Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions

Manicourt, Daniel; Altman, Roy D.; Williams, James M.; Devogelaer, J.-P.; Egeren, Anne Druetz Van; Lenz, Mary Ellen; Pietryla, Daniel; Thonar, Eugene J.‐M.A.

doi:10.1002/1529-0131(199906)42:6<1159::aid-anr12>3.0.co;2-q

Cited by 114 publications

(85 citation statements)

References 32 publications

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“…Few studies using bone resorption inhibitors to suppress bone remodeling in animal models of OA have been reported. In a canine ACLT model, the rate of bone and cartilage turnover, as determined by biomarkers, was found to be increased in the early stage of OA (41). Calcitonin, an inhibitor of osteoclastic bone resorption, reduced the severity of OA lesions, as assessed by histologic grading and the presence of osteophyte formation.…”

Section: Discussionmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

505

466

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Objective. It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.Methods. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 g/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor ␤ (TGF␤), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF␤.Results. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dosedependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF␤, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Conclusion. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and joint stiffness. Although OA has long been considered to be primarily a cartilage disorder associated with focal articular cartilage degradation, this disease is accompanied by well-defined changes in the subchondral and periarticular bone, including sclerosis and cyst and osteophyte formation (1). The importance of the bone changes in the initiation and progression of OA is still being debated. It has been suggested that increased subchondral bone stiffness reduces the ability to dissipate the load and distribute the strain generated within the joint. This increases peak dynamic forces in the overlying articular cartilage and can accelerate its damage over time (2). The functional integrity of the articular cartilage can therefore depend on the mechanical properties of the underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only upon repetitive loading over an already stiffened subchondral bone plate (3).Recent studies have demonstrated increased subchondral bone turnover accompanied by specific architectural changes in the subchondral trabecular bone in OA joints (4,5...

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Section: Discussionmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

505

466

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“…The investigators suggested that calcitonin worked in both prophylactic and therapeutic stages of OA. Studies in the ACL dog model [144,145] also showed that subcutaneous injections of calcitonin under therapeutic conditions reduced the progression of OA cartilage and subchondral bone changes as well as the level of serum markers of bone resorption up to 4 months after the surgery. A small phase II trial assessing the efficacy of oral salmon calcitonin in knee OA was recently published [146].…”

Section: Drugs/agents That Target Bone Remodellingmentioning

confidence: 96%

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

Tat

Lajeunesse

Pelletier

et al. 2010

Best Practice & Research Clinical Rheumatology

151

121

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Over the past few decades, significant progress has been made with respect to new concepts about the pathogenesis of osteoarthritis (OA). This article summarises some of the knowledge we have today on the involvement of the subchondral bone in OA. It provides substantial evidence that changes in the metabolism of the subchondral bone are an integral part of the OA disease process and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Thus, a strong rationale exists for therapeutic approaches that target subchondral bone resorption and/or formation, and data evaluating the drugs targeting bone remodelling raise the hope that new treatment options for OA may become available.

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“…In addition, sCT has been suggested as a possible intervention strategy for osteoarthritis [2,3]. Calcitonin is a small, 32-amino-acid peptide, with potent antiresorptive capacities, and in its natural form in vertebrates is believed to be secreted in response to excess calcium in serum [4].…”

Section: Introductionmentioning

confidence: 99%

Investigations of inter- and intraindividual relationships between exposure to oral salmon calcitonin and a surrogate marker of pharmacodynamic efficacy

Karsdal

Byrjalsen

Henriksen

et al. 2009

Eur J Clin Pharmacol

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Aims The aims of the study were to investigate interindividual variations in the bioavailability of salmon calcitonin (sCT) following single oral 0.8 mg doses at three different times of the day, and intraindividual variation in sCT bioavailability at each end of a 14-day treatment period. We also investigated correlations between exposure to sCT and levels of the bone resorption biomarker serum C-terminal telopeptide of collagen type I (CTX-I). Methods Participants were from two randomized, doubleblind, placebo-controlled studies. In study I, healthy postmenopausal women received a single dose of 0.8 mg of oral sCT or placebo at 08:00 (n=42), 17:00 (n=20), or at 22:00 (n=19). In study II, age-matched men or postmenopausal women with osteoarthritis received 0.8 mg oral sCT (n=26) or placebo (n=23) twice daily for 14 days,

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Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions

Cited by 114 publications

References 32 publications

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

Investigations of inter- and intraindividual relationships between exposure to oral salmon calcitonin and a surrogate marker of pharmacodynamic efficacy

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