Medication-induced ONJ is a severe AE of both denosumab and bisphosphonate therapies. Data from recent trials showed that higher dosing and prolonged duration of denosumab and bisphosphonate therapies further increased risk of ONJ by 1.8% and 1.3%, respectively.15 Careful history taking and discussions with the patient and if possible their dentist on how to reduce risk are recommended. It is good practice for the patient to complete a dental evaluation prior to starting IV bisphosphonates or denosumab. Dental evaluations should be performed routinely at 3- to 12-month intervals throughout therapy based on individualized risk assessment.23 The benefits of using bisphosphonates to prevent fractures associated with osteoporosis outweigh the risk of ONJ in high-risk populations, but not in all patients with PC. A case-by-case basis and evaluation of risk factors should be performed prior to administering bone-modifying therapy. The long-term safety of IV bisphosphonates has not been adequately studied in controlled trials, and concerns regarding long-term complications, including renal toxicity, ONJ, and atypical femoral fractures, remain with prolonged therapy.24,25
The CALGB 70604 (Alliance) trial compared 3-month dosing to monthly treatment with zoledronic acid (ZA), showing no inferiority to lower frequency dosing.26 A Cochrane review of clinical trials found that in patients with advanced PC, bisphosphonates were found to provide roughly 58 fewer SREs per 1000 on average.27 A phase 3 study showed a modest benefit to denosumab vs ZA in the CRPC group regarding incidence of SREs. The rates of SREs were 289 of 951 patients in the bisphosphonate group, and 241 of 950 patients in the denosumab group (30.4% vs 25.3%; hazard ratio [HR], 0.78; 95% CI, 0.66-0.93; P = .005).28 In 2020, the American Society of Clinical Oncology endorsed the Cancer Care Ontario guidelines for prostate bone health care.18 Adequate supplementation is necessary in all patients treated with a bisphosphonate or denosumab to prevent treatment-related hypocalcemia. Typically, daily supplementation with a minimum of calcium 500 mg and vitamin D 400 IU is recommended.16
Bone Health in Patients
Nonmetastatic Hormone-Sensitive PC
ADT forms the backbone of treatment for patients with local and advanced metastatic castration-sensitive PC along with surgical and focal radiotherapy options. Cancer treatment-induced bone loss is known to occur with prolonged use of ADT. The ZEUS trial found no prevention of bone metastasis in patients with high-risk localized PC with the use of ZA in the absence of bone metastasis. A Kaplan-Meier estimated proportion of bone metastases after a median follow-up of 4.8 years was found to be not statistically significant: 14.7% in the ZA group vs 13.2% in the control/placebo group.29 The STAMPEDE trial showed no significant overall survival (OS) benefit with the addition of ZA to ADT vs ADT alone (HR, 0.94; 95% CI, 0.79-1.11; P = .45), 5-year survival with ADT alone was 55% compared to ADT plus ZA with 57% 5-year survival.30 The RADAR trial showed that at 5 years in high Gleason score patients, use of ZA in the absence of bone metastasis was beneficial, but not in low- or intermediate-risk patients. However, at 10-year analysis there was no significant difference in any of the high-stratified groups with or without ZA.31
The PR04 trial showed no effect on OS with clodronate compared with placebo in nonmetastatic castration-sensitive PC, with a HR of 1.12 (95% CI, 0.89-1.42; P = .94). The estimated 5-year survival was 80% with placebo and 78% with clodronate; 10-year survival rates were 51% with placebo and 48% with clodronate.32 Data from the HALT trial showed an increased bone mineral density and reduced risk of new vertebral fractures vs placebo (1.5% vs 3.9%, respectively) in the absence of metastatic bone lesions and a reduction in new vertebral fractures in patients with nonmetastatic PC.33 Most of these studies showed no benefit with the addition of ZA to nonmetastatic PC; although, the HALT trial provides evidence to support use of denosumab in patients with nonmetastatic PC for preventing vertebral fragility fractures in men receiving ADT.
Metastatic Hormone-Sensitive PC
ZA is often used to treat men with metastatic castration-sensitive PC despite limited efficacy and safety data. The CALGB 90202 (Alliance) trial authors found that the early use of ZA was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the ZA group (95% CI, 24.2-40.3) and 29.8 months in the placebo group (stratified HR, 0.97; 95% CI, 0-1.17; 1-sided stratified log-rank P = .39).34 OS was similar between the groups (HR, 0.88; 95% CI, 0.70-1.12; P = .29) as were reported AEs.34 Results from these studies suggest limited benefit in treating patients with metastatic hormone-sensitive PC with bisphosphonates without other medical indications for use. Additional studies suggest similar results for treatment with denosumab to that of bisphosphonate therapies.35
Nonmetastatic CRPC
Reasonable interest among treating clinicians exists to be able to delay or prevent the development of metastatic bone disease in patients who are showing biochemical signs of castration resistance but have not yet developed distant metastatic disease. Time to progression on ADT to castration resistance usually occurs 2 to 3 years following initiation of treatment. This typically occurs in patients with rising prostate-specific antigen (PSA). As per the Prostate Cancer Working Group 3, in the absence of radiologic progression, CRPC is defined by a 25% increase from the nadir (considering a starting value of ≥ 1 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate serum testosterone < 50 ng/dL despite good adherence to an ADT regimen, with proven serologic castration either by undetectable or a near undetectable nadir of serum testosterone concentration. Therapeutic implications include prevention of SREs as well as time to metastatic bone lesions. The Zometa 704 trial examined the use of ZA to reduce time to first metastatic bone lesion in the setting of patients with nonmetastatic CRPC.36 The trial was discontinued prematurely due to low patient accrual, but initial analysis provided information on the natural history of a rising PSA in this patient population. At 2 years, one-third of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastasis and OS were not reached. Baseline PSA and PSA velocity independently predicted a shorter time to first bone metastasis, metastasis-free survival, and OS.36
