RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

Wyngaert, Tim Van den; Wouters, Kristien; Huizing, Manon; Vermorken, Jan B.

doi:10.1007/s00520-010-1061-0

Cited by 57 publications

(37 citation statements)

References 26 publications

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“…The more recent observation of ONJ in N-BP-naïve patients receiving RANKL antibodies (6-9) suggests that it may be the physiologic effect of strongly inhibiting bone resorption by any means, rather than through the specific use of an N-BP, that drives much of ONJ's pathophysiology. In this report, we show that rice rats with moderate/severe periodontitis develop ONJ-like lesions when co-administered oncologic doses of ZOL.…”

Section: Discussionmentioning

confidence: 99%

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Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis

Aguirre

Akhter

Kimmel

et al. 2012

Journal of Bone and Mineral Research

118

136

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Though osteonecrosis of the jaw (ONJ) is temporally-associated with the use of nitrogen-containing bisphosphonates (N-BPs), a cause/effect relationship has not yet been established. We hypothesize that ONJ is a two-stage process in which: a) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis, and b) powerful anti-resorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis. At age 28 days, rats (n=15/group) were placed on a high sucrose and casein diet to exacerbate the development of periodontitis. Animals were injected SC biweekly with vehicle or alendronate (ALN, 15μg/kg), or IV once monthly with vehicle, a low dose (LD), or a high dose (HD) of zoledronic acid (ZOL) and sacrificed after 6, 12, 18, and 24 wks. Mandibles and maxillae were analyzed to determine the effects on the: a) progression of periodontitis, b) integrity of alveolar bone, c) status of bone resorption and formation, d) vascularity, and e) osteocyte viability. We found that only HD-ZOL induced ONJ-like lesions in mandibles of rice rats after 18 and 24 wks of treatment. These lesions were characterized by areas of exposed necrotic alveolar bone, osteolysis, a honey comb-like appearance of the alveolar bone, presence of bacterial colonies, and periodontal tissue destruction. In addition, inhibition of bone formation, a paradoxical abolition of the antiresorptive effect of only HD-ZOL, increased osteocyte necrosis/apoptosis, and decreased blood vessel number were found after 18 and/or 24 wks. Our study suggests that only HD-ZOL exacerbates the inflammatory response and periodontal tissue damage in rice rats, inducing bone lesions that resemble ONJ.

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Section: Discussionmentioning

confidence: 99%

“…(6-9) However, no cause/effect relationship has yet been established. N-BPs are powerful antiresorptive agents which bind to bone surfaces.…”

Section: Introductionmentioning

confidence: 99%

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis

Aguirre

Akhter

Kimmel

et al. 2012

Journal of Bone and Mineral Research

118

136

View full text Add to dashboard Cite

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“…In fact the anti-angiogenic properties associated with BP treatment have been linked to the etiology of osteonecrosis of the jaw (ONJ), the most common side effect of BP treatment, and lower circulating VEGF levels are predictive of ONJ onset in patients receiving BP treatment (Vincenzi et al, 2012). Similar to BP treatment, ONJ has been reported in patients receiving denosumab (Smith et al, 2012), and the overall risk of ONJ was found to be slightly (but not significantly) elevated in patients receiving denosumab versus BP treatment for bone metastatic breast and prostate cancer (Van den Wyngaert et al, 2011), but the direct effects of denosumab on circulating VEGF levels in these patients have not been evaluated. Interestingly, patients receiving anti-angiogenic therapies are also at increased risk of developing ONJ (Greuter et al, 2008; Aragon-Ching et al, 2009; Christodoulou et al, 2009), likely due to angiogenic and osteogenic coupling.…”

Section: Therapeutic Potential Of Hif Targets In Bone Metastasismentioning

confidence: 99%

HIF targets in bone remodeling and metastatic disease

Johnson

Schipani

Giaccia

2015

Pharmacology & Therapeutics

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The bone marrow isa hypoxic microenvironment that is rich in growth factors and blood vessels and is readily colonized by tumor cells disseminated from numerous cancers including tumors of the breast, prostate, lung, and skin. The origin of metastatic growth promoting factors for tumor cells disseminated to the bone marrow is derived from multiple sources: the bone matrix, which is a reservoir for growth factors, and cells residing in the marrow and along bone surfaces, such as osteoblasts, osteoclasts, macrophages, and T cells, which secrete cytokines and chemokines. Low oxygen levels within the bone marrow induce hypoxia signaling pathways such as hypoxia inducible factor (HIF), which is regulated by oxygen requiring prolyl hydroxylases (PHDs) and von Hippel–Lindau (VHL) tumor suppressor. These hypoxia signaling pathways have profound effects on bone development and homeostasis. Likewise, hypoxic conditions observed in local breast and prostate tumors point to a role for hypoxia-inducible genes in metastasis to and colonization of the bone marrow. This review will explore the role of hypoxia-regulated factors in bone development and remodeling, and how these elements may contribute to solid tumor metastasis to the bone.

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“…In large meta-analyses of comparative trials in metastatic breast cancer patients, within 2 years of treatment no statistically significant difference in the incidence of ONJ could be detected between denosumab (2.0% of cases) and zoledronate (1.4%) [41,55,56,57]. Among nitrogen-containing bisphosphonates, there may be a higher risk of ONJ with zoledronate compared with pamidronate or ibandronate [12].…”

Section: Side Effects Of Osteoclast Inhibitorsmentioning

confidence: 99%

Side Effects of Bone-Targeted Therapies in Advanced Breast Cancer

Domschke

Schuetz²

2014

Breast Care

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In up to 75% of cases, advanced breast cancer patients eventually develop bone metastases with often debilitating skeletal-related events (SREs). Osteoclast inhibitors are commonly used as therapeutic mainstay with clinical studies showing superiority of denosumab over bisphosphonates (e.g., zoledronate) for the prevention of SREs. The present review discusses the adverse event profile of these agents, and addresses the prevention and management of untoward side effects. Adverse events associated with osteoclast inhibitors comprise osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab, particularly in severe renal dysfunction. During therapy, the appropriate prevention of these adverse events includes close attention to dental health, avoidance of invasive dental procedures, supplementation with calcium and vitamin D unless patients are hypercalcemic, and regular monitoring of relevant serum values. Relating to the risk of nephrotoxicity, bisphosphonates but not denosumab have been incriminated. Therefore, serum creatinine levels should be checked prior to each dose of zoledronate, and in severe renal dysfunction (creatinine clearance < 30 ml/min) zoledronate is contraindicated anyway. Acute-phase reactions are particularly linked to bisphosphonates. Consequently, if these adverse events predominate, switching to denosumab is recommended.

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RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?

Abstract: Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.

Cited by 57 publications

References 26 publications

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis

HIF targets in bone remodeling and metastatic disease

Side Effects of Bone-Targeted Therapies in Advanced Breast Cancer

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