Bone metastases in advanced prostate cancer: Management

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 recurrent or metastatic castration-sensitive prostate cancer".)

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 "Rehabilitative and integrative therapies for pain in patients with cancer" and "Interventional therapies for chronic pain".)

Systemic anticancer therapy — Systemic anticancer treatment is an important component of care for men with metastatic prostate cancer causing bone metastases. Systemic therapies for 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 bone-targeted 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 recurrent or metastatic castration-sensitive prostate cancer" 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 'Beta-emitting 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-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 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 10⁹/L, the platelet count should be ≥100 x 10⁹/L, and the hemoglobin should be ≥10 g/dL. Before subsequent administrations, the ANC should be ≥1 x 10⁹/L, and the platelet count should be ≥50 x 10⁹/L. Treatment should be discontinued if there is no recovery to these values within six to eight weeks of the last dose.

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].

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 recurrent or metastatic castration-sensitive prostate cancer".)

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 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 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 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 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 skeletal-related 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 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 castration-resistant disease, no benefit was seen when zoledronic acid was started during initial treatment 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 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".)

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^th to 6^th 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^th to 12^th 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)")

SUMMARY AND RECOMMENDATIONS

●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 recurrent or metastatic castration-sensitive prostate cancer".)

●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 decision-making 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 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.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.