Bisphosphonates: Environmental protection for the joint?

Goldring, Steven R.; Gravallese, Ellen M.

doi:10.1002/art.20383

Cited by 42 publications

(19 citation statements)

References 35 publications

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“…Given the fact that osteoclasts are primarily responsible for bone damage, this observation suggests that the elements needed to drive bone destruction are formed very early in the course of arthritis progression. Interestingly, bone erosion does not occur, even if arthritis is highly aggressive and longstanding, in animals in which osteoclasts have been targeted by genetic deletion of essential genes needed for osteoclast development or by administration of effective drugs that interfere with osteoclastogenesis (5)(6)(7)(14)(15)(16)(17)(18)(19)(20)(21)(22). Since osteoclasts are also a common feature in the joints of patients with RA, their contribution to the genesis of irreversible bone damage in human disease is quite likely (8,9,26,27).…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the kinetics of osteoclastogenesis in arthritic rats

Schett¹,

Stolina²,

Bolon³

et al. 2005

Arthritis & Rheumatism

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Objective. To analyze the kinetics of osteoclastogenesis in 2 models of chronic immune-mediated arthritis and 1 model of acute arthritis.Methods. Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Lewis rats were used as models of chronic arthritis. Acute arthritis was induced in Lewis rats by injecting carrageenan into the hind paw. Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis. The location, size, and nucleation of osteoclasts were also analyzed.Results. In both AIA and CIA, multinucleated and cathepsin K-positive osteoclasts first were observed on the day of disease onset. Initially, osteoclasts were localized at the periosteum next to the synovial membrane and in subchondral bone channels. The number, size, and nucleation of osteoclasts rapidly increased, leading to severe bone loss within days after disease onset. In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane. All osteoclasts (cathepsin K-positive, multinucleated, attached to bone) and osteoclast precursors (cathepsin K-positive, mononucleated or multinucleated, within synovial tissue) were also positive for a macrophage-specific marker. Upon induction of acute arthritis with carrageenan, osteoclasts formed transiently in subchondral bone, but regressed 7 days after disease onset. Conclusion.Functional osteoclasts are generated at the earliest stage of arthritis, and new precursors are continuously formed in the synovial membrane to replenish the osteoclast pool. These data indicate that antiresorptive therapies may provide the most effective bone protection, when treatment is started soon after the onset of arthritis.

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Section: Discussionmentioning

confidence: 99%

“…Agents that inhibit the action of osteoclasts, such as bisphosphonates or the RANKL-binding soluble receptor osteoprotegerin, can inhibit or even arrest bone erosion (5)(6)(7)(14)(15)(16)(17)(18)(19). Gene therapy with molecules that inhibit drivers of osteoclastogenesis effectively inhibit bone erosion (20).…”

mentioning

confidence: 99%

Analysis of the kinetics of osteoclastogenesis in arthritic rats

Schett¹,

Stolina²,

Bolon³

et al. 2005

Arthritis & Rheumatism

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“…One explanation is that ALN may promote differentiation of mesenchymal stem cells into osteoblasts [23]. As another possibility, this ALN-mediated bone formation could be the direct result of tissues inflammation associated with ALN local administration [24] Since CDs are generally known as biologically inert, it is quiet a surprise to find that ALN-β-CD is bone anabolic. Further literature search found that the only known application of a CD derivative as an active therapeutic agent is sugammadex or Org 25969 (per-6-(2-carboxyethylthio)-per-6-deoxy-γ-cyclodextrin), which was developed as a lead compound for antagonism of prolonged rocuronium-induced neuromuscular block [25][26][27].…”

Section: In Vivo Animal Studymentioning

confidence: 99%

Osteotropic β-cyclodextrin for local bone regeneration

Liu¹,

Wiswall²,

Rutledge³

et al. 2008

Biomaterials

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An osteotropic alendronate-β-cyclodextrin conjugate (ALN-β-CD) was developed as a bonetargeting delivery system for improved treatment of skeletal diseases. The conjugate shows very strong binding to hydroxyapatite (HA, main component of the skeleton). Its ability in forming molecular inclusion complex with prostaglandins E 1 (PGE 1 , a potent bone anabolic agent) was confirmed by phase-solubility experiments and differential scanning calorimetry (DSC). In a bilateral rat mandible model, ALN-β-CD/PGE 1 molecular complex was shown to stimulate strong local bone anabolic reaction. In the control study, ALN-β-CD itself was also found to be bone anabolic. To investigate this finding, other control groups were studied. The histomorphometry data suggests that ALN-β-CD itself could generate more new bone at the injection site than its complex with PGE 1 . Alendronate (ALN) injection could also cause new bone formation, which locates peripheral to the site of injection. PGE 1 , saline or ethanol injections do not have anabolic effect. These findings were also confirmed by micro-CT evaluation of mandibular bones. It is clear that the bone anabolic effect of ALN-β-CD is independent of mechanical stimuli of the periosteum or ALN injection alone. Further studies are warranted to understand the working mechanism of ALN-β-CD as a bone anabolic agent.

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“…Whether bisphosphonates retard the progression of structural damage in RA is however still a matter of debate [32]. Although there is clear evidence from experimental arthritis, which supports the use of bisphosphonates to inhibit structural damage in arthritis [33,34], no definitive proof has so far being gained from trials in human RA, which have to consider several confounding variables such as inflammatory disease activity, glucocorticoid intake or the use of diseasemodifying anti-rheumatic drugs.…”

Section: Molecules Supporting Osteoclast Formation and Their Inhibitionmentioning

confidence: 99%

Arthritis – a nightmare for bone

Schett

2006

Wien Klin Wochenschr

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Bisphosphonates: Environmental protection for the joint?

Cited by 42 publications

References 35 publications

Analysis of the kinetics of osteoclastogenesis in arthritic rats

Analysis of the kinetics of osteoclastogenesis in arthritic rats

Osteotropic β-cyclodextrin for local bone regeneration

Arthritis – a nightmare for bone

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