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Bone remodelling in osteoarthrosic subjects undergoing a physical exercise program
Clinica Chimica Acta 325 (2002) 97 – 104 www.elsevier.com/locate/clinchim
Bone remodelling in osteoarthrosic subjects undergoing a physical exercise program Simona Bellometti a,*, Francantonio Berte` b, Plinio Richelmi c, Tommaso Tassoni d, Lauro Galzigna e a
P.d’Abano Scientific Research Center, L.go Marconi 8, Abano T. (PD), Italy b Department of Pharmacology, University of Pavia, Pavia, Italy c Department of Toxicology, Insubria University, Varese, Italy d Department of Biology, University of Padua, Padua, Italy e Department of Diagnostic, University of Padua, Padua, Italy
Received 19 March 2002; received in revised form 4 July 2002; accepted 23 July 2002
Abstract Background: The connection between osteoarthritis (OA) and osteoporosis (OP) has attracted considerable attention but reports about bone mass density (BMD) in OA are often contradictory. Some data indicate that BMD is higher in OA patients than in healthy subjects, whereas other studies showed no differences. It has been observed that mud pack treatment (MPT) induces a decrease in cytokines with bone-resorbing effects. The aim of this study is to evaluate the response of bone and connective tissue to physical exercise and thermal treatment. Methods: Forty osteoarthrosic patients were divided in group A (physical exercise and MPT), and group B (physical exercise alone). Blood and urine samples were collected before and after the treatments to assay blood metabolic markers and urinary hydroxyproline. Results: In group A, some parameters show statistically significant differences before and after mud pack treatment (MPT). In group B, all parameters present no statistical significant changes before and after the physical exercise program. Conclusions: Few studies established the importance of exercise to maintain normal cartilage and bone metabolism. In group A of the present study, an influence on all the parameters of bone metabolism is evident. It is possible that physical exercise only if combined with MPT stimulates physiologic bone metabolism and favors skeletal health. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Osteoarthritis; Mud pack treatment; Exercise; Cartilage; Bone; Metabolic markers
1. Introduction Although osteoarthritis (OA) is primarily a cartilage disease, variable roles of synovium, muscle, ligaments and bone are considered [1]. * Corresponding author. Tel.: +39-49-8669877; fax: +39-498668845. E-mail address: [email protected] (S. Bellometti).
There is now good evidence that the initiation and progression of OA are processes with different associations and risk factors [2]. Radin et al. [3] and Radin and Rose [4] suggested an important role for subchondral bone changes in the early development of degenerative joint diseases. Of particular relevance is the suggestion that progression of knee OA is positively associated with osteoporosis (OP), whereas the disease initiation has long been known to be negatively
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associated with OP [5]. The connection between OA and OP has attracted considerable attention [6,7] and reports about bone mineral density (BMD) in OA are contradictory: there are data indicating that BMD of the lumbar spine and/or hip is higher in patients with OA than in healthy subjects [8,9], whereas studies of patients with knee OA showed no difference in BMD at some bone sites [10]. In contrast, recent data demonstrated that BMD in subchondral regions of knee joints in white women was significantly lower than that of normal joints [11]. Other studies demonstrate that patients with hip OA tend to have higher BMD measured by dual energy Xray absorptiometry (DEXA), while they have increased bone resorption but similar levels of bone formation compared to controls [12]. Local osteopenia may be the result of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFa), produced by the inflammatory process [13]. It is well known that the actions of estrogen on bone are modulated by various boneresorbing cytokines [14], and in menopause, an increase in cytokines production is observed related with bone resorption [15] and reversed by estrogen treatment [16]. Other hypotheses are related with the possibility that abnormal osteoblasts from subchondral bone in human OA occur due to an increased activity of growth factors and proteases present locally [17]. It is postulated that two major systems are involved in this process, that is, the insulin-like growth factor I (IGF-1) and the plasminogen activator system. It has been recently observed that thermal mud pack treatment (MPT) applied to osteoarthrosic patients is able to induce a significant decrease in IL-1 and TNFa [18]. It seems that MPT acts as a protective factor on cartilage and bone, suppressing prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) actions, and in particular, osteoclast recruitment and bone resorption [19,20]. We have chosen to evaluate the general response of bone and connective tissue to both physical exercise and thermal treatment and to evaluate the effect of the combined treatment with MPT and a physical exercise program. The aim of the present study was to evaluate the behavior of bone cells of osteoarthritic and normal
individuals, by examining specific biomarkers of bone metabolism such as urinary hydroxyproline, serum parathyroid hormone, osteocalcin, alkaline phosphatase and bone-specific alkaline phosphatase.
2. Materials and methods Forty female patients, aged 45– 65 years (mean F S.D. = 50.7 F 4.3), with osteoarthrosis, were enrolled for the study. The subjects were recruited in a group of osteoarthrosic patients following a 4-month program of physical activity for aged people. Enrolled participants satisfied the American College of Rheumatology classification criteria for knee and hip OA. The patients were recruited after the Ethical Committee of our Research Center approved the study design. None of the subjects had pathologies other than OA, nor took drugs known to affect calcium metabolism during the trial. All patients were chronic and no case of acute condition was considered. In accordance with the second declaration of Helsinki, all participants provided their informed consent. Patients were divided in two groups on the basis of the treatment: group A, consisting of 20 women following a 4-month physical activity program, underwent a 12-day cycle of mature mud pack treatment in a thermal establishment of the Euganean Basin, according to the standard protocol during the third month; group B, consisting of 20 women, followed only the program of physical activity (control group). MPT is a natural anti-inflammatory treatment consisting of a full body pack at 38 jC with natural clay mixed with bromine – iodine natural mineral thermal water after a process of maturation of at least 2 months at 70 jC. The maturation is due to the development of a typical thermophilic microflora mainly represented by blue-green algae (Cyanophyceae) and diatoms. In the scientific literature, it is reported that these microorganisms produce a sulfolipid compound with antiinflammatory properties [21] which is present in the thermal mud too [22]. Blood and urine samples were collected at baseline and at the end of the physical activity program (fourth month) for the assays of bone GLA protein (BGP), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BSAP), parathyroid hormone (PTH), and urinary hydroxyproline.
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Table 1 Serum levels of BGP, ALP, BSAP, PTH, hydroxyproline (HP) in group A, before and after MPT and in group B before and after physical exercise program (baseline vs. fourth month) Group A (mean F S.D.)
BGP (ng/ml) ALP (mU/ml) BSAP (U/l) PTH (pg/ml) HP (mg/l)
Before
After
p-Value
6.01 F 3.06 117.73 F 23.05 51.60 F 16.54 42.21 F 19.49 2.57 F 1.25
16.29 F 4.88 126.93 F 25.19 59.27 F 14.45 27.63 F 9.19 2.19 F 1.13
p < 0.01 p < 0.05 p>0.05 p < 0.01 p>0.05
The collected blood samples were promptly centrifuged and the serum was frozen at 20 jC until the assay, done in the same run for all the samples, following the test producers’ instructions. The amount of BGP in serum was measured by the human osteocalcin immunoradiometric (IRMA) assay (Immunotopics, San Clemente, CA), a two-site immunoradiometric assay for the measurement of intact osteocalcin and its large N-terminal midregion fragment in serum or plasma. The sensitivity of the assay is 0.05 ng/ml and its intra- and inter-assay coefficients of variation are 5.2% and 6.7%, respectively. Total alkaline phosphatase (AP) was assayed in serum by a standard laboratory automatic analyzer (Abbott Spectrum Systems). Bone-specific alkaline phosphatase was measured in serum by an enzyme-linked immunoassay (ELISA)
Absolute difference of means 10.28 F 2.69 9.20 F 16.08 14.58 F 15.64
Group B (mean F S.D.) Before
After
p-Value
8.12 F 4.20 124.13 F 38.59 61.60 F 19.85 27.16 F 7.60 2.58 F 1.03
9.79 F 3.74 126.67 F 18.95 53.80 F 15.25 28.78 F 12.90 2.84 F 1.48
p>0.05 p>0.05 p>0.05 p>0.05 p>0.05
(Metra Biosystem, Mountain View, CA) in a microtiter reader format which utilizes a monoclonal antibody against the bone alkaline phosphatase (BAP) isotype and has low crossreactivity with the liver (5%) and negligible activity with the intestinal and placental isoforms. The limit of detection is 0.7 U/l while intra- and inter-assay coefficients of variation are 3.5% and 7.9%, respectively. PTH was measured in serum by a two-site immunoradiometric assay for the measurement of the biologically intact 84-amino-acid chain of PTH (Allegro Intact PTH Immunoassay, Nichols Institute, San Juan Capistrano, CA). The sensitivity of the assay is 1.0 pg/ ml and its intra- and inter-assay coefficients of variation are 3.4% and 6.1%, respectively. Urinary hydroxyproline was determined on 2-h urine samples (Test of Nordin) by a spectrophotomet-
Fig. 1. Group A Alp serum levels before and after MPT.
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Fig. 2. Group A BGP serum levels before and after MPT.
ric method (Hypronosticon, Organon Teknika, Roma, Italia). The statistical analysis of the results was performed on the differences between group means before and after MPT in group A and before and after the physical exercise program in group B, tested for significance by the paired Student’s t-test. Comparison between variations within the group and correlation were calculated together with linear correlation and linear regression.
3. Results Table 1 shows the results, expressed as mean F S.D., in groups A and B with group A mean values of BGP and PTH showing highly significant statistic differences ( p < 0.01) before and after MPT. Also alkaline phosphatase shows a statistically significant difference ( p < 0.05). Table 1 and Figs. 1 – 3 show variations of BGP, alkaline phosphatase and PTH concentrations. Since
Fig. 3. Group A PTH serum levels before and after MPT.
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PTH plays a critical role in the maintenance of calcium homeostasis, in both blood and extracellular fluids [23,24], it would be interesting to investigate whether in response to the decrease of PTH level, an increment in serum calcium is observable. Bone-specific alkaline phosphatase and hydroxyproline percentage variations are not statistically significant ( p>0.05). It is important to recall that hydroxyproline is not a specific marker of bone resorption since up to 50% of urinary excretion emanates from non-osseous tissues and about 90% of hydroxyproline is metabolized in the liver [25,26]. In group B, all the markers present percentage variations of no statistical significance. The linear correlation between BGP and PTH is statistically significant (r = 0.590, p < 0.05). Regression analysis, with BGP as a dependent variable and PTH as an independent variable, shows a low value for R2 (0.348). We cannot explain the inverse correlation between BGP and PTH probably because the number of patients of both groups is too low [27].
4. Discussion Osteoarthrosis is the most common chronic condition affecting elderly people [28], whereas osteoporosis is the most prevalent disorder associated with a decreasing bone mass [29]. OA is always characterized by both degeneration of articular cartilage and simultaneous proliferation of new bone [30,31]. OP is characterized by an increase in bone brittleness and incidence of fractures [32]. OA and OP coexist quite frequently in the elderly and are associated with considerable morbidity and mortality [33] being the major cause of physical limitation in the elderly and accounting for as much disability and impairment in lower extremity function as any other disease [34]. OA and OP provoke bone and joint pain and induce disuse of the osteoarticular system which is detrimental to bone metabolism [35] and could increase bone resorption and fracture risk in aged people [36,37]. The disuse can damage articular cartilage too since even a temporarily decreased loading and motion of joints render the tissue more vulnerable and may provoke permanent loss of articular cartilage [38]. Nevertheless, since in group B no
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parameter presents statistically significant changes, it is possible that 4 months of physical activity, 2 h weekly, is too weak a stimulus for bone metabolism. Few studies have demonstrated the limitations in personal and social relations of OP and OA patients [39,40] and have established the importance of an adequate program of physical exercise to maintain normal cartilage, stimulate bone formation, avoid osteoporotic fractures and increase quality of life [41,42]. In our study, we have examined 40 women showing an increase in all the parameters related with the osteoblastic function such as serum BGP (a protein exclusively produced by osteoblasts and with serum levels correlated with bone formation) [43] and ALP (an enzyme mostly synthesized by osteoblasts and considered as a marker of bone formation) [44]. This confirms the influence of an adequate physical exercise on bone metabolism, as demonstrated by a controlled study involving elderly people [37]. In our study, an increase in the parameters of bone formation together with a reduction of serum PTH and urinary levels of hydroxyproline are also evident. Group A presents larger increases in anabolic parameters and reduction of bone resorption than group B, indicating that physical exercise and MPT are able to potentiate each other. BGP, PTH and alkaline phosphatase show significant modifications after the treatments and it is interesting that all the markers except BSALP are affected. It would be very important to know the length of the reduction period and if it is followed by an increase of the PTH level. In fact, this would be similar to the intermittent PTH administration, found to stimulate bone formation in animals, increasing trabecular bone density, bone strength and reducing fracture rate. On the basis of these results, PTH is expected to be effective in contrasting osteoporosis in those with suppressed bone remodelling. [45]. It has been recently demonstrated that several cytokines are implicated in osteoporosis of postmenopausal women [46]. The cytokines appear to stimulate osteoclasts precursor proliferation and activate mature osteoclast formation directly and possibly indirectly via osteoblasts [47]. TNFa and IL-1 may affect the cell – cell adhesion of osteoclasts which cover the bone surface and, in turn,
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facilitate the direct adhesion of osteoclasts on the calcified bone matrix surface. This would be a possible way to develop a subchondral bone resorption in specific phases of OA. In particular, IL-1 and TNFa induce bone resorption by stimulating the production of osteoclast-like multinucleated cells and by increasing the bone-resorbing activity of formed osteoclasts [48]. Since it has been demonstrated that MPT is able to induce a significant decrease in serum levels of IL-1 and TNFa in OA patients [49,50], it is possible to hypothesize its influence on bone metabolism, even by an indirect mechanism. Because of the accelerated bone loss seen in patients in the perimenopausal state, in those with prolonged bed rest and in those receiving corticosteroid for joint diseases [51], the role of regular physical activity in maintaining general health and avoiding the development of OA and OP can be recommended particularly if associated with a natural treatment such as MPT. The cyclooxygenase and the lipooxygenase pathways of arachidonic acid metabolism have been shown to lead to osteoclastic resorption [52] and since a previous paper demonstrated a decrease in PGE2 and LTB4 serum levels in patients undergoing MPT [19], it is possible to hypothesize an influence of the latter on skeletal tissue too. In fact, prostaglandin stimulates bone resorption by increasing the number and activity of osteoclasts and PGE2 is their most potent agonist [53]. A reduction of PGE2 production may be a strategy to modulate the mechanisms of bone loss and above all periarticular bone loss in inflammatory arthritis [54]. The stimulation of bone formation by impact loading can be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs) [55]. It is evident how important it is to maintain skeletal and bone health by ensuring physical exercise, avoid immobilization and reduce NSAIDs consumption, very often prescribed for the treatment of OA symptoms in aged people [55]. Although constant and adequate physical activity is certainly important, we suggest that only the combination of MPT and physical exercise is effective in modifying the pathological markers of OA, decreasing pain and regulating the main proinflammatory cytokines. MPT might also ensure a higher compliance to the physical exercise program and lower NSAIDs
consumption, besides exerting a direct beneficial influence on some biochemical markers of bone metabolism.
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Bone remodelling in osteoarthrosic subjects undergoing a physical exercise program Simona Bellometti a,*, Francantonio Berte` b, Plinio Richelmi c, Tommaso Tassoni d, Lauro Galzigna e a
P.d’Abano Scientific Research Center, L.go Marconi 8, Abano T. (PD), Italy b Department of Pharmacology, University of Pavia, Pavia, Italy c Department of Toxicology, Insubria University, Varese, Italy d Department of Biology, University of Padua, Padua, Italy e Department of Diagnostic, University of Padua, Padua, Italy
Received 19 March 2002; received in revised form 4 July 2002; accepted 23 July 2002
Abstract Background: The connection between osteoarthritis (OA) and osteoporosis (OP) has attracted considerable attention but reports about bone mass density (BMD) in OA are often contradictory. Some data indicate that BMD is higher in OA patients than in healthy subjects, whereas other studies showed no differences. It has been observed that mud pack treatment (MPT) induces a decrease in cytokines with bone-resorbing effects. The aim of this study is to evaluate the response of bone and connective tissue to physical exercise and thermal treatment. Methods: Forty osteoarthrosic patients were divided in group A (physical exercise and MPT), and group B (physical exercise alone). Blood and urine samples were collected before and after the treatments to assay blood metabolic markers and urinary hydroxyproline. Results: In group A, some parameters show statistically significant differences before and after mud pack treatment (MPT). In group B, all parameters present no statistical significant changes before and after the physical exercise program. Conclusions: Few studies established the importance of exercise to maintain normal cartilage and bone metabolism. In group A of the present study, an influence on all the parameters of bone metabolism is evident. It is possible that physical exercise only if combined with MPT stimulates physiologic bone metabolism and favors skeletal health. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Osteoarthritis; Mud pack treatment; Exercise; Cartilage; Bone; Metabolic markers
1. Introduction Although osteoarthritis (OA) is primarily a cartilage disease, variable roles of synovium, muscle, ligaments and bone are considered [1]. * Corresponding author. Tel.: +39-49-8669877; fax: +39-498668845. E-mail address: [email protected] (S. Bellometti).
There is now good evidence that the initiation and progression of OA are processes with different associations and risk factors [2]. Radin et al. [3] and Radin and Rose [4] suggested an important role for subchondral bone changes in the early development of degenerative joint diseases. Of particular relevance is the suggestion that progression of knee OA is positively associated with osteoporosis (OP), whereas the disease initiation has long been known to be negatively
0009-8981/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 9 - 8 9 8 1 ( 0 2 ) 0 0 2 8 6 - 3
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S. Bellometti et al. / Clinica Chimica Acta 325 (2002) 97–104
associated with OP [5]. The connection between OA and OP has attracted considerable attention [6,7] and reports about bone mineral density (BMD) in OA are contradictory: there are data indicating that BMD of the lumbar spine and/or hip is higher in patients with OA than in healthy subjects [8,9], whereas studies of patients with knee OA showed no difference in BMD at some bone sites [10]. In contrast, recent data demonstrated that BMD in subchondral regions of knee joints in white women was significantly lower than that of normal joints [11]. Other studies demonstrate that patients with hip OA tend to have higher BMD measured by dual energy Xray absorptiometry (DEXA), while they have increased bone resorption but similar levels of bone formation compared to controls [12]. Local osteopenia may be the result of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFa), produced by the inflammatory process [13]. It is well known that the actions of estrogen on bone are modulated by various boneresorbing cytokines [14], and in menopause, an increase in cytokines production is observed related with bone resorption [15] and reversed by estrogen treatment [16]. Other hypotheses are related with the possibility that abnormal osteoblasts from subchondral bone in human OA occur due to an increased activity of growth factors and proteases present locally [17]. It is postulated that two major systems are involved in this process, that is, the insulin-like growth factor I (IGF-1) and the plasminogen activator system. It has been recently observed that thermal mud pack treatment (MPT) applied to osteoarthrosic patients is able to induce a significant decrease in IL-1 and TNFa [18]. It seems that MPT acts as a protective factor on cartilage and bone, suppressing prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) actions, and in particular, osteoclast recruitment and bone resorption [19,20]. We have chosen to evaluate the general response of bone and connective tissue to both physical exercise and thermal treatment and to evaluate the effect of the combined treatment with MPT and a physical exercise program. The aim of the present study was to evaluate the behavior of bone cells of osteoarthritic and normal
individuals, by examining specific biomarkers of bone metabolism such as urinary hydroxyproline, serum parathyroid hormone, osteocalcin, alkaline phosphatase and bone-specific alkaline phosphatase.
2. Materials and methods Forty female patients, aged 45– 65 years (mean F S.D. = 50.7 F 4.3), with osteoarthrosis, were enrolled for the study. The subjects were recruited in a group of osteoarthrosic patients following a 4-month program of physical activity for aged people. Enrolled participants satisfied the American College of Rheumatology classification criteria for knee and hip OA. The patients were recruited after the Ethical Committee of our Research Center approved the study design. None of the subjects had pathologies other than OA, nor took drugs known to affect calcium metabolism during the trial. All patients were chronic and no case of acute condition was considered. In accordance with the second declaration of Helsinki, all participants provided their informed consent. Patients were divided in two groups on the basis of the treatment: group A, consisting of 20 women following a 4-month physical activity program, underwent a 12-day cycle of mature mud pack treatment in a thermal establishment of the Euganean Basin, according to the standard protocol during the third month; group B, consisting of 20 women, followed only the program of physical activity (control group). MPT is a natural anti-inflammatory treatment consisting of a full body pack at 38 jC with natural clay mixed with bromine – iodine natural mineral thermal water after a process of maturation of at least 2 months at 70 jC. The maturation is due to the development of a typical thermophilic microflora mainly represented by blue-green algae (Cyanophyceae) and diatoms. In the scientific literature, it is reported that these microorganisms produce a sulfolipid compound with antiinflammatory properties [21] which is present in the thermal mud too [22]. Blood and urine samples were collected at baseline and at the end of the physical activity program (fourth month) for the assays of bone GLA protein (BGP), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BSAP), parathyroid hormone (PTH), and urinary hydroxyproline.
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Table 1 Serum levels of BGP, ALP, BSAP, PTH, hydroxyproline (HP) in group A, before and after MPT and in group B before and after physical exercise program (baseline vs. fourth month) Group A (mean F S.D.)
BGP (ng/ml) ALP (mU/ml) BSAP (U/l) PTH (pg/ml) HP (mg/l)
Before
After
p-Value
6.01 F 3.06 117.73 F 23.05 51.60 F 16.54 42.21 F 19.49 2.57 F 1.25
16.29 F 4.88 126.93 F 25.19 59.27 F 14.45 27.63 F 9.19 2.19 F 1.13
p < 0.01 p < 0.05 p>0.05 p < 0.01 p>0.05
The collected blood samples were promptly centrifuged and the serum was frozen at 20 jC until the assay, done in the same run for all the samples, following the test producers’ instructions. The amount of BGP in serum was measured by the human osteocalcin immunoradiometric (IRMA) assay (Immunotopics, San Clemente, CA), a two-site immunoradiometric assay for the measurement of intact osteocalcin and its large N-terminal midregion fragment in serum or plasma. The sensitivity of the assay is 0.05 ng/ml and its intra- and inter-assay coefficients of variation are 5.2% and 6.7%, respectively. Total alkaline phosphatase (AP) was assayed in serum by a standard laboratory automatic analyzer (Abbott Spectrum Systems). Bone-specific alkaline phosphatase was measured in serum by an enzyme-linked immunoassay (ELISA)
Absolute difference of means 10.28 F 2.69 9.20 F 16.08 14.58 F 15.64
Group B (mean F S.D.) Before
After
p-Value
8.12 F 4.20 124.13 F 38.59 61.60 F 19.85 27.16 F 7.60 2.58 F 1.03
9.79 F 3.74 126.67 F 18.95 53.80 F 15.25 28.78 F 12.90 2.84 F 1.48
p>0.05 p>0.05 p>0.05 p>0.05 p>0.05
(Metra Biosystem, Mountain View, CA) in a microtiter reader format which utilizes a monoclonal antibody against the bone alkaline phosphatase (BAP) isotype and has low crossreactivity with the liver (5%) and negligible activity with the intestinal and placental isoforms. The limit of detection is 0.7 U/l while intra- and inter-assay coefficients of variation are 3.5% and 7.9%, respectively. PTH was measured in serum by a two-site immunoradiometric assay for the measurement of the biologically intact 84-amino-acid chain of PTH (Allegro Intact PTH Immunoassay, Nichols Institute, San Juan Capistrano, CA). The sensitivity of the assay is 1.0 pg/ ml and its intra- and inter-assay coefficients of variation are 3.4% and 6.1%, respectively. Urinary hydroxyproline was determined on 2-h urine samples (Test of Nordin) by a spectrophotomet-
Fig. 1. Group A Alp serum levels before and after MPT.
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Fig. 2. Group A BGP serum levels before and after MPT.
ric method (Hypronosticon, Organon Teknika, Roma, Italia). The statistical analysis of the results was performed on the differences between group means before and after MPT in group A and before and after the physical exercise program in group B, tested for significance by the paired Student’s t-test. Comparison between variations within the group and correlation were calculated together with linear correlation and linear regression.
3. Results Table 1 shows the results, expressed as mean F S.D., in groups A and B with group A mean values of BGP and PTH showing highly significant statistic differences ( p < 0.01) before and after MPT. Also alkaline phosphatase shows a statistically significant difference ( p < 0.05). Table 1 and Figs. 1 – 3 show variations of BGP, alkaline phosphatase and PTH concentrations. Since
Fig. 3. Group A PTH serum levels before and after MPT.
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PTH plays a critical role in the maintenance of calcium homeostasis, in both blood and extracellular fluids [23,24], it would be interesting to investigate whether in response to the decrease of PTH level, an increment in serum calcium is observable. Bone-specific alkaline phosphatase and hydroxyproline percentage variations are not statistically significant ( p>0.05). It is important to recall that hydroxyproline is not a specific marker of bone resorption since up to 50% of urinary excretion emanates from non-osseous tissues and about 90% of hydroxyproline is metabolized in the liver [25,26]. In group B, all the markers present percentage variations of no statistical significance. The linear correlation between BGP and PTH is statistically significant (r = 0.590, p < 0.05). Regression analysis, with BGP as a dependent variable and PTH as an independent variable, shows a low value for R2 (0.348). We cannot explain the inverse correlation between BGP and PTH probably because the number of patients of both groups is too low [27].
4. Discussion Osteoarthrosis is the most common chronic condition affecting elderly people [28], whereas osteoporosis is the most prevalent disorder associated with a decreasing bone mass [29]. OA is always characterized by both degeneration of articular cartilage and simultaneous proliferation of new bone [30,31]. OP is characterized by an increase in bone brittleness and incidence of fractures [32]. OA and OP coexist quite frequently in the elderly and are associated with considerable morbidity and mortality [33] being the major cause of physical limitation in the elderly and accounting for as much disability and impairment in lower extremity function as any other disease [34]. OA and OP provoke bone and joint pain and induce disuse of the osteoarticular system which is detrimental to bone metabolism [35] and could increase bone resorption and fracture risk in aged people [36,37]. The disuse can damage articular cartilage too since even a temporarily decreased loading and motion of joints render the tissue more vulnerable and may provoke permanent loss of articular cartilage [38]. Nevertheless, since in group B no
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parameter presents statistically significant changes, it is possible that 4 months of physical activity, 2 h weekly, is too weak a stimulus for bone metabolism. Few studies have demonstrated the limitations in personal and social relations of OP and OA patients [39,40] and have established the importance of an adequate program of physical exercise to maintain normal cartilage, stimulate bone formation, avoid osteoporotic fractures and increase quality of life [41,42]. In our study, we have examined 40 women showing an increase in all the parameters related with the osteoblastic function such as serum BGP (a protein exclusively produced by osteoblasts and with serum levels correlated with bone formation) [43] and ALP (an enzyme mostly synthesized by osteoblasts and considered as a marker of bone formation) [44]. This confirms the influence of an adequate physical exercise on bone metabolism, as demonstrated by a controlled study involving elderly people [37]. In our study, an increase in the parameters of bone formation together with a reduction of serum PTH and urinary levels of hydroxyproline are also evident. Group A presents larger increases in anabolic parameters and reduction of bone resorption than group B, indicating that physical exercise and MPT are able to potentiate each other. BGP, PTH and alkaline phosphatase show significant modifications after the treatments and it is interesting that all the markers except BSALP are affected. It would be very important to know the length of the reduction period and if it is followed by an increase of the PTH level. In fact, this would be similar to the intermittent PTH administration, found to stimulate bone formation in animals, increasing trabecular bone density, bone strength and reducing fracture rate. On the basis of these results, PTH is expected to be effective in contrasting osteoporosis in those with suppressed bone remodelling. [45]. It has been recently demonstrated that several cytokines are implicated in osteoporosis of postmenopausal women [46]. The cytokines appear to stimulate osteoclasts precursor proliferation and activate mature osteoclast formation directly and possibly indirectly via osteoblasts [47]. TNFa and IL-1 may affect the cell – cell adhesion of osteoclasts which cover the bone surface and, in turn,
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facilitate the direct adhesion of osteoclasts on the calcified bone matrix surface. This would be a possible way to develop a subchondral bone resorption in specific phases of OA. In particular, IL-1 and TNFa induce bone resorption by stimulating the production of osteoclast-like multinucleated cells and by increasing the bone-resorbing activity of formed osteoclasts [48]. Since it has been demonstrated that MPT is able to induce a significant decrease in serum levels of IL-1 and TNFa in OA patients [49,50], it is possible to hypothesize its influence on bone metabolism, even by an indirect mechanism. Because of the accelerated bone loss seen in patients in the perimenopausal state, in those with prolonged bed rest and in those receiving corticosteroid for joint diseases [51], the role of regular physical activity in maintaining general health and avoiding the development of OA and OP can be recommended particularly if associated with a natural treatment such as MPT. The cyclooxygenase and the lipooxygenase pathways of arachidonic acid metabolism have been shown to lead to osteoclastic resorption [52] and since a previous paper demonstrated a decrease in PGE2 and LTB4 serum levels in patients undergoing MPT [19], it is possible to hypothesize an influence of the latter on skeletal tissue too. In fact, prostaglandin stimulates bone resorption by increasing the number and activity of osteoclasts and PGE2 is their most potent agonist [53]. A reduction of PGE2 production may be a strategy to modulate the mechanisms of bone loss and above all periarticular bone loss in inflammatory arthritis [54]. The stimulation of bone formation by impact loading can be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs) [55]. It is evident how important it is to maintain skeletal and bone health by ensuring physical exercise, avoid immobilization and reduce NSAIDs consumption, very often prescribed for the treatment of OA symptoms in aged people [55]. Although constant and adequate physical activity is certainly important, we suggest that only the combination of MPT and physical exercise is effective in modifying the pathological markers of OA, decreasing pain and regulating the main proinflammatory cytokines. MPT might also ensure a higher compliance to the physical exercise program and lower NSAIDs
consumption, besides exerting a direct beneficial influence on some biochemical markers of bone metabolism.
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