Alendronate Research Articles

Major considerations of maxillary/mandible osteonecrosis caused by bisphosphonates in the dental implant scenario: a systematic review

Introduction: The literature has shown that several patients with a history of bisphosphonate treatment appear to be at risk for medication-related osteonecrosis of the jaw (MRONJ) osteonecrosis of the jaw. Objective: It was analyzing the use of BP associated with dentistry. Because it is a possible alternative for the reduction of loss and increase in bone density, as well as for the possibility of osteonecrosis, which requires therapeutic and preventive measures in the involvement of invasive practices such as dental implants. Methods: The PRISMA Platform systematic review rules were followed. The search was carried out from April to June 2024 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 85 articles were founded, and 54 articles were evaluated and 30 were included in this systematic review. Considering the Cochrane tool for risk of bias, the global assessment resulted in 24 studies with a high risk of bias and 18 studies that did not meet GRADE and AMSTAR-2. Most studies showed homogeneity in their results, with X2 =81.9% >50%. It was concluded that osteoporosis is a metabolic condition that affects alveolar bone density, but does not present problems for the installation of osseointegrated implants, as long as there is sufficient bone mass in the region where the tooth will be implanted. It suggests to the dental surgeons the knowledge of the diagnosis so that it makes a careful evaluation, directing the professional to observe the quality of the bone through routine image examinations. Further, alendronate sodium is used to decrease bone resorption, the drug should be considered as an adjunctive therapeutic agent for the treatment of osteoporosis.

Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling

Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Tooth-Binding Graphene Quantum Dots Silver Nanocomposites for Prevention of Dental Caries.

The objectives of this study were to develop a tooth-binding graphene quantum dots silver nanocomposites (ALN-GQDs-Ag) and evaluate their antibacterial, mineralising, and discolouring properties for the prevention of dental caries. In this study, ALN-GQDs-Ag were developed by synthesising nano silver (Ag) with graphene quantum dots (GQDs) and functionalised GQDs with alendronate (ALN). ALN-GQDs-Ag were characterised by transmission electron microscopy (TEM), zeta potential analysis, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and Raman spectroscopy. The cytotoxicity of ALN-GQDs-Ag against human gingival fibroblasts (HGF-1) and stem cells from human exfoliated deciduous teeth (SHED) was examined using a colorimetric assay with reference to silver nitrate solution. The affinity of ALN-GQDs-Ag for hydroxyapatite particles was investigated using inductively coupled plasma spectroscopy (ICP). The antibacterial properties of ALN-GQDs-Ag against Streptococcus mutans were evaluated by scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and colony-forming units counting (CFUs). The mineralisation properties of ALN-GQDs-Ag on human dentine were assessed using micro-computed tomography (micro-CT), scanning electron microscopy (SEM), and Fourier transform infrared in a biochemical cycling model. The discolouring properties of ALN-GQDs-Ag on artificial dentine caries were determined using spectrophotometry. TEM, Zeta potential, XPS, FTIR, and Raman spectroscopy confirmed the synthesis of stable spherical ALN-GQD-Ag nanocomposites with a 10.3 ± 5.5 nm diameter. The colorimetric assay demonstrated that ALN-GQDs-Ag were less cytotoxic than silver nitrate to HGF-1 and SHED (p<0.001). ICP showed that ALN-GQDs-Ag were bound to hydroxyapatite. SEM, CLSM, and CFUs showed that ALN-GQDs-Ag was bactericidal and inhibited biofilm growth of Streptococcus mutans. Micro-CT, SEM, and FTIR showed that ALN-GQDs-Ag repressed dentine demineralisation under a cariogenic challenge. Spectrophotometry revealed no significant discolouration of dentine caries in the ALN-GQDs-Ag. This study developed a biocompatible and tooth-binding ALN-GQDs-Ag with promising antibacterial, mineralising, and non-discolouring properties. ALN-GQDs-Ag could be a novel anti-caries agent for preventing dentine caries if translated for clinical use.

Risk of first hip fracture under treatment with zoledronic acid versus alendronate: a NOREPOS cohort study of 88,000 Norwegian men and women in outpatient care

SummaryWe 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.PurposeTo 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.MethodsNationwide 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.ResultsOf 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)).ConclusionsIn 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.

Differential effects of alendronate on chondrocytes, cartilage matrix and subchondral bone structure in surgically induced osteoarthritis in mice

Bisphosphonates (BP) are considered a treatment option for osteoarthritis (OA) due to reduction of OA-induced microtrauma in the bone marrow, stabilization of subchondral bone (SB) layer and pain reduction. The effects of high-dose alendronate (ALN) treatment on SB and articular cartilage after destabilization of the medial meniscus (DMM) or Sham surgery of male C57Bl/6J mice were analyzed. We performed serum analysis; histology and immunohistochemistry to assess the severity of OA and a possible pain symptomatology. Subsequently, the ratio of bone volume to total volume (BV/TV), epiphyseal trabecular morphology and the bone mineral density (BMD) was analyzed by nanoCT. Serum analysis revealed a reduction of ADAMTS5 level. The histological evaluation displayed no protective effect of ALN-treatment on cartilage erosion. NanoCT-analysis of the medial epiphysis revealed an increase of BV/TV in ALN-treated mice. Only the DMM group had significantly higher SB volume accompanied by decreased subchondral bone surface. Furthermore Nano-CT analysis revealed an increase in trabecular density and number, a decreased BMD and reduced osteophyte formation in the ALN mice. ALN treatment affected bone micro-architecture by reducing osteophytosis with simultaneous increasing subchondral bone plate thickness, trabecular thickness and BMD. Accordingly, ALN cannot be considered as a potential treatment strategy in general, however in a subgroup of patients with high bone turnover in an early-stage of OA, ALN might be an option when applied during a restricted time frame.

7253 Changes In Bone Density Observed After Transitioning From Denosumab To Alendronate Or Zoledronic Acid

Abstract Disclosure: A. Khan: None. B.P. Ramchandani: None. R.A. Zielinski: None. J. Liu: None. F.S. Mirza: None. Introduction: Discontinuation of denosumab (Dmab) results in rebound increase in bone turnover and increased risk of vertebral fracture. Guidelines recommend that discontinuation of denosumab should be followed by an oral or intravenous bisphosphonate (BP), hormone therapy or selective estrogen receptor modulator (SERM). Hypothesis: We hypothesize that patients who received weekly alendronate (ALEN) after discontinuation of Dmab will have less of a decline in bone mineral density (BMD) compared to patients who received once yearly zoledronic acid (ZA). Methods: We conducted a retrospective chart review to compare the change in BMD and factors affecting BMD loss in patients who received sequential therapy with ZA versus ALEN. IRB approval was obtained. Patients were selected using Epic SlicerDicer if they had taken Dmab therapy from 2018 (year of epic implementation) onwards and had been transitioned to a BP. A total of 251 patients were initially selected. 35 patients met the inclusion criteria of being transitioned off to ALEN or ZA at least 1 year prior to date of data acquisition; 21 transitioned to ZA and 14 to ALEN. The rest of the patients were continuing Dmab and excluded from the analysis. BMD gain after Dmab therapy was evaluated. BMD change after 1 year of receiving sequential therapy was compared between the two groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Results: A total of 35 patients were included in data analysis with mean age of 73.7 + 9 years. The mean percentage gain in BMD achieved after Dmab therapy was 9.9 + 8.5%, 4.6 + 10.6%, and 6 + 5.2% at the LS, FN and TH respectively. The mean duration of Dmab therapy was 4.4 + 2.1 years. One year following sequential therapy, mean percentage BMD loss at the LS was 4.5% with ALEN and 3.0% with ZA (p-value: 0.59, 95% CI: -0.04 to 0.08). Following sequential therapy, mean percentage loss at FN was 2.2% with ALEN and 0.2% with ZA (p-value: 0.1895% CI: (-0.01 to 0.04), mean percentage loss at TH was 2.0 % with ALEN and 2.2% with ZA (p-value: 0.78, 95% CI: -0.03 to 0.02). Mean vitamin D level of all patients at time of starting sequential therapy was 45.9 + 12.9 ng/ml. Duration of prior bisphosphonate use before starting Dmab therapy did not have any significant effect on BMD loss after sequential therapy. All patients had vitamin D level in a good range at the beginning and end of the study period. Conclusion: There is invariably some decline in BMD when transitioning from Dmab to BPs. Although our data showed somewhat greater BMD loss at LS and FN with ALEN compared to ZA, this difference was not statistically significant and failed to reject the null hypothesis. These findings need to be evaluated further in larger prospective studies. Presentation: 6/3/2024

6986 Efficacy and Safety of Weekly Liquid Alendronate Sodium Trihydrate in Korean Postmenopausal Women with Osteoporosis: A 12-Month, Multi-Center, Randomized Trial

Abstract Disclosure: Y. Rhee: None. S. Ahn: None. N. Hong: None. D. Seo: None. S. Hong: None. Background: Although alendronate is the most prescribed oral bisphosphonate for osteoporosis treatment, it can lead to gastrointestinal problems, impacting treatment compliance and efficacy. This study aimed to assess the efficacy and safety of once-weekly alendronate sodium trihydrate (ALN-S), an oral solution, compared to once-weekly alendronate sodium (ALN-T), an oral tablet, in Korean postmenopausal women with osteoporosis. Methods: Conducted as a 12-month, multi-center, prospective, randomized, open-labeled, parallel trial at two hospitals in Korea, 170 postmenopausal women were randomized to ALN-S (N=85) or ALN-T (N=85). Bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) was measured at baseline and after 12 months. Bone turnover markers, including C-telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP), were assessed at baseline, 6 months, and 12 months. The primary outcome was the percentage change in LS BMD, evaluated for non-inferiority. Results: After 12 months, both ALN-S and ALN-T groups exhibited a significant increase in LS, FN, and TH BMD, with no significant intergroup differences (ALN-S: LS 5.0 ± 0.6%, FN 1.8 ± 0.6%, TH 2.2 ± 0.5%; ALN-T: LS 5.2 ± 0.6%, FN 1.6 ± 0.6%, TH 1.8 ± 0.5%). ALN-S was found to be non-inferior to ALN-T for BMD change at LS (treatment difference: -0.22%, 95% CI: -1.84 to 1.40%), excluding the predefined non-inferiority margin of -2.29%. Changes in both CTX and P1NP over time did not significantly differ between the groups. There was no significant difference in the frequency of adverse events between the groups. Conclusion: Weekly liquid alendronate sodium trihydrate demonstrated non-inferiority to weekly tablet alendronate sodium in increasing LS BMD in Korean postmenopausal women with osteoporosis. Presentation: 6/2/2024

In vitro Preparation and Evaluation of Alendronate-modified Hyaluronic acid-based Nanomicelles as a Bone-Targeted Drug delivery system

Nanomicelles based on Hyaluronic acid (HA), a linear polysaccharide with high affinity to the CD44 receptor on cancerous cells, offer considerable potential to transport drugs to the target tissue while reducing exposure to normal tissues. The high affinity of alendronate (ALN) to hydroxyapatite crystals, the crucial component of bone, makes it an ideal candidate for bone-targeted delivering therapeutic nanoparticles. Here, we developed targeted and self-assembled nanocarriers by modifying HA nanomicelles with ALN to attach to hydroxyapatite. Curcumin (CUR), as a hydrophobic model drug, was used to evaluate the efficiency of developed nanomicelles. The size of blank and CUR-loaded nanomicelles was below 200 nm and their critical micelle concentrations were in the range of 38 μg/ml, which is suitable for delivery to bone tissue. The CUR-loaded ALN-HA-AC (CUR@ALN-HA-AC) nanomicelles showed a two-step release pattern, a first accelerated release period (12 % in 1 h) followed by a sustained release (65 % up to 50 h). The hydroxyapatite affinity experiment indicated that CUR@ALN-HA-AC nanomicelles exhibited significantly high affinity to the bone. Cytotoxicity studies on MG-63 cell lines demonstrated that CUR-loaded micelles exhibited much higher cytotoxic activity compared to free CUR, indicating that encapsulation in HA-ALN-AC micelles significantly enhanced the tumor cell-killing ability of CUR.

Injectable double-crosslinked bone cement with enhanced bone adhesion and improved osteoporotic pathophysiological microenvironment for osteoregeneration in osteoporosis

The osteoporotic bone defect caused by excessive activity of osteoclasts has posed a challenge for public healthcare. However, most existing bioinert bone cement fails to effectively regulate the pathological bone microenvironment and reconstruct bone homeostasis in the presence of osteoclast overactivity and osteoblast suppression. Herein, inspired by natural bone tissue, an in-situ modulation system for osteoporotic bone regeneration is developed by fabricating an injectable double-crosslinked PEGylated poly(glycerol sebacate) (PEGS)/calcium phosphate cement (CPC) loaded with sodium alendronate (ALN) (PEGS/CPC@ALN) adhesive bone cement. By incorporating ALN, the organic-inorganic interconnection within PEGS/CPC@ALN results in a 100 % increase in compression modulus and energy dissipation efficiency. Additionally, PEGS/CPC@ALN effectively adheres to the bone by bonding with amine and calcium ions present on the bone surface. Moreover, this in-situ regulation system comprehensively mitigates excessive bone resorption through the buffering effect of CPC to improve the acidic microenvironment of osteoporotic bone and the release of ALN to inhibit hyperactive osteoclasts, and facilitates stem cell proliferation and differentiation into osteoblasts through calcium ion release. Overall, the PEGS/CPC@ALN effectively regulates the pathological microenvironment of osteoporosis while promoting bone regeneration through synergistic effects of drugs and materials, thereby improving bone homeostasis and enabling minimally invasive treatment for osteoporotic defects.

Intelligent Supramolecular Modification for Implants: Endogenous Regulation of Bone Defect Repair in Osteoporosis.

Addressing osteoporosis-related bone defects, a supramolecular strategy is innovated for modifying carbon fiber reinforced polyether ether ketone (CF/PEEK) composites. By covalently attaching intelligent macromolecules via in situ RAFT polymerization, leveraging the unique pathological microenvironment in patients with iron-overloaded osteoporosis, intelligent supramolecular modified implant surface possesses multiple endogenous modulation capabilities. After implantation, surface brush-like macromolecules initially resist macrophage adhesion, thereby reducing the level of immune inflammation. Over time, the molecular chains undergo conformational changes due to Fe (III) mediated supramolecular self-assembly, transforming into mechanistic signals. These signals are then specifically transmitted to pre-osteoblast cell through the binding capacity of the KRSR short peptide at the molecular terminus, induced their osteogenic differentiation via the YAP/β-catenin signaling axis. Furthermore, osteoblasts secrete alkaline phosphatase (ALP), which significantly hydrolyzes phosphate ester bonds in surface macromolecular side groups, resulting in the release of alendronate (ALN). This process further improves the local osteoporotic microenvironment. This intelligent surface modification tailors bone repair to individual conditions, automatically realize multiple endogenous regulation once implanted, and truly realize spontaneous activation of a series of responses conducive to bone repair in vivo. It is evidenced by improved bone regeneration in iron-overloaded osteoporotic rabbits and supported by in vitro validations.

Long-term administration of alendronate sodium caused an atypical femoral shaft fracture in a 36-year-old woman: a case report and literature review.

Long-term bisphosphonate therapy is associated with atypical or insufficiency fractures, particularly in the proximal femur. We observed a case of an atypical femoral shaft fracture in a patient with a long-term history of alendronate therapy. A 36-year-old woman was admitted with a complaint of pain in her right mid-thigh following low-energy trauma. She had been taking alendronate for more than 15 years. X-rays indicated a fracture of the right femoral shaft. The patient was treated with proximal femoral nail antirotation (PFNA) fixation. This case highlights concerns regarding long-term bisphosphonate therapy and its potential complications.

Association between renal function and fracture incidence during treatment with teriparatide or alendronate: an exploratory subgroup analysis of the Japanese Osteoporosis Intervention Trial-05.

Incidence rate of morphometric vertebral fracture was lower under treatment with once-weekly teriparatide (TPTD) followed by alendronate (ALN) than under treatment with ALN throughout the study among elderly Japanese women at high fracture risk in JOINT-05. This is an exploratory subgroup analysis according to chronic kidney disease (CKD) status at baseline. Participants received sequential therapy with TPTD for 72weeks, followed by ALN for 48weeks (TPTD-ALN group, N = 483) or ALN monotherapy for 120weeks (ALN group, N = 496). Baseline CKD status was classified by the estimated glomerular filtration rate (eGFR) and categorized as: CKD 1/2 (eGFR ≥ 60mL/min/1.73 m2), CKD 3a (eGFR 45-59mL/min/1.73 m2), or CKD 3b/4 (eGFR < 45mL/min/1.73 m2). Incidences of vertebral fractures including morphometric fractures, non-vertebral fractures, and all fractures were evaluated during follow-up. Baseline characteristics were not different between treatment groups. Higher stages of CKD were associated with age and number of prevalent vertebral fracture. In CKD 1/2 patients (N = 556 with 90 incidents of morphometric vertebral fracture), the incidence of vertebral fractures was lower in the TPTD-ALN group than in the ALN group (p = 0.01). In CKD 3b/4 patients (N = 112 with 10 incidents of non-vertebral fracture), the incidence of non-vertebral fractures was lower in the ALN group than in the TPTD-ALN group, although the number of fractures was small. In the ALN group, the incidences of vertebral fractures, non-vertebral fractures, and all fractures remained constant across CKD stages. This exploratory analysis showed that fracture incidence on ALN was constant regardless of renal function. It also suggested that the incidence of vertebral fractures on TPTD-ALN was lower than ALN monotherapy in CKD 1/2 patients. These results provide important information for drug selection in the clinical practice of osteoporosis.

Comparison of the effects of recombinant human epidermal growth factor (rhEGF) and alendronate sodium on tibial fracture healing in rats: an experimental study

Purpose: The objective of this study is to compare the effects of recombinant human epidermal growth factor (rhEGF) on bone healing with those of alendronate, a bisphosphonate widely used in practice. Materials and Methods: An iatrogenic fracture was created in the tibial shaft of 24 Sprague-Dawley rats with osteotome and fixed with an intramedullary Kirschner wire (K-wire). After surgery, Group 1 was given 0.2 mg/kg/day of oral alendronate sodium on postoperative Day 1 to 28, Group 2 received a single dose of 0.5 mg/kg of intraosseous rhEGF on postoperative Days 1 and 14, and Group 3 was followed for a total of four weeks with oral saline. At the end of Week 4, the animals were euthanized and the lower extremities were removed by stripping the soft tissues without damaging the callus. Tissue samples of groups were prepared and and stained with hematoxylin-eosin. After staining, histological scoring was performed to evaluate the degree of union. Results: Alendronate sodium group demonstrated a mean histological score of 6.95± 1.28. The rhEGF group had a lower mean score of 4.85±1.66. The placebo group exhibited the least progress in bone healing with a mean score of 4.10±1.68. The histological score was significantly higher in the alendronate sodium group compared to both the rhEGF and placebo groups. There was also a statistically significant difference between the rhEGF and placebo groups in terms of scores. Conclusion: Alendronate sodium enhanced fracture healing processes in rats. The role of rhEGF in bone healing requires further exploration. As the understanding of bisphosphonates and growth factors in bone healing evolves, the strategies for optimizing patient care in orthopedic settings are expected to be developed.

An "All-in-One" Strategy to Reconstruct Temporomandibular Joint Osteoarthritic Microenvironment Using γ-Fe2O3@TA@ALN Nanoparticles.

Current clinical strategies for the treatment of temporomandibular joint osteoarthritis (TMJOA) primarily target cartilage biology, overlooking the synergetic effect of various cells and inorganic components in shaping the arthritic microenvironment, thereby impeding the effectiveness of existing therapeutic options for TMJOA. Here, γ-Fe2O3@TA@ALN magnetic nanoparticles (γ-Fe2O3@TA@ALN MNPs) composed of γ-Fe2O3, tannic acid (TA), and alendronate sodium (ALN) are engineered to reconstruct the osteoarthritic microenvironment and mitigate TMJOA progression. γ-Fe2O3@TA@ALN MNPs can promote chondrocytes' proliferation, facilitate chondrogenesis and anisotropic organization, enhance lubrication and reduce cartilage wear, and encourage cell movement. Magnetic-responsive γ-Fe2O3@TA@ALN MNPs also exhibit pH sensitivity, which undergoes decomposition within acidic environment to release ALN on demand. Under a 0.2 T static magnetic field, γ-Fe2O3@TA@ALN MNPs accelerate the synthesis of cartilage-specific proteins, and suppress catabolic-related genes expression and reactive oxygen species generation, affording additional protection to TMJ cartilage. In TMJOA mouse models, articular injection of γ-Fe2O3@TA@ALN MNPs effectively alleviates cartilage degeneration and subchondral bone loss in short and long terms, offering promising avenues for the development of therapeutic interventions for TMJOA.

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Transdermal delivery of bisphosphonates using dissolving and hydrogel-forming microarray patches: Potential for enhanced treatment of osteoporosis

As of 2023, more than 200 million people worldwide are living with osteoporosis. Oral bisphosphonates (BPs) are the primary treatment but can cause gastrointestinal (GI) side effects, reducing patient compliance. Microarray (MAP) technology has the potential to overcome GI irritation by facilitating the transdermal delivery of BPs. This study examines the delivery of alendronic acid (ALN) and risedronate sodium (RDN) using dissolving and hydrogel-forming MAPs for osteoporosis treatment. In vivo testing on osteoporotic female Sprague Dawley rats demonstrated the efficacy of MAPs, showing significant improvements in mean serum and bone alkaline phosphatase levels, bone volume, and porosity compared to untreated bilateral ovariectomy (OVX) controls. Specifically, MAP treatment increased mean bone volume to 55.04 ± 2.25 % versus 47.16 ± 1.71 % in OVX controls and reduced porosity to 44.30 ± 2.97 % versus 52.84 ± 1.70 % in the distal epiphysis of the femur. In the distal metaphysis, bone volume increased to 43.32 ± 3.24 % in MAP-treated rats compared to 24.31 ± 3.21 % in OVX controls, while porosity decreased to 55.39 ± 5.81 % versus 75.69 ± 3.21 % in OVX controls. This proof-of-concept study indicates that MAP technology has the potential to be a novel, patient-friendly alternative for weekly osteoporosis management.

Airway consequences of alendronic acid aspiration.

Bisphosphonates are commonly prescribed medications to prevent and treat osteoporosis. Although possessing low side effect profiles, the potential for severe topical effects is rare but important. Irritation of the upper gastrointestinal tract is well documented; however, the risk and effects of accidental aspiration are rarely reported.Attention is drawn to a case recently managed at a tertiary head and neck centre where a patient in their 70s was admitted in respiratory distress 3 days after aspirating alendronic acid. This case highlights the potential risk of topical chemical injury posed to the airway by bisphosphonates.Bisphosphonates should be prescribed with detailed and specific counselling regarding this risk. Pharmacological product literature should be updated to reflect the risk. Clinical teams should be aware of and vigilant for the delayed presentation and prolonged symptom course of such injuries. Prompt airway intervention and techniques to minimise further mucosal trauma ensure optimal outcomes.

Predictors of discontinuation of osteoporosis treatment: sub-analysis of the Japanese osteoporosis intervention trial-05 (JOINT-05).

To identify predictors of discontinuing treatment with teriparatide (TPTD) and alendronate (ALN), data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high risk of fracture were re-analyzed. Participants received sequential therapy with once-weekly TPTD for 72weeks followed by ALN for 48weeks (TPTD-ALN group) or monotherapy with ALN for 120weeks (ALN group). Background data including comorbidities, fracture prevalence, cognitive function, quality of life, activities of daily living, bone metabolism parameters, and nutrient intake were collected. The endpoints were 3 types of discontinuations by the reason: a poor compliance, adverse events (AEs), or any reason including those unrelated to AEs or poor compliance. Odds ratios (ORs) of baseline predictors of discontinuation were evaluated by single or multiple regression analysis. A total of 234 (49.0%) patients in the TPTD-ALN group and 167 (34.2%) patients in the ALN group discontinued. In the TPTD-ALN group, a lower serum calcium level was a significant predictor of compliance-related discontinuation. Serum 25-hydroxyvitamin D levels were lower in patients with lower serum calcium levels than with higher serum calcium levels. In the ALN group, poor cognitive function was significantly associated with compliance-related discontinuation, and higher body mass index and alcohol intake were predictors of AE-related discontinuation. Predictors of discontinuation were drug-specific. Lower serum calcium levels and poor cognitive function were predictors of discontinuing once-weekly TPTD and ALN, respectively. When starting TPTD and ALN treatment, careful attention to patients with lower serum calcium levels and poor cognitive function, respectively, may be needed for better treatment continuity.

Controlled release in sodium alendronate/halloysite/hydroxyapatite/gelatin nanocomposite scaffolds: A new insight into bone tissue engineering

The use of smart scaffolds with drug release capabilities is now widely recognized as a key approach in designing hard tissue substitutes. In this study, alendronate sodium (AL) was bound to halloysite nanotube (HNT) sheets through ionic and π-π interactions. Hydroxyapatite (HA) powder was synthesized using the co-precipitation method, and the drug/carrier complex was subsequently incorporated into a hydroxyapatite/gelatin (GEL) matrix. Composite scaffolds of GEL/HA/HNT/AL were then created using a freeze-drying technique. Different concentrations of HNT (0.5 %, 1 %, and 2 %) were tested to determine the optimal formulation. The scaffolds were subjected to extensive physical, chemical, and mechanical evaluations using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), compressive stress tests, and measurements of density and porosity. The release profile of alendronate sodium, scaffold swelling behavior in water, bioactivity, and in vitro performance were thoroughly assessed. Cell viability was tested using the MTT assay, while alkaline phosphatase (ALP) activity and cell adhesion studies were performed to evaluate osteogenic potential. The results revealed that the GEL/HA/1 % HNT/AL nanocomposite scaffold exhibited excellent properties, including efficient drug release, optimal swelling rates, and enhanced bioactivity. The MTT assay confirmed high cell viability, and both ALP activity and cell adhesion studies indicated strong potential for bone cell differentiation and repair. Thus, the GEL/HA/1 % HNT/AL nanocomposite scaffold is a highly promising platform for bone tissue engineering.