Of the 1303 publications related to radiotherapy for bone metastases, those whose citation count exceeded 100 were grouped as highly cited. Table 4 illustrates the top 10 cited references related to radiotherapy for bone metastases.

Co-cited reference is a reference that is co-cited in one or more publications (14). This interaction mechanism in the publication grows and contributes to the investigation of the dynamics of development and evolution for a particular discipline. Figure 6A illustrates the co-citation network of references whose co-citation exceeding 45.

Co-cited references are typically related to the content and subject. We use the Citespace clustering to find out the research cohesion among these co-cited references. There are 14 clusters presented in Figure 6B . The clustering structure is significant as Modularity Q is 0.7172. When Modularity Q exceeds 0.3, clustering is significant, and the distinction among different clusters is more apparent. The Silhouette S of Weighted Mean is 0.9015, indicating high similarity within the same cluster. When this value is more than 0.7, indicates strong clustering with high tightness and similarity within the cluster (14). The blue-to-red arrow is fading, which shows the cross-reference between each cluster. Red arrows identify the knowledge base, and the arrowhead points to the cluster that provides the knowledge. For example, the red arrow connecting #0 (stereotactic body radiotherapy) points to #6 (dose-fractionation schedule) and #8 (stereotactic radiosurgery), which indicates that the knowledge about #0 comes from #6 and #8. Figure 6C illustrates that research hotspots in the last few years have focused on #0 (stereotactic body radiotherapy), #1 (spinal metastases), and #7 (complicated bone metastases).

The top 20 reference with the strongest citation bursts are illustrated in Figure 7 . The reference with the strongest citation bursts (strength=35.96) was titled “Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline”, published in Internation Journal Of Radiation Oncology Physics by Lutz S et al. (15).This guideline have summarized controversial issues of radiotherapy for patients with bone metastases. The reference with the second strongest citation bursts (strength=33.02) was titled “Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicenter, randomized, controlled, phase 2/3 trial”, published in Lancet Oncology by Sahgal A et al. (16). This trial reported significant improvement of pain response rates of spinal metastases treated with SBRT as compared to external beam radiotherapy (EBRT).

With the continuous advancement of systemic treatment technologies, the survival rates of cancer patients have significantly improved. To more effectively provide lasting pain relief and prevent further damage to the spinal bones, higher-dose radiotherapy regimens are urgently needed for the treatment of spinal metastases. SBRT is capable of delivering high-dose radiation precisely to spinal lesions while strictly protecting surrounding normal tissues, creating an extremely steep dose gradient at the interface between the spinal cord and the tumor. This not only meets the therapeutic demand for dose optimization in spinal metastases but also ensures the intact function of the spinal cord.

SBRT achieves excellent local control (LC) in the treatment of spinal metastases, particularly in cases of oligometastatic spinal disease. A multicenter retrospective study conducted in Italy reported 1-year and 3-year LC rates of 90.3% and 84.3%, respectively (23). A recent meta-analysis, incorporating six prospective studies on SBRT LC and fourteen on pain response, demonstrated LC rates ranging from 80-95% at 1–2 years in a heterogeneous patient cohort. The overall and complete pain relief rates were 83.2% and 36%, respectively, with a median duration of pain response of 3 months (24). In a randomized controlled trial comparing spinal bone density in patients receiving EBRT versus SBRT, Sprave et al. observed that SBRT increased bone density in lytic metastases, while EBRT showed no significant change (25). However, the incidence of vertebral compression fractures (VCFs) at 3 months was higher in the SBRT group compared to the EBRT group (8.7% vs. 4.3%). The mechanism underlying SBRT-induced VCFs may involve high-dose radiation damaging the bone matrix, subsequently compromising spinal stability following lytic destruction (26). High-dose SBRT can elicit an acute and intense inflammatory response, and given the proximity of metastatic lesions to the spinal cord, inadequate radiation precision markedly increases the risk of myelitis, with potentially more severe consequences compared to EBRT.

The ESTRO clinical practice guideline provides practical recommendations for spinal SBRT based on current clinical evidence (27), including the utilization of specific imaging modalities such as magnetic resonance imaging (MRI) and positron emission tomography (PET/CT). PET/CT and MRI exhibit superior accuracy in identifying macroscopic bone lesions compared to conventional CT imaging. Specifically, in prostate cancer, delineating SBRT target volumes based on 68Ga-PSMA-PET/CT bone uptake can enhance the precision of radiotherapy for prostate cancer bone metastases (28). Recent advancements in software technology have led to the development of dedicated contouring and planning systems that assist clinicians in minimizing the uncertainties associated with the spinal SBRT workflow (29). These technologies maximize the safety and efficacy of spinal SBRT, ensuring optimal patient outcomes.

SBRT has been shown to have the potential to palliate pain caused by bone metastases compared with EBRT (30, 31). However, most of the previous studies have been retrospective or single-arm prospective studies. At present, many scholars are interested in conducting high-quality randomized trials and multicenter collaborative studies to determine whether SBRT could improve pain relief rates compared with EBRT. However, the results of the recent clinical studies of random trials comparing SBRT with EBRT in palliating pain from bone metastases were still indefinite (16, 32–36).

Sahgal et al. (16) reported a better pain relief rate of SBRT than that of EBRT, and in the Discussion section, Sahgal described that the results were different from the RTOG 0631 trial (35). Sahgal attributed this variation to the superior biologically effective doses achieved with multiple-fraction SBRT as opposed to single-fraction SBRT. Conversely, a randomized trial by Pielkenrood et al. (34) found no significant disparities between multifraction SBRT and EBRT. A recent systematic review and meta-analysis comparing the efficacy of SBRT versus EBRT in the treatment of spinal metastases revealed that, while SBRT did not demonstrate superior overall pain response compared to cEBRT, it may be associated with a higher likelihood of achieving complete pain response (37). One study suggested that single-fraction SBRT may offer better LC than multifraction SBRT (38). Consequently, the reasons for the inconsistencies in pain relief between multifraction SBRT and single-fraction SBRT remain unclear. Guckenberger et al. (39) found significantly better pain relief in the multifraction SBRT group. However, this study is different from other series because it used a dose-intensified SBRT of 48.5 Gy in 10 fractions, which is different from the 1–5 fraction commonly used for SBRT in previous reports. It provides a new treatment option for radiotherapy of bone metastases.

Most recent reports only provide the dose prescription, for example, 24 Gy in 2 fractions or 30 Gy in 3 fractions, but often neglect to evaluate coverage and minimum dose. To our knowledge, only Pielkenrood et al. (34) reported that the Clinical Target Volume (CTV) was treated by at least 80% of the prescribed dose, while we are not aware of other studies evaluating the dose received by the tumor. Reports detailed the delivery of 24 Gy in 1 fraction in the context of bone metastases, with 2-year LC of 98% when the D95 of the Planning Target Volume (PTV) was greater than 22.4 Gy. The 2-year LC was only 85% when the D95 was less than 16.5 Gy (40). We speculate that the coverage, too, is related to the rate of remission from pain. Furthermore, it is relevant to consider if the minimum dose is related to the rate of local relapse after pain remission.

Ongoing trials do not provide conclusive evidence that SBRT is superior to EBRT for painful bone metastases, with the caveat that SBRT has been shown to improve overall survival (OS) compared to EBRT, particularly in the oligometastatic setting (41). SBRT also provides more rapid pain relief (32). Oligometastatic bone metastases are likely the best candidates for SBRT (42). In terms of the histology of the metastatic tumor, cancers of the prostate and breast appear to be better responders to radiotherapy for bone metastases than lung cancer (43). Future studies should try to identify the patient characteristics that are associated with the greatest magnitude of benefit so that rational patient selection can be performed in the clinic.

Many previous large-scale studies excluded patients with vertebral compression fractures (VCF) or metastatic spinal cord compression (MSCC) (44). A recent report revealed that 34.4% of patients undergoing radiotherapy for bone metastases developed complicated bone metastases (45). Consequently, the issue of complicated bone metastases, particularly those affecting the spine, has garnered significant attention in the academic literature.

The combination of surgery and postoperative radiotherapy remains a viable option for eligible patients. However, there is limited research on the optimal timing of radiotherapy, and no definitive timing has been established (46). Presently, we recommend that 2 weeks between EBRT and surgery be maintained. The option to reduce this interval due to using SBRT without significantly increasing the risk of delayed or impaired wound healing is currently not validated by available data and thus inconclusive on the conclusion (47, 48).

It is suggested that LC in patients with MSCC can benefit from dose-escalating radiotherapy to over 30 Gy in 10 fractions (49). Higher total doses over long treatment durations may offer optimal LC, especially in terms of long follow-up (50). Future research should focus on evaluating the efficacy of high-precision radiotherapy techniques like SBRT and VMAT in managing MSCC. Some studies reported favorable LC with SBRT compared to EBRT (51), but VMAT showed superior therapeutic responses (52, 53).

A lot of research focuses on survival analysis in patients with complicated bone metastases. Such factors that are currently being considered to have an effect on survival in complicated bone metastasis include primary tumor histology, location of bone metastasis, risk of pathological fracture, presence of MSCC, pre-radiotherapy motor status, and expected survival time (54–56). Accurate prediction of the risk of paralysis and prognosis in such patients can help with time intervention and wisely select treatment, thus preventing both overtreatment and undertreatment.

The primary objective for most patients with bone metastases seeking radiation therapy is pain relief. However, nearly half of the patients who respond to initial radiation experience pain recurrence within a year (57), and 20% undergo re-irradiation. With the prolonging of survival in patients with bone metastases, active management of pain recurrence or progression becomes increasingly crucial. When considering re-irradiation, patient assessment should encompass three main scenarios: 1) no pain relief or recurrence after initial radiation, 2) patients with partial response to initial radiation seeking enhanced efficacy through further radiotherapy, and 3) radiological disease progression posing a risk of neurological compromise (58).Treatment strategies for re-irradiation may include EBRT and SBRT.

A large systematic review and meta-analysis focusing on non-responsive or recurrent bone metastases reported outcomes for 527 patients re-irradiated with EBRT across seven studies. Re-irradiation was effective in 58% of patients, with a response time of 3–5 weeks and duration of relief lasting 15–22 weeks (59).Although re-irradiation alleviates pain in bone metastasis patients, optimal dose fractionation data are lacking. A randomized controlled trial comparing single-fraction (8 Gy) to multi-fraction (20 Gy) radiotherapy found the single-fraction approach to be more effective with fewer toxicities (60).

For patients previously treated with radiotherapy, the risk of spinal toxicity from re-irradiation is greater than that from initial treatment. Thus, radiation techniques characterized by high conformity and steep dose gradients are advantageous for patients with longer expected survival. Regardless of whether patients initially received conventional radiotherapy (30 Gy in 10 fractions) or SBRT (24 Gy in 2 fractions), SBRT re-irradiation achieved 1-year local control rates of 70-80% without significant spinal toxicity or pathologic fractures (61–63).

While some patients may benefit from re-irradiation, potential toxicity risks must be considered. The extent and timing of disease recurrence, prior radiotherapy regimens, mechanical stability, and overall patient status should be evaluated through multidisciplinary discussion to determine an appropriate re-irradiation plan.