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

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.

Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative

“…Our results may partially elucidate why results differ between trials, observational studies, and meta-analyses (5,(11)(12)(13)(14)(15)(16)33) examining the benefit of bisphosphonates for various radiographic and symptomatic outcomes. Prior to examining effects, it is Weighted by stabilized and truncated (at the 5th and 95th percentile) inverse probability censor weights.…”

“…Our results may partially elucidate why results differ between trials, observational studies, and meta‐analyses ( 5,11–16,33 ) examining the benefit of bisphosphonates for various radiographic and symptomatic outcomes. Prior to examining effects, it is necessary to understand the interplay of OA risk factors, the potential mechanism of benefit that bisphosphonates may have, and in which populations these protective effects would demonstrate the most benefit.…”

“…As such, bisphosphonates are not currently recommended as therapy in knee OA clinical guidelines in the United States. (2) Many of these previous studies have focused on the effects of less potent, non-nitrogen-containing bisphosphonates that may not have long-term protective effects on bone turnover, such as clodronate (15)(16)(17) ; have measured outcomes over periods as short as 6 months (12) ; or have focused on broad cohorts (ie, no restriction to early stage OA, or non-overweight patients) or used binary (yes/no) pain and joint-space narrowing outcomes or hypothesis tests (whether average measurements were statistically different between bisphosphonate users versus nonusers). (13,14) Timeto-event (ie, survival) analysis lends itself to more insightful risk comparisons rather than associations (odds ratios) or p values alone.…”

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

“…This phenotypedependency has been demonstrated in pre-clinical research, where bisphosphonates are differentially effective in reducing pain and not only bone but also cartilage pathology in OA models with high versus low bone turnover. [106][107][108][109] Recently, clodronate (n=74) 110 and neridronate (n=64) 111 have been successfully used for the treatment of knee and hand OA, with an interesting efficacy on BMLs, although the sample sizes are small. An individual patient data meta-analysis for examining their efficacy in specific knee OA subtypes is still ongoing.…”

In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

“…Although Clo is commonly used as anti-osteoporotic drug, recently many evidences have shown that Clo has also been successfully tested in erosive osteoarthritis (OA) upon intra-articular and parenteral administration 8 , 10 , 11 . In this setting, Clo has been demonstrated to regulate the biosynthesis and the release of NO, expression of cycloxygenase 2 (COX 2 ) and pro-inflammatory cytokines such as TNF-α, IL-1β that are known to promote cartilage erosion, subchondral bone alterations and to inhibit progenitors maturation into chondrocytes in OA early stages 7 , 12 – 15 .…”