Anemic Events Post-Infusion of Zoledronic Acid and Osteonecrosis of the Jaws: Relationship of Cause or Effect?

AbstractTreatment with cumulative dosages of zoledronic acid (ZA) in elderly patients is a risk factor for the development of medication-related osteonecrosis of the jaws (MRONJ), mainly related to surgical triggers such as tooth extraction. However, animal models for the investigation and understanding of MRONJ pathophysiology in senescent and postmenopausal stages remains to be developed and characterized. The aim of this study was to analyze MRONJ development in senescent female mice treated with cumulative dosages of ZA. For this purpose, twenty 129/Sv female mice, 64 weeks old, were treated with 0.9% saline solution as Control group (n=10), and with ZA at 250µg/Kg (n=10), once a week, starting 4 weeks before the upper right incisor extraction and until the end of the experimental time points (7 days and 21 days). At 7 and 21 days, specimens were harvested for microCT, histological, birefringence and immunohistochemical analysis. Clinically, an incomplete epithelialization was observed in ZA group at 7 days and a delayed bone matrix mineralization and collagen maturation at 7 and 21 days compared to the controls. Controls revealed sockets filled with mature bone at 21 days as observed by microCT and birefringence, while ZA group presented delayed bone deposition at 7 and 21 days, as well increased leukocyte infiltration and blood clot at 7 days, and increased bone sequestrum and empty osteocyte lacunae at 21 days (p<0.05). Also, ZA group presented decreased quantity TGFb+ and Runx-2+ cells at 7 days, and decreased quantity of TRAP+ osteoclasts compared to the control at 21 days (p<0.05). Togheter, these data demonstrate the usefulness of this model to understanding the pathophysiology of MRONJ.

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Medication-Related Osteonecrosis of the Jaws Initiated by Zoledronic Acid and Potential Pathophysiology

Dentistry Journal ◽

10.3390/dj9080085 ◽

2021 ◽

Vol 9 (8) ◽

pp. 85

Author(s):

Aya Alsalih ◽

Annica Dam ◽

Pia Lindberg ◽

Anna Truedsson

Keyword(s):

Zoledronic Acid ◽

Dental Pulp ◽

Bone Remodelling ◽

Osteonecrosis Of The Jaw ◽

Inclusion Criteria ◽

Cellular Mechanisms ◽

Osteonecrosis Of The Jaws ◽

Current Review ◽

Dose Dependent

The aim of this systematic review is to present an up-to-date review of available publications investigating the cellular mechanisms initiating the development of medication-related osteonecrosis of the jaw caused by zoledronic acid. Electronic searches of MEDLINE/PubMed and Scopus were conducted on the 3 June, 2019. A total of 804 publications were identified, of which 11 met the inclusion criteria and were, therefore, included in this study. All the included studies were in vitro studies investigating various human cells. The current review found that zoledronic acid in various concentrations increased apoptosis and decreased migration and proliferation of epithelial cells, fibroblasts, osteoblasts, endothelial cells and dental pulp stem cells, which can affect local tissue homeostasis. The consequences of zoledronic acid were found to be both time- and dose-dependent. The pathophysiology of medication-related osteonecrosis of the jaw is likely a multifactorial process involving prolonged wound healing, chronic inflammation and altered bone remodelling following the administration of zoledronic acid. Further research is needed to identify the exact pathophysiology to optimise management and treatment.

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Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced solid tumor patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3042 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3042-3042

Author(s):

Shawn D Spencer ◽

William Douglas Figg ◽

Lee S. Rosen ◽

Michael S. Gordon ◽

Herbert Hurwitz ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Preliminary Evidence ◽

Volume Of Distribution ◽

Accumulation Factor ◽

Tumor Patients ◽

Normal Organ ◽

Dose Linearity ◽

Post Infusion ◽

Relationship Of

3042^ Background: CD105 is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced solid tumors and normal organ function were treated with escalating doses of intravenously administered TRC105 and assessed for safety and pharmacokinetics (PK). PK parameters for determining dose-linearity were estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was dose-limiting at 15 mg/kg weekly and was associated with TRC105 accumulation in serum from target saturation. Preliminary evidence of activity was observed with 21 of 45 evaluable patients progression-free at 2 months, including two ongoing responders. The AUC-single dose relationship of TRC105 revealed supra-proportionality in serum exposure at 15 mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power model revealed a nonlinear pharmacokinetic process (log[AUC] = 0.125*Dose+2.67, r2 = 0.92, ANOVA p<0.0035). The steady state volume of distribution was low (≈ 5.40 L/70kg) indicating TRC105 was confined to the vasculature with a low capacity target (i.e., low relative abundance) making it susceptible to saturation. The post-infusion Cmax however was linearly related to dose (r = 0.85) which suggested the nonlinearity in clearance was attributed to target-mediated disposition. The nonlinear disposition in the presence of low distribution indicated TRC105 bound avidly to endothelial cells. Concentrations expected to saturate CD105 binding were achieved continuously at 15 mg/kg dosed every 2 weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the accumulation factor at 56 days was 1.77-fold over single doses on C1D1. Conclusions: TRC105 clearance decreased above the MTD resulting in drug accumulation and hypoproliferative anemia with weekly dosing. The nonlinearity in clearance was attributed to saturating target-mediated disposition, consistent with binding to proliferating endothelial cells.

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Clinical Features and Management of Jaw Osteonecrosis in Patients Receiving Bisphosphonate Therapy.

Blood ◽

10.1182/blood.v110.11.4775.4775 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4775-4775 ◽

Cited By ~ 1

Author(s):

Fabio Alves ◽

José D. Prado ◽

André C. Rocha

Keyword(s):

Zoledronic Acid ◽

Scientific Literature ◽

Bisphosphonate Therapy ◽

Oral Bisphosphonates ◽

Single Institution ◽

Osteonecrosis Of The Jaws ◽

Dental Procedures ◽

Intravenous Bisphosphonates ◽

Pamidronate Therapy ◽

Dental Work

Abstract Osteonecrosis of the jaws (ONJ) in patients receiving bisphosphonates is currently being discussed in the scientific literature. Oral bisphosphonates such as alendronate are commonly used to treat osteoporosis and have rarely been associated with ONJ in the benign setting. There is a greater number of reported ONJ cases in patients using intravenous bisphosphonates such as pamidronate and zoledronic acid for cancer-related indications. Many authors have associated local factors, such as dental extraction, periodontal disease, abscesses, and other oral problems, with the development of ONJ, and some have also suggested risk factors other than dental irritation. The aim of this study was to describe the clinical data from oncology patients with ONJ from a single institution. A total of 18 ONJ cases were identified among all patients treated at or referred to our institute (Hospital do Cancer A C Camargo, Sao Paulo, Brazil). These patients had a variety of primary malignancies: breast cancer (n = 7), multiple myeloma (n = 4), prostate cancer (n = 3), lung cancer (n = 3), and renal cancer (n = 1). Current bisphosphonate therapy included zoledronic acid (n = 15; 7 [47%] had received prior pamidronate therapy), pamidronate (n = 2), and alendronate (n = 1). The ONJ cases were managed conservatively using local irrigation with 0.12% chlorhexidine gluconate, debridement, and antibiotics. A total of 29 local ONJ lesions were found: 13 patients had 1 lesion, 3 patients had 2 lesions, and 2 patients had 5 lesions. The majority (n = 16 [89%]) of the patients experienced some level of local discomfort/pain, 6 complained of halitosis, and only 2 patients were asymptomatic. Clinically, 62% of the ONJ lesions were associated with dental work and extractions; only 20% occurred spontaneously. The majority (59%) of the ONJ lesions completely healed in 9 patients. Overall, most of the ONJ lesions were associated with dental procedures, and pain was the symptom most frequently reported. Excellent dental hygiene was found to be important for preventing infections and ONJ and also to contribute to lesion healing in the majority of the cases.

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