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Intramuscular Clodronate in Long-Term Treatment of Symptomatic Knee Osteoarthritis: A Randomized Controlled Study

Identifieur interne : 000095 ( Pmc/Corpus ); précédent : 000094; suivant : 000096

Intramuscular Clodronate in Long-Term Treatment of Symptomatic Knee Osteoarthritis: A Randomized Controlled Study

Auteurs : Bruno Frediani ; Carmela Toscano ; Paolo Falsetti ; Antonella Nicosia ; Serena Pierguidi ; Alberto Migliore ; Stefano Giannotti ; Luca Cantarini ; Edoardo Conticini

Source :

RBID : PMC:7067729

Abstract

Background and Objective

Clodronate is a nitrogen-free bisphosphonate that is widely and effectively used in the treatment of many osteo-metabolic disorders. The objective of our study was to evaluate the effectiveness of clodronate in reducing pain and bone marrow edema in knee osteoarthritis.

Methods

In total, 74 patients were included in the study. Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months. Visual analog scale (VAS) scores were recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). We also evaluated functional status and use of paracetamol (T0, T1, T2, T3, T4, and T5) and changes in Whole Organ Magnetic Resonance Imaging Score (WORMS; T0, T2, and T5).

Results

Both groups had a statistically significant reduction in VAS score until 3 months. Group 1 then experienced further VAS reductions, whereas VAS scores for group 2 progressively increased. Pain, stiffness, and physical function also showed the same trend, as did bone marrow edema extension, which was evaluated with WORMS.

Conclusion

Our study indicates that intramuscular administration of a therapeutic dose of clodronate followed by a maintenance dose is effective in the management of symptomatic knee osteoarthritis, improving functional outcomes and reducing pain and bone marrow edema. Prolonged treatment increases the long-term efficacy of clodronate compared with the shorter schedule.


Url:
DOI: 10.1007/s40268-020-00294-4
PubMed: 32078147
PubMed Central: 7067729

Links to Exploration step

PMC:7067729

Le document en format XML

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<title>Background and Objective</title>
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<sec>
<title>Methods</title>
<p id="Par3">In total, 74 patients were included in the study. Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months. Visual analog scale (VAS) scores were recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). We also evaluated functional status and use of paracetamol (T0, T1, T2, T3, T4, and T5) and changes in Whole Organ Magnetic Resonance Imaging Score (WORMS; T0, T2, and T5).</p>
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<p id="Par4">Both groups had a statistically significant reduction in VAS score until 3 months. Group 1 then experienced further VAS reductions, whereas VAS scores for group 2 progressively increased. Pain, stiffness, and physical function also showed the same trend, as did bone marrow edema extension, which was evaluated with WORMS.</p>
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<div1 type="bibliography">
<listBibl>
<biblStruct>
<analytic>
<author>
<name sortKey="Lawrence, Rc" uniqKey="Lawrence R">RC Lawrence</name>
</author>
<author>
<name sortKey="Felson, Dt" uniqKey="Felson D">DT Felson</name>
</author>
<author>
<name sortKey="Helmick, Cg" uniqKey="Helmick C">CG Helmick</name>
</author>
<author>
<name sortKey="Arnold, Lm" uniqKey="Arnold L">LM Arnold</name>
</author>
<author>
<name sortKey="Choi, H" uniqKey="Choi H">H Choi</name>
</author>
<author>
<name sortKey="Deyo, Ra" uniqKey="Deyo R">RA Deyo</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Felson, Dt" uniqKey="Felson D">DT Felson</name>
</author>
<author>
<name sortKey="Chaisson, Ce" uniqKey="Chaisson C">CE Chaisson</name>
</author>
<author>
<name sortKey="Hill, Cl" uniqKey="Hill C">CL Hill</name>
</author>
<author>
<name sortKey="Totterman, Sm" uniqKey="Totterman S">SM Totterman</name>
</author>
<author>
<name sortKey="Gale, Me" uniqKey="Gale M">ME Gale</name>
</author>
<author>
<name sortKey="Skinner, Km" uniqKey="Skinner K">KM Skinner</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Felson, Dy" uniqKey="Felson D">DY Felson</name>
</author>
<author>
<name sortKey="Mclaughlin, S" uniqKey="Mclaughlin S">S McLaughlin</name>
</author>
<author>
<name sortKey="Goggins, J" uniqKey="Goggins J">J Goggins</name>
</author>
<author>
<name sortKey="Lavalley, Mp" uniqKey="Lavalley M">MP LaValley</name>
</author>
<author>
<name sortKey="Gale, Me" uniqKey="Gale M">ME Gale</name>
</author>
<author>
<name sortKey="Totterman, S" uniqKey="Totterman S">S Totterman</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Zanetti, M" uniqKey="Zanetti M">M Zanetti</name>
</author>
<author>
<name sortKey="Bruder, E" uniqKey="Bruder E">E Bruder</name>
</author>
<author>
<name sortKey="Romero, J" uniqKey="Romero J">J Romero</name>
</author>
<author>
<name sortKey="Hodler, J" uniqKey="Hodler J">J Hodler</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Saadat, E" uniqKey="Saadat E">E Saadat</name>
</author>
<author>
<name sortKey="Jobke, B" uniqKey="Jobke B">B Jobke</name>
</author>
<author>
<name sortKey="Chu, B" uniqKey="Chu B">B Chu</name>
</author>
<author>
<name sortKey="Lu, Y" uniqKey="Lu Y">Y Lu</name>
</author>
<author>
<name sortKey="Cheng, J" uniqKey="Cheng J">J Cheng</name>
</author>
<author>
<name sortKey="Li, X" uniqKey="Li X">X Li</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kazakia, Gj" uniqKey="Kazakia G">GJ Kazakia</name>
</author>
<author>
<name sortKey="Kuo, D" uniqKey="Kuo D">D Kuo</name>
</author>
<author>
<name sortKey="Schooler, J" uniqKey="Schooler J">J Schooler</name>
</author>
<author>
<name sortKey="Siddiqui, S" uniqKey="Siddiqui S">S Siddiqui</name>
</author>
<author>
<name sortKey="Shanbhag, S" uniqKey="Shanbhag S">S Shanbhag</name>
</author>
<author>
<name sortKey="Bernstein, G" uniqKey="Bernstein G">G Bernstein</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Yusuf, E" uniqKey="Yusuf E">E Yusuf</name>
</author>
<author>
<name sortKey="Kortekaas, Mc" uniqKey="Kortekaas M">MC Kortekaas</name>
</author>
<author>
<name sortKey="Watt, I" uniqKey="Watt I">I Watt</name>
</author>
<author>
<name sortKey="Huizinga, Tw" uniqKey="Huizinga T">TW Huizinga</name>
</author>
<author>
<name sortKey="Kloppenburg, M" uniqKey="Kloppenburg M">M Kloppenburg</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Maksymowych, Wp" uniqKey="Maksymowych W">WP Maksymowych</name>
</author>
<author>
<name sortKey="Jhangri, Gs" uniqKey="Jhangri G">GS Jhangri</name>
</author>
<author>
<name sortKey="Fitzgerald, Aa" uniqKey="Fitzgerald A">AA Fitzgerald</name>
</author>
<author>
<name sortKey="Leclercq, S" uniqKey="Leclercq S">S LeClercq</name>
</author>
<author>
<name sortKey="Chiu, P" uniqKey="Chiu P">P Chiu</name>
</author>
<author>
<name sortKey="Yan, A" uniqKey="Yan A">A Yan</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Varenna, M" uniqKey="Varenna M">M Varenna</name>
</author>
<author>
<name sortKey="Zucchi, F" uniqKey="Zucchi F">F Zucchi</name>
</author>
<author>
<name sortKey="Binelli, L" uniqKey="Binelli L">L Binelli</name>
</author>
<author>
<name sortKey="Failoni, S" uniqKey="Failoni S">S Failoni</name>
</author>
<author>
<name sortKey="Gallazzi, M" uniqKey="Gallazzi M">M Gallazzi</name>
</author>
<author>
<name sortKey="Sinigaglia, L" uniqKey="Sinigaglia L">L Sinigaglia</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Tran, Dqh" uniqKey="Tran D">DQH Tran</name>
</author>
<author>
<name sortKey="Duong, S" uniqKey="Duong S">S Duong</name>
</author>
<author>
<name sortKey="Bertini, P" uniqKey="Bertini P">P Bertini</name>
</author>
<author>
<name sortKey="Finlayson, Rj" uniqKey="Finlayson R">RJ Finlayson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Davis, Aj" uniqKey="Davis A">AJ Davis</name>
</author>
<author>
<name sortKey="Smith, To" uniqKey="Smith T">TO Smith</name>
</author>
<author>
<name sortKey="Hing, Cb" uniqKey="Hing C">CB Hing</name>
</author>
<author>
<name sortKey="Sofat, N" uniqKey="Sofat N">N Sofat</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Khan, Sa" uniqKey="Khan S">SA Khan</name>
</author>
<author>
<name sortKey="Mccloskey, Ev" uniqKey="Mccloskey E">EV McCloskey</name>
</author>
<author>
<name sortKey="Nakatsuka, K" uniqKey="Nakatsuka K">K Nakatsuka</name>
</author>
<author>
<name sortKey="Orgee, J" uniqKey="Orgee J">J Orgee</name>
</author>
<author>
<name sortKey="Coombes, Gm" uniqKey="Coombes G">GM Coombes</name>
</author>
<author>
<name sortKey="Kanis, Ja" uniqKey="Kanis J">JA Kanis</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Body, Jj" uniqKey="Body J">JJ Body</name>
</author>
<author>
<name sortKey="Coleman, Re" uniqKey="Coleman R">RE Coleman</name>
</author>
<author>
<name sortKey="Piccart, M" uniqKey="Piccart M">M Piccart</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Adami, S" uniqKey="Adami S">S Adami</name>
</author>
<author>
<name sortKey="Bolzicco, Gp" uniqKey="Bolzicco G">GP Bolzicco</name>
</author>
<author>
<name sortKey="Rizzo, A" uniqKey="Rizzo A">A Rizzo</name>
</author>
<author>
<name sortKey="Salvagno, G" uniqKey="Salvagno G">G Salvagno</name>
</author>
<author>
<name sortKey="Bertoldo, F" uniqKey="Bertoldo F">F Bertoldo</name>
</author>
<author>
<name sortKey="Rossini, M" uniqKey="Rossini M">M Rossini</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Douglas, Dl" uniqKey="Douglas D">DL Douglas</name>
</author>
<author>
<name sortKey="Kanis, Ja" uniqKey="Kanis J">JA Kanis</name>
</author>
<author>
<name sortKey="Paterson, Ad" uniqKey="Paterson A">AD Paterson</name>
</author>
<author>
<name sortKey="Beard, Dj" uniqKey="Beard D">DJ Beard</name>
</author>
<author>
<name sortKey="Cameron, Ec" uniqKey="Cameron E">EC Cameron</name>
</author>
<author>
<name sortKey="Watson, Me" uniqKey="Watson M">ME Watson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Shane, E" uniqKey="Shane E">E Shane</name>
</author>
<author>
<name sortKey="Baquiran, Dc" uniqKey="Baquiran D">DC Baquiran</name>
</author>
<author>
<name sortKey="Bilezikian, Jp" uniqKey="Bilezikian J">JP Bilezikian</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Saviola, G" uniqKey="Saviola G">G Saviola</name>
</author>
<author>
<name sortKey="Abdi Ali, L" uniqKey="Abdi Ali L">L Abdi-Ali</name>
</author>
<author>
<name sortKey="Campostrini, L" uniqKey="Campostrini L">L Campostrini</name>
</author>
<author>
<name sortKey="Sacco, S" uniqKey="Sacco S">S Sacco</name>
</author>
<author>
<name sortKey="Baiardi, P" uniqKey="Baiardi P">P Baiardi</name>
</author>
<author>
<name sortKey="Manfredi, M" uniqKey="Manfredi M">M Manfredi</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rossini, M" uniqKey="Rossini M">M Rossini</name>
</author>
<author>
<name sortKey="Adami, S" uniqKey="Adami S">S Adami</name>
</author>
<author>
<name sortKey="Fracassi, E" uniqKey="Fracassi E">E Fracassi</name>
</author>
<author>
<name sortKey="Viapiana, O" uniqKey="Viapiana O">O Viapiana</name>
</author>
<author>
<name sortKey="Orsolini, G" uniqKey="Orsolini G">G Orsolini</name>
</author>
<author>
<name sortKey="Povino, Mr" uniqKey="Povino M">MR Povino</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Frediani, B" uniqKey="Frediani B">B Frediani</name>
</author>
<author>
<name sortKey="Giusti, A" uniqKey="Giusti A">A Giusti</name>
</author>
<author>
<name sortKey="Bianchi, G" uniqKey="Bianchi G">G Bianchi</name>
</author>
<author>
<name sortKey="Dalle Carbonare, L" uniqKey="Dalle Carbonare L">L Dalle Carbonare</name>
</author>
<author>
<name sortKey="Malavolta, N" uniqKey="Malavolta N">N Malavolta</name>
</author>
<author>
<name sortKey="Cantarini, L" uniqKey="Cantarini L">L Cantarini</name>
</author>
<author>
<name sortKey="Saviola, G" uniqKey="Saviola G">G Saviola</name>
</author>
<author>
<name sortKey="Molfetta, L" uniqKey="Molfetta L">L Molfetta</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Frediani, B" uniqKey="Frediani B">B Frediani</name>
</author>
<author>
<name sortKey="Bertoldi, I" uniqKey="Bertoldi I">I Bertoldi</name>
</author>
<author>
<name sortKey="Pierguidi, S" uniqKey="Pierguidi S">S Pierguidi</name>
</author>
<author>
<name sortKey="Nicosia, A" uniqKey="Nicosia A">A Nicosia</name>
</author>
<author>
<name sortKey="Picerno, V" uniqKey="Picerno V">V Picerno</name>
</author>
<author>
<name sortKey="Filippou, G" uniqKey="Filippou G">G Filippou</name>
</author>
<author>
<name sortKey="Cantarini, L" uniqKey="Cantarini L">L Cantarini</name>
</author>
<author>
<name sortKey="Galeazzi, M" uniqKey="Galeazzi M">M Galeazzi</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kellgren, Jh" uniqKey="Kellgren J">JH Kellgren</name>
</author>
<author>
<name sortKey="Lawrence, Js" uniqKey="Lawrence J">JS Lawrence</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Peterfy, Cg" uniqKey="Peterfy C">CG Peterfy</name>
</author>
<author>
<name sortKey="Guermazi, A" uniqKey="Guermazi A">A Guermazi</name>
</author>
<author>
<name sortKey="Zaim, S" uniqKey="Zaim S">S Zaim</name>
</author>
<author>
<name sortKey="Tirman, Pf" uniqKey="Tirman P">PF Tirman</name>
</author>
<author>
<name sortKey="Miaux, Y" uniqKey="Miaux Y">Y Miaux</name>
</author>
<author>
<name sortKey="White, D" uniqKey="White D">D White</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Laslett, Ll" uniqKey="Laslett L">LL Laslett</name>
</author>
<author>
<name sortKey="Dore, Da" uniqKey="Dore D">DA Doré</name>
</author>
<author>
<name sortKey="Quinn, Sj" uniqKey="Quinn S">SJ Quinn</name>
</author>
<author>
<name sortKey="Boon, P" uniqKey="Boon P">P Boon</name>
</author>
<author>
<name sortKey="Ryan, E" uniqKey="Ryan E">E Ryan</name>
</author>
<author>
<name sortKey="Winzenberg, Tm" uniqKey="Winzenberg T">TM Winzenberg</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Varenna, M" uniqKey="Varenna M">M Varenna</name>
</author>
<author>
<name sortKey="Zucchi, F" uniqKey="Zucchi F">F Zucchi</name>
</author>
<author>
<name sortKey="Failoni, S" uniqKey="Failoni S">S Failoni</name>
</author>
<author>
<name sortKey="Becciolini, A" uniqKey="Becciolini A">A Becciolini</name>
</author>
<author>
<name sortKey="Berruto, M" uniqKey="Berruto M">M Berruto</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Cassisi, G" uniqKey="Cassisi G">G Cassisi</name>
</author>
<author>
<name sortKey="Sartori, L" uniqKey="Sartori L">L Sartori</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Varenna, M" uniqKey="Varenna M">M Varenna</name>
</author>
<author>
<name sortKey="Adami, S" uniqKey="Adami S">S Adami</name>
</author>
<author>
<name sortKey="Rossini, M" uniqKey="Rossini M">M Rossini</name>
</author>
<author>
<name sortKey="Gatti, D" uniqKey="Gatti D">D Gatti</name>
</author>
<author>
<name sortKey="Idolazzi, L" uniqKey="Idolazzi L">L Idolazzi</name>
</author>
<author>
<name sortKey="Zucchi, F" uniqKey="Zucchi F">F Zucchi</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Adami, S" uniqKey="Adami S">S Adami</name>
</author>
<author>
<name sortKey="Fossaluzza, V" uniqKey="Fossaluzza V">V Fossaluzza</name>
</author>
<author>
<name sortKey="Gatti, D" uniqKey="Gatti D">D Gatti</name>
</author>
<author>
<name sortKey="Fracassi, E" uniqKey="Fracassi E">E Fracassi</name>
</author>
<author>
<name sortKey="Braga, V" uniqKey="Braga V">V Braga</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Saviola, G" uniqKey="Saviola G">G Saviola</name>
</author>
<author>
<name sortKey="Abdi Ali, L" uniqKey="Abdi Ali L">L Abdi-Ali</name>
</author>
<author>
<name sortKey="Comini, L" uniqKey="Comini L">L Comini</name>
</author>
<author>
<name sortKey="Dalle Carbonare, Lg" uniqKey="Dalle Carbonare L">LG Dalle-Carbonare</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Saviola, Gianantonio" uniqKey="Saviola G">Gianantonio Saviola</name>
</author>
<author>
<name sortKey="Abdi Ali, Lul" uniqKey="Abdi Ali L">Lul Abdi-Ali</name>
</author>
<author>
<name sortKey="Povino, Maria Rosaria" uniqKey="Povino M">Maria Rosaria Povino</name>
</author>
<author>
<name sortKey="Campostrini, Lorella" uniqKey="Campostrini L">Lorella Campostrini</name>
</author>
<author>
<name sortKey="Sacco, Silvano" uniqKey="Sacco S">Silvano Sacco</name>
</author>
<author>
<name sortKey="Carbonare, Luca Dalle" uniqKey="Carbonare L">Luca Dalle Carbonare</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Valenti, Maria" uniqKey="Valenti M">Maria Valenti</name>
</author>
<author>
<name sortKey="Mottes, Monica" uniqKey="Mottes M">Monica Mottes</name>
</author>
<author>
<name sortKey="Biotti, Alessandro" uniqKey="Biotti A">Alessandro Biotti</name>
</author>
<author>
<name sortKey="Perduca, Massimiliano" uniqKey="Perduca M">Massimiliano Perduca</name>
</author>
<author>
<name sortKey="Pisani, Arianna" uniqKey="Pisani A">Arianna Pisani</name>
</author>
<author>
<name sortKey="Bovi, Michele" uniqKey="Bovi M">Michele Bovi</name>
</author>
<author>
<name sortKey="Deiana, Michela" uniqKey="Deiana M">Michela Deiana</name>
</author>
<author>
<name sortKey="Cheri, Samuele" uniqKey="Cheri S">Samuele Cheri</name>
</author>
<author>
<name sortKey="Dalle Carbonare, Luca" uniqKey="Dalle Carbonare L">Luca Dalle Carbonare</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Felson, Dt" uniqKey="Felson D">DT Felson</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Link, Tm" uniqKey="Link T">TM Link</name>
</author>
<author>
<name sortKey="Li, X" uniqKey="Li X">X Li</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Taljanovic, Ms" uniqKey="Taljanovic M">MS Taljanovic</name>
</author>
<author>
<name sortKey="Graham, Ar" uniqKey="Graham A">AR Graham</name>
</author>
<author>
<name sortKey="Benjamin, Jb" uniqKey="Benjamin J">JB Benjamin</name>
</author>
<author>
<name sortKey="Gmitro, Af" uniqKey="Gmitro A">AF Gmitro</name>
</author>
<author>
<name sortKey="Krupinski, Ea" uniqKey="Krupinski E">EA Krupinski</name>
</author>
<author>
<name sortKey="Schwartz, Sa" uniqKey="Schwartz S">SA Schwartz</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Liu, L" uniqKey="Liu L">L Liu</name>
</author>
<author>
<name sortKey="Igarashi, K" uniqKey="Igarashi K">K Igarashi</name>
</author>
<author>
<name sortKey="Kanzaki, H" uniqKey="Kanzaki H">H Kanzaki</name>
</author>
<author>
<name sortKey="Chiba, M" uniqKey="Chiba M">M Chiba</name>
</author>
<author>
<name sortKey="Shinoda, H" uniqKey="Shinoda H">H Shinoda</name>
</author>
<author>
<name sortKey="Mitani, H" uniqKey="Mitani H">H Mitani</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Chiu, Yg" uniqKey="Chiu Y">YG Chiu</name>
</author>
<author>
<name sortKey="Ritchlin, Dt" uniqKey="Ritchlin D">DT Ritchlin</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sims, Na" uniqKey="Sims N">NA Sims</name>
</author>
<author>
<name sortKey="Green, Jr" uniqKey="Green J">JR Green</name>
</author>
<author>
<name sortKey="Glatt, M" uniqKey="Glatt M">M Glatt</name>
</author>
<author>
<name sortKey="Schlict, S" uniqKey="Schlict S">S Schlict</name>
</author>
<author>
<name sortKey="Martin, Tj" uniqKey="Martin T">TJ Martin</name>
</author>
<author>
<name sortKey="Gillespie, Mt" uniqKey="Gillespie M">MT Gillespie</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Oelzner, P" uniqKey="Oelzner P">P Oelzner</name>
</author>
<author>
<name sortKey="Kunze, A" uniqKey="Kunze A">A Kunze</name>
</author>
<author>
<name sortKey="Henzgen, S" uniqKey="Henzgen S">S Henzgen</name>
</author>
<author>
<name sortKey="Thoss, K" uniqKey="Thoss K">K Thoss</name>
</author>
<author>
<name sortKey="Hein, G" uniqKey="Hein G">G Hein</name>
</author>
<author>
<name sortKey="Stein, G" uniqKey="Stein G">G Stein</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Osterman, T" uniqKey="Osterman T">T Osterman</name>
</author>
<author>
<name sortKey="Kippo, K" uniqKey="Kippo K">K Kippo</name>
</author>
<author>
<name sortKey="Lauren, L" uniqKey="Lauren L">L Laurén</name>
</author>
<author>
<name sortKey="Hannuniemi, R" uniqKey="Hannuniemi R">R Hannuniemi</name>
</author>
<author>
<name sortKey="Sellman, R" uniqKey="Sellman R">R Sellman</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bonabello, A" uniqKey="Bonabello A">A Bonabello</name>
</author>
<author>
<name sortKey="Galmozzi, Mr" uniqKey="Galmozzi M">MR Galmozzi</name>
</author>
<author>
<name sortKey="Bruzzese, T" uniqKey="Bruzzese T">T Bruzzese</name>
</author>
<author>
<name sortKey="Zara, Gp" uniqKey="Zara G">GP Zara</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Bonabello, A" uniqKey="Bonabello A">A Bonabello</name>
</author>
<author>
<name sortKey="Galmozzi, Mr" uniqKey="Galmozzi M">MR Galmozzi</name>
</author>
<author>
<name sortKey="Canaparo, R" uniqKey="Canaparo R">R Canaparo</name>
</author>
<author>
<name sortKey="Serpe, L" uniqKey="Serpe L">L Serpe</name>
</author>
<author>
<name sortKey="Zara, Gp" uniqKey="Zara G">GP Zara</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Muratore, M" uniqKey="Muratore M">M Muratore</name>
</author>
<author>
<name sortKey="Calcagnile, F" uniqKey="Calcagnile F">F Calcagnile</name>
</author>
<author>
<name sortKey="Quarta, E" uniqKey="Quarta E">E Quarta</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rovetta, G" uniqKey="Rovetta G">G Rovetta</name>
</author>
<author>
<name sortKey="Maggiani, G" uniqKey="Maggiani G">G Maggiani</name>
</author>
<author>
<name sortKey="Molfetta, L" uniqKey="Molfetta L">L Molfetta</name>
</author>
<author>
<name sortKey="Monteforte, P" uniqKey="Monteforte P">P Monteforte</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rovetta, G" uniqKey="Rovetta G">G Rovetta</name>
</author>
<author>
<name sortKey="Monteforte, P" uniqKey="Monteforte P">P Monteforte</name>
</author>
<author>
<name sortKey="Balestra, V" uniqKey="Balestra V">V Balestra</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Muratore, M" uniqKey="Muratore M">M Muratore</name>
</author>
<author>
<name sortKey="Canaparo, R" uniqKey="Canaparo R">R Canaparo</name>
</author>
<author>
<name sortKey="Della Pepa, C" uniqKey="Della Pepa C">C Della Pepa</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Ernst, Ds" uniqKey="Ernst D">DS Ernst</name>
</author>
<author>
<name sortKey="Brasher, P" uniqKey="Brasher P">P Brasher</name>
</author>
<author>
<name sortKey="Hagen, N" uniqKey="Hagen N">N Hagen</name>
</author>
<author>
<name sortKey="Paterson, Ah" uniqKey="Paterson A">AH Paterson</name>
</author>
<author>
<name sortKey="Macdonald, Rn" uniqKey="Macdonald R">RN MacDonald</name>
</author>
<author>
<name sortKey="Bruera, E" uniqKey="Bruera E">E Bruera</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Tubiana Hulin, M" uniqKey="Tubiana Hulin M">M Tubiana-Hulin</name>
</author>
<author>
<name sortKey="Beuzeboc, P" uniqKey="Beuzeboc P">P Beuzeboc</name>
</author>
<author>
<name sortKey="Mauriac, L" uniqKey="Mauriac L">L Mauriac</name>
</author>
<author>
<name sortKey="Barbet, N" uniqKey="Barbet N">N Barbet</name>
</author>
<author>
<name sortKey="Frenay, M" uniqKey="Frenay M">M Frenay</name>
</author>
<author>
<name sortKey="Monnier, A" uniqKey="Monnier A">A Monnier</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Rossini, M" uniqKey="Rossini M">M Rossini</name>
</author>
<author>
<name sortKey="Viapiana, O" uniqKey="Viapiana O">O Viapiana</name>
</author>
<author>
<name sortKey="Ramonda, R" uniqKey="Ramonda R">R Ramonda</name>
</author>
<author>
<name sortKey="Bianchi, G" uniqKey="Bianchi G">G Bianchi</name>
</author>
<author>
<name sortKey="Olivieri, I" uniqKey="Olivieri I">I Olivieri</name>
</author>
<author>
<name sortKey="Lapadula, G" uniqKey="Lapadula G">G Lapadula</name>
</author>
<author>
<name sortKey="Adami, S" uniqKey="Adami S">S Adami</name>
</author>
</analytic>
</biblStruct>
</listBibl>
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<journal-id journal-id-type="nlm-ta">Drugs R D</journal-id>
<journal-id journal-id-type="iso-abbrev">Drugs R D</journal-id>
<journal-title-group>
<journal-title>Drugs in R&D</journal-title>
</journal-title-group>
<issn pub-type="ppub">1174-5886</issn>
<issn pub-type="epub">1179-6901</issn>
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<publisher-name>Springer International Publishing</publisher-name>
<publisher-loc>Cham</publisher-loc>
</publisher>
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<article-meta>
<article-id pub-id-type="pmid">32078147</article-id>
<article-id pub-id-type="pmc">7067729</article-id>
<article-id pub-id-type="publisher-id">294</article-id>
<article-id pub-id-type="doi">10.1007/s40268-020-00294-4</article-id>
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<subj-group subj-group-type="heading">
<subject>Original Research Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Intramuscular Clodronate in Long-Term Treatment of Symptomatic Knee Osteoarthritis: A Randomized Controlled Study</article-title>
</title-group>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Frediani</surname>
<given-names>Bruno</given-names>
</name>
<address>
<email>fredianibruno60@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Toscano</surname>
<given-names>Carmela</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Falsetti</surname>
<given-names>Paolo</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nicosia</surname>
<given-names>Antonella</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Pierguidi</surname>
<given-names>Serena</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Migliore</surname>
<given-names>Alberto</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Giannotti</surname>
<given-names>Stefano</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cantarini</surname>
<given-names>Luca</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Conticini</surname>
<given-names>Edoardo</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1">
<label>1</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.9024.f</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1757 4641</institution-id>
<institution>Institute of Rheumatology,</institution>
<institution>University of Siena,</institution>
</institution-wrap>
Siena, Italy</aff>
<aff id="Aff2">
<label>2</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.414765.5</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1763 7550</institution-id>
<institution>Unit of Rheumatology,</institution>
<institution>San Pietro Fatebenefratelli Hospital,</institution>
</institution-wrap>
Rome, Italy</aff>
<aff id="Aff3">
<label>3</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.9024.f</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1757 4641</institution-id>
<institution>Orthopedics Unit,</institution>
<institution>University of Siena,</institution>
</institution-wrap>
Siena, Italy</aff>
</contrib-group>
<pub-date pub-type="epub">
<day>20</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>20</day>
<month>2</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="ppub">
<month>3</month>
<year>2020</year>
</pub-date>
<volume>20</volume>
<issue>1</issue>
<fpage>39</fpage>
<lpage>45</lpage>
<permissions>
<copyright-statement>© The Author(s) 2020</copyright-statement>
<license license-type="OpenAccess">
<license-p>
<bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1">
<sec>
<title>Background and Objective</title>
<p id="Par1">Clodronate is a nitrogen-free bisphosphonate that is widely and effectively used in the treatment of many osteo-metabolic disorders. The objective of our study was to evaluate the effectiveness of clodronate in reducing pain and bone marrow edema in knee osteoarthritis.</p>
</sec>
<sec>
<title>Methods</title>
<p id="Par3">In total, 74 patients were included in the study. Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months. Visual analog scale (VAS) scores were recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). We also evaluated functional status and use of paracetamol (T0, T1, T2, T3, T4, and T5) and changes in Whole Organ Magnetic Resonance Imaging Score (WORMS; T0, T2, and T5).</p>
</sec>
<sec>
<title>Results</title>
<p id="Par4">Both groups had a statistically significant reduction in VAS score until 3 months. Group 1 then experienced further VAS reductions, whereas VAS scores for group 2 progressively increased. Pain, stiffness, and physical function also showed the same trend, as did bone marrow edema extension, which was evaluated with WORMS.</p>
</sec>
<sec>
<title>Conclusion</title>
<p id="Par5">Our study indicates that intramuscular administration of a therapeutic dose of clodronate followed by a maintenance dose is effective in the management of symptomatic knee osteoarthritis, improving functional outcomes and reducing pain and bone marrow edema. Prolonged treatment increases the long-term efficacy of clodronate compared with the shorter schedule.</p>
</sec>
</abstract>
<custom-meta-group>
<custom-meta>
<meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2020</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body>
<sec id="FPar1">
<title>Key Points</title>
<p id="Par6">
<table-wrap id="Taba">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">Intramuscular clodronate is well-tolerated and effective for the management of symptomatic knee osteoarthritis.</td>
</tr>
<tr>
<td align="left">The efficacy of clodronate is directly proportional to the treatment duration.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec1">
<title>Introduction</title>
<p id="Par7">Osteoarthritis (OA) is highly prevalent worldwide and usually causes severe pain and disability [
<xref ref-type="bibr" rid="CR1">1</xref>
]. Since the early pathogenesis of the disease remains unknown, no drugs are yet available to stop the progression of OA. However, it is important that treatments to control pain and improve both physical activity levels and quality of life for patients are developed.</p>
<p id="Par8">The pathogenesis of pain in OA is also uncertain, but the extensive use of magnetic resonance imaging (MRI) over recent decades has enabled researchers to understand some important points. The radiological detection of bone marrow edema (BME) in symptomatic joints and its correlation with OA development was an important step in understanding the progression of the disease [
<xref ref-type="bibr" rid="CR2">2</xref>
–
<xref ref-type="bibr" rid="CR4">4</xref>
].</p>
<p id="Par9">Since an altered signal pattern seems related to lymphocytic infiltrates, fibrosis, increased vascularization, less mineralized bone, and real local edema, the preferred term in most recent literature OA is bone marrow lesions (BML).</p>
<p id="Par10">However, more recent studies found some important correlations between BML and progression of pain and OA. Indeed, all histopathological studies have involved patients with severe joint disease, in whom the only therapeutic option was a prosthesis [
<xref ref-type="bibr" rid="CR4">4</xref>
–
<xref ref-type="bibr" rid="CR7">7</xref>
].</p>
<p id="Par11">In recent years, bisphosphonates have proven their efficacy in the treatment of some diseases with a finding of BML and BME, especially at high dosages and with parenteral administration. However, continuous administration of bisphosphonates, even at lower dosages, has proven to have symptomatic effectiveness [
<xref ref-type="bibr" rid="CR8">8</xref>
–
<xref ref-type="bibr" rid="CR11">11</xref>
].</p>
<p id="Par12">Clodronate is a nitrogen-free bisphosphonate that is widely and effectively used in the treatment of many osteo-metabolic disorders [
<xref ref-type="bibr" rid="CR12">12</xref>
–
<xref ref-type="bibr" rid="CR16">16</xref>
]. In particular, we highlight its efficacy in the treatment of algodystrophic syndrome [
<xref ref-type="bibr" rid="CR17">17</xref>
], hand-erosive OA [
<xref ref-type="bibr" rid="CR18">18</xref>
], and knee OA (intra-articular clodronate) [
<xref ref-type="bibr" rid="CR19">19</xref>
].</p>
<p id="Par13">The aim of our study was to evaluate the efficacy of two therapeutic regimens of intramuscular clodronate, using identical initial therapeutic doses but different maintenance doses. The initial therapeutic dose was the same as used by Varenna et al. [
<xref ref-type="bibr" rid="CR17">17</xref>
] (intravenous clodronate 300 mg daily for 10 days) for the treatment of algodystrophy.</p>
<p id="Par14">The safety of our proposed regimen was evidenced by the overall low incidence of adverse events during clodronate treatment [
<xref ref-type="bibr" rid="CR20">20</xref>
] and by the safety reported by Frediani et al. [
<xref ref-type="bibr" rid="CR21">21</xref>
], who used intramuscular clodronate 100 mg once or twice weekly in the treatment of postmenopausal osteoporosis.</p>
</sec>
<sec id="Sec2">
<title>Materials and Methods</title>
<p id="Par15">We included all patients who attended the Rheumatology Department of Policlinico Le Scotte, Siena, Italy, for knee pain from January 2013 to December 2014 who were aged > 40 years and met the following inclusion criteria: knee OA according to American College of Rheumatology criteria [
<xref ref-type="bibr" rid="CR22">22</xref>
], Kellgren–Lawrence radiographic score ≥ 2 in the tibiofemoral joint [
<xref ref-type="bibr" rid="CR23">23</xref>
], worsening chronic knee pain lasting from 2 weeks to 43 months, visual analogue scale (VAS) > 40/100 mm, BML diameter > 0.5 cm as seen in a knee MRI, and lumbar or femoral T-score less than -2.5.</p>
<p id="Par16">The main outcome of the study was variations in pain intensity using a VAS score. VAS score was recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). As secondary endpoints, we evaluated functional status (Western Ontario and McMaster University Osteoarthritis Index [WOMAC] questionnaire—pain, stiffness and physical function—at T0, T1, T2, T3, T4, and T5), patient use of paracetamol (T0, T1, T2, T3, T4, and T5), and Whole Organ Magnetic Resonance Imaging Score (WORMS) modifications (T0, T2, and T5).</p>
<p id="Par17">The exclusion criteria were hypocalcemia; hypercalcemia; low glomerular filtration rate (< 30 mL/min); liver, kidney, heart, lung, or neurological diseases; diabetes; tumors; previous treatment with bisphosphonates; and knee pain due to trauma.</p>
<p id="Par18">Intra-articular injection of steroids and/or hyaluronic acid was not permitted during the study or in the 3 months before.</p>
<p id="Par19">During the study, patients were not permitted to use nonsteroidal anti-inflammatory drugs but were allowed to take paracetamol up to 3 g daily and were required to record consumption in their own diary. Paracetamol consumption was expressed in average grams per patient per day.</p>
<p id="Par20">All procedures that involved human participants were in accordance with the ethical standards of the national and Hospital of Siena research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients provided written consent to participate in the study.</p>
<sec id="Sec3">
<title>Randomization</title>
<p id="Par21">Patients were randomized into two parallel treatment groups: Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months.</p>
</sec>
<sec id="Sec4">
<title>Knee Magnetic Resonance Imaging</title>
<p id="Par22">Each patient underwent 3-D high-resolution MRI at T0, T2, and T5. Every MRI was evaluated by an expert musculoskeletal radiologist blinded to patient grouping. The images were acquired in coronal, axial, and sagittal planes, with a field of view of 18 cm and 256 × 256 matrix, with an 0.5 mm intersection gap.</p>
<p id="Par23">T1-weighted spin-echo MRI scans were acquired in coronal, axial, and sagittal planes (repetition time [TR] 580 ms, echo time [TE] 12 ms); T2-weighted spin-echo scans were acquired in axial and sagittal planes (TR 4000 ms, TE 30/100 ms); proton-density fat-suppression-weighted scans were acquired in a coronal plane (TR 2800 ms, TE 40 ms).</p>
<p id="Par24">Subchondral BMLs were identified as high-intensity signal areas on T2-weighted fat-suppression imaging and analyzed using WORMS [
<xref ref-type="bibr" rid="CR24">24</xref>
].</p>
<p id="Par25">BMLs were codified from 0 to 3 in each of the ten subregions of the medial and lateral tibiofemoral compartment and in each of the four subregions of the patellofemoral compartment by an experienced radiologist. The extent of lesions was evaluated using the WORMS scale (0 = no edema; 1 = < 25%; 2 = 25–50%; 3 = > 50%), and a total WORMS was calculated by adding the score for each subregion together.</p>
</sec>
<sec id="Sec5">
<title>Statistical Analysis</title>
<p id="Par26">We computed the statistical significance using a two-tailed test, with a significance level set at < 0.05.</p>
<p id="Par27">According to the results of previous studies of pain reduction in patients treated with zoledronate [
<xref ref-type="bibr" rid="CR25">25</xref>
] and neridronate [
<xref ref-type="bibr" rid="CR26">26</xref>
], we anticipated a VAS score reduction of > 20 mm in patients treated with clodronate.</p>
<p id="Par28">We analyzed results according to the “intention-to-treat” principle, including all randomized patients who received at least one dose of clodronate. Since our outcomes were not normally distributed (Shapiro–Wilk test), we used nonparametric tests.</p>
<p id="Par29">We used the Mann–Whitney
<italic>U</italic>
test to evaluate differences between the two groups and the Wilcoxon-signed rank test to evaluate the intra-group differences and WORMS score at T1, T2, T3, T4, and T5.</p>
<p id="Par30">Predictive factors for VAS and WORMS modifications were evaluated using univariate and multivariate regression analysis.</p>
<p id="Par31">We analyzed both absolute and percentage differences. All statistical tests were bilateral, with
<italic>p</italic>
 < 0.05, and evaluated using SPSS software (version 17.0; IBM, Armonk, NY, USA).</p>
</sec>
</sec>
<sec id="Sec6">
<title>Results</title>
<p id="Par32">A total of 74 patients were included in the study, equally distributed between the two groups. No patient withdrew before the end of the study. The two groups were similar at T0 (Table 
<xref rid="Tab1" ref-type="table">1</xref>
).
<table-wrap id="Tab1">
<label>Table 1</label>
<caption>
<p>Patient characteristics at baseline (T0)</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Characteristics</th>
<th align="left">Group 1 (
<italic>n</italic>
 = 37)</th>
<th align="left">Group 2 (
<italic>n</italic>
 = 37)</th>
<th align="left">
<italic>p</italic>
value</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Age (years)</td>
<td align="left">68.3 ± 13.7</td>
<td align="left">66.1 ± 12.1</td>
<td align="left">0.2</td>
</tr>
<tr>
<td align="left">Sex (F/M),
<italic>n</italic>
</td>
<td align="left">24/13</td>
<td align="left">20/17</td>
<td align="left">0.5</td>
</tr>
<tr>
<td align="left">BMI, kg/m
<sup>2</sup>
</td>
<td align="left">26.3</td>
<td align="left">26.8</td>
<td align="left">0.8</td>
</tr>
<tr>
<td align="left">Duration of pain, weeks</td>
<td align="left">12.7 ± 4.2</td>
<td align="left">11.1 ± 3.5</td>
<td align="left">0.1</td>
</tr>
<tr>
<td align="left">VAS score (0–100), mm</td>
<td align="left">62.4 ± 13.6</td>
<td align="left">68.7 ± 17.3</td>
<td align="left">0.2</td>
</tr>
<tr>
<td align="left">WOMAC score (pain)</td>
<td align="left">6.6 ± 2.0</td>
<td align="left">7.2 ± 2.4</td>
<td align="left">0.1</td>
</tr>
<tr>
<td align="left">WOMAC score (disability)</td>
<td align="left">20.6 ± 3.8</td>
<td align="left">22.1 ± 4.3</td>
<td align="left">0.3</td>
</tr>
<tr>
<td align="left">WOMAC score (stiffness)</td>
<td align="left">3.0 ± 1.5</td>
<td align="left">2.9 ± 1.9</td>
<td align="left">0.9</td>
</tr>
<tr>
<td align="left">WORMS</td>
<td align="left">6.9 ± 2.6</td>
<td align="left">7.6 ± 3.7</td>
<td align="left">0.2</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data are presented as mean ± standard deviation or
<italic>N</italic>
(%) unless otherwise indicated. Group 1: intramuscular clodronate 200 mg daily for 15 days, then once weekly for the next 11.5 months; group 2: intramuscular clodronate 200 mg daily for 15 days, then once weekly for the next 2.5 months</p>
<p>
<italic>BMI</italic>
body mass index,
<italic>F</italic>
female,
<italic>M</italic>
male,
<italic>VAS</italic>
visual analog scale,
<italic>WOMAC</italic>
Western Ontario and McMaster University Osteoarthritis Index,
<italic>WORMS</italic>
whole organ magnetic resonance imaging score</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par33">For both groups, VAS statistically significantly reduced until 3 months (T2), from 62.4 ± 13.6 (standard deviation) to 10.3 ± 8.9 in group 1 and from 68.7 ± 17.3 to 11.2 ± 9.4 in group 2. Group 1 then experienced a further VAS reduction at T3 (9.3 ± 7.8), with minimal changes at T4 (12.4 ± 8.7) and T5 (15.6 ± 9.8), whereas VAS scores for group 2 progressively increased (28.8 ± 20.3 at T3; 43.8 ± 30.1 at T4; 50.3 ± 31.9 at T5) (Fig. 
<xref rid="Fig1" ref-type="fig">1</xref>
).
<fig id="Fig1">
<label>Fig. 1</label>
<caption>
<p>VAS variation (%).
<italic>VAS</italic>
visual analog scale</p>
</caption>
<graphic xlink:href="40268_2020_294_Fig1_HTML" id="MO1"></graphic>
</fig>
</p>
<p id="Par34">The same trend was also observed for WOMAC score (pain, stiffness, physical function) (Table 
<xref rid="Tab2" ref-type="table">2</xref>
).
<table-wrap id="Tab2">
<label>Table 2</label>
<caption>
<p>Patient characteristics at different timepoints during the study</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" rowspan="2">Characteristics</th>
<th align="left" colspan="2">T0 (baseline)</th>
<th align="left" colspan="2">T1 (30 days)</th>
<th align="left" colspan="2">T2 (3 months)</th>
<th align="left" colspan="2">T3 (6 months)</th>
<th align="left" colspan="2">T4 (9 months)</th>
<th align="left" colspan="2">T5 (end of study; 12 months)</th>
</tr>
<tr>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
<th align="left">Group 1</th>
<th align="left">Group 2</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">VAS</td>
<td char="±" align="char">62.4 ± 13.6</td>
<td char="±" align="char">68.7 ± 17.3</td>
<td align="left">35.2* ± 11.2</td>
<td align="left">37.8* ± 13.1</td>
<td char="±" align="char">10.3* ± 8.9</td>
<td char="±" align="char">11.2* ± 9.4</td>
<td align="left">9.3* ± 7.8</td>
<td align="left">28.3** ± 10.3
<sup>††</sup>
</td>
<td char="±" align="left">12.4* ± 8.7</td>
<td char="±" align="left">43.8
<sup>†</sup>
 ± 30.1</td>
<td char="±" align="char">15.6* ± 9.8</td>
<td char="±" align="char">50.3
<sup>†</sup>
 ± 31.9</td>
</tr>
<tr>
<td align="left">WOMAC pain</td>
<td char="±" align="char">6.6 ± 2.0</td>
<td char="±" align="char">7.2 ± 2.4</td>
<td align="left">4.1** ± 0.9</td>
<td align="left">4.3** ± 0.7</td>
<td char="±" align="char">2.8* ± 0.7</td>
<td char="±" align="char">2.3* ± 0.9</td>
<td align="left">2.5* ± 1.0</td>
<td align="left">3.8** ± 1.9
<sup>††</sup>
</td>
<td char="±" align="left">3.0* ± 1.4</td>
<td char="±" align="left">5.2 ± 3.8
<sup>††</sup>
</td>
<td char="±" align="char">2.8* ± 1.2</td>
<td char="±" align="char">5.8 ± 4.1
<sup>†</sup>
</td>
</tr>
<tr>
<td align="left">WOMAC disability</td>
<td char="±" align="char">20.6 ± 3.8</td>
<td char="±" align="char">22.1 ± 4.3</td>
<td align="left">15.1** ± 4.3</td>
<td align="left">17.2** ± 5.2</td>
<td char="±" align="char">10.2* ± 4.3</td>
<td char="±" align="char">10.8* ± 5.0</td>
<td align="left">12.1* ± 4.8</td>
<td align="left">18.1
<sup>††</sup>
 ± 6.9</td>
<td char="±" align="left">13.2* ± 5.2</td>
<td char="±" align="left">20.3
<sup>††</sup>
 ± 9.9</td>
<td char="±" align="char">13.5* ± 5.7</td>
<td char="±" align="char">24.0 ± 11.9
<sup>†</sup>
</td>
</tr>
<tr>
<td align="left">WOMAC stiffness</td>
<td char="±" align="char">3.0 ± 1.5</td>
<td char="±" align="char">2.9 ± 1.9</td>
<td align="left">2.0** ± 1.2</td>
<td align="left">2.2** ± 1.3</td>
<td char="±" align="char">1.3* ± 0.9</td>
<td char="±" align="char">1.4* ± 0.7</td>
<td align="left">1.4* ± 0.9</td>
<td align="left">2.0** ± 1.9</td>
<td char="±" align="left">1.5* ± 1.1</td>
<td char="±" align="left">2.8
<sup>†</sup>
 ± 2.1</td>
<td char="±" align="char">1.7* ± 1.3</td>
<td char="±" align="char">3.2
<sup>†</sup>
 ± 2.7</td>
</tr>
<tr>
<td align="left">WORMS</td>
<td char="±" align="char">6.9 ± 2.6</td>
<td char="±" align="char">7.6 ± 3.7</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td char="±" align="char">2.1* ± 1.8</td>
<td char="±" align="char">2.0* ± 1.2</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td align="left">NA</td>
<td char="±" align="char">1.1* ± 0.8</td>
<td char="±" align="char">5.9
<sup>†</sup>
 ± 4.9</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>Data are presented as mean ± standard deviation. Group 1: intramuscular clodronate 200 mg daily for 15 days, then once weekly for the next 11.5 months; group 2: intramuscular clodronate 200 mg daily for 15 days, then once weekly for the next 2.5 months</p>
<p>
<italic>NA</italic>
not measured at this timepoint,
<italic>VAS</italic>
visual analog scale,
<italic>WOMAC</italic>
Western Ontario and McMaster University Osteoarthritis Index</p>
<p>T vs. T0: *
<italic>p</italic>
 < 0.01, **
<italic>p</italic>
 < 0.05; Group 1 vs. group 2:
<sup>†</sup>
<italic>p</italic>
 < 0.01;
<sup>††</sup>
<italic>p</italic>
 < 0.05</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par35">The consumption of paracetamol decreased in both groups until T2 (group 1: 1.16 ± 0.6 at T0; 0.72 ± 0.5 at T1; 0.55 ± 0.5 at T2; group 2: 1.13 ± 0.6 at T0; 0.72 ± 0.4 at T1; 0.64 ± 0.4 at T2). The average intake of paracetamol increased in group 2 (0.94 ± 0.6 at T3; 1.04 ± 0.7 at T4; 1.05 ± 0.7 at T5) but further reduced in group 1 at T3 and T4 (0.42 ± 0.4 and 0.28 ± 0.2, respectively), remaining substantially stable at T5 (0.29 ± 0.2).</p>
<p id="Par36">BML extension, evaluated by WORMS total score, progressively decreased (group 1: 6.9 ± 2.6 at T0 to 2.1 ± 1.8 at T2; group 2: 7.6 ± 3.7 at T0 to 2.0 ± 1.2 at T2) (Fig. 
<xref rid="Fig3" ref-type="fig">3</xref>
); in group 1, it continued to decrease until T5 (1.1 ± 0.8), whereas it increased in group 2 (5.9 ± 4.9 at T5) (Fig. 
<xref rid="Fig2" ref-type="fig">2</xref>
).
<fig id="Fig2">
<label>Fig. 2</label>
<caption>
<p>WORMS variation (%).
<italic>WORMS</italic>
Whole Organ Magnetic Resonance Imaging Score</p>
</caption>
<graphic xlink:href="40268_2020_294_Fig2_HTML" id="MO2"></graphic>
</fig>
</p>
<p id="Par37">No adverse events were reported during the study, as expected given the results reported by Frediani et al. [
<xref ref-type="bibr" rid="CR21">21</xref>
]. In particular, no difference in serum creatinine or creatinine clearance was found after 3, 6, 9, and 12 months of treatment (Fig. 
<xref rid="Fig3" ref-type="fig">3</xref>
).
<fig id="Fig3">
<label>Fig. 3</label>
<caption>
<p>MRI before and after clodronate therapy (T2 [3 months]).
<italic>MRI</italic>
magnetic resonance imaging</p>
</caption>
<graphic xlink:href="40268_2020_294_Fig3_HTML" id="MO3"></graphic>
</fig>
</p>
</sec>
<sec id="Sec7">
<title>Discussion</title>
<p id="Par38">Bisphosphonates have proven effective in several conditions characterized by BME and pain, and clodronate in particular is well-known for its anti-inflammatory and analgesic properties [
<xref ref-type="bibr" rid="CR8">8</xref>
,
<xref ref-type="bibr" rid="CR18">18</xref>
–
<xref ref-type="bibr" rid="CR20">20</xref>
] and good safety profile. Intravenous clodronate has proven effective against BME of algodystrophic syndrome when administered at a dose of 300 mg/day for 10 days [
<xref ref-type="bibr" rid="CR17">17</xref>
] and has been used to treat painful episodes of erosive OA of the hand [
<xref ref-type="bibr" rid="CR18">18</xref>
].</p>
<p id="Par39">Another case report described the effectiveness of intramuscular clodronate 100 mg in ankle algodystrophic syndrome in a patient with psoriatic arthritis [
<xref ref-type="bibr" rid="CR27">27</xref>
].</p>
<p id="Par40">More powerful molecules, such as amino-bisphosphonates, are widely described in the treatment of algodystrophic syndrome, namely neridronate [
<xref ref-type="bibr" rid="CR28">28</xref>
] and alendronate [
<xref ref-type="bibr" rid="CR29">29</xref>
]; however, their mechanism of action means they can cause well-known acute phase reactions, especially when administered intravenously.</p>
<p id="Par41">Only a few papers describe the role of bisphosphonates in OA, with the vast majority investigating clodronate. The role of clodronate in OA, summarized in the recent review by Saviola et al. [
<xref ref-type="bibr" rid="CR30">30</xref>
], is an intriguing matter of debate: it may represent a promising therapy even in erosive OA [
<xref ref-type="bibr" rid="CR31">31</xref>
], in which it was found to be superior over hydroxychloroquine in reducing pain and loss of strength [
<xref ref-type="bibr" rid="CR18">18</xref>
]. Moreover, clodronate, the role of which in bone metabolism has been previously summarized and widely described, may also have a role in chondrocyte differentiation, as outlined by Valenti et al. [
<xref ref-type="bibr" rid="CR32">32</xref>
], who reported that nanoparticles of clodronate led to SOX9 upregulation. However, none of these studies evaluated the effect of clodronate on BML.</p>
<p id="Par42">Two previous studies reported that the bisphosphonates neridronate [
<xref ref-type="bibr" rid="CR26">26</xref>
] and zoledronate [
<xref ref-type="bibr" rid="CR25">25</xref>
] were both effective in terms of reducing pain and physical impairment in knee OA, but neridronate appeared to have a faster onset of action and was better at reducing BML. However, further data on middle- and long-term efficacy are absent.</p>
<p id="Par43">A strong correlation between BML and pain has been assumed, as pain can be caused by impaired venous drainage, increased intra-osseous pressure, and local acidosis [
<xref ref-type="bibr" rid="CR33">33</xref>
].</p>
<p id="Par44">However, no consensus has been reached on what exactly defines a BML from a histopathologic viewpoint. According to the most recent literature, an altered signal pattern appears to be related to lymphocytic infiltrates, fibrosis, increased vascularization, and less mineralized bone, as well as real local edema [
<xref ref-type="bibr" rid="CR34">34</xref>
]; trabecular bone is also involved, and bony remodeling is a common finding [
<xref ref-type="bibr" rid="CR35">35</xref>
].</p>
<p id="Par45">Bisphosphonates are well-known to have both central and peripheral anti-inflammatory and analgesic effects. Interesting applications of bisphosphonates include studies in animal models of collagen-induced arthrosis, where rational use of the antiresorptive drug is described in recent scientific literature emphasizing the role of osteoclastic activation by pro-inflammatory cytokines in the genesis of structural bone damage and erosions. Inhibition of bone resorption, from this viewpoint, is a key point in arthritis therapy [
<xref ref-type="bibr" rid="CR36">36</xref>
,
<xref ref-type="bibr" rid="CR37">37</xref>
].</p>
<p id="Par46">However, in animal models, amino-bisphosphonates exacerbated joint inflammation [
<xref ref-type="bibr" rid="CR38">38</xref>
], despite their positive effects on structural bone damage, whereas clodronate had positive effects on inhibition of both structural damage and joint inflammation [
<xref ref-type="bibr" rid="CR39">39</xref>
,
<xref ref-type="bibr" rid="CR40">40</xref>
].</p>
<p id="Par47">In particular, Bonabello’s studies [
<xref ref-type="bibr" rid="CR41">41</xref>
,
<xref ref-type="bibr" rid="CR42">42</xref>
] in animal models highlighted a pain-relieving and antinociceptive effect of clodronate at both central and peripheral levels, independent of the antifracture effect. Several reports have highlighted the pain-relieving properties of clodronate in different fields [
<xref ref-type="bibr" rid="CR43">43</xref>
–
<xref ref-type="bibr" rid="CR48">48</xref>
]. Clodronate’s analgesic effect is known and commonly used in clinical practice, including in patients with vertebral fragility fractures [
<xref ref-type="bibr" rid="CR43">43</xref>
–
<xref ref-type="bibr" rid="CR45">45</xref>
], where the drug had a greater pain-killing effect than other amino-bisphosphonates, including neridronate [
<xref ref-type="bibr" rid="CR46">46</xref>
]. In addition, we cannot forget the analgesic role of clodronate in oncology, especially in patients with skeletal involvement [
<xref ref-type="bibr" rid="CR47">47</xref>
,
<xref ref-type="bibr" rid="CR48">48</xref>
].</p>
<p id="Par48">Moreover, a recent randomized controlled trial proved the effectiveness of intra-articular clodronate 2 mg per week for 4 weeks in reducing pain compared with NaCl 0.9% [
<xref ref-type="bibr" rid="CR19">19</xref>
]; the same working group proved the noninferiority of intra-articular clodronate versus hyaluronic acid [
<xref ref-type="bibr" rid="CR49">49</xref>
].</p>
<p id="Par49">As reported in studies using zoledronate [
<xref ref-type="bibr" rid="CR25">25</xref>
] and neridronate [
<xref ref-type="bibr" rid="CR26">26</xref>
] in OA, our paper indicates that clodronate reduces pain and BML. Our study is also the first to demonstrate that an initial higher dose of clodronate followed by intramuscular maintenance administration prevented increased BML and pain; patients who stopped treatment did not experience this effect.</p>
<p id="Par50">Our study has a limitation that should be noted: We used indirect instruments for the evaluation of drug efficacy, such as a pain questionnaire and WORMS. This score measures the extent of edema, but we acknowledge that edema may be related not only to OA but also to many other conditions (trauma, inflammation, and tumor, among others).</p>
</sec>
<sec id="Sec8">
<title>Conclusions</title>
<p id="Par51">Intramuscular clodronate at a therapeutic dose followed by a maintenance dose is effective in the management of symptomatic knee OA, improving functional outcomes and reducing pain and BML.</p>
<p id="Par52">Further studies are needed to create a universal treatment schedule for the use of clodronate in this complex disease. In particular, clodronate may offer enhanced protection in early-stage OA, so should be investigated in such patients.</p>
<p id="Par53">Higher doses of this drug than used in osteoporosis will be necessary, and the duration will need to be longer than that used in algodystrophic syndrome.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgements</title>
<p>Medical writing was performed by Luca Giacomelli, PhD; editorial assistance was provided by Aashni Shah (Polistudium SRL, Milan, Italy). This assistance was supported by internal funds.</p>
</ack>
<notes>
<title>Compliance with Ethical Standards</title>
<notes notes-type="COI-statement">
<title>Conflicts of Interest</title>
<p id="Par54">Bruno Frediani, Carmela Toscano, Paolo Falsetti, Antonella Nicosia, Serena Pierguidi, Alberto Migliore, Stefano Giannotti, Luca Cantarini and Edoardo Conticini have no conflicts of interest that are directly relevant to the content of this article.</p>
</notes>
<notes notes-type="funding">
<title>Funding</title>
<p id="Par55">No sources of funding were used to conduct this study or prepare this manuscript.</p>
</notes>
<notes>
<title>Ethical Standards</title>
<p id="Par56">All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.</p>
</notes>
<notes>
<title>Informed Consent</title>
<p id="Par57">Informed consent was obtained from all individual participants included in the study.</p>
</notes>
</notes>
<ref-list id="Bib1">
<title>References</title>
<ref id="CR1">
<label>1.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lawrence</surname>
<given-names>RC</given-names>
</name>
<name>
<surname>Felson</surname>
<given-names>DT</given-names>
</name>
<name>
<surname>Helmick</surname>
<given-names>CG</given-names>
</name>
<name>
<surname>Arnold</surname>
<given-names>LM</given-names>
</name>
<name>
<surname>Choi</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Deyo</surname>
<given-names>RA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II</article-title>
<source>Arthritis Rheum</source>
<year>2008</year>
<volume>58</volume>
<fpage>26</fpage>
<lpage>35</lpage>
<pub-id pub-id-type="pmid">18163497</pub-id>
</element-citation>
</ref>
<ref id="CR2">
<label>2.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Felson</surname>
<given-names>DT</given-names>
</name>
<name>
<surname>Chaisson</surname>
<given-names>CE</given-names>
</name>
<name>
<surname>Hill</surname>
<given-names>CL</given-names>
</name>
<name>
<surname>Totterman</surname>
<given-names>SM</given-names>
</name>
<name>
<surname>Gale</surname>
<given-names>ME</given-names>
</name>
<name>
<surname>Skinner</surname>
<given-names>KM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The association of bone marrow lesions with pain in knee osteoarthritis</article-title>
<source>Ann Intern Med</source>
<year>2001</year>
<volume>134</volume>
<fpage>541</fpage>
<lpage>549</lpage>
<pub-id pub-id-type="pmid">11281736</pub-id>
</element-citation>
</ref>
<ref id="CR3">
<label>3.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Felson</surname>
<given-names>DY</given-names>
</name>
<name>
<surname>McLaughlin</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Goggins</surname>
<given-names>J</given-names>
</name>
<name>
<surname>LaValley</surname>
<given-names>MP</given-names>
</name>
<name>
<surname>Gale</surname>
<given-names>ME</given-names>
</name>
<name>
<surname>Totterman</surname>
<given-names>S</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bone marrow edema and its relation to progression of knee osteoarthrtitis</article-title>
<source>Ann Inter Med</source>
<year>2003</year>
<volume>139</volume>
<fpage>330</fpage>
<lpage>336</lpage>
</element-citation>
</ref>
<ref id="CR4">
<label>4.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Zanetti</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Bruder</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Romero</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Hodler</surname>
<given-names>J</given-names>
</name>
</person-group>
<article-title>Bone marrow edema pattern in osteoarthritic knees: correlation between MR imaging and histologic findings</article-title>
<source>Radiology</source>
<year>2000</year>
<volume>215</volume>
<fpage>835</fpage>
<lpage>840</lpage>
<pub-id pub-id-type="pmid">10831707</pub-id>
</element-citation>
</ref>
<ref id="CR5">
<label>5.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saadat</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Jobke</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Chu</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Lu</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>X</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Diagnostic performance of in vivo 3-T MRI for articular cartilage abnormalities in human osteoarthritic knees using histology as standard of reference</article-title>
<source>Eur Radiol</source>
<year>2008</year>
<volume>18</volume>
<fpage>2292</fpage>
<lpage>2302</lpage>
<pub-id pub-id-type="pmid">18491096</pub-id>
</element-citation>
</ref>
<ref id="CR6">
<label>6.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kazakia</surname>
<given-names>GJ</given-names>
</name>
<name>
<surname>Kuo</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Schooler</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Siddiqui</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Shanbhag</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Bernstein</surname>
<given-names>G</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bone and cartilage demonstrate changes localized to bone marrow edemalike lesions within osteoarthritic knees</article-title>
<source>Osteoarth Cartil</source>
<year>2013</year>
<volume>21</volume>
<fpage>94</fpage>
<lpage>101</lpage>
</element-citation>
</ref>
<ref id="CR7">
<label>7.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Yusuf</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Kortekaas</surname>
<given-names>MC</given-names>
</name>
<name>
<surname>Watt</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Huizinga</surname>
<given-names>TW</given-names>
</name>
<name>
<surname>Kloppenburg</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review</article-title>
<source>Ann Rheum Dis</source>
<year>2011</year>
<volume>70</volume>
<fpage>60</fpage>
<lpage>67</lpage>
<pub-id pub-id-type="pmid">20829200</pub-id>
</element-citation>
</ref>
<ref id="CR8">
<label>8.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Maksymowych</surname>
<given-names>WP</given-names>
</name>
<name>
<surname>Jhangri</surname>
<given-names>GS</given-names>
</name>
<name>
<surname>Fitzgerald</surname>
<given-names>AA</given-names>
</name>
<name>
<surname>LeClercq</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Chiu</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Yan</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A six-month randomized, controlled, double-blind, dose response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis</article-title>
<source>Arthritis Rheum</source>
<year>2002</year>
<volume>46</volume>
<fpage>766</fpage>
<lpage>773</lpage>
<pub-id pub-id-type="pmid">11920413</pub-id>
</element-citation>
</ref>
<ref id="CR9">
<label>9.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Varenna</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Zucchi</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Binelli</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Failoni</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Gallazzi</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Sinigaglia</surname>
<given-names>L</given-names>
</name>
</person-group>
<article-title>Intravenous pamidronate in the treatment of transient osteoporosis of the hip</article-title>
<source>Bone</source>
<year>2002</year>
<volume>31</volume>
<fpage>96</fpage>
<lpage>101</lpage>
<pub-id pub-id-type="pmid">12110419</pub-id>
</element-citation>
</ref>
<ref id="CR10">
<label>10.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tran</surname>
<given-names>DQH</given-names>
</name>
<name>
<surname>Duong</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Bertini</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Finlayson</surname>
<given-names>RJ</given-names>
</name>
</person-group>
<article-title>Treatment of complex regional pain syndrome: a review of the evidence</article-title>
<source>Can J Anaesth</source>
<year>2010</year>
<volume>57</volume>
<fpage>149</fpage>
<lpage>166</lpage>
<pub-id pub-id-type="pmid">20054678</pub-id>
</element-citation>
</ref>
<ref id="CR11">
<label>11.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Davis</surname>
<given-names>AJ</given-names>
</name>
<name>
<surname>Smith</surname>
<given-names>TO</given-names>
</name>
<name>
<surname>Hing</surname>
<given-names>CB</given-names>
</name>
<name>
<surname>Sofat</surname>
<given-names>N</given-names>
</name>
</person-group>
<article-title>Are bisphosphonates effective in the treatment of osteoarthritis pain? A meta-analysis and systematic review</article-title>
<source>PLoS One</source>
<year>2013</year>
<volume>8</volume>
<fpage>e72714</fpage>
<pub-id pub-id-type="pmid">24023766</pub-id>
</element-citation>
</ref>
<ref id="CR12">
<label>12.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Khan</surname>
<given-names>SA</given-names>
</name>
<name>
<surname>McCloskey</surname>
<given-names>EV</given-names>
</name>
<name>
<surname>Nakatsuka</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Orgee</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Coombes</surname>
<given-names>GM</given-names>
</name>
<name>
<surname>Kanis</surname>
<given-names>JA</given-names>
</name>
</person-group>
<article-title>Duration of response with oral clodronate in Paget’s disease of bone</article-title>
<source>Bone</source>
<year>1996</year>
<volume>18</volume>
<issue>2</issue>
<fpage>185</fpage>
<lpage>190</lpage>
<pub-id pub-id-type="pmid">8833213</pub-id>
</element-citation>
</ref>
<ref id="CR13">
<label>13.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Body</surname>
<given-names>JJ</given-names>
</name>
<name>
<surname>Coleman</surname>
<given-names>RE</given-names>
</name>
<name>
<surname>Piccart</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>Use of bisphosphonates in cancer patients</article-title>
<source>Cancer Treat Rev</source>
<year>1996</year>
<volume>22</volume>
<issue>4</issue>
<fpage>265</fpage>
<lpage>287</lpage>
<pub-id pub-id-type="pmid">9025784</pub-id>
</element-citation>
</ref>
<ref id="CR14">
<label>14.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Adami</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Bolzicco</surname>
<given-names>GP</given-names>
</name>
<name>
<surname>Rizzo</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Salvagno</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Bertoldo</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Rossini</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy</article-title>
<source>Bone Miner</source>
<year>1987</year>
<volume>2</volume>
<issue>5</issue>
<fpage>395</fpage>
<lpage>404</lpage>
<pub-id pub-id-type="pmid">2975514</pub-id>
</element-citation>
</ref>
<ref id="CR15">
<label>15.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Douglas</surname>
<given-names>DL</given-names>
</name>
<name>
<surname>Kanis</surname>
<given-names>JA</given-names>
</name>
<name>
<surname>Paterson</surname>
<given-names>AD</given-names>
</name>
<name>
<surname>Beard</surname>
<given-names>DJ</given-names>
</name>
<name>
<surname>Cameron</surname>
<given-names>EC</given-names>
</name>
<name>
<surname>Watson</surname>
<given-names>ME</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Drug treatment of primary hyperparathyroidism: use of clodronate disodium</article-title>
<source>Br Med J</source>
<year>1983</year>
<volume>286</volume>
<issue>6365</issue>
<fpage>587</fpage>
<lpage>590</lpage>
<pub-id pub-id-type="pmid">6218861</pub-id>
</element-citation>
</ref>
<ref id="CR16">
<label>16.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shane</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Baquiran</surname>
<given-names>DC</given-names>
</name>
<name>
<surname>Bilezikian</surname>
<given-names>JP</given-names>
</name>
</person-group>
<article-title>Effects of dichloromethylene diphosphonate on serum and urinary calcium in primary hyperparathyroidism</article-title>
<source>Ann Intern Med</source>
<year>1981</year>
<volume>95</volume>
<issue>1</issue>
<fpage>23</fpage>
<lpage>27</lpage>
<pub-id pub-id-type="pmid">6264825</pub-id>
</element-citation>
</ref>
<ref id="CR17">
<label>17.</label>
<mixed-citation publication-type="other">Varenna M, Zucchi F, Ghiringhelli D, Binelli L, Bevilacqua M, Bettica P, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol 2000;27(6):1477–83.</mixed-citation>
</ref>
<ref id="CR18">
<label>18.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saviola</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Abdi-Ali</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Campostrini</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Sacco</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Baiardi</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Manfredi</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clodronate and hydroxychloroquine in erosive osteoarthritis: a 24-month open randomized pilot study</article-title>
<source>Mod Rheumatol</source>
<year>2012</year>
<volume>22</volume>
<issue>2</issue>
<fpage>256</fpage>
<lpage>263</lpage>
<pub-id pub-id-type="pmid">21853386</pub-id>
</element-citation>
</ref>
<ref id="CR19">
<label>19.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rossini</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Adami</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Fracassi</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Viapiana</surname>
<given-names>O</given-names>
</name>
<name>
<surname>Orsolini</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Povino</surname>
<given-names>MR</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Effects of intra-articular clodronate in the treatment of knee osteoarthritis: results of a double-blind, randomized placebo-controlled trial</article-title>
<source>Rheumatol Int</source>
<year>2015</year>
<volume>35</volume>
<issue>2</issue>
<fpage>255</fpage>
<lpage>263</lpage>
<pub-id pub-id-type="pmid">25080876</pub-id>
</element-citation>
</ref>
<ref id="CR20">
<label>20.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Frediani</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Giusti</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Bianchi</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Dalle Carbonare</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Malavolta</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Cantarini</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Saviola</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Molfetta</surname>
<given-names>L</given-names>
</name>
</person-group>
<article-title>Clodronate in the management of different musculoskeletal conditions</article-title>
<source>Minerva Med.</source>
<year>2018</year>
<volume>109</volume>
<issue>4</issue>
<fpage>300</fpage>
<lpage>325</lpage>
<pub-id pub-id-type="pmid">29947493</pub-id>
</element-citation>
</ref>
<ref id="CR21">
<label>21.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Frediani</surname>
<given-names>B</given-names>
</name>
<name>
<surname>Bertoldi</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Pierguidi</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Nicosia</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Picerno</surname>
<given-names>V</given-names>
</name>
<name>
<surname>Filippou</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Cantarini</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Galeazzi</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>Improved efficacy of intramuscular weekly administration of clodronate 200 mg (100 mg twice weekly) compared with 100 mg (once weekly) for increasing bone mineral density in postmenopausal osteoporosis</article-title>
<source>Clin Drug Investig</source>
<year>2013</year>
<volume>33</volume>
<issue>3</issue>
<fpage>193</fpage>
<lpage>198</lpage>
<pub-id pub-id-type="pmid">23456672</pub-id>
</element-citation>
</ref>
<ref id="CR22">
<label>22.</label>
<mixed-citation publication-type="other">Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K 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. Arthritis Rheum 1986;29:1039–49.</mixed-citation>
</ref>
<ref id="CR23">
<label>23.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Kellgren</surname>
<given-names>JH</given-names>
</name>
<name>
<surname>Lawrence</surname>
<given-names>JS</given-names>
</name>
</person-group>
<article-title>Radiological assessment of osteo-arthrosis</article-title>
<source>Ann Rheum Dis</source>
<year>1957</year>
<volume>16</volume>
<issue>4</issue>
<fpage>494</fpage>
<lpage>502</lpage>
<pub-id pub-id-type="pmid">13498604</pub-id>
</element-citation>
</ref>
<ref id="CR24">
<label>24.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Peterfy</surname>
<given-names>CG</given-names>
</name>
<name>
<surname>Guermazi</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Zaim</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Tirman</surname>
<given-names>PF</given-names>
</name>
<name>
<surname>Miaux</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>White</surname>
<given-names>D</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis</article-title>
<source>Osteoarth Cartil</source>
<year>2004</year>
<volume>12</volume>
<fpage>177</fpage>
<lpage>190</lpage>
</element-citation>
</ref>
<ref id="CR25">
<label>25.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Laslett</surname>
<given-names>LL</given-names>
</name>
<name>
<surname>Doré</surname>
<given-names>DA</given-names>
</name>
<name>
<surname>Quinn</surname>
<given-names>SJ</given-names>
</name>
<name>
<surname>Boon</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Ryan</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Winzenberg</surname>
<given-names>TM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial</article-title>
<source>Ann Rheum Dis</source>
<year>2012</year>
<volume>71</volume>
<fpage>1322</fpage>
<lpage>1328</lpage>
<pub-id pub-id-type="pmid">22355040</pub-id>
</element-citation>
</ref>
<ref id="CR26">
<label>26.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Varenna</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Zucchi</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Failoni</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Becciolini</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Berruto</surname>
<given-names>M</given-names>
</name>
</person-group>
<article-title>Intravenous neridronate in the treatment of acute painful knee osteoarthritis: a randomized controlled study</article-title>
<source>Rheumatology</source>
<year>2015</year>
<volume>54</volume>
<fpage>1826</fpage>
<lpage>1832</lpage>
<pub-id pub-id-type="pmid">25998450</pub-id>
</element-citation>
</ref>
<ref id="CR27">
<label>27.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cassisi</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Sartori</surname>
<given-names>L</given-names>
</name>
</person-group>
<article-title>Efficacy of intramuscular clodronate in Complex Regional Pain Syndrome type I: description of a case located in the astragalus in a patient with psoriatic arthritis</article-title>
<source>Acta Biomed</source>
<year>2009</year>
<volume>80</volume>
<fpage>268</fpage>
<lpage>277</lpage>
<pub-id pub-id-type="pmid">20578422</pub-id>
</element-citation>
</ref>
<ref id="CR28">
<label>28.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Varenna</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Adami</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Rossini</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Gatti</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Idolazzi</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Zucchi</surname>
<given-names>F</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study</article-title>
<source>Rheumatology (Oxford).</source>
<year>2013</year>
<volume>52</volume>
<issue>3</issue>
<fpage>534</fpage>
<lpage>542</lpage>
<pub-id pub-id-type="pmid">23204550</pub-id>
</element-citation>
</ref>
<ref id="CR29">
<label>29.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Adami</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Fossaluzza</surname>
<given-names>V</given-names>
</name>
<name>
<surname>Gatti</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Fracassi</surname>
<given-names>E</given-names>
</name>
<name>
<surname>Braga</surname>
<given-names>V</given-names>
</name>
</person-group>
<article-title>Bisphosphonate therapy of reflex sympathetic dystrophy syndrome</article-title>
<source>Ann Rheum Dis.</source>
<year>1997</year>
<volume>56</volume>
<issue>3</issue>
<fpage>201</fpage>
<lpage>204</lpage>
<pub-id pub-id-type="pmid">9135227</pub-id>
</element-citation>
</ref>
<ref id="CR30">
<label>30.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saviola</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Abdi-Ali</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Comini</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Dalle-Carbonare</surname>
<given-names>LG</given-names>
</name>
</person-group>
<article-title>Use of clodronate in the management of osteoarthritis: an update</article-title>
<source>J Biol Regul Homeost Agents.</source>
<year>2019</year>
<volume>33</volume>
<issue>5</issue>
<fpage>1315</fpage>
<lpage>1320</lpage>
<pub-id pub-id-type="pmid">31591875</pub-id>
</element-citation>
</ref>
<ref id="CR31">
<label>31.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Saviola</surname>
<given-names>Gianantonio</given-names>
</name>
<name>
<surname>Abdi-Ali</surname>
<given-names>Lul</given-names>
</name>
<name>
<surname>Povino</surname>
<given-names>Maria Rosaria</given-names>
</name>
<name>
<surname>Campostrini</surname>
<given-names>Lorella</given-names>
</name>
<name>
<surname>Sacco</surname>
<given-names>Silvano</given-names>
</name>
<name>
<surname>Carbonare</surname>
<given-names>Luca Dalle</given-names>
</name>
</person-group>
<article-title>Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial—The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation)</article-title>
<source>Clinical Rheumatology</source>
<year>2017</year>
<volume>36</volume>
<issue>10</issue>
<fpage>2343</fpage>
<lpage>2350</lpage>
<pub-id pub-id-type="pmid">28536825</pub-id>
</element-citation>
</ref>
<ref id="CR32">
<label>32.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Valenti</surname>
<given-names>Maria</given-names>
</name>
<name>
<surname>Mottes</surname>
<given-names>Monica</given-names>
</name>
<name>
<surname>Biotti</surname>
<given-names>Alessandro</given-names>
</name>
<name>
<surname>Perduca</surname>
<given-names>Massimiliano</given-names>
</name>
<name>
<surname>Pisani</surname>
<given-names>Arianna</given-names>
</name>
<name>
<surname>Bovi</surname>
<given-names>Michele</given-names>
</name>
<name>
<surname>Deiana</surname>
<given-names>Michela</given-names>
</name>
<name>
<surname>Cheri</surname>
<given-names>Samuele</given-names>
</name>
<name>
<surname>Dalle Carbonare</surname>
<given-names>Luca</given-names>
</name>
</person-group>
<article-title>Clodronate as a Therapeutic Strategy against Osteoarthritis</article-title>
<source>International Journal of Molecular Sciences</source>
<year>2017</year>
<volume>18</volume>
<issue>12</issue>
<fpage>2696</fpage>
</element-citation>
</ref>
<ref id="CR33">
<label>33.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Felson</surname>
<given-names>DT</given-names>
</name>
</person-group>
<article-title>The sources of pain in knee osteoarthritis</article-title>
<source>Curr Opin Rheumatol</source>
<year>2005</year>
<volume>17</volume>
<fpage>624</fpage>
<lpage>628</lpage>
<pub-id pub-id-type="pmid">16093843</pub-id>
</element-citation>
</ref>
<ref id="CR34">
<label>34.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Link</surname>
<given-names>TM</given-names>
</name>
<name>
<surname>Li</surname>
<given-names>X</given-names>
</name>
</person-group>
<article-title>Bone marrow changes in osteoarthritis</article-title>
<source>Semin Musculoskelet Radiol</source>
<year>2011</year>
<volume>15</volume>
<fpage>238</fpage>
<lpage>246</lpage>
<pub-id pub-id-type="pmid">21644197</pub-id>
</element-citation>
</ref>
<ref id="CR35">
<label>35.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Taljanovic</surname>
<given-names>MS</given-names>
</name>
<name>
<surname>Graham</surname>
<given-names>AR</given-names>
</name>
<name>
<surname>Benjamin</surname>
<given-names>JB</given-names>
</name>
<name>
<surname>Gmitro</surname>
<given-names>AF</given-names>
</name>
<name>
<surname>Krupinski</surname>
<given-names>EA</given-names>
</name>
<name>
<surname>Schwartz</surname>
<given-names>SA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology</article-title>
<source>Skelet Radiol</source>
<year>2008</year>
<volume>37</volume>
<fpage>423</fpage>
<lpage>431</lpage>
</element-citation>
</ref>
<ref id="CR36">
<label>36.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Liu</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Igarashi</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Kanzaki</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Chiba</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Shinoda</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Mitani</surname>
<given-names>H</given-names>
</name>
</person-group>
<article-title>Clodronate inhibits PGE(2) production in compressed periodontal ligament cells</article-title>
<source>J Dent Res.</source>
<year>2006</year>
<volume>85</volume>
<issue>8</issue>
<fpage>757</fpage>
<lpage>760</lpage>
<pub-id pub-id-type="pmid">16861295</pub-id>
</element-citation>
</ref>
<ref id="CR37">
<label>37.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chiu</surname>
<given-names>YG</given-names>
</name>
<name>
<surname>Ritchlin</surname>
<given-names>DT</given-names>
</name>
</person-group>
<article-title>Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis</article-title>
<source>Expert Opin Biol Ther.</source>
<year>2017</year>
<volume>17</volume>
<issue>1</issue>
<fpage>119</fpage>
<lpage>128</lpage>
<pub-id pub-id-type="pmid">27871200</pub-id>
</element-citation>
</ref>
<ref id="CR38">
<label>38.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sims</surname>
<given-names>NA</given-names>
</name>
<name>
<surname>Green</surname>
<given-names>JR</given-names>
</name>
<name>
<surname>Glatt</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Schlict</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Martin</surname>
<given-names>TJ</given-names>
</name>
<name>
<surname>Gillespie</surname>
<given-names>MT</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis</article-title>
<source>Arthritis Rheum</source>
<year>2004</year>
<volume>50</volume>
<issue>7</issue>
<fpage>2338</fpage>
<lpage>2346</lpage>
<pub-id pub-id-type="pmid">15248235</pub-id>
</element-citation>
</ref>
<ref id="CR39">
<label>39.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Oelzner</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Kunze</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Henzgen</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Thoss</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Hein</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Stein</surname>
<given-names>G</given-names>
</name>
<etal></etal>
</person-group>
<article-title>High-dose clodronate therapy prevents joint destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at the axial skeleton</article-title>
<source>Inflamm Res</source>
<year>2000</year>
<volume>49</volume>
<issue>8</issue>
<fpage>424</fpage>
<lpage>433</lpage>
<pub-id pub-id-type="pmid">11028760</pub-id>
</element-citation>
</ref>
<ref id="CR40">
<label>40.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Osterman</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Kippo</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Laurén</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Hannuniemi</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Sellman</surname>
<given-names>R</given-names>
</name>
</person-group>
<article-title>Effect of clodronate on established collagen-induced arthritis in rats</article-title>
<source>Inflamm Res</source>
<year>1995</year>
<volume>44</volume>
<issue>6</issue>
<fpage>258</fpage>
<lpage>263</lpage>
<pub-id pub-id-type="pmid">7583522</pub-id>
</element-citation>
</ref>
<ref id="CR41">
<label>41.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bonabello</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Galmozzi</surname>
<given-names>MR</given-names>
</name>
<name>
<surname>Bruzzese</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Zara</surname>
<given-names>GP</given-names>
</name>
</person-group>
<article-title>Analgesic effect of bisphosphonates in mice</article-title>
<source>Pain</source>
<year>2001</year>
<volume>91</volume>
<issue>3</issue>
<fpage>269</fpage>
<lpage>275</lpage>
<pub-id pub-id-type="pmid">11275384</pub-id>
</element-citation>
</ref>
<ref id="CR42">
<label>42.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bonabello</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Galmozzi</surname>
<given-names>MR</given-names>
</name>
<name>
<surname>Canaparo</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Serpe</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Zara</surname>
<given-names>GP</given-names>
</name>
</person-group>
<article-title>Long-term analgesic effect of clodronate in rodents</article-title>
<source>Bone</source>
<year>2003</year>
<volume>33</volume>
<issue>4</issue>
<fpage>567</fpage>
<lpage>574</lpage>
<pub-id pub-id-type="pmid">14555260</pub-id>
</element-citation>
</ref>
<ref id="CR43">
<label>43.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Muratore</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Calcagnile</surname>
<given-names>F</given-names>
</name>
<name>
<surname>Quarta</surname>
<given-names>E</given-names>
</name>
</person-group>
<article-title>Antalgic efficacy of the bisphosphonates in vertebral fractures of recent onset</article-title>
<source>Osteoporos Int</source>
<year>2004</year>
<volume>15</volume>
<issue>Suppl. 1</issue>
<fpage>S121</fpage>
</element-citation>
</ref>
<ref id="CR44">
<label>44.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rovetta</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Maggiani</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Molfetta</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Monteforte</surname>
<given-names>P</given-names>
</name>
</person-group>
<article-title>One-month follow-up of patients treated by intravenous clodronate for acute pain induced by osteoporotic vertebral fracture</article-title>
<source>Drugs Exp Clin Res</source>
<year>2001</year>
<volume>27</volume>
<issue>2</issue>
<fpage>77</fpage>
<lpage>81</lpage>
<pub-id pub-id-type="pmid">11392057</pub-id>
</element-citation>
</ref>
<ref id="CR45">
<label>45.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rovetta</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Monteforte</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Balestra</surname>
<given-names>V</given-names>
</name>
</person-group>
<article-title>Intravenous clodronate for acute pain induced by osteoporotic vertebral fracture</article-title>
<source>Drugs Exp Clin Res</source>
<year>2000</year>
<volume>26</volume>
<issue>1</issue>
<fpage>25</fpage>
<lpage>30</lpage>
<pub-id pub-id-type="pmid">10761534</pub-id>
</element-citation>
</ref>
<ref id="CR46">
<label>46.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Muratore</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Canaparo</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Della Pepa</surname>
<given-names>C</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Bisphosphonates antalgic activity in recent vertebral fracture: a clodronate vs neridronate comparison</article-title>
<source>Osteoporos Int</source>
<year>2004</year>
<volume>15</volume>
<issue>Suppl. 1</issue>
<fpage>S119</fpage>
</element-citation>
</ref>
<ref id="CR47">
<label>47.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ernst</surname>
<given-names>DS</given-names>
</name>
<name>
<surname>Brasher</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Hagen</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Paterson</surname>
<given-names>AH</given-names>
</name>
<name>
<surname>MacDonald</surname>
<given-names>RN</given-names>
</name>
<name>
<surname>Bruera</surname>
<given-names>E</given-names>
</name>
</person-group>
<article-title>A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain</article-title>
<source>J Pain Symptom Manage</source>
<year>1997</year>
<volume>13</volume>
<issue>6</issue>
<fpage>319</fpage>
<lpage>326</lpage>
<pub-id pub-id-type="pmid">9204651</pub-id>
</element-citation>
</ref>
<ref id="CR48">
<label>48.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tubiana-Hulin</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Beuzeboc</surname>
<given-names>P</given-names>
</name>
<name>
<surname>Mauriac</surname>
<given-names>L</given-names>
</name>
<name>
<surname>Barbet</surname>
<given-names>N</given-names>
</name>
<name>
<surname>Frenay</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Monnier</surname>
<given-names>A</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases</article-title>
<source>Bull Cancer</source>
<year>2001</year>
<volume>88</volume>
<issue>7</issue>
<fpage>701</fpage>
<lpage>707</lpage>
<pub-id pub-id-type="pmid">11495824</pub-id>
</element-citation>
</ref>
<ref id="CR49">
<label>49.</label>
<element-citation publication-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rossini</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Viapiana</surname>
<given-names>O</given-names>
</name>
<name>
<surname>Ramonda</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Bianchi</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Olivieri</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Lapadula</surname>
<given-names>G</given-names>
</name>
<name>
<surname>Adami</surname>
<given-names>S</given-names>
</name>
</person-group>
<article-title>Intra-articular clodronate for the treatment of knee osteoarthritis: dose ranging study vs hyaluronic acid</article-title>
<source>Rheumatology (Oxford)</source>
<year>2009</year>
<volume>48</volume>
<issue>7</issue>
<fpage>773</fpage>
<lpage>778</lpage>
<pub-id pub-id-type="pmid">19406908</pub-id>
</element-citation>
</ref>
</ref-list>
</back>
</pmc>
</record>

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