Real-World Evaluation of Primary Versus Secondary Prevention of Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. METHODS: Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98 646) who received continuous androgen deprivation therapy (n = 29 453), died of prostate cancer (2013-2018, n = 3864), and received life-prolonging therapy for mCRPC (n = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. RESULTS: Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n = 447) or started BTA only after first bone radiotherapy (n = 401). More patients received denosumab (n = 825, 77%) than zoledronic acid (n = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P = .023), de novo metastases (OR = 1.4, P = .005), medical oncologist involvement (OR = 2.0, P = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P = .034), and academic center (OR = 0.061, P = .007). CONCLUSION: A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy.

Excellent long-term pain response and local control following postoperative radiotherapy in patients with multiple myeloma.

PURPOSE: Multiple myeloma is associated with osteolytic bone lesions, often requiring surgery of the spine and postoperative radiotherapy (RT). Although common, data for clinical and informed decision-making are sparse. In this monocentric retrospective study, we aim to report the outcome of patients who underwent spinal surgery and postoperative RT due to multiple myeloma. METHODS: A total of 54 patients with multiple myeloma who underwent prior spinal surgery and postoperative RT at our institution between 2009 and 2020 were analyzed. Spinal instability neoplastic score (SINS) and Bilsky score, posttherapeutic adverse events, clinical data, and outcomes were collected and analyzed. The primary endpoint of this study was overall survival (OS), secondary endpoints were progression-free survival (PFS), pain response, local control, and skeletal-related events (SRE). RESULTS: The 3­ and 5­year overall survival (OS) was 74.9% (95% confidence interval [CI]: 63.5-88.4%) and 58% (95% CI: 44.5-75.6%), respectively. Median survival was not reached and 75% survival was 34.3 months (95% CI: 28.7-95.4 months). Median follow-up was 63 months (95% CI: 49-94 months). The number of patients with good to adequate performance status (Karnofsky performance score [KPS] ≥ 70) significantly increased after surgery (p < 0.01). We observed no grade 3/4 toxicity and only 13 (24%) grade 1/2 adverse events. Two patients (4%) experienced SRE. Overall, 92% of patients reported reduced pain after radiotherapy, with 66% reporting complete pain response. There was no difference in pain response between patients with different Bilsky scores. Bisphosphonate therapy and lower Bilsky score at the start of RT were associated with improved OS in univariate analysis (all p < 0.05). Multivariate Cox regression confirmed a Bilsky score of 2 or 3 as an independent negative prognostic factor (HR 3.89; 95 CI 1.4-10.7; p < 0.01). We observed no in-field recurrences. CONCLUSION: In this study, we were able to show that the current standard of RT after spinal surgery of osteolytic lesions is safe. In addition, we observed a very low rate of SRE (4%) and no in-field recurrences, demonstrating the local efficacy of RT in multiple myeloma patients. Higher Bilsky scores were associated with worse OS in multivariate analysis, but had no effect on pain response.

Factors associated with skeletal-related events in patients with bone metastatic melanoma: A retrospective study of 481 patients.

OBJECTIVES: Metastatic bone disease is estimated to develop in up to 17% of patients with melanoma, compromising skeleton integrity resulting in skeletal-related events (SREs), which impair quality of life and reduce survival. The objective of the study was to investigate (1) the proportion of melanoma patients developing SREs following diagnosis of bone metastasis and (2) the predictors for SREs in this patient cohort. METHODS: Four hundred and eighty-one patients with bone metastatic melanoma from two tertiary centers in the United States from 2008 to 2018 were included. The primary outcome was 90-day and 1-year occurrence of a SRE, including pathological fractures of bones, cord compression, hypercalcemia, radiotherapy, and surgery. Fine-Gray regression analysis was performed for overall SREs and pathological fracture, with death as a competing risk. RESULTS: By 1-year, 52% (258/481) of patients experienced SREs, and 28% (137/481) had a pathological fracture. At 90-day, lytic lesions, bone pain, elevated calcium and absolute lymphocyte, and decreased albumin and hemoglobin were associated with higher SRE risk. The same factors, except for decreased hemoglobin, were shown to predict development of SREs at 1-year. CONCLUSION: The high incidence of SREs and pathological fractures warrants vigilance using the identified factors in this study and preventative measures during clinical oncological care.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Factors Associated with Discharge Destination in Patients with Bone Metastases.

Background and Objectives: The discharge destination of patients with advanced cancer correlates with their quality of life. Patients with bone metastases often undergo lifestyle changes owing to pain and activity limitations. However, there are few reports on factors related to the discharge destination of patients with bone metastases. This study aimed to elucidate the factors associated with the discharge destination of patients with bone metastases. Methods: This study included 278 patients diagnosed with bone metastases who were admitted to the University of Tsukuba Hospital between April 2015 and March 2020. This study examined discharge destination, occurrence of skeletal-related events (SREs), primary lesions, locations of bone metastases, functional ambulation categories (FAC), age, and length of hospital stay. A binomial logistic regression analysis was conducted to compare the home and non-home discharge groups. Results: Of the 278 patients, 142 were discharged to home, 89 were discharged to somewhere other than home (non-home), and 47 died. The discharge destination was associated with spinal cord compression (SCC) (odds ratio [OR] 3.37, 95% confidence interval [CI] 1.35-8.43), hypercalcemia (OR 6.84, 95% CI 1.09-42.76), and FAC at admission (OR 0.45, 95% CI 0.35-0.58). The admission FAC cut-off value for discharge to home was determined to be 1.5 (area under the curve [AUC] 0.79, sensitivity 77.5%, specificity 68.5%). Conclusions: Factors associated with discharge destination were identified. The walking ability required for discharge to home was FAC 1.5, meaning that the patient needed one person to assist in preventing falls when walking on level ground. A cut-off value for FAC on admission for predicting outcomes was identified, suggesting the importance of gait ability assessment on admission.

Denosumab administration for bone metastases from solid tumors: a retrospective cross-sectional study.

BACKGROUND: Little is known on how denosumab reduces skeletal-related events (SREs) by bone metastases from solid tumors. We sought to evaluate the effect of denosumab administration in patients with bone metastases from solid tumors. METHODS: Data of patients treated with denosumab were collected from electronic medical charts (n = 496). Eligible participants in this study were adult patients (age ≥ 18 years) with metastatic bone lesions from solid tumors treated with denosumab. SREs, surgical interventions, the spinal instability neoplastic score (SINS) for spinal region, and Mirels' score for the appendicular region were evaluated. To assess whether denosumab could prevent SREs and associated surgery, the SINS and Mirels' score were compared between patients with and without SREs. RESULTS: A total of 247 patients (median age, 65.5 years old; median follow-up period, 13 months) treated with denosumab for metastatic bone lesions from solid tumors were enrolled in this study. SREs occurred in 19 patients (7.7%). SREs occurred in 2 patients (0.8%) who took denosumab administration before SREs. Surgical interventions were undertaken in 14 patients (5.7%) (spinal and intradural lesions in five patients and appendicular lesions in nine patients). The mean SINS of patients without SREs compared to those with SREs were 7.5 points and 10.2 points, respectively. The mean Mirels' scores of non-SREs patients and those with SREs were 8.07 points and 10.7 points, respectively. Patients with SREs had significantly higher Mirels' score than non-SREs patients (p < 0.01). Patients with SREs had higher SINS than non-SREs patients (p = 0.09). CONCLUSIONS: SREs occurred in patients with higher SINS or Mirels' scores. Two patients suffered from SREs though they took denosumab administration before SREs. Appropriate management of denosumab for patients with bone metastasis is significant. Surgical interventions may be needed for patients who with higher SINS or Mirel's scores.

Osteoblastic bone reaction in non-small cell lung cancer harboring epidermal growth factor receptor mutation treated with osimertinib.

BACKGROUND: Osteoblastic bone reaction (OBR) refers to an increase in bone density at the site of bone metastasis or the appearance of new sclerotic bone lesions after anticancer treatment. OBR can be misunderstood as disease progression. In this study, we aimed to investigate the prevalence and details of OBR and its association with clinical outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS: This was a single-center, retrospective cohort study. We reviewed patients who were diagnosed with EGFR-mutant NSCLC with bone metastasis and received osimertinib as a first-line treatment between February 2018 and October 2022. The OBR was evaluated by comparing baseline computed tomography (CT) scans with the first CT scan after treatment initiation. RESULTS: A total of 45 patients were included in this study. Thirty-seven patients (82%) developed OBR. OBR developed in 94% (n = 16) of patients with sclerotic bone lesions (n = 17) at baseline. Similarly, OBR developed in lytic and mixed bone lesions in 76% and 82% of patients with lytic and mixed lesions, respectively. Progression-free survival (PFS) did not differ significantly between patients with (OBR group) and without OBR (non-OBR group) (median PFS, 24 months vs. 17 months; hazard ratio (HR), 0.62; 95% CI, 0.24-1.6; p = 0.31). In univariate analysis, the OBR group showed a trend toward longer skeletal-related events-free survival (SRE-FS) than the non-OBR group (median SRE-FS, 26 months vs. 12 months; HR, 0.53; 95% CI, 0.21-1.33; p = 0.16). Multivariate analysis showed OBR was a significant independent predictor of SRE-FS (HR, 0.35; 95% CI, 0.13-0.92; p = 0.034). CONCLUSIONS: OBR developed in most patients with NSCLC and bone metastasis who received osimertinib treatment. The increased incidence of OBR in patients with EGFR-mutant NSCLC with bone metastasis treated with osimertinib should not be confused with disease progression, and treatment decisions should be made carefully.

A cross-sectional study on Chinese oncology nurses' knowledge of bone health among cancer patients.

OBJECTIVE: To understand the knowledge status, obstacle factors, and management confidence of oncology nurses on the bone health of cancer patients, and in addition to provide reference for establishing bone health knowledge training system for oncology nurses and guiding them to manage bone health of cancer patients. METHODS: A total of 602 nurses engaged in oncology nursing in 6 hospitals in Hebei Province were selected by cluster sampling, and an online anonymous survey was conducted by sending questionnaires to oncology nurses from the Hebei Cancer Prevention and Control Association. The questionnaire was developed by the study team. There are 4 parts, namely general information, nurses' role and job responsibilities, knowledge of skeletal-related events (SREs) and cancer treatment-induced bone loss (CTIBL), and understanding and confidence in bone health management, for a total of 33 questions. RESULTS: Thirty-seven percent of oncology nurses received training on bone health and other related contents; 40.48% of oncology nurses used domestic and foreign guidelines when managing patients with bone metastases or CTIBL. Only approximately one-third of oncology nurses had confidence in managing the side effects of bone metastases and bone modification drugs and identifying patients at risk of CTIBL and fracture; only 33.04% of oncology nurses believed that weight-bearing exercise can prevent bone loss; less than 50% of oncology nurses believed that aromatase inhibitor therapy, ovarian suppression therapy, androgen deprivation therapy, and low body weight were risk factors for pathological fractures. The reasons that hindered oncology nurses from optimizing the management of patients with bone metastases and understanding the preventive measures and risk factors for bone loss mainly included lack of relevant knowledge training, lack of understanding of effective intervention measures, and lack of training and professionalism of specialized nurses, including insufficient development time and guidelines for clinical nursing practice. CONCLUSION: Managers must continuously improve the training system of oncology nurses, enrich the content of training pertaining to bone health for cancer patients, formulate clinical nursing practice guidelines, and give oncology nurses more time for professional development.

Evaluation of denosumab in adult oncology patients for the prevention of skeletal related events across a large academic health system.

INTRODUCTION: Denosumab (Xgeva®) and zoledronic acid (Zometa®) are widely utilized for prevention of skeletal related events (SREs) in oncology patients. Drug costs, renal function, ease and logistics of administration, and adverse effect profile are factors frequently considered by patients and/or providers when selecting an optimal agent. Given the significantly higher drug cost of denosumab compared to zoledronic acid, an evaluation of our institution's denosumab use and investigation into opportunities to shift denosumab administrations to zoledronic acid and/or to lower cost sites-of-care was warranted. METHODS: A single-center, multi-site, retrospective, observational analysis of the electronic medical record (EMR) was conducted for adult oncology patients who received denosumab 120 mg for prevention of SREs from October 1st, 2018 to September 30th, 2019 at three institutions within our health system. Additional information was collected to characterize the patient population based on cancer diagnosis, renal function, and concomitant calcium and vitamin D supplementation. Our primary objective was to evaluate if the use of denosumab met current formulary restrictions of the health system. RESULTS: In total, 304 adult oncology patients received 1411 doses of denosumab for the prevention of SREs. The majority of reviewed patients had a primary oncology diagnosis of breast (35%) or lung (24%) cancer. Of the patients who received denosumab, 278 (93%) met the health system's current formulary restrictions. The majority of patients who did not meet formulary restrictions were those with multiple myeloma (MM) (20/22; 91%). Of the 304 patients reviewed, 70 had the appropriate parameters in the EMR to calculate creatinine clearance (CrCl) using Cockcroft-Gault Equation. Of those 70 patients, 59 (84%) would have been eligible to receive zoledronic acid instead of denosumab given that their CrCl >30 mL/min with no documented intolerance to bisphosphonates. Concurrent use of calcium and vitamin D is recommended when using denosumab. Based on the most recent prior to admission (PTA) medication list obtained from the 304 patients evaluated, 222 (73%) had both calcium and vitamin D listed as "taking". CONCLUSIONS: Within our health system, denosumab is restricted to those who meet formulary restrictions. Additional education is recommended to help limit the use of denosumab, specifically in MM, to reduce drug costs when zoledronic acid is also an appropriate first-line agent.

The Use of Human Amniotic Membrane (hAM) as a Treatment Strategy of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Systematic Review and Meta-Analysis of the Literature.

Background and objectives: Although it is very uncommon, medication-induced osteonecrosis of the jaw (also known as MRONJ) can have serious consequences. Traditionally, this adverse event has been recognised in patients who were treated with bisphosphonate (BP) drugs. Nevertheless, in recent years, it has been established that individuals having treatment with various types of medications, such as a receptor activator of nuclear factor kappa-Β ligand inhibitor (denosumab) and antiangiogenic agents, have had the same issue. The purpose of this research is to determine if the application of human amniotic membrane (hAM) may be used as a therapy for MRONJ. Material and Methods: A multi-source database (MEDLINE, EMBASE, AMED, and CENTRAL) systematic search was performed. The major objective of this study is to obtain an understanding of the efficacy of hAM when it is employed as a treatment modality for MRONJ. The protocol of this review was registered in the INPLASY register under the number NPLASY202330010. Results: The authors were able to include a total of five studies for the quality analysis, whereas for the quantity evaluation, only four studies were eligible. A total of 91 patients were considered for the investigation. After treatment with human amniotic membrane (hAM), a recurrence of osteonecrosis was observed in n = 6 cases (8.8%). The combined efficacy of surgical therapy and the use of hAM resulted in an overall success rate of 91.2%. Intraoperative complications were only documented in one article, and they were mostly caused by the positioning of the hAM, which led to wound breakdown at the surgical site. Conclusions: Based on the small amount of data and low-quality research included in this study, using human amniotic membranes to treat MRONJ might represent a feasible option. Nevertheless, further studies with a wider patient population are required to understand the long-term impacts.

Intramedullary nailing versus plate compound osteosynthesis in subtrochanteric and diaphyseal pathologic femoral fractures: a retrospective cohort study.

PURPOSE: Pathologic fractures of the extremities due to carcinoma metastases require individual and patient prognosis-related stabilization procedures. Quick remobilization of the patient to restore the quality of life is of high importance, especially in the case of subtrochanteric and diaphyseal femoral fractures. In our retrospective cohort study, we evaluated intraoperative blood loss, length of operation, complication rate, and regain of lower extremity function in plate compound osteosynthesis (PCO) versus intramedullary nailing (IM) for subtrochanteric and diaphyseal pathologic fractures of the femur. METHODS: Between January 2010 and July 2021, we retrospectively reviewed 49 patients who were treated at our institution for pathologic fractures of the subtrochanteric and diaphyseal femurs for group differences in terms of blood loss, length of operation, implant survival, and Musculoskeletal Tumor Society (MSTS) score. RESULTS: We included 49 stabilization procedures of the lower extremity due to pathologic fractures of the proximal or diaphyseal femur, with a mean follow-up of 17.7 months. IM (n = 29) had a significantly shorter operation time than PCO (n = 20) (112.4 ± 9.4 and 163.3 ± 15.96 min, respectively). We did not detect any significant differences in terms of blood loss, complication rate, implant survival, or MSTS score. CONCLUSION: Based on our data, pathologic subtrochanteric and diaphyseal fractures of the femur can be stabilized with IM, which has a shorter operation time than PCO, but the complication rate, implant survival, and blood loss remain unaffected.

Phase II Study of Cabozantinib in Patients With Bone Metastasis.

Bone metastases are often difficult to manage as they can be symptomatic and skeletal-related events (SREs) can contribute to significant morbidity and declines in performance status. We sought to identify a novel medical treatment for bone metastasis by testing the safety and efficacy of cabozantinib in patients with bone metastasis arising from non-breast, non-prostate, malignant solid tumors. Patients were administered cabozantinib as an oral drug starting at 60 mg per day and radiologic measurements were performed at baseline and every 8 weeks. Thirty-seven patients were enrolled. No SREs were observed throughout the study. Twenty patients had disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Four of 20 had a partial response by RECIST. An additional 12 patients had some decrease in tumor burden with nine of these having a decrease in tumor burden of at least 10% by RECIST. Six of the patients with at least a minor response had sarcoma. Sixteen patients had biomarkers of bone turnover measured before and after treatment. Most of these patients demonstrated decrease in urine and serum N-telopeptide and serum C-telopeptide. However, these changes in biomarkers of bone turnover did not correlate with radiographic changes measured by RECIST. This study demonstrates clinical activity and safety for cabozantinib in heavily pretreated patients with bone metastasis and shows activity for cabozantinib in patients with metastatic sarcoma.

Bone metastases from differentiated thyroid carcinoma: heterogenous tumor response to radioactive Iodine therapy and overall survival.

PURPOSE: Bone metastases (BM) from differentiated thyroid carcinoma (DTC) impact negatively the quality of life and the life expectancy of patients. The aim of the study was (a) to evaluate the overall survival (OS) and prognostic factors of OS and (b) to assess predictive factors of complete BM response (C-BM-R) using radioiodine treatment (RAI) either alone or in association with focal treatment modalities. METHODS: A total of 178 consecutive DTC patients harbouring BM, treated between 1989 and 2015, were enrolled in this retrospective study conducted in two tertiary referral centers. OS analysis was performed for the whole cohort, and only the 145 considered non-RAI refractory patients at BM diagnosis were evaluated for C-BM-R following RAI. RESULTS: The median OS from BM diagnosis was 57 months (IQR: 24-93). In multivariate analysis, OS was significantly reduced in the case of T4 stage, 18FDG uptake by the BM and RAI refractory status. Among the 145 DTC considered non-RAI refractory patients at BM diagnosis, 46 patients (31.7%) achieved a C-BM-R following RAI treatment, either alone in 32 (18%) patients or in association with focal BM treatment modalities in 14. The absence of extra-skeletal distant metastasis and of 18FDG uptake in BM were predictive for C-BM-R. CONCLUSIONS: In nearly one-third of DTC patients with RAI avid BM, RAI alone or in combination with BM focal treatment can induce C-BM-R. The presence of 18FDG uptake in BM is associated with an absence of C-BM-R and with a poor OS. 18FDG PET-CT should be performed when BM is suspected.

Long-term safety and efficacy of bisphosphonate therapy in advanced lung cancer with bone metastasis.

Aim: This retrospective, observational study evaluated the long-term (>12 months) safety and effectiveness of bisphosphonate. Methods: Data collected for 359 patients included quantity and proportion of adverse events (AEs) and skeletal-related events (SREs), and times to first AE and first SRE. Results: Patients in the ≤24-month group experienced significantly fewer AEs compared with the >24-month treatment group (p = 0.008), and treatment for >24 months was a potential risk factor for AEs (p = 0.05). Neither the proportion nor the risk of SRE was significantly associated with therapy duration (p = 0.525 and 0.084, respectively). Conclusion: Bisphosphonate treatment beyond 2 years may increase the risk of AEs, but may prolong SRE-free survival early after 24 months, compared with medication administered for ≤24 months.

The survival of patients with lung cancer with bone metastases has improved, just as the outcomes for many patients with cancer have improved. Bisphosphonate is the standard drug used for bone metastasis of lung cancer, but its safety and effectiveness when used for more than 2 years have not been finally decided. This study reviewed and analyzed the records of 359 patients who received bisphosphonate treatment for up to 24 months or longer than 24 months. It was determined that bisphosphonate used for more than 24 months may increase the risk of calcium deficiency in the bloodstream (hypocalcemia) and kidney disease, but may also delay the development of bone pain, fracture and spinal cord compression or the need for bone radiotherapy or surgery.

Symptomatic skeletal-related events in patients receiving longer term bone-modifying agents for bone metastases from breast and castration resistant prostate cancers.

BACKGROUND: The effect of longer-term use of bone-modifying agent (BMA) on symptomatic skeletal event (SSE) rates in patients with bone metastases remains unclear. This retrospective study of a cohort of patients in a randomized controlled trial evaluated SSEs in patients receiving BMAs at a single cancer center. METHODS: Data from patients with metastatic breast and castration-resistant prostate cancer (CRPC) were interrogated to evaluate the effects of longer-term use of BMAs on incidence, type, and risk factors for SSEs. RESULTS: Of 162 patients, 109 (67%) had breast cancer (BC) and 53 (33%) CRPC. Median age at diagnosis of bone metastases was 61.9 years (range 27.5-97.2) for BC patients and 72.1 (range 37.0-92.2) for CRPC patients. Median duration of BMA use was 2.3 years (range 0.1-9.9 years) for BC and 3.8 years (range 1.5-9.4) for CRPC patients. The initial BMAs in BC patients were pamidronate (46.8%), denosumab (31.2%), and zoledronate (22%). All CRPC patients received denosumab. During follow-up, 59% of BC and 75% of CRPC patients had at least one SSE. The number of patients experiencing ≥ 1 SSE per year was higher in the first year after bone metastasis diagnosis (63/162; 38.9%) compared with that in the second (26/149; 17.5%) and third years (30/123; 24.4%). Neither age, visceral disease, multiple bone metastases, nor biological markers for BC had a significant impact on time to first SSE. CONCLUSIONS: The risk for SSEs was greatest in the first year after diagnosis of bone metastasis. Studies evaluating de-escalation and even stopping of BMAs with longer-term use may therefore be warranted.

Risk factors of skeletal-related events in patients with bone metastatic castration-resistant prostate cancer undergoing treatment with zoledronate.

BACKGROUND: Skeletal-related events (SREs) are related to morbidity and mortality in patients with bone metastatic prostate cancer, and preventive strategies based on patient risk assessment are recommended. However, potentiating factors for SREs in patients with bone metastatic prostate cancer are not well elucidated. METHODS: We analyzed the clinical data from a controlled arm of a clinical trial comparing denosumab with zoledronate in patients with bone metastatic, castration resistant prostate cancer (ClinicalTrial.gov ID: NCT00321620) available at Project Data Sphere, a broad-access research platform. The primary endpoint was the first SRE after the inclusion to the trial, and the time to the first SRE was analyzed using Cox proportional hazards model based on patients' baseline characteristics including age, race, ECOG performance status (PS), Gleason score, TNM stage at diagnosis, metastasis pattern, and urine and serum laboratory data. RESULTS: Seven hundred ten patients without documented history of osteopenia or osteoporosis whose data was available in the zoledronate arm of the trial were analyzed. The median age of the patients was 71 years old, the median follow-up was 225 days, and 295 patients (42%) had at least one SRE during this period. The univariate analysis showed that history of SREs, Gleason score ≥ 7, elevated serum alkaline phosphatase (ALP), and high urine N-telopeptide cross-links/creatinine ratio (NTx/Cre) are significant baseline risk factors for SREs. Patients with the characteristics of history of SREs, Gleason score ≥ 7 and elevated serum ALP also showed a significantly higher hazard ratio of SREs in multivariate analysis. CONCLUSIONS: The incidence of SREs in patients with bone metastatic prostate cancer may be higher in those with history of SREs, Gleason ≥ 7, and elevated serum ALP.

Life-threatening sustained hypocalcemia following Denosumab use in metastatic prostate cancer.

INTRODUCTION: Prostate cancer is the second most frequently diagnosed cancer among men worldwide in 2020. Skeletal-related events (SRE) like pathologic fracture or spinal cord compression are commonly seen in metastatic prostate cancer. Denosumab, a monoclonal antibody, acts by inhibiting osteoclast-mediated bone resorption in bone metastasis from solid tumors and reduces bone turnover and destruction. However, there is an increased risk of life-threatening denosumab-induced hypocalcemia with an incidence of 0.1 to 12.8%. CASE REPORT: Our patient is a 69-year-old man with widespread skeletal metastatic disease from primary prostate cancer who presented to the hospital complaining of generalized fatigue and joint pain. Due to severe debilitating low back pain secondary to osteochondral lesions, the patient was started on Denosumab 120 mg. On presentation, serum calcium was found to be severely low at 5.9 mg/dl (serum calcium level prior to Denosumab was 9.1 mg/dl). MANAGEMENT AND OUTCOME: Denosumab was discontinued immediately, and the patient was started on IV calcium gluconate. Repeat serum calcium level continued to be low at 6.7 likely due to the long elimination half-life of Denosumab (25-30 days). He was transferred to a long-term acute care facility for long-term IV calcium replacement, where he succumbed to illness six weeks later. DISCUSSION: Denosumab, an anti-resorptive treatment for skeletal metastasis from solid tumors, is shown to cause severe life-threatening hypocalcemia. The maximum serum drug level of Denosumab reaches 7-21 days after administration. Sustained hypocalcemia is rare and life-threatening. Clinicians should use this medication with caution due to its unpredictable side effect profile.

Safety and efficacy of bone-modifying agents among multiple myeloma patients: A retrospective cohort study.

OBJECTIVE: To determine the incidence of skeletal-related events among multiple myeloma patients who received chemotherapy without a bone-modifying agent (zoledronic acid and denosumab) versus those who received chemotherapy with a bone-modifying agent. The secondary objective was to determine the incidence of skeletal-related events in patients without any prior history of skeletal-related events and who were treated with zoledronic acid every four weeks versus those who received zoledronic acid at an extended interval of every twelve weeks. Additional secondary objectives included the incidence of nephrotoxicity, hypocalcemia and osteonecrosis of the jaw in all patients. METHODS: This institutional review board-approved, retrospective cohort study included patients 18 to 89 years old with a diagnosis of multiple myeloma, who were being treated with chemotherapy between July 1, 2016 and October 31, 2019. Safety and efficacy were assessed through analysis of pertinent data collected: patient demographics, baseline skeletal-related events, development of new skeletal-related events, number and type of bone-modifying agent doses administered, and drug-related toxicities such as nephrotoxicity, hypocalcemia, and osteonecrosis of the jaw. RESULTS: A total of 73 patients were included. New skeletal-related events occurred in 12 patients (27%) in the chemotherapy without a bone-modifying agent group and in 5 patients (17%) in the chemotherapy with a bone-modifying agent group (OR = 0.56, 95% CI [0.172-1.8]; P = 0.32). The incidence of skeletal-related events was similar among patients receiving zoledronic acid every four weeks versus every twelve weeks in patients without a prior skeletal-related event (N = 0 vs. N = 2 respectively; P = 0.47). There were no statistically significant differences observed in each of the three secondary safety endpoints: incidence of hypocalcemia, nephrotoxicity and osteonecrosis of the jaw. CONCLUSION: Multiple myeloma patients receiving chemotherapy without a bone-modifying agent had higher rates of skeletal-related events compared to those being treated with chemotherapy and a bonemodifying agent. Our results highlight the benefit of utilizing bonemodifying agents for the prevention of skeletal-related events in all multiple myeloma patients being treated with chemotherapy.

Prevalence of skeletal-related events in hormone-naive prostate cancer in a low resource setting.

Background: Presentation with symptoms of advanced prostate cancer is prevalent in developing societies. The objective of this study was to determine the rate of and factors associated with skeletal-related events (SREs) at presentation with hormone-naïve prostate cancer. Methods: Records of 331 consecutive prostate cancer patients from January 2009 to April 2018 were reviewed. The prevalence of SRE at the presentation was determined. In addition, the relationships between SRE and age of patient, duration of clinical features, serum total prostate-specific antigen (tPSA) and biopsy Gleason score (GS) at presentation were evaluated. Analyses were done with IBM SPSS® version 25. Results: Mean age was 69.8 ± 8.0 years. While 43.8% of patients had lower urinary tract symptoms (LUTS) only, 51.4% had LUTS and other features of disease progression. Only 2.1% of the cases were confirmed from screen detection of elevated serum tPSA. SREs were observed in 11.8% at first presentations with hormone-naïve prostate cancer. Symptom duration (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.90-0.99; P = 0.02), anaemia that could not be attributed to gross haematuria or external blood loss (OR 9.6; 95% CI 3.12-29.52; P < 0.001) and transrectal biopsy GS (OR 1.61; 95% CI 1.17-2.22; P = 0.003 ) were significantly associated with SREs at presentation with hormone-naïve prostate cancer. Conclusions: Evidence exists that patients who present with SREs from more aggressive prostate cancers may have had more rapid symptom progression, but not a longer delay before presentation.

Impact of Extended-Interval Versus Standard Dosing of Zoledronic Acid on Skeletal Events in Non-Small-Cell Lung Cancer and Small-Cell Lung Cancer Patients With Bone Metastases.

BACKGROUND: Zoledronic acid every 4 weeks (Q4wk) reduces the incidence of skeletal-related events (SREs) in patients with metastatic lung cancer. Lung cancer patients were excluded from extended-interval dosing trials (every 12 weeks [Q12wk]) that demonstrated noninferiority of the 2 dosing schemes. To date, the optimal dosing of zoledronic acid in metastatic lung cancer remains unknown. OBJECTIVE: To determine whether zoledronic acid dosed Q12wk is similar to Q4wk dosing for prevention of SRE in patients with metastatic lung cancer. METHODS: A retrospective analysis was performed in patients with non-small-cell lung cancer and small-cell lung cancer with bone metastases who received Q12wk and Q4wk zoledronic acid. The primary outcome was incidence of SRE at 1 year. Secondary analyses included time to first SRE, overall survival (OS), incidence of osteonecrosis of the jaw (ONJ), kidney dysfunction, and hypocalcemia. RESULTS: A total of 34 patients received Q12wk and 46 patients received Q4wk zoledronic acid. Incidence of SRE at 1 year (Q12wk, 23.5%, vs Q4wk, 23.9%; 95% CI = -0.184 to 0.192; P = 0.968) and median time to SRE (not reached for either cohort; P = 0.530) did not differ. The Q12wk cohort had longer median OS (24.00 vs 8.97 months; P = 0.022). There were no differences in incidence of ONJ, kidney dysfunction, and hypocalcemia. CONCLUSION AND RELEVANCE: This is the first report examining extended-interval dosing of zoledronic acid in metastatic lung cancer. Incidence and time to SRE at 1 year were similar. This extended-interval dosing may be safe and reasonable for patients with lung cancer with bone metastases.