Bisphosphates and Denosumab: The Evidence and Impact in Advanced Prostate Cancer

It is estimated that prostate cancer comprises 14% of all new cancer diagnoses in the United States, with nearly 270,000 new cases in this nation each year.¹ The latest data supports a remarkable 5-year survival rate of 96.8%. However, the annual burden of metastatic prostate cancer is expected to increase by 42% by the year 2025.² Furthermore, an estimated 1.3 million cases of prostate cancer are expected worldwide. This statistic contributes to nearly 360,000 annual prostate cancer-related mortalities.³ The armamentarium for metastatic prostate cancer has evolved dramatically over the last decade, with the evolution of treatments for both hormone-sensitive and castration-resistant settings. Androgen deprivation therapy (ADT) is a critical component in the treatment of advanced prostate cancer. It suppresses androgen levels using either hormonal therapy or surgical castration.

Testosterone plays a significant role in male health, including mental health, bone health, and the maintenance of sexual function. One of the primary side effects of ADT is an increased risk of osteoporosis. This is due to the role testosterone plays in maintaining bone density and strength. According to the World Health Organization, osteoporosis is defined as a bone mineral density (defined as T-score) that is 2.5 standard deviations from the average for a young adult male.⁴ Shahinian and colleagues demonstrated that in patients with prostate cancer, those receiving ADT had a 6.8% higher rate of bone fractures compared with those not receiving ADT.⁵

The advanced prostate cancer guidelines issued by the American Urological Association, the American Society for Radiation Oncology, and the Society of Urologic Oncology currently advocate for preventative therapy utilizing bisphosphonates or denosumab in patients at high risk for fractures (Statement 37).⁶ Furthermore, in patients with metastatic castration-resistant prostate cancer (mCRPC) or with bony metastatic disease, the guidelines mandate prescription of denosumab or zoledronic acid (bisphosphonate) to prevent skeletal adverse events (Statement 38).⁶ In this review, we will briefly summarize the evidence regarding bisphosphate and denosumab therapy as well as the positive impact that bone-protective agents can have on patients with advanced prostate cancer.

Bisphosphonates first appeared in medical literature in the late 1960s-early 1970s and are a classic example of a medication class that successfully made the journey from the laboratory to clinical use.⁷ Bisphosphonates can be divided into 2 distinct classes based on mechanism of action. The non-nitrogen-based class of bisphosphonates, which includes Didronel (etidronate disodium), function by converting into “non-hydrolysable analogues” of adenosine triphosphate. Subsequently, they interfere with cellular pathways.⁷ The more commonly used and potent nitrogen-based class of bisphosphonates is Zoledronic acid (zoledronic acid, Novartis Pharmaceuticals). It is commonly used in patients with prostate cancer.

Nitrogen-based bisphosphonates function by inhibiting farnesyl pyrophosphate synthetase  (FPPS). This prevents the creation of GTP-binding proteins that are required for osteoclast function, thus reducing osteoclast resorptive capabilities.⁷ In a large-scale meta-analysis cited by the most recent advanced prostate cancer guidelines, bisphosphonate therapy had a significant effect on preventing skeletal fractures (RR 0.80) and slowing osteoporosis (RR 0.39).⁸ Furthermore, this meta-analysis demonstrated that among the bisphosphonates, Zoledronic acid was the best at treating both fractures and osteoporosis.⁸

Denosumab (Prolia) is another commonly used medication for the management of skeletal morbidity in both skeletal metastasis and osteoporosis. Denosumab functions by inhibiting the RANK ligand, which normally binds to the surface of osteoclasts to stimulate resorption.⁹ Denosumab is able to prevent osteoclast function and subsequently bone resorption by inhibiting this interaction.⁹ In randomized double-blind trials for patients with prostate cancer receiving ADT, denosumab was show to both increase bone mineral density and reduce the risk of fracture.¹⁰ In patients with mCRPC, there is also evidence to suggest that denosumab has a slight advantage over zoledronic acid  as it can delay the onset of adverse skeletal events (eg, fracture). In a large, phase 3 randomized trial comparing Zoledronic acid with denosumab in patients with mCRPC, patients receiving denosumab experienced a median time to skeletal event of 20.7 months compared to 17.1 months for patients receiving Zoledronic acid.¹¹

From a cost perspective, comparing the 2 modalities yields interesting findings. In a Markov simulation model, Snedecor and colleagues attempted to estimate costs between denosumab- and Zoledronic acid-based bone protective therapy. The authors found that although denosumab yielded overall lower skeletal-related events and  care costs, the overall drug-related costs and total treatment costs are generally higher for denosumab compared to Zoledronic acid.¹² A rare adverse side effect of both denosumab and bisphosphonate therapy is osteonecrosis of the jaw (ONJ). The estimated incidence of ONJ varies from 1% to 15% in patients with cancer  who were exposed to bisphosphonates or denosumab therapy.¹³ This is significantly higher than the 0.001%-0.01% seen in the general population.¹³ ONJ is generally defined by the American Association of Oral and Maxillofacial Surgeons as a patient with no prior radiation exposure who has an exposed bone or bone that can be probed by the surgeon with prior or active exposure to bisphosphonate or denosumab therapy.¹³ Most therapy focuses on prevention of ONJ by management of preexisting oral disease prior to starting these therapeutic agents, or, in patients requiring oral surgery, waiting until there is mucosal coverage of the surgical site.¹³

Administration schedules for both Zoledronic acid and denosumab vary based on indication. In the prostate cancer setting, Zoledronic acid is administered every 1-3 months for prevention of metastatic skeletal-related events. In the osteoporosis setting, it is administered annually.⁶ Overall, the impact of bone-protective agents in the prostate cancer sphere cannot be understated. In patients at high risk for fracture, such medications provide a reliable and safe mechanism for improving bone health and preventing adverse skeletal events such as bone fracture while facilitating appropriate cancer care.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

 

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