This study aimed to assess the efficacy and safety of three dosing regimens of JMT103 in patients with bone metastases from solid tumors. Eligible patients were randomly assigned to receive JMT103 subcutaneously, 120 mg every 4 weeks (Cohort 1), 120 mg every 8 weeks (Cohort 2), or 180 mg every 8 weeks (Cohort 3) for up to 49 weeks. The primary endpoint was change from baseline to Week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Two hundred and ninety-five patients were randomized, and 293 received at least one dose of JMT103, of whom 96 were assigned to Cohort 1, 97 were assigned to Cohort 2, and 100 were assigned to Cohort 3. The median (interquartile range) percentage reduction in uNTx/Cr at Week 13 was 80.0% (49.9%, 93.4%) in Cohort 1, 73.0% (34.5%, 94.0%) in Cohort 2, and 75.7% (40.4%, 92.0%) in Cohort 3, respectively. On-study skeletal-related events were reported by 3.1% of patients in Cohort 1, 6.2% in Cohort 2, and 7.0% in Cohort 3. Treatment-emergent adverse events occurred in 289 patients, 162 of whom were deemed treatment-related. The most common treatment-related adverse events were hypocalcemia (23.2%), hypophosphatemia (22.9%), and increased aspartate transaminase (11.9%). JMT103 demonstrated a good safety and a strong suppression of the bone turnover markers.

A comparative analysis of Denosumab (DMAB) and Zoledronic Acid (ZA) was conducted in a real-world cohort of 864 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with bone metastases, who were undergoing CDK4/6 inhibitors plus endocrine therapy. We evaluated the time to first skeletal-related events (SREs), progression-free survival (PFS), and overall survival (OS). To adjust for confounding variables, we utilized propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methodologies. In the unadjusted cohort, ZA was associated with a longer time to first SRE compared to DMAB (HR = 0.77, 95 % CI: 0.61-0.98, p = 0.031). Similar results were obtained in both the PSM (HR = 0.69, 95 % CI: 0.52-0.92, p = 0.011) and IPTW cohorts (HR = 0.74, 95 % CI: 0.63-0.87, p < 0.001), with ZA-treated patients showing an extended time to first SRE compared to those treated with DMAB. No differences in PFS and OS were observed between the two cohorts.

Hypercalcemia of malignancy (HCM), a major metabolic complication of cancer, is often managed with bisphosphonates (BP) and, increasingly, with denosumab. We aimed to compare the effectiveness and safety of denosumab with that of BP, with or without calcitonin, in treating HCM.

This retrospective cohort study was conducted at a tertiary hospital from 2017 to 2022 and included 317 patients treated for HCM. Participants were divided into three treatment groups: denosumab, intravenous (IV) BP only, and IV BP combined with calcitonin. The primary outcomes measured were changes in calcium levels and the incidence of hypocalcemia. Analysis of covariance was used to adjust for age, sex, body mass index, creatinine level, type of malignancy, and the use of furosemide and steroids.

The mean participant age was 65 years, and 37.5% were female. After adjustment, both denosumab and IV BPs were found to effectively lower calcium levels. Denosumab led to a decrease of 2.0 mg/dL (-15.9%), while IV BP alone resulted in a reduction of 1.8 mg/dL (-13.9%). The largest reduction, of 2.7 mg/dL (-20.9%), occurred with IV BP and calcitonin. Both denosumab and IV BP+calcitonin yielded their lowest calcium levels within 48 hours, whereas the IV BP only group reached a nadir within 72 hours. Despite these differences in treatment effectiveness, hypocalcemia occurred significantly less frequently in the denosumab group compared to the other groups.

Denosumab and IV BP were similarly effective in reducing calcium levels. However, IV BP combined with calcitonin yielded a more rapid and pronounced decrease.

Denosumab treatment is effective for the prevention of skeletal-related events in patients with bone metastases. However, hypocalcemia has been recognized as a serious adverse effect of denosumab. This study aimed to identify the risk factors for hypocalcemia in patients with bone metastases. In this prospective open-label study, 35 patients with bone metastases to be treated with denosumab were recruited. During the 3 months follow-up, 9 patients (25.7%) experienced hypocalcemia. Higher bone turnover status at baseline was observed in patients with hypocalcemia than in those without hypocalcemia following denosumab administration (total-P1NP, TRACP-5b, and S-NTX: all p < .05). Negative correlations were observed between the lowest calcium levels and baseline bone turnover markers (BTMs) levels (total-P1NP: r = -0.3987; TRACP-5b: r = -0.3664; S-NTX: r = -0.3672, all p < .05). Multivariate logistic regression analysis revealed that patients with high BTMs (BAP > 32.1 μg/L, total P1NP > 82.3 μg/L, TRACP-5b > 866 mU/dL, S-NTX > 30.8 nmol BCE/L) had a higher risk of hypocalcemia, even after adjusting for reported risk factors, such as age, baseline calcium levels, and renal function (BAP > 32.1 μg/L: OR = 10.4; total P1NP > 82.3 μg/L: OR = 22.07; TRACP-5b > 866 mU/dL: OR = 36.5; S-NTX > 30.8 nmol BCE/L: OR = 39.74, all p < .05). This study shows that denosumab significantly affects serum calcium levels in patients with bone metastases who have high bone turnover status. Bone turnover markers could serve as surrogate markers to predict hypocalcemia.

Background and Objectives: Bone metastases in patients can cause significant quality-of-life declines due to skeletal-related events (SREs). SRE is defined as the occurrence of radiotherapy for bone pain, pathologic fracture, bone surgery, spinal cord compression, or hypercalcemia. Bone-modifying agents (BMAs), such as denosumab and zoledronic acid, are crucial in reducing the frequency and severity of SREs. The inhibition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has emerged as the standard treatment for hormone receptor-positive metastatic breast cancer, demonstrating significant improvements in survival outcomes. This study aims to compare the effectiveness of denosumab and zoledronic acid in preventing SRE in patients receiving CDK4/6 inhibitors with endocrine therapy. Materials and Methods: This retrospective study included 328 patients diagnosed with bone metastatic breast cancer receiving first-line CDK4/6 inhibitor therapy (palbociclib or ribociclib). Patients were assigned to receive either subcutaneous denosumab or intravenous zoledronic acid every 4 weeks. Time to the first skeletal-related event post bone-modifying agent initiation, SRE incidence, and the safety data were evaluated. The data were analyzed using independent samples t-tests, chi-square tests, and Kaplan-Meier methods for time-to-event data. Results: In the denosumab group, the median time to the first skeletal-related event was significantly longer than in the zoledronic acid group (44.55 months and 29.16 months, respectively). Denosumab treatment was associated with a statistically significant reduction in the risk of developing the first SRE after bone-modifying agent initiation compared to zoledronic acid (HR: 0.56, p = 0.001). Additionally, ECOG PS and the number of metastatic bone sites were identified as independent prognostic factors for time to the first SRE. The safety profile was consistent with previous studies reported in the literature. Conclusions: Our study demonstrated that when used with CDK4/6 inhibitors, denosumab is associated with a delay in SREs and a lower SRE incidence than zoledronic acid in patients with bone metastases. These findings support the efficacy of denosumab in preventing SREs and suggest that CDK4/6 inhibitors may have distinct effects on the bone microenvironment, particularly when combined with denosumab.

Bone metastases (BM) in metastatic urothelial carcinoma (mUC) may impact patient outcomes, but their independent effect with immune checkpoint inhibitors (ICIs) is uncertain. We aimed to assess the impact of BM and PD-L1 status on outcomes in mUC patients treated with ICIs.

This post hoc analysis of the DANUBE study included 1032 mUC patients treated with durvalumab (D), D + tremelimumab (T), or standard chemotherapy (SoC). Patients were categorized by BM status and assessed for median overall survival (mOS) and median progression-free survival (mPFS) stratified by PD-L1 expression and treatment arm.  RESULTS: Among all patients enrolled in the study, those with BM had a lower mOS than those with no BM (8.7 vs. 15.8 months; P < .0001). Patients with BM and high PD-L1 expression, treated with D or D + T, had numerically longer mOS than patients with BM and low PD-L1 expression. In contrast, in the chemotherapy arm, there was no difference in mOS for BM or no BM, based on PD-L1 expression. Patients with BM had shorter mPFS compared to no BM (2.6 vs. 5.4 months; P < .0001). The study is limited by its post hoc nature.

Presence of BM was associated with worse outcomes across treatment arms. Patients with BM and high PD-L1 expression treated with D or D + T had longer mOS, suggesting potential benefits of ICIs in this subgroup. Consideration of BM and PD-L1 status in treatment decisions for mUC patients receiving ICIs may improve clinical outcomes.

The original World Health Organisation (WHO) cancer pain guidelines were published in 1986 and used globally. Updated guidance was released in 2018. This review compares the 'old' with the 'new' with a closer look at the relevance of the WHO analgesic ladder in the current climate.

The new guidelines provide a more evidence based, rigorously developed document including recommendations relating to radiotherapeutic management. There is a more detailed focus on safe opioid prescribing, opioid stewardship and the importance of integrating pain management expertise early on in the cancer journey. There remains a lack of evidence for certain therapies despite their widespread use particularly in relation to adjuvants. The pitfalls of the original renowned analgesic ladder are highlighted including a recognition that omitting 'step 2' is safe, feasible and cost effective.

The new guidelines offer more detailed recommendations relevant to clinical practice with a strong focus on safety of opioid prescribing making it relevant in the current climate. The original WHO analgesic ladder is no longer recommended as a strict protocol for cancer pain management.

Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks.

PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs).

The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33).

This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

The standard treatment for medication-related osteonecrosis of the jaw (MRONJ) is surgery. However, reports on the appropriate extent of bone resection are few. We aimed to examine the relationship between the extent of bone resection and postoperative outcomes in patients with mandibular MRONJ.

The clinical and imaging findings and treatment outcomes of 206 patients (258 surgeries) with mandibular MRONJ undergoing surgery were reviewed. Imaging findings were evaluated using computed tomography (CT) to sequestrum, osteolysis, periosteal reaction, and mixed-type osteosclerosis, and determine the extent of resection. In some cases, samples were taken from within the bone, and real-time polymerase chain reaction was used to confirm the presence of bacteria and fungi.

The three-year cumulative cure rate was 81.7%. Patients with malignant tumors showing no osteolysis and undergoing sequestrum removal or marginal mandibulectomy had significantly worse prognosis than those with osteoporosis showing osteolysis and undergoing segmental mandibulectomy. Furthermore, patients with residual osteolysis, periosteal reactions, and mixed-type osteosclerosis on CT were more likely to develop recurrence. Eleven patients showed no osteolysis on CT images. Patients with cancer administered with high-dose denosumab had significantly poorer prognosis. Bacteria and fungi were also detected in samples obtained from gap-type periosteal reaction and mixed-type osteosclerosis.

Surgery for MRONJ requires resection of the infected bone. Aside from the osteolysis area, the gap-/irregular-type periosteal reaction and mixed-type osteosclerosis must also be included in the resection area. Methods for determining the extent of bone resection in MRONJ without osteolysis are a future challenge.

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.

Purpose Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents such as bisphosphonates (BPs) and denosumab (DMB). We investigated whether a difference exists between BP- and DMB-related osteonecrosis of the jaw (ONJ). Patients and methods Histological images of 30 patients with BP-related ONJ and 13 patients with DMB-related ONJ were observed using hematoxylin-eosin and cathepsin K staining. Moreover, bone metabolism markers in the blood and bone mineral density were measured in 18 patients with BP-related ONJ and five patients with DMB-related ONJ. Furthermore, we conducted a quantitative analysis of local bone metabolism-related genes using surgical specimens through real-time reverse transcription polymerase chain reaction. Additionally, a retrospective study of 298 patients with MRONJ examined the differences in the characteristics of BP- and DMB-related ONJ and the factors associated with treatment outcomes. Results Histological examination revealed that patients treated with DMB had more severe osteoclast suppression than those treated with BP. No significant difference was observed in blood-bone metabolism markers between the two drugs; however, the suppression of local bone metabolism-related genes was stronger in patients treated with DMB. Clinical studies indicate that DMB-related ONJ is more frequently observed without osteolysis. Conclusion BP-associated ONJ and DMB-associated ONJ were shown to differ slightly. Clinical studies indicate that osteolysis is often unclear in DMB-related ONJ, and methods of bone resection during surgery need to be established.

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.

Bone metastases are associated with increased morbidity and decreased quality of life in patients with solid tumors. Identifying patients at increased risk of bone metastases at diagnosis could lead to earlier interventions. We sought to retrospectively identify the incidence and predictive factors for bone metastases at initial diagnosis in a large population-based dataset.

The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients 18 years-old or older diagnosed with solid cancers from 2010 to 2019. Patients with hematologic malignancies and primary tumors of the bone were excluded. We calculated the incidence and predictive factors for bone metastases according to demographic and tumor characteristics.

Among 1,132,154 patients identified, 1,075,070 (95.0%) had known bone metastasis status and were eligible for the study. Bone metastases were detected in 55,903 patients (5.2% of those with known bone metastases status). Among patients with bone metastases, the most common primary tumors arose from lung (44.4%), prostate (19.3%), breast (12.3%), kidney (4.0%), and colon (2.2%). Bone metastases at presentation were most common in small cell lung cancer (25.2%), non-small cell lung cancer (18.0%), and esophageal adenocarcinoma (9.4%). In addition to stage classification, predictors for bone metastases included Gleason score (OR 95.7 (95% CI 73.1 - 125.4) for Grade Group 5 vs 1 and OR 42.6 (95% CI 32.3 - 55.9) for Group 4 vs 1) and PSA (OR 14.2 (95% CI 12.6 - 16.0) for PSA > 97 vs 0 - 9.9) for prostate cancer, HER2 and hormonal receptor (HR) status (OR 2.2 (95% CI 1.9 - 2.6) for HR+/HER2+ vs HR-/HER2-) for breast cancer, histology (OR 2.5 (95% CI 2.3 - 2.6) for adenocarcinoma vs squamous) for lung cancer, and rectal primary (OR 1.2 (95% 1.1 - 1.4) vs colon primary) and liver metastases (OR 8.6 (95% CI 7.3 - 10.0) vs no liver metastases) for colorectal tumors.

Bone metastases at presentation are commonly seen in solid tumors, particularly lung, prostate, breast, and kidney cancers. Clinical and pathologic factors are associated with a significantly increased risk for bone metastases.

The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases.

To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study.

In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab.

Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49.

The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr).

Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups.

MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors.

ClinicalTrials.gov Identifier: NCT04812509.

As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements.

We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases. Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine.

We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr < 30 mL/min), but it is not completely known whether denosumab can be used in them. We aimed to determine the association between renal function and hypocalcemia development during denosumab treatment.

We included patients with solid cancer and bone metastases who started denosumab treatment between April 2017 and March 2019. They were classified into four groups based on creatinine clearance (Ccr; mL/min): normal (Ccr ≥ 80), mild (50 ≤ Ccr ˂80), moderate (30 ≤ Ccr ˂50), and severe (Ccr ˂30). Hypocalcemia was evaluated using the Common Terminology Criteria for Adverse Events (v5.0) based on the albumin-adjusted serum calcium levels; its incidence (stratified by renal function) and risk factors were investigated using a Chi-square test and logistic regression analysis.

Of 524 patients (age: 69 ± 11 years; 303 men), 153 had a normal renal function and 222, 117, and 32 had mild, moderate, and severe renal dysfunction. The albumin-adjusted serum calcium level was higher than the measured (total) calcium level in most patients. The incidence of grade ≥ 1 hypocalcemia was 32.0% in the normal group and 37.4%, 29.9%, and 62.5% in the mild, moderate, and severe renal dysfunction groups, respectively. It was, therefore, higher in the severe renal dysfunction groups than in the normal group (P = 0.002). The incidence of grade ≥ 3 hypocalcemia did not differ significantly among the groups. Pre-treatment low serum calcium levels and severe renal dysfunction were risk factors for hypocalcemia.

Evaluating denosumab-induced hypocalcemia required albumin adjustment, and its incidence was high among patients with severe renal dysfunction. Reduced serum calcium levels and severely impaired renal function were associated with an elevated hypocalcemia risk.

Bone health management for breast cancer spans the entire cycle of patient care, including the prevention and treatment of bone loss caused by early breast cancer treatment, the adjuvant application of bone-modifying agents to improve prognosis, and the diagnosis and treatment of advanced bone metastases. Making good bone health management means formulating appropriate treatment strategies and dealing with adverse drug reactions, and will help to improve patients' quality of life and survival rates. The Breast Cancer Expert Committee of the National Cancer Center for Quality Control organized relevant experts to conduct an in-depth discussion on the full-cycle management of breast cancer bone health based on evidence-based medicine, and put forward reasonable suggestions to guide clinicians to better deal with health issues in bone health clinics.

Cancer of unknown primary (CUP) is a challenging malignancy. The purpose of this study was to investigate the clinical characteristics and prognosis of bone metastatic CUP using the population-based Surveillance, Epidemiology, and End Results (SEER) database.

From the SEER database, we identified 1908 patients with bone metastatic CUP at initial presentation between 2010 and 2018. Histology was subdivided following International Classification of Diseases for Oncology codes as Adenocarcinoma, Squamous cell, Neuroendocrine, or Carcinoma not otherwise specified (NOS). Cox proportional hazard modeling was applied using factors of age, sex, ethnicity, histological subtype, and therapeutic intervention.

Among the 1908 patients, histology was Neuroendocrine in 240 patients, Squamous cell in 201 patients, Adenocarcinoma in 810 patients and NOS in 657 patients. In each subtype, patients tended to be predominantly male and white. Chemotherapy was introduced for 28% of patients and radiation for 34% in the entire cohort. Survival in patients with bone metastatic CUP was unfavorable, with a median survival of 2 months. Among the histological subtypes, Adenocarcinoma showed shorter survival than the other groups. In addition, treatment interventions such as chemotherapy and radiation therapy prolonged survival, particularly for Squamous cell, Adenocarcinoma and NOS, but not for Neuroendocrine.

Bone metastatic CUP showed extremely poor prognosis, but treatment interventions such as chemotherapy and radiation generally offered survival benefits. Further randomized clinical research is needed to confirm the present results.

The most prevalent type of fragility fractures is osteoporotic vertebral fractures (OVFs). However, only a few studies have examined the relationship between anti-osteoporosis treatments and malignancy-related mortality following an OVF. The goal of this study is to determine the effect of anti-osteoporosis therapy on mortality in OVF patients with and without cancer.

Data from older people over the age of 65 who were hospitalised for OVFs between 1 January 2003 and 31 December 2018 were analysed retrospectively. A total of 6139 persons getting osteoporosis treatment and 28,950 who did not receive treatment were analysed, together with 2 sets of patients, comprising cancer patients (794) and cancer-free patients (5342), using anti-osteoporosis medication or not, in 1:1 propensity score-matched analyses. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.

In all, 35,089 patients with OVFs were included in the population; 29,931 people (85.3%) were women, and the mean (standard deviation) age was 78.13 (9.27) years. Overall survival was considerably higher in those undergoing osteoporosis therapy. This was true both for those without cancer (adjusted HR 0.55; 95% CI 0.51-0.59; P<.0001) as well as those with cancer (adjusted HR 0.72; 95% CI 0.62-0.84; P<.0001). Even among cancer patients, those who received anti-osteoporotic drugs had a lower mortality rate than those who did not.

Our findings suggest that anti-osteoporosis therapy should be initiated regardless of the presence of cancer in the elderly, as it increases survival following OVFs.

Surgery is the standard treatment for medication-related osteonecrosis of the jaw (MRONJ). This study reviewed patients with mandibular MRONJ who underwent surgical treatment, and in particular the characteristics of non-osteolytic MRONJ with no evidence of osteolysis on CT were described.

We conducted a retrospective study of patients with mandibular MRONJ who underwent surgery between January 2016 and September 2022. Various clinical and imaging factors regarding treatment outcomes were investigated and analyzed. Additionally, the disease course of non-osteolytic MRONJ was examined in detail.

This study included 55 patients (66 surgeries) with a mean age of 74.7. The primary disease was osteoporosis (24 patients) and malignancy (31 patients); the type of antiresorptive agent was bisphosphonate (BP) in 21 patients and denosumab (DMB) in 26. BP was initially administered; however, it was changed to DMB in eight patients. Preoperatively, the cumulative cure rates for all 66 surgeries were 72.8% at 1 year and 77.3% at 2 years. Cure rates were significantly lower in patients with malignancy, those without osteolysis, and those who underwent sequestrum removal or marginal mandibulectomy than those with osteoporosis, osteolysis, and segmental mandibulectomy. Non-osteolytic MRONJ was observed in eight patients, all with malignancy and receiving high-dose DMB. Only two patients were cured after the initial surgery, and most patients ultimately underwent segmental mandibulectomy.

Surgical treatment yielded good treatment outcomes in most patients with mandibular MRONJ; however, the cure rate was lower in patients with malignancy who showed no osteolysis on CT images.

Bone-targeted therapy (BTT) including zoledronic acid (ZA) and denosumab decreases the risk of skeletal-related events (SREs) in patients with metastatic breast cancer (MBC) and bone metastasis. The impacts from prolonged BTT on SREs and BTT-associated harms are unknown and are becoming important to understand as these patients survive for longer periods.

We conducted a retrospective study of 224 patients with MBC and bone metastasis who survived for more than 2 years after diagnosis and received treatment at our institution between 2016 and 2021. We defined 3 BTT patterns: (1) ZA only, (2) denosumab only, (3) both ZA and denosumab. The association between these BTT patterns and SREs and harms was assessed using Fisher exact test and logistic regression.

Rates of SREs overall were 21.2% of patients given ZA only, 8.8% of those given denosumab only, and 20% of those given both, without statistically significant differences (p = .32). However, those treated with denosumab only had significantly fewer compression fractures (0.7%) (p = .02). BTT-associated harm was observed in 5.8% of the ZA-only group, 11.7% of the denosumab-only group, and 14.3% of the group given both, without statistically significant differences (p = .37).

Oncologists may have increased flexibility regarding the frequency of administration of BTT along with their choice of agent. Our study showed no significant difference in the prevention of overall SRE or development of BTT-associated harms between the BTT regimens evaluated.

Little is known on how denosumab reduces skeletal-related events (SREs) by bone metastases from solid tumors. We sought to evaluate the effect of denosumab administration in patients with bone metastases from solid tumors.

Data of patients treated with denosumab were collected from electronic medical charts (n = 496). Eligible participants in this study were adult patients (age ≥ 18 years) with metastatic bone lesions from solid tumors treated with denosumab. SREs, surgical interventions, the spinal instability neoplastic score (SINS) for spinal region, and Mirels' score for the appendicular region were evaluated. To assess whether denosumab could prevent SREs and associated surgery, the SINS and Mirels' score were compared between patients with and without SREs.

A total of 247 patients (median age, 65.5 years old; median follow-up period, 13 months) treated with denosumab for metastatic bone lesions from solid tumors were enrolled in this study. SREs occurred in 19 patients (7.7%). SREs occurred in 2 patients (0.8%) who took denosumab administration before SREs. Surgical interventions were undertaken in 14 patients (5.7%) (spinal and intradural lesions in five patients and appendicular lesions in nine patients). The mean SINS of patients without SREs compared to those with SREs were 7.5 points and 10.2 points, respectively. The mean Mirels' scores of non-SREs patients and those with SREs were 8.07 points and 10.7 points, respectively. Patients with SREs had significantly higher Mirels' score than non-SREs patients (p < 0.01). Patients with SREs had higher SINS than non-SREs patients (p = 0.09).

SREs occurred in patients with higher SINS or Mirels' scores. Two patients suffered from SREs though they took denosumab administration before SREs. Appropriate management of denosumab for patients with bone metastasis is significant. Surgical interventions may be needed for patients who with higher SINS or Mirel's scores.

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 Tomita, revised Tokuhashi and Tokuhashi lung scores are commonly used tools to predict the survival of patients with spinal metastases and to guide decisions regarding surgical treatment. These prognostic scores, however, tend to underestimate the prognosis of patients with lung cancer. We examined surgical outcome and hopefully provide a more accurate reference for management.

The consistency between predicted and actual survival was examined using the Tomita and Tokuhashi scores. Various factors that may influence survival were analyzed. Primary outcomes were overall survival (OS) and progression-free survival (PFS), defined as the ambulatory time after the initial surgery. Secondary outcomes included reoperation events, blood loss, and hospitalization days.

One hundred seventy-two patients were enrolled. Correct survival predictions were made for 28%, 42%, and 56% with the Tomita, revised Tokuhashi, and Tokuhashi lung scores, respectively. The Tokuhashi lung scores underestimated OS by 35%-40%. Body mass index ≥20, systemic treatment-naïve, good general condition, the use of denosumab, and adenocarcinoma were found to positively affect OS and PFS. There was no significant difference between palliative decompression and excisional surgery regarding OS and PFS.

Patients with spinal metastases from lung cancer had better prognosis than that predicted by the Tomita and Tokuhashi scores. Spine surgeons should acknowledge this discrepancy and treat these patients with at least the aggressiveness suggested. Patients with adenocarcinoma, amenable to target therapy, denosumab, good general condition, systemic treatment-naïve are better candidates for surgery. Those with cachexic status and unresectable visceral metastases are worse candidates.

Osteoporosis is the most common indication for antiresorptive drugs (ARDs). Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of ARDs. Multiple risk factors can increase the risk of MRONJ, one of which is the duration of ARD intake, which is usually prolonged for osteoporosis cases. Prevention of MRONJ relies on collaborative care between treating physicians and dental practitioners. Therefore, knowledge about MRONJ and its prevention strategies is crucial for both teams.

This study aimed to assess the knowledge and attitudes of physicians toward MRONJ in osteoporosis patients. Another aim was to develop recommendations for the prevention of MRONJ.

Through an online survey, basic information such as the practice location, training, knowledge, perceptions, and attitudes of physicians regarding ARDs and MRONJ in osteoporosis patients was collected. Statistical analysis was performed for all variables, and their correlations were explored.

A total of 221 physicians participated in the survey: 34.8% were rheumatologists, 25.3% were endocrinologists, 8.6% were family medicine physicians, 5.9% were orthopedists, and 5.9% were internal medicine physicians. Of them, 58.0% reported more than 6 years of experience. Only 78.7% were aware of MRONJ and recognized that bisphosphonates (BPs) can contribute to MRONJ. In contrast, 56.0% recognized denosumab as a causative factor for MRONJ. Duration of ARD therapy and pre- and post-ARD dental care were known to influence the risk of MRONJ by 62% and 65.6% of the participants, respectively. Only 41.6% and 31.2% of participants informed patients about MRONJ prior to BP and denosumab therapy, respectively. Only 25.3% and 20.8% referred patients to dentists before BP and denosumab therapy, respectively. Overall, 65.6% of the participants had a negative attitude toward MRONJ, and 34.4% had a positive attitude. A positive attitude was mostly observed among rheumatologists (55.8%) compared to other specialists (p <0.001). More years of experience were associated with a higher level of knowledge and positive attitude.

The findings of this study identified a notable gap in the awareness, knowledge and attitudes of physicians regarding MRONJ in osteoporosis patients. Continuing education programs about ARDs and MRONJ risk are highly recommended.

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.

Multiple myeloma (MM) is a hematological malignancy characterized by the exponential growth of malignant plasma cells. Individuals diagnosed with MM exhibit a deficiency in vitamin D and may suffer fatigue, a loss of muscular strength, persistent musculoskeletal aches, and pain. The objective of this systematic review and meta-analysis is to determine the prevalence of vitamin D insufficiency and deficiency in individuals diagnosed with MM.

We searched five electronic databases using relevant keywords. The quality of the included studies was evaluated using the critical appraisal tool developed by the Joanna Briggs Institute. We employed a random-effects model and presented the findings in the form of percentages accompanied by 95% confidence intervals (CI). This protocol has been officially registered in PROSPERO under the registration number CRD42021248710.

The meta-analysis comprised a total of eighteen studies and found that, among patients with MM, the occurrence of serum vitamin D deficiency and insufficiency was 39.4% (95% CI: 25.8 to 52.9, n = 3746) and 34.1% (95% CI: 20.9 to 47.2, n = 3559), respectively. The findings indicate that a greater proportion of newly diagnosed patients exhibited vitamin D deficiency and insufficiency, with rates of 43.0% and 41.6%, respectively, compared to those receiving treatment (rates of 41.6% and 32.3%, respectively). The findings of the sensitivity analyses were consistent, and most of the studies (72.2%) were deemed to be of high quality. The results of Egger's test indicated the absence of publication bias.

Patients diagnosed with MM have been found to exhibit significantly elevated levels of both vitamin D deficiency and insufficiency. Therefore, it is recommended to consider vitamin D testing as an additional parameter in the current criteria for the clinical evaluation of MM.

Medication-related osteonecrosis of the jaws (MRONJ) is a challenging situation in clinics. Previous studies have shown that pentoxifylline combined with tocopherol proved to be beneficial in patients with osteoradionecrosis, due to their antioxidant and antifibrotic properties. The aim of this randomized study was to evaluate the effect of pentoxifylline and tocopherol in patients that had developed MRONJ after tooth extractions. The study population consisted of 202 Stage I MRONJ female patients with an average age of 66.4 ± 8.3 years, who were divided into two groups. The test group (n = 108) received a pharmacological protocol with pentoxifylline and tocopherol (2 months pre-operatively and 6 months post-operatively). The control group (n = 94) had sequestrectomy operations without any pharmacological preparation. The main outcomes were clinical healing of the mucosa after 1 month, and clinical and radiographic healing of the bone lesion at 6 months. In the test group all patients had mucosal healing and there was only one relapse within 6 months. In the control group, in 17% of the patients the mucosa did not heal, 71% of the patients relapsed within two months, and 7% developed infectious complications (such as abscess or phlegmon). After 6 months, the control group patients with persisting issues were prescribed pentoxifylline and tocopherol, as in the test group. At a subsequent follow-up, all those patients healed completely. Patients were monitored for a period of 7.8 ± 0.3 years, during which no relapse or additional problems were reported. As a conclusion, pentoxifylline and tocopherol protocol seems to be beneficial in the management of MRONJ patients.

Denosumab entered the Chinese market for the first time in 2020. Since it is a short period of time, there is a lack of data on its effectiveness and safety in Chinese people. The objective of this study was to evaluate the effectiveness and safety of denosumab in delaying skeletal-related events (SREs) in patients with breast cancer metastatic to bone.

The study retrospectively analyzed data from breast cancer patients with bone metastases (BM) who were treated with denosumab in the First Affiliated Hospital of Nanjing Medical University from September 2020 to January 2022. The primary endpoint was SRE incidence at 1 year after receiving denosumab treatment. The secondary endpoints included time to first on-study SRE and safety. Descriptive analysis was utilized to display clinicopathological features. The Kaplan-Meier method was used to estimate the median time to first on-study SRE in total population and subgroups. Logistic regression analysis and χ2 test were employed to determine the potential factors influencing the occurrence of SREs.

Fifty breast cancer patients with BM were enrolled in our study, and 54.0% of the patients had 5 or more metastatic bone lesions. After a median follow-up of 17.00 months, 24% of the patients developed SREs at 1 year after receiving denosumab treatment, and the median time to first on-study SREs was not reached. Five or more metastatic bone lesions were an independent risk factor for SRE occurrence (odds ratio = 6.06, 95% CI: 1.09-33.54, P = .039). The adverse events (AEs) associated with denosumab mainly included hypocalcemia (68.0%), periodontitis (28.0%), and myalgia (14.0%). Only 3 cases of grade III/IV AEs were reported, and no serious AEs occurred.

Denosumab was effective and well tolerated in Chinese breast cancer patients with BM.

Denosumab is a fully human monoclonal antibody that binds to the receptor activator of nuclear factor kappa-Β ligand, an essential cytokine factor in bone resorption, which reduces bone resorption and has been shown to decrease the incidence of skeletal-related events in patients with malignancy and bone metastasis. Severe hypocalcemia is a rare and life-threatening adverse effect of denosumab therapy. Here, we discuss the case of a patient with stage 4 estrogen receptor-positive, progesterone receptor-negative, human epidermal growth factor receptor 2-negative breast cancer who was on treatment with denosumab for bony metastases and presented with severe refractory hypocalcemia.

Clinical trials have shown zoledronic acid as a potent bisphosphonate in preventing bone loss, but with varying potency between patients. Human osteoclasts ex vivo reportedly displayed a variable sensitivity to zoledronic acid > 200-fold, determined by the half-maximal inhibitory concentration (IC50), with cigarette smoking as one of the reported contributors to this variation. To reveal the molecular basis of the smoking-mediated variation on treatment sensitivity, we performed a DNA methylome profiling on whole blood cells from 34 healthy female blood donors. Multiple regression models were fitted to associate DNA methylation with ex vivo determined IC50 values, smoking, and their interaction adjusting for age and cell compositions.

We identified 59 CpGs displaying genome-wide significance (p < 1e-08) with a false discovery rate (FDR) < 0.05 for the smoking-dependent association with IC50. Among them, 3 CpGs have p < 1e-08 and FDR < 2e-03. By comparing with genome-wide association studies, 15 significant CpGs were locally enriched (within < 50,000 bp) by SNPs associated with bone and body size measures. Furthermore, through a replication analysis using data from a published multi-omics association study on bone mineral density (BMD), we could validate that 29 out of the 59 CpGs were in close vicinity of genomic sites significantly associated with BMD. Gene Ontology (GO) analysis on genes linked to the 59 CpGs displaying smoking-dependent association with IC50, detected 18 significant GO terms including cation:cation antiporter activity, extracellular matrix conferring tensile strength, ligand-gated ion channel activity, etc. CONCLUSIONS: Our results suggest that smoking mediates individual sensitivity to zoledronic acid treatment through epigenetic regulation. Our novel findings could have important clinical implications since DNA methylation analysis may enable personalized zoledronic acid treatment.

Bone modifying agents (BMAs) prevent skeletal related events among patients with metastatic, castration-resistant prostate cancer (mCRPC) involving bone and prevent osteoporotic fractures among patients at high risk. BMA utilization for patients with mCRPC has not been well quantified.