Introduction

Bones are one of the most common sites for metastasis of various solid cancers, particularly breast, prostate, and lung cancers, although kidney and malignant thyroid tumors also can metastasize to the bone.1,2 These metastases are associated with increased morbidity and mortality, as well as a higher risk of skeletal-related events (SREs).1,2

The incidence of bone metastases (BM) varies depending on tumor type, with the highest rates observed in prostate cancer (88.7%), followed by breast (53.71%), renal (38.65%), and lung cancer (33.5-36.9%).2 It has also been reported that the prevalence of BM exceeds 70% in breast and prostate malignancies, and approximately 30% in renal cell carcinoma.2

Carcinomas are the most common cause of metastatic bone cancer, and while the majority of BM occur via hematogenous spread, local invasion from soft tissue tumors is a also a possibility.1 The pathogenesis of BM involves tumor-stroma interactions mediated by CXCR4 and RANKL, promoting osteoclast activation through cytokines (IL-6, IL-8) and angiogenic factors (VEGF), resulting in osteolysis and tumor proliferation.1 Metastases may be osteoblastic (e.g., prostate), osteolytic (e.g., breast, lung, renal), or mixed, as in some breast cancers.1 Clinically, BM present with progressive pain or SREs such as spinal cord compression, hypercalcemia, pathological fractures, or myelophthisis, all of which significantly impair quality of life and pose therapeutic challenges.1

Current management of BM focuses on preserving quality of life, encompassing pain control and prevention of SREs, as well as local tumor control when possible. A multidisciplinary therapeutic approach is required, and management strategies must be tailored to the tumor type and consider factors such as cancer spread, functional status, and impending fractures.1

Therapeutic modalities include analgesics; osteoclast inhibitors (bisphosphonates, denosumab) to reduce both SREs and bone pain; external beam radiation, which is the standard treatment for painful lesions, providing pain relief in 50-80% of cases; stereotactic body radiotherapy, which allows precise radiation delivery while sparing normal tissue; and the use of bone-seeking radiopharmaceuticals, such as strontium-89 and radium-223, to systemically target osteoblastic lesions, with the added benefit of treating diffuse pain associated with these lesions.1 Furthermore, it has been reported that, when possible, systemic chemotherapy aimed at the primary tumor contributes to pain relief by reducing the tumor burden.1 Surgical stabilization is recommended for pathological or impending fractures of long bones to preserve function, while spinal decompression and stabilization may be indicated to prevent spinal cord compression and the subsequent neurologic involvement.1 Finally, patients with localized cancer spread (i.e., a single bone lesion) may benefit from en bloc resection of the BM, and local ablation techniques, such as radiofrequency ablation, cryoablation, and focused ultrasound, may be considered in refractory or recurrent pain cases.1

Nonetheless, the treatment of BM continues to be a challenge, and the implementation of a one-size-fits-all approach is made difficult by the biological variability between metastatic lesions, individual variations in the response to available treatments, and the prevalence of other health conditions in patients with advanced cancer.3-5 Moreover, resistance to systemic therapies and the persistent problem of managing refractory pain continue to hinder the provision of optimal patient care.

In light of these complexities, it is essential to review the most recent developments in the management of BM. Therefore, the objective of this systematic review is to provide an updated overview of the current management strategies for BM.

Methodology

This systematic review (PROSPERO registration number: CRD42024586182) was conducted in accordance with the PRISMA 2020 guidelines,6,7 thus following a structured approach.

Eligibility criteria

Population: Patients diagnosed with BM from any primary cancer.

Interventions: Various BM management strategies including surgical interventions, radiation therapy, systemic therapies (chemotherapy, hormone therapy, targeted therapy), and supportive care interventions.

Comparators: Different treatment modalities compared to one another or to standard care.

Types of studies: Randomized controlled trials (RCTs), clinical trials (CT), and observational studies (cohort and case-control studies).

Outcomes:

• Primary outcomes: Pain relief, functional status, and quality of life.
• Secondary outcomes: Survival rates, complication rates, and incidence of SREs such as fractures and spinal cord compression.

Inclusion criteria:

• Studies conducted in or involving patients with BM.
• Studies evaluating BM management strategies.
• Studies reporting data on the primary or secondary outcomes of interest.

• RCTs, CTs and observational studies (cohort studies case-control studies).
• Peer-reviewed articles published in English and Spanish.

Exclusion criteria:

• Studies that do not evaluate treatment strategies or do not report data on the outcomes of interest.
• Systematic reviews and meta-analysis, observational studies, narrative reviews, meeting abstracts, editorials, opinion pieces, commentaries, and letters to the editor.
• Studies published in languages other than English and Spanish.
• Non-peer-reviewed studies.

Information sources and search strategy

Searches were conducted in July 2024 in PubMed, ScienceDirect, and Scopus using terms related to BM. The following search strategy was used in the three databases: ((bone metastases) OR (bone metastasis) OR (skeletal metastases)) AND ((management) OR (treatment) OR (therapy)) AND ((surgery) OR (radiation therapy) OR (systemic therapy) OR (supportive care) OR (chemotherapy) OR (hormone therapy) OR (targeted therapy)) NOT ((Breast) OR (Prostate) OR (Lung)) AND (2020:2024[pdat]). The search was refined to include only studies published since January 2020. Additional searches were conducted in Google Scholar (first 10 pages) to identify any relevant studies published in journals not indexed in these databases.

Study screening and selection process

Records retrieved from the searches were entered into Rayyan, a web-based software.8 After duplicates were removed, two reviewers (MARB and JRSB) screened the titles and abstracts to exclude studies failing to meet one or more of the inclusion criteria. The remaining articles were subjected to a full-text review to assess their eligibility for final inclusion based on compliance with the inclusion criteria and the absence of any exclusion criteria. Disagreements between the reviewers were resolved through discussion until a consensus was reached.

Data extraction and quality assessment

Data extraction was conducted independently by two reviewers (MARB and JSRB) using a standardized template created in Microsoft Excel. Extracted data were systematically organized to ensure consistency across studies. Any discrepancies identified during the process were discussed until reaching a consensus. The following information was extracted from each included study: authors, year of publication, country of origin, study design, objective, sample size and main characteristics of patients (when available), and main results (comprehensive summary).

The risk of bias of the included studies was assessed using the Newcastle-Ottawa Scale (NOS)9 for both non-randomized and randomized studies to maintain consistency across risk of bias assessments. Although the NOS is not specifically intended to assess the quality of randomized trials, it was used as a pragmatic approach to provide a general quality appraisal across all study designs, acknowledging that this limits the ability to fully identify trial-specific methodological biases.

Three main domains were evaluated: selection of study groups, comparability of groups, and ascertainment of exposure or outcome. The specific criteria assessed included the adequacy of case definition with independent validation, whether cases formed a consecutive or clearly representative series, the appropriateness of control selection (community-based and without the outcome of interest), the comparability between cases and controls based on age and other relevant factors, and the ascertainment of exposure through secure records or structured interviews blinded to case/control status, consistency in exposure assessment methods across groups, and consideration of response rates. Each study was classified as having a low, moderate, or high risk of bias depending on the total score obtained in accordance with the predefined cutoffs.

Results

A total of 131 records were retrieved from the searches. After removing duplicates (n=1), 27 references were excluded in the title and abstract screening phase. Then, of the 103 studies assessed for eligibility through full-text reading, 76 were excluded because their objectives were irrelevant to the review (n=43) or did not meet the inclusion criteria (n=33). Finally, 27 studies were included for analysis in this systematic review. Figure 1 (PRISMA flowchart) shows the study identification, screening, and selection process.6

Figure 1. PRISMA flow diagram of the study identification, screening, and selection process.

Source: Own elaboration based on Haddaway et al.6

Characteristics of the studies included in the review

Of the 27 studies, 13 (48.15%) were RCTs, 7 (25.92%) were CTs, and 6 were cohort studies (22.23%); the last study was a case-control study (3.70%). Most of them were published in 2024 (n=11; 41%) and 2021 (n=8; 30%). Samples sizes varied from 8 to 9 832 patients, with an aggregate sample size of 14 672 individuals. Furthermore, all studies were published in English. The main characteristics of the studies are described in Table 2.

Table 2. Main characteristics of the studies included in the review (n=27).

Authors, publication year	Study design	Country & Language	Objective(s)	Sample size and characteristics	Intervention	Main results
Velev et al.,10 2023	CT	France, English	- To confirm the safety and efficacy of nivolumab in renal cell carcinoma (RCC) patients. -To evaluate the impact of BM on the prognosis, as well as the efficacy and safety of nivolumab use in RCC patients with BM included in the GETUG-AFU26-NIVOREN.	720 patients with RCC from 27 hospitals included in the GETUG-AFU26-NIVOREN study who had received at least one dose of nivolumab between February 2016 and July 2017; of these, 194 had BM at the time of inclusion in the study. In addition, information on the characteristics of BM at inclusion was obtained for 171 patients. Patients without BM: 514 with a median age of 64 (22;90) years; 404 males (78.6%) Patients with BM: 194 with a median age of 64 (33; 86) years, 144 males (74.2%)	Administration of nivolumab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity, death, or withdrawal consent. Median duration of treatment was 4.6 months and 5.6 months in patients with BM and without BM, respectively.	Patients with BM treated with nivolumab as second line treatment after antiangiogenic therapy for metastatic clear cell renal cell carcinoma have a poorer prognosis than those without BM, with a statistically shorter progression-free survival (2.8 vs. 4.6 months, p= 0.0045) and lower objective response rate (14.8% vs. 23.3%; p= 0.014). Also, skeletal-related events occurred in 59 (36%) of the 171 patients for which information on BM at the time of inclusion was obtained. Patients with BM receiving bone-targeted agents (BTA) at inclusion had a 64% reduction in the risk of suffering an SRE with nivolumab (OR: 0.367 [0.151; 0.895])
Liakouli et al.,11 2024	RCT	Greece, English	To compare three commonly used radiotherapy fractionation schedules for bone metastasis in terms of clinical and radiological effectiveness.	93 patients with osteolytic bone metastasis randomly allocated to three groups: Group A: 28 patients (15 male) with a median age of 70 (40-84) years. Group B: 33 patients (17 female) with a median age of 60 (47-81) years. Group C: 32 patients (12 female) with a median age of 68 (40-84) years.	Group A: 8 Grays in a single fraction Group B: 20 Grays in 5 fractions Group C: 30 Grays in 10 fractions	A statistically significant increase in bone density (measured through relative electron density -RED), quality of life (evaluated using the EORTC QLQ-C30 and the MD Anderson Symptom - MDAS instruments), and satisfaction with the treatment (self-assessment treatment tool) was observed in all groups (p<0.001) at 3 and 6 months after radiotherapy. In addition, compared to group A, the increase in RED was significantly higher in group C at 3 months after treatment (p=0.014). Group C was also superior to group A in terms of quality of life at three months post-treatment (QLQ.C30: 5.4 vs. 5.3; MDAS: 0.89 vs.1.91). Thus, it is concluded that multifractionated radiotherapy (particularly, ten-fraction) is superior to single fraction radiotherapy in terms of bone remineralization and improvement of quality of life at three months post-radiotherapy in patients with osteolytic bone metastasis.
Pielkenrood et al.,12 2022	RCT	The Netherlands, English	To compare changes in global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects after conventional radiation therapy (cRT) versus stereotactic body RT (SBRT).	110 patients with BM randomized in a 1:1 ratio to the cRT or SBRT arms.	-	Both cRT and SBRT improved quality of life over time (at 8 and 12 weeks) without significant differences between groups. However, improvement in functional inference and psychological aspects scores was significantly greater in the cRT group after 12 weeks (25.5 vs 14.1 points; effect size = 0.49, p=0.04) and 8 weeks (12.2 vs 7.3; effect size = 0.56, p=0.04), respectively. There were not clinically relevant differences between groups at 12 weeks in terms of global quality of life, physical functioning, emotional functioning, functional interference, and psychosocial aspects.
Ge et al.,13 2023	RCT	China, English	To describe the clinical outcomes of multisite percutaneous bone augmentation (PBA) for the treatment of incidental acetabular osteolytic metastases involving the articular surfaces.	8 patients (4 males and 4 females; mean age 55.00±10.14 years) with acetabular osteolytic metastases involving the articular surfaces who underwent a multisite PBA procedure between October 2014 and October 2019	Multisite (3 or 4 sites) PBA	Pain relief (assessed by means of the Visual Analogue Scale - VAS) and functional recovery (measured with the Harris Hip Score - Harris score) significantly improved after the surgical procedure: presurgical VAS score: 8.13±0.99 vs. 2.38±0.92 7 days after the procedure; pre-procedure Harris score: 38.00±18.06 vs. 75.50±11.50 7 days after the procedure. There were no significant differences in the two scores during the follow-up period (7 days after the procedure, one month after the procedure, and at the last follow-up). Based on these results, the authors conclude that the proposed multisite PBA procedure is effective and safe for the treatment of acetabular osteolytic metastases involving the articular surfaces.
Hu et al.,14 2023	RCT	China, English	To describe the pain relief and safety of microwave ablation (MWA) combined with percutaneous vertebroplasty (PVP) in the treatment of metastatic vertebral tumors.	67 participants with metastatic vertebral tumors treated between January 2018 and October 2019.	PVP: n = 35; MWA + PVP: n = 32	MWA + PVP was more effective in reducing pain long-term compared to PVP alone.
Pielkenrood et al.,15 2021	RCT	The Netherlands, English	The aim of the VERTICAL trial was to investigate whether stereotactic body radiation therapy (SBRT) improves pain response.	110 patients with painful bone metastases who gave broad informed consent for randomization were randomly assigned to cRT or SBRT.	44 patients in the cRT arm and 45 patients in the SBRT arm.	SBRT did not significantly improve pain response compared to conventional radiation therapy.
van der Linden et al.,16 2020	RCT	The Netherlands, English	To compare 2 dose schedules of dexamethasone versus placebo to prevent PF.	295 patients with oligometastatic disease (≤5 lesions within ≤3 organs).	To receive 8 mg dexamethasone before radiation therapy followed by 3 daily doses (group A), 8 mg dexamethasone followed by 3 doses of placebo (group B), or 4 doses of placebo (group C)	Dexamethasone delayed the occurrence of pain flare but did not reduce its incidence.
Hettwer et al.,17 2023	RCT	Denmark, English	To describe the use of the DERMABOND PRINEO-22 skin closure system in patients who underwent surgical treatment for metastatic bone disease involving the proximal femur.	70 patients with impending or de‐facto pathologic fracture of the proximal femur.	Patients were randomized to either occlusive wound closure (n=35), using the DERMABOND PRINEO‐22 skin closure system, or routine wound closure with conventional skin staples (n = 35)	Occlusive wound closure reduced duration and degree of postoperative wound discharge.
Shi et al.,18 2021	Cohort	China, English	To identify risk variables and develop a nomogram to predict the probability of intra-spinal canal cement leakage in elderly patients with spine metastases treated with percutaneous vertebroplasty (PVP).	Total patients: 163 elderly patients (≥65 years) randomly assigned to the training (n=100) and validation cohorts (n=63) Mean age: 74.77 ± 6.72 years Sex: 60.74% male Primary tumor types: Rapid growth: 54.60% Slow growth: 32.52% Intervention sites: mostly osteolytic lesions and 59.51% had ≥2 treated vertebrae Incidence of intra-spinal canal cement leakage: 9.82% (16/163)	Percutaneous vertebroplasty (PVP): minimally invasive procedure to stabilize metastatic vertebral lesions using PMMA bone cement.	Nomogram predicted intra-spinal canal cement leakage in elderly spine metastasis patients.
Shi et al.,19 2021	Cohort	China, English	To develop and validate the Peking University First Hospital Score (PUFHS), a predictive model for assessing the probability of vascular cement leakage in patients with spine metastases undergoing percutaneous vertebroplasty.	Total patients: 272 with spine metastases. 59.93% male, 40.07% female. Mean age 67.92 ± 10.21 years. Total vertebrae treated: 632. Vascular cement leakage incidence: 26.47% (72/272) Three-fourths of all enrolled patients were extracted as the training group (n=204) or the validation group (n = 204)	Percutaneous vertebroplasty: injection of polymethylmethacrylate (PMMA) into vertebral bodies to treat spine metastases.	PUFHS predicted vascular cement leakage in spine metastasis patients after PVP.
Gillespie et al.,20 2024	RCT	United States, English	To evaluate whether a multicomponent set of implementation strategies improves adherence to guideline-recommended short-course radiotherapy (≤5 fractions) for non-spine bone metastases.	Physicians: 45 radiation oncologists Patients: 714 individuals (343 women [48%]) Lesions treated: 838 non-spine bone metastases Median age at treatment: 67 years (IQR 59-75)	A set of 3 implementation strategies targeting radiation oncologists: Dissemination of consensus guidelines Personalized audit-and-feedback reports Email-based eConsult platform for expert input	Implementation strategies did not significantly increase short-course RT usage but practice improved over time.
Mercier et al.,21 2021	CT	Belgium, English	To evaluate the optimal dose and fractionation remain from SABR.	90 patients with European Cooperative Oncology Group performance status ≤1, an estimated life expectancy of at least 6 months, and histologically confirmed nonhematologic malignancy were eligible	5 fractions of 7.0 Gy versus 3 fractions of 10.0 Gy vs. a single fraction of 20.0 Gy.	All three SABR schedules were effective with low toxicity, with single-fraction being most convenient.
Deandreis et al.,22 2021	CT	France, English	Primary: Assess the efficacy of three radium-223 administrations (55 kBq/kg) on bone metastases from RAIR-DTC using 18F-FDG PET/CT (PERCIST criteria). Secondary: Evaluate six administrations via 18F-FDG PET/CT, 99mTc-HMDP bone scan, 18FNa PET/CT; assess clinical benefits, serum biomarkers (Tg, ALP, b-ALP), skeletal events, and safety.	10 patients enrolled (4 males, 6 females; median age: 74 years) All had RAIR differentiated thyroid cancer with bone metastases. Histologies included papillary (50%), follicular (20%), Hurthle cell (10%), poorly differentiated (20%). Median prior RAI cumulative dose: 15 GBq; many had prior bone treatments (surgery, external radiation, cementoplasty, cryoablation).	Radium-223 dichloride (Xofigo®), 55 kBq/kg IV every 4 weeks for 3 doses (extended to 6 if tolerated and no progression). Follow-up imaging and clinical evaluation monthly.	Radium-223 was not effective for bone metastases from RAIR thyroid cancer, with significant toxicity.
van de Ven et al.,23 2020	Cohort	Belgium, English	To compare pain response and quality of life (QoL) in patients with oligometastatic disease treated with conventionally fractionated 3-dimensional radiation therapy (3DCRT) or SBRT to bone metastases.	131 patients with oligometastatic disease.	66 patients were treated with 3DCRT and 65 patients with SBRT	SBRT reduced the need for re-irradiation but did not improve QoL compared to conventional therapy.
Huele et al.,24 2023	RCT	The Netherlands, English	Primary Objective:Assess the effectiveness of same-day stereotactic body radiotherapy (SBRT) followed by surgery versus the standard of care (surgery followed by radiotherapy) in terms of physical functioning at 4 weeks post-treatment. Secondary Objectives:Include pain response, duration of pain relief, hospital stay, return to systemic therapy, quality of life, local control, neurological deterioration, adverse events, survival, and cost-effectiveness.	Target: 100 patients (50 intervention, 50 control) Eligibility: Adults with symptomatic unstable spinal metastases from solid tumors requiring surgical stabilization and radiotherapy. Recruited from the PRESENT cohort at UMC Utrecht. Randomization stratified by renal cell carcinoma vs. other histologies.	Intervention group: same-day SBRT (≥18 Gy to affected vertebrae) followed by pedicle screw fixation (with or without decompression) within 24 hours. Control group: standard care - surgery followed by conventional radiotherapy (cRT) or SBRT after wound healing (≥1 week). TwiCs design: Control patients are not informed about the trial or randomization.	Same-day SBRT and surgical stabilization improved functional outcomes and pain relief.
Xu et al.,25 2023	Cohort	China, English	To compare the effects of combination therapy with PVP and iodine-125 (¹²⁵I) seed implantation on pain, physical condition, and survival and evaluated the clinical value of PVP combined with ¹²⁵I particle implantation.	62 patients with lumbosacral vertebral osseous metastases	Patients were divided into a combined treatment group and a pure PVP surgery group.	Combination therapy (PVP + 125I) reduced pain and improved survival compared to PVP alone.
Ghadjar et al.,26 2021	RCT	Germany, English	Primary Objective:Evaluate whether external yarrow liver compresses reduce general fatigue in patients with metastatic cancer undergoing radiation therapy, measured by the MFI-20 general fatigue subscale. Secondary Objectives:Assess psychological distress, quality of life, and symptoms using visual analogue scales (VAS).	39 patients randomized (only 24 analyzed: 12 in intervention, 12 in control) Adults with metastatic cancer receiving inpatient palliative radiation therapy (to brain or bone) Inclusion: At least minor baseline fatigue, life expectancy > 3 months, Karnofsky ≥ 60% Exclusions: Severe psychiatric conditions, liver metastases, anemia <8 g/dL, or conditions that cause fatigue	Control group: Standard radiation therapy (RT) Intervention group: Same RT + daily yarrow liver compresses during RT (mean 10.5 applications) Compress applied to the liver area for ~50-55 minutes each day using a yarrow infusion.	Liver compresses reduced fatigue and improved well-being in patients with metastatic cancer.
Napoli et al.,27 2023	CT	Italy, English	To compare safety and effectiveness data of MRI-guided focused ultrasound and EBRT in the treatment of bone metastases.	198 participants were assigned to a treatment group, with 100 assigned to the MRI-guided focused ultrasound group and 98 assigned to the EBRT group.	100 participants underwent MRI-guided focused ultrasound (mean age, 63 years ± 13 [SD]; 51 women), and 98 participants underwent EBRT (mean age, 65 years ± 14; 52 women)	Focused ultrasound showed better pain relief compared to EBRT, with lower adverse events.
Geerling et al.,28 2023	RCT	The Netherlands, English	To describe the additional effect of a nurse-led pain education program (PEP) on pain control and quality of life (QoL).	308 patients were randomized 1:1 to two groups: care as usual (control-group) or care as usual plus PEP and follow-up sessions by telephone (PEP-group)	PEP consisted of a structured interview and personalized education with follow-up phone calls.	Pain education program improved pain control and reduced time to control pain in patients receiving radiotherapy.
Gazendam et al.,29 2023	Cohort	Canada, English	To describe opioid consumption patterns and evaluate predictors of chronic opioid use in musculoskeletal oncology patients undergoing limb-salvage surgery and endoprosthetic reconstruction.	575 patients with musculoskeletal oncology patients undergoing lower-extremity endoprosthetic reconstruction.	The incidence of opioid consumption over the study period.	Metastatic bone disease was predictive of chronic opioid use after surgery.
Fallon et al.,30 2023	RCT	15 countries (Europe, Latin America, and Asia-Pacific), English	To compare the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy.	325 subjects were screened, 156 were randomized, and 155 received ≥1 dose of study medication.	Tanezumab 20 mg	Tanezumab reduced pain compared to placebo in patients with bone metastasis-related cancer pain.
Sakr et al.,31 2020	RCT	Egypt, English	To compare the palliative effect of radiotherapy between the standard fractionation schedule 20 Gy over 5 fractions (20Gy/5fr) and the high biological dose schedule 27 Gy over 3 fractions (27Gy/3fr), which is frequently used in stereotactic body radio-surgery (SBRT)	22 patients with painful bone metastases were included.	12 patients received (20Gy/5fr) and 10 patients received (27Gy/3fr).	27 Gy in 3 fractions provided better immediate pain relief compared to 20 Gy in 5 fractions.
Lou et al.,32 2022	Case-control	China, English	To describe the relationship between bone metastasis, pain, and cytokines before and after radiotherapy.	30 cancer patients with bone metastasis-related pain.	Patients were divided into the following groups: A, preradiotherapy; B, postradiotherapy; and C, healthy controls	Radiotherapy altered cytokine profiles and was associated with pain relief in bone metastasis patients.
Hardtstock et al.,33 2021	Cohort	Germany, English	To assess healthcare resource utilization (HCRU) and associated costs in bone-targeting agent (BTA)-naïve patients with bone metastases (BM) from solid tumors (ST), comparing those who experienced skeletal-related events (SREs) with those who did not.	Total patients: 9 832 (4 444 with ≥1 SRE; 5 388 without SRE) Matched cohort: 2 434 patients in each group (SRE vs. non-SRE) Mean age: ~71 years Female patients: ~39% in both cohorts Common ST types: lung (23.25%), prostate (18.20%), breast (15.16%).	No clinical intervention was administered. The study used observational claims data to compare outcomes between BTA-naïve BM patients with and without SREs. Patients were matched using hdPS based on 700 covariates.	Patients with SRE had higher healthcare costs and more hospitalizations than non-SRE patients.
Zeng et al.,34 2023	CT	Canada, English	To report local control and toxicity outcomes after dose-escalated 2-fraction spine SBRT.	A total of 947 segments were treated in 482 patients	301 segments in 159 patients received 28 Gy, and 646 segments in 323 patients received 24 Gy in 2 fractions.	28 Gy in 2 daily fractions improved local control compared to 24 Gy, without increasing vertebral compression fractures.
Muller et al.,35 2020	CT	United States, English	To describe an accelerated method in which CT simulation, treatment planning, quality control, and treatment delivery are performed in 1 day.	49 patients with 1 to 3 painful bone metastases	Patients were treated with treated with 1 fraction of stereotactic body radiation therapy using a same-day Scan-Plan-QA-Treat workflow, termed STAT RAD, in a phase 1/2 dose escalation trial from 8 Gy to 15 Gy per fraction	Single-fraction STAT RAD protocol was feasible, effective and safe with doses up to 15 Gy. Also, it improved patient satisfaction.
Harada et al.,36 2021	CT	Japan, English	To determine whether zoledronic acid hydrate and palliative radiotherapy could prevent local skeletal-related events.	27 patients with renal cell carcinoma were included in the study. The median age was 65 (range, 50-84) years.	Radiotherapy dose was 30 Gy for all patients except for 1 patient whose RT was terminated due to progression of brain metastases. Zoledronic acid hydrate was administered in a median of 12 (range, 0-34) times.	Zoledronic acid and radiotherapy reduced skeletal-related events in RCC patients with bone metastases.

CT: Clinical trial; RCT: Randomized clinical trial.

Source: Own elaboration.

Risk of bias

According to the methodological quality assessment of the studies using the NOS, 21 (77.8%) had a low risk of bias, whereas 6 (22.2%) showed an intermediate risk of bias, mainly in the selection and exposure domains. The results of this qualitative analysis are summarized in Table 3.

Table 3. Assessment of risk of bias in the 27 studies included in the review. NewCastle-Ottawa Scale.

Author	Year	Selection			Comparability			Exposure			Total quality score
		The case definition is adequate with independent validation	Consecutive or obviously representative series of cases	Community controls	Controls with no history of disease (end point)	Cases and controls with comparable ages	Cases and controls with comparability on any other factors	Ascertainment of exposure using secure records (e.g. surgical records) or structured interviews with blinding to case/control status	Ascertainment of exposure using the same method for cases and controls	Ascertainment of exposure with non-response rate for both groups
Liakouli et al.11	2024	*	*		*	*	*	*	*	*	8
Gillespie et al.20	2024	*	*		*	*	*	*	*	*	8
Velev et al.10	2023	*	*		*	*	*	*	*	*	8
Napoli et al.27	2023	*	*	*	*	*	*	*		*	8
Geerling et al.28	2023	*	*		*	*	*	*	*	*	8
Gazendam et al.29	2023	*	*		*	*			*	*	6
Ge et al.13	2023	*	*		*	*	*	*	*	*	8
Zeng et al.34	2023	*	*	*	*	*	*	*	*	*	9
Xu et al.25	2023	*	*		*	*	*	*	*	*	8
Fallon et al.30	2023	*	*	*	*	*	*	*		*	8
Huele et al.24	2023	*	*		*	*	*		*	*	7
Hu et al.14	2023	*	*		*	*	*	*	*	*	8
Hettwer et al.17	2023	*	*		*			*	*	*	6
Pielkenrood et al.12	2022	*	*		*	*	*	*	*	*	8
Lou et al.32	2022	*	*	*	*	*	*		*	*	8
Hardtstock et al.33	2021	*	*		*	*	*	*	*	*	8
Pielkenrood et al.15	2021	*	*		*	*		*	*	*	7
Mercier et al.21	2021	*	*	*	*		*		*	*	7
Deandreis et al.22	2021	*	*	*			*	*	*	*	7
Ghadjar et al.26	2021	*	*		*	*	*	*	*	*	8
Harada et al.36	2021	*	*	*	*	*	*	*	*	*	9
Shi et al.18	2021	*	*		*	*	*		*		6
Shi et al.19	2021	*	*		*	*	*	*	*	*	8
van der Linden et al.16	2020	*	*		*	*		*	*	*	7
van de Ven et al.23	2020	*	*		*	*	*	*	*	*	8
Muller et al.35	2020	*	*	*	*	*	*		*	*	8
Sakr et al.31	2020	*	*		*	*			*	*	6

Source: Own elaboration.

Synthesis of the results retrieved from the studies included in the review

Importance of predicting complications related to cement leakage during percutaneous vertebroplasty in patients with spinal metastases

Shi et al. (2021)18 developed a nomogram to predict intraspinal cement leakage in older patients with spinal metastases (Figure 2). The study included 163 patients over 65 years of age, with an overall prevalence of leakage of 9.82%. Multivariate analysis identified key risk factors, such as female sex, posterior wall cortical osteolytic destruction, and spinal load-bearing lines. The resulting nomogram showed acceptable predictive performance, with an area under the ROC curve (AUROC) of 0.75 in the training group and 0.64 in the validation group. Three risk groups were established: low (7.03%), intermediate (11.54%), and high (44.44%), demonstrating a significant difference in the odds of leakage between the groups (p<0.01).18

Figure 2. Predicting complications related to cement leakage during percutaneous vertebroplasty in patients with spinal metastases.18

Source: Own elaboration.

The same research team developed the Peking University First Hospital Score (PUFHS), a predictive model for vascular cement leakage in patients with spinal metastases treated with percutaneous vertebroplasty. This study included 272 patients and found that vascular cement leakage occurred in 26.47% of cases. Three predictive factors were identified: type of primary cancer, number of vertebral levels treated, and vertebral collapse.19

Contemporary approaches to the treatment of bone metastases

In the context of BM arising from renal cell carcinoma (RCC), the GETUG-AFU26-NIVOREN multicenter study7 evaluated the efficacy of nivolumab, an immune checkpoint inhibitor, in patients with BM who had failed antiangiogenic agents. Of the 720 patients treated with nivolumab, 194 had BM at baseline. Results showed that, compared with patients without BM, patients with BM had a shorter median overall survival (OS) (17.9 months vs. 26.1 months, p=0.0023). Progression-free survival (PFS) was also shorter in patients with BM (2.8 months vs. 4.6 months, p=0.0045), and the objective response rate (ORR) was lower (14.8% vs. 23.3%). Despite these unfavorable results, the use of bone-targeted agents (BTA) showed a significant reduction in the incidence of SREs (OR= 0.367, 95%CI [0.151-0.895]).10

Concerning radiotherapy, the study by Liakouli et al.11 compared three radiotherapy fractionation schemes in patients with osteolytic BM. The results revealed that multifractionated radiotherapy (30 Gy in 10 fractions) was superior to single-fraction radiotherapy (8 Gy) in terms of bone remineralization and quality of life (QoL) 3 months after treatment. In particular, the group treated with 30 Gy showed greater improvement in relative bone density (RBD) and quality of life parameters compared to the single-fraction group (p=0.014).11

On the other hand, the multisite percutaneous bone augmentation (PBA) technique for acetabular osteolytic metastases, introduced by Ge et al.13 (2023), was shown to be effective and safe for treating metastases involving articular surfaces. The results showed significant improvements in pain relief and joint function, with significantly better visual analogue scale (VAS) and Harris scores after the procedure and no obvious changes during follow-up (p<0.05).13

Regarding short-course radiotherapy for non-spinal BM, the study by Gillespie et al.20 explored the implementation of strategies to promote this treatment modality. Despite the lack of a significant increase in the utilization of short-course radiotherapy (≤5 fractions) (OR = 0.78; 95%CI [0.45-1.34]; p=0.40) following the implementation of strategies such as the dissemination of consensus guidelines and personalized audits, adherence to the recommendations improved over time, suggesting a positive trend towards the adoption of evidence-based practices.20

Pielkenrood et al.12 conducted a comparative analysis of stereotactic body radiotherapy (SBRT) and conventional radiotherapy (cRT), finding that both modalities improve QoL in patients with painful BM. However, cRT was slightly superior than SBRT in reducing functional interference and psychological aspects compared to SBRT, although the differences were not clinically relevant at 12 weeks (effect size = 0.49 and 0.56, respectively).12

In the STAT RAD trial, Muller et al.35 (2020) demonstrated that single-fraction SBRT (8–15 Gy administered in one day) is effective for pain relief in patients with painful BM, showing high patient satisfaction, low toxicity, and clinical feasibility. However, the durability of pain control was limited, with a moderate rate of retreatment observed. In contrast, Zeng et al.34 (2023) showed that a fractionated SBRT regimen (28 Gy in 2 fractions) provided significantly better local tumor control compared to 24 Gy, without increasing the risk of vertebral compression fractures, suggesting a potential benefit for long-term disease management.

In the study conducted by Harada et al.36 (2021), patients with BM from renal cell carcinoma received palliative radiotherapy (30 Gy in 3 Gy fractions) combined with zoledronic acid. At one year, the local skeletal event-free survival rate was 77.6%, with minimal grade 3 toxicities and no severe adverse events, highlighting the safety and effectiveness of the combined approach.

In turn, Mercier et al.21 (2021) conducted a phase 1 clinical trial to evaluate the efficacy and safety of three stereotactic ablative radiotherapy (SABR) fractionation regimens in patients with up to three non-spinal metastases. The results indicated that all three regimens were feasible and effective, with remarkably low toxicity rates and a high local control rate at 12 months.21 However, SABR is not the only modality being studied.

Deandreis et al.22 (2021) conducted a study to evaluate the efficacy of Radium-223, an alpha emitter, for the treatment of BM from radioactive iodine refractory differentiated thyroid cancer. Although the study was stopped due to a lack of response to Radium-223 and severe hematologic toxicity, the findings highlighted the need to continue searching for effective alternatives for this type of metastases.22

On the other hand, the analysis by van de Ven et al.23 (2020) compared pain response and quality of life in patients with oligometastatic cancer treated with SBRT versus conventional 3D radiotherapy. No significant differences in quality of life were observed between both groups, but SBRT demonstrated a lower need for re-irradiation, suggesting a potential benefit in terms of long-term management.23

With respect to radiotherapy combined with surgery, the study by Huele et al.24 (2023) evaluated the effectiveness of stereotactic radiotherapy followed by same-day surgery for symptomatic and unstable spinal metastases. This approach, which allows surgical stabilization within a few hours, showed promising results regarding functional recovery and pain control compared to standard treatment.24 In addition to these approaches, Xu et al.25 (2023) evaluated the impact of percutaneous vertebroplasty combined with ¹²⁵I seed implantation in lumbosacral BM. This combination therapy led to significant pain reduction, improvement in the patients’ physical condition, and longer survival compared to vertebroplasty alone.25

Furthermore, Ghadjar et al.26 (2021) investigated the use of external liver compresses to reduce fatigue in patients with metastatic cancer receiving radiotherapy, concluding that despite the lack of statistical significance, there may be a potential benefit for reducing fatigue and improving the overall well-being of patients.26

Finally, the study by Hettwer et al.17 (2023) on occlusive wound closure in patients undergoing endoprosthetic reconstruction of the proximal femur due to BM revealed that this technique reduces the frequency, degree, and duration of postoperative discharge, providing an additional advantage in reducing complications and improving surgical outcomes.17 The various treatment modalities available for BM are illustrated in Figure 3.

Figure 3. Treatment of bone metastases.10-12, 17, 20-26

Source: Own elaboration.

Pain management

In a phase II clinical trial conducted in Italy by Napoli et al.,27 the effectiveness of MRI-guided focused ultrasound was compared to external beam radiation therapy (EBRT) for pain relief in BM. This study included 198 patients and found that focused ultrasound showed an overall response rate of 91%, while EBRT exhibited a response rate of 67% at 1 month follow-up. In addition, focused ultrasound had a significantly higher complete response rate (43% vs. 16%).27

In The Netherlands, Geerling et al.28 investigated the additional effect of a nurse-led pain education program in patients undergoing radiotherapy for painful BM. The results showed that said program led to better and faster pain control compared to the control group, with no significant differences in quality of life between the groups.28

In Canada, Gazendam et al.29 analyzed opioid use patterns in musculoskeletal oncology patients undergoing endoprosthetic reconstruction surgery. They found that even though many patients used opioids preoperatively, most discontinued their use 1 year postoperatively. However, metastatic bone disease was predictive of chronic opioid use, highlighting the need for specific guidelines targeting this population.29

Another study conducted in the Netherlands by van der Linden et al.16 focused on the use of dexamethasone to prevent pain flare after palliative radiotherapy, finding that dexamethasone did not significantly reduce the incidence of pain flare, but it did delay its occurrence and reduced pain scores in the first few days.

A phase III randomized, double-blind, placebo-controlled parallel-group study of the Anti-Nerve Growth Factor Antibody Tanezumab was conducted in patients form 15 countries to evaluate the efficacy and safety of tanezumab in patients with cancer pain predominantly due to BM who were already receiving background opioid therapy.30 The results showed significant pain reduction in the tanezumab group (mean reduction of 2.03 on the pain scale) compared to the placebo group (mean reduction of 1.25). Although tanezumab met the primary efficacy endpoint at 8 weeks, conclusions about long-term efficacy were limited, as the study was not designed to assess the durability of the effect beyond this period. The safety of this monoclonal antibody was consistent with the adverse events expected in patients with pain from BM.30

On the other hand, a study performed in China by Hu et al.14 investigated the use of microwave ablation combined with percutaneous vertebroplasty for the treatment of metastatic vertebral tumors. Although the treatment cost was higher for the group receiving both therapies compared to the vertebroplasty-only group, the results showed a significant improvement in pain reduction and quality of life at 6 and 12 months in the combined group. This approach could be a safe and effective option for palliative pain treatment in vertebral metastases.14

In Egypt, Sakr et al.31 conducted a randomized pilot study to compare two radiotherapy regimens: 20 Gy in 5 fractions versus 27 Gy in 3 fractions. Although there was no significant difference in pain relief at 3 months between the two regimens, high biological dose radiotherapy (27 Gy in 3 fractions) showed superior immediate pain relief, although it was not statistically significant. This suggests that while both regimens are effective in the long term, SBRT radiotherapy might offer benefits in terms of rapid pain relief.31

Finally, a non-randomized study conducted in China analyzed the relationship between pain and peripheral blood cytokine expression in patients with BM treated with external radiotherapy. The results indicated that radiotherapy modified the cytokine profile in the local bone environment, and some cytokines, such as MIP-1δ and TNF-α, showed significant differences before and after radiotherapy. This finding highlighths that pain relief associated with BM may be partly mediated by radiotherapy-induced changes in cytokine production.32

Health system costs and resources related to bone metastases treatment

In a study conducted in Germany, Hardtstock et al.33 analyzed the impact of SREs on healthcare resource utilization and associated costs in patients with BM from solid tumors who have not received BTAs (Figure 3). The study, which used claims data from 2010 to 2018, compared a cohort of patients who experienced at least one SRE with a cohort that did not.33 The results showed that 45.20% of patients reported having experienced at least one SRE, while 54.80% did not report any. A total of 2 434 patients with and without SREs were matched for comparison.

The analysis presented significant differences in resource utilization and costs between the two cohorts. Patients with SREs had an average of 35.80 days of hospitalization per patient-year, as opposed to 30.80 days in patients without SREs. Inpatient care costs were also significantly higher in patients with SREs, with an average of EUR 14 199.27 versus EUR 10 787.31 per patient-year. The total cost in patients with SREs was EUR 23 689.54 per patient-year while in those without SREs was EUR 20 403.27, resulting in a total cost ratio of 1.16 (p<0.001). The study emphasizes on the challenges related to underutilization of BTAs in the clinical treatment of patients with BM in Germany and also underlines the considerable economic impact of treating SREs. Direct health care costs and increased utilization of inpatient care facilities among patients with SREs reflect the importance of addressing these events to improve the economic efficiency of treatments and the quality of life of patients.33

Discussion

The management of BM has undergone a substantial transformation in recent years, driven by advancements in both systemic and local therapies. This systematic review offers an up-to-date overview of the various strategies used for the management of patients with BM across multiple cancer types, highlighting both progress and ongoing challenges in the field.

One of the main findings of this review is the variety of treatment modalities currently employed, encompassing surgical interventions, radiotherapy, systemic therapies such as chemotherapy, hormonal treatments, and bone-targeted agents. Each of these approaches plays a critical role in improving outcomes for patients with BM; yet, there is not a singular optimal treatment strategy due to the heterogeneity of metastatic disease. The studies reviewed here reflect this complexity, demonstrating that tailored, patient-specific approaches are required for successful care.

Radiotherapy, both conventional and stereotactic, remains a cornerstone of treatment for BM, particularly for providing rapid pain relief and stabilizing bone integrity. However, there are notable differences in the effectiveness of different fractionation schemes. Multifractionated radiotherapy (30 Gy in 10 fractions) showed superior outcomes in terms of bone remineralization and quality of life compared to single-fraction radiotherapy.11 Similarly, SBRT demonstrated promising results,12,23,24,34,35 especially for reducing the need for re-irradiation, which could offer long-term benefits for patients with oligometastatic disease.23

The role of systemic therapies in BM management is increasingly expanding, with novel agents such as immune checkpoint inhibitors and targeted therapies being explored. For instance, a study assessing the safety and efficacy of nivolumab use in patients with RCC reported that patients with BM who were receiving BTAs at the time of nivolumab therapy initiation had a 64% reduced risk of having a SRE compared to those not treated with BTAs at inclusion.10 Similarly, another study found that the combined use of zoledronic acid and palliative radiotherapy reduced the risk of SREs in patients with BM from RCC.36 Emerging techniques, such as percutaneous vertebroplasty combined with ablative methods or seed implantation, also offer potential options for minimizing pain and improving quality of life in patients with spinal metastases.14 Furthermore, the study by Shi et al., (2021) which aimed to predict complications related to cement leakage during vertebroplasty, is particularly relevant, as it suggests that individualized treatment planning based on risk stratification could significantly reduce procedural complications, enhancing patient outcomes.18

While many of the reviewed studies reported favorable outcomes, challenges persist, especially with the prevention and management of complications such as pain flare, therapy resistance, and the high incidence of SREs. Moreover, the financial implications related to the treatment of skeletal complications, as demonstrated by studies analyzing healthcare costs,33 make evident the need for more cost-effective strategies and better utilization of BTAs to improve both patient quality of life and the economic sustainability of care.

Limitations

This systematic review has several limitations that should be acknowledged. First, even though risk of bias was assessed for all included studies using the NOS, this tool was originally developed for evaluating the quality of non-randomized studies, particularly cohort and case-control designs. In our review, the NOS was uniformly applied across the 27 studies, including RCTs, to ensure methodological consistency in quality assessment. However, this approach may have limited our ability to capture key domains specific to RCTs, such as random sequence generation, allocation concealment, blinding, and selective reporting. Established tools such as the Cochrane Risk of Bias 2.0 (RoB 2.0) or the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for RCTs are more suitable for evaluating these specific aspects.

The decision to use a single tool across various study designs aimed to streamline the evaluation process. However, it may have introduced a limitation that is inherent to accuracy of bias assessment for randomized studies, which constitute the majority of the included literature. Future reviews may benefit from applying design-specific tools to enhance the precision of quality assessment and risk of bias evaluation.

Conclusions

The management of BM has made significant progress in recent years, particularly in the areas of radiotherapy, systemic therapies, and minimally invasive surgical techniques, as shown by this systematic review. While each modality has its own advantages, the complexity of treating BM underscores the need for individualized, multimodal approaches that account for the specific characteristics of the metastases, the patient’s overall health status, and the primary cancer type. Clinicians can potentially extend the survival of patients suffering from this challenging cancer complication and improve their quality of life by continuing to refine treatment strategies and address current gaps in care.

Future research should focus on optimizing treatment protocols, enhancing predictive models for complications, and exploring novel therapies such as immune modulation and advanced radiation techniques. Furthermore, better integration of bone-targeted agents into treatment algorithms could significantly reduce the incidence of SREs and improve patient outcomes.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgments

None stated by the authors.

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