Search Results (550)

Background: Oral bisphosphonates (BPs) are the standard therapy for osteoporosis and skeletal metastases, and exhibit anti-tumor properties in preclinical models. Observational studies assessing their impact on colorectal cancer (CRC) risk have yielded inconsistent results. We aimed to systematically review and meta-analyze the association between oral bisphosphonate use and CRC risk, applying a unified exposure definition. Methods: A systematic search was conducted in PubMed, Embase, and Scopus (January 1966–April 2025) to identify cohort, nested case–control, or population-based case–control studies reporting adjusted estimates of relative risk, odds ratios (ORs), or hazard ratios (HRs) for CRC among oral bisphosphonate users. Two reviewers independently screened studies, extracted data, and assessed quality using the Newcastle–Ottawa Scale. Random-effects meta-analyses pooled risk estimates for “any use” of bisphosphonates, with subgroup analyses by duration of use (<1, 1–3, >3 years). We assessed publication bias through Egger’s test and the trim-and-fill method. Results: A total of eight studies published between 2010 and 2020, including 29,169 CRC cases, fulfilled the inclusion criteria. Any bisphosphonate use was not significantly associated with CRC risk (pooled OR 0.97; 95% C.I., 0.90–1.03). However, 1–3 years of use conferred a protective effect (OR 0.86; 95% C.I., 0.73–0.99), as did >3 years (OR 0.91; 95% C.I., 0.85–0.97). Heterogeneity was moderate, and no significant publication bias was detected. Conclusions: While overall oral bisphosphonate exposure is not significantly linked to CRC risk, prolonged use (≥1 year) appears to reduce risk. Prospective studies and randomized trials are needed to confirm these chemo-preventive effects and guide clinical recommendations. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition often associated with bisphosphonate use, leading to impaired bone healing and difficult clinical management. Given the lack of predictable therapeutic options, this study investigated the effects of systemic ozone therapy on MRONJ healing. This study aimed to analyze the effects of systemic ozone therapy on oral hard and soft tissue healing in senescent rats with medication-related osteonecrosis of the jaw (MRONJ) induced by antiresorptive therapy. Methods: Twenty-eight senescent Wistar rats, aged eighteen months and weighing ~350 g, were used for this study. The animals were divided into four groups. The negative control (SAL) group received saline applications, while the control-treated (SAL+OZ) group received saline applications and ozone therapy (0.7 mg/kg). The MRONJ (ZOL) group received Zoledronate, an intravenous antiresorptive drug (100 μg/kg), and the MRONJ-treated (ZOL+OZ) group received zoledronate application and was treated with systemic ozone therapy (0.7 mg/kg). All rats underwent molar extraction in the third week of the experiment and were euthanized in the seventh week of the experiment. The mandibles were resected, reduced, and prepared for microtomographic analysis, histopathological/histometric analysis, and immunohistochemistry. Results: The ZOL group presented characteristics of vitreous, non-vital, and dense bone, poor vascularization, and high values of inflammation markers compatible with MRONJ. In contrast, the ZOL+OZ group exhibited improvement in alveolar bone and soft tissue healing, a decrease in nonvital bone area, and modulation of local inflammation. Conclusions: It can be concluded that Ozone therapy improved oral hard and soft tissue healing of MRONJ in senescent female rats subjected to antiresorptive drugs and might be considered for future clinical applications. Full article

Background: Solid organ transplant (SOT) recipients are living longer and, consequently, more of them require elective total hip arthroplasty (THA) to restore mobility and improve quality of life. Because these patients are chronically immunosuppressed and often burdened by multiple comorbidities, their peri-operative risk profile may differ substantially from that of the general THA population. This study aimed to evaluate risk factors associated with acute medical and surgical complications, implant survivorship, and overall mortality in patients with a history of SOT who underwent THA. Methods: A total of 173 THA procedures were reviewed in patients with previous SOT. Among them, 64 had undergone liver transplantation (LT), 83 had received renal transplants (RT), and 26 had experienced more than one type of organ transplant (MT). Kaplan–Meier survival analysis was employed to estimate median survival. Complications were examined using univariate analysis through mixed-effects logistic regression, while Cox regression was utilized to assess mortality risk. The median follow-up period extended to 99 months. Results: The proportion of patients experiencing at least one acute medical event was 27% in the LT group, 33% in the RT group, and 38% in the MT group, with no statistically significant difference between groups (p = 0.5). American Society of Anesthesiologists Class (ASA) 4 (Odds Ratio (OR) = 28; p = 0.006) and treatment with bisphosphonates (OR = 2.25; p = 0.03) were associated with higher risk of acute medical complications. Increased age at the time of SOT was linked to a reduced likelihood of surgical complications (OR = 0.94, p = 0.008), as was older age at the time of undergoing THA (OR = 0.92, p = 0.001). The observed rates of reoperation and implant revision were 3% and 1%, respectively. The estimated patient survivorship rates at 1, 5, and 10 years were 98.6, 82, and 58.4%, respectively. Older age at SOT (Hazard Ratio (HR) = 1.06, p < 0.001), at THA (HR = 1.08, p < 0.001), ASA 4 at THA (HR = 7.57, p = 0.02), and atrial fibrillation (AFib) (HR = 3.13, p = 0.02) were associated with higher mortality. Conclusions: ASA 4 and bisphosphonates were associated with a higher risk of acute medical complications, whereas older age was associated with lower surgical complications. Additionally, older age, ASA 4, and AFib were associated with higher mortality. Full article

Background: Medication-related osteonecrosis of the jaw (MRONJ) is drug-induced bone destruction that is exposed for a minimum of 6 to 8 weeks in patients who have not received head and neck radiotherapy and who have not been diagnosed with facial bone metastases. MRONJ treatment outcomes are unpredictable. Therefore, alternative treatment methods are being explored, such as blood-derived platelet-rich preparations enriched with growth factors, including advanced platelet-rich fibrin (A-PRF). The presence of growth factors may enhance healing and reduce post-procedure complications. There are no studies examining the effect of A-PRF on the healing of patients with MRONJ. The aim of this study was to retrospectively evaluate treatment outcomes of patients with MRONJ surgically treated without and with the use of A-PRF. Materials and methods: This retrospective study included 28 patients who suffered from osteomyelitis due to MRONJ and underwent surgical treatment between 2019 and 2024. The patients were divided into two groups: the first group received surgical treatment without A-PRF, and the second group received surgical treatment with the application of A-PRF. This study analyzed demographic and clinical data, as well as treatment outcomes. Results: The patients were aged from 43 to 82 years. The most common cause of MRONJ was the administration of zoledronic acid for oncological reasons (22 patients, 78.6%), given intravenously. In 20 patients (71.4%), the antiresorptive treatment lasted longer than three years. The obtained healing distribution was binomial (presence or absence of healing). Estimation of the probability of healing using the maximum likelihood method provided a result of approximately 64%. The probability of ten or more healed patients in the A-PRF group was 41%. A-PRF helps with a probability of 59%, and without A-PRF, it was lower. Concomitantly, the differences between the group with A-PRF and without A-PRF were not statistically significant. Conclusions: The patients with MRONJ should have regular check-ups with radiological examinations at least every six months to detect possible recurrence. Treatment for MRONJ is long and difficult. Treatment of non-advanced lesions, without additional risk factors (such as treatment with zoledronate intravenously for oncological purposes for 3 years), showed a better prognosis. Sometimes, in addition to surgery, it is necessary to consider alternative methods. A-PRF may enhance MRONJ healing. However, there is no evidence of a significant effect of A-PRF on the healing of MRONJ. Full article

Prostate cancer with bone metastasis exhibits significant heterogeneity, complicating prognosis, and treatment. This study explores the potential of plasma, serum, and urine biomarkers to stratify patients and evaluate their prognostic value. Using two-step clustering, we analyzed baseline levels of Platelet-derived growth factor-BB (PDGF-BB), Insulin-like growth factor-binding protein 1 (IGFBP-1), Bone Morphogenetic Protein 2 (BMP-2), Vascular endothelial growth factor (VEGF) (plasma and urine), prostate-specific antigen (PSA), neuron-specific enolase (NSE), chromogranin A (CgA) and bone-specific alkaline phosphatase (BAP) (serum) and creatinine (Cr), and type I collagen-cross-linked N telopeptide (NTx) (urine) in 29 patients with prostate cancer and bone metastasis. Longitudinal biomarker dynamics were assessed at baseline, 6 months, and 12 months. Clinical outcomes were evaluated using Kaplan–Meier and multivariate analyses. Three distinct groups (C1, C2, and C3) were identified. C1 exhibited elevated pPDGF-BB and pVEGF levels, C3 had increased pBAP and uNTx/Cr, and C2 showed lower biomarker levels. Prior treatments influenced biomarker levels, with bisphosphonates reducing bone turnover markers and radiotherapy correlating with long-term changes in growth factors. Longitudinal analysis revealed unique biomarker dynamics within each group, with a tendency for pPDGF-BB and pVEGF levels to decrease over time in C1, and distinct trends in uNTx/Cr between groups. Despite individual biomarkers failing to predict survival, C3 patients demonstrated significantly worse survival than C1 and C2. Molecular clustering of peripheral blood and urinary biomarkers identifies distinct subgroups with metastatic castration-resistant prostate cancer patients outperforming traditional models in outcome prediction and supporting its potential for personalized treatment and prognosis. Full article

Bisphosphonates (BPs) are drugs used to cure metabolic diseases like osteoporosis and oncological conditions, such as multiple myeloma and bone metastases. The pharmacological activity of these compounds is mediated by their capacity to induce a systemic osteoclast depletion, finally resulting in reduced bone resorption. In spite of their efficacy, the clinical application of BPs is sometimes associated with a frightening side effect known as osteonecrosis of the jaw (ONJ). In principle, a therapeutic approach able to elicit the local re-activation of osteoclast production could counteract the onset of ONJ and promote the healing of its lesions. Using a vitamin D3-dependent model of osteoclast differentiation, it has been previously demonstrated that when used at supra-physiological concentrations, magnesium strongly favors the process under consideration, and its effect is furtherly enhanced by the presence of a BP called zoledronate. Here, we show that similar results can be obtained in a RANKL-dependent model of osteoclast differentiation, suggesting that a topical therapy based on magnesium may be also suitable for ONJ determined by denosumab in light of the ability of this monoclonal antibody to target RANKL. Full article

Bone metastases are a prevalent and debilitating consequence of various cancers, including breast and prostate carcinomas, which significantly compromise patient quality of life due to pain, fractures, and other skeletal-related events (SREs). This review examines the pathophysiology of bone metastases, emphasizing the role of the bone microenvironment in tumor progression through mechanisms such as osteotropism and the dysregulated bone remodeling cycle. The primary focus is on the emerging nano-drug delivery systems (DDS) designed to target the bone microenvironment and improve the therapeutic index of anticancer agents. Current treatments, mainly comprising bisphosphonates and radiotherapy, provide palliative benefits but often have limited efficacy and significant side effects. Innovative strategies, such as bisphosphonate-conjugated nanoparticles and targeted therapies that utilize the unique bone marrow niche, are explored for their potential to enhance drug accumulation at metastatic sites while minimizing systemic toxicity. These approaches include the use of liposomes, polymeric nanoparticles, and inorganic nanoparticles, which can be functionalized to exploit the biological barriers within the bone microenvironment. This review also discusses the challenges and future directions for nano-DDS in clinical settings, emphasizing the need for multidisciplinary research to effectively integrate these technologies into standard care protocols. Full article

Background/Objectives: Hydroxybisphosphonate-conjugated sitafloxacin (HBCS) was developed to achieve higher antibiotic concentrations within infected bone. Small animal studies supported further development, but the feasibility of HBCS treatment in a more clinically relevant and larger animal model is unknown. Methods: In this study, we present case reports on four sheep, each receiving four MRSA-contaminated tibial screws treated with different regimens of intravenous antibiotics. The first two sheep received two screws contaminated with 10³ CFU and two screws contaminated with 10⁵ CFU. Sheep 1 only received vancomycin, starting on day two. Sheep 2 received vancomycin, starting on day 2, but also received 7 doses of HBCS (2 mg/kg/48 h). The protocol for the final two sheep was revised, and both received four screws contaminated with 10³ CFU, and vancomycin was started preoperatively. Sheep 3 and 4 received 7 doses (starting on day 6) and 9 doses (starting on day 2) of HBCS (4 mg/kg/48 h), respectively. Bacteriology was performed on three screws per animal. Longitudinal radiography and histology (n = 1 screw) were assessed for signs of osteolysis and reactive bone formation. Electron microscopy (EM) was performed in the first two sheep to evaluate antibiotic-induced bacterial damage. Results: All sheep tolerated HBCS infusion without clinical signs of discomfort. In addition to a high bacterial load (~10⁴ CFU on all screws), Sheep 1 displayed extensive radiographic and histologic evidence of peri-implant osteolysis and reactive bone formation. Despite having a high bacterial load (~10⁴ CFU on all screws), Sheep 2 displayed only mild radiographic and histologic evidence of peri-implant osteolysis and periosteal reactive bone formation. Bacteriology in Sheep 3 and 4 demonstrated near MRSA eradication (<100 CFU on 2 screws). Both sheep displayed no evidence of osteolysis or new bone formation adjacent to the screw head. EM confirmed the presence of bacteria resorbing bone and replicating in biofilm in Sheep 1, while antibiotic-killed bacteria with ruptured septal planes were seen in Sheep 2. Conclusions: This study demonstrates the feasibility of HBCS therapy in a clinically relevant animal model and provides guidance on future efficacy studies, such as the use of an inoculum of 10³ CFU per screw, the initiation of antibiotic treatment commencing at the time of surgery, and the usability of antibiotic-killed bacteria within altered glycocalyx observed by TEM as a potential biomarker for HBCS efficacy. Full article

Background and Objectives: Osteoporosis is a common chronic condition after menopause that increases the risk of fractures. In South Korea, the prevalence of osteoporosis among adults aged 50 and older is 22.4%, with 94.4% of treated patients being women, highlighting its significant impact on postmenopausal health. In this study, we examine the sales trends of osteoporosis medications in Korea from 2018 to 2023 to understand current usage patterns and market dynamics. Materials and Methods: This study is a retrospective analysis based on pre-recorded sales data from Intercontinental Marketing Services (IMS). Data covering a five-year period (2018–2023) were analyzed to examine the sales trends of osteoporosis medications, including bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone analogs, denosumab, romosozumab, and others. Romosozumab, approved in November 2019, was included in the analysis. Given the nature of this study, no direct patient data or clinical interventions were involved. Results: The total market size for osteoporosis medications in South Korea reached USD 285.42 million in 2023, reflecting a 15.3% increase from 2022. Bisphosphonates, previously the dominant therapy, experienced an 11% decline in market share over five years. Meanwhile, denosumab, a receptor activator of the nuclear factor-κB ligand inhibitor, showed a remarkable growth rate of 957.6% from 2018 to 2023, surpassing bisphosphonates in their market share. Romosozumab, a newly introduced anabolic agent, accounted for 7.4% of the market, with sales increasing by 59% in 2023. Conclusions: This analysis revealed major shifts in treatment preferences, with newer drugs like denosumab and romosozumab gaining prominence over traditional bisphosphonates. These trends highlight the increasing clinical adoption of anabolic agents for high-risk patients and the impact of expanded reimbursement policies on osteoporosis management. Given the increasing use of advanced therapies, it is essential to monitor treatment access, patient adherence, and long-term clinical outcomes. Understanding these sales trends can aid healthcare professionals and policymakers in optimizing osteoporosis treatment strategies and ensuring better patient care. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a multifactorial condition defined as an adverse drug reaction that results in progressive jawbone destruction and necrosis in individuals treated with certain medications, occurring without a history of prior radiotherapy. These drugs are mainly bisphosphonates, denosumab, and other bone-modifying agents, anti-angiogenic agents such as anti-endothelial growth factor, tyrosine kinase inhibitors, and proteins classified as mammalian targets of rapamycin. The diagnosis of MRONJ is based on clinical (exposed jawbone, fistula with pus, hyperplasia of the mucosa overlying the necrotic bone tissue) and radiological evaluation. We report four cases of clinical and radiological evidence of osteonecrosis of the jaw that are unrelated to the use of antiresorptive or anti-angiogenic agents. In two instances, histological and microbiological evidence was also found (high concentration of Actinomyces, the microbe most commonly found in oral sites affected by MRONJ). These atypical cases are reported to highlight the possibility that other, previously undocumented, drugs may also contribute to the development of ONJ Full article

Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively. Full article

Background/Objectives: Osteoporosis is an important health issue worldwide, and bisphosphonates are commonly prescribed for its treatment. However, certain complications can occur with long-term bisphosphonate therapy. The complication highlighted in this study was atypical femoral fractures, which are rare but significant. The orthopedic consensus identifies surgical intervention as the gold-standard treatment for atypical femoral fractures, typically involving intramedullary or cephalomedullary nailing (CMN). The aim was to monitor patients for a follow-up period exceeding six months after surgical fixation with a CMN, with the majority of patients being followed up for more than 18 months after their initial surgery. Methods: This single-center analysis was conducted on a mixed cohort comprising a total of 10 patients. The study was conducted between September and November 2024. The inclusion criterion was surgical treatment for bisphosphonate-related atypical femoral fractures (AFFs) between June 2022 and November 2024 at a Level 1 Trauma Center, Cork University Hospital in the Republic of Ireland. The patients were monitored through a structured follow-up protocol that extended beyond six months, with the majority of patients being followed up for over 18 months. Follow-up assessments were conducted at defined intervals, including key evaluations at 3 and 6 months and at their final review. Clinical parameters such as pain, functional recovery, and radiological healing were considered. Results: No significant functional difference was observed at follow-up between the patients who sustained displaced fractures and those who presented with undisplaced fractures. Sixty percent of the patients remained pain-free from the 3-month postoperative follow-up, and the same percentage continued to be pain-free at the final follow-up. Conclusions: Cephalomedullary nailing is a safe option for the treatment of atypical femoral fractures. Patients with a bisphosphonate atypical femoral fracture should undergo bilateral screening and should be followed up for a longer period than the standard post-traumatic care intervals that are in place for typical femoral fractures. Full article

Osteonecrosis of the jaw (ONJ), including the maxilla and mandible, is considered a challenging therapeutic problem, mainly due to the lack of understanding of its pathogenesis. It is well known that ONJ is a severe side effect caused by certain medications used to treat bone metastasis and osteoporosis, such as bisphosphonates, which inhibit bone resorption. Other therapeutics with similar side effects are, for instance, receptor activators of nuclear factor kappa-B ligand (RANK-L) inhibitor (denosumab), tyrosine kinase inhibitors (sunitinib), and antiangiogenics (bevacizumab). The conservative or surgical treatment of these medication-related osteonecroses of the jaw (MRONJs) is generally effortful and still not entirely effective. Therefore, the research seeks alternative treatment options like tissue engineering and stem cell therapy, which predominantly represent mesenchymal stem cells (MSCs) and their derivatives, such as extracellular vesicles. Moreover, it was published that novel stem cell therapy could even prevent the onset of MRONJ. On the other hand, the administration of stem cells may also be accompanied by some other health risks, such as an increased chance of cancer metastasis occurrence in cancer patients. The current review paper summarizes the most recent progress in stem-cell-based and stem-cell-free treatment options for the ONJ. Similarly, we discuss this novel approach’s future perspectives and possible obstacles. Full article

This review examines the relationship between cholesterol and bone resorption. It seeks to elucidate the dependence of bone turnover on cholesterol metabolism by highlighting the common inhibitory effect of both statins and nitrogen-containing bisphosphonates on cholesterol biosynthesis and bone resorption as well as on bone density. Moreover, this paper also discusses the epidemiologic studies of the effects of nitrogen-containing bisphosphonates on all-cause and cardiovascular mortality using the latest publications to reinforce the relationship between bone resorption and cardiovascular disease. This review will also discuss the role of lipoproteins in supplying cholesterol to both osteoclasts and osteoblasts and the effects of doing so on both of these bone cells and their precursors. As inflammation is a major factor in both bone resorption and cardiovascular calcification, this article will also discuss the role of cholesterol in triggering inflammatory responses. Finally, this paper will raise questions unanswered to date that bear on the relationship between lipid metabolism, bone resorption, and cardiovascular disease. Full article

On 24 February 2024, Italian physicians, dentists and oral care specialists, students, nurses, psychologists, dental hygienists, and other professionals met (live or online) to discuss controversial issues about medication-related osteonecrosis of the jaw (MRONJ). One section hosted international experts who gave lectures about MRONJ experiences in North America, Europe, and Italy. A second section summarized the principal points of an Italian MRONJ position paper published in February 2024 by experts from the Italian Societies of Oral Pathology and Medicine (SIPMO) and Maxillofacial Surgery (SICMF). The following section collates expert opinions about open issues and required fields of research: different definitions of MRONJ and impact on staging; the assessment of individual MRONJ risk before the start of antiresorptive therapy; surgery and implantology in patients at risk for MRONJ; cancer patients without metastases and prevention of cancer-treatment-induced bone Loss (CTIBL); the role of dental hygiene professionals; combined (medical and surgical) and surgical therapy for MRONJ in-patients and out-patients; and legal aspects and claims related to MRONJ diagnosis and treatment. Scientific contributions from hospitals and universities all over Italy were presented in specific sessions (epidemiology; case series; special case reports; prevention experiences; MRONJ treatment). Conclusions: the conference confirmed the importance of the adequate imaging study of bone in the diagnosis and staging of MRONJ cases, the role of surgery in MRONJ treatment, and the value of oral hygiene in the MRONJ prevention. Full article