Bone-modifying Agents Research Articles

Antiresorptive agent-related osteonecrosis of the jaw risk in cancer patients before bone-modifying agent therapy: A retrospective study of 511 patients.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a serious adverse event associated with therapies for advanced cancer involving bone-modifying agents (BMAs). Although many studies have investigated the risk factors for ARONJ, none have provided sufficient clarifications. We aimed to determine whether there is a correlation between tooth extraction before BMA therapy and the development of ARONJ. We included 511 patients who were admitted to our department before BMA therapy. The incidence of ARONJ and its risk factors was retrospectively evaluated, focusing on tooth extraction before BMA therapy and radiological findings of the extracted tooth. Of the 511 patients, 135 underwent tooth extraction before undergoing BMA therapy. ARONJ was observed in 17.7% and 7.2% of patients in the extraction and non-extraction groups, respectively (p=0.0002). Regarding the findings of panoramic radiographs before tooth extraction, the incidence of periapical disease was significantly higher in the ARONJ group than that in the non-ARONJ group (50% and 27%, respectively, p=0.034), and the proportion of bone sclerotic changes in the surrounding teeth was significantly higher in the ARONJ group (58.3%) than in the non-ARONJ group (24.4%) (p=0.0004). The presence of a hopeless tooth that requires extraction prior to BMA therapy is a risk factor for MRONJ. However, extraction of such teeth should be considered, as this is known to decrease the risk of MRONJ development after BMA therapy initiation. Moreover, the radiological findings of periapical disease and bone sclerotic changes in the extracted teeth identified in this study can be used as novel predictive factors for ARONJ.

Impact of Bone Modifying Agent Initiation Time, Frequency, and Duration on Skeletal-Related Events in Patients with Multiple Myeloma

Background: Skeletal related events (SREs) including pathologic fractures, surgery or radiation to bone, and spinal cord compression contribute to diminished quality of life in patients with multiple myeloma. Bone modifying agents (BMA) such as denosumab or the bisphosphonates zoledronic acid and pamidronate, are used to inhibit osteoclast activity to prevent SREs. The Bone Working Group of the International Myeloma Working Group suggests monthly administration of zoledronic acid for 12 months in newly diagnosed myeloma patients. This is followed by an option to discontinue or decrease administration frequency to every 3, 6, or 12 months if a very good partial response or better is achieved. The ideal start time of BMA from diagnosis and the duration of administration has not been adequately established to optimize reduction of SREs. Methods: This was a retrospective, single-center study that included newly diagnosed myeloma patients treated at the Mayo Clinic between 9/1/2018 and 9/1/2020 who had received at least one dose of a BMA. The primary objective was to evaluate the impact of BMA dosing frequency and duration on SREs. Secondary objectives included time to BMA initiation, time to relapse or progressions following BMA start, and safety. Data was summarized using frequencies and percentages for categorical data, and medians and interquartile ranges (IQR) for continuous data. A spline plot and cut-point analysis were used to assess the association of time from multiple myeloma diagnosis to BMA initiation with skeletal related outcomes. Rates of SREs were estimated using the Aalen-Johansen method, where death was treated as a competing risk. Associations of factors with SREs were assessed using Cox proportional hazards regressions, and these associations were summarized using hazard ratios (HR) and corresponding 95% confidence intervals (CI). Variables that could change throughout follow-up including BMA frequency, cumulative BMA dose, and duration of BMA were treated as time-dependent covariates in the Cox proportional hazards models, where the information for these variables was updated each time an additional dose of BMA was given. All analyses were performed using SAS version 9.4 software (SAS Institute, Inc.; Cary, NC) and R version 4.2.2 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Results: Sixty-seven patients were included with a median age of 65 years old. The most frequently used BMA was zoledronic acid (88.1%), followed by pamidronate (7.5%), and denosumab (4.5%). Fifty-five patients (82.1%) had bone disease at baseline. Within 2 years of starting BMA, SREs occurred in 42.2% of patients with baseline bone disease and 8.3% of patients without (p=0.054). Median time to BMA initiation after diagnosis was 45 days (IQR 14-105) in patients with baseline bone disease and 87 (IQR 32-496) in patients without. Among the 26 patients with a SRE, median time from start of BMA to SRE was 170 days (IQR 32-496). No significant association was found between time to initiation and development of a SRE (Figure 1). BMA dosing frequencies of every 3 months and 6 months had a HR for SREs of 1.67 and 0.47, respectively compared to every 1 month, (P-values >0.25). After excluding patients without baseline bone disease, compared to every 1 month dosing, dosing every 3 months and every 6 months increased the risk of SRE, although the differences were not statistically significant (3 months: HR=1.92, 95% CI 0.76-4.88, p=0.17; and 6 months: HR=1.26, 95% CI 0.14-10.94, p=0.84). Patients without bone disease at baseline remained on BMAs for a median of 1.8 years while patients with bone disease received BMAs for a median of 2 years. There was no statistically significant difference found with varying duration or cumulative dose and SRE development (Table 1). Relapse or progression occurred in 32.1% of patients within 2 years of starting BMA, while death occurred in 7.5% of patients. Osteonecrosis of the jaw occurred in 1 patient with bone disease at baseline who received zoledronic acid every 3 months for a duration of 596 days. Conclusions: No significant association between time of BMA initiation, dosing frequency, or duration on development of SREs were observed. This suggests delaying the start time of BMAs to allow for dental clearance and initial treatment would not increase risk of SREs. Prospective trials are needed to confirm these findings.

Determinants of Bone-Modifying Agent Prescribing for Metastatic Castration-Resistant Prostate Cancer in a National Health Care Delivery System.

Despite guidelines recommending bone-modifying agents (BMAs) to decrease skeletal-related events (SREs) in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are underutilized. In this retrospective cohort study, we report the factors associated with BMA use in a national health care delivery system. We used the Veterans Affairs Corporate Data Warehouse to identify men with mCRPC between 2010 and 2017. BMA prescribing frequency was evaluated, and the association between patient- and disease-specific factors with BMA use was assessed using multivariable logistic regression. Among 3,980 men identified with mCRPC (mean age 73.5 years, 29% Black), 47% received a BMA; median time to BMA from start of mCRPC treatment was 102 days. Factors associated with BMA use included previous BMA use (adjusted odds ratio [aOR], 7.81 [95% CI, 6.48 to 9.47]), diagnosis code for bone metastases (aOR, 1.26 [95% CI, 1.08 to 1.46]), and concomitant corticosteroid use (aOR, 1.53 [95% CI, 1.29 to 1.82]). Decreased BMA use was associated with advancing age (aOR, 0.85 per 10 years [95% CI, 0.78 to 0.92]), Charlson comorbidity index ≥2 (aOR, 0.76 [95% CI, 0.63 to 0.93]), Black race (aOR, 0.83 [95% CI, 0.70 to 0.98]), and decreased estimated glomerular filtration rate (eGFR; aOR, 0.19 [95% CI, 0.11 to 0.32] for eGFR 0-29 mL/minutes; aOR, 0.76 [95% CI, 0.64 to 0.91] for 30-59 mL/minutes). Patients who are older, Black, or have more comorbidities are less likely to receive guideline concordant care to prevent SREs. These observations highlight the unique challenges of caring for patients with mCRPC and the need for future studies to increase BMA use in these populations.

Cost to Medicare from bone modifying agent overuse in castration-sensitive prostate cancer.

12 Background: Bone modifying agents (BMAs) prevent skeletal related events among patients with castration-resistant prostate cancer (mCRPC) and bone metastasis, but not among patients with castration sensitive prostate cancer (CSPC). However, approximately 1/3 of Medicare patients with CSPC receive BMAs unnecessarily, and the costs to Medicare resulting from this overuse have not been assessed. Methods: We used linked SEER registry and Medicare claims data for persons diagnosed with stage IV prostate adenocarcinoma during 2011-2015, identified those who subsequently received a cancer therapy used exclusively for mCRPC, and measured 1) the number of doses of zoledronic acid and denosumab received between diagnosis and initiation of mCRPC therapy and 2) presence of patient comorbidities which may warrant BMA therapy for fragility fracture prevention (eg., osteoporosis, osteopenia). We estimated excess BMA costs to Medicare by assessing the proportion of patients who received BMA therapy during their CSPC interval and did NOT have an indication for fragility fracture prevention, using the Medicare fee schedule for drug prices. We estimated adverse event costs using event frequency and costs estimates drawn from the peer-reviewed literature. The modeled outcome was the cost to Medicare from excess BMA use for the cohort of patients diagnosed with stage IV prostate cancer each calendar year. We conducted one-way sensitivity analysis for each model input by using the highest and lowest estimates available from peer-reviewed sources, monthly vs. every-three-month dosing frequencies for both drugs, and by +/-20% for all other inputs. Results: The median time from diagnosis to initiation of CRPC therapy was 387 days (IQR 253,573), during which time 42% received >=1 dose of denosumab (mean doses = 7) and 18% received >=1 dose of zoledronic acid (mean doses = 7). The estimated, annual excess BMA cost to Medicare was $45,392,377, comprised of $43,303,078 and $45,512 in drug costs for denosumab and zoledronic acid, respectively, and $1,625,869 and $419,917 in adverse event costs, respectively. The estimate was most sensitive to denosumab administration schedule (monthly vs. every-three-month) [estimate range: $29,487,144 - $101,060,692] and the duration of CSPC [estimate range: $37,853,180 - $101,754,921]. Conclusions: BMA overuse in CSPC incurs substantial cost to Medicare, largely due to denosumab drug costs. Our sensitivity analyses suggest we may overestimate costs if denosumab dosing frequency is now lower than during our observation period (eg., if more providers now use 3-month dosing), and we may underestimate costs if patients now experience CSPC for a longer duration (a plausible consequence from the introduction of ARSi therapy for CSPC in the post-LATITUDE era). Avoidable costs and toxicity may be reduced by greater adherence to guideline-concordant use of BMAs.

MO46-1 A retrospective study on the development of osteonecrosis of the jaws (ONJ) in patients treated with bone modifying agents (BMA)

MO46-1 A retrospective study on the development of osteonecrosis of the jaws (ONJ) in patients treated with bone modifying agents (BMA)

Denosumab versus pamidronate in the treatment of osteolytic bone metastases secondary to breast cancer: a multi-institutional analysis

Background Breast cancer is the most common cancer in women and most often metastasizes to the bone, resulting in skeletal-related events (SREs). Bone-modifying agents (BMAs) including denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappa-b ligand (RANKL), and pamidronate, a bisphosphonate, are used to prevent these adverse events. Methods To analyze the efficacy of denosumab versus pamidronate, we used the TriNetX research platform and compared the outcomes of pathologic fracture, spinal cord compression, and overall 5-year survival rate between each pharmacotherapy. Results There was no statistical difference for an increased risk in pathological fractures (2.7% vs. 2.8%, P = 0.88), spinal cord compression (2.6% vs. 2.7%, P = 0.88), or 5-year survival rate (45.5% vs. 52.4%, P = 0.78) for the denosumab cohort versus the pamidronate cohort. Conclusion Since neither therapy showed an increased risk in the adverse effects measured in this study, factors such as patient preference, financial costs, and additional side effects of each medication should be taken into consideration when choosing a therapy for bone metastases in patients with breast cancer.

Physician knowledge, practice patterns, and barriers encountered regarding guideline-concordant use of bone modifying agents for prostate cancer.

Guidelines recommend bone-modifying agents (BMAs) for patients with castrate-resistant prostate cancer (CRPC) and bone metastasis, but not for castrate-sensitive prostate cancer (CSPC). Physicians beliefs and practices regarding BMA therapy are poorly understood. This was a qualitative interview study with embedded Likert-scale elements. Study participants were physicians who treat prostate cancer, located within an academic cancer center or an affiliated community-based network. Participants were asked about their experiences and practice patterns regarding BMA therapy. Participants used Likert-scale items to identify the most common barriers to guideline-concordant BMA use and the most effective potential interventions. Participants were subsequently asked to rank the three most common barriers and the three most effective interventions to reduce underuse (for CRPC) and overuse (for CSPC). Nineteen physicians were invited and 15 participated; one physician did not answer some questions as outside of their practice scope. All were aware of the recommendation for BMAs in CRPC. 14% (2/14) were unaware of the recommendation against BMA use for CSPC; an additional 29% (4/14) believed that BMA use could be appropriate for CSPC depending on the metastatic disease burden. 36% (5/14) were unaware of recommendations for screening and treatment of low bone mineral density. The most common barriers (occurring "often" or "sometimes") were obtaining dental clearance (11/15) and insufficient clinic time (6/15). The interventions identified as most effective to reduce underuse were dental navigation (11/15) and electronic medical record (EMR)-based guidance (9/15). The interventions identified as most effective to reduce overuse were peer-to-peer education (14/15) and EMR-based guidance (13/15). Awareness of guideline recommendations for screening and treatment of low bone mineral density and against BMA use for CSPC was good, but not complete. Dental navigation, peer-to-peer education, and EMR-based guidance were preferred intervention strategies to improve guideline-concordant use.

Evaluating Route of Administration for Bisphosphonates in Patients with Metastatic Breast Cancer to the Bone: A Literature Review

Introduction: Metastatic bone disease, the condition where tumor cells spread from their origin tissue to bone, is common for breast and prostate cancer. Two main hypotheses, referred to as Paget’s “seed and soil” theory and Ewing’s anatomical theory, describe the homing of cancer cells to the bone. When breast cancer becomes metastatic and the tumor spreads to the bone, skeletal-related events can occur. Many patients use bone-modifying agents such as bisphosphonates (BPs) to manage skeletal deterioration. Given the longstanding history of BPs, this review aims to evaluate the efficacy and side effects of oral versus intravenous BPs as adjuvant treatment options for patients with metastatic breast cancer. Methods: Relevant literature was sourced through a search of the PubMed and Google Scholar databases, using established inclusion criteria for screening papers published between 1889 and the present. Results: Currently, there are three generations of BPs. Literature on the different generations reports that studies mainly use first-generation BPs for Paget’s disease and there is no significant effect of first-generation BPs on breast cancer survival rate. Second-generation BPs showed effectiveness in prolonging the progression of bone metastasis and decreasing distant recurrences to the bone in breast cancer patients. In attempts to improve the health outcomes of BPs, researchers examined third-generation BPs and found that they decreased skeletal-related events and pain levels. Discussion: Comparing oral to intravenous administration of BPs, both had overall similar effects in reducing skeletal complications; however, the side effects resulting from BP use vary depending on the route of administration. Patients administered intravenous BPs exhibit an acute phase response and renal complications, while oral BPs cause disruptions in the gastrointestinal tract. Cost-effectiveness varied by study depending on assumptions made in the analytic models. Conclusion: This novel review investigates the development of each generation of BPs to compare the implications of oral and intravenous administration. By accounting for differences across the three generations, healthcare providers can make informed decisions about BPs and create treatment plans tailored to the individual patient. Future research may explore how preexisting risk factors contribute to the occurrence of adverse effects of BP use.

Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

2059P The impact of a dental oncology clinic for patients (pts) prescribed bone-modifying agents (BMA) in a cancer centre

2059P The impact of a dental oncology clinic for patients (pts) prescribed bone-modifying agents (BMA) in a cancer centre

Classification of Patients with Painful Tumors to Predict the Response to Palliative Radiotherapy

Palliative radiotherapy is an effective and commonly used treatment for pain relief in metastatic cancer patients. This study aimed to classify the patients to predict their response to palliative radiotherapy. This study used the data from our single-center, prospective observational study (UMIN000044984), which included all patients undergoing palliative radiotherapy for the painful tumor, except for postoperative setting or brain metastases. The eligibility criteria were as follows: (1) numerical rating scale (NRS) was two or more before treatment, and (2) underwent palliative radiotherapy between August 2021 and September 2022. Questionnaires for pain site, NRS, and presence/dose of opioids were obtained before, on the last day of treatment, two weeks later, one month later, three months later, and every three months after that. Patients with severe performance status (PS) were contacted by telephone. Pain response was defined to reduce NRS 2 or more at the treated site without an analgesic increase. The primary outcome was the response rate within three months of the treatment. We used multivariable logistic regression to find the independent prognostic factors for the response based on the following covariates: age, sex, PS, body mass index, NRS, history of radiotherapy, treated site, radiographic features (lytic/sclerotic/mixed), metastatic complication, presence/dose of opioids, bone-modifying agents, radiation dose, type of primary tumor, radiosensitivity, number of metastases, and days from diagnosis to treatment. A classification model was created using significant factors, and response rates were calculated for each class. Statistical significance was defined as P<0.05. Among 488 targets of 300 patients registered, 366 targets of 261 patients met the criteria. The median age was 65 years, 44% were female, and PS (0/1/2/3/4) was 6/63/18/9/4%. The major type of tumor was gastrointestinal (32%), lung (19%), and breast (12%). Bone metastases were 75% at treated sites. Opioids were used by 72%, BMA was 27%, and chemotherapy was 50%. Re-irradiation rate was 22%. With a median follow-up of 5.8 months, 113 patients were alive, 129 had died, and 20 were lost follow-up. The average NRS was reduced from 6.1 to 3.1 from pretreatment to 3 months later per evaluable 232 targets, resulting in a pain relief rate of 60%. Opioids use (P<0.001) and re-irradiation (P<0.001) were significant factors of poor response in multivariate analysis. In our classification model, 89 targets were classified as class 1 (no opioids & no irradiation history), 211 were class 2 (other than class 1 and 3), and 66 were class 3 (opioids & re-irradiation), were 75/61/36% (P<0.001) of response rate. The 6-month cumulative pain progression rate was 12/22/32% (P<0.001), respectively. Palliative radiotherapy is highly effective for patients with painful tumors especially for those without previous irradiation history or use of opioids.

Medication-related osteonecrosis of the jaws associated with the use of bone-modifying agents: new studies

The relevance of the study is associated with the widespread use of osteomodifying agents in patients with bone metastases and osteoporosis. A serious complication associated with the use of bisphosphonates and other osteomodifying agents is known — medical osteonecrosis of the jaws, but the pathogenesis of this disease has not been fully studied. With drug-induced osteonecrosis of the jaws in oncological patients with bone metastases, therapy with osteomodifying agents is suspended, which can cause a decrease in the patient's life span. This is due to the importance of prevention, early diagnosis, and rapid treatment of patients with drug-induced osteonecosis. The aim of the work was to analyze the studies carried out in 2021—2023 on new methods of diagnosis, treatment, prevention of medical osteonecrosis of the jaws. The literature review is based on the analysis of published studies according to the PubMed electronic resource.&#x0D; The analysis of the literature data showed that bisphosphonates and other osteomodifying agents are widely used in oncology and the profile of age-related changes in the human bone system. The use, therapeutic effects and complications of therapy with osteomonefying agents are being investigated all over the world. Cone-beam computed tomography remains the "gold standard" in the diagnosis of medicamental osteonecrosis of people. Antibiotic therapy is considered as an effective method of treatment. It is proposed to use hyperbaric oxygenation, laser treatment, bone resection under fluorescence control, photodynamic therapy, introduction of a biomaterial based on tricalcium phosphate, administration of teriparatide and atorvastatin as additional treatment methods. Regular dental examinations are the most effective means of preventing drug-induced osteonecrosis. The study of pathogenesis, new methods of therapy and prevention of drug-induced osteonecrosis of the jaws remains urgent.

Teriparatide-induced alleviation of medication-related osteonecrosis of the jaw: Potential molecular mechanisms

Medication-related osteonecrosis of the jaw (MRONJ) is a significant side effect of drugs such as bone modifying agents (BMA) or angiogenesis inhibitors. The incidence has been rising but the clinical prognosis is dismal. Teriparatide (TPTD), a synthetic derivative of parathyroid hormone (PTH), is occasionally demonstrated to efficiently reduced the clinical incidence of MRONJ in particular patients. However, the precise signaling mechanisms involved in TPTD-induced MRONJ repair are unknown. Currently, MRONJ progression is involved with decreased expression of the Wnt/β-catenin signaling pathway, inhibition of angiogenic function, and up-regulated inflammatory cytokines (IL-1β, TNF-α, and IL-6). Notably, in animal model experiments, TPTD increased β-catenin expression in alveolar bone and skeletal muscle; similarly, TPTD was able to reduce the area of cerebral infarction, restore cerebral blood flow, and improve neovascularization by increasing the number of blood vessels in bone tunnels and enlarging the diameter of blood vessels in the bone marrow. Furthermore, TPTD can also treat osteoarthritis in animals by suppressing inflammatory markers such as TNF- and IL-6. Thus, we propose that TPTD can cure MRONJ by dynamically modulating various signaling pathways (stimulation of the Wnt/β-catenin signaling pathway, promotion of angiogenesis, and down-regulation of inflammatory markers).

Editorial Comment to Bone-modifying agents are protective for symptomatic skeletal events in radium-223 treatment.

Editorial Comment to Bone-modifying agents are protective for symptomatic skeletal events in radium-223 treatment.

Bone-modifying agents are protective for symptomatic skeletal events in Radium-223 treatment.

Radium-223 (Ra-223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Bone-modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra-223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra-223 in real-world practice. We included 73 patients treated with Ra-223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. We used univariate analysis to ascertain the association between variables and SSE. During a median follow-up of 12.7 months (interquartile range, 7-21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1-year SSE-free survival rate from Ra-223 treatment initiation was 82.4% (95% CI, 69.4%-90.2%). BMA use was associated with favorable SSE-free survival (hazard risk, 0.23; 95% confidence interval, 0.061-0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017). This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

Validation of JSBMR's CTIBL manual for Japanese men receiving androgen deprivation therapy for prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer causes cancer treatment-induced bone loss (CTIBL), increases the fracture risk 2-3 times, and worsens life prognoses. The Japan Society of Bone and Mineral Research (JSBMR) created a CTIBL treatment manual in 2020; however, no study has validated its use in patients with ADT/CTIBL prostate cancer. This study classified 124 patients with prostate cancer without bone metastasis who received ADT into high- and low-risk groups using the JSBMR CTIBL algorithm. Comparisons were made with the period to incident vertebral fracture and the existing International Osteoporosis Foundation (IOF) classification. The median age was 74years; the median observation period was 81months. At 1, 3, 5, 7, and 9years, the prevalence of incident vertebral fractures was, respectively, 3.3%, 10.7%, 17.9%, 21.4%, and 31.2% in the entire population; 13%, 27%, 36%, 42%, and 58% in the high-risk group (19%); and 1%, 7%, 14%, 17%, and 25% in the low-risk group (81%). The hazard ratio between the two groups was 3.57 (p = 0.0004). Based on multivariate analysis, age, previous vertebral fracture and femoral neck bone density were significant risk factors for incidental vertebral fracture. The JSBMR had a hazard ratio of 3.26 (p = 0.04) relative to 1.13 (p = 0.84) for the IOF, indicating the JSBMR classification performed better. Taking preventive measures against fractures is necessary, including starting bone-modifying agents early in patients with a high fracture risk. The JSBMR CTIBL manual may be useful for this purpose.

Pentoxifylline and tocopherol as prophylaxis for osteonecrosis of the jaw due to bone-modifying agents in patients with cancer submitted to tooth extraction: a case series.

To assess the prophylaxis effect of pentoxifylline and tocopherol (PENTO) on the frequency and severity of medication-related osteonecrosis of the jaw (MRONJ) diagnosed at three months in patients with cancer submitted to tooth extractions during the treatment with bone-modifying agents. This case series was conducted at the outpatient dental clinic of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) between April 2021 and April 2022. Patients ≥ 18years old were included; those with maxillary metastasis or who performed head or neck radiotherapy were excluded. The PENTO protocol was prescribed two weeks before and two weeks after the tooth extraction, and patients were reassessed one week, one month, and three months after the extraction. The main outcome was the development of MRONJ. Of the 114 screened patients, 17 were included; they were aged between 43 and 73years and were mostly female (88.2%). Thirty-two tooth extractions were performed (22 in the maxilla and 10 in the mandible). Breast cancer was the most predominant neoplasm (70.6%), being metastatic in 35.3% of patients. Also, all patients used intravenous bisphosphonates. Stage 1 MRONJ was diagnosed in three patients (17.6%), representing three (9.4%) of all tooth extractions. The repair of MRONJ was achieved 30days after the PENTO protocol. The prophylaxis use of PENTO reduced the severity of injuries, was well-tolerated, and showed patient compliance.

The Dental Oncology Complication that Wouldn’t go Away

Background: Bone modifying agents are used throughout cancer care and their utilisation can optimise advanced stage cancer cases with bone metastases, by reducing skeletal-related events, treatment-induced bone loss and treatment hypercalcaemia. They are also used in patients with a curative intent such as early breast cancer, reducing recurrence and increasing survival rates. Medication-related osteonecrosis of the jaw (MRONJ) is a potential complication following bone modifying agents (BMAs). It represents exposed bone in the maxillofacial region which significantly compromises the quality of life for these patients. Dental disease is the most common initiating factor of MRONJ. We report a case in which MRONJ has dominated cancer care despite its successful treatment. Case presentation: A 69-year-old female was diagnosed with a breast cancer (grade 1, infiltrating ductal carcinoma, pT1c pN1mi(sc) Mx), for which she was treated with a wide local excision and axillary lymph-node clearance. Seven years after initial presentation, the patient presented with metastatic disease involving the left supraclavicular fossa, bone, peritoneum, and liver. Her BMA regime included zoledronic acid intravenous (IV) every month for 12 months and switched to oral zoledronic acid for a subsequent year due to poor venous access. Two years after her diagnosis of metastatic disease, the patient presented with exposed bone in her anterior maxilla, which represented advanced stage MRONJ (AAOMS 3). The exposed bone in the maxilla was treated surgically by sequestrectomy and fistula closure. Three years later (12 years after initial breast cancer diagnosis), the patient was re-admitted with a cervical fascial space infection involving the right mandible. The patient developed another site of advanced- stage MRONJ (AAOMS 3) in the right mandible associated with an orocutaneous fistula. The patient had a marginal resection of her mandible, fistula closure and extraction of the remaining teeth under general anesthetic. Conclusion: The practicing oncologist needs to be cognisant of the possibility of MRONJ in both the curative and palliative setting. Traditionally, oncology care has required a significant degree of self-reliance on patients to navigate dental treatment pathways. Integration of dental clinics into oncology pathways would help eliminate this need for self-reliance. MRONJ is an inevitable risk for a large cohort of oncology patients and active engagement of dental-oncology specialities will ensure optimal care for patients.

Resemblances and differences between osteoradionecrosis of the jaw and medication-related osteonecrosis of the jaw.

The aim of this retrospective study was to identify the clinical, radiological, and histological characteristics of patients diagnosed with osteonecrosis of the jaw (ONJ) and treated at the Oral and Maxillo-Facial Surgery Clinic of the Emergency Clinical County Hospital of Targu Mures between 2017 and 2022. The study aimed to analyze correlations between patient characteristics, particularly their history of bone modifying agent use or local radiotherapy during cancer treatment, in order to identify specific patient profiles that could aid in evaluating treatment response and guide individualized treatment strategies. Fifty-two patients diagnosed with ONJ were included in the study. The patients were divided into two groups based on their medical history: the bone modifying agent use group and the radiotherapy group. Clinical, radiological, and histological data were collected and analyzed. Statistical analysis, including p-values, was performed to compare patient characteristics between the two groups. Patients in the radiotherapy group were significantly older than those in the bone modifying agent use group (66 years vs. 56.9 years, p=0.001). There was a higher proportion of males in the radiotherapy group compared to the bone modifying agent use group (90% vs. 22%, p<0.001). Jaw involvement was more prevalent in the radiotherapy group compared to the bone modifying agent use group (95% vs. 66%, p=0.018). Histological analysis showed a similar frequency of Actinomyces species in both groups (50% vs. 34%, p=0.264). The findings of this study suggest the existence of two distinct patient profiles based on their treatment history (bone modifying agent use vs. radiotherapy) in ONJ. Patients in the radiotherapy group were older, predominantly male, and exhibited a higher prevalence of jaw involvement. Histological analysis revealed no significant differences in Actinomyces species frequency between the two groups. These distinct patient profiles may indicate different responses to treatment, emphasizing the need for individualized treatment strategies tailored to specific patient characteristics. Further research is warranted to validate these findings and develop personalized approaches for managing ONJ.

Clinical factors associated with prescribing patterns of bone modifying agents in men with metastatic castration-resistant prostate cancer.

e18878 Background: Bone metastases occur in up to 90% of men with metastatic prostate cancer and cause skeletal-related events (SREs) such as fracture and spinal cord compression. Although bone modifying agents (BMAs) have been shown to decrease the risk of SREs in men with metastatic castration-resistant prostate cancer (mCRPC), BMAs are not widely used in this patient population. In this retrospective study, we report the prescribing patterns of BMAs and predictors of BMA use in a large national cohort. Methods: We used the VA corporate data warehouse to identify patients with mCRPC who were treated with first-line mCRPC therapy (abiraterone, enzalutamide, docetaxel, or ketoconazole) between 2010 and 2017. BMA prescribing frequency and patterns were analyzed. Multivariable regression analysis was used to evaluate clinical and disease-specific factors associated with BMA use which are presented as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: In the final cohort of 4,079 patients, the median age at mCRPC diagnosis was 73 years (IQR 66-81). 29% of patients in the cohort were Black. Diagnosis codes identified bone metastases at mCRPC diagnosis in 48% of the cohort (ICD-9 and 10 coding for sites of metastases are known to underestimate the actual incidence of metastases). Only 48% of patients received a BMA following initiation of treatment for mCRPC, 47% of which had already received a BMA 6 months prior to mCRPC diagnosis. For those who were new BMA starts, the median time to BMA administration from mCRPC treatment was 3.4 months (IQR 1.2-8.8). Factors associated with BMA use were having an ICD-9 or 10 diagnosis code for bone metastases at time of mCRPC treatment (OR 1.28, 95% CI 1.10-1.48), concurrent corticosteroid use (OR 1.90, 95% CI 1.53-2.38), and docetaxel use as first-line mCRPC therapy (OR 1.78, 95% CI 1.45-2.18). Factors associated with decreased BMA use were Charlson comorbidity index score of ≥ 2 (OR 0.75, 95% CI 0.62-0.90), advancing age (OR 0.86 per 10 years, 95% CI 0.79-0.94), and decreased eGFR (eGFR 30-59, OR 0.81, 95% CI 0.68-0.96; eGFR 0-29, OR 0.23, 95% CI 0.14-0.37). Having a diagnosis code for a SRE before mCRPC diagnosis (e.g., bone fracture and cord compression) did not impact BMA use, but the incidence of those events was low. Conclusions: Less than half of this VA cohort received a BMA after starting therapy for mCRPC. Key factors associated with BMA use were corticosteroid use and first-line docetaxel use, which likely represented more aggressive disease. Notably, patients who were older and had more comorbid conditions were less likely to receive a BMA despite being highest risk for frailty and SREs. Future quality improvement efforts aimed at increasing BMA use may address the needs of the geriatric mCRPC patient population.