Zoledronic acid treatment for cancerous bone metastases: a phase IV study in Taiwan

Prostate cancer: Interventions aimed at improving morbidity, mortality

Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: A 12-year longitudinal nationwide healthcare database study

Should bisphosphonates be used routinely in patients with prostate cancer metastatic to bone?

Bone metastases are a significant clinical problem in many major cancers, especially in breast and prostate cancer where 70-90% of advanced patients develop bone metastases. Myeloma bone disease is associated with similar clinical problems than bone metastases, including increased risk of fractures and bone pain that decrease the quality of life. Current cancer therapies can only partially decrease tumor growth, resulting in only 5% of bone metastatic patients being alive 5 years after the diagnosis. Bone metastases are therefore a high unmet medical need with a high demand for effective therapies. Lack of appropriate preclinical bone metastasis models that would exhibit the same clinical features that are observed in bone metastatic patients has made it difficult to advance therapy development at early stages. This study describes the establishment of three preclinical bone metastasis models, a breast cancer model using 4T1 mouse triple-negative breast cancer cells in BALB/c mice, a prostate cancer model using RM-1 mouse androgen-insensitive prostate cancer cells in C57BL/6 mice, and a multiple myeloma model using human RPMI 8226 cells in immunodeficient NPG mice. The cancer cells were inoculated intratibially into the bone marrow to model tumor growth in bone. Tumor growth was monitored by bioluminescence imaging (BLI), cancer-induced bone changes by X-ray imaging, and bone pain by Von Frey filaments (mechanical allodynia). In the 4T1 breast cancer model, 100% of the mice had bone metastases at day 7, and maximum study duration was 21 days. Osteolytic bone lesions were clearly observed and bone pain was detected at day 7. In the RM-1 prostate cancer model, 83% of the mice had bone metastases at day 7, and 100% of the mice at day 14, and maximum study duration was 28 days. Bone pain was observed at day 7, and osteolytic-mixed bone metastases were visible at day 14. In the RPMI 8226 multiple myeloma model, 100% tumor take rate was detected at day 7. Osteolytic bone metastases were visible at day 21, and maximum study duration was 100 days. We have established a clinically relevant Bone Metastasis Technology Platform (BMTP©) that currently includes preclinical bone metastasis models for breast and prostate cancer and multiple myeloma. These models have clinical features that are similar to those observed in bone metastatic patients. In preclinical models established in BMTP, tumor burden is monitored by BLI, the type and extent of cancer-induced bone loss is visualized by X-ray imaging, and bone pain is analyzed to provide a clinically relevant readout about the quality of life. We conclude that BMTP is a clinically relevant translational tool for evaluating efficacy of cancer therapies on bone metastasizing cancers. Citation Format: Tiina E. Kähkönen, Jie Wen, Ru Yang, Yuyang Xu, Michael Zhang, Jussi M. Halleen. Bone Metastasis Technology Platform: Establishing clinically relevant bone metastasis models for breast and prostate cancer and multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3927.

Interruption of Bisphosphonates (BP) Therapy in Multiple Myeloma (MM) Patients and Osteonecrosis of the Jaw (ONJ).

Osteonecrosis of the jaw (ONJ) risk in breast cancer patients after zoledronic acid treatment

Commentary: Role of Bone-Modifying Agents in Metastatic Breast Cancer

Production of TRAIL by Multiple Myeloma Cells: a Potential Prediction Marker for Skeletal-Related Events

e19645 Background: Nitrogen containing bisphosphonates (BIS) have been shown to decrease SRE and improve survival in patients with MM. BIS use has been tempered by the occurrence of ONJ. Little is known about the prognosis incidence of SRE in MM patients with ONJ. Could the development of ONJ be a biomarker of enhanced sensitivity to BIS, with reduced SRE and better survival? Methods: In this retrospective cohort study, 11 MM patients who met diagnostic criteria for ONJ between June 2005 and June 2010 were matched to 39 MM patients without ONJ from our institution’s database. Patients were matched based on age, stage, histology, gender, ethnicity, and performance status. Skeletal surveys were used to evaluate bone disease at the start of BIS infusions and during follow-up. SRE’s were defined as: a pathological fracture, surgery to treat pathological fractures, radiation to bone, spinal cord compression or hypercalcemia. SRE were recorded from start of BIS, events needed to be > 21 days apart to be counted. All data was censored at either death or last clinic visit. Results: ONJ patients were followed for median 4.3 ± 2.4 years, Controls 3.9 ± 2.1 years (p =0.6). Time from diagnosis to transplant was non significant (NS) between ONJ and controls. Diffuse vs. limited bone disease on skeletal survey at start of BIS was NS. ONJ patients got 20.8 ± 18.0 infusions of BIS, cases 25.6 ± 17.7 (p=0.4). Only one patient in the ONJ group died (9%), 14 of the 39 control patients died (36%) (p = 0.13). Odds ratio (OR) of death in the ONJ group was 0.179 (with 95% CI (0.021, 1.544). Log-rank test to examine overall survival between ONJ and control group tended to significance (p= 0.08). SMR (skeletal morbidity rate = SRE/ patient-year) was 0.1019 events/patient-year in ONJ patients (95% C.I. 0, 0.26) and was 0.1620 events/patient-yr in controls (95% C.I. 0.05, 0.26). The odds ratio for SRE in patients with ONJ was estimated to be 0.54 (95% C.I. 0.13-2.15) p-= 0.38. Conclusions: The low odds ratios of SRE and deaths in the ONJ group support the hypothesis that ONJ might mark for increased BIS sensitivity (and hence different prognosis), but small sample sizes underpower the result.

Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab, inhibit key pathways in the vicious cycle of bone metastases. To assess the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC).To assess the effect of denosumab on SREs, bone pain and (QoL) in women with (BCBM). We searched the Specialised Register maintained by the Cochrane Breast Cancer Group (CBCGSR), MEDLINE, EMBASE and the WHO International Cancer Trials Registry Platform (WHO ICTRP) on 30 April 2011. We conducted additional handsearching of journals and proceedings of key meetings. We included randomised controlled trials (RCTs) comparing: (a) bisphosphonates and control, or different bisphosphonates in women with BCBM; (b) denosumab and bisphosphonates in women with BCBM; (c) bisphosphonates and control in women with ABC; (d) bisphosphonates and control in women with EBC; and (e) early versus delayed bisphosphonate treatment in women with EBC. Two review authors (MW and NP) independently assessed the trials and extracted the data. We collected toxicity information from the trials. We included thirty-four RCTs. In nine studies (2806 patients with BCBM), comparing bisphosphonates with placebo or no bisphosphonates, bisphosphonates reduced the SRE risk by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). This benefit was most certain with intravenous (i.v.) zoledronic acid (4 mg) (RR 0.59; 95% CI 0.42 to 0.82); i.v. pamidronate (90 mg) (RR 0.77; 95% CI 0.69 to 0.87); and i.v. ibandronate (RR 0.80; 95% CI 0.67 to 0.96). A direct comparison of i.v. zoledronic acid and i.v. pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients with BCBM), compared with bisphosphonates, subcutaneous (s.c.) denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < 0.00001).Bisphosphonates reduced the SRE rate in 12 studies (median reduction 28%, range 14% to 48%), with statistically significant reductions reported in 10 studies. Women with BCBM treated with bisphosphonates showed significant delays in the median time to SREs. Compared with placebo or no bisphosphonates, treatment with bisphosphonates significantly improved bone pain in six out of eleven studies. Improvements in global QoL with bisphosphonates compared to placebo were reported in two out of five studies (both ibandronate studies). Treatment with bisphosphonates did not appear to affect survival in women with BCBM. Compared to i.v. zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs and prolonged the time in developing pain for patients with no or mild pain at baseline; but there was no difference in survival between patients treated with denosumab and zoledronic acid.Bisphosphonates in women with ABC without clinically evident bone metastases did not reduce the incidence of bone metastases, or improve survival in three studies (320 patients).In seven studies (7847 patients with EBC), currently there is no evidence supporting bisphosphonates in reducing the incidence of bone metastases compared to no bisphosphonates (RR 0.94; 95% CI 0.82 to 1.07; P = 0.36). In three studies (2190 patients with EBC), early bisphosphonate treatment also did not significantly reduce the incidence of bone metastases compared to delayed bisphosphonate treatment (RR 0.73; 95% CI 0.40 to 1.33; P = 0.31). Currently, there is insufficient evidence to make a conclusion about the role of adjuvant bisphosphonates in reducing visceral metastases, locoregional recurrence and total recurrence, or improving survival. There was strong heterogeneity in EBC studies examining the outcomes of total recurrence and survival.Reported toxicity was generally mild. Renal toxicity and osteonecrosis of the jaw (ONJ) have been identified as potential problems with bisphosphonate use. ONJ was reported at similar rates for patients on denosumab compared to zoledronic acid. This highlighted a need for maintaining good oral care, prior to and during treatment, for patients who received long-term bone agents. In women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs. Some bisphosphonates may also reduce bone pain and may improve QoL. The optimal timing and duration of treatment for patients with BCBM remains uncertain. There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC. However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.

e19619 Background: Metastatic bone disease is a common complication of several malignancies, including breast cancer, prostate cancer, and multiple myeloma (MM), resulting in significant morbidity. Intravenous bisphosphonates (IBP) have been proven to be effective at reducing skeletal related events (SRE) from bone metastasis. Although guidelines are clear regarding dosage and infusion rates for IBPs, they fail address duration of use, especially beyond two years of use. Methods: We conducted a multi-center retrospective chart review of 92 patients who received IBPs (pamidronate or zoledronic acid) for >24 months. Patients were >18 years of age and had tumor-associated bone disease. Age, sex, tumor type, baseline and subsequent serum creatinine levels, treatment interval and duration, first time to SREs, skeletal morbidity rate (SMR) and serious toxicities [e.g., osteonecrosis of the jaw (ONJ) and renal failure] were available for analysis. Results: 92 patients were included in the study, of whom 43% (n=40) had MM, 26% (n=24) had breast cancer, 26% (n=24) had prostate cancer, and 4% (n=4) had other solid tumors. Median duration of treatment was 36 (range 24.7-128) months with a median treatment interval of 4.8 (range 3.5-15) weeks. 13 patients experienced renal toxicity, although the serum creatinine returned to normal in 9 of the patients after brief or permanent cessation of therapy. T-test analysis revealed significant differences between the baseline and highest creatinine levels (p <0.001), and no significant difference between the baseline and final creatinine levels (p<0.0713). ONJ occurred in 5 patients. A total of 44 SREs occurred among 23 (29.3%) patients. 17 (74%) had SREs in the first 2 years of treatment, while 6 (24%) had SREs in subsequent years. Mean time to first SRE was 515 days (95% confidence interval, 248; 782). SMR in the first 2 years of treatment was 0.70, while SMR in subsequent years was 0.16 Conclusions: After 2 years of IBP therapy for skeletal metastasis, patients experience SREs with less frequency. Like the first 2 years of treatment, significant toxicities such as renal failure and ONJ were uncommon. No significant financial relationships to disclose.

Patients with bone metastasis secondary to prostate or breast cancer or multiple myeloma are predisposed to skeletal-related events (SREs), such as surgery or radiation to the bone, pathologic fracture, and spinal cord compression. Inpatient costs of these and other SREs represent an estimated 49%-59% of total costs related to SREs. However, information on payer costs for hospitalizations associated with SREs is limited, especially for costs associated with specific SREs by tumor type. To examine costs from a payer perspective for SRE-associated hospitalizations among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer. Patients with SRE hospitalizations were selected from the MarketScan commercial and Medicare databases (January 1, 2003, through June 30, 2009). Sampled patients had at least 2 medical claims with primary or secondary ICD-9-CM diagnosis codes for prostate cancer, breast cancer, or multiple myeloma and at least 1 subsequent hospitalization with principal diagnosis or procedure codes indicating bone surgery, pathologic fracture, or spinal cord compression. For patients with prostate cancer or breast cancer, a diagnosis code for bone metastasis was also required. If secondary diagnoses or procedure codes for SREs were present in the claim, they were used to more precisely identify the type of SRE for which the patient was treated, resulting in 3 mutually exclusive categories: spinal cord compression with or without pathologic fracture and/or surgery to the bone; pathologic fracture with or without surgery to the bone; and only surgery to the bone. Related readmissions within 30 days of a previous SRE-associated hospitalization date of discharge were excluded to minimize the risk of underestimating costs. Mean health plan payments per hospitalization, measured as net reimbursed amounts paid by the health plan to a hospital after subtracting patient copayments and deductibles, were analyzed by cancer type and type of SRE. A total of 555 patients contributed 572 hospitalizations that met the study criteria for prostate cancer, 1,413 patients contributed 1,542 hospitalizations for breast cancer, and 1,361 patients contributed 1,495 hospitalizations for multiple myeloma. The mean age range was 61 to 72 years, and the mean length of stay per admission was 5.9 to 11.6 days across the 3 tumor types. The ranges of mean health plan payment per hospital admission across tumor types were $43,691-$59,854 for spinal cord compression, with or without pathologic fracture and/or surgery to the bone; $22,390-$26,936 for pathologic fracture without spinal cord compression, with or without surgery to the bone; and $31,016-$42,094 for surgery to the bone without pathologic fracture or spinal cord compression. The inpatient costs associated with treating SREs are significant from a payer perspective. Our study used a systematic process for patient selection and mutually exclusive categorization by SRE type and provides a per episode estimate of the inpatient financial impact of cancer related SREs assessed in this study from a third-party payer perspective.

Prevalence and significance of vitamin D deficiency in multiple myeloma patients

Real-world patient-reported outcomes of breast cancer or prostate cancer patients receiving antiresorptive therapy for bone metastases: Final results of the PROBone registry study

e19519 Background: Although the overall survival of MM patients has improved with new treatment options, few studies have evaluated prognostic factors since these new therapies have become available. Monthly ZOL has been incorporated into many of these regimens to reduce skeletal complications. Side effects from ZOL have been reported but their frequency and outcomes have not been well-defined. This retrospective study aimed to identify key baseline and on-treatment prognostic factors among MM patients treated with ZOL. Methods: Three hundred patient charts were consecutively reviewed. Data was collected from the date of MM diagnosis to the date of chart review. Patient chart inclusion criteria required a diagnosis of MM and having received at least one dose of ZOL. Results: The median survival of among patients in this study was 131 months. Significant early risk factors for overall survival included skeletal-related events (SRE), increased serum creatinine, elevated serum calcium, and ISS Stage II or III at diagnosis. Fourteen patients (4.7%) developed osteonecrosis of the jaw (ONJ) after 9–96 months of ZOL treatment. Notably, there was a trend toward an increased risk of ONJ among diabetic patients. Thirteen patients with ONJ remain alive and currently are in remission or with stable disease. One patient with ONJ died while in remission from a myocardial infarction. Among the patients with a follow up of 4–49 months from the diagnosis of ONJ, 2 showed some worsening of this complication, 5 remained stable, while 7 improved or resolved. Patients with ONJ showed an improved overall survival using both landmark and time-dependent analysis. In addition, the overall skeletal morbidity rate (SMR; SREs/year) was 0.16. Notably, patients who developed ONJ had a lower SMR than among patients who did not develop ONJ. Conclusions: These results suggest that skeletal complications are an important prognostic factor for MM. Although ONJ occurs in MM patients, most patients show improvement with proper management and this complication appears to be associated with a reduced risk of SREs and improved overall survival. [Table: see text]