Prevention Of Skeletal-related Events Research Articles

6539 Hungry Bone Syndrome & Osteoblastic Metastasis In The Setting Of Prostate Cancer : A Rare Cause Of Hypocalcemia

Abstract Disclosure: B. Sharma: None. M. Khan: None. A. Rao: None. P. Guido: None. Background: Hungry bone syndrome (HBS) is due to excessive calcium and phosphorus sequestration in the bone, manifesting as hypocalcemia and hypophosphatemia.It is most commonly seen as a postoperative complication of parathyroidectomy.Advanced prostate cancer with osseous metastasis has been previously described as is a rare cause of HBS. Clinical Case: A 65 year old male was admitted to the hospital with acute congestive heart failure and severe hypocalcemia.He exhibited symptoms of muscle spasms and perioral paraesthesias. Physical exam was positive for Trousseau's sign.Initial tests were consistent with severe hypocalcemia (corrected non-ionized calcium 6.8 [8.8-10.2] mg/dL), low ionized calcium (0.58 [1.10-1.30] mmol/L). Three weeks prior to admission, corrected non-ionized calcium was 9.8 mg/mL. Other labs showed normal magnesium, normal phosphorus, elevated alkaline phosphatase (1044 [45-117] U/L), low Vitamin D (12 [>30] ng/mL ), elevated iPTH (567 [19-88] pg/mL) and low PTH-rp (9 [11-20] pg/mL]. His electrocardiogram showed regular rate and rhythm with Qtc prolongation (497 ms).He had a significant oncological history of prostate cancer and multiple myeloma in remission.He was previously treated with zoledronic acid, discontinued 1 year prior to admission, for reducing skeletal complications while being treated for multiple myeloma. He had a recent workup with medical oncology for recurrence of prostate cancer due to elevated Prostate-specific antigen (380 [<4.00] ng/mL).Computed tomography imaging showed diffuse osteoblastic metastatic disease in the axial skeleton, pelvis and proximal femur. During hospital admission hypocalcemia was persistent, likely also due to concurrent furosemide use, necessitating the administration of intravenous calcium infusion and use of cholecalciferol and calcitriol.He was discharged on calcium carbonate 4500 mg twice a day, cholecalciferol 50 000 units weekly for 12 weeks and calcitriol 2 mcg twice a day. Conclusion: Hypocalcemia in the setting of prostate cancer is most commonly due to the use of bisphosphonates or Receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitors. Hypocalcemia in this case was due to sequestration of calcium in the bone by osteoblastic metastasis. This case illustrates the importance of recognising osteoblastic metastasis as a differential in protracted and severe hypocalcemia in malignancy.High doses of calcium, vitamin D, and calcitriol replacement are often needed as the hypocalcemia is usually severe and refractory with some cases requiring prolonged IV calcium infusion.Treatment of the underlying cancer and bone metastases with chemotherapy has been shown to improve hypocalcemia and reduce the requirement of calcium and vitamin D supplementation.There is limited data to suggest if bisphosphonates can be safely used in these cases for prevention of skeletal related events. Presentation: 6/1/2024

Routine use of denosumab for prevention of skeletal-related events in patients with bone metastases from prostate carcinoma in Bulgaria: a prospective observational study

Bulgarian real-world data on denosumab use for the prevention of skeletal-related events (SREs) associated with bone metastases (BM) from prostate cancer (PC) are lacking. This observational study enrolled 100 adult PC patients with ≥1 BM receiving denosumab (EUPAS26983). Patients’ routine treatment was observed retrospectively for ≤6 months and prospectively for 12 months. Denosumab use and safety, SRE incidence, denosumab persistence (allowing ≤2 missed doses), and pain severity were evaluated using descriptive statistics. Denosumab was initiated at a median (Q1, Q3) of 1.8 (0.6, 9.6) months following BM diagnosis with earlier initiation in hormone-sensitive (HSPC; 1.5 [0.6; 4.2]; n = 74) than castration-resistant PC (CRPC; 7.9 [0.8; 16.4]; p = .082; n = 26) and in younger (<65 years; 1.2 [0.3; 2.8]; n = 19) than older patients (≥65 years; 2.0 [0.7; 9.6]; p = .161; n = 81). Ten SREs were recorded during the retrospective and 10 during the prospective period; none were symptomatic. Denosumab was used for a median of 472 (387, 599) days overall and for 443–464 days without missing more than two doses (persistence). The proportion of patients reporting acceptable pain (score ≤4 of 10) increased from 6% at baseline to 22% at month 12. Twenty-four denosumab-related adverse events were reported, 2 were serious (osteomyelitis, osteitis) and 5 were related to osteonecrosis of the jaw. In Bulgarian clinical practice, denosumab use was associated with the prevention of symptomatic SREs and pain improvement. Denosumab was mostly used persistently. No symptomatic SREs were reported. Safety findings were consistent with previous reports of denosumab use in PC.

Incidence and prevention of skeletal-related events in multiple myeloma patients: A population-based real-world experience.

Novel treatments in multiple myeloma (MM) could influence the incidence of skeletal-related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real-world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow-up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow-up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26-33) per 100 person years. 48% experienced>1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

Abstract PO1-12-02: Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients

Abstract Denosumab (Dmab), an inhibitor of osteoclast activity and proliferation is approved for treatment of women on aromatase inhibitor (AI) therapy for early breast cancer (60 mg Q 6-months) and metastatic disease (120 mg Q 4-weeks) to protect against bone loss and prevention of skeletal-related events (SREs). 60 mg given twice a year has shown fracture reduction, especially in women on aromatase inhibitor therapy, and recent data supports benefits in disease free survival, bone-metastasis free-survival and overall survival with Dmab in early breast cancer. It appears superior in reduction of SREs versus zoledronic acid (ZA) in established skeletal metastatic disease; thus, a preferred choice in the oncology setting. In the osteoporosis setting, withdrawal of Dmab therapy leads to a “rebound” increase of bone resorption, rapid bone loss and potential vertebral fractures. Increased risk of spontaneous and multiple vertebral fractures has been seen in this patient population. To prevent this, after discontinuation of Dmab, the addition of another anti-resorptive such as ZA is initiated. Dmab withdrawal events are uncommonly reported in patients with metastatic skeletal disease due to generally poor prognosis. Dmab given as 120 mg/month in this setting may need to be curtailed for a variety of indications including hypocalcemia, major dental procedures, osteonecrosis of the jaw or atypical femoral fracture. In the oncologic setting, it is unclear if discontinuation of Dmab will lead to rebound bone resorption or increased incidence of fractures. We describe the case is of a 32-year-old woman with a history of T2N3M1, oligometastatic breast cancer (solitary bone metastases at L1, biopsy-proven) that was ER/PR/HER2 positive. She was treated with neoadjuvant trastuzumab, pertuzumab, taxotere and carboplatin followed by bilateral mastectomy, and radiation to chest wall and L1. She received total estrogen blockade initially with GnRH-agonist and exemestane and ultimately bilateral salpingo-oophorectomy plus exemestane. She continues pertuzumab and trastuzumab (80 treatments to date) for the past 5 years and denosumab 120 mg/month for 14 treatments and then every 3 months, 20 total treatments. Development of hip pain (regular runner) and concern for atypical fracture vs metastatic disease led to bone scan and PET/CT. Metastatic disease was ruled out and stress reaction was diagnosed. Dmab therapy was discontinued with monitoring of her metabolic bone turnover. 1 year after her last Dmab injection, bone turnover markers began to increase and ultimately demonstrated a very significant “rebound phenomenon.” Subsequently, a single dose of 120 mg denosumab decreased bone markers to previously low levels which remain low on routine monitoring, table below. In future, ZA will be initiated and continued on a yearly basis. Dmab has replaced ZA in managing bone health in breast cancer patients. Many oncologists use this without the assistance of bone health endocrinologists, who are an integral part of our cancer center. Bone modifying agents are often discontinued without consideration of the negative impact this may have. As this is a major survivorship issue, we document this case with literature review, to raise awareness for oncologists prescribing these medications. Citation Format: Susan Tannenbaum, Alvaro Alvarez Soto, Pamela Taxel. Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-02.

Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients With Breast Cancer With Bone Metastasis in India.

Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.

Thermal Ablation Combined with Immune Checkpoint Blockers: A 10-Year Monocentric Experience.

We report a 10-year experience in cancer therapy with concomitant treatment of percutaneous thermal ablation (PTA) and immune checkpoint blockers (ICBs). This retrospective cohort study included all patients at a single tertiary cancer center who had received ICBs at most 90 days before, or 30 days after, PTA. Feasibility and safety were assessed as the primary outcomes. The procedure-related complications and immune-related adverse events (irAEs) were categorized according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Efficacy was evaluated based on overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) according to the indication, ablation modality, neoplasm histology, and ICB type. Between 2010 and 2021, 78 patients (57% male; median age: 61 years) were included. The PTA modality was predominantly cryoablation (CA) (61%), followed by radiofrequency ablation (RFA) (31%). PTA indications were the treatment of oligo-persistence (29%), oligo-progression (14%), and palliation of symptomatic lesions or prevention of skeletal-related events (SREs) (56%). Most patients received anti-PD1 ICB monotherapy with pembrolizumab (n = 35) or nivolumab (n = 24). The feasibility was excellent, with all combined treatment performed and completed as planned. Ten patients (13%) experienced procedure-related complications (90% grade 1-2), and 34 patients (44%) experienced an irAE (86% grade 1-2). The only factor statistically associated with better OS and PFS was the ablation indication, favoring oligo-persistence (p = 0.02). Tumor response was suggestive of an abscopal effect in four patients (5%). The concomitant treatment of PTA and ICBs within 2-4 weeks is feasible and safe for both palliative and local control indications. Overall, PTA outcomes were found to be similar to standards for patients not on ICB therapy. While a consistently reproducible abscopal effect remains elusive, the safety profile of concomitant therapy provides the framework for continued assessment as ICB therapies evolve.

Bone-Targeted Therapy Regimen and Skeletal-Related Events in Patients Surviving Longer Than 2 Years With Metastatic Breast Cancer and Bone Metastasis

BackgroundBone-targeted therapy (BTT) including zoledronic acid (ZA) and denosumab decreases the risk of skeletal-related events (SREs) in patients with metastatic breast cancer (MBC) and bone metastasis. The impacts from prolonged BTT on SREs and BTT-associated harms are unknown and are becoming important to understand as these patients survive for longer periods. Methods and MaterialsWe conducted a retrospective study of 224 patients with MBC and bone metastasis who survived for more than 2 years after diagnosis and received treatment at our institution between 2016 and 2021. We defined 3 BTT patterns: (1) ZA only, (2) denosumab only, (3) both ZA and denosumab. The association between these BTT patterns and SREs and harms was assessed using Fisher exact test and logistic regression. ResultsRates of SREs overall were 21.2% of patients given ZA only, 8.8% of those given denosumab only, and 20% of those given both, without statistically significant differences (p = .32). However, those treated with denosumab only had significantly fewer compression fractures (0.7%) (p = .02). BTT-associated harm was observed in 5.8% of the ZA-only group, 11.7% of the denosumab-only group, and 14.3% of the group given both, without statistically significant differences (p = .37). ConclusionOncologists may have increased flexibility regarding the frequency of administration of BTT along with their choice of agent. Our study showed no significant difference in the prevention of overall SRE or development of BTT-associated harms between the BTT regimens evaluated.

Prevention of Skeletal-Related Events With Extended-Interval Denosumab: A Review of the Literature.

To review published clinical trial data related to efficacy and safety of administering denosumab at extended dosing intervals for prevention of skeletal-related events (SREs) in cancer patients. A literature search of PubMed was performed (January 2006 to February 2023) using the following search terms: denosumab, bone metastasis, bone lesions, and lytic lesions. Abstracts from conferences, article bibliographies, and product monographs were also reviewed. Relevant English-language studies were considered. Early phase II denosumab trials included treatment arms that utilized extended-interval denosumab, and various retrospective reviews, meta-analyses, and prospective trials have included extended-interval regimens. Most recently, the ongoing randomized REDUSE trial is comparing the efficacy and safety of extended-interval denosumab to standard dosing. At this time, the best available data are restricted to small, randomized trials not designed to compare efficacy and safety of extended-interval denosumab to conventional dosing and did not use consistent endpoints. Furthermore, primary endpoints of available trials largely consisted of surrogate markers of efficacy that may not be reflective of clinical outcomes. Historically, denosumab has been dosed at 4-week intervals for prevention of SREs. If efficacy is maintained, extending the dosing interval could potentially reduce toxicity, drug cost, and clinic visits compared to every 4-week dosing. At this time, data demonstrating efficacy and safety of extended-interval denosumab remain limited, and the results of the REDUSE trial are eagerly anticipated to help answer remaining questions.

Radiation Therapy for Painful Bone Metastases: Fractionation, Recalcification, and Symptom Control

Bone is a common site for metastases, which may cause pain and other skeletal-related events (SRE) in patients with advanced cancer. Since the 1980s, prospective clinical trials have demonstrated the high efficacy of external beam radiotherapy (EBRT) for pain relief from focal, symptomatic lesions. In uncomplicated bone metastases, which include those without pathologic fracture, evidence of cord compression, or prior surgical intervention, improvement or complete pain relief with radiotherapy is as high as 60%, with no difference in efficacy when radiotherapy is delivered in a single or multiple fractions. The ability to treat with a single fraction makes EBRT an attractive therapy even for patients with poor performance status and/or life expectancy. Even in patients with complicated bone metastases (eg cord compression), several randomized trials have demonstrated similar rates of pain relief in addition to improved functional outcomes such as ambulation. In this review, we summarize the role of EBRT for alleviating painful bone metastases and explore its role for other endpoints including functional outcomes, recalcification, and prevention of SREs.

Abstract P4-07-06: Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients

Abstract Background: In 2019, a quality improvement (QI) research project was conducted at UChicago Medicine (UCM) to evaluate bone modifying agent (BMA) use for skeletal-related event (SRE) prevention in patients with metastatic breast cancer and metastatic castration-resistant prostate cancer. Denosumab was the preferred BMA agent at UCM in this setting. Compared to zoledronic acid (ZA), denosumab was associated with higher drug cost and lower adherence rate mainly due to the difficulty of maintaining the 4-weekly frequency. Studies have shown that ZA can be de-escalated from 4-weekly to 12-weekly for SRE prevention. There is still no convincing evidence to show that this de-escalated schedule can be applied to denosumab. One study evaluated the noninferiority of 12-weekly compared with 4-weekly denosumab suggested that the health-related quality of life was non-inferior (Clemons et al., 2021). However, the study was not powered to evaluate the statistical difference in SRE rates. Based on the results of the 2019 QI project, a BMA pathway was generated at UCM in September 2020 with the purpose of guiding physician prescribing patterns, improving adherence rate, and reducing drug costs. This pathway recommended using ZA as the preferred agent for SRE prevention instead of denosumab. Methods: This was a retrospective study that included 198 patients who had metastatic breast cancer and received at least one dose of ZA or denosumab from UCM outpatient oncology clinic for SRE prevention. All included patients must have bone metastases. 107 patients from the pre-implementation study period (July 1st, 2018 to June 30th, 2019) and 91 patients from the post-implementation study period (November 10th, 2020 to November 10th, 2021) were included. Patients were divided into four groups based on study time (pre- or post-implementation period) and BMA agent (ZA and denosumab). The primary outcome was BMA therapy adherence rate, which was defined by those who received greater than or equal to 80% of appropriately scheduled doses. Secondary outcomes included the percentage of patients on ZA or denosumab, SREs, BMA-associated adverse effects, and BMA cost. Descriptive statistics were used SREs and BMA-associated adverse effects. Results: The percentage of patients on ZA significantly increased from 12% to 64% after BMA pathway implementation (P&amp;lt; 0.0001). Denosumab use decreased from 88% to 36% (P&amp;lt; 0.0001). The overall BMA adherence rate including both ZA and denosumab patients during the post-implementation period was 68%, which was not significantly different compared to the overall adherence rate of 74% during the pre-implementation period (P=0.5461). The adherence rates in denosumab groups (63% in pre and 30% in post) were lower than in ZA groups (100% in pre and 90% in post). The most common reason for the lower adherence rates in denosumab groups was scheduling convenience. During the study period, there were 2, 0, 3, and 3 patients who had SREs in the above four groups respectively. The predominant adverse events among all groups were hypocalcemia and hypophosphatemia. The cost analysis showed using ZA as the primary BMA agent saved 1.1 million dollars of drug costs during the post-implementation study period at UCM. Conclusion: Implementing a BMA pathway encouraged the providers to choose ZA as the preferred agent for SRE prevention in metastatic breast cancer patients with bone metastasis, which dramatically reduced drug costs. The overall BMA adherence rate was not significantly improved with the implementation. The difficulty of maintaining a 4-weekly denosumab frequency continued to exist. Citation Format: Kun Lin, Jordan Baur, Sandeep Parsad, Heng Yang. Implementation of A Bone Modifying Agent Pathway at UChicago Medicine for Metastatic Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-06.

Barriers to guideline-concordant use of bone modifying agents for prostate cancer.

68 Background: NCCN Guidelines recommend the use of bone-modifying agents (BMAs) to prevent skeletal-related events (SRE) for patients with castrate-resistant prostate cancer (CRPC) and bone metastasis, but not for castrate-sensitive prostate cancer (CSPC). Prior studies have identified both underuse of BMAs for CRPC and overuse for CSPC, but the clinical circumstances underlying these apparent gaps in care are unknown. Methods: Qualitative interview study, with physicians who treat prostate cancer within an academic cancer center and an affiliated network of community-based practices. Using a semi-structured interview guide, an experienced moderator probed participants’ experiences and perceptions around NCCN Guidelines recommendations, guideline adherence and non-adherence, and barriers to adherence. Interviews also probed participants’ views of potential interventions to promote guideline-concordant BMA use. Participants used Likert-scale items to rate the likely effectiveness of each intervention in influencing BMA practice patterns. They also identified the 3 most helpful interventions for reducing BMA underuse and overuse separately. Results: 19 physicians were invited, of whom 15 agreed to participate; 1 physician did not respond to some questions as outside scope of practice. All were aware of the recommendation for use of 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 burden of bony metastatic disease. 36% (5/14) were unaware of recommendations for baseline DEXA scan and BMA for patients with low bone mineral density. The most commonly reported barriers (occurring “often” or “sometimes”) to BMA use for CRPC were obtaining dental clearance (11/15) and insufficient time in clinic (6/15). The interventions perceived as most helpful to reduce underuse for CRPC were dental navigation (11/15) and EMR-based guidance (9/15). The interventions identified as most helpful to reduce overuse for CSPC were peer-to-peer education (14/15) and EMR-based guidance (13/15). Conclusions: Among physicians treating prostate cancer in our study, there was incomplete awareness of guideline recommendations for screening and treatment of low bone mineral density, and against BMA use for SRE prevention in CSPC. Dental navigation, peer-to-peer education, and EMR-based guidance were preferred implementation strategies to reduce underuse and overuse of BMAs.

Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer.

Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4-12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.

Economic evaluation of denosumab in the prevention of skeletal-related events in patients with multiple myeloma in Mexico

Economic evaluation of denosumab in the prevention of skeletal-related events in patients with multiple myeloma in Mexico

Hypocalcemia After the Administration of Denosumab in a Patient With Osteoporotic Fracture and Vitamin D Deficiency

Denosumab is a potent antiresorptive agent used for the treatment of osteoporosis and the prevention of skeletal-related events in patients with multiple myeloma or bone metastasis from solid tumors. Although denosumab generally seems to be safe and well tolerated, denosumab-associated hypocalcemia may occur, and the majority of cases are asymptomatic or mild. Underlying malignancy, renal failure, calcium or vitamin D deficiency, and high bone turnover have been reported as risk factors for hypocalcemia. Here, the author reports a case of hypocalcemia and hypophosphatemia following the administration of denosumab for the treatment of osteoporotic fracture in a patient with underlying but unrecognized severe vitamin D deficiency. Following the supplementation of calcium, vitamin D, and phosphorus, serum calcium and phosphorus levels returned to normal levels after about 2 weeks. To avoid denosumab-associated hypocalcemia, calcium and vitamin D status, as well as renal function should be assessed and corrected if appropriate. J Endocrinol Metab. 2022;12(3):111-115 doi: https://doi.org/10.14740/jem810

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach

BackgroundClinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. PurposeWe aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. MethodsUsing the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. ResultsA total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19–89) years with a median duration of denosumab treatment of 253 (range, 88–2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. ConclusionThis analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient’s need to continue denosumab treatment and improve patient outcomes.

Abstract P1-20-02: A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer

Abstract Background: The anti-RANKL monoclonal antibody denosumab has been demonstrated to be superior to the bisphosphonate zoledronate in preventing skeletal-related events (SREs) among patients with incident bone metastases (BMs) from solid tumors (STs), including breast cancer. Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥2 years. However, the denosumab treatment duration is often &amp;lt;1 year in the US. We applied a supervised machine learning approach using real-world data to estimate patient-level SRE risk following cessation of denosumab and determine risk factors associated with increased SRE risk. The method selected prior SREs, shorter denosumab treatment duration, and higher number of clinic visits as the top-ranked risk factors among a diverse group of patients with BMs from STs (Stopeck et al., ASCO 2021). Here, we report the top-ranked risk factors for the subgroup of patients with BMs from breast cancer. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BMs from a primary ST between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients must have received ≥2 consecutive 120 mg denosumab doses on every 4-week (±14 days) schedule and had a minimum follow-up ≥1 year after the last denosumab dose or an SRE occurrence between days 84 and 365 following denosumab cessation. An SRE risk prediction model was developed using extreme gradient boosting and evaluated on an independent test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential risk factors for SREs. After denosumab cessation, the impact and relative importance of these factors were extracted from the model using Shapley Additive Explanations (SHAP). In addition, findings from univariate analyses on risk factors with high importance from the breast cancer model were reported. Results: Of 1414 patients who met the inclusion criteria, 563 (40%) had BMs from breast cancer. Following denosumab cessation, 167 (30%) patients in the breast cancer subgroup experienced ≥1 SRE. The breast cancer model performance was meaningful, as evidenced by the area under the receiver operating characteristic (AUROC) score of 73%. SHAP resulted in several significant factors that predicted an increased SRE risk for the subgroup following denosumab cessation, including denosumab treatment duration of ≤8 months, prior SREs, and an average of &amp;gt;2 clinic visits per month (Table). Univariate analyses showed a positive correlation between increased SRE risk and prior SREs, while they revealed an inverse relationship between increased SRE risk and longer durations of denosumab. Conclusion: Shorter denosumab treatment duration, prior SREs, and higher number of clinic visits are top-ranked risk factors associated with SREs after discontinuation of denosumab treatment in patients with BMs from STs, including breast cancer. A machine learning approach to SRE risk factor identification may help clinicians assess the risks of discontinuing denosumab treatment and improve clinical outcomes for patients with BMs from breast cancer. SHAP Risk Factors That Increase SRE Risk 3-12 Months After Denosumab Cessation in Patients With BMsDenosumab therapy decisions: denosumab duration ≤8 months, time to denosumab initiation ≤2 months after BM diagnosisPrior SREs: ≥2 cumulative number of SREs since baseline up to cessationa, SRE occurrence (from denosumab initiation to cessation)Comorbidities: patients with anxietyVisits: &amp;gt;2 average number of visits per month (hospitalization, emergency room, and other visits [excluding nonphysician interaction]), ≥1 hospitalization, ≥1 emergency room visitaBaseline was defined as 180 days before the date of initial BM diagnosis. BM, bone metastasis; SHAP, Shapley Additive Explanations; SRE, skeletal-related event Citation Format: Alison Stopeck, Celestia Higano, David Henry, Basia Bachmann, Marko Rehn, Dionna Jacobson, Benoit Cadieux, Hossam Saad. A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-20-02.

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

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. 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. 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". 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.

Expert consensus on diagnosis and treatment of renal cell cancer bone metastasis (2021 edition)

Bone is a common metastatic site of renal cell carcinoma (RCC), with about 30% of metastatic RCC patients are suffering from bone metastasis. More than 70% of RCC patients with bone metastasis may experience skeletal related events (SREs), which may severely impair patients' quality of life and even shorten their survival time. Therefore, SREs prevention has become one of the treatment objectives of RCC bone metastasis. Bone-modifying agents are the basic treatment of bone metastases in addition to anti-tumor therapy. The treatment of RCC bone metastasis also requires multi-disciplinary team and individualized comprehensive treatment strategies. To standardize the diagnosis and treatment of RCC bone metastasis in China, the expert group of Genitourinary Oncology Committee, Chinese Anti-cancer Association has formulated the expert consensus for the reference of clinical practice, to improve the general therapeutic level of RCC with bone metastasis and benefit more patients.

Prophylactic Effect of Liaison Treatment on the Occurrence of Skeletal-Related Events in Patients with Metastatic Spinal Tumours: An Exploratory Interrupted Time Series Study.

Introduction There is a growing momentum for the collaboration between multiple disciplines for the prevention and treatment of skeletal-related events (SREs) in patients with metastatic spinal tumors. However, the effectiveness of multidisciplinary approaches remains unclear. Hence, we conducted an exploratory study to examine the impact of liaison treatment for metastatic spinal tumor (LMST) on the prevention of SREs among patients with a metastatic spinal tumor. Methods This study was an exploratory interrupted time series conducted in a single medical center. Overall, 1,043 patients with a metastatic spinal tumor diagnosed between January 2011 and December 2020 were included. The LMST was implemented in January 2014. The LMST team consisted of the orthopedic surgery, thoracic surgery, breast and thyroid surgery, clinical oncology, urology, and radiology departments. Monthly joint conferences were held for patients with spinal instability, and the incidence of SRE was measured at 6-month intervals. Results Throughout the study period, we identified 66 SRE incidences. After the implementation of the LMST, a level change of −5.2% (95% confidence interval [CI]: −11.7 to 1.3, p = 0.11) was observed. Subsequently, a post-implementation trend change of −0.3% (95% CI: −2.0 to 1.5, p = 0.75) beyond the baseline was noted. Conclusions We suggest both immediate and gradual effects of the introduction of the LMST on deterring the development of SREs. Our results support the global trend of introducing a multidisciplinary approach for the treatment of metastatic spinal tumors.

Risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from solid tumors: A real-world machine learning approach.

1567 Background: The anti-RANKL monoclonal antibody denosumab has been shown to be superior to the bisphosphonate zoledronate for the prevention of skeletal-related events (SREs) in patients with incident bone metastases (BM) from solid tumors (ST). Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥ 2 years. However, real-world treatment patterns in the U.S. suggest that the denosumab treatment duration is often &lt; 1 year. Applying a machine learning approach, we sought to identify risk factors associated with SRE incidence following cessation of denosumab to help inform optimal clinical SRE prevention strategies. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BM from a primary ST between 1 Jan 2007 and 1 Sep 2019 were evaluated for inclusion in the study. Eligible patients had to receive ≥ 2 consecutive 120 mg denosumab doses on an every 4-week (± 14 days) schedule and have a minimum follow-up ≥ 1 year after the last denosumab dose or an SRE occurring between days 84 and 365 after denosumab cessation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Impact and relative importance of available medical, clinical, and treatment factors on SRE risk following denosumab cessation were extracted from the model using Shapley additive explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 patients (breast, n = 563 [40%]; prostate, 421 [30%]; lung, 180 [13%]; other cancers, 250 [17%]) met inclusion criteria, with a median of 253 (min, 88; max, 2726) days of denosumab treatment; 490 (35%) experienced ≥ 1 SRE following denosumab cessation. With a meaningful model performance based on an area under the receiver operating characteristic (AUROC) score of 77%, SHAP identified several significant factors that predicted an increased SRE risk following denosumab cessation, including prior SREs, shorter denosumab treatment duration, and a higher number of clinic visits as the top-ranked factors (Table). Conclusions: A machine learning approach to SRE risk factor identification may help clinicians better assess the individualized patient’s need for denosumab treatment persistence and improve patient outcomes. Results from tumor-specific groups will be presented at the meeting.[Table: see text]