The sequelae of bone metastases include pain, hypercalcemia, and skeletal-related events (which comprises pathologic fracture, spinal cord compression, need for orthopedic surgery, and external beam radiotherapy to the bone). Men on ADT with a history of a skeletal-related event have a ~3 month worse survival disadvantage compared to men on ADT without a skeletal-related event. At the initiation of ADT, patients should have a baseline bone density scan (DXA: dual-energy x-ray absorptiometry), with osteopenia defined as a T-score of -1.0 to -2.5, and osteoporosis defined as a T-score <= -2.5. Bone mineral density scans should be repeated at 1 year on ADT and then every 1-2 years thereafter. Initial blood tests should include baseline calcium, creatinine, and 25-(OH) vitamin D.
The Advanced prostate cancer AUA/ASTRO/SUO 2020 guideline makes several comments on bone health, noting that clinicians should:
- Discuss the risk of osteoporosis associated with ADT and assess the risk of fragility fracture
- Recommend preventative treatment for fractures and skeletal-related events, including supplemental calcium, vitamin D, smoking cessation, and weight-bearing exercise, to patients on ADT
- Recommend preventative treatments with bisphosphonates or denosumab to patients at high fracture risk due to bone loss and recommend referral to physicians who have familiarity with the management of osteoporosis
- Prescribe a bone-protective agent (denosumab or zoledronic acid) for mCRPC patients with bony metastases to prevent skeletal-related events.
With regards to vitamin D and calcium supplementation, the 2020 AUA guidelines suggest that patients should receive 1000-1200 mg of calcium and 1000 IU vitamin D daily. Alternatively, the National Osteoporosis Foundation guidelines (for all men >50 years of age), suggest 1200 mg of calcium and 800-1000 IU of Vitamin D3 daily. Specific to calcium, there is better absorption when the dose is divided, and calcium citrate absorbs better than calcium carbonate. Calcium supplementation is particularly important when treating prostate cancer patients with zoledronic acid or denosumab, given the risk of hypocalcemia with these agents.
Zoledronic acid is a bisphosphonate that inhibits bone resorption and is given as an IV infusion (4 mg every 4 weeks). Zoledronic acid is the only bisphosphonate to demonstrate a benefit in mCRPC by decreasing the incidence of skeletal-related events compared to placebo, however, there are several notable toxic effects, including osteonecrosis of the jaw (perform a dental exam first), hypocalcemia (provide calcium supplementation and monitor calcium levels), and nephrotoxicity (dose reduced if the patient has impaired renal function). Importantly, zoledronic acid may be associated with myalgias and arthralgias (~15-30%), which occurs within 12-48 hours of treatment and is most common during the first dose (less severe with subsequent treatments). The zoledronic acid renal guidelines for initiating therapy are as follows:
Denosumab is a human monoclonal antibody versus the RANK ligand, a receptor activator of nuclear factor kappaB ligand, which inhibits osteoclast-mediated bone destruction. Denosumab is given as a sub-Q injection (120 mg every 4 weeks) with notable toxicities including osteonecrosis of the jaw (perform a dental exam first) and hypocalcemia (provide calcium supplementation and monitor calcium levels).
Clinical features of suspected osteonecrosis of the jaw include exposed bone in the maxillofacial area that occurs in association with dental surgery, or spontaneously with no evidence of healing. Risk factors for osteonecrosis of the jaw are many, including cancer, radiation therapy, corticosteroids, poor dental hygiene, poor diet, dental work, trauma, alcohol or tobacco use, coagulopathy, chemotherapy, infection, and bisphosphonate or denosumab therapy. There are several ways to minimize the risk of osteonecrosis of the jaw:
- Excellent oral hygiene (best prophylaxis)
- Limit alcohol and tobacco use
- Obtain a dental assessment prior to starting bone directed therapy
- Every six-month dental visits are recommended
- Avoid extraction (increases risk of osteonecrosis of the jaw from 1% to 20%) and dental procedures once bone-targeted therapy has started
- Warn patients about ill-fitting dentures
If osteonecrosis of the jaw develops while on therapy, clinicians should weigh the risk/benefit ratio, but it is generally advised to hold the bisphosphonate or denosumab until the site has healed or stabilized. Current treatment of osteonecrosis of the jaw is empirical and management usually entails conservative approaches, such as antibiotics, oral rinses, pain control, and limited debridement (by an oral surgeon). Cases refractory to conservative management may benefit from more extensive treatment such as surgical resection or hyperbaric oxygen therapy.
To assess the optimal bone-protective agent, Fizazi and colleagues performed a phase 3 study of men with mCRPC, of which 1,904 men were randomized to either denosumab or zoledronic acid.1 The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. Median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8-24.9) with denosumab compared with 17.1 months (15.0-19.4) with zoledronic acid (HR 0.82, 95% CI 0.71-0.95; p = 0.0002 for non-inferiority; p = 0.008 for superiority). Between the two groups, there was no difference in overall survival or time to disease progression. Hypocalcemia (13% vs 6%, p<0.001) was more common in the denosumab group compared to the zoledronic acid group with no difference in incidence of osteonecrosis of the jaw (2% vs 1%, p=0.09). As such, denosumab is a category 1 preferred agent for bone antiresorptive therapy in men with M1 CRPC in the NCCN guidelines.
The role of bone-modifying agents in non-mCRPC patients on ADT to prevent bone loss is based on the FRAX algorithm which was released by the World Health Organization. This is an online calculator for 10-year fracture risk based on clinical parameters such as age and BMI. Treatment with a bone-modifying agent should be considered if the 10-year probability of hip fracture is >=3%, or the 10-year probability of a major osteoporosis-related fracture is >= 20%.
Dr. Boorjian concluded this portion of his talk on bone health and bone-targeting agents with the following take-home messages:
- Bone health issues are related to bone loss plus bone metastasis
- Patients with advanced prostate cancer on ADT should be offered calcium plus vitamin D supplementation
- Patients with bone mCRPC should be offered zoledronic acid or denosumab (preferred), however, the clinician should be aware of hypocalcemia and osteonecrosis of the jaw
- Patients on ADT should have baseline plus ongoing assessments of risk of fracture (DXR + FRAX) and clinicians can consider bone-modifying agents pending FRAX assessment
Dr. Boorjian then discussed radiopharmaceuticals in advanced prostate cancer, which is an important topic of interest given that ~90% of mCRPC patients have bone metastases. Furthermore, bone metastases are associated with disability, decreased quality of life, increased cost, and decreased survival. Prior to 2013, systemic radionuclide agents in mCRPC included Strontium-89 and Samarium-153, which were given IV and associated with no survival benefit. Usually, these were reserved for palliative indications for symptomatic bone pain for patients not responding to palliative therapy and not candidates for localized external beam radiotherapy. The primary toxicity of these agents is bone marrow suppression.
Radium-223 mimics calcium (chemically similar) and targets the bone by forming complexes with bone mineral hydroxyapatite at areas of increased bone turnover (ie. metastases). Radium-223 is an alpha-emitting radiopharmaceutical, with a short wavelength and high energy, inducing double-strand DNA breaks in cancer cells. The short range of the alpha-radiation is associated with minimal exposure to surrounding bone marrow and surrounding tissue, with no contact restrictions during treatment. Radium-223 is given as an IV infusion once every four weeks for a total of six treatments, with the ability to perform this infusion (takes ~1 minute) in the office, but with some special setup prior to utilization. Excretion is through the gastrointestinal tract, which may cause nausea and diarrhea, and may cause lymphocytopenia (20% grade 3-4).
The pivotal phase III ALSYMPCA trial of radium-223 demonstrated an improvement in both overall survival and skeletal-related events for patients with mCRPC and bone metastases who had previously received docetaxel were docetaxel ineligible or declined docetaxel.2 An initial, pre-specified, interim analysis was undertaken when 314 deaths had occurred. This demonstrated longer median overall survival among patients who received radium-223 (14.9 months) than those receiving placebo (11.3 months) with a resulting 30% decrease in the risk of death (HR 0.70, 95% CI 0.58 to 0.83).
Radium-223 was also significantly prolonged in the time to first symptomatic skeletal-related event (15.6 months) compared to placebo (9.8 months) with a hazard ratio of 0.66 (95% CI 0.52-0.83).
Importantly, the benefit of radium-223 was observed across several subgroups including previous docetaxel treatment, total alkaline phosphatase level at randomization, current bisphosphonate use, baseline ECOG score (0/1 vs 2), extent of disease (<6 metastases, 6-20 metastases, >20 metastases, and superscan), and opioid use. Overall, radium-223 in the ALSYMPCA trial was very well tolerated with a number of adverse events lower in the Radium-223 arm, and no clinically meaningful differences in frequency of grade 3-5 adverse events or treatment discontinuation due to adverse events. The AUA guidelines state that clinicians should offer Radium-223 to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy greater than 3 cm. There are several ongoing clinical trials that include Radium-223 as highlighted by Dr. Boorjian in the following table:3
Dr. Boorjian concluded this portion of his talk discussing radiopharmaceuticals for advanced prostate cancer with the following summary statements:
- Radium-223 represents standard management in patients with symptomatic bony metastases in the absence of visceral metastases or lymph nodes >3 cm. It can be used pre or post-docetaxel, is well tolerated and improves overall survival. During treatment, it is important to monitor routinely for lymphocytopenia
- Future directions include assessing patient selection for sequencing of treatments, combination therapies, and the impact of novel imaging/enhanced lesion detection
Presented by: Stephen A. Boorjian, MD, Carl Rosen Professor of Urology, Vice Chair of Research, Department of Urology, Director, Urologic Oncology Fellowship, Mayo Clinic, Rochester, MN
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.
- Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomized, double-blind study. Lancet 2011;377(9768):813-822.
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.
- Van der Doelen MJ, Mehra N, Hermsen R, et al. Patient Selection for Radium-223 Therapy in Patients with Bone Metastatic Castration-Resistant Prostate Cancer: New Recommendations and Future Perspectives. Clin Genitourin Cancer. 2019 Apr;17(2):79-87.