Abstract
Introduction
Bone metastasis in breast cancer patients can lead to poor quality of life and cause significant morbidity. First-line treatments for bone metastases include bone modifying agents that inhibit osteoclast activity to reduce bone resorption. The most commonly used bone modifying agents include zoledronic acid and denosumab. It is currently unknown whether a therapy change from zoledronic acid to denosumab would result in greater symptom control or improved disease outcomes in breast cancer patients. In this single institution retrospective cohort study, we aimed to identify the reasons why patients transitioned from zoledronic acid to denosumab and to determine whether denosumab, as a second-line therapy, led to reduced narcotic use for metastatic bone pain.
Materials and Methods
Breast cancer patients with bone metastases treated at The Ohio State University Comprehensive Cancer center from 2011-2018 with a bone modifying agent were examined. Nineteen patients who received second-line denosumab following previous exposure to zoledronic acid were identified and included in this study.
Results
The two most common reasons patients switched from zoledronic acid to denosumab were related to side effect burden (28%) and bone metastasis progression (28%). No reduction in narcotic use due to bone pain was observed six months after starting denosumab. None of the patients developed new skeletal related events after switching to Denosumab.
Conclusion
Overall, denosumab as a second-line therapy appeared to be well-tolerated in our cohort, as we did not observe any treatment-related toxicity. Patients who switched to denosumab did not experience improved pain control.
Plain Language Summary
When breast cancer spreads to the bone, it can cause pain and poor quality of life. The first-line treatments used are bone-strengthening agents, which work by slowing down bone breakdown. The two most commonly used drugs are zoledronic acid and denosumab. However, it is not known whether switching from zoledronic acid to denosumab provides better symptom control or outcomes. In this study, we looked at why patients switched to denosumab and whether this change helped with bone pain and reduced pain medication use. We reviewed breast cancer patients with bone metastasis who were treated at The Ohio State University Comprehensive Cancer Center between 2011 and 2018. Nineteen patients who received denosumab after first being treated with zoledronic were included. The most common reasons for switching to denosumab were side effects from zoledronic acid and worsening bone disease. Overall, denosumab was well tolerated as a second-line treatment. However, switching to denosumab did not appear to improve pain control in our group of patients.
Introduction
Bone is the most common site of metastasis in breast cancer, occurring in 70% of metastatic cases. 1 Risk factors for developing bone metastasis from breast cancer include large tumor size, high-grade tumor, lymph node involvement, estrogen receptor (ER) positivity, luminal breast cancer subtype, and young age. 2 Patients with bone metastases are at risk of developing skeletal related events (SREs), which include pathologic bone fractures, spinal cord compression, the need for surgery or radiation therapy to prevent fractures, and hypercalcemia. In addition, bone-related pain can be difficult to manage and is often undertreated. Overall, these symptoms can lead to significant morbidity and adversely affect quality of life. Thus, bone-targeted treatments to prevent SREs are critically important in advanced breast cancer.
Bone remodeling is the physiologic process that maintains bone homeostasis. 3 The two cell types that mediate this process are osteoblasts and osteoclasts. Osteoblasts regulate new bone formation while osteoclasts are responsible for bone resorption. A delicate balance between bone formation and resorption is required to maintain bone health and prevent loss of microarchitecture over time. In patients with bone metastases, this balance is disrupted, leading to bone destruction and/or aberrant bone formation. Agents that inhibit osteoclastic bone resorption have been shown to reduce the total frequency of SREs and delay onset to first SRE 4
The two main classes of pharmacological inhibitors of osteoclasts include bisphosphonates (e.g., pamidronate, zoledronic acid) and monoclonal antibodies to the receptor activator of NFκB ligand (RANKL; e.g., denosumab) (Figure 1). Zoledronic acid, a commonly used anti-resorptive agent in breast cancer patients, is a nitrogen-containing bisphosphonate that acts as a potent inducer of apoptosis in osteoclast cells.
5
Denosumab is a monoclonal antibody that inhibits bone resorption by targeting RANKL, which is necessary and sufficient for osteoclast formation, activation, and survival.6-9 Zoledronic acid or the bisphosphonate pamidronate was the standard of care for cancer-related bone complications for many years until 2010, when denosumab became FDA-approved as a first-line therapy for the treatment of bone metastases. Although the data are limited, denosumab is favored as a more potent osteoclast inhibitor compared to zoledronic acid.
10
Denosumab has also been shown to improve health-related quality of life, independent of baseline pain, compared to zoledronic acid.
11
Furthermore, denosumab is associated with lengthen time to first SRE, decrease total number of SREs, and increase time to pain relative to zoledronic acid.
12
Despite evidence suggesting that denosumab is a more favorable option for bone metastasis, zoledronic acid is still widely used due to its affordability, less cumbersome dosing regimen (every 12 weeks vs. every 4 weeks), and comparable efficacy. Characterization of the transition from zoledronic acid to denosumab is limited. The effects on symptom control and disease outcome following therapy change from zoledronic acid to denosumab are currently unknown. In this retrospective study, we aimed to summarize the frequency and duration of use of denosumab in the second-line setting in breast cancer patients with bone metastases. Additionally, we identified the reasons for change to denosumab following prior exposure to zoledronic acid. Lastly, we, determined whether denosumab, as a second-line therapy, was well tolerated and resulted in improved pain control in patients with bone metastases. Mechanism of action of zoledronic acid and denosumab
Methods
Study Design and Eligibility
This retrospective cohort study utilized data extracted from patients’ electronic medical records (EMR) at The Ohio State University Comprehensive Cancer Center (OSUCCC). Approval for the study was obtained from OSUCCC’s institutional review board (IRB) prior to study initiation on December 09, 2024 (approval #2024C0114). The requirement for informed consent was waived by the IRB. Any female patient who was diagnosed with breast cancer that had metastasized to the bone and was treated with second-line denosumab following previous exposure to zoledronic acid, between January 1, 2011 and December 31, 2018, was eligible for inclusion in this study. Patients who did not have bone metastases and were receiving denosumab (60 mg every 6 months) for osteoporosis, as well as those who received denosumab (120 mg every 4 weeks) as first-line therapy for bone metastases, were excluded. The EMRs of 166 patients were reviewed, and patients were selectively included according to the inclusion criteria described above. Patient’s demographic data including age, race, ethnicity, height, and weight at diagnosis were collected. The following clinical characteristics were collected: initial stage of diagnosis, grade, genetic testing, ER status, progesterone receptor (PR) status, HER2 receptor status, and comorbidities. The following treatments and outcomes were also collected: type of surgery for breast cancer, radiation for localized breast cancer, chemotherapy, date of death, date of metastasis to bone, incidence of osteonecrosis of the jaw, documented dental clearance, radiation for metastatic disease, new fracture post-denosumab, radiation for metastatic disease after denosumab, surgery for metastatic disease and change in narcotic use within six months of starting denosumab. Serum creatinine, creatinine clearance, serum calcium, serum alkaline phosphatase, and Eastern Cooperative Oncology Group (ECOG) score within 30 days of initiation of denosumab and 3 months after initiation of denosumab were also obtained. To address potential information bias, standardized data collection was utilized. The reporting of this study conforms to the STROBE guidelines. 13 All patient details have been de-identified.
Statistical Methods
Demographic variables, clinical characteristics, treatment, outcomes and dosing for the 19 subjects were summarized using descriptive statistics. These included frequency and percent for categorical variables and mean/standard deviations or medians and interquartile range and minimum/maximum for continuous variables. The differences between serum creatinine, creatinine clearance, serum calcium, serum alkaline phosphatase measured within 30 days of initiation of denosumab and three months after initiation of denosumab were compared using a Wilcoxon signed-rank test. All data analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).
Results
Patient Demographics
In our retrospective study, we identified nineteen breast cancer patients with bone metastases who received monthly denosumab as a second-line therapy following previous exposure to zoledronic acid at our institution (Figure 2). The median patient age was 60.37 years (range 37.77-76.85 years) and 84% were Caucasian. The median follow-up was 4.84 years. Summary of patient’s clinical characteristics can be found in Table 1. In the study cohort, there were twelve patients with invasive ductal carcinoma, six patients with invasive lobular carcinoma and one patient with an unknown histologic type. Most patients had ER positive (n=18) and PR positive (n=16) breast cancer. Two patients had low grade tumors, five patients had intermediate grade tumors, and twelve patients had high grade tumors. Fourteen patients had metastatic disease at the time of initial diagnosis. Bone was the most common site of metastasis. Nine patients received radiation therapy to the metastatic bone site, and four patients underwent surgery at the metastatic bone site. None of the patients within the study cohort had a prior history of osteoporosis. Tumor characteristics are summarized in Table 2. Flow chart outlining patient selection Patient Demographic Summary of Tumor Characteristics
Reason for Initiation of Denosumab
On average, patients received 4.7 doses of zoledronic acid (4 mg) before switching to denosumab. After exposure to zoledronic acid, all nineteen patients were transitioned to denosumab, which was administered as a 120 mg monthly subcutaneous injection. Prior to initiation of denosumab, there was documented dental clearance for seventeen of the nineteen patients. The most common reasons for transition from zoledronic acid to denosumab were intolerance to side effects (28%) and progression of bone metastases (28%). Reported side effects included trismus, jaw pain, and throat pain. A rise in creatinine (22%) after initiation of zoledronic acid also led some patients to switch to denosumab. Other reasons for transition to denosumab as a second-line therapy included new pathologic fractures (11%) and hypercalcemia (11%).
Tolerability to Treatment and Patient Outcomes
Among the cohort of patients studied, there were no reported cases of osteonecrosis of the jaw, a rare adverse event associated with both zoledronic acid and denosumab. There was no significant change in serum calcium, creatinine clearance and serum creatinine following initiation of denosumab (Figure 3). However, alkaline phosphatase levels were significantly reduced following treatment. ECOG performance score remained largely unchanged (Table 3). Ten of the nineteen patients (53%) were on opioids for bone pain due to bone metastases. There was no reduction in opioid requirement within six months of initiating denosumab. Notably, none of the patients in the cohort developed a new pathologic fracture after receiving denosumab as a second-line therapy following zoledronic acid. The mean number of denosumab doses that patients received before discontinuation was 22.2. The most common reason for discontinuing denosumab was the decision to transition to hospice. Serum creatinine (A), creatinine clearance (B), serum calcium (C) and alkaline phosphatase (D) levels before and after denosumab treatment Pre- and Post-Exposure to Denosumab
Discussion
We conducted a small retrospective study examining breast cancer patients with bone metastases who received denosumab as a second-line therapy following exposure to zoledronic acid between 2011 and 2018 at our institution. For many years, zoledronic acid was the standard of care for breast cancer patients with bone metastases until denosumab was approved as a first-line therapy. Although current National Comprehensive Cancer Network (NCCN) guidelines recommend starting zoledronic acid, denosumab or pamidronate in patients with bone metastases, many patients receive denosumab in the second-line setting for various reasons. 14 Our study aimed to delineate these reasons and to summarize the frequency and duration of use of denosumab in the second-line setting at our institution. In addition, we sought to determine whether denosumab was well-tolerated as a second-line therapy and whether use of denosumab resulted in improved symptom control, which was assessed by change in narcotic use.
At our institution, nineteen breast cancer patients were started on denosumab as a second-line therapy after receiving zoledronic acid for bone metastases. One of the most common reasons for transition to denosumab was intolerance to side effects. These side effects included trismus, jaw pain, and throat pain which are all previously reported symptoms associated with bisphosphate use. 15 Patients were also switched to denosumab for progression of bone metastasis or new pathologic fracture. Denosumab is a recommended treatment for those with refractory hypercalcemia after receiving a bisphosphonate. 16 Thus, patients who were noted to have hypercalcemia even after starting zoledronic acid were switched to denosumab. Patients with rising creatinine levels after zoledronic acids were also switched to denosumab due to concerns for nephrotoxicity, an adverse effect often seen with zoledronic acid use. 17
Overall, denosumab appears to be well-tolerated when administered as a second-line therapy. We did not observe any treatment-related toxicity as measured by serum calcium and serum creatinine levels pre- and post-denosumab. Osteonecrosis of the jaw was another adverse effect measured in this study. Although osteonecrosis of the jaw is associated with both zoledronic acid and denosumab, previous studies have suggested that denosumab is associated with higher risk of developing this adverse event when compared to zoledronic acid.18,19 Despite this increased risk, there was no incidence of osteonecrosis of the jaw in patients who received denosumab.
Denosumab has been associated with reduced pain severity and delayed need for high dose opioids when compared to zoledronic acid. 20 Therefore, we hypothesized that denosumab may be effective in improving bone-related pain and reducing opioid use. However, we did not observe any reduction in narcotic medications within six months of initiating denosumab. Although this finding suggests that second-line therapy with denosumab may not effectively reduce bone-related pain, there are a few factors to consider when interpreting this data. First, patients’ other systemic therapies within six months of initiating denosumab were not evaluated, making any therapy changes potential confounding factors in our findings. Furthermore, pain due to any new or worsening metastatic lesions outside the bone would not be expected to improve with a switch to denosumab.
Denosumab has been associated with lengthen time to first SRE and decrease total number of SREs. 21 Therefore, we examined the time to next SRE after receiving denosumab as a second-line therapy. No patients in our study developed a new SRE within six months of transitioning to denosumab.
There were several limitations to this retrospective study. One major limitation is the small sample size originating from a single institution. Unfortunately, only nineteen patients among the reviewed EMRs were eligible for inclusion. Among these patients, a wide range of denosumab dosages were administered. This may have impacted the results of this study as denosumab-induced adverse events may be dose-dependent. In addition, the study population lacked racial andethnic diversity. Therefore the findings may not be representative of the broader population. Finally, clinical diversity was limited, as the study cohort consisted predominantly of ER and PR positive tumors. Thus, outcomes of this study cannot be generalized to other subtypes of breast cancer.
Conclusion
In summary, patients with breast cancer bone metastases who transitioned to denosumab as a second-line therapy, after prior exposure to zoledronic acid, appeared to tolerate denosumab well. Denosumab did not notably improve bone-related cancer pain in our small subset of patients. Given the limited sample size, larger studies are needed to definitively characterize the clinical benefits associated with transitioning from zoledronic acid to denosumab in breast cancer patients with bone metastases. Future studies should include multiple institutions to allow for more diverse patient populations and ensure that findings are broadly applicable. Additional questions for future investigation include whether specific patient demographics or tumor characteristics are associated with different clinical outcomes when switching to denosumab in the second-line setting. Importantly, future studies may also identify patients who are most likely to transition to denosumab and determine whether these individuals may be better candidates for denosumab in the first-line setting.
Footnotes
Ethical Considerations
This study received ethical approval from The Ohio State University IRB (approval # 2024C0114) on December 09,2024.
Consent to Participate
This is an IRB-approved retrospective study, all patient information was de-identified and patient consent was waived.
Author Contributions
Briana To and Doreti Doto conducted the data collection. Briana To and Laura E Wright wrote the manuscript. Julie Stephans and Marilly Palettas performed the data analysis. Kai C Johnson, Mathew Cherian, Daniel Stover, Ashley Davenport, Margaret Gatti-Mays, Robert Wesolowski, Dionisia Quiroga, Sagar Sardesai, Gilbert Bader and Nicole Williams reviewed and edited the manuscript. Bhuvaneswari Ramaswamy designed the study.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
De-identified data is available upon request to the corresponding author.