Bone metastases in advanced prostate cancer. Management

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®

Official reprint from UpToDate

www.uptodate.com© 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Bone metastases in advanced prostate cancer:

Management

Authors: A Oliver Sartor, MD, Steven J DiBiase, MD

Section Editors: Nicholas Vogelzang, MD, W Robert Lee, MD, MS, MEd, Jerome P Richie, MD, FACS

Deputy Editor: Diane MF Savarese, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2022. | This topic last updated: Nov 24, 2021.

INTRODUCTION

Metastatic prostate cancer may arise after treatment of a clinically localized tumor or be

present at the time of initial diagnosis. Metastatic prostate cancer is an important clinical

problem in terms of the number of men who are affected, its impact on quality of life, and as a

cause of mortality.

Osteoblastic lesions in bone are the most common site of metastasis. These frequently are

symptomatic and can cause pain, debility, and functional impairment. The treatment of bone

metastases in men with prostate cancer is palliative. The goals of treatment are to improve

survival, relieve pain, improve mobility, and prevent complications (eg, pathologic fractures,

epidural spinal cord compression).

The management of men with bone metastases from advanced prostate cancer is reviewed

here, including treatments to palliate pain and therapies to prevent complications of osseous

metastasis. The clinical presentation and evaluation of bone metastases and the overall

approach to the management of men with advanced prostate cancer are discussed separately.

(See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and

"Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis" and

"Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive

prostate cancer and local treatment for patients with metastatic disease".)

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COMPLICATIONS FROM BONE METASTASES

The term "skeletal related events" (SREs) refers to a constellation of complications (pain,

fracture, epidural spinal cord compression, need for radiation therapy or surgery for a bone

metastasis) that arise in patients who have bone metastases. Symptomatic SREs are clinically

detectable events that do not depend on routine acquisition of imaging. Pain is the most

common symptom in metastatic bone disease. (See "Epidemiology, clinical presentation, and

diagnosis of bone metastasis in adults", section on 'Clinical presentation'.)

MANAGING PATIENTS WITH SYMPTOMATIC BONE METASTASES

There are several approaches to managing pain and other skeletal-related events (SREs) in men

with metastatic prostate cancer. In general, systemic therapy is an important component of

patient management for controlling symptoms and slowing progression of bone metastases.

External beam radiation therapy (EBRT) is the treatment of choice for men with metastatic

prostate cancer and bone pain that is not responsive to systemic therapy and limited to one or

a limited number of sites.

The utility of other therapies, including bone-targeted radioisotopes, bisphosphonates, focused

ultrasound, and surgery, is limited to selected populations and is reviewed in the sections

below.

Analgesics — A range of pharmacologic agents are available to treat cancer-related bone pain

that is not adequately controlled by measures specifically directed against the metastatic

disease. In addition to opioids, which are a mainstay of treatment for painful bone metastases,

these include adjuvants, such as nonsteroidal anti-inflammatory drugs, and osteoclast

inhibitors, such as bisphosphonates. (See 'Bisphosphonates' below.)

A wide variety of issues relating to optimal pain management in cancer patients are discussed

separately. (See "Cancer pain management: General principles and risk management for

patients receiving opioids" and "Cancer pain management with opioids: Optimizing analgesia"

and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory

drugs" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and

"Psychological, rehabilitative, and integrative therapies for cancer pain" and "Cancer pain

management: Interventional therapies".)

Systemic anticancer therapy — Systemic anticancer treatment is an important component of

care for men with metastatic prostate cancer causing bone metastases. Systemic therapies for


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metastatic castration-resistant prostate cancer (CRPC) such as abiraterone/prednisone,

enzalutamide, Radium-233 (Ra-223), docetaxel, cabazitaxel, and mitoxantrone have all been

shown to reduce SREs and improve bone pain and health-related quality of life in men with

metastatic CRPC. Specific examples of some of these treatments are outlined in the table (

table 1). However, the optimal sequencing or combination of these therapies with bonetargeted

agents (including Ra-223) is unclear [1,2].

The use of androgen deprivation therapy as initial therapy for castration-sensitive metastatic

disease, and various other modalities for castration-resistant metastatic prostate cancer are

discussed separately. (See "Overview of systemic treatment for advanced, recurrent and

metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic

disease" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

External beam radiation therapy — EBRT is the treatment of choice for men with CRPC and

bone pain that is not responsive to systemic therapy and limited to one or a limited number of

sites [1,2]. For most men, we suggest using a single fraction of 8 Gy to the involved area. The

benefits of radiation therapy (RT) in this setting, a discussion of optimal treatment schedules

(eg, single- versus multiple-fractionation RT), and the use of stereotactic body radiotherapy as

an alternative to EBRT are discussed separately. (See "Radiation therapy for the management of

painful bone metastases".)

Bone-targeted radioisotopes — Ra-223, an alpha particle-emitting agent, is the only

radiopharmaceutical that prolongs overall survival and decreases symptomatic SREs in

appropriately selected men with CRPC. Beta particle-emitting radioisotopes, such as strontium-

89 and samarium-153 ethylenediamine tetramethylene phosphonate, may provide palliation of

pain, but they do not significantly prolong overall survival. (See 'Radium-223' below and 'Betaemitting

radioisotopes' below.)

These radioisotopes, which vary in their physical properties ( table 2), are mainly used in men

with advanced prostate cancer who are symptomatic from multiple osteoblastic bone

metastases. A prerequisite for bone-targeted radioisotope treatment is the presence of uptake

on bone scan due to metastatic disease at the sites that correlate with pain.

Radium-223 — For men with symptomatic metastatic CRPC and bone pain who have

predominantly bony metastases and no evidence of visceral or large nodal metastases, Ra-223

is an option to reduce symptomatic SREs (including bone pain) and improve health-related

quality of life. A beneficial role for combinations of Ra-223 with systemic therapy has not been

established, and at least some data suggest detrimental outcomes when Ra-223 is combined

with abiraterone. We suggest against initiating Ra-223 and abiraterone at the same time. Ra-


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223 can permanently reduce bone marrow reserves, and this may affect decision-making on the

timing and use of this agent if a patient remains a candidate for palliative cytotoxic

chemotherapy.

Ra-223 is a bone-seeking alpha particle-emitting agent, and its decay allows the deposition of

high-energy radiation over a much shorter distance than that with beta particle-emitting

radioisotopes, thus potentially treating the tumor while minimizing toxicity to normal bone

marrow.

Ra-223 has been shown to prolong overall survival and decreases symptomatic SREs due to

bone disease in men with multifocal symptomatic bone metastases [1-5]. Ra-223 is indicated for

the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral

metastases. However, the optimal selection of candidates for Ra-223 is not established [6],

especially given that new agents such as enzalutamide and abiraterone were not utilized in the

pivotal phase III Ra-223 study (ALSYMPCA trial) that demonstrated a survival benefit from use of

this agent.

ALSYMPCA trial — Ra-223 increased both overall survival and time to first symptomatic

SRE in the phase III ALSYMPCA trial [7,8]. Symptomatic skeletal events were defined as external

beam RT to relieve skeletal symptoms, new symptomatic pathologic fracture, occurrence of

spinal cord compression, or tumor-related orthopedic surgical intervention.

In the ALSYMPCA trial, all patients had castration-resistant prostate cancer with multiple bone

metastases and had either progressed on docetaxel chemotherapy or were not candidates for

docetaxel chemotherapy. Patients were required to have two or more bone metastases and no

known visceral metastases. Overall, 921 patients were randomly assigned in a 2:1 ratio to best

supportive care plus Ra-223 (one dose every four weeks for six cycles) or best supportive care

plus placebo. Best supportive care options included a second-line variety of hormonal therapies

and bisphosphonates. Approximately 80 percent had six or more lesions on bone scan, and 40

percent had 20 or more lesions. Almost 60 percent had received prior docetaxel chemotherapy.

Key results included the following [7-10]:

●

Overall survival, the primary endpoint of the trial, was significantly prolonged with Ra-223

compared with placebo (median 14.9 versus 11.3 months, hazard ratio [HR] 0.70, 95% CI

0.58-0.83) [7]. The survival benefit was consistent across all patient subgroups, including

both those who had and had not received prior docetaxel.

●

The time to first symptomatic skeletal event (which included first use of EBRT for symptom

relief, new pathologic fracture, spinal cord compression, or tumor-related orthopedic


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surgery intervention) was significantly increased (median 15.6 versus 9.8 months, HR 0.66,

95% CI 0.52-0.83) [8]. When the symptomatic skeletal events were analyzed individually,

the differences were statistically significant for use of EBRT for symptom relief (HR 0.67),

and for spinal cord compression (HR 0.52). Differences were not statistically significant for

new pathologic fracture (0.62) or for orthopedic surgery intervention (0.72), but the

number of such events was limited. Routine radiographs were not utilized during this trial,

and, thus, all symptomatic skeletal events were detected clinically.

●

●

●

In a prespecified subset analysis, Ra-223 had similar efficacy in those who had received

prior docetaxel and in those who were docetaxel naïve [9]. Treatment was well tolerated

irrespective of prior docetaxel use, although the incidence of grade 3 to 4

thrombocytopenia was higher in patients who had previously received docetaxel (9 versus

3 percent).

Treatment with Ra-223 was associated with a favorable safety profile, with a lower

frequency of all adverse events compared with placebo; there were no clinically

meaningful differences in the incidence of grade 3 or 4 adverse events. A final analysis of

long-term safety data for up to three years after the last dose of Ra-223 confirms that

treatment was well tolerated and that there were no new safety issues. Only one patient

out of 405 who entered long-term follow-up developed bone marrow failure, and there

were no cases of acute myelogenous leukemia, myelodysplastic syndrome, or new

primary bone cancers [10]. Treatment with Ra-223 was accompanied by a better quality of

life during the period of study drug administration [7].

On the other hand, updated safety data in the United States Prescribing Information for

Ra-223 indicate that 2 percent of patients receiving the drug developed bone marrow

failure following treatment, compared with none in the placebo arm, and there were two

deaths due to bone marrow failure. The updated information recommends that

hematologic evaluation be performed at baseline and prior to each dose. Before the first

administration, the absolute neutrophil count (ANC) should be ≥1.5 x 10 /L, the platelet

count should be ≥100 x 10 /L, and the hemoglobin should be ≥10 g/dL. Before subsequent

administrations, the ANC should be ≥1 x 10 /L, and the platelet count should be ≥50 x

9

10 /L. Treatment should be discontinued if there is no recovery to these values within six

to eight weeks of the last dose.

9

9

9

The clinical trial used six doses of Ra-223 every four weeks, and this is the approved schedule

for Ra-223 administration that is endorsed in expert guidelines [1,2]. The use of a higher dose

of Ra-223 or an extended schedule of up to 12 cycles did not show any benefit in a randomized

trial [11].


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Data from a limited number of patients indicate that a second course of six injections can be

given with minimal hematologic toxicity and some early effects on limiting disease progression

[12]. Additional experience will be required to further assess the role of retreatment.

There are no randomized trials that compare Ra-223 with other agents known to prolong

overall survival in patients with metastatic CRPC ( table 1). The optimal selection of candidates

for Ra-223 is not established [6]. The factors influencing the sequencing and combinations of

different therapies are discussed separately. (See "Overview of systemic treatment for

advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for

patients with metastatic disease".)

Radium-223-based combinations — Ra-223 is being studied in combination with other

agents for the treatment of metastatic CRPC. However, a beneficial role for such combinations

has not been established, and at least some data suggest detrimental outcomes when Ra-223 is

combined with abiraterone. In view of these data, for most men, we suggest against initiating

Ra-223 and abiraterone at the same time. For men already receiving abiraterone, whether the

addition of Ra-223 might be safe and yield clinical benefit is unknown. If such an approach is

chosen, it would seem wise to ensure that the patient is also receiving a bone-modifying agent,

such as zoledronic acid or denosumab. Guidelines from the American Society of Clinical

Oncology (ASCO) specifically recommend against simultaneously initiating Ra-223 with

abiraterone and prednisone [1]. There is insufficient evidence to support concurrent use of Ra-

223 with other secondary therapies known to prolong survival in metastatic CRPC.

●

In a seminal phase III trial [13], 806 men with bone-predominant metastatic CRPC who

were asymptomatic or minimally symptomatic and had received no prior chemotherapy

were treated with abiraterone plus prednisone/prednisolone and then randomized to

either Ra-223 or placebo. At a median follow-up of 22 months, more patients in the Ra-223

group had had at least one symptomatic SRE or had died (49 versus 47 percent of patients

in the placebo group). The primary endpoint was not met (median symptomatic SRE-free

survival was 22.3 months with Ra-223 plus abiraterone versus 26 months with abiraterone

alone), which translated into a 22 percent increased risk of skeletal events with Ra-223.

Fractures occurred in 29 percent of patients receiving combined therapy versus 11 percent

of the control group. Notably, only approximately 40 percent of the patients in either

group were receiving osteoclast inhibitors. The decrease in overall survival in the Ra-223

group, while potentially clinically meaningful, was not statistically significant (30.7 versus

33.3 months, HR 1.195, 95% CI 0.950-1.505).

These findings led Health Canada to recommend against the use of Ra-223 in combination

with abiraterone acetate plus prednisone/prednisolone, and led the European Medicines


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Agency to restrict the use of Ra-223 to patients who had at least two previous treatments

for metastatic prostate cancer with bone metastases or to those who could not use any

other treatment. Based on the published data, we agree with these restrictions and do not

recommend Ra-223 in conjunction with abiraterone.

●

●

●

Notably, a protective effect of osteoclast inhibitors on fracture rates was noted in a

subsequent randomized trial, the PEACE III (EORTC 1333) trial, which compared

enzalutamide plus Ra-223 versus enzalutamide alone in asymptomatic or mildly

symptomatic men with metastatic CRPC. Following the release of the ERA 223 results, the

protocol was amended to mandate the use of osteoclast inhibitors in all men. In the most

recent preliminary report of a subset of 253 treated patients, the risk of fracture at 1.5

years with combined therapy versus enzalutamide alone (without an osteoclast inhibitor)

was 46 versus 22 percent, and this elevated risk was significantly reduced by mandatory

continuous administration of an osteoclast inhibitor (the risk of fracture at 1.5 years with

combined therapy was 2.8 versus 3.9 percent with enzalutamide alone) [14].

In two nonrandomized studies, a total of 299 patients were treated with Ra-223 plus

abiraterone or enzalutamide [15,16]. Neither study identified a new safety signal in the

subset of patients who received concomitant denosumab and there was a suggestion of

improved survival, but randomized data do not support this approach.

In a phase II trial, 53 patients with chemotherapy-naïve CRPC and two or more bone

metastases were randomly assigned to docetaxel plus Ra-223 or to docetaxel alone [17].

Combined therapy was associated with more durable decreases in serum tumor markers

(prostate-specific antigen and bone alkaline phosphatase). There was a higher rate of

febrile neutropenia with docetaxel alone (15 versus 0 percent). However, there are no

long-term safety data for this combination, and its use remains experimental. Additional

information will be available from the DORA trial (docetaxel every three weeks versus Ra-

223 plus docetaxel every six weeks), which is ongoing.

Beta-emitting radioisotopes — Multiple beta-emitting radioisotopes had been evaluated and

used clinically prior to the development of Ra-223 ( table 2). The most widely studied are

strontium-89 and samarium-153. Other isotopes studied include phosphorus-32, rhenium-186,

and rhenium-188 [18].

●

Multiple clinical trials have evaluated the efficacy of strontium-89 in men with prostate

cancer bone metastases [19-22]. In the largest of these trials (757 patients), treatment

with strontium-89 was integrated with docetaxel chemotherapy [22]. No statistically


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significant differences were noted in either overall survival or clinical progression-free

survival in the intent-to-treat analysis.

●

Two small randomized phase III trials compared samarium-153 with placebo. Both found

that treatment with samarium-153 was more effective than placebo in providing pain relief

[23,24].

Myelosuppression is the predominant toxicity associated with beta particle-emitting

radioisotopes and was more prominent with strontium than samarium. This toxicity has limited

their usage, and there is no evidence that beta emitting radioisotopes prolong survival, in

contrast to alpha emitting radioisotopes [4].

Bisphosphonates — Bone modifying agents such as bisphosphonates or denosumab are

indicated for men with bone metastases from castration resistant prostate cancer, whether they

are symptomatic or not. (See "Osteoclast inhibitors for patients with bone metastases from

breast, prostate, and other solid tumors", section on 'Indications for osteoclast inhibitor

therapy'.)

In addition, intravenous ibandronate or other bisphosphonates may offer some degree of

analgesia, and represent an alternative to EBRT for the management of pain due to bone

metastases in men with CRPC who are not already on an osteoclast inhibitor. However, these

agents are not approved for this indication in the United States.

Intravenous bisphosphonates can be effective for palliation of bone pain, but they are probably

not as effective as RT:

●

One meta-analysis of three trials (876 participants) comparing bisphosphonates with no

bisphosphonates in men with metastatic CRPC showed no statistically significant

difference in pain response (RR 1.15, 95% CI 0.93-1.43; 3 trials; 876 participants; low quality

evidence). In absolute terms, bisphosphonates resulted in a pain response in 40 more

participants per 1000 (19 fewer to 114 more) and no clinically relevant differences in the

proportion of patients with decreased analgesic consumption (RR 1.19, 95% CI 0.87-1.63)

[25]. Higher rates of nausea, renal adverse effects, and jaw osteonecrosis were observed

with the bisphosphonates.

●

IV bisphosphonates were directly compared with single-fraction RT in a multicenter trial in

which 470 men with prostate cancer and pain due to bone metastases were randomly

assigned to either one dose of intravenous ibandronate (6 mg) or RT (8 Gy) given in a

single-fraction treatment [26]. Crossover to the alternative treatment was allowed for

patients who did not have pain relief at four weeks. There was no statistically significant


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difference in pain relief with the two treatment approaches at either 4 or 12 weeks. The

treatment crossover rates were not significantly different (31 percent in those initially

managed with ibandronate versus 24 percent in those initially given RT); there was no

statistically significant difference in overall survival (median 12.9 versus 12.2 months).

There are no trials comparing zoledronic acid versus RT.

Although RT remains the standard of care for most patients with localized bone pain resulting

from metastases, intravenous bisphosphonates represent an effective treatment option for

patients who do not respond to RT and for special clinical situations such as patients with

contraindications to RT. The use of intravenous bisphosphonates for palliation of bone pain is

endorsed as an alternative to bone-targeted radioisotopes by Cancer Care Ontario (CCO) and

the American Society of Clinical Oncology (ASCO) [1,27].

Focused ultrasound — Magnetic resonance-guided focused ultrasound is a technique to

provide palliation for painful bone metastases in patients who have either failed on standard RT

or are not candidates for RT [28]. The focused ultrasound waves raise the temperature at the

imaged focal point and, thus, produce thermal tissue ablation.

The regulatory approval of this device was based on an international multicenter trial that

demonstrated the activity and safety of this approach [29]. (See "Image-guided ablation of

skeletal metastases", section on 'Outcomes'.)

Surgery and vertebroplasty/kyphoplasty — The use of surgery or vertebroplasty/kyphoplasty

for bone lesions in men with metastatic prostate cancer is generally reserved for patients with

pathologic fractures or epidural spinal cord compression. (See "Overview of therapeutic

approaches for adult patients with bone metastasis from solid tumors", section on 'Indications

for surgical consultation' and "Overview of therapeutic approaches for adult patients with bone

metastasis from solid tumors", section on 'Vertebroplasty and kyphoplasty' and "Treatment and

prognosis of neoplastic epidural spinal cord compression" and "Clinical presentation and

evaluation of complete and impending pathologic fractures in patients with metastatic bone

disease, multiple myeloma, and lymphoma".)

PREVENTION OF BONE METASTASIS COMPLICATIONS

Complications from bone metastases (termed skeletal-related events [SREs]) include pain,

pathologic fractures, the need for radiation therapy (RT) to bone, tumor-related orthopedic

surgery intervention, and spinal cord compression. The bone metastases observed in prostate

cancer are primarily osteoblastic, but there is a significant osteolytic component that is


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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


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post hoc analyses of phase III studies have suggested that the addition of an osteoclast

inhibitor to contemporary therapies for CRPC, such as abiraterone and enzalutamide, may also

contribute to extending survival in addition to preventing skeletal complications [30-32].

For many patients, denosumab may be preferred over zoledronic acid, based on superior

efficacy in a large randomized trial [33]. However, others prefer zoledronic acid because there

are 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 important

considerations. Data on the comparative efficacy of bisphosphonates and denosumab in

individuals with metastatic bone disease, including in men with CRPC are discussed in detail

elsewhere. (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-indicated

doses. 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 recommendation

is consistent with guidelines from CCO and ASCO [1,2].

Although there are sufficient data in men with CRPC to support dosing of zoledronic acid every

12 weeks rather than every 4 weeks for most men we and others still prefer every-4-week

dosing, at least initially, for patients who have extensive or highly symptomatic bone

metastases, including all patients who are receiving Ra-223. Specific recommendations are

provided 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 osteoclast

inhibitor for prevention of SREs is not established. The pivotal trials treated patients for a

maximum of 24 months [1,33,34]. The incidence of jaw osteonecrosis has been higher with

longer duration of therapy [35]. Because of this, many clinicians, including some of the authors

and editors associated with this topic, discontinue osteoclast inhibitors after 12 doses. These

issues are described in detail elsewhere. (See "Medication-related osteonecrosis of the jaw in

patients with cancer", section on 'Osteoclast inhibitor therapy' and "Osteoclast inhibitors for

patients 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-sensitive

prostate 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 castrationresistant

disease, no benefit was seen when zoledronic acid was started during initial treatment


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with ADT in men with bone metastases. In the CALGB 90202 trial, 645 men were randomly

assigned to zoledronic acid or placebo [36]. The trial was discontinued prematurely when the

corporate sponsor withdrew support. With a median follow-up of 24 months, there was no

statistically significant difference in the time to first SRE (median 31.9 versus 29.8 months, HR

0.97). Overall survival also was not significantly different (median 38 versus 36 months, HR 0.88,

95% CI 0.70-1.12).

There are no data on denosumab for the prevention of SREs in patients with castration-sensitive

disease.

Published guidelines from CCO and ASCO state that there is insufficient evidence to make a

recommendation regarding the use of any bone-modifying agent in men with bone metastases

and castration-sensitive prostate cancer [1,2]. On the other hand, year 2020 guidelines on bone

health from the European Society of Medical Oncology specifically recommend against the

routine use of bone targeted agents such as bisphosphonates in men with metastatic

castration-sensitive prostate cancer [3].

Prevention or delay of bone metastases — We suggest against the use of osteoclast

inhibitors to prevent or delay the appearance of bone metastases in men with high-risk

nonmetastatic prostate cancer. Randomized trials with both bisphosphonates and denosumab

have failed to demonstrate a favorable risk-benefit ratio for men with nonmetastatic CRPC. This

position is consistent with guidelines from CCO and ASCO [1,2].

Bisphosphonates — Although preclinical data suggest that bisphosphonates have an

antitumor effect in prostate cancer, the adjuvant use of bisphosphonates in men with CRPC

without bone metastases has never been shown to significantly decrease the incidence of bone

metastases:

●

In the phase III ZEUS trial, 1433 patients with high-risk nonmetastatic prostate cancer

(prostate-specific antigen [PSA] ≥20 ng/mL, Gleason 8 to 10, or node-positive disease)

were randomly assigned to zoledronic acid (4 mg every three months) for four years [37].

After a median follow-up of 4.8 years, there was no significant difference in the incidence

of bone metastases (four-year incidence 14.7 with zoledronic acid versus 13.2 percent in

the control group).

●

A smaller trial using clodronate also failed to demonstrate a decrease in the incidence of

bone metastases [38].

Denosumab — The potential value of denosumab to prevent bone metastases was

addressed in a phase III trial, in which 1432 men with nonmetastatic CRPC were randomly


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assigned to denosumab or placebo [35]. All patients either had undergone bilateral

orchiectomy or had received continuous treatment with a gonadotropin-releasing hormone

agonist or antagonist for at least six months. Patients were castration resistant based on three

consecutive rising PSA determinations. Patients were classified as high risk for the development

of bone metastases based on a serum PSA ≥8 mcg/L or a PSA doubling time <10 months.

Denosumab significantly increased the bone metastasis-free survival compared with placebo

(29.5 versus 25.2 months, HR 0.85, 95% CI 0.73-0.98), but there was no significant difference in

overall survival (median 44 versus 45 months, HR 1.01).

Osteonecrosis of the jaw was observed in 5 percent of patients treated with denosumab and

was not observed with placebo. Hypocalcemia was more common with denosumab (1.7 versus

0.3 percent).

Calcium and vitamin D — Calcium and vitamin D levels should be assessed, and low levels

corrected, prior to initiating therapy with an osteoclast inhibitor. If there are no

contraindications (eg, pre-existing hypercalcemia, recurrent renal stones), all patients receiving

an osteoclast inhibitor should receive calcium and vitamin D supplementation to prevent

secondary hyperparathyroidism and hypocalcemia and to ensure sufficient calcium for bone

repair/healing. This subject is discussed elsewhere. (See "Osteoclast inhibitors for patients with

bone metastases from breast, prostate, and other solid tumors", section on 'Considerations

prior to initiating an osteoclast inhibitor' and "Osteoclast inhibitors for patients with bone

metastases from breast, prostate, and other solid tumors", section on 'Monitoring during

therapy'.)

Side effects — Although the benefits of osteoclast inhibition have been well established in

large randomized clinical trials, these agents can cause serious toxicity in rare cases. Important

potential side effects include:

●

●

●

Osteonecrosis of the jaw

Hypocalcemia

Renal impairment (a concern with bisphosphonates but not denosumab)

The potential risk for complications should not preclude the use of osteoclast inhibitors. Careful

patient selection, avoidance of the use of these agents in patients in high-risk settings, and

continued awareness of the potential for complications during treatment are important to

minimize the risk of serious complications [39,40].

The prevention and management of complications associated with osteoclast inhibitors

(bisphosphonates and denosumab) are discussed separately. (See "Risks of therapy with bone

antiresorptive agents in patients with advanced malignancy".)


6/20/22, 12:19 AM 17128

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC

The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas

where viral transmission rates are high include balancing the risk from delaying cancer

treatment versus harm from COVID-19, minimizing the use of potentially immunosuppressive

cancer treatments whenever possible, mitigating the negative impacts of social distancing

during care delivery, and appropriately and fairly allocating limited health care resources. These

and other recommendations for cancer care during active phases of the COVID-19 pandemic

are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions

around the world are provided separately. (See "Society guideline links: Diagnosis and

management of prostate cancer" and "Society guideline links: Cancer pain" and "Society

guideline links: Management of bone metastases in solid tumors".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the

Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given

condition. These articles are best for patients who want a general overview and who prefer

short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more

sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading

level and are best for patients who want in-depth information and are comfortable with some

medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print

or e-mail these topics to your patients. (You can also locate patient education articles on a

variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●

Basics topics (see "Patient education: Bone metastases (The Basics)")

th

th

th

th

SUMMARY AND RECOMMENDATIONS


6/20/22, 12:19 AM 17128

●

●

●

●

●

Goals of treatment – The axial skeleton is the most frequent site of metastasis in men

with advanced prostate cancer. The goals of palliative treatment for men with bone

metastases include pain relief, improved mobility, and prevention of complications such as

pathologic fracture or epidural spinal cord compression. (See 'Complications from bone

metastases' above.)

Analgesic agents – A range of pharmacologic agents are available to treat cancer-related

bone pain that is not adequately controlled by measures specifically directed against the

metastatic disease. In addition to opioids, which are a mainstay of treatment for painful

bone metastases, these include adjuvants, such as nonsteroidal anti-inflammatory drugs,

and osteoclast inhibitors, such as bisphosphonates. (See 'Analgesics' above.)

Systemic anticancer therapy – Systemic anticancer therapy may control symptoms and

slow progression of bone metastases. (See "Overview of systemic treatment for advanced,

recurrent and metastatic castration-sensitive prostate cancer and local treatment for

patients with metastatic disease".)

External beam RT – External beam radiation therapy (EBRT) is the treatment of choice for

men with bone pain that is not responsive to systemic therapy and limited to one or a

limited number of sites. For most men, a single fraction of 8 Gy to the involved area is

preferred over multifractionated regimens. Specific recommendations are provided

separately. (See "Radiation therapy for the management of painful bone metastases".)

Bone-targeting radioisotopes – For patients with castration-resistant prostate cancer

(CRPC) and multifocal symptomatic osteoblastic bone metastases that are not controllable

with systemic therapy or EBRT, bone-targeting alpha particle-emitting radioisotopes (eg,

radium-223 [Ra-223]) may offer significant palliative benefit. (See 'Bone-targeted

radioisotopes' above.)

• Ra-223 should be restricted to men with castration-resistant symptomatic metastases,

and no known visceral metastatic disease. (See 'ALSYMPCA trial' above.)

Ra-223 can permanently reduce bone marrow reserves, and this may affect decisionmaking

on the timing and use of this agent if a patient remains a candidate for

palliative cytotoxic chemotherapy.

• For most men with advanced CRPC, we suggest against initiating Ra-223 and

abiraterone at the same time (Grade 2B). A beneficial role for combining Ra-223 with

systemic therapy has not been established, and some data suggest detrimental

outcomes when Ra-223 and abiraterone are initiated concurrently. For men already


6/20/22, 12:19 AM 17128

receiving abiraterone, whether the addition of Ra-223 might be safe and yield clinical

benefit is not yet established. If such an approach is chosen, patients should also be

receiving a bone-modifying agent, such as zoledronic acid or denosumab. (See

'Radium-223-based combinations' above.)

●

Role of osteoclast inhibitors

• For men with CRPC and bone metastases, an osteoclast inhibitor (denosumab or

zoledronic acid) is indicated to prevent or delay skeletal complications in patients with

bone metastases. For many patients, denosumab may be preferred over zoledronic

acid, based on superior efficacy in a large randomized comparative trial. However,

others prefer zoledronic acid because there are sufficient data in CRPC to support

dosing every 12 rather than every 4 weeks. Zoledronic acid may also be a preferred

alternative if cost and/or reimbursement are important considerations. Data on

efficacy of bisphosphonates, denosumab, and comparative efficacy in men with CRPC

are discussed in detail elsewhere. (See "Osteoclast inhibitors for patients with bone

metastases from breast, prostate, and other solid tumors", section on 'Efficacy and

dosing considerations for individual agents'.)

Both agents should be dosed at bone-metastasis-indicated dosing (denosumab 120 mg

subcutaneously every four weeks, zoledronic acid 4 mg intravenous every three to four

weeks). (See 'Castration-resistant disease' above.)

Although there are sufficient data in men with CRPC to support dosing of zoledronic

acid every 12 weeks rather than every 4 weeks for most men we still prefer every-4-

week dosing, at least initially, for patients with extensive or highly symptomatic bone

metastases, including all patients who are receiving Ra-223. Specific recommendations

are provided separately. (See "Osteoclast inhibitors for patients with bone metastases

from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

• For men with bone metastases and castration-sensitive prostate cancer, we suggest

against the use of osteoclast inhibitors to prevent or delay complications from bone

metastases (Grade 2B). (See 'Castration-sensitive disease' above.)

• We also suggest against the use of osteoclast inhibitors to prevent or delay the

appearance of bone metastases in men with high-risk nonmetastatic prostate cancer

(Grade 2B). (See 'Prevention or delay of bone metastases' above.)

Use of UpToDate is subject to the Terms of Use.


6/20/22, 12:19 AM 17128

REFERENCES

1. Saylor PJ, Rumble RB, Tagawa S, et al. Bone Health and Bone-Targeted Therapies for

Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline. J Clin Oncol 2020;

38:1736.

2. Alibhai SMH, Zukotynski K, Walker-Dilks C, et al. Bone Health and Bone-Targeted Therapies

for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis. Ann Intern

Med 2017; 167:341.

3. Coleman R, Hadji P, Body JJ, et al. Bone health in cancer: ESMO Clinical Practice Guidelines.

Ann Oncol 2020; 31:1650.

4. Terrisse S, Karamouza E, Parker CC, et al. Overall Survival in Men With Bone Metastases

From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A

Meta-analysis of Individual Patient Data From Randomized Clinical Trials. JAMA Oncol 2020;

6:206.

5. McHugh D, Tagawa S, Moryl N, et al. A Phase II, Nonrandomized Open Trial Assessing Pain

Efficacy with Radium-223 in Symptomatic Metastatic Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2021; 19:447.

6. 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; 17:79.

7. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic

prostate cancer. N Engl J Med 2013; 369:213.

8. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic

skeletal events in patients with castration-resistant prostate cancer and bone metastases:

results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014; 15:738.

9. Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in

patients with castration-resistant prostate cancer and symptomatic bone metastases, with

or without previous docetaxel use: a prespecified subgroup analysis from the randomised,

double-blind, phase 3 ALSYMPCA trial. Lancet Oncol 2014; 15:1397.

10. Parker CC, Coleman RE, Sartor O, et al. Three-year Safety of Radium-223 Dichloride in

Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from

Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. Eur Urol 2018;

73:427.

11. Sternberg CN, Saad F, Graff JN, et al. A randomised phase II trial of three dosing regimens

of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Ann

Oncol 2020; 31:257.


6/20/22, 12:19 AM 17128

12. Sartor O, Heinrich D, Mariados N, et al. Re-treatment with radium-223: first experience

from an international, open-label, phase I/II study in patients with castration-resistant

prostate cancer and bone metastases. Ann Oncol 2017; 28:2464.

13. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and

prednisone or prednisolone in patients with castration-resistant prostate cancer and bone

metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet

Oncol 2019; 20:408.

14. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bo

ne protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide

versus enzalutamide alone: An updated safety analysis (abstract). J Clin Oncol 39, 2021 (sup

p15; abstr 5002). Abstract available online at https://meetinglibrary.asco.org/record/19674

4/abstract (Accessed on June 17, 2021).

15. Saad F, Carles J, Gillessen S, et al. Radium-223 and concomitant therapies in patients with

metastatic castration-resistant prostate cancer: an international, early access, open-label,

single-arm phase 3b trial. Lancet Oncol 2016; 17:1306.

16. Etchebehere EC, Milton DR, Araujo JC, et al. Factors affecting (223)Ra therapy: clinical

experience after 532 cycles from a single institution. Eur J Nucl Med Mol Imaging 2016;

43:8.

17. Morris MJ, Loriot Y, Sweeney CJ, et al. Radium-223 in combination with docetaxel in patients

with castration-resistant prostate cancer and bone metastases: a phase 1 dose

escalation/randomised phase 2a trial. Eur J Cancer 2019; 114:107.

18. Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and

89Sr in the treatment of painful skeletal metastases. Nucl Med Commun 2007; 28:623.

19. Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase-III trial to evaluate the

efficacy of strontium-89 adjuvant to local field external beam irradiation in the

management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys

1993; 25:805.

20. Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and

external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994; 31:33.

21. Oosterhof GO, Roberts JT, de Reijke TM, et al. Strontium(89) chloride versus palliative local

field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of

the European Organisation for Research and Treatment of Cancer, Genitourinary Group.

Eur Urol 2003; 44:519.

22. James ND, Pirrie SJ, Pope AM, et al. Clinical Outcomes and Survival Following Treatment of

Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89,


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Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial. JAMA Oncol 2016; 2:493.

23. Serafini AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone

cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J

Clin Oncol 1998; 16:1574.

24. Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-Lexidronam complex for treatment of

painful bone metastases in hormone-refractory prostate cancer. Urology 2004; 63:940.

25. Macherey S, Monsef I, Jahn F, et al. Bisphosphonates for advanced prostate cancer.

Cochrane Database Syst Rev 2017; 12:CD006250.

26. Hoskin P, Sundar S, Reczko K, et al. A Multicenter Randomized Trial of Ibandronate

Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate

Cancer. J Natl Cancer Inst 2015; 107.

27. Alibhai SMH, Zukotynski K, Walker-Dilks C, et al. Bone Health and Bone-targeted Therapies

for Prostate Cancer: a Programme in Evidence-based Care - Cancer Care Ontario Clinical

Practice Guideline. Clin Oncol (R Coll Radiol) 2017; 29:348.

28. Bone Metastases, MR-guided Focused Ultrasound Treatment. Available at: https://www.insi

ghtec.com/us/treatments/oncology/bone-mets/overview (Accessed on March 26, 2020).

29. Hurwitz MD, Ghanouni P, Kanaev SV, et al. Magnetic resonance-guided focused ultrasound

for patients with painful bone metastases: phase III trial results. J Natl Cancer Inst 2014;

106.

30. Francini E, Montagnani F, Nuzzo PV, et al. Association of Concomitant Bone Resorption

Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant

Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as

First-Line Therapy. JAMA Netw Open 2021; 4:e2116536.

31. Saad F, Shore N, Van Poppel H, et al. Impact of bone-targeted therapies in chemotherapynaïve

metastatic castration-resistant prostate cancer patients treated with abiraterone

acetate: post hoc analysis of study COU-AA-302. Eur Urol 2015; 68:570.

32. McGregor B, Zhang L, Gray KP, et al. Bone targeted therapy and skeletal related events in

the era of enzalutamide and abiraterone acetate for castration resistant prostate cancer

with bone metastases. Prostate Cancer Prostatic Dis 2021; 24:341.

33. 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 randomised, doubleblind

study. Lancet 2011; 377:813.

34. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic

acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst


6/20/22, 12:19 AM 17128

2002; 94:1458.

35. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men

with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled

trial. Lancet 2012; 379:39.

36. Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in

men with castration-sensitive prostate cancer and bone metastases: results of CALGB

90202 (alliance). J Clin Oncol 2014; 32:1143.

37. Wirth M, Tammela T, Cicalese V, et al. Prevention of bone metastases in patients with highrisk

nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results

of the Zometa European Study (ZEUS). Eur Urol 2015; 67:482.

38. Mason MD, Sydes MR, Glaholm J, et al. Oral sodium clodronate for nonmetastatic prostate

cancer--results of a randomized double-blind placebo-controlled trial: Medical Research

Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007; 99:765.

39. Clarke NW. Balancing toxicity and efficacy: learning from trials and treatment using

antiresorptive therapy in prostate cancer. Eur Urol 2014; 65:287.

40. Gartrell BA, Coleman RE, Fizazi K, et al. Toxicities following treatment with bisphosphonates

and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced

prostate cancer. Eur Urol 2014; 65:278.

Topic 17128 Version 62.0


6/20/22, 12:19 AM 17128

GRAPHICS

Overview of non-targeted therapies for metastatic castration-resistant

prostate cancer (CRPC)

Approach

Indications

Route,

schedule

Steroids

Symptoms,

disease

burden

Contraindications

Abiraterone

Metastatic

CRPC

Oral, daily Required – Severe liver

dysfunction,

hypokalemia, heart

failure

Enzalutamide

Metastatic

CRPC

Oral, daily Not required – Seizures

Sipuleucel-T

Pre- or post-

IV, every 2

Possibly

Asymptomatic

Steroids, opioids for

docetaxel

weeks for

contraindicated

or minimally

cancer-related pain,

3 doses

symptomatic

GM-CSF, liver

metastases

Docetaxel

Metastatic

IV, every 3

Required – Moderate liver

CRPC

weeks

dysfunction,

cytopenias

Cabazitaxel

Post-

IV, every 3

Required – Moderate liver

docetaxel,

weeks

dysfunction,

metastatic

cytopenias

CRPC

Radium-223

Symptomatic

IV, every 4

Not required

Symptomatic

Visceral metastases

bone

weeks

bone

metastases

metastases

with no

known

visceral

metastases


6/20/22, 12:19 AM 17128

PSA: prostate-specific antigen; HR: hazard ratio; IV: intravenous; GM-CSF: granulocyte-macrophage

colony-stimulating factor.

* Docetaxel is also indicated for castration-sensitive disease in combination with androgen

deprivation therapy for metastatic prostate cancer.

References:

1. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate

cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.

Lancet Oncol 2012; 13:983.

2. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in

chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival

analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16:152.

3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J

Med 2012; 367:1187.

4. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J

Med 2010; 363:411.

5. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced

prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 2008; 26:242.

6. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant

prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010;

376:1147.

7. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J

Med 2013; 369:213.

Graphic 127197 Version 2.0


6/20/22, 12:19 AM 17128

Physical properties of radionuclides for patients with bone metastases

Radionuclide Particle Physical half-life Particle energy

223radium Alpha 11.4 days 5.99 MeV

153samarium Beta 1.9 days 0.81 MeV

89strontium Beta 50.5 days 1.46 MeV

32phosphorus

Beta 14.3 days 1.71 MeV



6/20/22, 12:19 AM 17128

Skeletal events during systemic treatment for metastatic prostate cancer

Drugs

Definition

of skeletal

events

Method

of

assessing

skeletal

events

Median

time to

first SRE

(months)

Hazard

ratio

(95%

CI)

p

value

Saad, et al

Zoledronic acid

Pathologic

Periodic

16.0 versus

0.68 <0.01

(2002,

(n = 214) versus

fractures;

radiologic

10.5

2004)

placebo (n =

EBRT to bone,

review:

208)

surgery to

skeletal

bone; SCC;

surveys

change in

every 3

neoplastic

months

therapy for

bone pain

Fizazi, et al

Denosumab (n =

Pathologic

Periodic

20.7 versus

0.82 <0.001

(2011)

950) versus

fracture; EBRT

radiologic

17.1

zoledronic acid

to bone; SCC;

review:

(n = 951)

surgery to

skeletal

bone

surveys

every 12

weeks

Scher, et al

Enzalutamide (n

Pathologic

No periodic

16.7 versus

0.69 <0.01

(2012)

= 800) versus

fracture, EBRT

radiologic

13.3

placebo (n =

to bone; SCC,

review

399)

surgery to

bone; change

in

antineoplastic

therapy for

bone pain

Logothetis,

Abiraterone plus

Pathologic

No periodic

25.0 versus

0.62 <0.001

et al (2012)

prednisone (n =

fracture; EBRT

radiologic

20.3

797) versus

to bone, SCC,

review

placebo plus

or surgery to

prednisone (n =

bone

398)

Parker, et

Radium-

Pathologic

No periodic

15.6 versus

0.66 <0.001

al (2013)

223 plus BSC (n

fracture; EBRT

radiologic

9.8

= 614) versus

to bone; SCC;

review


6/20/22, 12:19 AM 17128

placebo plus

BSC (n = 307)

surgery to

bone

SRE: skeletal-related event; EBRT: external beam radiation therapy; SCC: spinal cord compression;

BSC: best supportive care.

References:

1. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications

in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96:879.

2. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with

hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458.

3. 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 randomised, double-blind study. Lancet 2011; 377:813.

4. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J

Med 2012; 367:1187.

5. Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and

prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate

cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012; 13:1210.

6. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J

Med 2013; 369:213.



6/20/22, 12:19 AM 17128

Contributor Disclosures

A Oliver Sartor, MD Grant/Research/Clinical Trial Support: Advanced Accelerator Applications [Prostate

cancer]; AstraZeneca [Prostate cancer]; Bayer [Prostate cancer]; Constellation [Prostate cancer]; Endocyte

[Prostate cancer]; Invitae [Prostate cancer]; Janssen [Prostate cancer]; Merck [Prostate cancer]; Progenics

[Prostate cancer].Consultant/Advisory Boards: Advanced Accelerator Applications [Prostate cancer];

Astellas [Prostate cancer]; AstraZeneca [Advanced prostate cancer]; Bavarian Nordic, Bristol Myers Squibb

[Advanced prostate cancer]; Bayer [Advanced prostate cancer]; Blue Earth Diagnostics, Inc [Advanced

prostate cancer]; Clarity Pharmaceuticals [Prostate cancer]; Clovis [Advanced prostate cancer];

Constellation [Prostate cancer]; Dendreon [Prostate cancer]; EMD Serono [Prostate cancer]; Fusion

[Prostate cancer]; Hinova [Prostate cancer]; Isotopen Technologien Meunchen [Prostate cancer]; Myovant

[Prostate cancer]; Myriad [Prostate cancer]; Myriad [Advanced prostate cancer]; Novartis [Bone

metastases]; Noxopharm [Advanced prostate cancer]; NRG Oncology [Genitourinary cancer]; Pfizer

[Prostate cancer]; Pfizer [Prostate cancer]; POINT Biopharma [Prostate cancer]; Progenics [Prostate

cancer]; Progenics [Prostate cancer]; Sanofi [Prostate cancer]; Sanofi [Prostate cancer]; Telix [Prostate

cancer]; Tenebio [Prostate cancer]; Theragnostics [Prostate cancer].Other Financial Interest: Sanofi

[Prostate cancer].All of the relevant financial relationships listed have been mitigated. Steven J DiBiase,

MD No relevant financial relationship(s) with ineligible companies to disclose. Nicholas Vogelzang,

MD Equity Ownership/Stock Options: Caris [Genetic testing].Grant/Research/Clinical Trial Support: AbbVie

[Prostate cancer];Amgen [Prostate cancer];Aravive [Advanced renal cancer];Arrowhead [Advanced solid

tumors];Arvinas [Metastatic castration-resistant prostate cancer];AstraZeneca [Metastatic castrationresistant

prostate cancer];Bristol-Myers Squibb [Renal cancer];Clovis [Prostate cancer];Dendreon [Prostate

cancer];Eisai [Renal cancer];Endocyte [Metastatic castration-resistant prostate cancer];Epizyme [Metastatic

castration-resistant prostate cancer];ESSA [Metastatic castration-resistant prostate cancer];Exelixis [Renal

and prostate cancers];Genentech [Advanced solid tumors];Gilead [Bladder cancer];Kangpu [Metastatic

castration-resistant prostate cancer];Kintor Suzhou [Metastatic castration-resistant prostate

cancer];MacroGenics [Advanced solid tumors];Merck [Advanced solid tumors];Mirati [Bladder

cancer];Modra [Metastatic castration-resistant prostate cancer];Myovant [Hormone-sensitive prostate

cancer];Novartis [Renal cancer];Rhovac [Prostate cancer];SDPO [Advanced solid tumors];Seagen [Bladder

cancer];Sotio [Prostate cancer];Vasgene [Bladder].Consultant/Advisory Boards: Arvinas [Metastatic

castration-resistant prostate cancer];Astellas [Renal cancer];AstraZeneca [Metastatic castration-resistant

prostate cancer];Aveo [Renal cancer];Cancer Expert Now [Advanced solid tumors];Caris [Advanced solid

tumors];Clovis [Prostate cancer];Eisai [Advanced solid tumors, renal cancer];ESSA [Metastatic castrationresistant

prostate cancer];Exelixis [Advanced solid tumors, renal and prostate cancers];Fujifilm [Bladder

cancer];Genentech [Advanced solid tumors];Helsinn [Bladder cancer];Janssen [Prostate cancer];Kintor

Suzhou [Metastatic castration-resistant prostate cancer];Merck [Advanced solid tumors, genitourinary

cancer];Modra [Metastatic castration-resistant prostate cancer];Novartis/AAA [Renal cancer];OnQuality

Pharma [Renal cancer];Pfizer [Genitourinary cancer];Propella [Prostate cancer];Sanofi-Genzyme [Prostate

cancer];SDPO [Advanced solid tumors];SWOG [Genitourinary cancer].Speaker's Bureau: AstraZeneca

[Metastatic castration-resistant prostate cancer];Bayer [Prostate cancer];Caris [Advanced solid

tumors];Clovis [Prostate cancer];Sanofi Genzyme [Prostate cancer];Seagen [Bladder cancer].Other

Financial Interest: Merck [Legal consulting];Novartis [Legal consulting].All of the relevant financial

relationships listed have been mitigated. W Robert Lee, MD, MS, MEd Equity Ownership/Stock Options:

Augmenix Inc [Prostate cancer].All of the relevant financial relationships listed have been

mitigated. Jerome P Richie, MD, FACS No relevant financial relationship(s) with ineligible companies to

disclose. Diane MF Savarese, MD No relevant financial relationship(s) with ineligible companies to

disclose.


6/20/22, 12:19 AM 17128

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are

addressed by vetting through a multi-level review process, and through requirements for references to be

provided to support the content. Appropriately referenced content is required of all authors and must

conform to UpToDate standards of evidence.

Conflict of interest policy


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