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Glycosphingolipids (GSLs) are key constituents of membrane bilayers playing a role in structural integrity, cell signalling in microdomains, endosomes and lysosomes, and cell death pathways. Conversion of ceramide into GSLs is controlled by GCS (glucosylceramide synthase) and inhibitors of this enzyme for the treatment of lipid storage disorders and specific cancers. With a diverse range of functions attributed to GSLs, the ability of the GSC inhibitor, eliglustat, to reduce myeloma bone disease was investigated. In pre-clinical models of multiple myeloma, osteoclast-driven bone loss was reduced by eliglustat in a mechanistically separate manner to zoledronic acid, a bisphosphonate that prevents osteoclast-mediated bone destruction. Autophagic degradation of TNF receptor-associated factor 3 (TRAF3), a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. By altering GSL composition, eliglustat prevented lysosomal degradation whilst exogenous addition of missing GSLs rescued TRAF3 degradation to restore osteoclast formation in bone marrow cells from myeloma patients. This work highlights the clinical potential of eliglustat as a therapy for myeloma bone disease. Furthermore, using eliglustat as a lysosomal inhibitor in osteoclasts may widen its therapeutic uses to other bone disorders such as bone metastasis, osteoporosis and inflammatory bone loss.

Background: Giant cell reparative granulomas are nonneoplastic, benign lesions that can expand and dissolve bone. Fibrous dysplasia is a benign condition in which normal bone tissue is replaced by abnormally proliferating immature reticular bone and fibrous tissue. The combination of giant cell reparative granuloma and fibrous dysplasia is extremely rare and can pose diagnostic and therapeutic challenges because of the complexity of clinical presentation. Case Presentation: We here present a patient who had a combination of fibrous dysplasia of bone and a giant cell reparative granuloma. An elderly male was admitted to the hospital with a blood‐streaked nasal discharge, blurry vision in his right eye, and an enlarged mass under the chin. A CT scan revealed that the lesion had infiltrated the head and face extensively, including the right maxillary sinus, sieve sinus, and the right nasal cavity, contraindicating surgery. The patient received a total dose of 30 Gy of 6 MV x‐ray radiotherapy delivered through helical tomotherapy over 15 sessions, with a single dose of 2 Gy being administered five times a week. Concurrently, The dose is 4 mg of zoledronic acid administered intravenously once every 21 days. After treatment, the patient's nasal congestion was significantly relieved, the vision of the right eye improved, and the mandibular lesion was significantly reduced. Conclusions: Treatment with radiotherapy combined with zoledronic acid for our patient's inoperable osteolytic giant cell reparative granuloma adjacent to vital nerves and blood vessels was extremely effective and safe. This case report provides a reference for the management of this rare combination. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of zoledronic acid on muscle metabolism in mice with osteoporosis and sarcopenia and elucidate the possible underlying mechanism. Methods: Twenty-four 8-week-old male C57BL/6J mice were randomly divided into four groups: non-suspension (N-SUS), suspension (SUS), suspension + zoledronic acid (ZA), and suspension + PTH(PTH) groups. Equal doses of saline, zoledronic acid, and PTH were administered subcutaneously. After 4 weeks, the mice were sacrificed, and body weight and muscle mass (gastrocnemius and soleus) were measured, the right tibia of mice was taken for micro-CT examination, and the muscle specimens were analyzed using HE staining, ATPase staining, western blotting, and real-time PCR. Results: Compared with the N-SUS group, the bone mineral density (BMD), trabecular bone relative volume (BV/TV) and trabecular bone number (Tb.N) were significantly decreased in the SUS group (P < 0.01), the trabecular bone separation(Tb.Sp)was significantly increased (P < 0.01), which was reversed in ZA and PTH group (P < 0.01).Compared to the SUS group, the body and muscle weights of the ZA and PTH groups were significantly increased. Compared to the SUS group, the muscle structure was less damaged, the proportion of type I muscle fibers was increased, and the protein expression of β-catenin and AKT were upregulated in the ZA and PTH groups(P < 0.05). In addition, the mRNA expression levels of Wnt3a, Wnt16, Myf5, and PI3K were significantly increased (P < 0.05), where as those of Myogenic Differentiation Antigen(MyoD)and Myogenin (MyoG) were significantly decreased (P < 0.05). No significant differences were observed between the ZA and PTH groups. Conclusions: Zoledronic acid can reduce muscle loss and damage by upregulating the mRNA expression of Wnt and PI3K and the protein expression of β-catenin and AKT.Our results provide a novel basis for the development of drugs for the treatment of osteoporosis combined with sarcopenia. [ABSTRACT FROM AUTHOR]

Medication-related osteonecrosis of the jaw is a rare but severe complication with challenging treatment protocols. Cold atmospheric plasma (CAP) has shown promising effects in wound healing, cell proliferation and viability. This study investigated the effect of CAP on osteoblasts in a culture medium containing bisphosphonates. Pilot study was designed to determine the optimal setting of CAP. MG-63 cells were exposed to zoledronic acid at a concentration of 10 micromolar for 72 h. Study groups with the best MTT assay results, were chosen for assessing OPG and RANKL genes by RT-PCR. Cell viability was significantly higher in groups 9 kV.1 mm.90 s, 10 kV.1 mm.60 s, and 12 kV.1 mm.60 s (P < 0.05). Expression of RANKL in these groups was significantly lower than the positive control group (medium culture without zoledronic and plasma treatment) and higher than the BP group (culture with zoledronic without plasma treatment), except for the 12 kV.1 mm.60 s group, which did not differ significantly from the positive control group (P > 0.05). OPG decreased in all test groups compared to BP (p < 0.05), except for the 12 kV.1 mm.60 s group, which did not significantly differ from BP (P > 0.05). RANKL/OPG ratio in groups 9 kV.1 mm.90 s and 12 kV.1 mm.60 s significantly increased compared to BP (P < 0.05).CAP treatment may enhance the viability of osteoblasts exposed to bisphosphonates, increase their activity levels, enhance osteoclast activity, and improve bone turnover rates. [ABSTRACT FROM AUTHOR]

Background: Osteonecrosis of the jaw (ONJ) stands as a severe complication linked to the use of bisphosphonates, particularly zoledronic acid, which is widely prescribed for managing conditions like osteoporosis and bone metastasis. This study is geared towards the development and validation of a clinical prediction model for ONJ in patients undergoing zoledronic acid treatment. Methods: We harnessed data from the FDA Adverse Event Reporting System (FAERS) as our training dataset, while the Canada Vigilance Adverse Reaction (CVAR) database served as the testing dataset. The study encompassed patients treated with zoledronic acid and subsequently diagnosed with ONJ. We analysed a range of predictive factors, including breast cancer, bone metastasis, osteoporosis, vitamin D and calcium levels, comorbidities, the number of concomitant medications, dosage, age, weight, and gender. Logistic regression and nomogram analysis were the chosen methodologies for constructing the predictive model. To evaluate the model's performance, we utilized receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The study encompassed a total of 2,126 patients in the training cohort, 911 patients in the internal test cohort from the FAERS database, and 121 patients in the external test cohort from the CVAR database. Notable predictors for ONJ included bone metastasis (OR: 1.65, 95% CI: 1.22–2.24), osteoporosis (OR: 0.33, 95% CI: 0.21–0.52), the number of concomitant medications (OR: 1.07, 95% CI: 1.05–1.09), and the dosage of zoledronic acid (OR: 1.24, 95% CI: 1.10–1.39). The nomogram exhibited robust discriminatory power, evidenced by an area under the curve (AUC) of 0.77 in the training cohort, 0.76 in the internal test cohort, and 0.90 in the external test cohort. Calibration plots demonstrated a strong alignment between observed and predicted probabilities. Furthermore, DCA highlighted the prediction model's significant net benefit across various threshold probabilities. Conclusion: By leveraging data from both the FAERS and Canadian databases, this study has successfully developed and validated a clinical prediction model for ONJ in patients receiving zoledronic acid. This model stands as a valuable tool for clinicians, enabling them to pinpoint high-risk patients and make evidence-based treatment decisions to minimize the risk of ONJ. [ABSTRACT FROM AUTHOR]

Intravenous zoledronic acid is an established and generally well tolerated form of antiresorptive therapy for osteoporosis. Although mild arthralgias are a well-documented manifestation of the acute phase response to intravenous bisphosphonates, more severe musculoskeletal reactions manifesting as debilitating pain and joint effusions have been rarely documented in the current literature. In this case report, we discuss the case of a 55-year-old woman who developed severe painful bilateral knee effusions within 1 week of her first zoledronic acid infusion for osteoporosis. Prescribing physicians and patients should be made aware of this uncommon but important adverse effect to zoledronic acid. [ABSTRACT FROM AUTHOR]

Accelerated sub-lesional bone loss is common in the first 2–3 years after traumatic spinal cord injury (TSCI), particularly in the distal femur and proximal tibia. Few studies have explored efficacy of antiresorptives for acute bone loss prevention post-TSCI, with limited data for knee bone mineral density (BMD) or beyond two years follow-up. An open-label non-randomized study was performed at Royal North Shore Hospital and Royal Rehab Centre, Sydney between 2018 and 2023. An 'acute interventional cohort' (n = 11) with TSCI (duration ≤ 12-weeks) received a single infusion of 4 mg zoledronic acid (ZOL) at baseline. A 'chronic non-interventional cohort' (n = 9) with TSCI (duration 1–5-years) did not receive ZOL. All participants underwent baseline and 6-monthly blood tests (including CTx and P1NP) and 12-monthly DXA BMD scans (including distal femur and proximal tibia). Participants were predominantly Caucasian and male (mean age 38.4 years). At baseline, the 'acute' cohort had higher serum CTx, P1NP and sclerostin concentrations, while the 'chronic' cohort had lower left hip and knee BMD. Majority with acute TSCI experienced an acute phase reaction after ZOL (9/11; 82%). In the acute cohort, left hip BMD fell by mean ~ 15% by 48 months. Left distal femoral and proximal tibial BMD declined by mean ~ 6–13% at 12 months and ~ 20–23% at 48 months, with a tendency towards greater BMD loss in motor-complete TSCI. A single early ZOL infusion in acute TSCI could not attenuate rapidly declining hip and knee BMD. Prospective controlled studies are required to establish the optimal strategy for preventing early bone loss after acute TSCI. [ABSTRACT FROM AUTHOR]

Carpal navicular fractures are the most common carpal fractures. This study intends to explore the specific mechanism of Zoledronic Acid (ZA) in carpal navicular fracture healing via long non-coding RNA (lncRNA) growth arrest specificity 5 (GAS5) to mediate microRNA (miR)-29a-3p. A fractured rat model was constructed. Two weeks later, a subcutaneous injection of systemic ZA was implemented, and an injection of plasmid vectors interfered with GAS5 or miR-29a-3p expression was performed on the fracture site. Osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2) were determined, as well as serum levels of alkaline phosphatase (ALP), osteopontin (OPN) and osteoprotegerin (OPG) and bone mineral density. MC3T3-E1 cells were transfected with plasmid vectors interfering with GAS5 or miR-29a-3p, and cell proliferation and apoptosis were analyzed. GAS5 and miR-29a-3p expression in fractured rats was tested, together with their binding relationship. ZA promoted OCN and BMP-2 expression, increased bone mineral density and serum levels of ALP, OPN and OPG in fractured rats. GAS5 was upregulated and miR-29a-3p was down-regulated in fractured rats. Downregulation of GAS5 or upregulation of miR-29a-3p further promoted bone healing in fractured rats. GAS5 targets miR-29a-3p, and down-regulation of miR-29a-3p can reverse the effect of down-regulation of GAS5 on bone healing in fractured rats. ZA promoted the proliferation of MC3T3-E1 cells and inhibited apoptosis by regulating the GAS5/miR-29a-3p axis. ZA regulates miR-29a-3p expression by down-regulating GAS5 to promote carpal navicular fracture healing, promote MC3T3-E1 cell proliferation, and inhibit cell apoptosis. [ABSTRACT FROM AUTHOR]

Purpose To assess the safety of zoledronic acid (ZOL) and denosumab (Dmab) administered following hip fracture in a hospital setting. Methods Patients older than 65 years were treated by a fracture liaison service following hip fracture. Generally, patients who had a glomerular filtration rate (eGFR) > 35 mL/min were treated with ZOL, whereas patients who had previously received bisphosphonates or had a eGFR between 20 and 35 mL/min were treated with Dmab. Adverse events included hypocalcemia (calcium corrected for albumin less than 8.5 mg/day), renal functional impairment (0.5 mg/dL or more increase in serum creatinine) within 30 days of treatment, or a fever (>38 °C) within 48 hours of drug administration. Results Two hundred twenty-eight and 134 patients were treated with ZOL and Dmab, respectively. Mean body temperature was elevated following ZOL administration (0.18 °C P <.001) but remained below 38 °C. Hypocalcemia occurred in 18% and 29% of the ZOL and Dmab groups, respectively (P =.009). Renal functional impairment was observed in 9 and 6 patients (4% and 5%) in the ZOL and Dmab groups, respectively (P =.8). Pretreatment calcium above 9.3 mg/dL was associated with a lower risk of posttreatment hypocalcemia (odds ratio 0.30, 95% confidence interval 0.13-0.68, P =.004). While the absolute risk of hypocalcemia was higher in the Dmab group, multivariate analysis did not find that the choice of drug was predictive of hypocalcemia. Conclusion In-hospital parenteral osteoporosis treatment was rarely associated with fever or renal function impairment but was associated with hypocalcemia. Posttreatment hypocalcemia risk did not vary significantly between patients receiving ZOL or Dmab. [ABSTRACT FROM AUTHOR]

Summary: We aimed to investigate the risk of hip fracture associated with zoledronic acid treatment compared to alendronate on a population level. The risk of hip fracture was lower in women using zoledronic acid and higher in women who had discontinued treatment. The findings support the effectiveness of intravenous bisphosphonate. Purpose: To investigate whether zoledronic acid (ZOL) was associated with a lower risk of the first hip fracture than alendronate (ALN) in Norway using real-world data. Methods: Nationwide data on drugs dispensed in outpatient pharmacies were individually linked with all hospital-treated hip fractures. Individuals aged 50–89 years without previous hip fracture were included at their first filling of a prescription for ALN or ZOL during 2005–2016. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for first hip fracture by time-varying exposure to ZOL versus ALN were estimated in sex-stratified flexible parametric survival analyses. Covariates included time-varying accumulated ALN exposure and comorbidity level expressed by the prescription-based Rx-Risk Comorbidity Index, marital status, education, and residential urbanity. Results: Of 75,250 women who initiated treatment, 72,614 (96.5%) were exposed to ALN and 6366 (8.5%) to ZOL. Of 12,739 men who initiated treatment, 12,311 (96.6%) were exposed to ALN and 784 (6.2%) to ZOL. In women, the HR for first hip fracture was 0.75 (95% CI: 0.61–0.91) for ZOL versus ALN. In men, the corresponding HR was 0.59 (95% CI: 0.32–1.07). Discontinued treatment was associated with increased risk compared with current ALN treatment in women (HR: 1.33; 95% CI: 1.24–1.42, men: HR 1.13 (95% CI: 0.95–1.35)). Conclusions: In women, the risk of first hip fracture when treated with ZOL was 25% lower than when treated with ALN. Discontinued treatment was associated with a 33% increase in hip fracture risk. Similar, albeit statistically non-significant, results were observed in men. [ABSTRACT FROM AUTHOR]

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, non-infectious inflammatory disease with a prevalence of 1 to 2/106, causing multiple lytic bone lesions. There are no established protocols for treating CRMO; thus, current practice is largely empirical. Data on the use of zoledronic acid (ZA) in juvenile CRMO are scarce. A 12-year-old male child with a history of multiple aseptic osteomylitis, affecting the chest wall, right ankle, and wrist, had no fever. Cultures and a bone biopsy ruled out infection or malignancy. The patient's condition stayed stable while taking naproxen (20 mg/kg/day) and methotrexate (10 mg/week) for 1.5 years until he experienced right elbow pain, swelling, no overlying skin erythema, and a restricted range of motion. The laboratory tests all came back normal, including white blood cell (WBC) count, erythrocyte sedimentation rate, C-reactive protein, and immunoglobin assays. The magnetic resonance imaging showed a focal lesion in the medial humeral condyle with increased signal intensity on T2 and short tau inversion recovery, mild joint effusion, and no cortical break. Thus, intravenous ZA infusion commenced at 0.0125 mg/kg initially, followed by 0.025 mg/kg 3 months later, with a marked improvement in the patient's clinical symptoms and radiological findings. Non-steroidal anti-inflammatory drugs and methotrexate were initially effective in treating our patient's condition, but a recurrence necessitated treatment modification. To the best of our knowledge, this case is the first documented instance of the use of ZA in CRMO in Iraq and Arab nations. [ABSTRACT FROM AUTHOR]

SAPHO syndrome, a rare inflammatory disorder of bone, joints, and skin, is named based on the presence of synovitis, acne, pustulosis, hyperostosis, and osteitis. The hallmark of SAPHO syndrome includes osteoarticular and dermatologic manifestations, however, rarer associations with inflammatory bowel disease (particularly Crohn's disease) have been documented. The literature on the relationship between SAPHO syndrome and inflammatory bowel disease (IBD), especially ulcerative colitis (UC), remains limited. We report an unusual case of SAPHO syndrome in a patient with UC. Chest x‐ray and MRI showed enlargement of the right first rib and adjacent sternum. Bone scintigraphy revealed hyperostosis and ankylosis of the costochondral junction, and bone biopsy revealed reactive bone and costal cartilage without findings of infection or malignancy. Complete resolution of symptoms was achieved 4 months after starting zoledronic acid without significant adverse events. The diagnosis of SAPHO syndrome in IBD patients is rare, even more so in UC patients, likely attributable to underdiagnosis given the clinical heterogeneity of SAPHO syndrome and overlap with the extra‐intestinal manifestation of IBD. Our treatment approach provides critical data to the underreported literature on diagnosis and managing SAPHO syndrome in UC. [ABSTRACT FROM AUTHOR]

Background: Osteonecrosis of the jaw (ONJ) stands as a severe complication linked to the use of bisphosphonates, particularly zoledronic acid, which is widely prescribed for managing conditions like osteoporosis and bone metastasis. This study is geared towards the development and validation of a clinical prediction model for ONJ in patients undergoing zoledronic acid treatment. Methods: We harnessed data from the FDA Adverse Event Reporting System (FAERS) as our training dataset, while the Canada Vigilance Adverse Reaction (CVAR) database served as the testing dataset. The study encompassed patients treated with zoledronic acid and subsequently diagnosed with ONJ. We analysed a range of predictive factors, including breast cancer, bone metastasis, osteoporosis, vitamin D and calcium levels, comorbidities, the number of concomitant medications, dosage, age, weight, and gender. Logistic regression and nomogram analysis were the chosen methodologies for constructing the predictive model. To evaluate the model's performance, we utilized receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results: The study encompassed a total of 2,126 patients in the training cohort, 911 patients in the internal test cohort from the FAERS database, and 121 patients in the external test cohort from the CVAR database. Notable predictors for ONJ included bone metastasis (OR: 1.65, 95% CI: 1.22-2.24), osteoporosis (OR: 0.33, 95% CI: 0.21-0.52), the number of concomitant medications (OR: 1.07, 95% CI: 1.05-1.09), and the dosage of zoledronic acid (OR: 1.24, 95% CI: 1.10-1.39). The nomogram exhibited robust discriminatory power, evidenced by an area under the curve (AUC) of 0.77 in the training cohort, 0.76 in the internal test cohort, and 0.90 in the external test cohort. Calibration plots demonstrated a strong alignment between observed and predicted probabilities. Furthermore, DCA highlighted the prediction model's significant net benefit across various threshold probabilities. Conclusion: By leveraging data from both the FAERS and Canadian databases, this study has successfully developed and validated a clinical prediction model for ONJ in patients receiving zoledronic acid. This model stands as a valuable tool for clinicians, enabling them to pinpoint high-risk patients and make evidence-based treatment decisions to minimize the risk of ONJ. [ABSTRACT FROM AUTHOR]

Summary: Brief rationale: Zoledronic acid treatment against osteoporosis is limited by APR. Main result: Combination therapy (hydrocortisone plus non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone) reduced intolerable APR levels and provided complete symptom relief in most patients. Significance of the paper: Combination therapy can enhance patient outcomes in osteoporosis management. Purpose: Osteoporosis is a common condition associated with high morbidity rates, often requiring treatment with bisphosphonates such as zoledronic acid. However, the persistence to zoledronic acid infusion is commonly limited by acute phase response (APR). This retrospective study aimed to evaluate the efficacy of a novel combination therapy in preventing APR symptoms. Methods: A retrospective case–control study was conducted on 931 patients who received their first zoledronic acid infusion between 2011 and 2021. We evaluated the efficacy of combination therapy comprising a single dose of hydrocortisone prior to the infusion and a 3-d oral regimen of non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone following the infusion. Patients were divided into protocol (receiving combination therapy) and control groups (without treatment). Baseline characteristics, APR incidence, and the efficacy of symptom control were compared between groups using Fisher's exact test and Student's t-test. Results: There was no difference in APR incidence between the protocol (n = 507) and control group (n = 407; p = 0.1442). However, the protocol group exhibited lower intolerable APR levels (3.72% vs. 16.71%; p < 0.0001) and complete symptom relief in 96.28% of cases. Conclusion: The combination therapy protocol effectively reduced intolerable APR and relieved symptoms in most patients following zoledronic acid infusion. This study highlights the importance of proactive management strategies for APR and emphasizes the potential of combination therapy in alleviating APR symptoms and reducing the occurrence of severe APR in patients undergoing osteoporosis management. [ABSTRACT FROM AUTHOR]

Summary: Administering zoledronic acid (ZA) to older hip fracture patients during the hospital stay has faced safety concerns. However, in this study of 161 patients, no ZA-related side effects or readmissions were observed, demonstrating that ZA administration during hospitalization is safe and effective for secondary fracture prevention. Purpose: According to the 2022 Dutch 'Osteoporosis and fracture prevention' guideline, zoledronic acid (ZA) is the preferred osteoporosis treatment for hip fracture patients. Less than 25% of hip fracture patients visit the outpatient fracture liaison service, therefore inpatient administration of ZA during the hip fracture hospitalization is now recommended in patients > 75 years. In the OLVG Hospital, inpatient administration of ZA during hospitalization for hip fracture in older patients has been standard of care since 2020. Methods: This single center retrospective observational follow-up study included hip fracture patients > 75 years admitted to the orthogeriatric ward of the OLVG Hospital, and treated with 5 mg of ZA intravenously on the day of hospital discharge between June 2020 and December 2022. Life expectancy estimated < 12 months, creatinine clearance < 35 ml/min, hypocalcemia, and high risk of osteonecrosis of the jaw were contra-indications. During three months of follow-up (FU) adverse events, emergency room visits, hospital readmissions, and death were recorded. Results: In 161 consecutive hospitalized hip fracture patients (mean age 86 ± 6 years, 65% female, 18% nursing home) ZA was administered and no adverse events were recorded. During 3 months of FU, 8 patients (5%) visited the emergency room, 19 patients (12%) were re-admitted to the hospital, 3 with a new fracture (2 contralateral hip, 1 radius), and 17 patients (11%) died of reasons unrelated to ZA. Conclusion: This study shows that inpatient administration of zoledronic acid during hip fracture hospitalization is safe and feasible to prevent future fragility fractures in older hip fracture patients. [ABSTRACT FROM AUTHOR]

Background: Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. Methods: PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). Result: The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82–1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30–0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12–0.91], p = 0.33). Conclusion: This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA. [ABSTRACT FROM AUTHOR]

Osteoporosis in children and young adults is relatively rare. Hereditary causes are often overlooked in the absence of a positive family history. We report a 29-year-old male presenting with recurrent fragility fractures since 6 years of age. Secondary causes, such as celiac disease, inflammatory disorders, and hypogonadism, were ruled out. Family history was negative for any bone disease. Exome sequencing revealed 2 variants of LRP5 gene—intron 5 c.1015 + 1G > A and exon 5 c.892C > T. Although the former variant has been described in literature as a cause of osteoporosis in homozygous state only, it manifested as osteoporosis in our patient, in the heterozygous state, in presence of a second variant of uncertain significance. However, eye involvement, which is classically seen in "osteoporosis-pseudoglioma syndrome" homozygote, was absent in our patient. Genetic analysis of the parents revealed father to be a carrier of intron 5 c.1015 + 1G > A and mother exon 5 c.892C > T variants of the LRP5 gene. However, none of them had osteoporosis on bone densitometry. The patient was subsequently treated with IV zoledronic acid (planned to be administered annually) and showed improvement in bone density by 11% at the spine and 9.5% at the left femur; there were no further fractures over 1 year of follow-up. [ABSTRACT FROM AUTHOR]

Objectives: Investigation of the therapeutic effect of zoledronic acid (ZA) in a preclinical model of jaw osteosarcoma (JO). Materials and Methods: The effect of 100 μg/kg ZA administered twice a week was assessed in a xenogenic mouse model of JO. The clinical (tumor growth, development of lung metastasis), radiological (bone microarchitecture by micro‐CT analysis), and molecular and immunohistochemical (TRAP, RANK/RANKL, VEGF, and CD146) parameters were investigated. Results: Animals receiving ZA exhibited an increased tumor volume compared with nontreated animals (71.3 ± 14.3 mm3 vs. 51.9 ± 19.9 mm3 at D14, respectively; p = 0.06) as well as increased numbers of lung metastases (mean 4.88 ± 4.45 vs. 0.50 ± 1.07 metastases, respectively; p = 0.02). ZA protected mandibular bone against tumor osteolysis (mean bone volume of 12.81 ± 0.53 mm3 in the ZA group vs. 11.55 ± 1.18 mm3 in the control group; p = 0.01). ZA induced a nonsignificant decrease in mRNA expression of the osteoclastic marker TRAP and an increase in RANK/RANKL bone remodeling markers. Conclusion: The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Prevention of aseptic loosening, the main reason for secondary surgery of bone implants, is of great crucial clinical importance. As a promising bioactive material to promote bone regeneration, the piezoelectric materials for preventing aseptic loosening has not been reported. Here, a surface coating is presented for implants based on piezoelectric poly(L‐lactic acid) (PLLA). The coating ingeniously utilizes zoledronic acid (ZA), a drug used to treat osteoporosis, as a nucleating agent to enhance the piezoelectricity of PLLA. The coating can not only provide a continuous porous piezoelectric environment to stimulate osteogenic differentiation without intervention, but also effectively inhibit the osteolytic activity of osteoclasts through the slow release of ZA, achieving long‐term effectiveness with a single implantation. The rat femur cavity implantation experiment suggests that, the PLLA/ZA coating can rapidly initiate osseointegration of the implant and effectively mitigate the risk of aseptic loosening, even in the presence of metal submicroscopic particles that induce aseptic loosening. This strategy of piezo‐enhanced PLLA drug‐loaded coating may provide a new idea for the surface modification of bone implants. [ABSTRACT FROM AUTHOR]