The Rationale for the Intra-Articular Administration of Clodronate in Osteoarthritis

Abstract

Background: Several pharmacological therapeutic approaches have been proposed to manage osteoarthritis (OA), including intra-articular (IA) injections. Although the discovery of clodronate, a bisphosphonate, dates back to the 1960s and the effects of its IA administration have been investigated for decades in animal models, mechanisms of action of this drug are not quite clear, particularly in OA. This scoping review is an overview of the biological as well as the clinical role of clodronic acid in OA. Method: A scoping review based on the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model was performed to characterize the mechanisms of action of IA clodronate in OA and to evaluate its efficacy from a clinical point of view. Results: Several effects of clodronate have been observed in animal models of OA, including depletion of synovial lining cells that results in reduced production of chemokines (IL-1, TNF- α), growth factors (TGF-β, BMP 2/4), and metalloproteases (MMP 2/3/9); prevention of cartilage damage, synovial hyperplasia, and proteoglycans loss; reduction in joint inflammation, joint swelling, and osteophyte formation. From a clinical perspective, patients with knee OA treated with IA clodronate experienced improvements in pain and joint mobility. Conclusion: Clodronate appears to have different mechanisms of action interfering with the pathogenic processes contributing to OA development and progression. This intervention demonstrated positive effects for patients affected by knee OA.

Therapeutic applications of adipose-derived stromal vascular fractions in osteoarthritis

“…Combined with HA, clodronate can also relieve pain and reduce bone marrow lesions in early OA. In the future, it may be used in conjunction with SVF for better results[ 71 ].…”

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

“… 87 Activation of osteoclasts can result in pain genesis through developing acidic conditions at the osteochondral junction, thereby activating acid-sensing receptors of sensory neurons. 88 , 89 Subchondral bone also undergoes remarkable alterations in both composition and structural organization, leading to adverse effects on the overlying articular cartilage. 90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research.…”

Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs)

“…64 It reduced the generation of cytokines (IL-1, TNF-α) and metalloproteases (MMP 2/3/9) in the synovium and cartilage in animal models. 65 In a small study including 74 patients with knee OA, a reduction of pain and BMLs was reported after providing a higher dose of intramuscular clodronate than used for osteoporosis (200 mg daily for 15 days and then once weekly for the next 11.5 months), compared with a shorter maintenance regimen (2.5 months). 32 In non-overweight individuals in whom weight-bearing damage is not a driving cause of OA progression, a bone-related abnormality and remodelling may play a crucial role.…”