Search Results (141)

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

This study aimed to evaluate the effects of laser photobiomodulation (PBM) therapy in SaOs-2 osteosarcoma cells treated with zoledronic acid (ZA), a bisphosphonate, in vitro, mimicking a bisphosphonate-related osteonecrosis of the jaw (BRONJ) situation. Cells were treated with 100 μM ZA for 24 h and subjected to PBM using wavelengths of 660 nm and 808 nm at energy delivered of 1, 5, 10, and 20 J. After 24 h, metabolic activity, apoptosis, and BAX and BCL-2 gene expression were analyzed. Data were compared using one-way ANOVA followed by Tukey’s post hoc test (p < 0.05). ZA significantly reduced metabolic activity (p < 0.05), an effect attenuated by PBM at 808 nm with 1 J, while BCL-2 expression increased with 1 J at 660 nm and with 1 J and 20 J at 808 nm. However, PBM did not reverse ZA-induced apoptosis. In conclusion, PBM modulated the response of SaOs-2 osteoblastic cells treated with ZA in a wavelength- and dose-dependent manner. PBM at 808 nm and 1 J stimulated cell metabolic activity and upregulated BCL-2 expression, suggesting a potential protective effect against ZA-induced cytotoxicity. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication of antiresorptive and antiangiogenic drugs with no consensus on optimal treatment. This study aimed to evaluate the clinical outcomes of MRONJ patients managed at a tertiary referral center over a 15-year period. Methods: We conducted a retrospective cohort study of 130 patients diagnosed with MRONJ (per AAOMS criteria) at a single tertiary hospital between 2006 and 2021. Data on demographics, underlying disease, drug history, MRONJ stage, triggering events, and treatment (conservative vs. surgical) were collected from medical records. Treatment outcomes were categorized as complete resolution, stable disease, or progression. Univariate and multivariate logistic regression analyses were performed to identify predictors of resolution. Results: Most patients (84.6%) had an underlying malignancy. The primary causative agents were zoledronic acid (47.7%) and denosumab (30.0%), the most frequent site was the mandible (66.2%), and the main trigger was dental extraction (59.2%). Crude resolution rates were 20.3% for conservative management versus 83.6% for surgical management. Treatment was stage-driven, with surgery common in advanced stages. At 12 months, 43.1% of all patients achieved complete resolution, and 52.3% remained stable. Multivariate analysis confirmed surgical treatment as the only independent predictor of complete resolution (OR = 20.1, 95% CI: 8.1–50). Conclusions: In this cohort, conservative care was generally sufficient for Stage I disease, while surgical intervention was the strongest predictor of healing and provided reliable outcomes for advanced MRONJ. These findings support an individualized, stage-appropriate treatment strategy. Full article

Diabetes is a significant risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ), a severe oral complication with limited treatment options. Salivary testing offers a noninvasive approach for monitoring BRONJ risk; however, few studies have investigated salivary biomarkers in BRONJ. This study screened salivary biomarkers that reflect the progression of BRONJ under diabetic conditions. A diabetic BRONJ rat model was established to screen for diabetes-related biochemical biomarkers in saliva. Streptozotocin (STZ) administration elevated blood glucose and glycated albumin levels and altered lipid and renal function markers, confirming diabetes induction. Subsequent zoledronic acid (ZA) administration and extraction of the maxillary first molar delayed epithelialization, inflammatory cell infiltration, bone exposure, and necrosis in extraction sockets, indicating successful establishment of a diabetic BRONJ model. This model showed reductions in submandibular and sublingual gland size, as well as in acinar cell number. Although salivary secretion volume was reduced, saliva samples were successfully collected from all groups. Screening identified elevated urea nitrogen (UN) and total ketone bodies (T-KB) in the STZ + ZA group. These findings suggest that salivary UN and T-KB may reflect disease progression and serve as potential biomarkers for predicting BRONJ risk under diabetic conditions. Full article

Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 µM, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 µg/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress. Full article

Two diphosphonates, etidronic acid (HEDP) and zoledronic acid (ZOL), were radiolabelled with ¹⁶¹Tb and evaluated as potential bone-targeting radiopharmaceuticals. Radiolabeling was performed at pH 7, achieving high radiolabeling yields (greater than 98%) and demonstrating excellent in vitro stability in saline and human serum. Both radiolabeled complexes exhibited hydrophilic behavior, a strong binding affinity to hydroxyapatite, and moderate to high plasma protein binding. Biodistribution studies in healthy Wistar rats demonstrated that ¹⁶¹Tb-HEDP and ¹⁶¹Tb-ZOL achieve high and stable skeletal uptake with rapid blood clearance and minimal soft tissue accumulation. ¹⁶¹Tb-HEDP favored higher initial bone localization, while ¹⁶¹Tb-ZOL showed lower renal and hepatic accumulation, indicating higher safety and selectivity. Compared to unchelated ¹⁶¹TbCl₃, both diphosphonate complexes exhibited significantly higher bone-to-kidney and bone-to-liver ratios, resulting in superior targeting. Complementary experiments with non-radioactive terbium were performed to investigate the redox behavior and confirm complex formation, providing valuable insight into the stability and binding modes of the ligands. Both terbium and the ligands displayed well-defined redox behavior within the potential range of −1 to 1.7 V, with complex formation evidenced by shifts in the oxidation peaks. Density functional theory (DFT) calculations further supported these findings, showing that both phosphonate groups of a ligand coordinate to Tb³⁺, while the hydroxyl groups in HEDP enable intermolecular hydrogen bonding, contributing to additional structural stabilization. Results encourage further investigations of ¹⁶¹Tb-labeled diphosphonates as promising candidates for radionuclide therapy of bone metastases and other skeletal diseases. Full article

Introduction: This study evaluates the efficacy of a nurse practitioner-managed, computer algorithm-supported institutional fracture liaison service (FLS) that provides treatment recommendations for patients with hip fractures. Methods: A retrospective study included patients hospitalized in the Orthopedic ward with hip fractures between April 1 and October 31. The decision-making algorithm recommends zoledronic acid as the default medication, except for patients younger than 65 years, with estimated glomerular filtration rate (eGFR) <35 or prior osteoporosis therapy, who are ordered to undergo endocrinology consultation. Patients with vitamin D deficiency/insufficiency are given a loading dose. Results: Two hundred and eight hip fracture patients were identified. The cohort was predominantly female (137/208, 65.9%); the mean age was 79.9 ± 9.6 years. Nurse practitioner evaluation was performed in 200/208 patients (96.2%). The algorithm provided a treatment recommendation in 140 out of 200 (70.0%), while 60 out of 200 (30.0%) required an endocrinology consultation. A Vitamin D loading dose was given in 89/99 (89.9%) deficiency and 44/62 (71.0%) insufficiency cases. Conclusions: This simplified algorithm-based FLS model demonstrated practicality and feasibility in providing therapeutic recommendations with minimal physician intervention. Full article

Background: This retrospective study compared the effectiveness and preliminary cost evaluation of denosumab and zoledronic acid (ZA) in patients with bone metastases from breast, prostate, and lung cancer. Methods: Patients treated with ZA or denosumab between January 2016 and August 2023 were analyzed. Outcomes included the incidence of skeletal-related events (SREs), time to first SRE, and cost per prevented SRE. An incremental cost-effectiveness analysis (ICER framework) was also performed, using prevention of SREs as the effectiveness outcome. Results: A total of 192 patients in the denosumab group and 239 in the ZA group were included. Denosumab significantly reduced the incidence of SREs compared with ZA (34.8% vs. 51.8%, p < 0.001). The median time to first SRE was longer with denosumab (34.5 vs. 29.1 months), but the difference was not statistically significant (p = 0.593). Stratified analyses showed significant benefit in breast (29.5% vs. 49.2%, p = 0.002) and prostate cancer (43.9% vs. 66.0%, p = 0.035), but not in lung cancer (39.1% vs. 45.9%, p = 0.484). Denosumab was more costly, with an additional USD 4686 per prevented SRE. Conclusions: Denosumab was more effective than ZA in reducing SREs, particularly in breast and prostate cancer patients, but it was associated with higher costs. These findings should be interpreted as preliminary due to the retrospective design and the absence of QALY-based outcomes. Full article

Background/Objectives: The efficacy of zoledronic acid (ZOL) compared to denosumab (DMAB) after teriparatide (TPTD) is largely unknown. We compared the effect of ZOL or DMAB treatment after TPTD on BMD changes and fracture (FX) occurrence. Methods: We retrospectively revised data from 77 patients treated at Fondazione IRCCS Ca’Granda Milan, Italy, with TPTD (≥18 months), given at withdrawal (T0), single ZOL 5 mg (Group A, N = 56) or DMAB 60 mg/6 months (Group B, N = 21). BMD changes and incident FX were assessed after 24 months (T1) in all patients and after 48 months (T2) in 46 patients (Group A1, N = 15, treated with a single ZOL at T0; Group A2, N = 17, treated with ZOL at T0 and T1; Group B, N = 14, treated with DMAB since T0 to T2). Results: During the T0–T1 period, in all groups, both spine (LS) and total hip (TH) T-scores improved (mean ± SD, T0 vs. T1): Group A (LS −2.5 ± 1.2 vs. −2.3 ± 1.3, p = 0.006; TH −2.2 ± 1.0 vs. −2.0 ± 1.1, p = 0.002) and Group B (LS −2.4 ± 1.4 vs. −1.8 ± 1.4, p < 0.001; TH −2.4 ± 1.0 vs. −2.2 ± 1.0, p = 0.003). At T2 vs. T0, all groups showed an increase in TH-BMD (A1 −1.8 ± 0.9 vs. −1.4 ± 1.0, p = 0.008; A2: −1.8 ± 0.8 vs. −1.6 ± 0.9, p = 0.032; B: −2.6 ± 0.7 vs. −2.2 ± 0.7, p < 0.001), while LS-BMD increased only in Group B (−2.7 ± 1.4 vs. −2.0 ± 1.2, p = 0.002), with stability in A1 and A2. No significant differences in incident FX between groups were observed. Conclusions: At 24 months after TPTD withdrawal, both ZOL and DMAB improved BMD at all sites; after 48 months, both ZOL (1 or 2 infusions) and DMAB led to BMD improvement at TH, whereas only DMAB led to an increase in LS-BMD. Full article

Background/Objectives: The combination of denosumab treatment with biological disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) in patients with inflammatory rheumatic diseases (IRD) may raise safety concerns for clinicians, particularly regarding infections. In this study, we investigated whether the risk of infection increases in patients who receive bDMARDs or tsDMARDs for IRD and are simultaneously treated with denosumab for osteoporosis (OP). Methods: As a control group, we evaluated patients receiving bDMARDs or tsDMARDs concomitantly with zoledronic acid (ZA), which is not clearly associated with infections. A total of 88 patients—including 30 patients receiving bDMARDs or tsDMARDs with ZA and 58 patients receiving bDMARDs or tsDMARDs with denosumab—met the criteria and were included in this study. The groups were compared in terms of the ratio/risk of serious infections requiring hospitalisation and infections requiring outpatient treatment after applying the inverse probability of treatment weighting (IPTW) to the control for confounding factors. The Cox proportional hazards regression model was used to compare the risks of infection, taking confounding factors into account. Results: The mean age of patients in the ZA group was 59.07 years (±SD: 13.65), while that of patients in the denosumab group was 69.93 years (±SD: 11.72). Comorbidities occurred more frequently in the denosumab group (n = 44, 75.86%) than in the ZA group (n = 14, 46.66%). The median duration of medication use in the denosumab group was 24 months (minimum: 6 months; maximum: 72 months). The median duration of medication use in the ZA group was 24 months (minimum: 12 months; maximum: 60 months). When comparing the groups regarding the risk of infection, denosumab was not associated with an increased risk of either a serious infection requiring hospitalisation (Hazard Ratio (HR): 0.37; 95% Confidence Interval (CI): 0.14–0.94) or an infection requiring outpatient treatment (HR: 0.29; 95% CI: 0.12–0.71). Conclusions: In conclusion, the combination of denosumab treatment with bDMARD or tsDMARD treatments is safe for short-term use. Full article

Osteoporosis compromises bone quality and impairs implant osseointegration. Since an adequate bone bed is essential for implant stability and success, this study evaluated the effects of implant surface functionalization with zoledronic acid (ZOL), alone or combined with ruterpy (TERPY), on peri-implant bone healing in healthy (SHAM) and osteoporotic (OVX) rats. ZOL has antiresorptive properties, while TERPY exhibits osteoinductive potential. The hypothesis was that ZOL + TERPY would act synergistically by inhibiting bone resorption and promoting new bone formation. Sixty-six female Wistar rats (3 months old) were divided into six groups (n = 11) according to systemic condition (SHAM or OVX) and implant type: conventional (CONV), ZOL, or ZOL + TERPY. Surgeries (sham or bilateral ovariectomy) were performed on day 0, and implants were placed in the tibial metaphysis on day 90. Fluorochromes were administered on days 104 (calcein) and 114 (alizarin), and euthanasia was performed on day 118. Samples were analyzed histologically via confocal microscopy and micro-computed tomography (Micro-CT). The ZOL + TERPY groups demonstrated significantly accelerated peri-implant bone repair, showing greater bone formation and organization; improved BV/TV, Tb.N, and I.S.; and reduced Tb.Sp and Po.Tot compared to CONV and ZOL-alone groups. In conclusion, ZOL + TERPY enhances and speeds bone healing, even under osteoporotic conditions. Full article

Background and Clinical Significance: Zoledronic acid (ZA) is a widely used bisphosphonate for the prevention of skeletal-related events in patients with metastatic bone disease. While it is generally well tolerated, rare immune-mediated complications may be underrecognized. To date, myocarditis has not been reported in association with ZA. Case Presentation: A 35-year-old woman with metastatic pheochromocytoma developed acute, non-exertional chest pain approximately 36 h after receiving her first intravenous ZA infusion. Laboratory testing revealed elevated high-sensitivity troponin T, peaking at 1182 ng/L. Cardiac magnetic resonance imaging (CMR) demonstrated myocardial edema and subepicardial late gadolinium enhancement, consistent with acute myocarditis per the 2018 revised Lake Louise criteria. An extensive diagnostic workup excluded infectious, autoimmune, and ischemic causes. Symptoms and troponin levels improved following ZA discontinuation and supportive care. In the absence of alternative etiologies, and given the close temporal association with ZA administration, the diagnosis of presumed ZA-associated myocarditis was supported by clinical presentation, biochemical markers, and CMR findings, recognizing that histopathological confirmation is rarely pursued in clinically stable patients. Conclusions: To our knowledge, this is the first reported case of presumed zoledronic acid–associated myocarditis confirmed by cardiac MRI. This report highlights the diagnostic utility of CMR in suspected drug-related cardiac inflammation and the importance of considering myocarditis in patients presenting with unexplained chest pain following ZA infusion, particularly when other causes have been excluded. Full article

Despite the increasing number of novel therapies to treat newly diagnosed multiple myeloma (NDMM), preventing skeletal-related events (SREs) remains a challenge. This review summarizes the mechanistic causes of myeloma bone disease, data supporting the use of bisphosphonates and RANKL inhibitors, and the optimal management of preventing SREs in NDMM patients. Both zoledronic acid (ZA) and denosumab are acceptable treatment options with comparable safety and efficacy profiles. However, in patients who are candidates for autologous stem cell transplant (ASCT), denosumab may be preferred over ZA due to a progression-free survival (PFS) benefit observed in post hoc analyses when used with proteasome inhibitor-based regimens. The optimal duration of bone-directed therapy is unclear, but it is typically given for two years. Supportive care should include dental evaluation at baseline, annually, and if symptoms appear, given the risk for jaw osteonecrosis with both ZA and denosumab. Both drugs should be held in the setting of dental work. Patients should receive adequate calcium and vitamin D supplementation. Supportive procedures such as cement augmentation, radiation, and orthopedic surgery can also help treat compression fractures, uncontrolled pain, cord compression, and pathologic fractures. We conclude with our approach for managing SREs and a review of novel therapies and targets. Full article

A total of 38% of Americans do not meet the Recommended Dietary Allowance (RDA) for calcium including those at risk for osteoporosis. To increase the percentage of patients at risk for osteoporosis who achieve goal calcium RDA intake, a collaborative specialty pharmacy-registered dietitian-nutritionist (RDN) quality improvement program was developed. Patients aged 18 to 90 years old receiving osteoporosis therapy (denosumab, teriparatide, zoledronic acid) or medications that increase bone loss (elagolix, oral prednisone) were provided with a structured assessment and educational intervention. Daily calcium intake included patient self-reported dietary intake plus supplement use. Written and verbal education on increasing dietary intake based on patient preferences was provided with 5 calcium-rich food-source store coupons. Recommendations for supplement selection (citrate vs. carbonate) and/or medication-related problem resolution were provided. Follow-up occurred at 3–6 months. Fifty patients enrolled [94% female, mean age 66.6 years (SD 15.3)] were taking denosumab (36), teriparatide (1), zoledronic acid (1), elagolix (7) and prednisone (5). The mean baseline daily dietary calcium intake was 500 mg (SD 247) with none achieving goal intake with diet alone. Average calcium supplement use in 22 (44%) patients was 686 mg daily (SD 284). At baseline, 17 (34%) met goal daily calcium intake compared to 30 (60%) at post intervention follow-up (p = 0.009). Over half of the store coupons were redeemed. A specialty pharmacy-RDN customized intervention program provides a model for aiding patients to modify calcium intake. Full article

In this study, 3D Mg scaffolds were obtained by the spark plasma sintering (SPS), and a calcium phosphate coating was then obtained on the samples by the plasma electrolytic oxidation. A hybrid coating with vancomycin, zoledronic acid, and menaquinone MK-7 was formed to improve biocompatibility. The mechanical properties of the formed specimens were studied. According to XRD, XRF, SEM, EDS, and OSP studies obtained scaffolds have developed morphology and contain hydroxyapatite as well as bioactive substances. Formation of coatings improves the wettability of samples (contact angle decreases from 123.8 ± 3.1° to 26.9 ± 4.1°) and increases the surface roughness by more than 3 times. This makes them promising for use as a new generation of implantation materials. The results are important for the development of personalized implants with improved functional characteristics. Full article