Mazabraud's syndrome in female patients: Two case reports.

BACKGROUND: Mazabraud's syndrome (MS) is a rare and slowly progressive benign disease characterized by the concurrent presence of fibrous dysplasia of bone and intramuscular myxoma, and is thought to be associated with mutations of the GNAS gene. To date, only about 100 cases of MS have been reported in the literature, but its standard treatment strategy remains unclear. CASE SUMMARY: We report two cases of MS in young women who underwent different treatments based on their symptoms and disease manifestations. The first patient, aged 37, received internal fixation and intravenous bisphosphonate for a pathological fracture of the right femoral neck, excision of a right vastus medialis myxoma was subsequently performed for pain control, and asymptomatic psoas myxomas were monitored without surgery. Genetic testing confirmed a GNAS gene mutation in this patient. The second patient, aged 24, underwent right vastus intermedius muscle myxoma resection, and conservative treatment for fibrous dysplasia of the ilium. These patients were followed-up for 17 months and 3 years, respectively, and are now in a stable condition. CONCLUSION: Various treatments have been selected for MS patients who suffer different symptoms. The main treatment for myxomas is surgical resection, while fibrous dysplasia is selectively treated if the patient experiences pathological fracture or severe pain. However, given the documented instances of malignant transformation of fibrous dysplasia in individuals with MS, close follow-up is necessary.

Treatment of Medication-Related Osteonecrosis of the Jaws (MRONJ) with Topical Therapy Using Active Oxygen Gel.

Medication-related osteonecrosis of the jaw (MRONJ) can be a debilitating complication that can arise in patients who took or are taking antiresorptive (including bisphosphonates) or antiangiogenic agents, leading to visible bone or a fistula that continues for more than eight weeks, without any history of radiotherapy. This clinical case aimed to describe the treatment of MRONJ with topical active oxygen therapy using blue®m oral gel. A 63-year-old female patient that had been taking weekly sodium alendronate (70 mg) for four years by oral via, presented discomfort and implant movement in the #46 region, by that underwent surgical extraction of the implant. After three months the patient returned and was diagnosed with MRONJ. Initially, conventional therapies were performed, including surgical debridement and antibiotic therapy, but without success. The patient still had clinical signs of osteonecrosis six months after the implant extraction. The entire socket was then filled with blue®m oral gel by topical application. The patient was instructed to continue applying the gel to the region every 8 hours for 15 days. After this period, the patient returned, and it was observed that the wound was in the healing process, with the presence of epithelialized tissue and without bone exposure. The 2-year clinical follow-up showed the lesion had healed entirely, and a new implant was installed. After the osseointegration period, the final prosthesis was placed. The patient remains under clinical follow-up. Therefore, it can be concluded that the application of blue®m oral gel in this clinical case assisted in the recovery of the osteonecrosis lesion.

Detection times of clodronic acid in horses with orthopedic disease.

Clodronic acid is designated as a controlled medication for competition horses by the International Federation for Equestrian Sports and, according to the International Federation of Horseracing Authorities, clodronic acid is not to be administered to racehorses younger than 3.5 years or within 30 days prior to a race. In this study, 35 horses involved in competition were treated with a single dose of 1.53 mg clodronic acid/kg bodyweight intramuscularly. Plasma samples were obtained before treatment and 10, 20, 30, and 40 days post-administration. Clodronic acid concentrations were measured using a validated method, and the data were fitted using a nonlinear mixed effects model. The estimated depletion half-life of clodronic acid was 10.6 days (inter-individual variability: 17.9%). Age, body weight, sex, disease severity, dose, training days, training, and competition did not significantly impact the depletion half-life. The percentage of horses predicted via simulation to have clodronic acid concentrations below the assay's limit of quantification of 1.0 ng/mL was 93.9% at day 30 and 99.4% at Day 40. This study provides rationale to the equestrian federations and horse racing authorities to reliably establish a detection time for clodronic acid, assisting equine veterinarians in recommending a competition withdrawal time for the horses under their care.

Clinically relevant doses of tiludronate do not affect bone remodelling in pasture-exercised horses.

BACKGROUND: Bisphosphonates are widely used in equine athletes to reduce lameness associated with skeletal disorders. Widespread off-label use has led to concern regarding potential negative effects on bone healing, but little evidence exists to support or refute this. OBJECTIVES: To investigate the influence of clinically relevant doses of tiludronate on bone remodelling and bone healing. STUDY DESIGN: Randomised, controlled in vivo experiments. METHODS: Each horse had a single tuber coxae biopsied (Day 0), then were divided into a treatment (IV tiludronate) or control (IV saline) group. Treatments were administered 30 and 90 days following initial biopsy. Biopsy of the tuber coxae was repeated on Day 60 to evaluate bone healing following a single treatment. Oxytetracycline was administered on Days 137 and 147 to label bone formation. The contralateral tuber coxae was biopsied on Day 150 to evaluate effects of repeated treatment. Bone biopsies were evaluated with micro-computed tomography and/or dynamic histomorphometry using standard techniques. RESULTS: Nineteen horses completed the study, with no complications following the biopsies and treatments. No significant differences in the trabecular bone parameters or bone formation rate were observed between treatment groups. MAIN LIMITATIONS: The use of a first-generation bisphosphonate may mean some effects of these drugs are underrepresented using this model. The results pertain to the tuber coxae and may not reflect injury or the healing response that occurs in long bones in training or racing. CONCLUSIONS: In this model, tiludronate did not affect normal bone remodelling in the horse, despite repeat dosages.

Atypical Fracture of the Scapular Spine: A Case Report.

Atypical fractures are gaining attention as a severe potential side effect of long-term treatment with bone-modifying agents (e.g., bisphosphonate and denosumab) for osteoporosis. Most atypical fractures occur in weight-bearing bones; the femur is the most frequent site. Atypical fractures occurring in non-weight-bearing bones are extremely rare. We describe an atypical fracture of the scapular spine in a 92-year-old Japanese woman with osteoporosis who had been treated with minodronate for ~7 years. Although the dislocation of the fracture site remained after conservative treatment, there was no obstacle to her daily life.

Bisphosphonates synergistically enhance the antifungal activity of azoles in dermatophytes and other pathogenic molds.

Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As current treatment options are limited, recent research has explored drug synergy with azoles for dermatophytoses. Bisphosphonates, which are approved to treat osteoporosis, can synergistically enhance the activity of azoles in diverse yeast pathogens but their activity has not been explored in dermatophytes or other molds. Market bisphosphonates risedronate, alendronate, and zoledronate (ZOL) were evaluated for antifungal efficacy and synergy with three azole antifungals: fluconazole (FLC), itraconazole (ITR), and ketoconazole (KET). ZOL was the most active bisphosphonate tested, displaying moderate activity against nine dermatophyte species (MIC range 64-256 µg/mL), and was synergistic with KET in eight of these species. ZOL was also able to synergistically improve the anti-biofilm activity of KET and combining KET and ZOL prevented the development of antifungal resistance. Rescue assays in Trichophyton rubrum revealed that the inhibitory effects of ZOL alone and in combination with KET were due to the inhibition of squalene synthesis. Fluorescence microscopy using membrane- and ROS-sensitive probes demonstrated that ZOL and KET:ZOL compromised membrane structure and induced oxidative stress. Antifungal activity and synergy between bisphosphonates and azoles were also observed in other clinically relevant molds, including species of Aspergillus and Mucor. These findings indicate that repurposing bisphosphonates as antifungals is a promising strategy for revitalising certain azoles as topical antifungals, and that this combination could be fast-tracked for investigation in clinical trials. IMPORTANCE: Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.

Best Bisphosphonate Threshold for 10-Year Vertebral and Non-vertebral Fracture Mitigation.

AIMS: This study was aimed to determine the ideal thresholds for bone mineral densities in our tested Jordanian cohort to initiate bisphosphonate pharmacotherapeutics in order to establish a national protocol for prescribing bisphosphonates that is tailored to the local population, rather than relying on global T and Z scores standards. METHODS: This retrospective study analyzed the entire population of adult patients at Prince Rashid bin Al-Hussein Hospital Rehabilitation and Rheumatology Center between August and October 2023 for the purpose of screening, monitoring, diagnosing, and treating osteoporosis. The study included 328 clients suspected to have osteoporosis, selected based on criteria such as primary osteoporosis or potential secondary osteoporosis. The study used two fracture risk assessment tools (FRAX) dichotomized states: <3% (negative state) and ≥3% (positive state), as well as <20% (negative state) and ≥20% (positive state). Binary logistic regression analysis, receiver-operating characteristic, and sensitivity analysis tests were performed sequentially to analyze the performance of prognosticators and sensitivity indices to evaluate their sensitivity, specificity, and accuracy indexes. RESULTS: The study involved 328 clients at a rehabilitation clinic, with 82.62% (271) females and 17.38% (57) males. The majority were aged between 60 and 69 years, with a slightly higher obesity rate in females. The study found that initiation of bisphosphonates in Jordanian cohorts with optimal bone mineral density thresholds of 0.775 g/cm2 may significantly reduce the risk of hip osteoporosis over 10 years, with sensitivity, specificity, and accuracy indexes of 78.6%, 88.46%, and 50.61%, respectively, with a performance utility of 0.896±0.026 (p-value<0.001), 95% CI (0.846-0.946). CONCLUSION: Due to ethnicity differences, exploring regional or national specific bone mineral density thresholds for bisphosphonates initiation may be a better optional choice than adopting global T-score standards.

The Potential of Radiolabeled Bisphosphonates in SPECT and PET for Bone Imaging.

Skeletal-related events due to bone metastases can be prevented by early diagnosis using radiological or nuclear imaging techniques. Nuclear medicine techniques such as Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been used for diagnostic imaging of bone for decades. Although it is widely recognized that conventional diagnostic imaging techniques such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) have high sensitivity, low cost and wide availability, the specificity of both techniques is rather low compared to nuclear medicine techniques. Nuclear medicine techniques, on the other hand, have improved specificity when introduced as a hybrid imaging modality, as they can combine physiological and anatomical information. Two main radiopharmaceuticals are used in nuclear medicine: [99mTc]-methyl diphosphonate ([99mTc]Tc-MDP) from the generator and [18F]sodium fluoride ([18F]NaF) from the cyclotron. The former is used in SPECT imaging, while the latter is used in PET imaging. However, recent studies show that the role of radiolabeled bisphosphonates with gallium-68 (68Ga) and fluorine-18 (18F) may have a potential role in the future. This review, therefore, presents and discusses the brief method for producing current and future potential radiopharmaceuticals for bone metastases.

Targeted delivery of anti-osteoporosis therapy: Bisphosphonate-modified nanosystems and composites.

Osteoporosis (OP) constitutes a significant health concern that profoundly affects individuals' quality of life. Bisphosphonates, conventional pharmaceuticals widely employed in OP treatment, encounter limitations related to inadequate drug targeting and a short effective duration, thereby compromising their clinical efficacy. The burgeoning field of nanotechnology has witnessed the development and application of diverse functional nanosystems designed for OP treatment. Owing to the bone tissue affinity of bisphosphonates, these nanosystems are modified to address shortcomings associated with traditional drug delivery. In this review, we explore the potential of bisphosphonate-modified nanosystems as a promising strategy for addressing osteoporotic conditions. With functional modification, these nanosystems exhibit a targeted and reversible effect on osteoporotic remodeling, presenting a promising solution to enhance precision in drug delivery. The synthesis methods, physicochemical properties, and in vitro/in vivo performance of bisphosphonate-modified nanosystems are comprehensively examined in this review. Through a thorough analysis of recent advances and accomplishments in this field, we aim to provide insights into the potential applications and future directions of bisphosphonate-modified nanosystems for targeted and reversible osteoporotic remodeling.

Spectrum of activity and mechanisms of azole-bisphosphonate synergy in pathogenic Candida.

Candidiasis places a significant burden on human health and can range from common superficial vulvovaginal and oral infections to invasive diseases with high mortality. The most common Candida species implicated in human disease is Candida albicans, but other species like Candida glabrata are emerging. The use of azole antifungals for treatment is limited by increasing rates of resistance. This study explores repositioning bisphosphonates, which are traditionally used for osteoporosis, as antifungal synergists that can improve and revitalize the use of azoles. Risedronate, alendronate, and zoledronate (ZOL) were tested against isolates from six different species of Candida, and ZOL produced moderate antifungal activity and strong synergy with azoles like fluconazole (FLC), particularly in C. glabrata. FLC:ZOL combinations had increased fungicidal and antibiofilm activity compared to either drug alone, and the combination prevented the development of antifungal resistance. Mechanistic investigations demonstrated that the synergy was mediated by the depletion of squalene, resulting in the inhibition of ergosterol biosynthesis and a compromised membrane structure. In C. glabrata, synergy compromised the function of membrane-bound multidrug transporters and caused an accumulation of reactive oxygen species, which may account for its acute sensitivity to FLC:ZOL. The efficacy of FLC:ZOL in vivo was confirmed in a Galleria mellonella infection model, where combinations improved the survival of larvae infected with C. albicans and C. glabrata to a greater extent than monotherapy with FLC or ZOL, and at reduced dosages. These findings demonstrate that bisphosphonates and azoles are a promising new combination therapy for the treatment of topical candidiasis. IMPORTANCE: Candida is a common and often very serious opportunistic fungal pathogen. Invasive candidiasis is a prevalent cause of nosocomial infections with a high mortality rate, and mucocutaneous infections significantly impact the quality of life of millions of patients a year. These infections pose substantial clinical challenges, particularly as the currently available antifungal treatment options are limited in efficacy and often toxic. Azoles are a mainstay of antifungal therapy and work by targeting the biosynthesis of ergosterol. However, there are rising rates of acquired azole resistance in various Candida species, and some species are considered intrinsically resistant to most azoles. Our research demonstrates the promising therapeutic potential of synergistically enhancing azoles with non-toxic, FDA-approved bisphosphonates. Repurposing bisphosphonates as antifungal synergists can bypass much of the drug development pipeline and accelerate the translation of azole-bisphosphonate combination therapy.

Novel Histopathological Findings of Micro Bone Fragments and Epithelial Response in the Oral Mucosa in Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurs in the jawbone and interfacing oral mucosa of patients treated with bisphosphonates. Herein, we report novel histopathological findings in the oral mucosa of a surgical specimen obtained from a 61-year-old man with BRONJ. The resected jawbone and adjacent oral mucosa were separated for histological examination. The mucosal tissue was examined using Von Kossa staining and immunohistochemical (CK5/6, p63) staining of non-decalcified paraffin sections. Pseudoepitheliomatous hyperplasia (PEH), a microscopic feature of the mucosal epithelium in BRONJ, was observed in soft tissue specimens, concomitant with inflammatory cell infiltration. Von Kossa staining revealed small fragments of necrotic bone, tens to hundreds of micrometers in size, scattered within the connective tissues; the PEH forefront contacted some of the bone fragments. Immunohistochemical staining demonstrated that occasionally, the PEH not only contacted but also encompassed the bone fragments. To our knowledge, this is the first report of presence of micro bone fragments and their association with PEH in the oral mucosa in BRONJ.

Does the use of bisphosphonates during pregnancy affect fetal outcomes? A systematic review.

PURPOSE: This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. METHODS: A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. RESULTS: From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. CONCLUSION: Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.

The effect of long-term alendronic acid treatment on Modic changes in the lumbar spine: a gender and age-matched study.

BACKGROUND: Low back pain (LBP) affects a significant proportion of the adult population. Potent anti-resorptive drugs such as intravenous zoledronic acid have been demonstrated to reduce Modic changes (MCs) upon magnetic resonance imaging (MRI) of the spine and concomitantly decrease associated LBP. It is uncertain whether oral alendronic acid has a similar effect. METHODS: 82 subjects were recruited in this case-control study. Treatment subjects (n = 41) received oral alendronic acid treatment for at least 1-year and were matched by gender and age (± 2) to control subjects (n = 41) not receiving any anti-osteoporotic medication. The prevalence, type, and extent of MCs were quantified upon T1 and T2-weighted MRIs of the lumbosacral spine. RESULTS: Treatment subjects received oral alendronic acid for 124.0 ± 62.1 weeks at the time of MRI assessment and exhibited a lower prevalence of MCs over the lumbosacral spine (18/41 vs. 30/41, p < 0.001) as compared to control subjects. Amongst both groups, type 2 MCs were predominant. Quantification of type 2 MCs in treatment subjects revealed a significant reduction in area (113 ± 106 mm2 vs. 231 ± 144 mm2, p < 0.01) and volume (453 ± 427 mm3 vs. 925 ± 575 mm3, p < 0.01) affected by type 2 MCs in comparison to matched controls. CONCLUSION: Oral alendronic acid may be useful in the treatment of MC-associated LBP in patients with concomitant osteoporosis.

Radiographical Diagnostic Evaluation of Mandibular Cortical Index Classification and Mandibular Cortical Width in Female Patients Prescribed Antiosteoporosis Medication: A Retrospective Cohort Study.

Osteoporosis is often detected late and becomes severe because of a lack of subjective symptoms. Digital panoramic radiography (DPR) has been reported to be useful for osteoporosis screening based on the morphological classification of the mandibular inferior cortex. The purpose of this study was to evaluate the sensitivity and specificity of the mandibular cortical index (MCI) in the diagnosis of osteoporosis in a group of patients who were and were not using antiosteoporosis medication (AOM). Three hundred and fifty female patients aged 40 years or older who had DPR imaging performed during a 6-year period from December 2015 to February 2022 met the selection criteria. Two examiners recorded mandibular cortical width and MCI from the images. These results were statistically examined together with the patients' demographic data. Forty-nine patients were using AOM (13 nonbisphosphonate/denosumab and 36 bisphosphonate/denosumab). MCI type 3 was the most common in the AOM group. In the MCI classification, DPR imaging among the AOM group was more sensitive (0.95) than that of the control group. This method of estimating osteoporosis based on MCI classification using DPR images has high sensitivity, especially in patients using AOM, suggesting that this method is useful as a screening test.

Bilateral Atypical Femoral Fracture in a Bisphosphonate-Naïve Patient with Prior Long-Term Denosumab Therapy: A Case Report of the Management Strategy and a Literature Review.

The benefits of denosumab as an antiresorptive therapy and in reducing fragility fractures are well documented. However, its association with atypical femur fractures (AFFs), especially in the absence of prior bisphosphonate use, remains poorly understood and warrants further investigation. This case report presents a rare instance of bilateral AFFs in a 78-year-old bisphosphonate-naïve patient with a history of long-term denosumab therapy for previous metastatic breast cancer. Management involved intramedullary nail fixation after initial presentation with a unilateral AFF and a recommendation to cease denosumab therapy. However, the patient subsequently experienced a contralateral periprosthetic AFF below a total hip implant 5 months thereafter and was treated with open reduction internal fixation. This case report highlights the critical need for orthopedic surgeons to maintain a high level of suspicion and vigilance in screening for impending AFFs, especially in patients with a prolonged history of denosumab therapy without prior bisphosphonate use. Furthermore, the growing report of such cases emphasizes the urgent need for comprehensive research aimed at refining treatment protocols that balance the therapeutic benefits of denosumab and its associated risks of AFFs.

Comparison of the Clinical Efficacy of Anabolic Agents and Bisphosphonates in the Patients With Osteoporotic Vertebral Fracture: Systematic Review and Meta-analysis of Randomized Controlled Trials.

Objective: We investigated the clinical efficacy of anabolic agents compared with bisphosphonates (BPs) for the incidence of new osteoporotic vertebral fracture (OVF) and fracture healing of OVF in the patients with OVF via meta-analyses of randomized controlled trials (RCTs). Methods: Electronic databases, including PubMed, Embase, and Cochrane Library were searched for published RCTs till December 2022. The RCTs that recruited participants with osteoporosis at high-/very high-risk of fracture (a history of osteoporotic vertebral or hip fracture) or fresh OVF were included in this study. We assessed the risk of bias on every included RCTs, estimated relative risk (RR) for the incidence of new OVF and fracture healing of OVF, and overall certainty of evidence. Meta-analyses were performed by Cochrane review manager (RevMan) version 5.3. Cochrane risk of bias 2.0 and GRADEpro/GDT were applied for evaluating methodological quality and overall certainty of evidence, respectively. Results: Five hundred eighteen studies were screened, and finally 6 eligible RCTs were included in the analysis. In the patients with prevalent OVF, anabolic agents significantly reduced the incidence of new OVF (teriparatide and romosozumab vs alendronate and risedronate [RR = 0.57, 95% CI 0.45 - 0.71; p < 0.00001; high-certainty of evidence]; teriparatide vs risedronate [RR = 0.50, 95% CI 0.37 - 0.68; p < 0.0001; high-certainty of evidence]. However, there was no evidence of teriparatide compared to alendronate in fracture healing of OVF (RR = 1.23, 95% CI 0.95 - 1.60; p = 0.12; low-certainty of evidence). Conclusion: In the patients with prevalent OVF, anabolic agents showed a significant superiority for preventing new OVF than BPs, with no significant evidence for promoting fracture healing of OVF. However, considering small number of RCTs in this study, additional studies with large-scale data are required to obtain more robust evidences.

Adjunctive recombinant human parathyroid hormone agents for the treatment of medication-related osteonecrosis of the jaw: a report of three cases.

Teriparatide has been effective in treating people diagnosed with medication-related osteonecrosis of the jaw (MRONJ). However, its efficacy is not well established to be accepted as a standard of care. The objective of this paper was to investigate the efficacy of recombinant human parathyroid hormone for the treatment of MRONJ. We report three cases of MRONJ patients with osteoporosis as the primary disease who were treated with a teriparatide agent along with other adjunctive measures. Each patient was administered a teriparatide injection subcutaneously for 16 weeks, 36 weeks, or 60 weeks. Surgical intervention including partial resection, sequestrectomy, decortication, and saucerization took place during the teriparatide administration. Complete lesion resolution was identified clinically and radiographically in all three patients. In patients diagnosed with MRONJ, teriparatide therapy is an efficacious and safe therapeutic option to improve healing of bone lesions. These findings demonstrate that teriparatide in combination with another therapy, especially bone morphogenetic protein, platelet-rich fibrin, or antibiotic therapy, can be an effective protocol for MRONJ.

Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials.

Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.

The effect of antiresorptive therapy on the prevalence and severity of oral lichen planus: a retrospective study.

BACKGROUND: Antiresorptive therapy (AR) disrupts osseous homeostasis and can induce direct irritation over the gastrointestinal mucosa; however, its possible erosive effects on the oral epithelium have not been totally described. Among the most frequent oral erosive lesions, oral lichen planus (OLP) frequently presents as painful mucosal ulcerations, arising from basal membrane inflammatory damage. Thus, the aim of this retrospective study was to describe the association between AR and the incidence of OLP. METHODS: This case-control study included data from 148 patients (17 patients undergoing AR therapy (AR group) / 131 without AR therapy (Control group)). Each patient record was systematically processed and the association between AR drugs and OLP clinical characteristics within both groups was assessed. RESULTS: The erosive form of OLP was significantly more frequent in the AR group than in the Control group (p = 0.029). Indeed, the AR treatment using alendronic acid (41.2%) was the most frequently reported. Additionally, the erosive form of OLP showed the strongest association with pain and burning sensation among the OLP types (p < 0.050). However, disease worsening and AR consumption were not significantly associated (p = 0.150). CONCLUSIONS: Patients under AR therapy show more clinical symptoms associated to the erosive type of OLP. Regardless of the AR therapy, the erosive type of OLP is associated with more severe symptoms.

Hydroxychloroquine and a low activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effects.

Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation and thus have limited effect in preventing osteoporotic fracture. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.