Introduction
Colorectal cancer (CRC) is a major global health challenge, ranking as the third most common cancer worldwide and the second most common cause of cancer-related mortality [ 1 ]. In 2020 alone, it accounted for over 1.9 million new cases and 930,000 deaths, and roughly 10 % of all annual cancer diagnoses and cancer-related death [2] , [3] . It ranks as the second and third most common cancer in women (9.2 %) and in men (10 %) respectively [ 4 ], with a 25 % lower incidence and mortality in women. CRC is most seen in developed countries, and the incidence of CRC is projected to increase to 2,5 million new cases by 2035 which can be attributed to several factors including lifestyle, obesity, genetics and a growing implementation of CRC screening [ 3 ]. Moreover, the increase in CRC incidence in developed countries for the past decade is possibly due to the growing elderly population, poor dietary habits, obesity, smoking and low physical activity [ 5 ]. Other risk factors for CRC include ageing, male sex and positive family history that was found in 10–20 % of all CRC patients [ 3 ].
Metastases are responsible for 90 % of CRC- related deaths with documented 5-year survival rates inferior to 20 % [ 6 ]. The liver was the most common site of other common metastatic sites including the lungs, peritoneal cavity and rarely the bone which was reported in only 6–10 % of CRC cases[ 7 ]. bone metastasis is commonly seen in conditions like multiple myeloma, breast, and prostate cancer, but remains uncommon in gastrointestinal tumors (3–5 %) [ 8 ]. Around 80 % of malignant solid tumors commonly metastasize to the bone[ 9 ]. Most studies report a bone metastasis incidence between 2.7 and 7 % in CRC patients, with a higher chance in those with already metastatic CRC. The recent increase of bone metastasis incidence in CRC may be linked to new treatments. In fact, significant survival improvements for patients with metastatic CRC have been observed over the last two decades, leading to longer survival [ 10 ]. This increases the probability of bone metastasis occurring throughout the progression of the disease. Consequently, managing rare, late-stage metastatic patterns has become more clinically important, since bone metastasis in CRC suggests a poor prognosis while independently predicting a shorter OS [11] , [12] . Unfortunately, bone metastasis is usually diagnosed in the late stages of CRC despite having a significant impact on patient survival and the high incidence of skeletal-related events (62–70 %) – including pain, spinal cord compression, pathological fractures, and hypercalcemia −- that severely affect the patients’ quality of life. Multidisciplinary management is required to treat pain and complications and improve mobility. The median survival of CRC patients with bone metastasis is 5–18 months, which is significantly lower than the median survival of those without bone involvement [7] , [9] , [13] .
Because of its rare occurrence, the topic of bone metastasis was often disregarded in the context of CRC patients [ 7 ]. This has resulted in significant gaps in the available scientific data a lack of high-level evidence from prospective trials. Therefore, this review aims to consolidate current knowledge by summarizing the pathophysiology, clinical presentation, prognostic factors, survival outcomes and available treatments for bone metastases in patient with colorectal cancer which is crucial for is crucial for highlighting these knowledge gaps and guiding future patient management.
Search strategy and selection criteria
This article is a comprehensive narrative review. Important literature was selected through an initial search using the PubMed Database and was completed in May 2025. The search strategy did not adhere to any restrictions such as publication date since the main goal of the review was to give an overview of the topic while using the foundational and recent available data spanning from 1994 to 2025.
A combination of keywords and MeSH terms were employed on PubMed including: “Colorectal cancer,” “Bone Metastasis,” “pathophysiology,” “prognostic factors,” “survival,” and “treatment strategies,” “Bisphosphonate,” “Chemotherapy,” “Radiotherapy”, “Surgery”. Relevant studies that contained substantive information while adhering to the reviews’ core topics were selected by the authors based on abstract and when needed using full-text review.
In addition, some of the studies included in this review were identified through citation tracking, where the referenced works were deemed relevant to the review's scope and objectives.
Terminology: • Isolated Bone Metastasis (IBM) refers to bone-only disease (no visceral metastases). • Solitary Bone Metastasis refers to the number of metastatic lesions (a single site).
Pathophysiology
Metastasis begins with the dissociation of cancerous cells due to the inhibition of the expression of junction elements like E-cadherin. Then, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (u-PA) produced by CRC cells degrade the basal membrane enabling CRC cells to infiltrate the interstitial tissue. This triggers the release of pro-angiogenic mediators, such as vascular endothelial growth factor (VEGF) and other cytokines, which drive angiogenesis and lymphangiogenesis, creating a microenvironment that facilitates the infiltration of tumor cells into the vasculature [ 14 ]. After entering the blood, malignant cells link with white blood cells and platelets through specific mechanisms. In bone metastasis, C-X-C Chemokine Receptor 4 (CXCR4) on tumor cells binds to C-X-C motif chemokine 12 (CXCL12) in bone marrow, anchoring tumor cells to the bone marrow. The receptor activator of nuclear factor kappa-Β ligand (RANKL) binds with marrow cells, releasing various growth factors and cytokines like interleukin (IL)-6, IL-8, and VEGF. These growth factors enhance tumor growth and stimulate osteoclasts[ 15 ] ( Fig. 1. ). Fig. 1 depicting the physiopathology of colorectal carcinoma bone metastases.
CRC most frequently spreads to the liver, with 50 % of CRC patients developing liver metastasis, and also to the lungs (10–15 %), the peritoneum, and the brain. bone metastasis are rarer and often appear at advanced stages accompanied by metastases to other locations, mainly the liver. However, isolated bone metastases have been found in CRC in a few cases. [ 16 ] bone metastasis are particularly common in bones rich in marrow and trabeculae, where vascularization and high bone turnover increase the likelihood of tumor cell infiltration [ 17 ]. Therefore, the main sites of bone metastasis are the spine and the pelvis due to the communication between the deep pelvic vein and the internal venous plexus via Batson’s plexus. Less frequently, CRC metastasizes to the skull, femur or humerus. Rarely, solitary scapular metastasis can be observed in CRC patients[ 18 ].
Clinical presentation and symptoms
Patients with bone metastasis typically present with severe bone pain (80 %) [ 19 ]. Other signs include pathological fractures, spinal cord compression, and hypercalcemia. Eventually these skeletal-related events (SREs) will reduce the patient’s mobility, worsen the quality of life, and increase medical costs. bone metastasis s may require surgical or radiation therapy[ 20 ].
Originally, X-rays were the imaging modality of choice to identify and assess bone metastasis, but due to their low resolution, were unable to detect bone metastasis s at early stages. On the other hand, computed tomography (CT) scans deliver a more sensitive assessment of cortical and trabecular bone lesions, allowing for better staging and surgical planning. Magnetic resonance imaging (MRI) is the most sensitive modality, detecting early marrow involvement and spinal cord compression with 95 % sensitivity. Nuclear imaging, including bone scans, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) scans, identifies metabolic activity in affected bones, PET/CT (especially 18F-NaF PET/CT), providing the highest accuracy[ 15 ].
Furthermore, blood tests such as serum calcium, alkaline phosphatase, and bone turnover markers can also detect bone resorption or metabolic anomalies. In conclusion, merging imaging and laboratory findings is crucial for early detection, disease monitoring, and treatment planning, helping improve survival and quality of life[ 15 ].
Risk factors and prognosis ( Table 2 )
Due to the rarity of bone metastasis in CRC, it is difficult to determine factors indicative of prognosis in this setting. The available literature consists primarily of retrospective cohort studies. However, there is a general agreement that CRC patients with bone metastasis usually have a poor prognosis, with a median survival of 7 to 18 months following diagnosis [ 9 ]. This is substantially less than patients with isolated liver metastases, who may often benefit from potentially curative resection [ 10 ].
The main risk factors for developing bone metastasis appear to be lymph node invasion at primary tumor surgery, rectal cancer and lung metastases[ 12 ]. Therefore, routine bone imaging is essential in CRC patients with lung metastases [ 20 ] ( Fig. 2. ) . On the other hand, a retrospective study found no relationship between bone metastasis occurrence and other factors such as age, histological type, and differentiation of the primary tumor [ 7 ]. Also, there was strong evidence that men are more likely to develop bone metastasis than women [7] , [21] . Fig. 2 Clinical decision tree for the management of suspected colorectal cancer bone metastases.
Once bone metastasis is diagnosed in CRC patients, prognosis is influenced by several categories of factors.
Genetics factors
Despite its prognostic and predictive roles in metastatic CRC [ 22 ], evidence of rat sarcoma virus (RAS) mutation as a potential risk factor for bone metastasis remains inconclusive, as noted in a 2018 systematic review [ 12 ].
RAS mutation in metastatic CRC is linked to worse outcomes with a large retrospective cohort study (n = 918) finding that RAS -mutant patients had a significantly shorter median OS of 47 months, compared to 81 months for RAS wild-type patients (p < 0.001). The same study identified RAS mutation as an independent predictor of developing bone metastasis (HR: 1.62, p = 0.012). This was supported by the two-year cumulative incidence rate for bone metastasis, which was double in the RAS -mutant group (8.8 % vs 4.4 %, p = 0.024) [ 23 ].
However, this finding is not consistent. A more recent, smaller retrospective real-world data study from Turkey (n = 150) found that while 46 % of CRC patients with bone metastasis had a KRAS mutation, no NRAS (Neuroblastoma RAS viral oncogene homolog) or BRAF v-Raf murine sarcoma viral oncogene homolog B1) mutations nor microsatellite instability were found in those patients, making it difficult to draw a firm conclusion [ 24 ]. Therefore, while RAS mutation is a strong candidate, its specific role as a risk factor for bone metastasis requires further validation.
Serum biomarkers
CEA levels : In a large retrospective cohort study (n = 242), it was determined that high carcinoembryonic antigen (CEA) levels is an independent prognostic factor for poor outcomes. In contrast, normal CEA levels were strongly associated with good prognosis [ 7 ]. This is likely because high CEA levels indicate a larger tumor burden and, therefore, shorter survival [ 25 ]. For this reason, CEA serum level measurement may be useful in management, prognosis and monitoring relapse after primary tumor resection of CRC patients [26] , [27] .
ALP, NLR, CA-19 – 9 and LDH levels ( Fig. 2. ): Elevated serum Alkaline Phosphatase (ALP) is consistently reported as an independent factor for poor prognosis in CRC patients with bone metastasis [7] , [24] , [28] . The biological mechanism for this is that elevated ALP indicates accelerated bone metabolism resulting from osteoblast activation in metastatic bone lesions [ 29 ]. The prognostic impact has been quantified in a large retrospective study by Park et al. (n = 11,551 CRC patients, including 321 with bone metastasis), which found that patients with high ALP (≥ 123 U/L) and high neutrophil-to-lymphocyte ratio NLR ≥ 2.7 had a median survival of only 5.6 months, compared to 12.2 months for those with low levels [ 11 ]. This finding is supported by other retrospective cohorts, including one by Karabulut et al. (n = 150) which also identified high ALP and CA-19–9 levels as indicators of poor prognosis [ 24 ]. Furthermore, another study (n = 242) specifically identified elevated ALP as an independent poor prognostic factor in the subset of patients with isolated bone metastasis [ 7 ]. In addition to being a prognostic factor, high ALP levels along with lactate dehydrogenase (LDH) have also been found to increase the likelihood of CRC spreading to the bone, resulting in poor prognosis [ 28 ].
Metastasis-related factors
Disease extent and organ metastasis : The degree of metastatic spread is a key determinant of prognosis. A retrospective cohort study (n = 242) found isolated bone metastasis to be an independent prognostic factor for a favorable outcome, since patients with isolated bone metastasis had a remarkably longer median survival time compared to those with concurrent bone metastasis and visceral metastases (29.1 vs 12.8 months, p = 0.003). However, this study provided a critical nuance, showing that this prognostic benefit is highly dependent on the extent of the bone disease: Among isolated bone metastasis cases, patients with single-site bone metastasis survived far longer than those with multiple bone metastasis sites (29.2 vs. 9.3 months). Furthermore, patients with multiple sites of bone metastasis without other metastatic locations had similar prognosis to patients with bone metastasis and visceral metastasis [ 7 ].
The poor prognosis associated with metastatic disease is confirmed by other studies. A retrospective study (n = 150) identified the presence of brain metastases as an indicator of poor prognosis [ 24 ]. Similarly, another Japanese retrospective study (n = 104) showed that having more than two extraosseous metastatic locations are linked to a shorter OS. Consequently, the poor prognosis of CRC patients with bone metastasis can be explained by the fact that 80 to 90 % of these patients present with extraosseous metastasis, mainly involving the lung and liver [ 9 ]. On the other hand, a large cohort study (n = 725 mCRC patients) showed that liver metastases in CRC patients could be a protective factor for bone metastasis suggesting that CRC with liver metastasis might have distinct biological and molecular features, reducing the propensity of CRC to spread to the bone, a finding that requires further investigation[ 28 ].
Skeletal-Related Events (SREs): The presence of SREs at diagnosis is a significant indicator of poor prognosis. A retrospective study (n = 104) found that patients presenting with pathologic fractures (HR: 1.91) or hypercalcemia (HR: 3.75) had significantly shorter OS [9] , [24] .
Primary tumor characteristics and metastatic timing
Several characteristics of the primary tumor, as well as the timing of metastasis, serve as important prognostic markers.
Tumor sidedness : Primary tumor sidedness has been identified as a potential prognostic marker. This is supported by at least two retrospective studies. A retrospective study by Karabulut et al. (n = 150) identified right-sided colon cancer as an indicator of poor prognosis [ 24 ]. Similarly, a multivariable Cox regression analysis by Li et al. (n = 178) also found that a right-sided primary tumor was associated with a poorer prognosis in CRC patients with bone metastasis [ 30 ].
Staging and perineural invasion:
Primary tumor staging at diagnosis is a key marker. A multivariable Cox regression analysis by Li T et al. (n = 178) found that N0 stage (no nodal involvement) at the time of initial CRC diagnosis was associated with a better prognosis for patients who later developed bone metastasis [ 30 ].
The role of perineural invasion (PNI) is more complex. While one retrospective study by Liu et al. (n = 242) identified PNI as an independent poor prognostic factor in the specific subgroup of CRC patients with isolated bone metastasis [ 7 ], its general prognostic role in all bone metastasis patients remains unclear. Moreover, several studies found an increased chance of metastatic CRC in patients with perineural invasion at the time of tumor resection. The leading theory behind PNI pathogenesis is the migration of tumor cells along neural sheaths. Multiple growth factors such as nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 might be involved in this mechanism[ 31 ].
A contradictory finding was reported regarding T-stage. A population-based study by Li X et al. (n = 381) on synchronous bone metastasis patients reported the counter-intuitive finding that CRC patients with low T stage (T1/T2) presenting synchronous bone metastasis had a shorter survival than high T stage (T3/T4) (7 vs 10 months). Therefore, the authors note that further research is needed to clarify the significance of primary tumor T in this setting [ 32 ].
Timing of Metastasis: Patients with synchronous bone metastasis and metachronous bone metastasis exhibited distinct clinicopathological features, requiring different treatment approaches, which influenced their prognosis. Both CRC patients with synchronous and metachronous bone metastasis showed a median cancer specific survival of 11 months in a retrospective cohort study (n = 201). On the other hand, the Li X et al. study focused only on CRC patients with synchronous bone metastasis and reported a poorer median OS of 9 months [ 32 ]. Furthermore, among metachronous bone metastasis patients, those diagnosed at an early CRC stage displayed longer survival than late-stage CRC, suggesting that prior treatment and disease history are important variables [ 33 ].
Prognostic nomograms
Two novel risk and prognostic nomograms from the study by Wang et al. (n = 725) exhibited solid results in predicting the risk of bone metastasis development in CRC patients along with prognosis making it a potential useful and cost-effective tool for screening ahead of bone imaging in metastatic CRC and in the prediction of prognosis. The bone metastasis risk nomogram including seven variables − degree of tumor differentiation, N-stage, ALP, LDH, CEA, liver metastasis and lung metastasis − presented with a sensitivity of 71.3 %, a specificity of 89.4 % and a C-statistic of 0.846 [95 % CI, 0.793 to 0.898] and 0.792 (95 % CI, 0.750 to 0.834) in the training and validation cohort, respectively. In addition, the prognostic nomogram including five variables − tumor differentiation, number of extra- bone metastasis organs, number of bone metastasis lesions, ALP, and LDH − presented with a C-statistic of 0.723 (95 % CI, 0.657 to 0.789) and 0.682 (95 % CI, 0.638 to 0.726) in the training and validation cohort, respectively [ 28 ].
Another cohort study by Li X et al. (n = 381) constructed a nomogram to help clinicians predict survival and offer optimal treatment based on independent prognostic factors, including histological type, T stage of the primary tumor, differentiation grade, CEA level, systemic chemotherapy and liver or lung metastasis. However, this model is not ready for clinical use and needs further investigations to confirm its practicality since it presented with a C-index of 0.72 (95 % CI 0.69–0.75) and 0.57 (95 % CI 0.46–0.68) in the internal and external validation, respectively [ 32 ].
Survival ( Table 1 )
Table 1 A study with long-term follow-up showed that the median survival time of CRC patients with bone metastasis was 17.8 months. Three- and five-year overall survival (OS) rates were 25.4 % and 5.7 % respectively [ 34 ]. A study determined that the median OS for patients with bone metastasis in CRC is 5.5 months (range: 2–36 months), and the 1-year survival rate was 20–30 % [18] , [35] . Another investigation by Nozue et al. found that in their small series, the two patients who presented with solitary bone metastasis (single site) both survived for more than one year [ 35 ]. In CRC patients with bone metastasis, median OS was significantly higher in patients without extraosseous involvement (22 months vs. 3 months). Additionally, CRC patients without liver metastases also had significantly higher survival compared to those with extraosseous involvement excluding the liver (18 months vs. 3 months). Thus, extraosseous and liver involvement were linked to reduced survival. This could be explained by the fact that hepatic and pulmonary metastases are asymptomatic at early stages and not detected by routine testing, while bone metastases are symptomatic, even at an early course of the disease. Consequently, patients with isolated bone metastasis are treated earlier than patients with isolated liver or lung metastases. Therefore, systematic imaging examination is helpful to determine the outcome of patients’ bone metastasis. The most common cause of death in CRC patients with non-isolated bone metastasis in CRC was pulmonary failure [ 18 ]. Table 1 Survival of CRC patients with BM. Study Type of study Number of patients Survival Findings Liu et al., 2016 7 Retrospective study 242 Median survival time after diagnosis of BM in CRC patients: 15.6 months (95 % CI, 12.74–18.46 months) Median survival time of patients with Isolated bone metastases was remarkably longer than that of patients with BM and visceral metastases (29.1 vs 12.8 months, p = 0.003). Kawamura et al.,2018 9 Retrospective study 129 Median survival time after diagnosis of BM in CRC patients: 5.0 months (95 %CI, 4.0–9.0 months) 1-year survival rate: 30.0 % (95 % CI, 21.1 %-39.4 %) Baek et al., 2016 34 Retrospective study 63 OS: 17.8 months 3-year survival rate: 25.4 % 5-year survival rate: 5.7 % Nozue et al., 2002 35 Retrospective study 12 OS: 5.5 months 1 year survival rate: 20–30 % The most common causes of death in CRC patients with BM are pulmonary failure (n = 7), liver failure (n = 1), and DIC (n = 1). Suresh Babu et al., 2017 18 Retrospective study 10 mOS: 22 months (no extraosseous involvement) vs 3 months (with extraosseous metastases), P = 0.008 mOS was significantly higher in patients without extraosseous involvement (22 months vs. 3 months). mOS for patients without liver metastases was significantly higher survival compared to those with extraosseous involvement excluding the liver (18 months vs. 3 months) CRC patients with BM without extraosseous metastases had better survival outcomes. Extraosseous and liver involvement were linked to reduced survival in patients with Bm. Unsignificant trend towards lo longer survival in men (10 vs 3 months, p = 0.058) and patients without vertebral involvement (3 vs. 10 months, p = 0.082) Ma et al., 2020 33 Retrospective study 201 Median cancer-specific survival (cancer specific survival): 11 months for both synchronous and metachronous BM. Synchronous BM is often more aggressive Table 2 Prognosis and risk factors for BM in CRC patients. Study Number of patients Type of analysis Factors associated with prognosis in CRC patients with BM Other findings Liu et al., 2016 7 242 CRC patients with BM Isolated bone metastases group (n = 52) Multivariate analysis Isolated bone metastases group: high ALP ≥ 150 U/L (HR: 3.342, p = 0.037) and perineural invasion with of primary cancer (HR:3.457, p = 0.022) were factors of poor prognosis For CRC patients with BM: high CEA level was a poor prognosis factor (HR: 3.300, p < 0.001) and single isolated bone metastases was associated with better prognosis than multiple BM (29.2 months vs 9.3 months, p = 0.008). Median survival time: 15.6 months Median survival time of isolated bone metastases significantly higher than the BM & visceral metastases group: 29.1 vs 12.8 months (p = 0.003). Patients with BM & visceral metastases had equivalent prognosis to the isolated bone metastases group. Median survival time of high CEA group was 11.1 months vs 21.9 for normal CEA group (HR: 3.300, p < 0.001). Median survival time of isolated bone metastases group was 29.1 months vs 12.8 in the no isolated bone metastases group. Median survival time of high ALP in the isolated bone metastases group was 8.5 vs 29.1 months for the normal ALP group (HR: 3.342, p = 0.037). Median survival time of the isolated bone metastases group with positive perineural invasion was 9.3 months vs 29.2 months for the isolated bone metastases group with no perineural invasion (HR; 3.457, p = 0.022)‘. Yaeger et al., 2015 23 RAS WT mCRC with BM (n = 3, 0.6 %) RAS WT mCRC (n = 477) RAS Mutant mCRC (n = 441) RAS Mutant mCRC with BM (n = 4, 0.9 %) Multivariate analysis RAS mutation was identified as an independent predictor of BM (HR: 1.62, p = 0.012) after adjusting for age, tumor location, synchronous tumor, and diagnosis of lung metastasis. mOS: 81 months for patients with RAS wild-type mCRC vs 47 months for patients with RAS mutant (p < 0.001) The cumulative incidence of RAS mutation 2 years after the diagnosis of metastatic CRC was linked to a higher incidence of bone (8.8 % vs 4.4 %, p = 0.024), lung (32.5 % vs 19 %, p = 0.001) and brain metastasis (1.4 % vs 0.2 %, p < 0.01) Wang et al., 2021 28 725 mCRC patients including 274 patients with BM Multivariate Cox regression analysis The risk and prognostic nomogram for BM in CRC patients included the following factors: tumor differentiation, ALP, LDH number of extra-BM organs and the number of BM lesions with an R 2 of 0.284 and a C-statistic of 0.723 The number of extra-BM organs (p = 0.002, HR: 2.357) and LDH levels (p = 0.032, HR: 1.961) were significant prognostic factors for OS in CRC patients with BM mOS: 8.6 months 6-month OS rate: 63.4 % 1-year OS rate: 32.7 % 2-year OS rate: 8.9 % Liver metastasis was a protective factor for BM (P < 0.05) This nomogram showed good performance as a potential screening tool for BM risk and prognosis in CRC patients Kawamura et al.,2018 9 104 CRC patients with BM Multivariate analysis Two or more extra-bone metastatic organs (p < 0.001), pathological fracture (HR:1.91, p = 0.033) and hypercalcemia (HR: 3.75, p < 0.001) were poor prognostic factors for OS in CRC patients with BM Median survival time from diagnosis of BM from CRC: 5.0 months 1-year survival rate: 30.0 % Park et al.,2020 11 11,551 CRC patients including 321 with BM Multivariate analysis Multiple organ metastasis (HR: 2.43), peritoneal metastasis (HR: 1.47), NLR ≥ 2.7 (HR: 1.54) and ALP ≥ 123 (HR:1.76) were independent factors for OS. Patients with low levels of NLR or ALP presented with prolonged survival compared to patients with high levels of NLR or ALP (mOS, NLR: 12.2 months vs. 5.6 months, p < 0.001; ALP: 11.2 months vs. 5.2 months, p < 0.001) mOS: 8 months Palliative chemotherapy extended survival in CRC patients with BM (HR: 0.25). mOS of isolated bone metastases patients: 20.4 months patients with peritoneal metastasis presented with shorter survival (mOS: 9.2 months vs. 4.3 months, p < 0.001) Karabulut et al., 2024 24 150 CRC patients with BM Multivariate analysis Right-sided colon cancer (p = 0.02), brain metastases (p = 0.01), high CA19-9 and ALP levels (p = 0.04, p < 0.001, respectively) were indicators of poor prognosis Median survival time from BM diagnosis: 8.3 months 3-year survival rate: 76.9 % Li X et al., 2021 32 381 CRC patients with synchronous BM Multivariate Cox regres- sion analysis A nomogram was constructed to predict OS in CRC patients with BM based on the following prognostic factors: Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, liver metastasis and lung metastasis. The newly developed nomogram showed good predictive performance in internal validation (C-index: 0.72, 95 % CI: 0.69–0.75), while external validation yielded a lower C-index of 0.57 (95 % CI: 0.46–0.68). T1/T2 stage was an unfavourable prognostic factor (HR = 1.510, p = 0.006), with patients exhibiting significantly shorter survival compared to those with T3/T4 stage tumors (7.0 vs 10.0 months, p = 0.031). The prognosis of synchronous bone metastases in CRC patients was poor (mOS: 9 months). No chemotherapy and brain metastases were associated with poor survival (mOS: 2.0–3.0 months). This nomogram estimates 0.5 to 1 year survival outcomes, however more research is needed to applicability of this model. Li et al., 2023 30 178 CRC patients with BM multivariable cox regression mode N staging, site of BM, and primary tumor sidedness (PTS). PTS and N staging could be potential prognostic markers for BM in CRC patients. Right-sided CRC patients with BM had a poorer prognosis and N0 stage CRC with BM showed better prognosis.
Table 1
Survival of CRC patients with BM.
| Study | Type of study | Number of patients | Survival | Findings |
| Liu et al., 2016 7 | Retrospective study | 242 | Median survival time after diagnosis of BM in CRC patients: 15.6 months (95 % CI, 12.74–18.46 months) | Median survival time of patients with Isolated bone metastases was remarkably longer than that of patients with BM and visceral metastases (29.1 vs 12.8 months, p = 0.003). |
| Kawamura et al.,2018 9 | Retrospective study | 129 | Median survival time after diagnosis of BM in CRC patients: 5.0 months (95 %CI, 4.0–9.0 months) 1-year survival rate: 30.0 % (95 % CI, 21.1 %-39.4 %) | |
| Baek et al., 2016 34 | Retrospective study | 63 | OS: 17.8 months 3-year survival rate: 25.4 % 5-year survival rate: 5.7 % | |
| Nozue et al., 2002 35 | Retrospective study | 12 | OS: 5.5 months 1 year survival rate: 20–30 % | The most common causes of death in CRC patients with BM are pulmonary failure (n = 7), liver failure (n = 1), and DIC (n = 1). |
| Suresh Babu et al., 2017 18 | Retrospective study | 10 | mOS: 22 months (no extraosseous involvement) vs 3 months (with extraosseous metastases), P = 0.008 mOS was significantly higher in patients without extraosseous involvement (22 months vs. 3 months). mOS for patients without liver metastases was significantly higher survival compared to those with extraosseous involvement excluding the liver (18 months vs. 3 months) | CRC patients with BM without extraosseous metastases had better survival outcomes. Extraosseous and liver involvement were linked to reduced survival in patients with Bm. Unsignificant trend towards lo longer survival in men (10 vs 3 months, p = 0.058) and patients without vertebral involvement (3 vs. 10 months, p = 0.082) |
| Ma et al., 2020 33 | Retrospective study | 201 | Median cancer-specific survival (cancer specific survival): 11 months for both synchronous and metachronous BM. | Synchronous BM is often more aggressive |
Table 2
Prognosis and risk factors for BM in CRC patients.
| Study | Number of patients | Type of analysis | Factors associated with prognosis in CRC patients with BM | Other findings |
| Liu et al., 2016 7 | 242 CRC patients with BM Isolated bone metastases group (n = 52) | Multivariate analysis | Isolated bone metastases group: high ALP ≥ 150 U/L (HR: 3.342, p = 0.037) and perineural invasion with of primary cancer (HR:3.457, p = 0.022) were factors of poor prognosis For CRC patients with BM: high CEA level was a poor prognosis factor (HR: 3.300, p < 0.001) and single isolated bone metastases was associated with better prognosis than multiple BM (29.2 months vs 9.3 months, p = 0.008). | Median survival time: 15.6 months Median survival time of isolated bone metastases significantly higher than the BM & visceral metastases group: 29.1 vs 12.8 months (p = 0.003). Patients with BM & visceral metastases had equivalent prognosis to the isolated bone metastases group. Median survival time of high CEA group was 11.1 months vs 21.9 for normal CEA group (HR: 3.300, p < 0.001). Median survival time of isolated bone metastases group was 29.1 months vs 12.8 in the no isolated bone metastases group. Median survival time of high ALP in the isolated bone metastases group was 8.5 vs 29.1 months for the normal ALP group (HR: 3.342, p = 0.037). Median survival time of the isolated bone metastases group with positive perineural invasion was 9.3 months vs 29.2 months for the isolated bone metastases group with no perineural invasion (HR; 3.457, p = 0.022)‘. |
| Yaeger et al., 2015 23 | RAS WT mCRC with BM (n = 3, 0.6 %) RAS WT mCRC (n = 477) RAS Mutant mCRC (n = 441) RAS Mutant mCRC with BM (n = 4, 0.9 %) | Multivariate analysis | RAS mutation was identified as an independent predictor of BM (HR: 1.62, p = 0.012) after adjusting for age, tumor location, synchronous tumor, and diagnosis of lung metastasis. | mOS: 81 months for patients with RAS wild-type mCRC vs 47 months for patients with RAS mutant (p < 0.001) The cumulative incidence of RAS mutation 2 years after the diagnosis of metastatic CRC was linked to a higher incidence of bone (8.8 % vs 4.4 %, p = 0.024), lung (32.5 % vs 19 %, p = 0.001) and brain metastasis (1.4 % vs 0.2 %, p < 0.01) |
| Wang et al., 2021 28 | 725 mCRC patients including 274 patients with BM | Multivariate Cox regression analysis | The risk and prognostic nomogram for BM in CRC patients included the following factors: tumor differentiation, ALP, LDH number of extra-BM organs and the number of BM lesions with an R 2 of 0.284 and a C-statistic of 0.723 The number of extra-BM organs (p = 0.002, HR: 2.357) and LDH levels (p = 0.032, HR: 1.961) were significant prognostic factors for OS in CRC patients with BM | mOS: 8.6 months 6-month OS rate: 63.4 % 1-year OS rate: 32.7 % 2-year OS rate: 8.9 % Liver metastasis was a protective factor for BM (P < 0.05) This nomogram showed good performance as a potential screening tool for BM risk and prognosis in CRC patients |
| Kawamura et al.,2018 9 | 104 CRC patients with BM | Multivariate analysis | Two or more extra-bone metastatic organs (p < 0.001), pathological fracture (HR:1.91, p = 0.033) and hypercalcemia (HR: 3.75, p < 0.001) were poor prognostic factors for OS in CRC patients with BM | Median survival time from diagnosis of BM from CRC: 5.0 months 1-year survival rate: 30.0 % |
| Park et al.,2020 11 | 11,551 CRC patients including 321 with BM | Multivariate analysis | Multiple organ metastasis (HR: 2.43), peritoneal metastasis (HR: 1.47), NLR ≥ 2.7 (HR: 1.54) and ALP ≥ 123 (HR:1.76) were independent factors for OS. Patients with low levels of NLR or ALP presented with prolonged survival compared to patients with high levels of NLR or ALP (mOS, NLR: 12.2 months vs. 5.6 months, p < 0.001; ALP: 11.2 months vs. 5.2 months, p < 0.001) | mOS: 8 months Palliative chemotherapy extended survival in CRC patients with BM (HR: 0.25). mOS of isolated bone metastases patients: 20.4 months patients with peritoneal metastasis presented with shorter survival (mOS: 9.2 months vs. 4.3 months, p < 0.001) |
| Karabulut et al., 2024 24 | 150 CRC patients with BM | Multivariate analysis | Right-sided colon cancer (p = 0.02), brain metastases (p = 0.01), high CA19-9 and ALP levels (p = 0.04, p < 0.001, respectively) were indicators of poor prognosis | Median survival time from BM diagnosis: 8.3 months 3-year survival rate: 76.9 % |
| Li X et al., 2021 32 | 381 CRC patients with synchronous BM | Multivariate Cox regres- sion analysis | A nomogram was constructed to predict OS in CRC patients with BM based on the following prognostic factors: Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, liver metastasis and lung metastasis. The newly developed nomogram showed good predictive performance in internal validation (C-index: 0.72, 95 % CI: 0.69–0.75), while external validation yielded a lower C-index of 0.57 (95 % CI: 0.46–0.68). T1/T2 stage was an unfavourable prognostic factor (HR = 1.510, p = 0.006), with patients exhibiting significantly shorter survival compared to those with T3/T4 stage tumors (7.0 vs 10.0 months, p = 0.031). | The prognosis of synchronous bone metastases in CRC patients was poor (mOS: 9 months). No chemotherapy and brain metastases were associated with poor survival (mOS: 2.0–3.0 months). This nomogram estimates 0.5 to 1 year survival outcomes, however more research is needed to applicability of this model. |
| Li et al., 2023 30 | 178 CRC patients with BM | multivariable cox regression mode | N staging, site of BM, and primary tumor sidedness (PTS). PTS and N staging could be potential prognostic markers for BM in CRC patients. | Right-sided CRC patients with BM had a poorer prognosis and N0 stage CRC with BM showed better prognosis. |
Median cancer specific survival was both 11 months for patients with synchronous bone metastasis and metachronous bone metastasis. Synchronous bone metastases are usually more aggressive, but the similar median OS may be attributed to the fact that metachronous patients were already treated by chemotherapy for their primary lesion while synchronous bone metastasis patients were more likely to be chemotherapy naïve. Additionally, a retrospective study showed that CRC patients with synchronous and metachronous bone metastasis had better cancer specific survival (following primary tumor resection which is likely a result of the minimization of tumor-induced complications such as systemic inflammation, perforation hemorrhage and obstruction. However, survival advantage was unlikely with targeted therapy in both metachronous and synchronous bone metastasis [ 33 ].
There was a non-significant trend toward longer OS in males (10 vs 3 months, p = 0.058) and in patients without vertebral involvement (3 vs. 10 months, P = 0.082). Vertebral involvement is linked to poor prognosis due to its potential to cause spinal compression, increase the risk of pathological fractures, its proximity to vital organs, and its association with more aggressive disease [ 18 ].
Management ( Table 3 )
Treatment choices for metastatic CRC are guided by therapy goals, treatment toxicity and the tumor’s mutational profile. Chemotherapy regimens consisting of fluoropyrimidine, oxaliplatin, and/or irinotecan are widely used in metastatic CRC, sometimes in combination with targeted therapy, depending on the tumor biomarkers [ 36 ].
Currently, available effective treatments for bone metastasis in CRC patients are limited. Therapeutic options include bisphosphonates to reduce SREs, systemic chemotherapy for tumor control, and radiotherapy or surgery for symptom management, as well as analgesic agents. A clear gap exists, as there is no effective chemotherapy specifically targeting bone metastasis lesions, highlighting the need for early detection [ 28 ] Table 3 . Table 3 Treatment options for CRC patients with BM. Study Type of study Number of patients Treatment Outcome Kawamura et al., 2018 9 Retrospective study 104 CRC patients with BM Chemotherapy group (n = 47) Radiotherapy group(n = 66) Chemotherapy after BM diagnosis showed a median OS of 5 months and 1 year survival rate of 30 % Radiotherapy is associated with improved survival (median OS: 7 months) Rahbari et al., 2024 37 RCT 393 patients with synchronous visceral unresectable metastases Primary tumour resection + chemotherapy group (n = 187) Chemotherapy alone group (n = 206) Primary tumour resection before chemotherapy did not show significant improvement in OS compared to chemotherapy alone (16.7 months vs 18.6 months; P = 0.191) SAEs were more common in the no primary tumour resection compared to the primary tumour resection group (18.0 % vs 10.2 %; P = 0.027) Aliseda et al., 2024 38 Systematic review and meta -analysis 2120 patients with locally advanced CRC Neoadjuvant chemotherapy group Tumour resection group Non-metastatic CRC patients presented with better survival after receiving Neoadjuvant chemotherapy (5-year OS: 79.9 % vs 72.6 %; P < 0.001) and disease-free survival rates (73.1 % vs 64.5 %;P = 0.028) No significant difference was found between the two groups in terms of perioperative mortality (OR: 0.97), overall complications (OR: 0.95,), anastomotic leakage and intra-abdominal abscess. Liu et al., 2016 7 Retrospective cohort study 242 CRC patients with BM Chemotherapy (n = 171) Bisphosphonate (n = 108) Radiotherapy (n = 172) Median survival time of the isolated bone metastases group was remarkably longer than te Median survival time of BM& visceral metastases group (29.1 vs 12.8 months, p = 0.003) In CRC patients with BM + visceral metastases systemic chemotherapy was recommended as a first line treatment. In isolated bone metastases patients, radiotherapy + bisphosphonates were recommended to control pain, but it did not improve survival. Park et al., 2020 11 Retrospective study 11,551 CRC patients including 231 with BM Palliative chemotherapy group (n = 212) No palliative chemotherapy group (n = 109) isolated bone metastases subgroup (n = 28) Palliative chemotherapy offered extended OS compared to radiotherapy (median OS: 6.7 vs 4.3 months, P < 0.001) Palliative chemotherapy was associated with better survival in CRC patients with concurrent BM and visceral metastases and did not show survival benefit in the isolated bone metastases subgroup. Ma et al., 2020 33 Retrospective cohort study 201 patients CRC + synchronous bone metastases (n = 63) CRC + metachronous bone metastases (n = 138) Bisphosphonates in synchronous bone metastases (n = 25) Bisphosphonates in metachronous bone metastases (n = 61) Radiotherapy in synchronous bone metastases (n = 14) Radiotherapy in metachronous bone metastases (n = 43) Patients receiving radiotherapy presented with improved cancer specific survival in the metachronous bone metastases group compared to patients who did not receive radiotherapy (18 vs 10 months, P < 0.001) Bisphosphonates use was linked to better cancer specific survival in synchronous bone metastases compared to patients who did not receive bisphosphonates (16 vs 9 months, P < 0.001) Santini et al., 2012 13 Retrospective study 264 CRC patients with BM Zoledronic acid (n = 126) No data of bisphosphonates use (n = 107) No intravenous bisphosphonates (n = 31) mOS: 7 months Zoledronic acid administration increased median time to first SRE (2 vs 1 months, P = 0.0009) and was linked to toward better survival (mOS:10) compared to patients who did not receive zoledronic acid (mOS: 6 months) Heras et al., 2007 41 Clinical trial 73 CRC patients with BM Intravenous Ibandronate Ibandronate reduced SREs (39 % vs. 78 %; P = 0.019), extended the time to the first SRE by at least 6 months, reduced skeletal morbidity rate (2.36 vs 3.14; P = 0.018) and extended the time to bone lesion progression (214 days vs 81 days; P = 0.018) SAEs: very rare grade 3 or 4 toxicity Rangel Jaimes et al., 2022 44 Case report Intrathecal neurolysis Remarkable pain relief following an intrathecal neurolytic block using 96 % absolute alcohol at the intervertebral space (L5-S1) with reduction of opioids use in a CRC patient with sacral BM No neurological impairment or complications were found following this procedure CEA: carcinoembryonic antigen. ALP: alkaline phosphatase. RCT: randomized control trial. OS: overall survival. SAEs: severe adverse events. BM: bone metastases. CRC: colorectal cancer. SREs: skeletal related events. OS: overall survival. NLR: neutrophil-to-lymphocyte ratio.
Table 3
Treatment options for CRC patients with BM.
CEA: carcinoembryonic antigen. ALP: alkaline phosphatase. RCT: randomized control trial. OS: overall survival. SAEs: severe adverse events. BM: bone metastases. CRC: colorectal cancer. SREs: skeletal related events. OS: overall survival. NLR: neutrophil-to-lymphocyte ratio.
| Study | Type of study | Number of patients | Treatment | Outcome |
| Kawamura et al., 2018 9 | Retrospective study | 104 CRC patients with BM | Chemotherapy group (n = 47) Radiotherapy group(n = 66) | Chemotherapy after BM diagnosis showed a median OS of 5 months and 1 year survival rate of 30 % Radiotherapy is associated with improved survival (median OS: 7 months) |
| Rahbari et al., 2024 37 | RCT | 393 patients with synchronous visceral unresectable metastases | Primary tumour resection + chemotherapy group (n = 187) Chemotherapy alone group (n = 206) | Primary tumour resection before chemotherapy did not show significant improvement in OS compared to chemotherapy alone (16.7 months vs 18.6 months; P = 0.191) SAEs were more common in the no primary tumour resection compared to the primary tumour resection group (18.0 % vs 10.2 %; P = 0.027) |
| Aliseda et al., 2024 38 | Systematic review and meta -analysis | 2120 patients with locally advanced CRC | Neoadjuvant chemotherapy group Tumour resection group | Non-metastatic CRC patients presented with better survival after receiving Neoadjuvant chemotherapy (5-year OS: 79.9 % vs 72.6 %; P < 0.001) and disease-free survival rates (73.1 % vs 64.5 %;P = 0.028) No significant difference was found between the two groups in terms of perioperative mortality (OR: 0.97), overall complications (OR: 0.95,), anastomotic leakage and intra-abdominal abscess. |
| Liu et al., 2016 7 | Retrospective cohort study | 242 CRC patients with BM | Chemotherapy (n = 171) Bisphosphonate (n = 108) Radiotherapy (n = 172) | Median survival time of the isolated bone metastases group was remarkably longer than te Median survival time of BM& visceral metastases group (29.1 vs 12.8 months, p = 0.003) In CRC patients with BM + visceral metastases systemic chemotherapy was recommended as a first line treatment. In isolated bone metastases patients, radiotherapy + bisphosphonates were recommended to control pain, but it did not improve survival. |
| Park et al., 2020 11 | Retrospective study | 11,551 CRC patients including 231 with BM | Palliative chemotherapy group (n = 212) No palliative chemotherapy group (n = 109) isolated bone metastases subgroup (n = 28) | Palliative chemotherapy offered extended OS compared to radiotherapy (median OS: 6.7 vs 4.3 months, P < 0.001) Palliative chemotherapy was associated with better survival in CRC patients with concurrent BM and visceral metastases and did not show survival benefit in the isolated bone metastases subgroup. |
| Ma et al., 2020 33 | Retrospective cohort study | 201 patients CRC + synchronous bone metastases (n = 63) CRC + metachronous bone metastases (n = 138) | Bisphosphonates in synchronous bone metastases (n = 25) Bisphosphonates in metachronous bone metastases (n = 61) Radiotherapy in synchronous bone metastases (n = 14) Radiotherapy in metachronous bone metastases (n = 43) | Patients receiving radiotherapy presented with improved cancer specific survival in the metachronous bone metastases group compared to patients who did not receive radiotherapy (18 vs 10 months, P < 0.001) Bisphosphonates use was linked to better cancer specific survival in synchronous bone metastases compared to patients who did not receive bisphosphonates (16 vs 9 months, P < 0.001) |
| Santini et al., 2012 13 | Retrospective study | 264 CRC patients with BM | Zoledronic acid (n = 126) No data of bisphosphonates use (n = 107) No intravenous bisphosphonates (n = 31) | mOS: 7 months Zoledronic acid administration increased median time to first SRE (2 vs 1 months, P = 0.0009) and was linked to toward better survival (mOS:10) compared to patients who did not receive zoledronic acid (mOS: 6 months) |
| Heras et al., 2007 41 | Clinical trial | 73 CRC patients with BM | Intravenous Ibandronate | Ibandronate reduced SREs (39 % vs. 78 %; P = 0.019), extended the time to the first SRE by at least 6 months, reduced skeletal morbidity rate (2.36 vs 3.14; P = 0.018) and extended the time to bone lesion progression (214 days vs 81 days; P = 0.018) SAEs: very rare grade 3 or 4 toxicity |
| Rangel Jaimes et al., 2022 44 | Case report | Intrathecal neurolysis | Remarkable pain relief following an intrathecal neurolytic block using 96 % absolute alcohol at the intervertebral space (L5-S1) with reduction of opioids use in a CRC patient with sacral BM No neurological impairment or complications were found following this procedure |
1- Chemotherapy ( Fig. 2. )
The impact of chemotherapy and radiotherapy for bone metastasis in CRC patient is understudied [ 12 ]. A Japanese retrospective study (n = 104) showed a median survival time of 5 months and 1-year survival rate of 30 % in CRC patients who received chemotherapy after bone metastasis diagnosis [ 9 ]. In contrast, a recent RCT (n = 393) for CRC patients with synchronous unresectable visceral metastases showed better survival with a median OS of 16.7 months for patients who underwent a primary tumor resection followed by chemotherapy compared to 18.6 months for patients who received chemotherapy alone [ 37 ]. Additionally, a meta -analysis (n = 2120) found that neoadjuvant chemotherapy improved survival in patients with non-metastatic CRC (5-year OS = 79.9 %) [ 38 ]. Systemic chemotherapy was recommended as a first-line treatment for CRC patients with bone metastasis and visceral metastasis ( Fig. 2. ). One analysis (n = 242) determined that systemic chemotherapy prolonged survival, however it does not produce survival benefits in the group of patients with isolated bone metastasis. Thus, improved survival after systemic chemotherapy may apply only to CRC patients with concurrent visceral and bone metastases [ 7 ]. Since bone metastasis in CRC is known for its poor prognosis, palliative chemotherapy offers better survival for these patients. In a retrospective study (n = 11,551), CRC patients with bone metastasis treated with palliative chemotherapy presented with an extended OS (16.7 months) compared to those receiving only optimal supportive care such as radiotherapy (4.3 months) in the low-risk group. Additionally, the survival benefit was less important in the high-risk group. Consequently, the potential benefit of chemotherapy for bone metastasis patients from CRC highlights a critical gap; the need for predictive biomarkers to guide treatment decisions [ 11 ]. A recent study (n = 178) found that high expression of heat shock protein 47 (SERPINH1) was linked to poor survival. This novel biomarker was not predictive of chemotherapy response but could be a potential target for new therapeutic agents in CRC patients with bone metastasis [ 39 ].
2- Radiotherapy and bisphosphonates
The role of radiotherapy in managing bone metastasis is debated. A combination of radiotherapy and bisphosphonate was recommended for isolated bone metastasis patients to control pain from bone metastasis, given the limited efficacy of chemotherapy [ 7 ] ( Fig. 2. ). Another study on patients with bone metastasis found that radiotherapy should be recommended to all bone metastasis patients with poor prognosis to reduce pain and improve QoL [ 40 ] ( Fig. 2. ) . Additionally, one study (n = 104) found radiotherapy prolong OS [ 9 ]. However, the evidence is conflicting. A study by Liu et al. (n = 242) determined that radiotherapy and bisphosphonates did not improve survival in CRC patients with bone metastasis [ 7 ]. Furthermore, the use of bisphosphonates in CRC patients with synchronous bone metastasis was linked to an improved cancer specific survival, suggesting a difference between bisphosphonates sensitivity compared to metachronous bone metastasis. Radiotherapy in metachronous bone metastasis patients was associated with better cancer specific survival compared to synchronous bone metastasis (18 vs 11 months) [ 33 ].
Bisphosphonates work by binding to osteolytic lesions, preventing cluster formation, activating osteophages, and blocking osteolysis[ 34 ]. An Italian multicenter retrospective study (n = 264) found that the administration of zoledronic acid in CRC patients with bone metastasis increased the median time to first SRE (2 vs 1 month) and created a trend toward better OS than seen in patients who did not receive zoledronic acid [ 13 ]. Similarly, a clinical trial (n = 73) found that intravenous ibandronate, a single-nitrogen bisphosphonate significantly reduced SRE incidence (39 % vs. 78 %), morbidity and extended the time to bone lesion progression (214 vs. 81 days), and increased the time to the first SRE (≥6 vs. 3 months) compared to patients who did not receive ibudronate [ 41 ] ( Fig. 2. ). . In addition, a single CRC patient case with refractory bone metastasis pain experienced an initial pain relief after receiving intravenous pamidronate, but efficacy declined progressively, highlighting the need for further adjustments in pain management strategies for CRC patients with bone metastasis [ 42 ].
3- Opioids and intrathecal neurolysis
In a Japanese retrospective study, an increase in the use of opioids (oxycodone , fentanyl , morphine and tramadol) was observed in bone metastasis patients after experiencing SREs, underscoring symptoms severity and the increasing need for opioids responsible for pain relief [ 43 ].
A case report of a CRC patient with sacral bone metastases who had severe refractory pain despite opioids use underwent intrathecal neurolytic block at the intervertebral space (L5-S1) using 96 % absolute alcohol, resulting in a considerable pain relief and decrease in opioids consumption with no neurological side effects. This procedure can potentially be used as a substitute for refractory pain management in CRC patients with bone metastasis [ 44 ]. Despite its advantage in providing immediate analgesia and pain control in cancer patients, this technique has not been evaluated in any randomized controlled trials, highlighting a knowledge gap since the literature consists only of observational studies and case reports [ 45 ].
4- surgical intervention
Several studies showed that surgery in CRC patients with bone metastasis is primarily palliative. However, there is a lack of knowledge in the literature regarding this topic due to the rarity and limited indications of the surgical approach in bone metastasis patients with CRC. Indications typically involve managing complications such as impending or pathologic fractures to the long bones (femur, humerus, tibia), or solitary spinal metastases with acute neurological compromise such as spinal compression, requiring decompression and stabilization. A small retrospective study (n = 36) found that CRC patients with bone metastasis needing surgical treatment presented with a mean survival of 6 month with only 10 % of patients surviving after a year, and with a worse prognosis than CRC patient with bone metastasis who did not need surgery. However, post- operative local and systemic complications were common (30 %), and the surgical failure rate was important [ 46 ]. The Mirels score is a widely used tool for assessing fracture risk in long bones with metastatic lesions, and this score often informs the decision to operate [ 47 ]. Procedures such as vertebroplasty and kyphoplasty can be employed to treat spinal metastasis, providing pain relief from vertebral compression fractures [ 20 ]. The three main surgeries for bone metastasis are preventive osteosynthesis, osteosynthesis to stabilize a fracture, reconstruction and resections based on the patient’s presentation. A preoperative multidisciplinary evaluation is crucial for determining candidates for surgical treatment. On the other hand, single bone metastases, whether in the pre-fracture stage or with an associated fracture, should be treated with extensive resections and reconstructions to significantly improve survival. Similarly, osteosynthesis or reconstruction should be considered in bone metastasis patients with a pathological fracture [ 48 ].
Conclusion
Bone metastasis in CRC are often associated with metastases to other organs mostly the liver. However, in some cases, bone metastasis can be detected earlier due to its symptomatology, most frequently presenting with severe bone pain, considerably impairing patients’ quality of life. Addressing this challenge through adequate pain management, including radiotherapy for symptomatic relief, is crucial for improving patient quality or life. Bisphosphonates play an important role in the prevention and delay of SREs, making all patients with a confirmed bone metastasis diagnosis potential candidates for bisphosphonates therapy. The evidence particularly supports their use in patients with isolated bone metastasis and those with synchronous bone metastasis, where they have been linked to improved cancer specific survival and reduced SRE-related events. Surgery also has a palliative role, specifically in stabilizing fractures or spinal decompression but lacks high-level comparative evidence against non-surgical management.
Several biomarkers (CEA, CA 19-9, and ALP) correlate with poorer outcomes and can be used for diagnosis, prognosis and disease monitoring. Other factors like PNI, tumor sidedness and nodal staging were found to be a potential prognostic factor, however additional investigation is needed.
Combining these laboratory markers with imaging, favorably PET/CT scan help in early detection and treatment planning for bone metastasis patients with CRC. There is a strong link between lung and bone metastases which lead to consider lung metastases as a primary risk factor for developing bone metastasis. Therefore, based on this key clinical finding, we strongly recommend that clinicians consider routine bone imaging for all CRC patients diagnosed with lung metastases to screen for synchronous bone metastasis, even in asymptomatic patients, which may lead to earlier intervention and potentially improve patients’ outcomes.
Synchronous and metachronous bone metastasis present different prognosis and distinct management approaches. Differentiating between these two groups is essential to guide targeted treatment and improve patient outcomes.
Systemic chemotherapy was only recommended in CRC patient with concurrent bone metastasis and visceral metastases, with no benefit to isolated bone metastasis patients. Since palliative chemotherapy may extend survival, a critical gap remains in identifying predictive biomarkers for chemotherapy response to improve patient care.
Understanding bone metastasis in CRC is significant impact on survival and quality of life is essential. This review highlights critical knowledge gaps—such as the need for predictive chemotherapy biomarkers, clearer understanding of prognostic factors like PNI/T-stage, and lack of high-level evidence for interventions like intrathecal neurolysis—that must guide future research. Further research is essential to develop and validate novel nomograms that could be used to predict prognosis, personalize management, optimize treatment strategies and improve patient outcomes.
Limitations
Finally, the non-systematic nature for data collection in this comprehensive narrative review is a fundamental limitation. While a broad, balanced and date-unrestricted search was conducted in the process of selecting the studies, this review is still subject to the author’s selection bias.
CRediT authorship contribution statement
Lea Hatoum: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Rita El Murr: Writing – original draft, Data curation. Ahmad Assi: Writing – review & editing, Supervision, Conceptualization. Rami Mohanna: Visualization, Software, Conceptualization. Amer Sebaaly: Writing – review & editing, Supervision, Project administration, Conceptualization. Hampig-Raphaël Kourie: Writing – review & editing, Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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