Zoledronic Acid in the Spotlight: Unraveling its Bone Health Supportive Role in Combination Treatments of Bone Metastatic Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced type of prostate cancer which spreads beyond the prostate gland to bones, lymph nodes, and other organs. It is typically more challenging to treat than earlier stages of prostate cancer. Radium-223 dichloride, marketed under the brand name Xofigo®, is a radioactive therapeutic agent has been approved to treat patients with mCRPC that has spread to bones but not to other organs. The drug specifically targets metastases in bones as radium-223 mimics calcium, and therefore, accumulates into areas of increased bone turnover, such as bone metastases. Once there, the drug emits alpha particles that induce double-stranded DNA breaks in adjacent cells, including cancer cells and disease-promoting osteoblasts.

Previous clinical trials, including the pivotal phase 3 trial ALSYMPCA, have demonstrated the efficacy of radium-223 in improving overall survival and quality of life in patients with CRPC metastasized to bone. Radium-223 in combination with other approved drugs has been investigated in patients with mCRPC to improve treatment outcomes by increasing survival and reducing skeletal-related events, including the combination of radium-223, abiraterone acetate, and prednisone/prednisolone. In a recent phase 3 trial ERA 223, an increased risk of fractures was observed in patients with bone metastatic CRPC treated with the combination of radium-223, abiraterone acetate, and prednisone. Therefore, radium-223 is now contraindicated in combination with abiraterone acetate and prednisone/prednisolone. However, concurrent administration of bone-protecting agents, such as zoledronic acid, seemed to reduce the number of fractures in patients in the ERA 223 trial. Zoledronic acid is an bisphosphonate used in the clinics to prevent skeletal-related complications as it inhibits the activity of osteoclasts, the cells responsible for breaking down bone tissue. In a new study published in Cancers by Mari Suominen from Pharmatest Services Ltd., together with Matias Knuuttila, Birgitta Sjöholm, Timothy Wilson, and Sanna-Maria Käkönen from Aurexel Life Sciences Ltd., Esa Alhoniemi from Inoi Oy, and Dominik Mumberg and led by Arne Scholz from Research & Development, Pharmaceuticals at Bayer AG in Germany, the researchers focused on evaluating the efficacy and potential bone health-related effects of various treatments in an intratibial LNCaP prostate cancer xenograft model, which closely mimics bone metastatic prostate cancer. Their goal was to understand the mechanisms behind the increased fracture risk observed in patients with mCRPC treated with a combination of radium-223, abiraterone acetate, and prednisone.

The team used male NOD.scid mice, a type of immunodeficient mouse model. The mice were inoculated intratibially (directly into the tibia bone) with LNCaP human prostate cancer cells, creating a model that replicates bone metastatic environment of prostate cancer. The researchers divided the mice into various treatment groups and received either vehicle (control), radium-223, abiraterone, prednisone, zoledronic acid, or combinations of these for 28 days. They monitored serum levels of PSA to assess cancer cell growth in tibiae. The team analyzed bone structure and quality using micro-computed tomography (microCT), a 3-point bending assay, and dynamic histomorphometry. These techniques allowed the researchers to evaluate the microarchitecture and biomechanical properties of the bone. They also measured the incorporation of radium-223 into bone, given its role as a targeted alpha therapy in bone metastases. Moreover, they conducted blood sampling and analysis for biomarkers related to bone resorption and formation, such as TRACP 5b, PINP, CTX-I, and ALP. Furthermore, at the end of the study, ex vivo radiography was performed on the tumor-bearing tibiae to analyze abnormal bone areas. Additionally, the authors carried out histological analysis to assess tumor area, cortical and trabecular bone areas, and the presence of fibrotic and necrotic areas in the bone.

The authors found that the combination of radium-223, abiraterone, and prednisone induced a transient increase in bone resorption, as indicated by elevated levels of TRACP 5b, a marker of osteoclast activity. The combination treatment also resulted in reduced periosteal and trabecular new bone formation and a decrease in the number of osteoblasts. However, the overall bone structure and biomechanical quality were not significantly affected. One of the key observations in their study was that the combination treatment decreased radium-223 incorporation into tumor-bearing bone. This finding might explain the lack of additional antitumor efficacy observed with this combination therapy. The authors also noted changes in other bone turnover biomarkers. For instance, a radical decrease in PINP levels, a marker of bone formation, was observed in all groups receiving prednisone, suggesting an inhibition of osteoblast activity. Similarly, transient changes were observed in total ALP levels with certain treatments. When the authors performed histomorphometry analysis, they showed a reduction in bone formation in non-tumor-bearing tibiae, particularly in the mineralizing surface of both trabecular and periosteal bone.

It is noteworthy to mention that zoledronic acid, when used concurrently with the radium-223, abiraterone, and prednisone combination, inhibited the increased bone resorption associated with this treatment. This was evidenced by the decreased levels of TRACP 5b. Furthermore, zoledronic acid did not interfere with radium-223’s antitumor efficacy or its incorporation into bone, suggesting its potential as a supportive treatment to mitigate bone resorption. Moreover, ex vivo radiography showed that zoledronic acid, along with the combination treatment, inhibited abnormal bone growth in tumor-bearing bone more efficiently compared to other groups receiving radium-223. The statistical analysis provided robust evidence to support these findings, with various models demonstrating significant differences between treatment groups and the control.

In summary, the preclinical study conducted by Dr. Arne Scholz and colleagues demonstrated that concurrent zoledronic acid treatment inhibits the bone resorption induced by the combination treatment of radium‑223, abiraterone, and prednisone. Dr. Arne Scholz comments: “Although the addition of zoledronic acid to this combination mitigates the bone-resorptive effects on bone and may abolish one of the mechanisms contributing to the increased fracture risk observed in the ERA 223 trial, these preclinical results support the current practice that radium-223 is not indicated with abiraterone and prednisone, even if given concomitantly with bone-protecting agents”. All in all, these new findings might have significant implications for the clinical management of mCRPC, particularly in the context of preserving bone health while maximizing antitumor efficacy.