Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management.

Bone-modifying agents (BMA) are extensively used in treating patients with prostate cancer with bone metastases. However, this increases the risk of medication-related osteonecrosis of the jaw (MRONJ). The safety of long-term BMA administration in clinical practice remains unclear. We aimed to determine the cumulative incidence and risk factors of MRONJ. One hundred and seventy-nine patients with prostate cancer with bone metastases treated with BMA at our institution since 2008 were included in this study. Twenty-seven patients (15%) had MRONJ during the follow-up period (median, 19 months; interquartile range, 9-43 months). The 2-year, 5-year, and 10-year cumulative MRONJ incidence rates were 18%, 27%, and 61%, respectively. Multivariate analysis identified denosumab use as a risk factor for MRONJ, compared with zoledronic acid use (HR 4.64, 95% CI 1.93-11.1). Additionally, BMA use at longer than one-month intervals was associated with a lower risk of MRONJ (HR 0.08, 95% CI 0.01-0.64). Furthermore, six or more bone metastases (HR 3.65, 95% CI 1.13-11.7) and diabetes mellitus (HR 5.07, 95% CI 1.68-15.2) were risk factors for stage 2 or more severe MRONJ. MRONJ should be considered during long-term BMA administration in prostate cancer patients with bone metastases.

Rodents as an animal model for studying tooth extraction-related medication-related osteonecrosis of the jaw: assessment of outcomes.

OBJECTIVE: To assess the outcomes of several rodent animal models for studying tooth extraction-related medication-related osteonecrosis of the jaw (MRONJ). DESIGN: After a search of the databases, 2004 articles were located, and 118 corroborated the inclusion factors (in vivo studies in rodents evaluating tooth extraction as a risk factor for the development of MRONJ). RESULTS: Numerous studies attempting to establish an optimal protocol to induce MRONJ were found. Zoledronic acid (ZA) was the most used drug, followed by alendronate (ALN). Even when ZA did not lead to the development of MRONJ, its effect compromised the homeostasis of the bone and soft tissue. The association of other risk factors (dexamethasone, diabetes, and tooth-related inflammatory dental disease) besides tooth extraction also played a role in the development of MRONJ. In addition, studies demonstrated a relationship between cumulative dose and MRONJ. CONCLUSIONS: Both ZA and ALN can lead to MRONJ in rodents when equivalent human doses (in osteoporosis or cancer treatment) are used. Local oral risk factors and tooth-related inflammatory dental disease increase the incidence of MRONJ in a tooth extraction-related rodent model.

Incidence of giant cell arteritis after bisphosphonate exposure: A retrospective cohort study.

OBJECTIVES: Bisphosphonates may cause autoimmune reactions via a cytokine-mediated acute phase response. A case of giant cell arteritis (GCA) after zoledronate injection was recently reported. We aimed to evaluate this association by reviewing the incidence of GCA after bisphosphonate administration. METHODS: This was a retrospective study using the medical claims data of elderly patients in the 20% Medicare random sample from 2008-2014 who had received zoledronate or ibandronate. Patients who had a diagnosis claim of GCA within the past year before receiving either bisphosphonate were excluded. The development of GCA was assessed in 2 ways: GCA diagnosis claim within 28 days of bisphosphonate injection and another claim within 90 days of initial claim; and temporal artery biopsy claim within 28 days of bisphosphonate injection and GCA diagnosis claim within 90 days of biopsy. Due to the Centers for Medicare & Medicaid Services reporting requirements we excluded numbers less than 11 from analysis. RESULTS: The incidence of GCA was 0.010% and 0.013% after zoledronate and ibandronate injection respectively. In the zoledronate group incidence was highest in patients aged 75-85 years (0.011%), in Whites (0.011%), in the northeast census region (0.013%) and higher in females (0.011% vs 0.009%). All GCA cases noted in the ibandronate group involved White females. We are unable to report incidences by age and region due to the paucity of data. CONCLUSION: The incidence of GCA after bisphosphonate injection was not increased compared to the generally reported incidence in the USA.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy.

Aim: The approved indication for denosumab (120 mg) was expanded in 2018 to include skeletal-related event (SRE) prevention in patients with multiple myeloma (MM). Therefore, a cost-effectiveness analysis was conducted comparing denosumab with zoledronic acid (ZA) for SRE prevention in patients with MM from the national healthcare system perspective in a representative sample of European countries: Austria, Belgium, Greece, and Italy. Methods: The XGEVA global economic model for patients with MM was used to calculate incremental cost-effectiveness ratios (ICERs) for denosumab vs ZA over a lifetime horizon. Clinical inputs were derived from the denosumab vs ZA randomized, phase 3 study ("20090482") in patients newly-diagnosed with MM, and comprised real-world adjusted SRE rates, serious adverse event (SAE) rates, treatment duration, dose intensity, progression-free survival (PFS), and overall survival (OS). Economic inputs comprised country-specific denosumab and ZA acquisition and administration costs, SRE and SAE management costs, and discount rates. Health utility decrements associated with MM disease progression, SRE and SAE occurrence, and route of administration were included. Results: Estimated ICERs (cost per quality-adjusted life-year [QALY] gained) for denosumab vs ZA in Austria, Belgium, Greece, and Italy were €26,294, €17,737, €6,982, and €27,228, respectively. Using 1-3 times gross domestic product (GDP) per capita per QALY as willingness to pay thresholds, denosumab was 69-94%, 84-96%, 79-96%, and 50-92% likely to be cost-effective vs ZA, respectively. Limitations: Economic inputs were derived from various sources, and time to event inputs were extrapolated from 20090482 study data. Conclusions: Denosumab is cost-effective vs ZA for SRE prevention in patients with MM in Austria, Belgium, Greece, and Italy, based on often-adopted World Health Organization thresholds. This conclusion is robust to changes in model parameters and assumptions. Cost-effectiveness estimates varied across the four countries, reflecting differences in healthcare costs and national economic evaluation guidelines.

Nitrogen-containing bisphosphonate therapy-Part II: Assessment of alveolar bone tissue inflammatory response in rats-A blind randomized controlled trial.

This study aimed to evaluate the alveolar bone tissue inflammatory response in rats undergoing zoledronic acid therapy. The study sample was composed of 28 Wistar rats. Animals from the test group GTa received a weekly intraperitoneal dose of 0.2 mg/kg of zoledronic acid for 3 weeks, while test group GTb received the same dose for 8 weeks. A physiological saline dose, equivalent to that of the medication, was administered to the controls in groups GCa and GCb. A defect was created in the dental crown of the lower first molars using a drill to simulate pulp and periapical injury. Data were evaluated regarding image grey levels by cone-beam computed tomography and histologically by assigning scores for the presence of inflammatory infiltrate, type of infiltrate, vascularization, bone necrosis and dental resorption. Grey levels in the 3-week therapy group (GTa) showed more pronounced changes in comparison with those seen in the GCa group (P < 0.05). Evaluation of the scores demonstrated no association between any of the variables amongst the groups (>0.05). However, bone remodelling decreased in the groups receiving the medication. Bone necrosis was present more frequently in group GTb than in the control group GCb. The results suggest that the drug interfered in the reaction capacity of the alveolar bone tissue as test group GTa showed higher grey levels in comparison to the control group GCa. In addition, there was less bone remodelling activity, with the appearance of bone necrosis zones and intense acute inflammatory infiltrate associated with the 8-week therapy group GTb.