rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2013-1538rsp-1333Research ArticleСтатьиArticlesЭффективность и безопасность пероральной формы стронция ранелата при лечении остеоартроза коленного сустава: обоснование и дизайн рандомизированного двойного слепого плацебоконтролируемого исследованияEfficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trialCooperCyrusCooperCyruscc@mrc.soton.ac.ukReginsterJ-YReginsterJ-Ycc@mrc.soton.ac.ukChapurlatRChapurlatRcc@mrc.soton.ac.ukChristiansenCChristiansenCcc@mrc.soton.ac.ukGenantHGenantHcc@mrc.soton.ac.ukBellamyNBellamyNcc@mrc.soton.ac.ukBensenWBensenWcc@mrc.soton.ac.ukNavarroFNavarroFcc@mrc.soton.ac.ukBadurskiJBadurskiJcc@mrc.soton.ac.ukНасоновЕвгенийNasonovEcc@mrc.soton.ac.ukChevalierXChevalierXcc@mrc.soton.ac.ukSambrookP NSambrookP Ncc@mrc.soton.ac.ukСовет по медицинскому исследованию, Отдел эпидемиологии жизненного цикла Саутгемптонского университета и Отдел биомедицинских исследований костно-мышечной системы Оксфордского университета, ВеликобританияВеликобританияMRC Lifecourse Epidemiology Unit, University of Southampton and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, UKUnited KingdomОтдел эпидемиологии общественного здоровья и экономики здравоохранения Льежского университета, Льеж, БельгияБельгияDepartment of Public Health Epidemiology and Health Economics, University of Liege, Liege, BelgiumBelgiumСлужба ревматологии и костной патологии при больнице Эдуарда Хэрриота, Лион, ФранцияФранцияService de Rhumatologie et Pathologie Osseuse, Hopital Edouard Herriot, Lyon, FranceFranceCCBR, Synarc, Баллеруп, ДанияДанияCCBR, Synarc, Ballerup, DenmarkDenmarkКафедра медицины, эпидемиологии и ортопедической медицины Калифорнийского университета в Сан-Франциско, штат Калифорния, СШАСоединённые Штаты АмерикиMedicine, Epidemiology and Orthopaedic Surgery, University of California, San Francisco; and Synarc, San Francisco, CA, USAUnited StatesCONROD, Квинслендский университет, Херстон, штат Квинсленд, АвстралияАвстралияCONROD, University of Queensland, Herston, Queensland, AustraliaAustraliaУниверситет Мак-Мастер в Гамильтоне, провинция Онтарио, КанадаКанадаMcMaster University Hamilton, Ontario, CanadaCanadaУниверситетская больница Девы Макарены, Севилья, ИспанияИспанияHospital Universitario Virgen Macarena, Sevilla, SpainSpainЦентр остеопороза и остеоартроза, Бялысток, ПольшаПольшаCentre of Osteoporosis and Osteoarticular Diseases, Bialystok, PolandPolandФГБУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой» РАМН, Москва, Российская ФедерацияРоссияState Institute of Rheumatology, Russian Academy of Medical Sciences, Moscow, Russian FederationRussian FederationСлужба ревматологии при Больнице Анри Мондора в Кретей, ФранцияФранцияService de Rhumatologie, Hopital Henri Mondor, Creteil, FranceFranceИнститут по исследованию костей и суставов, Королевская больница Святого Леонарда на Северном Берегу, Новый Южный Уэльс, АвстралияАвстралияInstitute of Bone and Joint Research, Royal North Shore Hospital, St Leonards NSW, AustraliaAustralia201330112013515481494Copyright © Cooper C., Reginster J., Chapurlat R., Christiansen C., Genant H., Bellamy N., Bensen W., Navarro F., Badurski J., Насонов Е., Chevalier X., Sambrook P.N., 20132013Cooper C., Reginster J., Chapurlat R., Christiansen C., Genant H., Bellamy N., Bensen W., Navarro F., Badurski J., Насонов Е., Chevalier X., Sambrook P.N.Cooper C., Reginster J., Chapurlat R., Christiansen C., Genant H., Bellamy N., Bensen W., Navarro F., Badurski J., Nasonov E., Chevalier X., Sambrook P.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/1333Цель

Цель. Препарат для лечения остеопороза (ОП) стронция ранелат разобщает процессы ремоделирования костной ткани. Он подавляет резорбцию субхондральной кости и стимулирует синтез хрящевого матрикса in vitro. В отчетах о поисковых исследованиях по ОП сообщается о том, что стронция ранелат снижает уровень биомаркеров распада хряща, а также замедляет прогрессирование и уменьшает выраженность клинических симптомов остеоартроза (ОА) позвоночника. Это свидетельствует о влиянии препарата на структуру тканей при ОА и о его симптом-модифицирующей активности. В настоящей статье приводится обоснование и описывается дизайн рандомизированного исследования, в котором оцениваются эффективность и безопасность стронция ранелата при ОА коленного сустава. 

Дизайн исследования, методы и результаты. В настоящее двойное слепое плацебоконтролируемое исследование (с участием 98 центров в 18 странах) включены мужчины и женщины белой расы в возрасте 50 лет и старше, получающие амбулаторное лечение по поводу первичного ОА коленного сустава в тибиофеморальном отделе (стадии 2 и 3 по классификации Kellegren и Lawrence) с шириной суставной щели (ШСЩ) от 2,5 до 5 мм и болями в колене в течение большинства дней за предыдущий месяц (интенсивность ≥40 мм по визуальной аналоговой шкале). Пациенты будут рандомизированы на три группы (получающие стронция ранелат 1 или 2 г в сутки либо плацебо). Наблюдение в динамике будет проводиться в течение 3 лет. Основным оцениваемым показателем является изменение ШСЩ на рентгенограмме на фоне приема стронция ранелата 1 и 2 г и плацебо по сравнению с исходной шириной. Основным клиническим вторичным показателем является оценка по шкале WOMAC (Western Ontario and MacMasters Universities Osteoarthritis Index – индекс остеоартроза университетов Западного Онтарио и МакМастера) для коленного сустава. Безопасность лечения оценивается во время каждого посещения. Установлено, что для определения статистической значимости с мощностью >90% (0,2 мм ± 10% разницы между группами в изменении ШСЩ за 3 года) необходимо обследовать 1600 пациентов. Набор пациентов был начат в апреле 2006 г. Результаты исследованияожидаются весной 2012 г. 

Регистрация клинического исследования. Исследование зарегистрировано на сайте www.controlledtrials.com (№ ISRCTN41323372). 

Выводы

Выводы. Настоящее рандомизированное двойное слепое плацебоконтролируемое исследование позволит установить возможности улучшения структуры и уменьшения симптомов на фоне применения стронция ранелата у больных с ОА коленного сустава.

Objective

Objective: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trialsreport that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describethe rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis.

Research design, methods, and results: This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoralcompartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ±10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012.

Clinical trial registration: The trial is registered on www.controlled-trials.com (number ISRCTN41323372).

Conclusions

Conclusions: This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.

базисные противовоспалительные препаратыширина суставной щелиостеоартроз коленного суставарентгенограмма коленарандомизированное клиническое исследованиестронция ранелатструктурно-модифицирующее лечениебазисные противовоспалительные препаратыширина суставной щелиостеоартроз коленного суставарентгенограмма коленарандомизированное клиническое исследованиестронция ранелатструктурно-модифицирующее лечениеReferences<div><p>Lawrence RC, Felson DT, Helmick CG et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthr Rheum 2008;58:26–35.</p><p>Dawson J, Linsell L, Zondervan K et al. Epidemiology of hip and knee pain and its impact on overall health status in older adults. Rheumatology (Oxford) 2004;43:497–504.</p><p>Zhang W, Nuki G, Moskowitz RW et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthr Cartilage 2010;18:476–99.</p><p>Matthews GL, Hunter DJ Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs 2011;16:479–91.</p><p>Bingham CO III, Buckland-Wright JC, Garnero P et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteo-arthritis structural arthritis study. Arthr Rheum 2006;54:3494–507.</p><p>Spector TD, Conaghan PG, Buckland-Wright JC et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthr Res Ther 2005;7:R625–33.</p><p>Clegg DO, Reda DJ, Harris CL et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795–808.</p><p>Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthr Cartilage 2009;17:1393–401.</p><p>Brandt KD, Mazzuca SA, Katz BP et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthr Rheum 2005;52:2015–25.</p><p>Kwan TS, Lajeunesse D, Pelletier JP et al. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol 2010;24:51–70.</p><p>Karsdal MA, Leeming DJ, Dam EB et al. Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthr Cartilage 2008;16:638–46.</p><p>Marie PJ. Strontium ranelate: new insights into its dual mode of action. Bone 2007;40:S5–8.</p><p>Brennan TC, Rybchyn MS, Green W et al. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol 2009;157:1291–300.</p><p>Chattopadhyay N, Quinn SJ, Kifor O et al. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol 2007;74:438–47.</p><p>Chang W, Tu C, Chen TH et al. Expression and signal transduction of calcium-sensing receptors in cartilage and bone. Endocrinology 1999;140:5883–93.</p><p>Atkins GJ, Welldon KJ, Halbout P et al. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 2009;20:653–64.</p><p>Caverzasio J. Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone 2008;42:1131–6.</p><p>Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with post-menopausal osteoporosis. N Engl J Med 2004;350:459–68.</p><p>Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in post-menopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816–22.</p><p>Tat SK, Pelletier JP, Mineau F et al. Strontium ranelate inhibits key factors affecting bone remodelling in human osteoarthritic subchondral bone osteoblasts. Bone 2011;49:559–67.</p><p>Henrotin Y, Labasse A, Zheng SX et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res 2001;16:299–308.</p><p>Alexandersen P, Karsdal MA, Qvist P et al. Strontium ranelate reduces the urinary level of cartilage degradation biomarker CTX-II in postmenopausal women. Bone 2007;40:218–22.</p><p>Alexandersen P, Karsdal MA, Byrjalsen I et al. Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis. Climacteric 2010;14:236–43.</p><p>Bruyere O, Delferriere D, Roux C et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis 2008;67:335–9.</p><p>Lane NE, Nevitt MC, Genant HK et al. Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration. J Rheumatol 1993;20:1911–8.</p><p>Altman R, Asch E, Bloch D et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthr Rheum 1986;29:1039–49.</p><p>Kellgren MJ. The Epidemiology of Chronic Rheumatism: Atlas of Standard Radiographs, 2nd ed. Oxford, UK: Ingersleben Blackwell Scientific, 1963</p><p>Kothari M, Guermazi A, Von Ingersleben G et al. Fixed-flexion radiography of the knee provides reproducible joint space width measurements in osteoarthritis. Eur Radiol 2004;14:1568–73.</p><p>Gensburger D, Arlot M, Sornay-Rendu E et al. Radiologic assessment of age-related knee joint space changes in women: a 4-year longitudinal study. Arthr Rheum 2009;61:336–43.</p><p>Gensburger D, Roux JP, Arlot M et al. Influence of blinding sequence of radiographs on the reproducibility and sensitivity to change of joint space width measurement in knee osteoarthritis. Arthr Care Res (Hoboken) 2010;62:1699–705.</p><p>Felson DT, Nevitt MC. Blinding images to sequence in osteoarthritis: evidence from other diseases. Osteoarthr Cartilage 2009;17:281–3.</p><p>Botha-Scheepers S, Watt I, Breedveld FC, Kloppenburg M. Reading radiographs in pairs or in chronological order influences radiological progression in osteoarthritis. Rheumatology (Oxford) 2005;44:1452–5.</p><p>Altman RD, Abadie E, Avouac B et al. Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis. Osteoarthr Cartilage 2005;13:13–9.</p><p>Bellamy N, Buchanan WW, Goldsmith CH et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–40.</p><p>Sowers MF, Karvonen-Gutierrez CA, Yosef M et al. Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women. Osteoarthr Cartilage 2009;17:1609–14.</p><p>Garnero P, Piperno M, Gineyts E et al. Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage. Ann Rheum Dis 2001;60:619–26.</p><p>Raynauld JP, Kauffmann C, Beaudoin G et al. Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. Osteoarthr Cartilage 2003;11:351–60.</p><p>Peterfy CG, Guermazi A, Zaim S et al. Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthr Cartilage 2004;12:177–90.</p><p>Emrani PS, Katz JN, Kessler CL et al. Joint space narrowing and Kellgren–Lawrence progression in knee osteoarthritis: an analytic literature synthesis. Osteoarthr Cartilage 2008;16:873–82.</p><p>Sawitzke AD, Shi H, Finco MF et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthr Rheum 2008;58:3183–91.</p><p>Kahan A, Uebelhart D, De VF et al. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthr Rheum 2009;60:524–33.</p></div><br /><div><p>Lawrence RC, Felson DT, Helmick CG et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthr Rheum 2008;58:26–35.</p><p>Dawson J, Linsell L, Zondervan K et al. Epidemiology of hip and knee pain and its impact on overall health status in older adults. Rheumatology (Oxford) 2004;43:497–504.</p><p>Zhang W, Nuki G, Moskowitz RW et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthr Cartilage 2010;18:476–99.</p><p>Matthews GL, Hunter DJ Emerging drugs for osteoarthritis. Expert Opin Emerg Drugs 2011;16:479–91.</p><p>Bingham CO III, Buckland-Wright JC, Garnero P et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteo-arthritis structural arthritis study. Arthr Rheum 2006;54:3494–507.</p><p>Spector TD, Conaghan PG, Buckland-Wright JC et al. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthr Res Ther 2005;7:R625–33.</p><p>Clegg DO, Reda DJ, Harris CL et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795–808.</p><p>Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthr Cartilage 2009;17:1393–401.</p><p>Brandt KD, Mazzuca SA, Katz BP et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthr Rheum 2005;52:2015–25.</p><p>Kwan TS, Lajeunesse D, Pelletier JP et al. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol 2010;24:51–70.</p><p>Karsdal MA, Leeming DJ, Dam EB et al. Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthr Cartilage 2008;16:638–46.</p><p>Marie PJ. Strontium ranelate: new insights into its dual mode of action. Bone 2007;40:S5–8.</p><p>Brennan TC, Rybchyn MS, Green W et al. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol 2009;157:1291–300.</p><p>Chattopadhyay N, Quinn SJ, Kifor O et al. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem Pharmacol 2007;74:438–47.</p><p>Chang W, Tu C, Chen TH et al. Expression and signal transduction of calcium-sensing receptors in cartilage and bone. Endocrinology 1999;140:5883–93.</p><p>Atkins GJ, Welldon KJ, Halbout P et al. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int 2009;20:653–64.</p><p>Caverzasio J. Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone 2008;42:1131–6.</p><p>Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with post-menopausal osteoporosis. N Engl J Med 2004;350:459–68.</p><p>Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in post-menopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816–22.</p><p>Tat SK, Pelletier JP, Mineau F et al. Strontium ranelate inhibits key factors affecting bone remodelling in human osteoarthritic subchondral bone osteoblasts. Bone 2011;49:559–67.</p><p>Henrotin Y, Labasse A, Zheng SX et al. Strontium ranelate increases cartilage matrix formation. J Bone Miner Res 2001;16:299–308.</p><p>Alexandersen P, Karsdal MA, Qvist P et al. Strontium ranelate reduces the urinary level of cartilage degradation biomarker CTX-II in postmenopausal women. Bone 2007;40:218–22.</p><p>Alexandersen P, Karsdal MA, Byrjalsen I et al. Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis. Climacteric 2010;14:236–43.</p><p>Bruyere O, Delferriere D, Roux C et al. Effects of strontium ranelate on spinal osteoarthritis progression. Ann Rheum Dis 2008;67:335–9.</p><p>Lane NE, Nevitt MC, Genant HK et al. Reliability of new indices of radiographic osteoarthritis of the hand and hip and lumbar disc degeneration. J Rheumatol 1993;20:1911–8.</p><p>Altman R, Asch E, Bloch D et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthr Rheum 1986;29:1039–49.</p><p>Kellgren MJ. The Epidemiology of Chronic Rheumatism: Atlas of Standard Radiographs, 2nd ed. Oxford, UK: Ingersleben Blackwell Scientific, 1963</p><p>Kothari M, Guermazi A, Von Ingersleben G et al. Fixed-flexion radiography of the knee provides reproducible joint space width measurements in osteoarthritis. Eur Radiol 2004;14:1568–73.</p><p>Gensburger D, Arlot M, Sornay-Rendu E et al. Radiologic assessment of age-related knee joint space changes in women: a 4-year longitudinal study. Arthr Rheum 2009;61:336–43.</p><p>Gensburger D, Roux JP, Arlot M et al. Influence of blinding sequence of radiographs on the reproducibility and sensitivity to change of joint space width measurement in knee osteoarthritis. Arthr Care Res (Hoboken) 2010;62:1699–705.</p><p>Felson DT, Nevitt MC. Blinding images to sequence in osteoarthritis: evidence from other diseases. Osteoarthr Cartilage 2009;17:281–3.</p><p>Botha-Scheepers S, Watt I, Breedveld FC, Kloppenburg M. Reading radiographs in pairs or in chronological order influences radiological progression in osteoarthritis. Rheumatology (Oxford) 2005;44:1452–5.</p><p>Altman RD, Abadie E, Avouac B et al. Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis. Osteoarthr Cartilage 2005;13:13–9.</p><p>Bellamy N, Buchanan WW, Goldsmith CH et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–40.</p><p>Sowers MF, Karvonen-Gutierrez CA, Yosef M et al. Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women. Osteoarthr Cartilage 2009;17:1609–14.</p><p>Garnero P, Piperno M, Gineyts E et al. Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage. Ann Rheum Dis 2001;60:619–26.</p><p>Raynauld JP, Kauffmann C, Beaudoin G et al. Reliability of a quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. Osteoarthr Cartilage 2003;11:351–60.</p><p>Peterfy CG, Guermazi A, Zaim S et al. Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthr Cartilage 2004;12:177–90.</p><p>Emrani PS, Katz JN, Kessler CL et al. Joint space narrowing and Kellgren–Lawrence progression in knee osteoarthritis: an analytic literature synthesis. Osteoarthr Cartilage 2008;16:873–82.</p><p>Sawitzke AD, Shi H, Finco MF et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthr Rheum 2008;58:3183–91.</p><p>Kahan A, Uebelhart D, De VF et al. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthr Rheum 2009;60:524–33.</p></div><br />

The authors declare that there are no conflicts of interest present.