differ between the three groups. In RA patients there was a tendency to high serum leptin levels and leptin strongly correlated with fat mass (r = 0.83, P<0.0001), but not with bone mass measurements or inflammatory parameters. There were no differences for lean mass, GH and leptin between CC and HC.

Conclusion. Our results suggest that these GH and leptin modifications could have an influence on both bone mass and body composition in RA.

KEY WORDS: Bone mineral density, Bone metabolism, Leptin, Growth hormone, Insulin-like growth factors


    Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a chronic joint disease involving the synovial membrane which becomes inflamed and releases inflammatory cytokines, causing damage to joint components, cartilage and bone. Bone involvement is a well-described complication of RA as a localized or juxta-articular osteoporosis, which is directly related to the inflammatory process, and also as a generalized osteoporosis which is still debated in RA [1, 2]. However, cross-sectional and longitudinal studies have shown an increased rate of bone loss at both the spine and the hip, especially in early RA patients [3–5]. RA is also characterized by a higher frequency of fractures [1]. The pathogenesis of this generalized bone loss remains controversial but previous studies have linked it to disease activity, loss of mobility and corticosteroid treatment [1, 2].

Bone mineral density (BMD) is usually measured by dual X-ray absorptiometry (DEXA). Quantitative ultrasound (QUS) is another technique which is rapid and radiation free and provides information about bone quality [6]. In RA, bone density has been extensively studied using DEXA while there is only limited information about QUS measurements [7].

Since the introduction of total body DEXA, it has been possible to evaluate the bone mass in different parts of the skeleton and also the soft tissue composition. Body composition is also affected in RA patients [8]. Moreover, fat mass is known to influence bone mass, especially in post-menopausal women. Markers of bone turnover and sex hormones have been well studied in RA [1] while there are limited data about other factors involved in bone mass and body composition such as insulin-like growth factor-I (IGF-I) or somatomedin C.

IGF-I is a bone-promoting peptide which mediates the effects of growth hormone (GH) at the tissue level, including bone [9]. It has markedly anabolic actions on bone. IGF-I is regulated by GH itself and also by its binding proteins (IGFBPs). IGFBP-3 is the predominant protein that is linked to IGF-I [9]. Furthermore, IGF-I has been found to be a predictive factor for osteoporotic fractures independently of BMD in post-menopausal women [10]. Another factor which may play a role in bone mass and body composition is the product of the LEP (previously denoted OB) gene, i.e. leptin. Leptin is secreted by white adipose tissue and is strongly correlated to fat mass [11]. It has emerged as a potential candidate for explaining the protective effect of fat mass on bone [12]. However, leptin has been rarely evaluated in RA as well as IGF-I and its main binding protein.

Since osteoporosis and changes in body composition are observed in RA patients, we aimed in this study to evaluate hormonal and bone growth factors involved in the regulation of bone remodelling and soft tissue composition in assessing the GH–IGF-I–IGFBP-3 axis and serum leptin in patients with RA and sought for a relation between these factors and bone status including bone mass and bone remodelling.


    Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
Rheumatoid arthritis
Thirty-eight RA patients responding to the 1987 ACR criteria were included [13]. The data collected were age, sex, body mass index [BMI = weight/height2 (kg/m2)], disease duration, extra-articular manifestations, tender and swollen joint counts (28 joint counts) and Health Assessment Questionnaire (HAQ). All the patients received corticosteroids, and thus the duration of treatment, the mean daily dose and the cumulative dose were recorded. For inclusion, the daily corticosteroid dosage (prednisolone) had to be ≤10 mg for 3 months before entering the study. Disease activity was only assessed by laboratory parameters of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels]. The disease-modifying anti-rheumatic drugs (DMARDs) were also recorded. The radiological destruction of the hands was evaluated using the method of Larsen [14].

Corticosteroid controls (CC)
All our RA patients received corticosteroids, and thus we have to compare the bone mass of these patients with an adequate age-matched control group also receiving corticosteroids. Thus, 14 subjects with a condition requiring corticosteroid treatment were also assessed in this study. This group included patients with asthma (n = 2), polymyalgia rheumatica (n = 4), sarcoidosis (n = 1), pemphigus vulgaris (n = 2) or psoriatic arthritis (n = 3), Sjögren's syndrome (n = 1) and mixed connective tissue disease (n = 1). Age, sex and BMI were recorded. The duration of corticosteroid treatment, mean daily dose and cumulative dose were also available.

Healthy controls (HC)
Thirty-two healthy subjects without a history of inflammatory disease or a condition responsible for bone loss were also assessed.

Subjects excluded from this study were post-menopausal women, subjects with diabetes mellitus, the obese (BMI> 30 kg/m2), the underweight (BMI<18 kg/m2), those with renal or liver disease, or a condition which might alter the bone mineral content and/or metabolism (including alcoholism, Paget's disease, hypogonadism, hyperthyroidism, hyperparathyroidism, thyroxine and anticonvulsant treatment). Patients with a daily prednisolone dose >10 mg were also excluded. No patients were under bisphosphonates at the moment of the study and for 6 months before participating in the study.

Informed written consent was obtained from all subjects before participation. This study was approved by our local ethics committee.

Methods
Serum and urinary bone markers
Fasting venous blood samples were taken at 8.00 a.m. from each subject and the sera were stored at –20°C. Twenty-hour urine was collected for each subjects. The following serum bone markers were evaluated: procollagen type I C-terminal propeptide (PICP) for bone formation and urinary free deoxypyridinoline (Udpyr) for bone resorption. Procollagen type I C-terminal propeptide and Udpyr were measured by ELISA (PICP, Prolagen-C and Udpyr, Pyrilinks-D, Metra Biosystems, Mountain View, CA, USA). Urinary free deoxypyridinoline was expressed as the Udpyr/creatinine ratio (Udpyr/creat). Growth hormone, IGF-I and IGFBP-3 were measured by specific RIA assays (IRMA, Immunotech France). Insulin serum levels were also evaluated (EIA Tosoh, AIA Pack France). Leptin serum concentrations were measured using radioimmunoassay (Linco Research, St Charles, MO, USA). CRP and ESR were determined by routine laboratory procedures, as well as fasting glycaemia. Rheumatoid factors were detected using nephelometry. The between-run coefficients of variation (CV) were 7.2% for PICP, 7.6% for Udpyr, 6.3% for GH, 6.2% for IGF-I, 6.2% for IGFBP-3 and 5.7% for leptin.

Bone mineral density
Measurements of BMD of the L2–L4 lumbar spine and the left femoral neck were carried out using a Lunar DPX-IQ (Lunar, Madison, WI, USA). The results were given as BMD (g/cm2) (the normal ranges were given by the manufacturers of the bone densitometer). The CV was 1% for the lumbar spine and 1.5% for the femoral neck.

Body composition
A total body scan was performed using the same Lunar densitometer. Measurements were given for body composition from the total body scan with lean mass (g) and fat mass (g). The reproducibility for total body measurements was 0.7%.

Quantitative ultrasound
QUS measurements of the right calcaneus were performed using an Achilles plus device (Lunar). Three parameters were measured: broadband ultrasound attenuation (BUA, dB/MHz); speed of sound (SOS, m/s) and stiffness, a combination of the two previous parameters, calculated as follows: 0.67 BUA + 0.28 SOS – 420. This index was established by Lunar. The CV, calculated in 10 healthy volunteers was 3.64% for BUA, 0.59% for SOS. The CV given by the manufacturer were BUA 1.7% and SOS 0.3%.

Statistical analysis
Results were given as mean±SEM. Age, BMI, ESR, CRP, biochemical parameters of bone turnover, GH, IGF-I, IGFBP-3, leptin levels and bone density measurements (lumbar spine, femoral neck, total body BMD, lean and fat masses and QUS parameters) were compared between the three groups of subjects using the Kruskal–Wallis test. When a significant difference was found, the exact P values were calculated using the Mann–Whitney U-test. Qualitative data (sex) were analysed by the {chi}2 test. The relationships between the different variables (DEXA and QUS values, biochemical parameters of bone turnover, growth factors and/or hormone, leptin) were analysed by the Spearman r-test. The statistical level was 0.05 and the Statview software (Alsyd SAS, Meylan France) was used for these statistical tests.


    Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The demographics, clinical characteristics, inflammatory markers and radiological characteristics of the studied subjects are listed in Table 1. Age and BMI did not differ between the three groups (P>0.05). There were more females in the RA group compared with the HC (P = 0.01) and RA patients had higher ESR and CRP levels compared with the two other groups (each P<0.0001). The cumulative dose and the duration of corticosteroid treatment did not differ between RA and CC subjects (P>0.05) while RA patients had a lower prednisolone dosage (P = 0.02).


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TABLE 1. Clinical, biological and radiological data of rheumatoid arthritis, corticosteroid controls and healthy controls

 
The three groups differed regarding the biochemical parameters of bone turnover, PICP and Udpyr/creat, and for GH, femoral neck and total body BMD, lean mass and QUS parameters (all P<0.05) (Table 2). For lumbar spine BMD, there was a tendency for a difference between the three groups, but without reaching the level of significance (P = 0.08). There was no difference in leptin levels between the three groups (P = 0.19), but mean leptin tended to be higher in patients with RA than in CC and HC (14.3±1.9 vs 10.4±2.7 vs 9.2±1.3 ng/ml, respectively) (Table 2). Pairwise tests showed that RA patients had higher Udpyr/creat and GH levels than HC (P = 0.01 and P<0.0001, respectively). The femoral neck and total body BMD and the lean mass were lower in RA compared with HC (P = 0.0004, P<0.0001 and P = 0.008, respectively) as well as QUS measurements (BUA, P = 0.0009; SOS, P<0.0001; stiffness, P<0.0001).


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TABLE 2. Bone density, hormonal and biochemical parameters of the studied subjects

 
In the RA group, there was a marked correlation between Udpyr/creat and ESR (r = 0.42; P = 0.01) and a similar tendency with CRP levels (r = 0.29, P = 0.06). No relations were found between spine, femoral neck, total body BMD and ESR or CRP and between lean mass and ESR or CRP. Similarly, leptin serum levels did not correlate with ESR or CRP. Body mass index and fat mass strongly correlated with leptin (r = 0.67, P<0.0001 and r = 0.83, P<0.0001, respectively) while there were no significant correlations between leptin and spine, femoral neck or total body BMD.

When analysing the data between RA and CC (Table 2), we found no differences for Udpyr/creat, femoral neck and total body BMD, lean mass and QUS measurements. GH was higher in RA patients than in CC but the difference was not significant (P = 0.06). In addition, CC had higher PICP levels than RA (P = 0.003).

Finally, when comparing CC and HC, we did not observe any difference for GH or Udpyr/creat concentrations. PICP was higher in CC compared with HC (P = 0.02). Femoral neck and total body measurements were significantly decreased in CC (P = 0.03 and P = 0.005, respectively) while lean mass and BUA did not differ between the two groups. However, SOS and stiffness tended to be lower in CC (SOS, P = 0.06; stiffness, P = 0.08).

The RA group was characterized by a higher number of female patients than the other two groups and it is well known that serum levels of leptin show a marked sexual difference, being higher in female than in males. Thus, we excluded the female patients from the analysis and compared the serum leptin levels between male RA (n = 20), male CC (n = 10) and male HC (n = 26): we also observed higher leptin levels in RA, without reaching the level of significance (RA vs CC vs HC: 10.9±1.6 vs 8.6±2.3 vs 7.2±0.7 ng/ml; P = 0.4).

When examining the relationships between DEXA measurements and QUS parameters in the whole series of subjects, we found that DEXA values strongly correlated with QUS parameters (all P<0.0005) (Table 3).


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TABLE 3. Correlation between DEXA measurements and QUS parameters

 

    Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our results show that RA patients had a decreased bone mass compared with HC at the femoral neck and also the total body skeleton, confirming the fact that bone loss in RA is not restricted to juxta-articular sites. The question of bone involvement in RA has been widely investigated, and taken together, most of these studies showed that RA is characterized by a low bone mass as evaluated by DEXA, occurring both in the appendicular and the axial skeleton [1, 3–5]. Moreover, longitudinal studies have showed that this bone loss begins early after disease onset. Our patients did not have recent disease but our results on bone mass are in accordance with these previous data.

We also evaluated bone mass in our patients using QUS. Our results show significantly lower values of QUS parameters as compared with HC. Previous studies of bone mass assessment in RA using QUS showed decreased values in patients receiving or not receiving corticosteroids [16, 17]. Moreover, strong correlations between QUS parameters and DEXA values, both at the spine and femoral neck, were obtained in our study. These data suggest that QUS may be used to evaluate bone mass in RA, but further studies are needed to better define the real place of this technique and the additional information given compared with DEXA.

Whatever the technique used, we did not observe any difference in bone mass measurements between RA and CC. This could reflect the influence of corticosteroid treatment on bone mass. On the other hand, our CC had an inflammatory disease which may also influence bone mass. Indeed, polymyalgia rheumatica, psoriatic arthritis, Sjögren's syndrome and sarcoidosis are conditions which have been associated with bone loss. These conditions (as well asthma and pemphigus) are responsible for the production of inflammatory mediators which could influence the bone turnover. And accordingly, femoral neck and total body BMD were decreased in CC when compared with HC. Thus, we are not able to discriminate between the influence of the disease itself and the role of corticosteroids for explaining the bone loss observed in these CC.

Body composition was altered in our RA patients, with a decreased lean mass contrasting with normal fat mass. The loss of lean mass could be related to the disease activity since RA is responsible for the production of inflammatory cytokines such as TNF-{alpha} which favours hypermetabolism. These changes could also be related to the reduced mobility induced by the disease itself and by corticosteroid treatment. However, in our study we failed to observe a relationship between lean mass and inflammatory markers. Previous studies evaluating body composition in RA found similar results to ours. Westhovens et al. [8] observed a clear decreased lean mass and a higher fat mass at all body sites with a shift of fat mass to the abdomen. One study found no changes in lean and fat masses [7]. These discrepancies might be caused in part by differences in the age of patients, treatment and levels of disease and physical activity. Furthermore, these changes in body composition prompted us to assess hormonal factors which play a role in soft tissue composition.

Since IGF-I mediates the anabolic actions of GH and thus plays a role in growth, metabolism and several cellular functions, we specifically evaluated in this study the GH–IGF-I–IGFBP-3 system [9]. Reduced serum levels of IGF-I have been observed in osteoporosis [20] and IGF-I and IGFBP-3 are decreased in conditions characterized by reduced lean mass and decreased strength, such as juvenile chronic arthritis and osteoarthritis [9]. We previously reported reduced IGFBP-3 serum levels in ankylosing spondylitis, a condition also characterized by low bone mass [21]. Inappropriate serum levels of IGF-I have been previously observed in RA patients, with concomitant higher or depressed IGFBP-3 [22, 23]. We did not observe changes in IGF-I and IGFBP-3 in our RA patients and this could be explained by differences in habitual exercise and degree of disability. However, and by contrast, we observed high GH levels in our RA patients. Growth hormone affects several tissues including liver, muscle and bone, playing a role in the regulation of longitudinal bone growth but also in bone formation and resorption [24]. In RA, GH has been investigated by means of dynamic changes during insulin-induced hypoglycaemia. An abnormal response has been found reflecting a GH axis involvement in RA patients [25]. In another study, GH secretory kinetics were found to be similar between RA patients and healthy controls [26]. In the adjuvant arthritic rat model, a significantly increased concentration of GH has been observed [27]. The changes of GH levels in RA could be related to factors that stimulate its secretion, such as substance P, a mediator of pain which is known to act on the anterior pituitary gland. Another factor which may play a role is IL-1, an inflammatory cytokine involved in RA, also known to stimulate GH release [24]. Corticosteroids may also influence GH levels, but it has been demonstrated that this situation is associated with a lower GH secretion and an IGF-I increase [28, 29]. In fact, if GH is secreted at a higher level in RA, as observed in our patients (and not in the CC), this could influence bone mass and other tissues such as muscle. However, in our study, IGF-I and IGFBP-3 did not parallel the changes in GH and this could limit the potential effects of this GH increase. Another explanation could be a resistance of GH receptors at the tissue levels.

We also observed in our RA patients a tendency towards high serum leptin levels compared to the other groups. Leptin, the product of the LEP gene, has multiple biological effects on nutritional status, metabolism and also the neuroimmunoendocrine axis [11]. Leptin strongly correlates with body fat mass and BMI, but the relationship of leptin with BMD still remains controversial [11, 30]. Some authors found a positive association between serum leptin levels and BMD [12] while others failed to find such a relationship [31]. In our study, and whatever the site of measurement was, we did not find a relationship between BMD and serum leptin. However, we found a strong correlation between fat mass, BMI and serum leptin in RA patients. We also observed a significant elevated GH in these patients and this might also affect their body composition. Indeed, GH, IGF-I and leptin are interrelated. It is known that leptin can modulate the GH–IGF-I pathway and it has been demonstrated that gender, BMI and IGFBP-3 are the parameters explaining the variability of serum leptin in a multiple regression analysis [32]. However, the parallel increase in GH and leptin in our RA patients did not merely influence their body composition, since we did not observe changes in fat mass but only in lean mass. This suggests that the hormonal modifications of our RA patients have a limited (or specific) influence on soft tissue by targeting lean mass. Conversely, elevation of GH did not positively benefit lean mass and this could be explained by the lack of parallel increase in IGF-I. We can also explain these apparent discrepancies between GH and leptin results and changes in body composition by the disease activity itself which certainly favours hypermetabolism while anabolic processes can be depressed.

In addition, changes in serum leptin could influence the immune system [33]. A situation of hyperleptinaemia can contribute to the inflammatory response. However, in our study we failed to demonstrate a correlation between markers of inflammation and serum leptin. Leptin has been previously evaluated in RA, but no changes in serum leptin levels were found in one study [34] while leptin levels were found to be significantly higher in plasma and synovial fluid samples from RA patients than in control samples in another study [35].

The influence of corticosteroids should also be discussed. Indeed, all our RA patients received corticosteroids, and glucocorticosteroids increase leptin secretion [32]. However, in our study, only RA (and not CC) patients showed a tendency to have high leptin levels.

Surprisingly, we found high PICP levels in CC patients, suggesting a high rate of bone formation in this group of patients while corticosteroids are drugs known to depress bone formation. These results could perhaps be explained by the heterogeneity of this group of patients, including their different diseases.

In conclusion, our corticosteroid-treated RA patients had low bone mass at the femoral neck and total body and a low lean mass, associated with elevated GH and a tendency to high serum leptin levels contrasting with normal IGF-I and IGFBP-3 serum levels. These modifications could influence both bone mass and soft tissue and seem specific for RA. However, the mechanisms explaining such hormonal modifications remain to be elucidated but may have potential bone and soft tissue influences.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Submitted 26 June 2004; revised version accepted 27 August 2004.



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