Development of a zoledronate-modified functional alginate hydrogel with effects of promoting osteogenesis for potential osteoporosis treatment.

Osteoporosis is one of the most prevalent age-related diseases worldwide. It is characterized by a systemic deterioration in bone strength (bone density and bone mass), leading to an increase in fragility fractures. The complex pathological environment of osteoporosis presents a significant challenge to the induction of bone regeneration under osteoporotic conditions. Therefore, the development of a system for local delivery of active substances with osteoinductive effects is of practical significance in the clinical treatment of osteoporosis. In this study, we successfully loaded the anti-osteoporotic small molecule drug zoledronate (ZOL) into calcium alginate to prepare a biologically functional hydrogel, designated as ALG-ZOL-Ca. The prepared ALG-ZOL-Ca hydrogel gels quickly, making the hydrogel easy to inject and adapt to irregularly shaped bone defects, and simultaneously exhibits good bioactivity and osteoconductivity. The RT-qPCR results suggested that this hydrogel effectively promoted the expression levels of ß-catenin and Axin2, which indicating a stimulative effect on the Wnt/ß-catenin pathway in vitro. Moreover, ALG-ZOL-Ca hydrogel effectively promoted the expression of the OCN and SP7 genes. Therefore, this study proposes a new functional composite hydrogel that provides a potential treatment strategy for osteoporosis.

Randomized controlled trial of pre-transplant zoledronate versus observation for prevention of bone loss in allogeneic hematopoietic cell transplantation.

Background: Approximately half of allogeneic hematopoietic cell transplantation (HCT) recipients experience significant bone loss in the early post-HCT period. Only recently have international guidelines started recommending early screening. However, the guidance for intervention remains conservative. In this study, we sought to evaluate the efficacy of pre-transplant prophylactic zoledronate in preventing early bone loss in allogeneic HCT recipients. Methods: This was an open-label, investigator-initiated, phase 2 randomized controlled trial (RCT) of prophylactic zoledronate versus observation to prevent bone loss in allogeneic HCT recipients. Recipients aged ≥ 18 years of age were included after informed consent and randomized to prophylactic zoledronate 4 mg pre-HCT or observation in a 1:1 ratio. The primary outcome of the study was bone mineral density (BMD) loss at the femoral neck (FN), total hip (TH), and lumbar spine (LS), as assessed using dual-energy X-ray absorptiometry (DXA) on day+100 post-HCT. The secondary outcomes included BMD loss on day+365 and Z scores on day+100 and day+365 at the FN, TH, and LS sites. Results: The trial was terminated because the interim analysis showed a significant benefit in the intervention arm, with 50% planned recruitment. A total of 40 patients were randomized to the zoledronate and control arms. Both arms were matched for age, sex, diagnosis, pre-HCT steroid exposure, body mass index, human leukocyte antigen (HLA) match, and conditioning intensity. The grade 2-4 acute graft versus host disease (GVHD) incidences were comparable. The primary endpoint of BMD loss at FN and TH at day+100 was significant (5.62% vs. -6.78%, p = 0.009, -1.59 vs. -3.98, p = 0.016, respectively). There was no difference in the secondary endpoint of BMD loss on day+365 compared to that on day+100 or baseline at any BMD site. There was no difference in the Z-scores at any site on day+100 or day+365. Conclusions: Prophylactic zoledronate prevented early bone loss on day+100. The indicated preemptive zoledronate beyond day+100 in recipients prevented further bone loss. Patients receiving prophylactic zoledronate may benefit from a supplementary dose of the indicated preemptive zoledronate.

Bone health ECHO case report: Orbital inflammation after zoledronate infusion.

Prior to the initiation of intravenous bisphosphonate therapy for osteoporosis, the impact on ocular health is not routinely discussed with patients. This is due to the scarcity of data on the association between bisphosphonates and ocular side effects, resulting in lack of provider awareness to effectively counsel patients. Furthermore, there is little consensus among clinicians on the safety of re-challenging with intravenous bisphosphonate treatment following ocular complications. This is a case report of a patient who developed orbital inflammation four days after receiving a zoledronate infusion. This case was discussed amongst health care providers and osteoporosis experts during a meeting of Bone Health Extension for Community Healthcare Outcomes (ECHO) virtual platform, which was established in 2015.

Zoledronate alleviates subchondral bone collapse and articular cartilage degeneration in a rat model of rotator cuff tear arthropathy.

OBJECTIVE: To evaluate the humeral head bone volume of patients with cuff tear arthropathy (CTA) and examine the therapeutic effect of zoledronate in a rat modified model of CTA (mCTA). DESIGN: The bone mass in patients with CTA was measured using Hounsfield units from CT images. The mCTA was induced by transecting the rotator cuff, biceps brachii tendon, and superior half of the joint capsule in adult rat shoulders. A single subcutaneous injection of zoledronate was followed by bone histomorphometry and immunohistochemistry of the humeral head, as well as the Murine Shoulder Arthritis Score (MSAS) assessment. RESULTS: The humeral head bone volume was decreased in patients with CTA. In the mCTA model, M1 macrophages were increased in the synovium and were decreased by zoledronate treatment. The increased expressions of TNF-α, IL-1ß and IL-6 in mCTA synovium and articular cartilage were suppressed in the zoledronate-treated mCTA group. The expression of catabolic enzymes in the articular cartilage and MSAS showed similar results. The zoledronate-treated mCTA group showed a decreased subchondral bone collapse with a decreased RANKL/OPG expression ratio and a suppressed number of osteoclasts compared with the control mCTA group. The enhanced expressions of HMGB1 and S100A9 in the mCTA shoulders were eliminated in the zoledronate-treated mCTA group. CONCLUSIONS: The humeral head subchondral bone was decreased in patients with CTA. In the mCTA model, the collapse and osteoarthritic changes were prevented by zoledronate administration. Zoledronate seemed to suppress the number of M1 macrophages in the synovium and osteoclasts in the subchondral bone.

Transmembrane protein 53 craniotubular dysplasia (OMIM # 619727): The skeletal disease and consequent blindness of this new disorder.

Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation. Consequently, defective TMEM53 accelerates osteogenesis. Herein, an American boy is compound heterozygous for a novel deletion and a novel missense mutation within TMEM53. His vision and sensorineural hearing became impaired. Radiographic survey revealed diploic thickening of his skull, broad calvarial and facial bones, skeletal modeling errors, vertebral body flattening, wide ribs, and osteopenia of expanded bones. DXA areal bone density (gm/cm2) Z-scores were low. His optic, auditory, and spinal canals were narrow. Mineral metabolism was intact. Serum alkaline phosphatase and osteocalcin levels were normal yet CTX was high. Iliac crest histomorphometry documented accelerated bone formation. His acute vision loss briefly improved following prednisone administration, optic canal decompression, and optic nerve sheath fenestration, but then progressed despite further surgeries and zoledronate treatment aimed to suppress bone turnover. Next generation sequencing of genes associated with elevated skeletal mass, including from high bone turnover, did not suggest an etiology. Whole genome sequencing then revealed within TMEM53: i) a paternally transmitted 54-base deletion, which included the mRNA splice acceptor site for exon 2 as well as 31 bases of exonic sequence (c. 62-23_92del), and ii) a maternally transmitted missense variant (c.650C > T, p.Ser217Leu: NM_024587.4/NP_078863.2) which is extremely rare in gnomAD (frequency = 0.000036), replaces Ser217 highly conserved across species, and is scored as damaging by SIFT and Mutation Taster. We call this new osteopathy TMEM53 craniotubular dysplasia.

Case report: A severe case of zoledronate-associated diffuse orbital inflammation and uveitis in a patient with metastatic breast cancer.

Introduction: Zoledronate is a commonly prescribed medication to maintain bone health; however, a rare side effect includes ocular inflammation. We report a case of simultaneous anterior uveitis and orbital inflammation associated with zoledronate infusion in a patient with metastatic breast cancer. We also performed a literature search to provide an up-to-date summary of cases with zoledronate-associated ocular inflammation. Methods: This is a case report with literature review. Literature search (timeline 2010 to 2023) was performed using PubMed with the search team: (zoledronate) AND (uveitis OR scleritis OR orbital inflammation OR ocular inflammation). Results: A 48-year-old female presented with left eye pain, swelling, and decreased vision 2 days after receiving zoledronic acid infusion. An ophthalmic exam showed non-granulomatous anterior uveitis. CT orbits and ocular ultrasound showed signs of posterior scleritis and orbital inflammation. Ocular inflammation caused by an infection or metastatic cancer was ruled out. The patient was treated with both topical and systemic corticosteroids. Complete resolution of the inflammation occurred after 2.5 weeks. Conclusion: Orbital inflammation and uveitis are an uncommon side effect of zoledronate but needs to be promptly recognized and treated to prevent sight-threatening complications.

Farnesyl pyrophosphate synthase inhibitors with antiosteoporosis efficacy in ovariectomized rats: A mixed binding approach beyond bisphosphonates.

The primary focus of bisphosphonate medications is on targeting human farnesyl pyrophosphate synthase (hFPPS), an essential regulator of mammalian isoprenoids. Yet, these drugs encounter limitations due to their restricted "druglike" properties and their effectiveness primarily in treating skeletal disorders. In this study, we synthesized novel non-bisphosphonate compounds, using 4,4'-(ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde) (1) as a starting compound, with the aim of targeting hFPPS through a mixed binding approach. Among the various compounds tested, compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC50 values of 1.108 and 1.24 µM, respectively. Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. In an in vivo study conducted on ovariectomized rats, various biochemical markers including osteocalcin, estradiol, osteoprotegerin, bone mineral content, and density were negatively impacted, while levels of bone specific alkaline phosphatase, receptor activator of nuclear factor kappa-Β ligand, serum/urinary calcium, and phosphate increased. Notably, compound 4a exhibited antiresorptive properties similar to zoledronate, effectively restoring most of the perturbed biochemical estimations. These findings suggest the potential of compound 4a, a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis.

A randomised trial comparing 6-monthly adjuvant zoledronate with a single one-time dose in patients with early breast cancer.

PURPOSE: While adjuvant bisphosphonate use in early breast cancer (EBC) is associated with improvements in breast cancer-specific outcomes, questions remain around optimal bisphosphonate type, dose and scheduling. We evaluated a single zoledronate infusion in a prospective randomised trial. METHODS: Postmenopausal patients with EBC were randomised to receive a single infusion of zoledronate (4 mg IV) or 6-monthly treatment for 3 years. Outcomes measured were; Quality of Life (QoL; EQ-5D-5L), bisphosphonate-related toxicities, including acute phase reactions (APRs), recurrence-free survival (RFS), bone metastasis-free survival (BMFS) and overall survival (OS). RESULTS: 211 patients were randomized to either a single infusion (n = 107) or six-monthly treatment (n = 104). After 3 years of follow up there were no significant differences between the arms for QoL and most toxicity endpoints. APRs following zoledronate occurred in 81% (171/211) of patients (77.6% in single infusion arm and 84.6% in the 6-monthly group). While the frequency of APRs decreased over 3 years in the 6-monthly arm, they still remain common. Of 34/104 (32.7%) patients who discontinued zoledronate early in the 6-monthly treatment group, the most common reason was APRs (16/34, 47%). At the 3 year follow up, there were no differences between arms for RFS, BMFS or OS. CONCLUSION: A single infusion of zoledronate was associated with increased patient convenience, less toxicity, and lower rates of treatment discontinuation. Despite the common clinical impression that APRs decrease with time, this was not observed when patients were specifically questioned. While the study is not powered for non-inferiority, longer-term follow-up for confirmation of RFS and OS rates is ongoing.

Difficult Diagnosis and Management of Concealed Cushing.

BACKGROUND: Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. CASE REPORT: A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. CONCLUSION: ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

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.

Bisphosphonate alternative regimens for the prevention of osteoporotic fragility fractures: BLAST-OFF, a mixed-methods study.

Background: Bisphosphonates are a class of medication commonly used to treat osteoporosis. Alendronate is recommended as the first-line treatment; however, long-term adherence (both treatment compliance and persistence) is poor. Alternative bisphosphonates are available, which can be given intravenously and have been shown to improve long-term adherence. However, the most clinically effective and cost-effective alternative bisphosphonate regimen remains unclear. What is the most cost-effective bisphosphonate in clinical trials may not be the most cost-effective or acceptable to patients in everyday clinical practice. Objectives: 1. Explore patient, clinician and stakeholder views, experiences and preferences of alendronate compared to alternative bisphosphonates. 2. Update and refine the 2016 systematic review and cost-effectiveness analysis of bisphosphonates, and estimate the value of further research into their benefits. 3. Undertake stakeholder/consensus engagement to identify important research questions and further rank research priorities. Methods: The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: • Stage 1A - we elicited patient and healthcare experiences to understand their preferences of bisphosphonates for the treatment of osteoporosis. This was undertaken by performing a systematic review and framework synthesis of qualitative studies, followed by semistructured qualitative interviews with participants. • Stage 1B - we updated and expanded the existing Health Technology Assessment systematic review and clinical and cost-effectiveness model, incorporating a more comprehensive review of treatment efficacy, safety, side effects, compliance and long-term persistence. • Stage 2 - we identified and ranked further research questions that need to be answered about the effectiveness and acceptability of bisphosphonates. Results: Patients and healthcare professionals identified a number of challenges in adhering to bisphosphonate medication, balancing the potential for long-term risk reduction against the work involved in adhering to oral alendronate. Intravenous zoledronate treatment was generally more acceptable, with such regimens perceived to be more straightforward to engage in, although a portion of patients taking alendronate were satisfied with their current treatment. Intravenous zoledronate was found to be the most effective, with higher adherence rates compared to the other bisphosphonates, for reducing the risk of fragility fracture. However, oral bisphosphonates are more cost-effective than intravenous zoledronate due to the high cost of zoledronate administration in hospital. The importance of including patients and healthcare professionals when setting research priorities is recognised. Important areas for research were related to patient factors influencing treatment selection and effectiveness, how to optimise long-term care and the cost-effectiveness of delivering zoledronate in an alternative, non-hospital setting. Conclusions: Intravenous zoledronate treatment was generally more acceptable to patients and found to be the most effective bisphosphonate and with greater adherence; however, the cost-effectiveness relative to oral alendronate is limited by its higher zoledronate hospital administration costs. Future work: Further research is needed to support people to make decisions influencing treatment selection, effectiveness and optimal long-term care, together with the clinical and cost-effectiveness of intravenous zoledronate administered in a non-hospital (community) setting. Limitations: Lack of clarity and limitations in the many studies included in the systematic review may have under-interpreted some of the findings relating to effects of bisphosphonates. Trial registration: This trial is registered as ISRCTN10491361. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR127550) and is published in full in Health Technology Assessment; Vol. 28, No. 21. See the NIHR Funding and Awards website for further award information.

Bisphosphonates are drug treatments commonly used to treat osteoporosis. Alendronate is the most used and is taken by mouth, weekly at a specific time of the week, which can be challenging. Less than one in four people continue this treatment beyond 2 years. Alternative bisphosphonates are available, which vary in frequency and how they are administered. The most acceptable and best value-for-money regimen is unclear. Our aim was to determine how effective alternative bisphosphonates are compared to alendronate at preventing fractures and whether reduction in fracture risk was achieved at a reasonable financial cost, but acceptable to patients. The study was conducted in two stages, stages 1A and 1B in parallel, followed by stage 2: Stage 1A: a review of the published evidence on patients' and doctors' views, experiences and preferences regarding different bisphosphonate treatment regimens, followed by interviews with patients and healthcare professionals. Stage 1B: an update of an existing study on how effective bisphosphonates are in preventing fragility fractures caused by osteoporosis and whether they are good value for money. Stage 2: identification of questions that need to be answered about the effectiveness and acceptability of bisphosphonate treatments. Taking bisphosphonate medication often involves quite a lot of effort by patients, particularly when taking alendronate tablets. A yearly infusion of zoledronate treatment was more acceptable, easier to engage with and the most effective treatment compared to alendronate. However, the cost of administering zoledronate in hospital made alendronate better value for money. Bisphosphonates are effective in reducing the risk of fracture, but 'continuing with treatment', particularly alendronate tablets, remains a challenge. A yearly infusion of zoledronate offers an acceptable and effective treatment, but further research is needed to support patients and healthcare professionals in making decisions about the various treatments, benefits and cost savings of administering zoledronate outside of hospital and in the community.

The potential role of SNHG16/ miRNA-146a/ TRAF6 signaling pathway in the protective effect of zoledronate against colorectal cancer and associated osteoporosis in mouse model.

Bone fracture as a consequence of colorectal cancer (CRC) and associated osteoporosis (OP) is considered a risk factor for increasing the mortality rate among CRC patients. SNHG16/ miRNA-146a/ TRAF6 signaling pathway is a substantial contributor to neoplastic evolution, progression, and metastasis. Here, we investigated the effect of zoledronate (ZOL) on the growth of CRC and associated OP in a mouse model. Thirty Balb/c mice were divided into Naïve, azoxymethane (AOM)/dextran sodium sulfate (DSS), and ZOL groups. Body weight and small nucleolar RNA host gene 16 (SNHG16) expression, microRNA-146a, and TRAF6 in bone, colon, and stool were investigated. Samples of colon and bone were collected and processed for light microscopic, immunohistochemical staining for cytokeratin 20 (CK20), nuclear protein Ki67 (pKi-67), and caudal type homeobox transcription factor 2 (CDx2) in colon and receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) in bone. A computerized tomography (CT) scan of the femur and tibia was studied. ZOL produced a significant decrease in the expression of SNHG16 and TRAF6 and an increase in miRNA-146a in the colon and bone. ZOL administration improved the histopathological changes in the colon, produced a significant decrease in CK20 and Ki-67, and increased CDx2 expressions. In bone, ZOL prevented osteoporotic changes and tumour cell invasion produced a significant decrease in RANK and an increase in OPG expressions, alongside improved bone mineral density in CT scans. ZOL could be a promising preventive therapy against colitis-induced cancer and associated OP via modulation expression of SNHG16, miRNA-146a, and TRAF6.

Zoledronate After Denosumab Discontinuation: Is Repeated Administrations More Effective Than Single Infusion?

BACKGROUND: After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. METHODS: We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. RESULTS: Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, P = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P = .009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P = .014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. CONCLUSION: In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX.

Comparison of the Efficacy of Zoledronate and Denosumab in Patients with Acute Osteoporotic Vertebral Compression Fractures: A Randomized Controlled Trial.

Background: The comparison of the efficacy of zoledronate and denosumab for treating osteoporosis is controversial, and few randomized controlled trials have compared these two drugs in practical patients with acute osteoporotic vertebral compression fractures (OVCFs). We conducted a randomized controlled study to compare the efficacy of zoledronate and denosumab in patients with acute OVCF, with a focus on the occurrence of new OVCF. Methods: We enrolled 206 subjects who had their first acute OVCF, without any previous history of osteoporosis medication. The patients were randomly assigned to receive either intravenous zoledronate once a year or subcutaneous denosumab twice a year. We investigated the OVCF recurrence, clinical outcome, bone mineral density (BMD), and bone turnover markers over 12 months. Results: The final cohort comprised 89 participants (mean age of 75.82 ± 9.34 years, including 74 women [83.15%]) in the zoledronate group and 86 patients (mean age of 75.53 ± 10.23 years, including 71 women [82.56%]) in the denosumab group. New OVCFs occurred in 8 patients (8.89%) in the zoledronate group and 11 patients (12.79%) in the denosumab group (odds ratio, 1.485 [95% confidence interval, 0.567-3.891], p = 0.419). No significant difference was observed in the survival analysis between the two groups (p = 0.407). The clinical outcome, including the visual analog scale score for pain and simple radiographic findings, did not differ between the two groups. The changes in BMD and bone turnover markers were also not significantly different between the two groups. Additionally, drug-related adverse events did not differ between the groups in terms of safety. Conclusions: The efficacy of zoledronate was comparable to that of denosumab in terms of the occurrence of new OVCFs, as well as of the overall clinical course in patients with their first acute OVCF. Notably, this study represents the first comparison of these two drugs in patients with acute OVCF. However, further research with large-scale and long-term follow-up is necessary.

Real-World Evaluation of Primary Versus Secondary Prevention of Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. METHODS: Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98 646) who received continuous androgen deprivation therapy (n = 29 453), died of prostate cancer (2013-2018, n = 3864), and received life-prolonging therapy for mCRPC (n = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. RESULTS: Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n = 447) or started BTA only after first bone radiotherapy (n = 401). More patients received denosumab (n = 825, 77%) than zoledronic acid (n = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P = .023), de novo metastases (OR = 1.4, P = .005), medical oncologist involvement (OR = 2.0, P = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P = .034), and academic center (OR = 0.061, P = .007). CONCLUSION: A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy.

Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: Promising therapy against post-COVID-19 pulmonary fibrosis.

BACKGROUND: Rho kinase (ROCK) pathway plays a critical role in post-COVID-19 pulmonary fibrosis (PCPF) and its intervention with angiotensin-converting enzyme 2 (ACE2) and vascular endothelial growth factor (VEGF) will be a potential therapeutic target. OBJECTIVES: The present study was conducted to investigate the efficacy of zoledronate (ZA) on carbon tetrachloride (CCl4) induced pulmonary fibrosis (PF) in rats through targeting ACE2, ROCK, and VEGF signaling pathways. METHODS: Fifty male Wistar rats were divided into five groups: control, vehicle-treated, PF, PF-ZA 50, and PF-ZA 100 groups. ZA was given in two different doses 100 and 50 µg/kg/week intraperitoneally. After anesthesia, mean arterial blood pressure (MBP) was measured. After scarification, lung coefficient was calculated. Lung levels of ACE 2, interleukin-1ß (IL-1ß), transforming growth factor-ß (TGF-ß), VEGF, glutathione (GSH), and superoxide dismutase (SOD) were measured. Expression of ROCK, phosphorylated myosin phosphatase target subunit 1 (P-MYPT1), and matrix metalloproteinase (MMP-1), along with histopathological changes and immune-histochemical staining for lung α-smooth muscle actin (α-SMA), tumor necrosis factor-alpha (TNFα), and caspase-3, were evaluated. RESULTS: ZA significantly prevented the decrease in MBP. ZA significantly increased ACE2, GSH, and SOD and significantly decreased IL-1ß, TGF-ß, and VEGF in lung in comparison to PF group. ZA prevented the histopathological changes induced by CCl4. ZA inhibited lung expression of ROCK, P-MYPT1, MMP-1, α-SMA, TNFα, and caspase-3 with significant differences favoring the high dose intervention. CONCLUSION: ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.

Effects of neoadjuvant zoledronate and radiation therapy on cell survival, cell cycle distribution, and clinical status in canine osteosarcoma.

Introduction: Zoledronic acid (ZOL) is a third-generation bisphosphonate with a higher affinity for bone resorption areas than earlier bisphosphonates (i.e., pamidronate, PAM). In human medicine, ZOL provides improved bone pain relief and prolonged time to skeletal-related events compared to its older generational counterparts. Preclinical studies have investigated its role as an anti-neoplastic agent, both independently and synergistically, with radiation therapy (RT). ZOL and RT act synergistically in several neoplastic human cell lines: prostate, breast, osteosarcoma, and fibrosarcoma. However, the exact mechanism of ZOL's radiosensitization has not been fully elucidated. Methods: We investigated ZOL's ability to induce apoptosis in canine osteosarcoma cell lines treated with various doses of megavoltage external beam radiotherapy. Second, we evaluated cell cycle arrest in ZOL-treated cells to assess several neo-adjuvant time points. Finally, we treated 20 dogs with naturally occurring appendicular OS with 0.1 mg/kg ZOL IV 24 h before receiving 8 Gy of RT (once weekly fraction x 4 weeks). Results: We found that apoptosis was increased in all ZOL-treated cell lines compared to controls, and the combination of ZOL and RT resulted in dissimilar apoptosis between Abrams and D-17 and HMPOS cell lines. Cell cycle arrest (G2/M phase) was minimal and variable between cell lines but perhaps greatest at 48 h post-ZOL treatment. Only 10% of dogs treated with ZOL and RT developed pathologic fractures, compared to 44% of dogs historically treated with PAM and RT (p = 0.027). Discussion: ZOL and RT appear to be a well-tolerated combination treatment scheme for non-surgical candidates; future studies must elucidate the ideal timing of ZOL.

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells.

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells. Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo. Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.