Search Results (646)

Background: The combination of pharmacological therapy and exercise is frequently recommended for osteoporosis management; however, whether antiresorptive agents may interfere with exercise-induced bone adaptation remains unclear. This study aimed to investigate the independent and combined effects of zoledronate and treadmill exercise on bone microarchitecture and mechanical strength in an ovariectomized rat model. Methods: Twenty-four female Sprague Dawley rats underwent ovariectomy and were assigned to four groups: Control, zoledronate (ZA), treadmill exercise (T), and combined zoledronate and exercise (ZA + T). An additional sham-operated group was included. Zoledronate was administered as a single subcutaneous injection, and a 6-week treadmill exercise routine was implemented. Bone microarchitecture was assessed using micro-computed tomography, and a three-point bending test was employed for evaluation of mechanical properties. Results: The combined ZA + T group demonstrated significant improvements in trabecular bone parameters, including bone volume/tissue volume and trabecular number, compared with the Control group. Mechanical strength parameters, including maximum load and stiffness, were also significantly enhanced in the ZA + T group. Cortical bone parameters exhibited no significant changes. Conclusions: Treadmill exercise did not attenuate the effects of zoledronate, and may offer additive benefits in enhancing trabecular bone microarchitecture and mechanical strength. These findings suggest that exercise therapy can complement bisphosphonate treatment and contribute to optimizing therapeutic strategies for osteoporosis, supporting the potential utility of combined pharmacological and exercise-based interventions for improving bone health. Full article

Background: Skeletal-related events (SREs), including pathological fractures, spinal cord compression, radiotherapy to bone, and bone surgery, substantially worsen quality of life in breast cancer with bone metastases. Denosumab, a monoclonal antibody targeting RANKL, mechanistically differs from bisphosphonates and is not renally cleared, offering potential clinical advantages. In practice, an increasing number of patients transition from bisphosphonates to denosumab. However, the comparative effectiveness of sequential therapy versus initial denosumab remains unclear. Methods: We retrospectively analyzed 165 patients with breast cancer and radiologically confirmed bone metastases treated between 1 January 2019 and 30 April 2024 at a tertiary center in China. Patients were categorized into an initial denosumab group (n = 67) or a sequential bisphosphonate-to-denosumab group (n = 98). The primary endpoint was time to first on-treatment SRE; the 12-month first on-treatment SRE rate was also reported as a descriptive summary measure. Secondary endpoints included cumulative SRE incidence and safety. Kaplan–Meier and log-rank tests compared SRE-free survival; Cox regression explored prognostic factors. Results: The median age at bone-metastasis diagnosis was 54.7 years. Median time from diagnosis to bone-targeted agents (BTAs) initiation was 0.9 months in both groups; median follow-up was longer in the sequential group (22.5 vs. 11.3 months). At diagnosis, 46 of 165 patients (27.9%) presented with synchronous SREs, more frequent in the initial denosumab group (37.3% vs. 21.4%; p = 0.040). During follow-up, 31 patients (18.8%) developed SREs: 25 of 98 (25.5%) in the sequential group versus 6 of 67 (9.0%) in the initial denosumab group (p = 0.008). After BTA initiation, on-treatment SREs occurred in 28 of 165 patients (17.0%): 25 of 98 (25.5%) in the sequential group versus 3 of 67 (4.7%) in the initial denosumab group (p < 0.001). The 12-month first on-treatment SRE rate was 15.7% (95% CI 8.1–22.7) for sequential therapy and 5.9% (0–12.3) for initial denosumab. In Cox analysis, second-line systemic therapy increased SRE risk (HR = 2.651, p = 0.021). Safety outcomes were generally manageable and consistent with known class effects, with no clear exposure-adjusted safety advantage of one strategy over another. Conclusions: Initial denosumab was associated with fewer and delayed SREs compared with sequential bisphosphonate-to-denosumab therapy, supporting early denosumab initiation as a potentially preferable BTA strategy. Prospective studies are warranted to confirm these findings. Full article

Background: Contemporary dentistry increasingly relies on tools and methods derived from the exact sciences, particularly mathematics and physics, to better understand the complexity of biological processes. One such tool is fractal analysis (FA), which enables the characterization and quantification of irregular, complex, self-similar structures commonly observed in nature in the form of the fractal dimension (FD). In oral radiology, it has been found useful for describing structural changes in bone tissue. Objective: The aim of this review is to present the current state of knowledge regarding the application of fractal analysis in the management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ), with particular emphasis on its diagnostic and prognostic potential. This paper summarizes key research findings, and discusses the principal challenges and limitations associated with the use of this method of analysis in MRONJ cases. Materials and Methods: The inclusion criteria were as follows: original papers, the presence of MRONJ, and fractal analysis. In order to find relevant studies, international databases, including PubMed and Google Scholar, were searched. The last search was performed on 29 November 2025. Six articles were included in the systematic review. Results: The majority of the review studies show lower FD values for MRONJ patients and healthy control groups. The values are the lowest for necrotic lesions and highest for perinecrotic bone tissue. Conclusions: FD values calculated from radiological images of the jaws can be used to differentiate healthy and MRONJ-affected patients and to describe necrotic lesions. Fractal analysis has potential to be used in the diagnosis and monitoring of MRONJ after further studies and standardization of methodology. Full article

Breast cancer is the second most common malignancy worldwide, and over 70% of new diagnosis are of the hormone receptor-positive (HR+) and HER2-negative (HER2−) subtype. The cornerstone in management of early stage HR+ breast cancer has historically consisted of chemotherapy and endocrine therapies. Genomic assays in early stage HR+HER2− breast cancer has provided a prognostic tool for recurrence and a predictive tool to select patients for adjuvant chemotherapy. The introduction of bone-modifying agents and adjuvant CDK 4/6 inhibitors into early stage disease represents new therapeutic modalities aimed at reducing risk in high-risk HR+HER2− cancers. This manuscript aims to provide a comprehensive overview of the evidence behind endocrine therapy and recommended duration of treatment, genomic assays to guide chemotherapy delivery, data guiding use of bisphosphonate therapy to reduce bone recurrence, and indications for incorporating CDK 4/6 inhibitors. In addition, novel endocrine agents and targeted therapies under investigation are highlighted. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a clinically significant side effect related to antiresorptive therapies, such as denosumab and bisphosphonates. MRONJ may develop following oral surgical procedures or spontaneously. Although the pathophysiological processes underlying MRONJ are not well clarified, infections, commonly occurring after oral surgery, seem to have an important contribution in its development. Consequently, the role of the oral microbiota warrants investigation. This study investigates the possible contribution of the salivary microbiota to the onset of osteonecrosis in subjects treated with zoledronate or denosumab. Methods: Three groups of subjects were analyzed: patients treated with zoledronate or denosumab who had developed MRONJ (cases); those who did not (controls) and healthy subjects. Oral microbioma was evaluated through next-generation sequencing. Results: A total of 55 individuals were enrolled: 16 healthy subjects (29.1%), 21 controls (38.2%), and 18 cases (32.7%). Differences in the abundance of certain bacterial taxa were observed both among the three groups and in pairwise comparisons. Furthermore, a cut-off value of 5.51% for Streptococcus spp. was identified as being associated with the development of MRONJ. Conclusions: For the first time, this preliminary study highlights differences in the salivary microbiota among healthy subjects, controls, and cases, suggesting a potential cut-off value for Streptococcus spp. Despite the limited sample size, these findings provide initial insights. Further studies in larger cohorts are warranted. Full article

Glucocorticoids (GCs) are widely used for their potent anti-inflammatory and immunosuppressive effects, but their use is strongly associated with negative impacts on bone health. Rapid bone loss and an increased risk of fragility fractures are characteristics of glucocorticoid-induced osteoporosis (GIOP), the most common type of secondary osteoporosis. While oral GCs are a well-known cause of GIOP, growing evidence suggests that non-oral routes of administration may also negatively affect the skeleton. This review summarizes current knowledge on the pathophysiology of GIOP, highlighting the complex relationship between direct and indirect mechanisms. It examines the effects of various routes of GC administration—oral, intravenous, inhaled, topical, and epidural—on bone mineral density, microarchitecture, and fracture. While parenteral GCs may have fewer systemic effects than oral therapy, long-term exposure or high cumulative doses may still cause clinically significant skeletal deterioration. This review also discusses current methods for assessing, preventing, and treating the fracture risk associated with GIOP. These strategies include lifestyle modifications, calcium and vitamin D supplements, and medications such as denosumab, bisphosphonates, and anabolic agents. Reducing the incidence of glucocorticoid-associated fractures and improving prevention and treatment requires an understanding of how GCs impact bone. Full article

Segmental mandibular resection may be indicated as a treatment in, for example, advanced stages of oral squamous cell carcinoma (OSCC). Osseous reconstruction of these defects is a fundamental part of static and dynamic masticatory rehabilitation, particularly when dental implants are required. The Segmental Mandibular Defect Reconstruction (SMDR) Registry aims to generate real-world evidence on SMDR through an international, prospective, multicentre case series designed as a registry. While OSCC is a common indication for segmental mandibular resection, the SMDR Registry also aims to capture outcomes for rarer mandibular conditions and the increasing number of collateral damage cases resulting from systemic medication therapies (antiresorptive drugs, immunotherapeutics) or irradiation, which may likewise lead to medication-related osteonecrosis of the mandible (MRONJ) or osteo(radio)necrosis with tumour-like segmental resection of the mandible, highlighting the value of an international database for these less frequent pathologies. Primary objectives are to describe the patient population and current treatment modalities, describe the outcomes and adverse events (AEs) for different treatment modalities, and identify potential predictors for successful autologous reconstruction of SMDs. Approximately 300 patients with a mandibular lesion resulting from bisphosphonate- and immunomodulatory drug-induced osteonecrosis of the mandible, ameloblastoma or osteosarcoma of the mandible, oral metastases related mandibular lesions indicated for segmental resection, or OSCC undergoing SMDR or intending to undergo one- or two-stage reconstruction will be prospectively recruited over a 36-month period. Baseline information, treatment details, and outcome measures will be documented. All treatments will be per the usual practice at participating sites. Outcome measures include clinical, patient-reported, and radiological outcomes; AEs related to the condition and/or treatment with a possible influence on the outcome will be recorded. Full article

Copper–organic compounds are being investigated as antitumor candidates. Besides their efficacy as cytotoxic agents alone, the oxidative potential of electrochemical Cu²⁺-to-Cu¹⁺ transition emerges as an attractive approach for elimination of tumor cells otherwise resistant to chemotherapy. To minimize side effects of the potent oxidative burst upon Cu(II) reduction, the metal cations should be delivered to the tumor site. Taking advantage of the ability of bisphosphonates to accumulate in the bone, we synthesized a Cu(II) complex of zoledronic acid (ZA), an FDA-approved drug for prevention of bone destruction. The CuZA complex obtained upon precipitation of ZA and different copper salts (sulfate, chloride or perchlorate) were structurally identical, consisting of two organic moieties coordinated by three metal cations. Combined treatment with water-soluble formulations of CuZA and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of CuZA and cysteine alone. Importantly, the K562 chronic myelogenous leukemia cells that demonstrated an attenuated response to the 3d generation Bcr-Abl tyrosine kinase inhibitor in the medium conditioned by bone marrow-derived fibroblasts, were readily killed by CuZA–cysteine combination. Thus, oxidative burst upon metal reduction in CuZA complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment. Full article

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is characterized by exposed necrotic bone that often progresses with increasing pain and impaired quality of life. Zoledronate, the most potent and widely used bisphosphonate, has been strongly associated with BRONJ development following invasive dental procedures. Given the rising incidence of BRONJ, understanding and implementing effective preventive strategies have become imperative. Biomaterials based on synthetic hydroxyapatite and beta-tricalcium phosphate have been investigated as potential preventive agents. Their therapeutic rationale is supported by two key principles: the well-documented chemical interaction of calcium phosphates with bisphosphonates when used as drug carriers, and the established clinical use of synthetic calcium phosphate biomaterials in dentistry for bone regeneration. This review examines the underlying mechanisms of this preventive therapeutic strategy and evaluates studies investigating synthetic calcium phosphate biomaterials for BRONJ prevention through zoledronate adsorption at jaw wound sites, thereby reducing soft tissue toxicity and promoting healing. The evidence supports the protective effect of these biomaterials as a scientifically grounded preventive approach for BRONJ. Full article

Background/Objectives: The limited targeting efficiency and systemic toxicity of conventional medicine present significant challenges in the treatment of skeletal disorders, such as bone tuberculosis. To address these limitations, we developed a bone-targeting nanomicelle delivery system functionalized with alendronate (ALN), designated ALN-PLGA-mPEG@RPT, to improve the targeted delivery and therapeutic efficacy of rifapentine (RPT) in bone tissue. Methods: The ALN-PLGA-mPEG blank micelles, prepared in accordance with our research group’s optimized protocol, were loaded with RPT and subjected to systematic formulation optimization. The resulting nanomicellar system was comprehensively characterized in terms of its physicochemical properties, including particle size and polydispersity index (PDI). Additionally, drug-loading capacity, encapsulation efficiency, and in vitro release curve were evaluated. Bone-targeting efficacy was assessed using in vivo imaging techniques, while biodistribution and safety profiles were determined through in vivo distribution studies and histopathological examination. Results: The optimized ALN-PLGA-mPEG@RPT nanomicelles exhibited a mean particle size of 101.90 ± 4.17 nm, and a PDI of 0.242 ± 0.021. The formulation achieved a drug loading of 16.74 ± 0.51% with an encapsulation efficiency of 50.27 ± 1.91%. In vitro release studies confirmed a sustained-release profile, with only 25% of RPT released within 12 h. In vivo imaging revealed significantly enhanced bone-targeting capability in the ALN-modified group, showing a 1.93-fold higher drug accumulation in bone tissue compared to blood. Histopathological analysis indicated no observable pathological alterations in major organs. Conclusions: The ALN-PLGA-mPEG@RPT nanomicelle system exhibits favorable bone-targeting efficiency, sustained-release properties, and biocompatibility, representing a promising strategy for the precise treatment of bone tuberculosis and other skeletal diseases. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging complication in patients receiving antiresorptive therapy. Management strategies range from conservative pharmacological approaches to extensive surgical resection of necrotic bone. This clinical audit retrospectively evaluated the clinical outcomes of patients undergoing sequestrectomy for MRONJ, comparing those treated with antibiotics alone with those receiving antibiotics in combination with the pentoxifylline–tocopherol (PENTO) protocol. The PENTO protocol was introduced at our institution in 2021 and has since been routinely prescribed for all MRONJ patients. Methods: We analyzed 92 MRONJ sites treated with sequestrectomy. Conservative management consisted of antibiotic therapy, with or without adjunctive PENTO (pentoxifylline 800 mg/day and tocopherol 800 IU/day, administered both preoperatively and postoperatively). The primary outcome was healing at three months post-surgery, while the secondary outcome was disease recurrence during longer-term follow-up. Results: Complete healing was achieved in 56 of the 92 sites, with a mean follow-up of 9.98 ± 12.76 months among healed cases. No statistically significant differences in healing rates were observed between the PENTO and antibiotic-only groups. The overall recurrence rate was 12.5%, with no significant difference between the groups. Conclusions: Overall, surgical management of MRONJ resulted in favorable outcomes in a substantial proportion of patients. Within the limitations of this retrospective clinical audit, the addition of PENTO to antibiotic therapy appeared generally well tolerated, but could not result in a significant improvement in healing rates or reduction in recurrences, compared with antibiotic therapy alone, in this patient cohort. Full article

Background: Bone-seeking radiopharmaceuticals based on bisphosphonates enable targeted therapy of skeletal metastases. They are suitable carriers for therapeutic radionuclides such as terbium-161 (¹⁶¹Tb), a β⁻ emitter that additionally releases short-range conversion and Auger electrons, which may enhance radiation dose delivery to small lesions. This study explored the potential of the well-established DOTA conjugated bisphosphonate BPAMD (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10 tetraazacyclododec-1-yl)acetic acid) radiolabeled with ¹⁶¹Tb as a bone-targeted radiopharmaceutical, focusing on the theranostic and radiophysical advantages conferred by the radionuclide. Methods: BPAMD was radiolabeled with ¹⁶¹Tb and ¹⁷⁷Lu under mild conditions (pH 4.5, 95 °C, 30 min); subsequently, the radiochemical purity was assessed by radio-TLC. Physicochemical properties (charge, lipophilicity, protein binding), in vitro stability (saline and human serum, 48 h), and hydroxyapatite (HAP) binding were evaluated for [¹⁶¹Tb]Tb-BPAMD. Biodistribution was investigated in healthy Wistar rats (n = 3 per time point) at 2 h, 24 h, and 7 days post-injection. Computational density functional theory (DFT) analyses were performed to explore the coordination chemistry of Tb³⁺ and Lu³⁺ with BPAMD. Results: Both complexes achieved a radiochemical yield of greater than 98%. [¹⁶¹Tb]Tb-BPAMD exhibited negative charge, high hydrophilicity (logP = −3.92 ± 0.13), low protein binding (19.07 ± 1.01%), excellent radiochemical stability under simulated physiological conditions (>97% at 48 h), and strong hydroxyapatite affinity (>98% with ≥10 mg HAP). Biodistribution showed high, stable bone uptake (8.06% ID/g at 2 h; 6.70% ID/g at 24 h; 5.31% ID/g at 7 d) with rapid blood clearance (<0.001% ID/g at 24 h) and low non-target retention. To contextualize its performance, [¹⁶¹Tb]Tb-BPAMD was compared with [¹⁷⁷Lu]Lu-BPAMD, which demonstrated similarly strong skeletal retention (8.74% ID/g at 2 h; 8.08% ID/g at 24 h; 5.25% ID/g at 7 d) but comparatively higher non-target organ uptake. DFT calculations indicate that both Tb³⁺ and Lu³⁺ favor octa-coordinated BPAMD complexes. Conclusions: [¹⁶¹Tb]Tb-BPAMD exhibits excellent radiochemical and pharmacokinetic properties, with enhanced biodistribution selectivity over [¹⁷⁷Lu]Lu-BPAMD. Combined with the radiobiological advantages of ¹⁶¹Tb, it represents a promising theranostic candidate for targeted therapy of bone metastases. Full article

Background and Objectives: Paraneoplastic hypercalcemia represents a rare but clinically significant complication of penile squamous cell carcinoma (PSCC); however, limited information is available for this condition. Therefore, this systematically conducted narrative review aimed to comprehensively evaluate the pathophysiological mechanisms, clinical presentation, therapeutic strategies and prognostic outcomes of tumor-induced hypercalcemia in PSCC. Methods: A comprehensive literature search was conducted across PubMed/MEDLINE and Scopus databases from their inception to December 2024. Cases were included if they documented histopathologically confirmed PSCC with biochemically verified hypercalcemia and objective evidence of paraneoplastic etiology. Data extraction included tumor characteristics, severity of hypercalcemia, mechanistic classification, therapeutic interventions and survival outcomes. The search methodology followed PRISMA 2020 guidelines adapted for narrative synthesis. Given the absence of comparative studies for this rare condition, all study types were eligible for inclusion, resulting in an evidence base that consisted exclusively of case reports and case series. Results: Twelve published cases spanning six decades (1965–2024) met the inclusion criteria. The median age at presentation was 56 years, with 91.6% of patients presenting with advanced disease. Severe hypercalcemia (≥14 mg/dL) occurred in 66.7% of cases, with a median calcium level of 15.45 mg/dL. Two established pathophysiological mechanisms were identified: PTHrP-mediated humoral hypercalcemia and bone metastasis-associated hypercalcemia. By contrast, three cases with unmeasured PTHrP levels had an undetermined mechanism. Despite biochemical correction, median overall survival was 9 weeks following diagnosis of hypercalcemia. Conclusions: Paraneoplastic hypercalcemia in PSCC represents a rare metabolic emergency. While aggressive management can achieve biochemical correction, the occurrence of hypercalcemia uniformly indicates advanced tumor biology with limited survival benefit. Early recognition and prompt multidisciplinary intervention remain essential for symptomatic relief and preserving quality of life. Reporting future cases and collaborating with international registries will be necessary to improve understanding of this rare paraneoplastic entity. Full article

Background/Objectives: Bisphosphonates, a class of drugs that are widely used in the treatment of neoplastic diseases, can lead to the development of medication-related osteonecrosis of the jaw (MRONJ). This condition is challenging to manage due to the high incidence of postoperative complications: superinfections, local wound dehiscence, or fractures in pathological bone. The aim of this study is to evaluate the therapeutic role of bovine-derived xenografts in the management of MRONJ. Methods: This retrospective observational study evaluates the clinical outcomes of patients with confirmed stage II or III MRONJ, after surgical treatment with Bio-Oss application. All patients had received zoledronic acid therapy, which was discontinued for a minimum of four months prior to surgical intervention. The surgical protocol included local debridement, sequestrectomy, and grafting of the residual defect with a bone substitute, followed by periodic clinical evaluations and monitoring of local healing with a follow-up period of up to one year. Results: Of the total number of patients treated according to this surgical protocol, 85.71% achieved favorable healing without complications at 8 weeks. Cases with poor local healing results were more likely to have prolonged zoledronic acid administration. Conclusions: Within the limits of this retrospective observational study, the use of bovine-derived xenografts following sequestrectomy in stage II–III MRONJ was associated with satisfactory local healing in several cases. However, considering the limited sample size and lack of a comparator group, these findings should be interpreted cautiously. To better understand the connection between the length of antiresorptive therapy, surgical management techniques, and postoperative outcomes, more prospective, multicenter trials with bigger patient cohorts are needed. Full article

Objective: Bone-modifying agents (BMA) are central to the prevention of skeletal-related events (SREs) in patients with cancer bone metastases, yet evidence guiding agent selection in very old patients remains limited. This study aimed to compare the effectiveness and safety of Denosumab versus bisphosphonates in patients aged ≥75 years with solid tumour-related bone metastases using a target trial emulation framework. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to emulate a hypothetical randomised trial. Patients aged ≥75 years with solid tumour-related bone metastases initiating Denosumab or bisphosphonates were included. After 1:1 propensity score matching (PSM), 10,662 patients were analysed in each treatment group. The primary outcome was time to first SRE. Secondary outcomes included individual SRE components, all-cause mortality, and safety events. Results: Among 21,324 matched patients (mean age, 75.6 years), bisphosphonate use was associated with a higher risk of SREs compared with Denosumab (hazard ratio [HR], 1.15; 95% CI, 1.06–1.25). The excess risk was driven by pathological fractures (HR, 1.28; 95% CI, 1.10–1.49), whereas other SRE components did not differ significantly. All-cause mortality was higher among bisphosphonate users (HR, 1.41; 95% CI, 1.33–1.49, p < 0.001). Hypocalcaemia occurred more frequently with Denosumab (5.7% vs. 2.4%), while risks of acute kidney injury and end-stage renal disease (ESRD) were similar. Findings were consistent across sensitivity and subgroup analyses. Conclusions: In patients aged ≥75 years with solid tumour-related bone metastases, Denosumab was associated with lower risks of skeletal-related events—particularly pathological fractures—and reduced all-cause mortality compared with bisphosphonates. These results extend randomised trial evidence to a clinically vulnerable population and support Denosumab as a preferred BMA in older adults. Full article