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Effects of Spa therapy on serum leptin and adiponectin levelsin patients with knee osteoarthritis Antonella Fioravanti • Luca Cantarini •Maria Romana Bacarelli • Arianna de Lalla •Linda Ceccatelli • Patrizia Blardi Received: 13 October 2009 / Accepted: 27 February 2010Ó Springer-Verlag 2010 Adipocytokine, including leptin and adiponec- with other clinical parameters. In conclusion, our data show tin, may play an important role in the pathophysiology of that spa therapy can modify plasma levels of the adipocy- osteoarthritis (OA). Spa therapy is one of the most com- tokines leptin and adiponectin, important mediators of monly used non-pharmacological approaches for OA, but its cartilage metabolism. Whether this effect may play a mechanisms of action are not completely known. The aim of potential role in OA needs further investigations.
the present study was to assess whether spa therapy modifiedplasma levels of leptin and adiponectin in thirty patients with Osteoarthritis Á Leptin Á Adiponectin Á knee OA treated with a cycle of a combination of daily locally applied mud-packs and bicarbonate–sulphate min-eral bath water. Leptin and adiponectin plasma levels wereassessed at baseline and after 2 weeks, upon completion of the spa treatment period. The concentrations of leptin andadiponectin were measured by ELISA. At basal time, Leptin is a peptidic molecule synthesized almost exclu- plasma leptin levels were significantly correlated with body sively by adipocytes, which regulates appetite and energy mass index (BMI) and gender, but no significant correlation expenditure at the hypothalamic level []. In the past few was found with patient age, duration of disease, radiographic years, additional actions have been attributed to this mol- severity of knee OA, VAS score or Lequesne index. There ecule, specifically, modulating the immune response and was no correlation between plasma adiponectin level and affecting the bone and cartilage metabolism [, BMI, gender and age, duration of the disease, radiographic Adiponectin is also synthesized by adipose tissue, and severity of knee OA and VAS score. A significant correla- one of its main actions is to improve insulin sensitivity tion of plasma adiponectin levels was found only with the In skeletal joints, adiponectin may act as a pro-inflamma- Lequesne index. At the end of the mud-bath therapy cycle, tory agent and may be involved in matrix degradation serum leptin levels showed a slight but not significant In patients with osteoarthritis (OA), leptin and adiponectin increase, while a significant decrease (P \ 0.05) in serum are detected in both synovial fluid and in plasma []. The adiponectin levels was found. However, leptin and adipo- adipokines exhibit different patterns of distribution in the nectin concentrations after treatment were not correlated joint and the circulating compartment: plasma levels ofadiponectin exceed those in the paired synovial fluid,whereas leptin concentrations in synovial fluid are higher A. Fioravanti (&) Á L. Cantarini Á M. R. Bacarelli Rheumatology Unit, Department of Clinical Medicine Spa treatments have been applied for therapeutic pur- and Immunological Sciences, University of Siena,Viale Bracci, 1, 53100 Siena, Italy poses in rheumatic diseases since ancient times The mechanism by which mud-packs and/or balneo- therapy improves the symptoms of rheumatic diseases is A. de Lalla Á L. Ceccatelli Á P. Blardi still not fully understood The effects of thermal baths Center of Clinical Pharmacology, University of Siena,Siena, Italy are, in part, related to temperature and balneotherapy also induces a neuroendocrine reaction that causes an 15 min, for a total of 12 applications carried out over a increase in serum levels of corticosteroids and catechola- mines ] and a reduction in circulation levels of tumour It was recommended to patients that they should con- necrosis factor a (TNF-a) and interleukin-1b (IL-1 b) tinue their established non-pharmacological treatments Since serum levels of leptin and adiponectin are influ- (physical exercise) and non-steroidal anti-inflammatory enced by temperature [, ], catecholamines [cor- drugs (NSAIDs; 150 mg Diclofenac tablets, 20 mg Pirox- icam tablets, 750 mg Naproxen tablets, 200 mg Aceclofe- evaluated whether spa therapy modify plasma levels of nac tablets) and/or analgesics (500 mg acetaminophen leptin and adiponectin in patients with OA treated with a tablets), which were to be consumed liberally and noted cycle of a combination of daily locally applied mud-packs daily in a diary. Furthermore, we advised patients not to and bicarbonate–sulphate mineral bath water.
utilize corticosteroids or hyaluronic acid infiltrations.
Leptin and adiponectin plasma levels were assessed at baseline time and after 2 weeks, upon completion of thespa treatment period.
As a part of a recently published randomized single-blind Baseline blood samples (6 ml) were drawn from an controlled clinical trial [on the efficacy of spa therapy antecubital vein, in the supine position in the morning after in knee OA, we included thirty patients of both sexes with an overnight fast, and again after 2 weeks under the same knee OA fulfilling the ACR criteria [Radiological conditions. The blood was immediately centrifuged and staging was carried out using the Kellgren method [ patients with a radiological score of I–III were included in Plasma leptin levels were determined by enzyme-linked immunosorbent assay method using ready kits of Quanti- Exclusion criteria for the study were previously pre- kineÒ human Leptin Immunoassay (R&D Systems Europe, sented [In addition, for the purposes of this study, we excluded patients with history of diabetes mellitus, instable Sensitivity of undiluted samples was 7.8 pg/ml. Inter- weight history, those treated with medications known to and intra-assay coefficients of variation were 5.4 and 3.3%, affect body weight and heavy smokers.
All selected patients resided in the area near the spa at Plasma adiponectin levels were detected by enzyme- Rapolano Terme (Siena, Italy) and continued to live at linked immunosorbent assay method using ready kits of home and go about their normal daily routines.
QuantikineÒ human Adiponectin Immunoassay (R&DSystems) Sensitivity of undiluted samples was 0.246 ng/ml. Inter- and intra-assay coefficients of variationwere 6.9 and 4.7, respectively.
The patients were treated daily at the spa centre at Rapo-lano Terme with a combination of mud-packs applied on both knees for 20 min at an initial temperature of 45°C andwith bicarbonate–sulphate mineral bath water at 38°C for All the patients were evaluated on a 0–100 mm visualanalogue scale (VAS) with 0 for the absence of pain, as Table 1 Baseline characteristics in 30 patients with knee OA treated well as the Lequesne Index of severity of knee OA [ Acetaminophen consumption was calculated by the number of daily tablet intake. The NSAID consumptionscore was expressed as mg equivalence of diclofenac, according to a previously validated and published scale [ The clinical assessments were performed before and at the end of the period of spa therapy.
All the parameters of this study are expressed as mean and standard deviation (SD). For all tests, a p value less than F female, M male, BMI body mass index, OA osteoarthritis 0.05 was considered as statistically significant.
The difference in clinical parameters (VAS, Lequesne Table 2 Assessment and biochemical parameters before and after Index, NSAID and analgesic consumption) and the plasma leptin and adiponectin levels before and after spa therapy was assessed using the Student’s paired t-test.
Correlation analysis was performed using Pearson’s correlation coefficient or Spearman’s rank correlation For all analyses, SAS System v. 9.0 statistical software VAS visual analogue scale for spontaneous pain * P \ 0.05; ** P \ 0.001 versus basal time The baseline recorded variables in this series of 30 patients a NSAIDs non-steroidal anti-inflammatory drugs (daily consumption with OA treated with spa therapy are shown in Table .
At basal time, plasma leptin levels were significantly b Acetaminophen (daily consumption as tablets) correlated with BMI (r = 0.41, P \ 0.001) and gender(r = 0.61, P \ 0.001). However, no significant correlation adiponectin in patients with OA treated with mud-packs was found between serum leptin and patient age at the time and balneotherapy. Our results demonstrated only a slight, of the study (r = 0.04, P = NS), duration of the disease but not significant, increase in plasma leptin after 2 weeks (r = 0.07, P = NS), radiographic severity of knee OA of spa therapy with no evident correlation with parameters according to Kellgren and Lawrence’s score (r = 0.18, P = NS), VAS score (r = 0.20, P = NS) or Lequesne Leptin induces the expression of growth factors such as IGF-1 and TGF-b1, stimulates proteoglycan and collagen There was no correlation between the plasma adipo- synthesis, and increases the stimulatory effects of pro- nectin level and BMI (r = -0.30, P = 0.06), gender inflammatory cytokines on nitric oxide (NO) production in (r = 0.04, P = 0.82), age (r = 0.20, P = 0.22), duration chondrocytes []. Leptin may also trigger cartilage of the disease (r = 0.05, P = NS), radiographic severity of destruction by increasing matrix metalloproteases (MMP)-9 knee OA (r = 0.21, P = NS) or VAS score (r = 0.19, and MMP-13 ]. The present study shows for first time P = NS). However, a significant correlation of plasma that there is no significant change in leptin concentration following a cycle of spa therapy. However, leptin concen- tration, measured after the treatment, did not correlate with After spa treatment (2 weeks), we observed a statisti- the clinical parameters (VAS, Lequesne Index).
cally significant reduction (P \ 0.001), in spontaneous In our study, spa therapy produced a significant decrease pain and in the Lequesne index score for gonarthrosis (P \ 0.05) in serum adiponectin levels in patients with (Table ). This symptomatic effect was confirmed by the significant reduction in NSAID consumption.
There is some evidence that adiponectin in skeletal At the end of the cycle of mud-bath therapy, serum joints may have pro-inflammatory effects and may be leptin levels showed a slight, but not significant increase, while we found a significant decrease (P \ 0.05) in serum Lago et al. recently demonstrated that adiponectin adiponectin levels (Table ). However, leptin and adipo- induced the expression of type-2 nitric oxide synthase nectin concentrations after the treatment were not corre- (NOS) and stimulated IL-6, MMP-3, MMP-9 and mono- lated with other clinical parameters (VAS and Lequesne cyte chemoattractant protein-1 (MCP-1) release In index score) described in Table (data not shown).
view of these recent findings, the decrease in adiponectin Finally, it should be noted that no changes whatsoever after spa therapy demonstrated in our study may play a were made in terms of diet or physical activity levels, and no modifications in body weight were observed.
However, adiponectin presents metabolic properties as it increases insulin sensitivity, improves glucose metabolismand decreases plasma triglycerides, and has antiatheroge- netic actions []. Furthermore, plasma levels ofadiponectin are low in obese individuals and in those with This preliminary report was designed to investigate the cardiovascular disease [, , ]; obesity and cardiomet- possible effect of spa therapy on plasma levels of leptin and abolic syndrome are frequently associated with OA [ Thus, it is important to study the effects of spa therapy on 12. Imbeault P, De´pault I, Haman F (2009) Cold exposure increases certain cardiovascular risk factors.
adiponectin levels in men. Metabolism 58:552–559 13. Trayhurn P, Duncan JS, Hoggard N, Rayner DV (1998) Regu- Finally, it remains to be clarified which of the mecha- lation of leptin production: a dominant role for the sympathetic nisms of action of spa therapy –may have deter- nervous system? Proc Nutr Soc 57:413–419 mined the changes in plasma levels of leptin and, above all, 14. Miell JP, Englaro P, Blum WF (1996) Dexamethasone induces an adiponectin that we observed. One possible hypothesis is acute and sustained rise in circulating leptin levels in normalhuman subjects. Horm Metab Res 28:704–707 that local application of heat, by causing an increase in the 15. Zumback MS, Boehme MW, Wahl P, Stremmel W, Zeigler R, internal temperature of the knee, may determine a change Nawroth PP (1997) Tumour necrosis factor increases serum in serum adipocytokine levels, probably due to localized leptin levels in humans. J Clin Endocrinol Metab 82:4080–4082 production thereof Nevertheless, our study and other 16. Delaigle AM, Jonas JC, Bauche IB, Cornu O, Brichard SM (2004) Induction of adiponectin in skeletal muscle by inflam- currently available data do not allow for specific identifi- matory cytokines: in vivo and in vitro studies. Endocrinology cation of any specific mechanism of action.
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