Skeletal metastases occur in approximately 80% of advanced breast, 70% of advanced prostate, and 30% of lung cancers, and place patients at increased risk of skeletal related events (SRE). Bone modifying agents (BMAs) have been shown to prevent or delay SRE development. Our objective was to summarize the role of these agents in the management of these three cancers.

Total 52 studies met our inclusion criteria. These highlighted the benefit of BMAs in reducing SREs in metastatic breast and castrate resistant prostate cancer (mCRPC), with less clear impact on reducing SRE in lung cancer, or on improving progression-free and overall survival due to significant heterogeneity in trial design and outcomes. Benefits in SRE reduction occurred with bisphosphonates and denosumab, however when compared, denosumab was superior. Denosumab however is not more cost effective, and multiple trials support potential de-escalation to either 12 weekly dosing or other reduced duration.

There is a large body of evidence to support the role of BMAs in reducing SREs in metastatic breast and mCRPC. Impact on survival outcomes is heterogeneous, and future large database trials would be helpful in identifying which subgroups of patients truly have survival benefit from BMAs.

Bone is a common secondary site of dissemination during the course of cancer. Bone metastases (BM) can be associated with skeletal-related events (SRE) such as disabling pain, hypercalcemia, and bone instability that leads to pathological fractures or spinal cord compression. SRE contribute to high morbidity as well as, mortality, and have a negative economic impact. Modern management of BM integrates focal treatments (such as radiotherapy, surgery, and interventional radiology), orthoses, and antiresorptive and systemic oncological treatment. The choice of a metastasis-directed therapy depends on the objective of the treatment, the patient characteristics, and the complete assessment of the bone lesion (pain, neurological risk, and instability). In the narrative review present herein, we aim to provide an updated summary of the literature, with description of the advantages and disadvantages of current and emerging strategies in the multimodal treatment of BM and, based on these data, an updated algorithm for the management of BM.

Osteoclasts are specialized cells that degrade the bone matrix to create space for bone regeneration. During tumorigenesis, cancer cells metastasize to bone by disrupting bone's natural remodeling cycle. However, the mechanisms underlying critical bone-tumor interactions are poorly understood due to challenges in isolating osteoclasts from human bone. Thus, the conventional method to obtain osteoclasts for in vitro studies is via the differentiation of peripheral blood monocytes, which results in mixed cultures containing progenitor cells and osteoclasts of varying maturity and nuclearity. Presently, we hypothesized that the transcriptomic signatures of mature, multinucleated osteoclasts are distinct from osteoclasts with fewer nuclei. We established a live cell biomarker expression-based sorting protocol to allow purification of mature osteoclasts while maintaining viability and function. We observed that mature, multinucleated osteoclasts were transcriptomically distinct from those with fewer nuclei and that mature osteoclasts showed higher expression of genes that are associated with osteoclast fusion and function.

Bone metastasis is associated with a poor prognosis. Bone-modifying agents (BMA) are commonly used for the prevention or treatment of skeletal-related events (SRE) in patients with bone metastasis; however, whether or not treatment with BMA improves survival remains unclear. In this study, we investigated whether BMA was involved in post-bone metastasis survival.

A total of 539 cancer patients were retrospectively analyzed to identify significant independent factors in post-bone metastasis survival.

Among the overall population, patients with the following cancers had a median survival longer than 24 months: thyroid, 97.2 months; breast, 51.5 months; prostate, 47.2 months; and kidney, 38.8 months. In contrast, median post-bone metastasis survival was significantly shorter in gastrointestinal (GI) (6.5 months), head and neck (6.3 months), and urinary tract (3.4 months) cancers. In non-small cell lung cancer (NSCLC), the log-rank test demonstrated that the epidermal growth factor receptor (EGFR) mutation was a significant factor for post-bone metastasis survival: EGFR mutation (-) n = 67, median post-bone metastasis survival 11.5 months (95% CI: 6.0-15.2); EGFR mutation (+) n = 39, median post-bone metastasis survival 28.8 months (95% CI: 18.1-35.7) (p < 0.05). Intriguingly, treatment with BMA was a significant positive prognostic factor: BMA (-) n = 203, median post-bone metastasis survival 7.8 months (95% CI: 5.8-12.5); BMA (+) n = 336, median post-bone metastasis survival 21.9 months (95% CI: 16.1-26.4) (p < 0.001). Moreover, the Cox proportional hazards model showed that this was particularly evident in cancer types with poor prognosis such as GI cancer (hazard ratio [HR]: 0.62, 95% CI: 0.40-0.95; p < 0.05) and NSCLC without the epidermal growth factor receptor (EGFR) mutation (HR: 0.56, 95% CI: 0.34-0.91; p < 0.05).

Treatment with BMA is recommended not only for the prevention and/or treatment of SRE, but also may have a positive impact on post-bone metastasis survival, particularly in cancers with typically poor post-bone metastasis survival such as GI cancer and NSCLC without the EGFR mutation.

Background: The prognosis for patients with lung cancer bone metastases has improved with the use of novel systemic agents. These patients might need surgery or radiotherapy to alleviate symptoms or maintain function. However, there is currently no disease specific algorithm to guide multidisciplinary decisions. Methods: The inclusion criteria encompassed studies with ≥10 patients offering multivariate analysis data on survival that were published after 2000 until September 2023. Clinical factors were categorized based on their characteristics and the pooled hazard ratios (HRs) for each category were calculated. A treatment algorithm was proposed based on clinical importance and the pooled HRs. Results: Fifteen studies involving 3759 patients with lung cancer bone metastases were included. The median survival ranged between 1.8-28.3 months (median: 12.4). Among the studies involving patients with EGFR+ or treated with TKIs, the median survival ranged between 19.5-28.3 months. The most reported significant factor was ECOG performance (nine studies) followed by chemotherapy use (six studies). In the pooled analyses, the pooled HR [95% confidence interval (CI)] of the EGFR status category was 2.109 (1.345-3.305); the ECOG performance category was 2.007 (1.536-2.622); the visceral metastases category was 2.060 (1.370-3.098); the bone metastases characteristics category (e.g., multiplicity, weight-bearing bone metastases) was 1.910 (1.443-2.527); the body weight category was 1.805 (1.334-2.442); the anti-absorbants category was 1.784 (1.448-2.196); the systemic treatment category was 1.695 (1.407-2.041); the skeletal-related event category was 1.616 (1.063-2.458); the smoking status category was 1.530 (1.306-1.793); the gender category was 1.482 (1.270-1.729); and the histology category was 1.450 (1.186-1.772). Conclusions: Oncological prognoses are influenced by various interrelated factors. Our treatment algorithm supports multidisciplinary strategies for managing NSCLC bone metastases, considering the complex factors influencing prognosis.

Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.

In recent years, the integration of immunotherapy in the treatment of lung cancer has marked a significant evolution in the field. This is evidenced by the surge in the volume of scientific publications, reflecting rapid advances over time. This paper presents a bibliometric analysis of lung cancer and immunotherapy research from January 2012 to December 2022, drawing on the Web of Science literature database and using the citexs data analysis platform to examine the shifts in topic hotspots over the decade. A total of 8,722 publications were retrieved, with annual publication numbers soaring from 79 in 2012 to 2,112 in 2021. The most prolific country in terms of publication volume was China (n = 3,363, 38.56%), with The University of Texas MD Anderson Cancer Center making the most significant institutional contribution (n = 156, 1.79%). Notably, the most productive authors in this domain were Benjamin Besse and Marina Chiara Garassino, who have collectively published 35 articles to date. Predominant research themes include PD1/PDL1, clinical trials, pembrolizumab, nivolumab, and immune checkpoint inhibitors. Moreover, this paper visualizes the analysis of journals, keywords, key genes and targets, and associated diseases, aiming to provide a systematic review and a forward-looking perspective on research in lung cancer and immunotherapy. By exploring current research dynamics and hotspots and identifying areas for improvement, this study seeks to provide valuable insights for future investigations in this burgeoning field.

The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen.

Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated.

The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors.

Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Breast cancer (BC) remains a significant health concern, particularly in advanced stages where the prognosis is poor. The combination of endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has improved outcomes for advanced BC (aBC) patients. However, resistance to CDK4/6i remains a challenge, with no validated biomarkers to predict response. The receptor activator of the nuclear factor-kB (RANK) pathway has emerged as a key player in aBC, particularly in luminal BC. RANK overexpression has been associated with aggressive phenotypes and resistance to therapy. In view of these findings, we proceeded to investigate the potential involvement of the RANK pathway in luminal BC resistance to CDK4/6i. The objective was to evaluate the effectiveness of denosumab in increasing overall survival (OS) and progression-free survival (PFS).

In this retrospective analysis, 158 BC patients with bone metastases were included. Patients with human epidermal growth factor receptor-2 (HER2)-negative and hormone receptor-positive BC who received palbociclib or ribociclib in addition to antiresorptive medication were included. Patients received either denosumab or zoledronic acid (ZA) therapy. The primary endpoint was OS, with PFS as a secondary endpoint.

Although the PFS and OS of denosumab were better than ZA in this study, it did not show a significant difference between the two drugs. Meanwhile, mOS was not achievable in patients in the denosumab group, while it was 34.1 months in patients in the ZA group. The hazard ratio (HR) showed a significant improvement for the denosumab group in patients under 60 of age (HR: 0.33, p<0.01), patients with a score of 1 HER2 overexpression (HR: 0.09, p=0.01), and patients with resistant endocrine (HR: 0.42, p=0.02) compared to ZA.

This study highlights the potential clinical relevance of the RANK pathway in BC treatment, and our findings suggest that denosumab may offer significant benefits in terms of PFS and OS for certain subgroups, particularly those with HER2 scores of 1, patients under 60, and those with endocrine-resistant BC. In conclusion, considering that RANK pathway status may be a predictive biomarker for CDK4/6i treatment and may cause treatment resistance, our results demonstrate the clinical relevance of the combination of CDK4/6i + ET with RANKL inhibition.

Hepatocellular carcinoma (HCC), commonly known as primary liver cancer, is a major cause of malignant tumors and cancer-related deaths in China, accounting for approximately 85% of all cancer cases in the country. Several guidelines have been used to diagnose and treat liver cancer. However, these guidelines provide a broad definition for classifying advanced liver cancer, with an emphasis on a singular approach, without considering treatment options for individual patients. Therefore, it is necessary to establish a comprehensive and practical expert consensus, specifically for China, to enhance the diagnosis and treatment of HCC using the Delphi method. The classification criteria were refined for Chinese patients with HCC, and the corresponding optimal treatment regimen recommendations were developed. These recommendations took into account various factors, including tumor characteristics, vascular tumor thrombus grade, distant metastasis, liver function status, portal hypertension, and the hepatitis B virus replication status of patients with primary HCC, along with treatment prognosis. The findings and recommendations provide detailed, scientific, and reasonable individualized diagnosis and treatment strategies for clinicians.

The juxtaposition of two seemingly disparate physiological phenomena within the human body-namely, cancer and pregnancy-may offer profound insights into the intricate interplay between malignancies and the immune system. Recent investigations have unveiled striking similarities between the pivotal processes underpinning fetal implantation and successful gestation and those governing tumor initiation and progression. Notably, a confluence of features has emerged, underscoring parallels between the microenvironment of tumors and the maternal-fetal interface. These shared attributes encompass establishing vascular networks, cellular mobilization, recruitment of auxiliary tissue components to facilitate continued growth, and, most significantly, the orchestration of immune-suppressive mechanisms.Our particular focus herein centers on the phenomenon of immune suppression and its protective utility in both of these contexts. In the context of pregnancy, immune suppression assumes a paramount role in shielding the semi-allogeneic fetus from the potentially hostile immune responses of the maternal host. In stark contrast, in the milieu of cancer, this very same immunological suppression fosters the transformation of the tumor microenvironment into a sanctuary personalized for the neoplastic cells.Thus, the striking parallels between the immunosuppressive strategies deployed during pregnancy and those co-opted by malignancies offer a tantalizing reservoir of insights. These insights promise to inform novel avenues in the realm of cancer immunotherapy. By harnessing our understanding of the immunological events that detrimentally impact fetal development, a knowledge grounded in the context of conditions such as preeclampsia or miscarriage, we may uncover innovative immunotherapeutic strategies to combat cancer.

Immune checkpoint inhibitors (ICIs) have left a deep impression in the treatment of non-small cell lung cancer (NSCLC), however, not all patients benefit from it. The purpose of this study was to investigate the prognostic value of baseline bone mineral density (BMD) derived from chest computed tomography (CT) scans in NSCLC patients treated with ICIs.

This study included patients with advanced NSCLC who underwent ICI treatment at the Wuhan Union Hospital from March 2020 to October 2022. Baseline BMD was evaluated at non-contrast chest CT at the level of first lumbar vertebra. Patients were divided into BMD-lower group and BMD-higher group according to the optimal cutoff value calculated by X-tile software. Baseline characteristics of the two groups were compared and variables between the two groups were balanced by propensity score matching (PSM) analysis. We calculated the objective response rate (ORR) and disease control rate (DCR) of the two groups and analyzed overall survival (OS) and progression-free survival (PFS) using BMD and other clinical indexes through Cox regression models and Kaplan-Meier survival curves.

A total of 479 patients were included in this study, and all patients were divided into BMD-lower group (n=270) and BMD-higher group (n=209). After PSM analysis, each group consisted of 150 patients. ORR (43.3% vs. 43.5% before PSM, P = 0.964; 44.7% vs. 44.7% after PSM, P = 1.000) and DCR (91.1% vs. 94.3% before PSM, P = 0.195; 93.3% vs. 96.7% after PSM, P =0.190) were similar in two groups. There was no statistically significant relationship between BMD degree and PFS before (16.0 months vs. 18.0 months, P = 0.067) and after PSM analysis (17.0 months vs. 19.0 months, P = 0.095). However, lower BMD was associated with shorter OS both before (20.5 months vs. 23.0 months, P< 0.001) and after PSM analysis (20.0 months vs. 23.0 months, P = 0.008).

Lower baseline BMD is associated with worse clinical outcomes in NSCLC patients treated with ICIs. As a reliable and easily obtained individual prognostic biomarker, BMD can become a routine detection indicator before immunotherapy.

This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non-small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR-tyrosine kinase inhibitors (TKIs).

The study included patients with stage IV EGFR-mutated NSCLC who were receiving first-line treatment with EGFR-TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not.

The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression-free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM.

The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes.

This study aimed to assess the overall incidence of osteonecrosis of the jaw (ONJ) caused by bisphosphonates and denosumab when used for controlling bone cancer metastasis or as adjuvant therapy.

A systematic search of the PubMed, Embase, and Cochrane Library databases and major meetings' proceedings as of July 30, 2022, identified randomized controlled trials (RCTs) and observational trials that evaluated ONJ caused by denosumab or bisphosphonates. The total incidence and risk ratio (RR) for ONJ were calculated using a random-effects model.

A total of 42 003 patients with various solid tumors reported in 23 RCTs were included. The overall ONJ incidence in cancer patients receiving denosumab or bisphosphonates was 2.08% (95% CI 1.37-2.91; p < .01; I2  = 94.99%). Patients receiving denosumab had a higher ONJ incidence than those receiving bisphosphonates (RR 1.64, 95% CI 1.10-2.44; p < .05; I2  = 65.4%). Subgroup analyses showed that prostate cancer patients receiving denosumab and receiving zoledronic acid had the highest ONJ incidences, 5.0% and 3.0%, respectively. The incidence of ONJ induced by different doses was also different.

The incidence of ONJ caused by denosumab and bisphosphonates is low, the dose of the drug and the type of cancer have certain influence on ONJ. Therefore, clinicians should use the drug reasonably to improve the quality of life of patients.

This review was implemented to examine the impact of bone metastasis on the prognosis of non-small cell lung cancer patients (NSCLC) treated with immune checkpoint inhibitors (ICIs).

A literature search was conducted in the PubMed, CENTRAL, Web of Science, and Embase databases up to 4th September 2022. Multivariable adjusted data were pooled in a random-effects model.

13 studies were included. On a combined analysis of 10 studies, it was noted that bony metastasis was associated with poor overall survival (OS) in NSCLC patients treated with ICIs (HR: 1.55 95% CI 1.24, 1.94 I2 = 69% p = 0.001). Meta-analysis of seven studies showed that bony metastasis was not associated with poor progression-free survival (PFS) in NSCLC patients treated with ICIs (HR: 1.31 95% CI 0.85, 2.01 I2 = 85% p = 0.22). Meta-regression analysis using the moderator's age, male gender, smoking history, squamous histology, and ICI as 1st line therapy for the outcome OS was not statistically significant.

The presence of bone metastasis is a predictor of poor OS in NSCLC treated with ICIs. However, PFS does not seem to be influenced by the presence of bone metastasis. Clinicians should prioritize the management of NSCLC patients with bone metastasis and explore the use of combination therapies to achieve optimal results. Further studies taking into account different combination therapies for such patients would strengthen the evidence.

This study aimed to assess the awareness of the risk of medication-related osteonecrosis of the jaw (MRONJ) among general dental practitioners (GDPs) and primary care physicians (PCPs), focusing on the clinical implications and coordination of treating or identifying high-risk patients.

Two Google Forms electronic questionnaires were distributed to 724 GDPs and 617 PCPs in primary care settings. One for PCPs with eight multiple choice questions and the other for GDPs with 10 multiple choice questions. A clinical case scenario and a section on open-ended comments were included in both questionnaires. The data obtained from each group were statistically analyzed and compared.

A total of 239 GDPs and 220 PCPs participated in the study, with a response rate of 34.23%. The mean age of participants was 29.5 years and 54.35% were females (51.2% and 57.5% in the GDPs and PCPs group, respectively). Most participants had graduated from Saudi Arabia. Almost all dentists were aware of osteonecrosis of the jaw (95.1%), 68.3% of them were aware of the guidelines regarding bisphosphonate-related osteonecrosis of the jaw (BRONJ) and MRONJ, 60.5% rated their general knowledge about MRONJ as very poor to poor, and 91.8% did not know any guidelines regarding BRONJ or MRONJ. Among the participants, 75.3% did not know how MRONJ was present in the oral cavity. A total of 69.9% of participants were unaware of other factors associated with an increased risk of MRONJ.

MRONJ risk awareness varies greatly between dentists who diagnose and manage patients in dental clinics and physicians who write about medicines and therapies. Counseling sessions and greater coordination between dental and medical specialists are strongly suggested while prescribing antiresorptive drugs to prevent the consequent development of MRONJ.

This study shows a significant lack of knowledge regarding MRONJ among GDPs and PCPs, which may affect the prevention and treatment of patients. Therefore, we urge GDPS and PCPs to take more information from scientific sources on this topic and more cooperation from specialties for the benefit of patients. How to cite this article: Aljohani MH, Aljohani AS, Aljohani RM, et al. Medical and Dental Professions' Varying Levels of Awareness Regarding Medication-related Osteonecrosis of the Jaw in Saudi Arabia? A Cross-sectional Study. J Contemp Dent Pract 2024;25(1):62-67.

As the only humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) for giant cell tumour of bone (GCTB) therapy, denosumab has limited antitumour effect on neoplastic stromal cells. Nevertheless, its mechanism of action has not yet been clarified. A previous study has revealed that p62 may play an important role in the antitumour activity of denosumab.

The study aimed to investigate if the mechanism by which denosumab inhibits GCTB neoplastic stromal cells growth is via p62 modulation and other related mechanisms.

p62 expression before and after denosumab therapy was analysed by RT‒qPCR, western blot, ELISA, and immunohistochemical assays. Two primary neoplastic stromal cells were isolated from fresh GCTB tumour tissue (L cell) and metastatic tissue (M cell). Cell proliferation, migration, apoptosis, and autophagy were investigated in p62 knockdown neoplastic stromal cells transfected by short hairpin RNA lentivirus in vitro. Tumor growth was evaluated in the chick chorioallantoic membrane model in vivo.

p62 expression was found to be downregulated following denosumab therapy. The patients with a decrease in p62 expression had lower recurrence-free survival rates. The proliferation of M cells was not inhibited by denosumab therapy, but it was restored by p62 knockdown. Moreover, p62 knockdown inhibited tumour growth in vivo. Denosumab induced M cell apoptosis and arrested the cell cycle at the G1/G0 transition and these effects were also enhanced by p62 knockdown. Autophagic flux assays revealed p62 modulation to be dependent on autophagy following denosumab incubation.

Denosumab induced neoplastic stromal cells apoptosis via p62 downregulation dependent on autophagy pathway. The combination of p62 and RANKL knockdown might be a better strategy than RANKL knockdown alone for GCTB targeted therapy.

Lung cancer is the leading cause of cancer-related deaths worldwide. Bone is a common metastatic site of lung cancer, about 50% of bone metastatic patients will experience skeletal related events (SREs). SREs not only seriously impact the quality of life of patients, but also shorten their survival time. The treatment of bone metastasis requires multi-disciplinary therapy (MDT) and development of individualized treatment plan. In order to standardize the diagnosis and treatment of bone metastasis in lung cancer, the expert group of the MDT Committee of the Chinese Medical Doctor Association has developed the expert consensus on the diagnosis and treatment of lung cancer bone metastasis.

Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon complication of antiresorptive therapy (ART) in patients receiving higher and more frequent doses of osteoclast inhibitors. The jaws are the most common site, as they have high bone turnover. The oral structures are exposed to various types of stresses, like mastication and dental diseases, which lead to microtrauma and increased bone remodeling. The hallmark feature of MRONJ is the area of exposed, necrotic, nonhealing, asymptomatic bone for more than eight weeks. Objective signs are pain in the jaw and oral cavity, loose teeth, gingival swelling, ulceration, soft tissue infection, and paresthesia in the trigeminal nerve branches' territory. Clinically, the MRONJ has been defined in four stages, from stage 0 to stage 3. Close coordination between the dentist and oncologist is critical for optimal treatment. Conservative management should be preferred over surgical management. There is significant underreporting and misdiagnosis of MRONJ cases in regular clinical practice. There needs to be more awareness among treating physicians about this sporadic complication of bisphosphonate therapy. This narrative review has given a detailed insight into the subject, starting with etiology, pathogenesis, incidence, clinical presentation, workup, staging, and various management strategies. The review article focuses mainly on practical aspects of MRONJ, which every clinician dealing with the disease must know. With a better awareness of this potential complication, healthcare practitioners dealing with at-risk patients can better diagnose, prevent, address, and provide necessary care.

Bone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown.

Data from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike's information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables.

Of 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9-12.8) versus (vs) 6.8 m (95% CI 4.0-9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4-14.2) vs 3.5 m (95% CI 2.9-4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6-4.4) vs 1.8 m (95% CI 1.6-2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1-30.7) vs 3.5 m (95% CI 2.9-4.1) p = 0.002].

In the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.

Zoledronic Acid (ZA) has been shown to inhibit Osteosarcoma (OSA) progression in preclinical studies. However, the use of ZA as an intervention for OSA treatment and management remains controversial. A systematic review and meta-analysis of randomized-controlled trials comparing the use of ZA with standard treatment vs. standard treatment alone for OSA patients after resection was conducted. Primary outcomes assessed event-free survival (EFS) and overall survival (OS) rates, while secondary outcomes assessed impact of ZA on metastatic spread, histological response and adverse events occurrence. A literature search was conducted using EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials. The Cochrane risk of bias tool (version 2) was used to assess trial quality. RevMan v5.4 was used for the meta-analysis. The between-trial heterogeneity was assessed using the Chi2 test and the I2 statistic and the GRADE methodology was utilized to assess certainty of evidence. Two studies were considered eligible for qualitative synthesis and meta-analysis. ZA had no benefit on EFS (HR, 0.95; 95% CI, 0.48-1.88; p-value 0.88), however, when compared to standard treatment it reduced OS (HR, 1.98; 95% CI, 1.49-2.64; p-value < 0.00001). ZA did not deter lung metastasis (RR, 2.56; 95% CI, 0.35-18.60; p-value 0.35), and neither did it increase good histological response (RR, 0.97; 95% CI, 0.90-1.05; p-value 0.48). ZA treatment was associated with higher risk of adverse events. Based on existing data, the use of ZA as adjuvant therapy is not recommended for the treatment of OSA patients.

In this multi-institutional retrospective cohort study, we compared the long-term risk of osteonecrosis of the jaw following the use of denosumab vs. bisphosphonates in osteoporotic patients. After 2-year use, the likelihood of osteonecrosis of the jaw is lower with denosumab compared to bisphosphonates, and the difference increases with time.

To compare the long-term risk of osteonecrosis of the jaw (ONJ) between osteoporotic patients treated with bisphosphonates (BPs) and denosumab.

This multi-institutional retrospective cohort study included patients aged > 40 years with osteoporosis between January 2010 and December 2018. Patients who met the eligibility criteria were divided into BPs and denosumab groups by propensity score matching (PSM). The risk of ONJ of denosumab vs. BPs was estimated using a Cox proportional hazards model and was described by the cumulative incidence rate using the Kaplan-Meier method.

A total of 84,102 patients with osteoporosis were enrolled, among whom, 8962 were eligible for inclusion based on their first-line drug use (denosumab, n = 3,823; BPs, n = 5,139). Following PCM matching (1:1), the BPs and denosumab groups included 3665 patients each. The incidence density of ONJ in the denosumab and BPs matching groups was 1.47 vs. 2.49 events (per 1000 person-years), respectively. The hazard ratio of ONJ in the denosumab vs. BPs group was estimated as 0.581 (95% confidence interval: 0.33-1.04, p = 0.07). The cumulative incidence rates of ONJ in both groups were similar for the first and second years of drug use (p = 0.062), but significantly different from the third year onwards (p = 0.022). The severity of ONJ was not significantly different between the two groups.

In osteoporotic patients, after 2 years of use, the likelihood of ONJ being induced by denosumab is lower than that of BPs, and the difference increases with time.

The RANK-RANKL-OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL is a ligand that binds to RANK, a receptor expressed on osteoclasts, dendritic cells, T cells, and other cells. RANKL signaling promotes osteoclast differentiation and activation, which leads to bone resorption. OPG is a decoy receptor that binds to RANKL and inhibits its signaling. In cancer cells, RANKL expression is often increased, which can lead to increased bone resorption and the development of bone metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown to be effective in the treatment of skeletal-related events, including osteoporosis or bone metastases, and cancer. This review will provide a comprehensive overview of the functions of the RANK-RANKL-OPG system in bone metabolism, mammary epithelial cells, immune function, and cancer, together with the potential therapeutic implications of the RANK-RANKL pathway for cancer management.

To review the current evidence on the relationship between agents that affect bone homeostasis and dental implant failures.

Electronic searches for bisphosphonates, denosumab, methotrexate, corticosteroids, romosozumab, sunitinib, and bevacizumab were performed using PubMed, MEDLINE (OVID), EMBASE (OVID), Cochrane Central Register of Controlled Trials (Cochrane Library), Cochrane Oral Health Group Trials Register (Cochrane Library) and Web of Science (Thomson Reuters). Manual searches were also conducted to complement the digital searches for recent issues.

Previous publications suggested that bisphosphonates do not compromise the survival of dental implants. However, one study documented an increased risk of implant failure in patients who had received high-dose of intravenous bisphosphonate therapy after implant rehabilitation. There has been an issue of MRONJ around implants in patients who have successfully received implant therapy before and after antiresorptive therapy, leading to late implant failure. Despite evidence on the detrimental effects of denosumab, methotrexate and corticosteroids on bone metabolism, their role in implant survival is not conclusive.

At present, there is insufficient evidence to establish a potential connection between agents that affects bone homeostasis and implant failure. However, some studies have reported negative results for implant therapy. In addition, implant-related sequestration in patients who received anti-resorptive therapy, despite of successful osseointegration, is also noticeable. Although limited studies are available at present, clinicians should still carefully consider the potential hazards and take appropriate precautions to minimize the risks associated with the medications and implant therapy.

Bone metastasis is common in advanced lung cancer, with the incidence reported to be 30%, and radiotherapy (RT) is used for pain relief from bone metastasis. The present study aimed to identify factors affecting local control (LC) of bone metastasis from lung cancer and to assess the significance of moderate RT dose escalation. This was a retrospective cohort study, where LC of bone metastasis from lung cancer that had received palliative RT was reviewed. LC at RT sites was evaluated with follow-up computed tomography (CT). The influence of treatment-, cancer- and patient-related risk factors for LC was assessed. A total of 317 metastatic lesions in 210 patients with lung cancer were evaluated. The median RT dose (biologically effective dose calculated using an α/β of 10 Gy; BED10) was 39.0 Gy (range, 14.4-50.7 Gy). The median follow-up time for survival and median radiographic follow-up time were 8 (range, 1-127) and 4 (range, 1-124) months, respectively. The 0.5-year overall survival and LC rates were 58.9 and 87.7%, respectively. The local recurrence rate in RT sites was 11.0%, and bone metastatic progression, except in RT sites, was observed in 46.1% at the time of local recurrence or the last follow-up CT of the RT sites. According to multivariate analysis, RT sites, pre-RT neutrophil to lymphocyte ratio (NLR), post-RT non-administration of molecular-targeting agents (MTs), and non-administration of bone modifying agents (BMAs) were significant unfavorable factors for LC of bone metastasis. Moderate RT dose escalation (BED10 >39 Gy) tended to improve the LC of RT sites. In cases without MTs, moderate dose escalation of RT dose improved the LC of RT sites. In conclusion, treatment (post-RT MTs and BMAs), cancer (RT sites) and patient (pre-RT NLR)-related risk factors had a large impact on improving the LC of RT sites. Moderate RT dose escalation seemed to have a small impact on improving the LC of RT sites.

Bone metastasis is one of the most important factors associated with poor prognosis for patients with prostate, breast, thyroid, and lung cancer. In the past two decades, 651 clinical trials, including 554 interventional trials, were being registered in ClinicalTrials.gov and pharma.id.informa.com to combat bone metastases from different perspectives. In this review, we comprehensively analyzed, regrouped, and discussed all the interventional trials on bone metastases. Clinical trials were re-grouped into bone-targeting agents, radiotherapy, small molecule targeted therapy, combination therapy, and others, based on the different mechanisms of action including modifying the bone microenvironment and preventing the growth of cancer cells. We also discussed the potential strategies that might improve overall survival and progression-free survival of patients with bone metastases in the future.

During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include musculoskeletal pain, pathologic fractures, spinal cord compression, and hypercalcemia. We discuss the efficacy of bone-modifying agents (BMAs) in reducing skeletal-related events (SREs) and improving cancer-related outcomes, particularly in patients with stage IV non-small-cell lung cancer with bone metastases. In addition, the combined effects of BMAs with radiotherapy or immunotherapy in reducing SREs in patients with lung cancer and bone metastases are explored.

Zoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain.

We conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival.

Between November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities.

An eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/RANK in physiology and pathophysiology and discuss underlying principles and strategies to modulate the RANKL/RANK pathway as a therapeutic target in immune-mediated cancer treatment.

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.

Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.

To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.

We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.

We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.

The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients' values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking.

To develop guidelines for the treatment of adults with HCM.

A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations.

The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity.

The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

Medication-related osteonecrosis of the jaw (MRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS) as the presence of an exposed bone area in the maxillofacial region, present for more than eight weeks in patients treated with the use of antiresorptive or antiangiogenic agents, with no history of radiation or metastatic disease. Bisphosphonates (BF) and denosumab (DS) are widely used in adults for the management of patients with cancer and osteoporosis, and recently there has been an increase in their use in child and young patients for the management of disorders such as osteogenesis imperfecta (OI), glucocorticoid-induced osteoporosis, McCune-Albright syndrome (MAS), malignant hypercalcemia, and others. There are differences between case reports in adults compared to child and young patients related to the use of antiresorptive/antiangiogenic drugs and the development of MRONJ. The aim was to analyze the presence of MRONJ in children and young patients, and the relation with oral surgery. A systematic review, following the PRISMA search matrix based on the PICO question, was conducted in PubMed, Embase, ScienceDirect, Cochrane, Google Scholar, and manual search in high-impact journals between 1960 and 2022, publications in English or Spanish, including randomized and non-randomized clinical trials, prospective and retrospective cohort studies, cases and controls studies, and series and case reports. A total of 2792 articles were identified and 29 were included; all of them published between 2007 and 2022, identifying 1192 patients, 39.68% male and 36.24% female, aged 11.56 years old on average, using these drugs mainly for OI (60.15%); 4.21 years on average was the therapy time and 10.18 drug doses administered on average; oral surgery was observed in 216 subjects, reporting 14 cases of MRONJ. We concluded that there is a low presence of MRONJ in the child and youth population treated with antiresorptive drugs. Data collection is weak, and details of therapy are not clear in some cases. Deficiencies in protocols and pharmacological characterization were observed in most of the included articles.

The Musculoskeletal Tumor Society, in partnership with American Society of Clinical Oncology and American Society for Radiation Oncology, has developed a clinical practice guideline to assist providers with the care of patients with metastatic carcinoma and myeloma of the femur. The guideline was developed by an Expert Panel consisting of representatives of all three organizations by American Academy of Orthopaedic Surgeons (AAOS) methodologists using the AAOS standardized guideline development process. A systematic review of the available evidence was conducted, and the identified evidence was rated was rated for quality and potential for bias. Recommendations were developed based on this evidence in a standardized fashion. The guideline was approved by the guideline approval bodies of all three organizations. Thirteen recommendations were synthesized covering relevant subtopics such as imaging, use of bone-modifying agents, radiation therapy, and surgical reconstruction. The consensus of the expert panel was that bone-modifying agents may assist in reducing the incidence of femur fracture, regardless of tumor histology. The panel recommended the use of radiation therapy to decrease the rate of femur fractures for patients considered at increased risk. The panel recommended arthroplasty be considered to improve patient function and decrease the need of postoperative radiation therapy in patients with pathologic fractures in the femur.