Introduction

Bone is the most frequent site of distant metastasis, and progression of bone metastasis is the primary cause of death in prostate cancer. Approximately 5–10% of men with newly diagnosed prostate cancer reportedly have bone metastases [1, 2], and these rates increase substantially in patients with elevated prostate-specific antigen (PSA) levels, and advanced tumor grade (Gleason Score) and local tumor (T) stage [1,2,3]. Accordingly, patients with PSA level 20 ng/ml or greater, Gleason score 8 or greater, or locally advanced disease are at higher risk of bone metastases and should be considered for further evaluation [2].

Androgen deprivation therapy (ADT) including castration, luteinizing hormone-releasing hormone agonists or antagonists, and anti-androgens, is the main systemic therapy used for prostate cancer with bone metastasis. However, eventually, the disease will progress from a castration-sensitive (metastatic castration-sensitive prostate cancer; mCSPC) to a castration-resistant state (metastatic castration-resistant prostate cancer; mCRPC). Since the bone is the predominant site of disease progression, the management of bone metastasis is key to the management of mCRPC.

Anatomical pattern and distribution of bone metastasis

In 1940, Batson first reported the vertebral system of veins, including the periprostatic, pelvic, paravertebral, intrathoracic, and intracranial veins, after a series of cadaver experiments using contrast liquid [4]. He described how the distribution of bone metastases from prostatic cancer follows the course of the vertebral venous system, especially veins that surround the sacrum, pelvis, and lumbar spine, and that tumor cells disseminate through the spinal veins as a result of venous reflux that occurs after an increase in intra-abdominal pressure caused by the Valsalva maneuver.

Bubendorf et al. analyzed the autopsy reports of 1589 men with prostate cancer [5], finding that the spine was the most common site (90%) of metastasis. In 100 such patients with detailed information available, metastases were most common at the lumbar (97%) followed by the thoracic (66%) and cervical spine (38%). The results support Batson's proposal that the vertebral venous route is the predominant pathway of bone metastasis from prostate cancer.

Prognosis-based classification

The prognosis of patients with prostate cancer and bone metastasis is heterogenous. Patients can be simply and intuitively classified according to metastatic volume and the time of metastatic disease occurrence (synchronous vs. metachronous) [6] (Fig. 1). De Bruycker et al. assessed the patterns of recurrence after primary prostate cancer treatment (radical prostatectomy and/or radiotherapy), finding that bone metastasis accounted for 18% of all recurrences, followed by lymph node metastasis. They showed that low-volume disease recurrence (local recurrence or ≤ 3 metastases) was associated with longer time to CRPC than high-volume recurrence (≥ 4 metastases) [7].

Fig. 1
figure 1

Classification of metastatic castration-sensitive prostate cancer based on prognosis. mCSPC metastatic castration-sensitive prostate cancer, PSMA-PET prostate-specific membrane antigen-positron emission tomography, WB-MRI whole-body magnetic resonance imaging

Full size image

Sridharan et al. [8] showed a clear prognostic gradient according to the number of bony metastatic sites after ADT + radiation therapy. These results have led to great interest in local therapy for oligometastasis.

In 1995, Hellman and Weichselbaum [9] proposed that oligometastatic presentation is an intermediate state of cancer spread between localized and disseminated metastatic cancer. In this state, eradication of oligometastases may be curative in some but not all patients, because these visible lesions are simply the initial manifestations of a more widespread metastatic process. Therefore, the appropriate use of diagnostic modalities to distinguish between disease states is crucial when planning definitive eradication in patients with metastatic disease, including those with prostate cancer.

Imaging studies

99mTc-bone scan

The 99mTc-bone (BS) scan is a sensitive, standard imaging method for assessing the distribution of active bone formation in the skeleton, which is associated with both malignant and benign disease. Since osteoblastic lesions are the predominant type of bone metastasis in prostate cancer, BS is commonly used to detect bone metastasis at the initial diagnosis as well as biochemical recurrence after local treatment (radical prostatectomy/radiation therapy). However, the positive scan rate is low among patients with low serum PSA levels and Gleason grades at the initial diagnosis [2]. Thus, it is recommended that BS should be avoided in patients with PSA < 2 ng/mL after radical prostatectomy [10]. At the initial post-treatment scan, there may be bone scan flares or an osteoblastic healing reaction; therefore, caution is required when used to assess therapeutic efficacy. Single photon emission computed tomography is mostly used to further elucidate the anatomy and improve the diagnostic accuracy of BS.

Whole-body magnetic resonance imaging

Magnetic resonance imaging (MRI) provides excellent contrast resolution of the bone and soft tissue and helps distinguish equivocal lesions found on BS, thus achieving excellent sensitivity and specificity for detecting bone metastases [11]. While the limited field of view and long examination time were problems before the introduction of whole-body MRI (WB-MRI) [12], the development of multichannel coils and tabletop extenders has enabled whole-body scanning to be performed in a single session [13, 14]. Takahara et al. [15] adapted diffusion-weighted imaging (DWI) for WB malignancy screening and reported the utility of DWI with background body signal suppression (DWIBS) in 2004. Since their seminal report, DWIBS has been commonly performed along with WB-MRI for the detection of bone metastases from prostate cancer as well as other malignancies.

WB-MRI has been shown to be more effective than BS and computed tomography (CT) in the detection of bone metastasis from prostate cancer and the evaluation of treatment response [16]. A meta-analysis showed that WB-MRI had a similarly high specificity (99% vs. 95%) and a higher sensitivity (94% vs. 80%) for bone metastases compared to BS [17].

Prostate-specific membrane antigen-positron emission tomography

Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein with folate hydrolase activity produced by the prostatic epithelium [18]. PSMA is negatively regulated by androgens, and is upregulated by many folds in prostate cancer and metastatic disease [19]. Its expression correlates with aggressive [20] as well as androgen-independent prostate cancer [19]. There is accumulating evidence of the utility of PSMA-positron emission tomography (PET) in detecting nodal and skeletal disease in prostate cancer [21, 22]. In fact, PSMA-PET has greater sensitivity and specificity for the detection of pelvic lymph node and distant metastases than CT and BS, as well as other PET tracers [23,24,25,26].

The Food and Drug Administration approved Ga-68 PSMA-11 as the first PSMA-targeted PET imaging tracer in 2020, which was followed by piflufolastat F-18 in 2021. The use of these tracers is indicated in patients with suspected prostate cancer metastasis who are potentially curable, as well as those with suspected recurrence based on elevated PSA levels. However, PSMA is reportedly be expressed in both neoplastic and non-neoplastic tissues [27]. Furthermore, tracer uptake by ganglia and unspecific uptake by bone means that caution must be exercised when interpreting PSMA-PET findings [28, 29].

Management of skeletal-related events

Skeletal-related events (SREs) are common complications associated with bone metastasis, and include pathologic fractures, spinal cord compression, radiation, or surgery to bone [30]. SREs can cause impaired quality of life and increased mortality [31]. Therefore, the prevention of SREs is critical to the management of prostate cancer patients with bone metastasis. Symptomatic SREs are those that are clinically detectable, irrespective of radiographic findings, and have been commonly employed as more relevant endpoints in recent clinical trials for prostate cancer with bone metastasis [30] (Table 1).

Table 1 Skeletal-related events during systemic treatment for metastatic prostate cancer
Full size table

Bone pain

Analgesics such as opioids and nonsteroidal anti-inflammatory drugs are commonly used for bone pain. In addition, bone-modifying agents (BMAs), such as zoledronic acid, may also achieve modest improvement in pain [32].

Pain relief can be achieved by external beam radiation therapy (EBRT) to a single or limited number of painful bone metastases. The American Society for Radiation Oncology recommends single-fraction EBRT at a dose of 8 Gy, for which there is no evidence of increased acute or late toxicity [33]. Other regimens, such as 20 Gy in 5 fractions, 24 Gy in 6 fractions, and 30 Gy in 10 fractions, may be reasonable options for patients with longer life expectancy given that they are associated with a lower incidence of retreatment [33].

Spinal cord compression

Spinal metastases may lead to spinal cord compression, which can cause pain, irreversible loss of neurologic function, and deterioration of quality of life. The natural course of spinal metastases arising from prostate cancer has changed considerably given the revolution in treatment options and timing of interventions. Spinal cord compression is an oncologic emergency requiring correct diagnosis and prompt treatment [34]. MRI of the entire spine is recommended, and immediate treatment consisting of glucocorticoids, pain management, and radiation therapy, with or without surgery, is required [34].

Risk of bone fracture

The risk of bone fracture is likely to rise with increasing age, potentially owing to increased bone loss by various mechanisms [35]. ADT can also induce loss of bone density, which can lead to osteoporotic fractures. This effect may be further exacerbated by the presence of bone metastases. In addition, concomitant medications, such as androgen-receptor-axis-targeted therapy (ARAT) agents abiraterone, enzalutamide, and apalutamide; and glucocorticoids, also reportedly increase the incidence of bone fractures [36,37,38,39,40]. Abiraterone blocks the synthesis of testosterone, and thus needs to be used with glucocorticoids. Meanwhile, enzalutamide and apalutamide inhibit androgen receptor activity, which may interfere with the bone-protecting effect of androgens. They are also associated with central nervous system toxicities, leading to falls and traumatic fractures (Table 2).

Table 2 Androgen-receptor-axis-targeted therapy agents and risk of bone fracture
Full size table

Bone-modifying agents

The role of BMAs, such as zoledronic acid and denosumab, in reducing the incidence of SREs as well as delaying their onset in patients with bone metastases from prostate cancer has been well characterized. The results from clinical trials support their use for patients with bone metastasis in mCRPC setting [32]. The ALLIANCE 90202 trial found that zoledronic acid use in men with mCSPC was not associated with reduced risk of SREs [41]. A phase III trial compared denosumab and zoledronic acid among patients with mCRPC and bone metastasis [42]. The results showed that denosumab was superior for the prevention of SREs (median time to first SRE 20.7 months vs. 17.1 months; hazard ratio: 0.82; p = 0.008), but there was no difference in overall survival and time to disease progression. Regarding adverse events, hypocalcemia occurred more frequently in the denosumab arm (13% vs. 6%; p < 0.0001), while osteonecrosis of the jaw (ONJ) was infrequent in both arms (2% vs. 1%).

The standard doses are 120 mg subcutaneous denosumab every 4 weeks, and 4 mg intravenous zoledronic acid every 3–4 weeks, which is consistent with the guidelines from Cancer Care Ontario and the American Society of Clinical Oncology [32]; however, the optimal duration for safe administration of BMAs has not been established. The incidence of ONJ has been shown to increase with longer exposure to BMAs [43]. A retrospective study of patients with prostate cancer and bone metastasis showed that the 2-year ONJ incidence rate was 8.9%, and low serum calcium, use of chemotherapeutic agents, and use of denosumab were possible risk factors [44].

There are data supporting the administration of zoledronic acid every 12 rather than every 4 weeks [45]. Thus, prolonging the interval of BMAs may help avoid the risk of ONJ without compromising SRE prevention. More importantly, a dental check-up is essential prior to the start of BMA because poor oral hygiene and invasive dental treatment are common predisposing factors for ONJ [46].

Radiation therapy to oligometastatic disease in prostate cancer

There have been no large randomized controlled trials focused on radiotherapy to metastatic disease, and no consensus has been reached on its efficacy. Meanwhile, retrospective and single-arm studies have reported its effectiveness, including delayed progression and initiation of ADT [47, 48]. Stereotactic body radiotherapy (SBRT) is a newly introduced approach that has helped improve treatment efficacy while reducing treatment-associated adverse events.

The efficacy of metastasis-directed therapy (radiation therapy/metastasectomy) in recurrent, metachronous oligometastatic CSPC after curative treatment has been demonstrated in two randomized phase II trials [49, 50]. The STOMP trial in Europe evaluated the efficacy of SBRT for 1 to 3 recurrent metastatic lesions, and showed an improved median ADT-free survival of 21 months compared with 13 months in the surveillance group [49]. The ORIOLE study in the U.S. showed that PSA progression at 6 months was 19% in the SBRT group compared to 61% in the follow-up group, indicating significant improvement (median progression-free survival: not reached vs. 5.8 months; hazard ratio: 0.30; p = 0.002) [50].

Radium-223

Radium-223 (Ra-223) is a radioisotope that emits α particles with a physical half-life of 11.43 days. It accumulates in areas of intense bone metabolism, replacing calcium. The α particles of Ra-223 have a very short range, about 0.1 mm, which has little effect on surrounding tissues, especially the bone marrow [51]. Ra-223 may induce DNA double-strand breaks not only in cancer cells, but also in osteoblasts and osteoclasts [52]. Therefore, it is not effective against soft tissue lesions such as lymph node and visceral metastases.

Ra-223 showed clinical benefits over placebo in patients with CRPC and bone metastases in terms of both overall survival (median, 14.9 months vs. 11.3 months) and time to first symptomatic SRE (median, 15.6 months vs. 9.8 months) in the phase III ALSYMPCA trial [53, 54]. However, Ra-223 was associated with a slightly higher frequency of G4 hematologic adverse events than placebo (anemia, 2% vs. 1%; thrombocytopenia, 3% vs. < 1%; neutropenia, 1% vs. 0%). Ra-223 is administered in 6 injections at 4-week intervals, at a dose of 55 kBq per kg body weight. Indications for introduction of Ra-223 are CRPC with bone metastasis, absence of visceral disease, and preserved bone marrow function [53].

The ERA-223 trial compared concurrent abiraterone and Ra-223 with abiraterone alone [55] in patients at an earlier stage of CRPC with bone metastasis than those in the ALSYMPCA trial. The addition of Ra-223 to abiraterone did not improve symptomatic SREs and overall survival rates, but rather increased the risk of clinical fractures compared with abiraterone alone. Thus, concurrent use of abiraterone and Ra-223 is not recommended. Another new hormonal agent, enzalutamide, is similarly being evaluated in combination with Ra-223 in the PEACEIII trial (NCT02194248). Although the final results have not been published yet, the bone fracture rate was improved following a protocol amendment mandating the use of a BMA [56].

The optimal timing, sequence, and combination of Ra-223 with other agents remain undetermined. In the European Union, Ra-223 is indicated for use after at least two prior lines of systemic therapy for mCRPC or for patients who are ineligible for other systemic treatments [57]. The National Comprehensive Cancer Network guideline (Version 4.2022) [58] gives a category 1 recommendation for Ra-223 in symptomatic bone metastasis, regardless of its timing with respect to docetaxel or novel hormone therapy agents. An analysis of the early access to Ra-223 program showed a longer overall survival in the cohort with no or minimal pain and/or PS0 than in that with moderate or severe pain and/or PS1-2 [59]. Yamamoto et al. [60] reported that a short PSA-doubling time (< 3 months), a greater volume of bone metastases (≥ 20), and later use of Ra-223 (as 4th–5th line of treatment) are poor prognostic factors. Thus, some patients in the earlier stages of mCRPC may still benefit from Ra-223.

Radioligand therapy with 177Lu-PSMA

Several radioligands of PSMA have been developed such as 177-Lu-PSMA-617 and 177-Lu-PSMA-I&T as beta particle emitters. According to a systematic review and meta-analysis [61], PSA decline of > 50% was observed in approximately 30–70% of patients treated with these radioligands, and the median overall survival was 13.7 months. The most frequent toxicities were myelosuppression, nephrotoxicity, and salivary gland toxicity (dry mouth), most of which were mild.

In the VISION trial [62], 831 patients underwent randomization in a 2:1 ratio to receive either 177Lu-PSMA-617 plus standard care or standard care alone. All patients had PSMA-avid mCRPC and had been previously treated with one to two taxanes and an ARAT agent. 177-Lu-PSMA-617 significantly improved median radiographic progression-free survival (8.7 months vs. 3.4 months), median overall survival (15.3 months vs. 11.3 months), and median time to first symptomatic skeletal event (11.5 months vs. 6.8 months). Most adverse events observed in the 177Lu-PSMA-617 group were of grade 1 or 2.

The TheraP trial [63] compared 177-Lu-PSMA-617 with cabazitaxel in men with mCRPC who had previously received ARAT and docetaxel.177-Lu-PSMA-617 achieved superior rates of ≥ 50% PSA decline (66% vs. 37%) and pain response (60% vs. 43%) compared with cabazitaxel. Overall survival was similar with both therapies [64]. Further studies are being conducted to determine which patients are candidates for 177-Lu-PSMA therapy [65, 66].

Systemic therapy

Conventionally, the main component of systemic therapy for CSPC with bone metastasis has been ADT with or without vintage anti-androgens, such as bicalutamide or flutamide. However, the tumor will eventually progress to mCRPC, where androgen receptor axis signaling is reactivated and induces further progression (Fig. 2). Docetaxel or the novel ARATs abiraterone and enzalutamide were originally developed for this population and have shown a survival benefit [67,68,69]. Furthermore, cabazitaxel has demonstrated a survival benefit in patients with mCRPC who had received docetaxel [70].

Fig. 2
figure 2

Progression of prostate cancer with bone metastasis and treatment options. ADT androgen deprivation therapy, LH-RH luteinizing hormone-releasing hormone, 177-Lu-PSMA-617 177-lutetium prostate-specific membrane antigen-617, BMA bone-modifying agent, RT radiation therapy

Full size image

Over the past 5 years, ADT plus docetaxel or a novel ARAT, including abiraterone, enzalutamide, and apalutamide, have shown improved clinical outcomes over ADT alone in patients with mCSPC [71,72,73]. However, there is no consensus on the optimal treatment choice among abiraterone, enzalutamide, and apalutamide. Furthermore, recent clinical trials have shown that the addition of an ARAT (abiraterone or darolutamide) to ADT plus docetaxel (triplet therapy) achieves longer survival than ADT plus docetaxel in patients with mCSPC [74, 75]. Although these trials showed the superiority of triplet therapy over ADT plus docetaxel, its superiority to ADT plus an ARAT, and which mCSPC patients would benefit the most from it remains unclear. Given that mCSPC eventually progresses to mCRPC in most patients, determining the optimal treatment sequence will be the most significant challenge in the future.

Conclusion

The life expectancy of patients with prostate cancer and bone metastasis has been prolonged owing to the development of a variety of systemic therapies. During the therapies, maintaining bone health is an essential part for preserving QOL of the patients. In the future, metastasis-directed therapy will be applied for selected patients with oligometastatic bone disease by the utility of new imaging techniques such as WB-MRI and PSMA-PET.