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 males 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 males 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 males 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 males 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 males with metastatic prostate cancer. In general, systemic therapy is an important component of patient management for controlling symptoms and slowing the progression of bone metastases. External beam radiation therapy (EBRT) is the treatment of choice for males with metastatic prostate cancer and bone pain that is not responsive to systemic therapy and is 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 males 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 males 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 males 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 males, 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".)

Radioisotopes — Radioisotopes, which vary in their physical properties (table 2), are often used in males 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. Radioisotopes can be alpha particle emitting agents such as Radium-223 (Ra-223) or beta particle emitting agents such as strontium-89, samarium-153, or lutetium-177.

In some males with CRPC radioisotope therapy has demonstrated an improvement in overall survival and health-related quality of life compared with other standard therapies. Radioisotope therapy is an appropriate option for patients who have had progression on a prior taxane and an androgen receptor pathway inhibitor (ARPI). The sequencing of radioisotopes with other systemic therapies is discussed in further detail elsewhere. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

In patients for whom a radioisotope is appropriate, we suggest lutetium Lu-177 vipivotide tetraxetan (previously referred to as 177-Lu-PSMA-617) if there is prostate-specific membrane antigen (PSMA) positivity, rather than Ra-223. Ra-223 can cause hematologic toxicity that can impact the ability to offer cytotoxic therapy in the future. However, in tumors without PSMA activity, lutetium Lu-177 does not have benefit; Ra-223 may be used in such cancers if there is bone-only (ie, no visceral) disease.

Lutetium Lu-177 vipivotide tetraxetan — For individuals with taxane and ARPI-refractory, PSMA-positive, metastatic CRPC, we offer lutetium Lu-177 vipivotide tetraxetan over Ra-223 or cabazitaxel. Lutetium Lu-177 vipivotide tetraxetan is a radioligand therapy that can be used in males with CRPC with and without bone metastases. In comparison to cabazitaxel lutetium Lu-177 vipivotide tetraxetan has similar long-term outcomes, more favorable side effect profile, and better patient-reported outcomes. In addition, in males previously treated with hormonal therapy and a taxane Lutetium Lu-177 delayed the time to development of a skeletal event compared with standard of care therapies such as hormonal therapy, bisphosphonates, and radiotherapy [3]. Lutetium Lu-177 vipivotide tetraxetan is also less likely to cause significant bone marrow failure, which could limit future therapeutic options in comparison with Ra-223. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'PSMA-positive refractory tumors'.)

Radium-223 — For males with symptomatic metastatic CRPC and bone pain who have bony metastases only (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. Ra-223 is a bone-seeking alpha particle-emitting agent. Its decay allows the deposition of high-energy radiation over a much shorter distance compared with beta particle-emitting radioisotopes, thus potentially treating the tumor while minimizing toxicity to normal bone marrow. However, Ra-223 can permanently reduce bone marrow reserves, which can limit the ability to offer future palliative cytotoxic chemotherapy. The use of lutetium Lu-177 vipivotide tetraxetan has largely replaced Ra-223 due to this concern in areas where it is available. In addition, there are no randomized trials that compare Ra-223 with other agents known to prolong overall survival in patients with metastatic CRPC (table 1).

Hematologic evaluation should 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.

●Ra-223 alone – Ra-223 improves overall survival and decreases symptomatic SREs due to bone disease in males with multifocal symptomatic bone metastases relative to best supportive care (BSC) [1,2,4-6]. In the ALSYMPCA trial, all patients had CRPC with multiple bone metastases and had either progressed on docetaxel chemotherapy or were not candidates for docetaxel chemotherapy [7-10]. Overall, 921 patients were randomly assigned in a 2:1 ratio to BSC plus Ra-223 (one dose every four weeks for six cycles) or BSC plus placebo. 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. In addition, the time to the first symptomatic SRE was significantly increased (median 15.6 versus 9.8 months; HR 0.66, 95% CI 0.52-0.83) [8].

Long-term follow-up of patients indicate that 2 percent of patients receiving Ra-223 developed bone marrow failure following treatment, compared with none in the placebo arm, and there were two deaths due to bone marrow failure [11].

●Ra-223 in combination with other agents – No beneficial role for combinations of Ra-223 with systemic therapy have been established, and prospective data indicate more fractures when Ra-223 is combined with abiraterone [12]. We do not initiate Ra-223 and abiraterone at the same time. Guidelines from the American Society of Clinical Oncology (ASCO) specifically recommend against simultaneously initiating Ra-223 with abiraterone and prednisone [1]. In addition, there is insufficient evidence to support concurrent use of Ra-223 with other secondary therapies known to prolong survival in metastatic CRPC.

Other beta-emitting radioisotopes — In addition to the radioisotope Lutetium-177, which is used in the radioligand lutetium Lu-177 vipivotide tetraxetan, other beta-emitting radioisotopes have been evaluated and used clinically (table 2). The most widely studied are strontium-89 and samarium-153. Other isotopes studied include phosphorus-32, rhenium-186, and rhenium-188 [13].

●Multiple clinical trials have evaluated the efficacy of strontium-89 in males with prostate cancer bone metastases [14-17]. In the largest of these trials (757 patients), treatment with strontium-89 was integrated with docetaxel chemotherapy [17]. 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 [18,19].

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 alone prolong survival, in contrast to alpha emitting radioisotopes [5].

Bisphosphonates — Bone modifying agents such as bisphosphonates or denosumab are indicated for males 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 males 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 males 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) [20]. 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 males 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 [21]. 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) [1,22].

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 [23]. 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 [24]. (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 males 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 males 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 males with symptomatic metastatic disease.

Osteoclast inhibitors

Prevention of skeletal-related events

Castration-resistant disease — In males 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, Ra-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 [25-27].

For many patients, denosumab may be preferred over zoledronic acid, based on superior efficacy in a large randomized trial [28]. 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 males 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 males with CRPC to support dosing of zoledronic acid every 12 weeks rather than every 4 weeks for most males 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 [1,28,29]. The incidence of jaw osteonecrosis has been higher with longer duration of therapy [30]. 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 males 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 males with castration-resistant disease, no benefit was seen when zoledronic acid was started during initial treatment with ADT in males with bone metastases. In the CALGB 90202 trial, 645 males were randomly assigned to zoledronic acid or placebo [31]. 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 males 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 males with metastatic castration-sensitive prostate cancer [4].

Prevention or delay of bone metastases — We suggest against the use of osteoclast inhibitors to prevent or delay the appearance of bone metastases in males with high-risk nonmetastatic prostate cancer. Randomized trials with both bisphosphonates and denosumab have failed to demonstrate a favorable risk-benefit ratio for males 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 males 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 [32]. 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 [33].

Denosumab — The potential value of denosumab to prevent bone metastases was addressed in a phase III trial, in which 1432 males with nonmetastatic CRPC were randomly assigned to denosumab or placebo [30]. 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 [34,35].

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 males with advanced prostate cancer. The goals of palliative treatment for males 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 males with bone pain that is not responsive to systemic therapy and limited to one or a limited number of sites. For most males, 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 – In some males with castration-resistant prostate cancer (CRPC) radioisotope therapy has demonstrated an improvement in overall survival and health-related quality of life compared with other standard therapies. However, the selection about which radioisotope to offer is dependent on prostate-specific membrane antigen (PSMA) positivity and prior therapies. (See 'Radioisotopes' above.)

•For individuals with taxane and androgen receptor pathway inhibitor-refractory, PSMA-positive, metastatic CRPC, we offer lutetium Lu-177 vipivotide tetraxetan rather than Radium-223 or cabazitaxel. Further discussion of this therapy is discussed elsewhere. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'PSMA-positive refractory tumors'.)

•For males 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. However, 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 not used in combination with the hormonal agents such as abiraterone or enzalutamide. (See 'Radium-223' above.)

●Role of osteoclast inhibitors

•For males 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 males 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 males with CRPC to support dosing of zoledronic acid every 12 weeks rather than every 4 weeks for most males 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 males 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 males with high-risk nonmetastatic prostate cancer (Grade 2B). (See 'Prevention or delay of bone metastases' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Nicholas Vogelzang, MD, who contributed to earlier versions of this topic review.