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The clinical impact of physical-chemical characteristics of different hyaluronic acids as a treatment for osteoarthritis
International Journal of Biological Macromolecules 38 (2006) 300–301
Letter to the Editor
The clinical impact of physical-chemical characteristics of different hyaluronic acids as a treatment for osteoarthritis Synovial fluid is formed by plasma transudation from the fenestrated capilliaries of the synovial membrane. It contains only small solute molecules, including hyaluronic acid and certain glycoproteins secreted by the synovial cells. The main component of synovial fluid is hyaluronic acid, providing synovial fluid with most of its properties. When up against weak shear forces, such as the knee when walking, its behaviour is viscous. With rapid movements, such as running, it is elastic and thereby reduces the force applied to the cartilage, protecting it from overload peaks. This brisk change from viscous to elastic is typical of hyaluronic acid solutions (it is much more progressive in other polymer solutions). The reduction in concentration and molecular weight of hyaluronic acid in some arthropathies rapidly alters the properties of synovial fluid. Also present in an anionic complex on the cartilage surface, is a small amount of proteins (1–2%), which intervene likewise in lubrication. The characteristics of the cartilage help the sliding action, since it is deformed under pressure which tends to stretch the articular load interline, and being porous, water and solutes migrate towards neighbouring areas of maximum load and transudate to the surface in front of and behind this load area, aiding movement. In summary, glycoproteins play an important role in lubrication at movement start and during slow movements, including load-free. During quick movements, the viscosity of the synovial fluid, dependent on hyaluronic acid, leads to the lowest friction coefficients. Based on the bibliography available, it seems evident that we can consider intra-articular injections of hyaluronic acid an effective treatment for osteoarthritis, in line with that described by authors such as Dougados et al. [1], and multicentre studies such as that published by Adams et al. [2]. In more recent articles, Jubb et al. [3] reviews the effect of 500–730 kDa hyaluronic acid (Hyalgan) compared with placebo at 1 year, and concludes that hyaluronic acid is effective in the initial stages of osteoarthritis. Articles published before that of Prieto et al. [4] compare different commercial preparations of hyaluronic acid without touching on its degradation, and were based on its static properties. The conclusions they came to could therefore be called into question, if we consider current results. Articles such as that written by Wobig et al. [5] do not even consider 0141-8130/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijbiomac.2006.03.002
HA degradation or the long-term evolution of the molecule, and ignore factors which increase degradation such as ultrasound, used in the rehabilitation of patients with early stage osteoarticular problems. This is relevant if we consider that more and more studies are being published that underline the importance of conservative treatment for osteoarthritis [6], the use of local treatment avoiding systemic medication [7], as well as the benefits obtained by treatment combined with physiotherapy (ultrasound) and supervised exercise, both passive and active, on the knee [8]. Not mentioned is the interaction of hyaluronic acid with other medication taken systemically, which interferes with its degradation—antibiotics of the tetracycline family, which however, are currently under study due to their possible positive effect in the treatment of osteoarthritis, since doxycycline could inhibit metalloproteinase [9], and also protect the cartilage and subchondral bone [10,11]. Considering the great quantity and variability of hyaluronic acids on the market, and the clear idea of viscosupplementation in patients with osteoarthritis, it would be necessary to establish scientific criterium to classify them and determine their suitability. The perfect method to analyze their degradation and therapeutic half-life, is without doubt, the human articular model, but considering the impossibility of experimenting in humans, for both ethical and technical reasons, we are obliged to find similar models depending on the parameters to be studied. An experimental in vitro model is therefore proposed that would simulate the conditions to which patients with osteoarthritis are exposed, these patients being susceptible to treatment with hyaluronic acid. Once the model has been developed, degradation would be studied using ultrasonic methods and antibiotic derivates of tetracyclines, among others. A comparison of different hyaluronic acid formulas would be necessary in order to understand the acting and degradation processes in the joint. Also, to obtain a scientifically corroborated value judgement for when it comes to prescribing these treatments. In accordance with the results obtained by Prieto et al. [4] in a study titled “Comparative study of hyaluronic derivatives: rheological behaviour, mechanical and chemical degradation”, the molecular weight of hyaluronic acid, along with its concentration, are factors which could determine the intra-articular viability of the molecule; those of lower molecular weight being the most stable, those preparations with higher molecular weight being more susceptible to depolymerization due to chemical products and physical factors. This becomes important when treatment with hyaluronic acid is included as a part of
Letter to the Editor / International Journal of Biological Macromolecules 38 (2006) 300–301
a complex interrelated knee-patient system, or rather, that it is not enough to try and create a large molecule complying with theoretical conditions of viscosupplementation, but it is essential to study how this structure behaves in real-life situations, therefore revealing the drug’s behaviour once introduced into the knee, as this study does. An example would be the significant degradation of high molecular weight hyaluronic acid at 35 ◦ C, submitted to mechanical stress. In this study it was also proved, by means of ultrasonic degradation, that HA with long polymer chains (high mw), were more easily degradable by ultrasound due to the fact that greater stress was accumulated in these chains than the molecular links were able to cope with, meaning that long chains broke more frequently than short ones. When degradation was stimulated by tetracycline derivates, a similar pattern could be observed; degradation is greater in molecules with high molecular weight. This degradation depends on the concentration of oxytetracyclines, exposure time (up to a maximum 48 h action), and the HA concentration. Although it is believed that greater HA concentration is beneficial due to its viscoelastic properties, an interesting result was obtained in this study. The drugs that were more degraded by the tetracyclines were those with extreme concentrations; first those with the highest concentration, followed by those with the lower one. The use of tetracyclines in this study could be refuted in the general belief that they are little used, but new glycilglycans such as minocycline are appearing on the market, with new indications exceeding those of the old tetracyclines, without forgetting to mention their use in metycyllin-resistant bacteria and in those patients allergic to penicillin [12]. But, when concentrating on the area of musculoskeletal diseases, we can find, when revising the bibliography, treatment protocols for rheumatoide arthritis [13], and studies on the benefits of tetracyclines in these kinds of arthritis [14]. In accordance with the results obtained in the study with tetracyclines, there remains the doubt of the interaction of HA with other drugs and antibiotics, if any. It is therefore essential to use the compounds with the most stables molecules, until new studies are performed. In conclusion, there are many factors implied in the efficacy of treatment of osteoarthritis with intra-articular injections of
301
hyaluronic acid. The physical-chemical properties of different molecules and the interactions between them can condition the final therapeutic response of the product, the final concentration being most relevant. Future studies investigating the interactions of HA must be done to determine HA treatment safety and efficacy. References [1] M. Dougados, M. Nguyen, V. Listrat, B. Amor, Osteoarthritis Cartilage 1 (1993) 97–103. [2] M.E. Adams, M.H. Atkinson, A.J. Lussier, J.I. Schulz, K.A. Siminovitch, J.P. Wade, Osteoarthritis Cartilage 3 (1995) 213–225. [3] R.W. Jubb, S. Piva, L. Beinat, J. Dacre, P. Gishen, Int. J. Clin. Pract. 57 (2003) 467–474. [4] J.G. Prieto, M.M. Pulido, J. Zapico, A.J. Molina, M. Gimeno, P. Coronel, A.I. Alvarez, Int. J. Biol. Macromol. 35 (2005) 63–69. [5] M. Wobig, G. Bach, P. Beks, A. Dickhut, J. Runzheimer, G. Schwieger, G. Vetter, E. Balazs, Clin. Ther. 21 (1999) 1549–1562. [6] B. Kladny, W.F. Beyer, Orthopade 30 (2001) 848–855. [7] L. Sharma, Curr. Opin. Rheumatol. 14 (2002) 603–607. [8] G.D. Denle, N.E. Henderson, R.L. Matekel, M.G. Ryder, M.B. Garber, S.C. Allison, Ann. Intern. Med. 132 (2001) 173–181. [9] B.V. Shlopov, J.M. Stuart, M.L. Gumanovskaya, K.A. Hasty, J. Rheumatol. 28 (2001) 835–842. [10] J. Cylwik, K. Kita, M. Barwijuk-Machala, J. Reszec, P. Klimiuk, S. Sierakowski, S. Sulkowski, Folia Morphol. (Warsz) 63 (2004) 237–239. [11] C.K. Pardy, J.R. Matyas, R.F. Zernicke, J. Appl. Physiol. 97 (2004) 1254–1260. [12] M. Rodr´ıguez Rodr´ıguez, J. Gund´ıan Gonz´alez-Pi˜nera, J. Barreto Peni´e, N. Lim Alonso, A. Areu, A. Pardo Nu˜nez, Acta Medica 8 (1998) 75–79. [13] G.S. Alarcon, Expert Opin. Investig. Drugs 9 (2000) 1491–1498. [14] P. Langevitz, A. Livneh, I. Bank, M. Pras, Drug Saf. 22 (2000) 405–414.
J. S´anchez-L´azaro ∗ L. D´ıaz-G´allego Orthopaedic Department, Le´on Hospital, Le´on, Spain ∗ Corresponding
author. Tel.: +34 629038978/978237400x1391. E-mail address: [email protected] (J. S´anchez-L´azaro) 31 January 2006 Available online 7 March 2006
Letter to the Editor
The clinical impact of physical-chemical characteristics of different hyaluronic acids as a treatment for osteoarthritis Synovial fluid is formed by plasma transudation from the fenestrated capilliaries of the synovial membrane. It contains only small solute molecules, including hyaluronic acid and certain glycoproteins secreted by the synovial cells. The main component of synovial fluid is hyaluronic acid, providing synovial fluid with most of its properties. When up against weak shear forces, such as the knee when walking, its behaviour is viscous. With rapid movements, such as running, it is elastic and thereby reduces the force applied to the cartilage, protecting it from overload peaks. This brisk change from viscous to elastic is typical of hyaluronic acid solutions (it is much more progressive in other polymer solutions). The reduction in concentration and molecular weight of hyaluronic acid in some arthropathies rapidly alters the properties of synovial fluid. Also present in an anionic complex on the cartilage surface, is a small amount of proteins (1–2%), which intervene likewise in lubrication. The characteristics of the cartilage help the sliding action, since it is deformed under pressure which tends to stretch the articular load interline, and being porous, water and solutes migrate towards neighbouring areas of maximum load and transudate to the surface in front of and behind this load area, aiding movement. In summary, glycoproteins play an important role in lubrication at movement start and during slow movements, including load-free. During quick movements, the viscosity of the synovial fluid, dependent on hyaluronic acid, leads to the lowest friction coefficients. Based on the bibliography available, it seems evident that we can consider intra-articular injections of hyaluronic acid an effective treatment for osteoarthritis, in line with that described by authors such as Dougados et al. [1], and multicentre studies such as that published by Adams et al. [2]. In more recent articles, Jubb et al. [3] reviews the effect of 500–730 kDa hyaluronic acid (Hyalgan) compared with placebo at 1 year, and concludes that hyaluronic acid is effective in the initial stages of osteoarthritis. Articles published before that of Prieto et al. [4] compare different commercial preparations of hyaluronic acid without touching on its degradation, and were based on its static properties. The conclusions they came to could therefore be called into question, if we consider current results. Articles such as that written by Wobig et al. [5] do not even consider 0141-8130/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijbiomac.2006.03.002
HA degradation or the long-term evolution of the molecule, and ignore factors which increase degradation such as ultrasound, used in the rehabilitation of patients with early stage osteoarticular problems. This is relevant if we consider that more and more studies are being published that underline the importance of conservative treatment for osteoarthritis [6], the use of local treatment avoiding systemic medication [7], as well as the benefits obtained by treatment combined with physiotherapy (ultrasound) and supervised exercise, both passive and active, on the knee [8]. Not mentioned is the interaction of hyaluronic acid with other medication taken systemically, which interferes with its degradation—antibiotics of the tetracycline family, which however, are currently under study due to their possible positive effect in the treatment of osteoarthritis, since doxycycline could inhibit metalloproteinase [9], and also protect the cartilage and subchondral bone [10,11]. Considering the great quantity and variability of hyaluronic acids on the market, and the clear idea of viscosupplementation in patients with osteoarthritis, it would be necessary to establish scientific criterium to classify them and determine their suitability. The perfect method to analyze their degradation and therapeutic half-life, is without doubt, the human articular model, but considering the impossibility of experimenting in humans, for both ethical and technical reasons, we are obliged to find similar models depending on the parameters to be studied. An experimental in vitro model is therefore proposed that would simulate the conditions to which patients with osteoarthritis are exposed, these patients being susceptible to treatment with hyaluronic acid. Once the model has been developed, degradation would be studied using ultrasonic methods and antibiotic derivates of tetracyclines, among others. A comparison of different hyaluronic acid formulas would be necessary in order to understand the acting and degradation processes in the joint. Also, to obtain a scientifically corroborated value judgement for when it comes to prescribing these treatments. In accordance with the results obtained by Prieto et al. [4] in a study titled “Comparative study of hyaluronic derivatives: rheological behaviour, mechanical and chemical degradation”, the molecular weight of hyaluronic acid, along with its concentration, are factors which could determine the intra-articular viability of the molecule; those of lower molecular weight being the most stable, those preparations with higher molecular weight being more susceptible to depolymerization due to chemical products and physical factors. This becomes important when treatment with hyaluronic acid is included as a part of
Letter to the Editor / International Journal of Biological Macromolecules 38 (2006) 300–301
a complex interrelated knee-patient system, or rather, that it is not enough to try and create a large molecule complying with theoretical conditions of viscosupplementation, but it is essential to study how this structure behaves in real-life situations, therefore revealing the drug’s behaviour once introduced into the knee, as this study does. An example would be the significant degradation of high molecular weight hyaluronic acid at 35 ◦ C, submitted to mechanical stress. In this study it was also proved, by means of ultrasonic degradation, that HA with long polymer chains (high mw), were more easily degradable by ultrasound due to the fact that greater stress was accumulated in these chains than the molecular links were able to cope with, meaning that long chains broke more frequently than short ones. When degradation was stimulated by tetracycline derivates, a similar pattern could be observed; degradation is greater in molecules with high molecular weight. This degradation depends on the concentration of oxytetracyclines, exposure time (up to a maximum 48 h action), and the HA concentration. Although it is believed that greater HA concentration is beneficial due to its viscoelastic properties, an interesting result was obtained in this study. The drugs that were more degraded by the tetracyclines were those with extreme concentrations; first those with the highest concentration, followed by those with the lower one. The use of tetracyclines in this study could be refuted in the general belief that they are little used, but new glycilglycans such as minocycline are appearing on the market, with new indications exceeding those of the old tetracyclines, without forgetting to mention their use in metycyllin-resistant bacteria and in those patients allergic to penicillin [12]. But, when concentrating on the area of musculoskeletal diseases, we can find, when revising the bibliography, treatment protocols for rheumatoide arthritis [13], and studies on the benefits of tetracyclines in these kinds of arthritis [14]. In accordance with the results obtained in the study with tetracyclines, there remains the doubt of the interaction of HA with other drugs and antibiotics, if any. It is therefore essential to use the compounds with the most stables molecules, until new studies are performed. In conclusion, there are many factors implied in the efficacy of treatment of osteoarthritis with intra-articular injections of
301
hyaluronic acid. The physical-chemical properties of different molecules and the interactions between them can condition the final therapeutic response of the product, the final concentration being most relevant. Future studies investigating the interactions of HA must be done to determine HA treatment safety and efficacy. References [1] M. Dougados, M. Nguyen, V. Listrat, B. Amor, Osteoarthritis Cartilage 1 (1993) 97–103. [2] M.E. Adams, M.H. Atkinson, A.J. Lussier, J.I. Schulz, K.A. Siminovitch, J.P. Wade, Osteoarthritis Cartilage 3 (1995) 213–225. [3] R.W. Jubb, S. Piva, L. Beinat, J. Dacre, P. Gishen, Int. J. Clin. Pract. 57 (2003) 467–474. [4] J.G. Prieto, M.M. Pulido, J. Zapico, A.J. Molina, M. Gimeno, P. Coronel, A.I. Alvarez, Int. J. Biol. Macromol. 35 (2005) 63–69. [5] M. Wobig, G. Bach, P. Beks, A. Dickhut, J. Runzheimer, G. Schwieger, G. Vetter, E. Balazs, Clin. Ther. 21 (1999) 1549–1562. [6] B. Kladny, W.F. Beyer, Orthopade 30 (2001) 848–855. [7] L. Sharma, Curr. Opin. Rheumatol. 14 (2002) 603–607. [8] G.D. Denle, N.E. Henderson, R.L. Matekel, M.G. Ryder, M.B. Garber, S.C. Allison, Ann. Intern. Med. 132 (2001) 173–181. [9] B.V. Shlopov, J.M. Stuart, M.L. Gumanovskaya, K.A. Hasty, J. Rheumatol. 28 (2001) 835–842. [10] J. Cylwik, K. Kita, M. Barwijuk-Machala, J. Reszec, P. Klimiuk, S. Sierakowski, S. Sulkowski, Folia Morphol. (Warsz) 63 (2004) 237–239. [11] C.K. Pardy, J.R. Matyas, R.F. Zernicke, J. Appl. Physiol. 97 (2004) 1254–1260. [12] M. Rodr´ıguez Rodr´ıguez, J. Gund´ıan Gonz´alez-Pi˜nera, J. Barreto Peni´e, N. Lim Alonso, A. Areu, A. Pardo Nu˜nez, Acta Medica 8 (1998) 75–79. [13] G.S. Alarcon, Expert Opin. Investig. Drugs 9 (2000) 1491–1498. [14] P. Langevitz, A. Livneh, I. Bank, M. Pras, Drug Saf. 22 (2000) 405–414.
J. S´anchez-L´azaro ∗ L. D´ıaz-G´allego Orthopaedic Department, Le´on Hospital, Le´on, Spain ∗ Corresponding
author. Tel.: +34 629038978/978237400x1391. E-mail address: [email protected] (J. S´anchez-L´azaro) 31 January 2006 Available online 7 March 2006