Bone metastases in advanced prostate cancer. Management
6/20/22, 12:19 AM 17128mediated by osteoclasts. Pathologic fractures do occur, although they are generally lessfrequent than in cancers with predominantly osteolytic disease. (See "Osteoclast inhibitors forpatients with bone metastases from breast, prostate, and other solid tumors" and "Mechanismsof bone metastases", section on 'Osteolytic versus osteoblastic bone metastases'.)Another factor is that treatment with androgen deprivation therapy (ADT) can cause increasedbone resorption and bone loss, which increases the risk of osteoporotic fractures in thesepatients. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis andbone fractures'.)Prevention of SREs in men with metastatic prostate cancer includes the use of bone-modifyingagents (bisphosphonates, denosumab), adequate supplementation with calcium and vitamin D,and systemic therapies, such as radium-223 (Ra-223) [1,2].Radium-223 — In addition to its role in treating symptoms (ie, pain) caused by known bonemetastases, Ra-223 has been demonstrated to significantly decrease the incidence ofsymptomatic skeletal events in patients with symptomatic bone metastases ( table 3). (See'Radium-223' above.)The definitive clinical trials with Ra-223 were limited to patients with symptomatic disease, andRa-223 has not been explored in the management of patients with asymptomatic bonemetastases. Guidelines from Cancer Care Ontario (CCO) and the American Society of ClinicalOncology (ASCO) limit their recommendations for Ra-223 to men with symptomatic metastaticdisease.Osteoclast inhibitorsPrevention of skeletal-related eventsCastration-resistant disease — In men with bone-metastatic castration-resistantprostate cancer (CRPC), use of a bone-modifying agent is indicated to prevent or delay skeletalrelatedcomplications. (See "Osteoclast inhibitors for patients with bone metastases frombreast, prostate, and other solid tumors", section on 'Denosumab' and "Osteoclast inhibitors forpatients with bone metastases from breast, prostate, and other solid tumors", section on'Bisphosphonates'.)Most of the data derived on the benefits of osteoclast inhibitors in CRPC were conducted beforecontemporary drug approvals of agents such as abiraterone, enzalutamide, radium-223, andcabazitaxel, all of which have been shown to extend survival and reduce the risk of SREs. Morerecently, although data from randomized trials are lacking, multiple retrospective analyses andhttps://www.uptodate.com/contents/17128/print 10/27
6/20/22, 12:19 AM 17128post hoc analyses of phase III studies have suggested that the addition of an osteoclastinhibitor to contemporary therapies for CRPC, such as abiraterone and enzalutamide, may alsocontribute to extending survival in addition to preventing skeletal complications [30-32].For many patients, denosumab may be preferred over zoledronic acid, based on superiorefficacy in a large randomized trial [33]. However, others prefer zoledronic acid because thereare sufficient data in CRPC to support dosing every 12 weeks rather than every 4 weeks.Zoledronic acid may also be a preferred alternative if cost and/or reimbursement are importantconsiderations. Data on the comparative efficacy of bisphosphonates and denosumab inindividuals with metastatic bone disease, including in men with CRPC are discussed in detailelsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate,and other solid tumors", section on 'Efficacy and dosing considerations for individual agents'.)Regardless of which agent is chosen, they should be administered at bone metastasis-indicateddoses. Standard doses in this setting are denosumab 120 mg subcutaneously every four weeks,and zoledronic acid 4 mg intravenous infusion every three to four weeks. This recommendationis consistent with guidelines from CCO and ASCO [1,2].Although there are sufficient data in men with CRPC to support dosing of zoledronic acid every12 weeks rather than every 4 weeks for most men we and others still prefer every-4-weekdosing, at least initially, for patients who have extensive or highly symptomatic bonemetastases, including all patients who are receiving Ra-223. Specific recommendations areprovided elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast,prostate, and other solid tumors", section on 'Dosing interval'.)Duration of therapy — The optimal duration of monthly therapy with an osteoclastinhibitor for prevention of SREs is not established. The pivotal trials treated patients for amaximum of 24 months [1,33,34]. The incidence of jaw osteonecrosis has been higher withlonger duration of therapy [35]. Because of this, many clinicians, including some of the authorsand editors associated with this topic, discontinue osteoclast inhibitors after 12 doses. Theseissues are described in detail elsewhere. (See "Medication-related osteonecrosis of the jaw inpatients with cancer", section on 'Osteoclast inhibitor therapy' and "Osteoclast inhibitors forpatients with bone metastases from breast, prostate, and other solid tumors", section on'Duration of therapy'.)Castration-sensitive disease — For men with bone metastases and castration-sensitiveprostate cancer, we suggest against the use of osteoclast inhibitors to prevent complications.In contrast to the results of both bisphosphonates and denosumab in men with castrationresistantdisease, no benefit was seen when zoledronic acid was started during initial treatmenthttps://www.uptodate.com/contents/17128/print 11/27
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mediated by osteoclasts. Pathologic fractures do occur, although they are generally less
frequent than in cancers with predominantly osteolytic disease. (See "Osteoclast inhibitors for
patients with bone metastases from breast, prostate, and other solid tumors" and "Mechanisms
of bone metastases", section on 'Osteolytic versus osteoblastic bone metastases'.)
Another factor is that treatment with androgen deprivation therapy (ADT) can cause increased
bone resorption and bone loss, which increases the risk of osteoporotic fractures in these
patients. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and
bone fractures'.)
Prevention of SREs in men with metastatic prostate cancer includes the use of bone-modifying
agents (bisphosphonates, denosumab), adequate supplementation with calcium and vitamin D,
and systemic therapies, such as radium-223 (Ra-223) [1,2].
Radium-223 — In addition to its role in treating symptoms (ie, pain) caused by known bone
metastases, Ra-223 has been demonstrated to significantly decrease the incidence of
symptomatic skeletal events in patients with symptomatic bone metastases ( table 3). (See
'Radium-223' above.)
The definitive clinical trials with Ra-223 were limited to patients with symptomatic disease, and
Ra-223 has not been explored in the management of patients with asymptomatic bone
metastases. Guidelines from Cancer Care Ontario (CCO) and the American Society of Clinical
Oncology (ASCO) limit their recommendations for Ra-223 to men with symptomatic metastatic
disease.
Osteoclast inhibitors
Prevention of skeletal-related events
Castration-resistant disease — In men with bone-metastatic castration-resistant
prostate cancer (CRPC), use of a bone-modifying agent is indicated to prevent or delay skeletalrelated
complications. (See "Osteoclast inhibitors for patients with bone metastases from
breast, prostate, and other solid tumors", section on 'Denosumab' and "Osteoclast inhibitors for
patients with bone metastases from breast, prostate, and other solid tumors", section on
'Bisphosphonates'.)
Most of the data derived on the benefits of osteoclast inhibitors in CRPC were conducted before
contemporary drug approvals of agents such as abiraterone, enzalutamide, radium-223, and
cabazitaxel, all of which have been shown to extend survival and reduce the risk of SREs. More
recently, although data from randomized trials are lacking, multiple retrospective analyses and
https://www.uptodate.com/contents/17128/print 10/27
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