Clodronate improves lameness in horses without changing bone turnover markers

Mitchell, Alexis; Wright, Gabriëla; Sampson, Sarah N.; Martin, Mary E.; Cummings, Kevin J.; Gaddy, Dana; Watts, Ashlee E.

doi:10.1111/evj.13011

Cited by 21 publications

(22 citation statements)

References 48 publications

(72 reference statements)

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“…Subjective lameness and subjective joint effusion scores were reported as ordinal variables but analysed using a repeated measures two‐way ANOVA to take into consideration related, non‐independent groups, sampled over multiple time points. Although this analysis is consistent with multiple previous publications, a non‐parametric analysis could have been performed on these data. Due to the potential controversial nature of this analysis, both subjective lameness and subjective effusion were also assessed by continuous variables (vector sum and joint circumference), and the authors confirmed that analysis of the groups at 6, 12 and 24 h using a nonparametric statistical test (Wilcoxon matched pairs signed rank test) was also unable to identify a difference between groups (data not shown).…”

Section: Discussionsupporting

confidence: 86%

Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Colbath

Dow

Hopkins

et al. 2019

Equine Veterinary Journal

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Summary Background Allogeneic bone marrow‐derived mesenchymal stem cells (BMDMSCs) could provide multiple advantages over autologous BMDMSCs, including creating an ‘off‐the‐shelf’ treatment together with the ability to control for donor variation. Objectives The objective of the study was to compare the clinical and synovial fluid response of the normal equine joint to autologous and pooled‐allogeneic BMDMSCs while controlling for individual variation and joint variations in response to intra‐articular injections. We hypothesised that, by controlling for individual animal and joint variation, we could identify differences between allogeneic vs. autologous BMDMSCs in noninflamed joints. Study design Randomised‐controlled experiment. Methods Bone marrow was harvested from eight horses. Autologous BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. For allogeneic BMDMSC treatments, four horses' BMDMSCs were culture expanded, pooled, cryopreserved and thawed immediately prior to use. Ten million (autologous or pooled‐allogeneic) BMDMSCs were administered into contralateral forelimb metacarpophalangeal joints so that every autologous and allogeneic injection could be compared within the same animal. Clinical parameters included subjective lameness, objective lameness (Lameness Locator™), response to flexion, joint circumference and joint effusion. Arthrocentesis was performed for assessment of the nucleated cell count, differential cell count, total protein, and synovial concentrations of prostaglandin E2 (PGE2) and c‐reactive protein (CRP). All parameters were measured at baseline, 6, 12, 24, 72, 168 and 336 h post‐injection. Results No difference was detected in any parameters between forelimb metacarpophalangeal joints administered autologous or pooled‐allogeneic BMDMSCs. Main limitations This study did not attempt to measure efficacy of BMDMSCs for musculoskeletal disease and should be followed by properly controlled efficacy trials. Conclusions The study did not identify any clinical or cytological differences in the normal joint response to allogeneic or autologous BMDMSCs. A larger study to prove equivalence is warranted as allogeneic BMDMSCs may be a feasible alternative to autologous BMDMSCs.

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Section: Discussionsupporting

confidence: 86%

Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Colbath

Dow

Hopkins

et al. 2019

Equine Veterinary Journal

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“…In this light, we recently reported the results of a small equine study in which the bone turnover markers C-terminal collagen-I telopeptide (CTX-I) and osteocalcin were measured following a single clodronate injection (IM) (1.4 mg/kg). Weekly blood draw and analysis revealed no significant effects on bone turnover markers, but did appear to reduce lameness [22]. These findings are consistent with the work of others [27] that showed tiludronate and clodronate ( Fig.…”

Section: Introductionsupporting

confidence: 90%

“…Given the rampant BP use in the equine industry, there are only a few reports demonstrating a positive effect of either BP approved for use in horses with navicular syndrome [15,16,27] and none report bone-related complications. However there is a report that documented lack of change in bone resorption following tiludronate (1 mg/kg IV) or clodronate (1.8 mg/kg IM) treatment [27] as well as a lack of any significant change in serum markers of bone turnover following clodronate (1.4 mg/ kg IM) treatment [22]. In contrast, the majority of human studies report both beneficial and not so beneficial effects of BP therapy in the treatment of postmenopausal osteoporosis and bone metastasis [9,10,12,[29][30][31][32].…”

Section: That Is Important Information But What Are the Down Sides?mentioning

confidence: 99%

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Bisphosphonate use in the horse: what is good and what is not?

et al. 2019

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Background: Bisphosphonates (BPs) are a family of molecules characterized by two key properties: their ability to bind strongly to bone mineral and their inhibitory effects on mature osteoclasts and thus bone resorption. Chemically two groups of BPs are recognized, non-nitrogen-containing and nitrogen-containing BPs. Non-nitrogen-containing BPs incorporate into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to cytotoxic effects and osteoclast apoptosis. Nitrogen-containing BPs primarily inhibit cholesterol biosynthesis resulting in the disruption of intracellular signaling, and other cellular processes in the osteoclast. Body: BPs also exert a wide range of physiologic activities beyond merely the inhibition of bone resorption. Indeed, the breadth of reported activities include inhibition of cancer cell metastases, proliferation and apoptosis in vitro. In addition, the inhibition of angiogenesis, matrix metalloproteinase activity, altered cytokine and growth factor expression, and reductions in pain have been reported. In humans, clinical BP use has transformed the treatment of both post-menopausal osteoporosis and metastatic breast and prostate cancer. However, BP use has also resulted in significant adverse events including acute-phase reactions, esophagitis, gastritis, and an association with very infrequent atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ). Conclusion: Despite the well-characterized health benefits of BP use in humans, little is known regarding the effects of BPs in the horse. In the equine setting, only non-nitrogen-containing BPs are FDA-approved primarily for the treatment of navicular syndrome. The focus here is to discuss the current understanding of the strengths and weaknesses of BPs in equine veterinary medicine and highlight the future utility of these potentially highly beneficial drugs.

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“…As lameness evaluation is a very subjective process and taken together with the fact both studies are "multicentric", the accuracy of the outcome evaluation is questionable. Unlike more recent studies on the topic (Mitchell, A. et al 2019 and Whitfield, C.T. et al 2016), no inertial sensor system nor ground-mounted stationary force plate system was employed.…”

Section: Appraisal Application and Reflectionmentioning

confidence: 99%

Distal tarsal joints osteoarthritis: Evidence behind bisphosphonates and NSAIDs to improve lameness

Dubuc

2020

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PICO question In lame horses affected by osteoarthritis of the distal tarsal joints (bone spavin), are bisphosphonates more effective than NSAIDs in long-term alleviation of lameness? Clinical bottom line Category of research question Treatment The number and type of study designs reviewed Two papers were critically reviewed. There was one field study and a multicentric randomised double-blind placebo control study Strength of evidence Weak Outcomes reported Each study looked at the effect of either Tiludronate or Firocoxib on alleviation of tarsal lameness. Both Tiludronate and Firocoxib, while administered independently, provided some degree of relief (for up to 120 days) and improved the lameness related to tarsal osteoarthritis. Conclusion Since no study was found to directly compare the use of non-steroidal anti-inflammatory drugs and bisphosphonates and that none evaluate the long-term effects of these treatment options on lameness, it is not possible to recommend one treatment option over the other to alleviate lameness caused by tarsal osteoarthritis in horses. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

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Clodronate improves lameness in horses without changing bone turnover markers

Cited by 21 publications

References 48 publications

Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Allogeneic vs. autologous intra‐articular mesenchymal stem cell injection within normal horses: Clinical and cytological comparisons suggest safety

Bisphosphonate use in the horse: what is good and what is not?

Distal tarsal joints osteoarthritis: Evidence behind bisphosphonates and NSAIDs to improve lameness

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