Denosumab and bisphosphonates: Different mechanisms of action and effects

Baron, Roland; Ferrari, Serge; Russell, R. G. G.

doi:10.1016/j.bone.2010.11.020

Cited by 601 publications

(542 citation statements)

References 172 publications

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“…In comparison, Siglec-15 is an osteoclast-intrinsic receptor with a highly restricted expression pattern, making it a favorable target with regards to specificity. It is also notable that although existing osteoclast-targeted therapies induce osteoclast cell death (bisphosphonates, (37)) or prevent their differentiation at an early stage (denosumab, (38)), Siglec-15 antibodies inhibit osteoclast differentiation at a relatively late stage. Thus, inhibiting Siglec-15 might preserve the coupled communication between osteoclasts and osteoblasts (35).…”

Section: Discussionmentioning

confidence: 99%

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

Stuible

Moraitis

Fortin

et al. 2014

Journal of Biological Chemistry

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Background: Bone-resorbing osteoclasts express the Siglec-15 receptor on their plasma membrane. Results: Siglec-15 antibodies inhibit osteoclast differentiation and induce receptor endocytosis and degradation. Conclusion: These results establish that Siglec-15 antibodies target osteoclasts in vivo and reveal a likely mechanism of action. Significance: Siglec-15 could serve as a target of novel therapeutics for osteoporosis and cancer-associated bone loss.

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Section: Discussionmentioning

confidence: 99%

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

Stuible

Moraitis

Fortin

et al. 2014

Journal of Biological Chemistry

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“…The most widely used antiosteolytic treatments are nitrogen-containing bisphosphonates, which induce osteoclast apoptosis, and denosumab, a humanized monoclonal antibody to RANKL that inhibits osteoclast differentiation. An important issue with those treatments is that they also strongly affect bone formation 2 . This is suspected to contribute to clinical complications such as atypical subtrochanteric femur fractures and osteonecrosis of the jaw and reduce responsiveness to the bone anabolic factor parathyroid hormone [3][4][5] .…”

mentioning

confidence: 99%

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

et al. 2015

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Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires Dock5, a guanine nucleotide exchange factor for the small GTPase Rac, and C21, a chemical inhibitor of Dock5, decreases bone resorption by cultured osteoclasts. Here we show that C21 directly inhibits the exchange activity of Dock5 and disrupts osteoclast podosome organization. Remarkably, C21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, C21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of Dock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.

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“…(80) Regarding the potential mechanisms that operate following treatment with different classes of antiresorptives, clinical observations suggest two main differences between denosumab and bisphosphonate treatment. (81) With denosumab, there is both a continuous BMD gain for 3 to 6 years, which is observed both at the spine and hip, and a rebound of BTMs above baseline accompanied by a prominent BMD loss upon discontinuation. As the antibody is cleared, basic multicellular units (BMUs) are reactivated and bone remodeling recurs, a process that can only be stopped by re dosing.…”

Section: Discussionmentioning

confidence: 98%

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

Boonen¹,

Ferrari²,

Miller³

et al. 2012

Journal of Bone and Mineral Research

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Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head ''offset'' data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies. ß

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Denosumab and bisphosphonates: Different mechanisms of action and effects

Cited by 601 publications

References 172 publications

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

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