Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Calcifediol (25-hydroxyvitamin D) improvement and calcium-phosphate metabolism of alendronate sodium/vitamin D3 combination in Chinese women with postmenopausal osteoporosis: a post hoc efficacy analysis and safety reappraisal.

BACKGROUND: Vitamin D (VD) insufficiency or deficiency is a frequent comorbidity in Chinese women with postmenopausal osteoporosis (PMO). The present study aimed to investigate 25-hydroxyvitamin D [25(OH) D] improvement and calcium-phosphate metabolism in Chinese PMO patients treated with 70 mg of alendronate sodium and 5600 IU of vitamin D3 (ALN/D5600). METHODS: Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders. RESULTS: Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%). CONCLUSION: Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 µg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage.

Zoledronic acid and alendronate sodium and the implications in orthodontic movement.

OBJECTIVE: To evaluate orthodontic tooth movement (OTM) in rats treated with two types of bisphosphonates (BPs), alendronate sodium (A) and zoledronic acid (Z). DESIGN: In all, 15 male Wistar rats were randomly divided into three groups. Group OTM+A: orthodontic tooth movement and subcutaneous administration of alendronate sodium (2.5 mg/kg); Group OTM+Z: orthodontic tooth movement and subcutaneous administration of zoledronic acid (0.02 mg/kg), and Group OTM: orthodontic tooth movement and subcutaneous injection of saline. The BPs were administered once a day during 25 days before OTM started and during 10 days of OTM. The left upper first molar was moved with a stainless-steel closed coil spring which delivered an initial force of 0.4N. OTM was measured with a digital caliper comparing the moved and the contralateral side. The histomorphometric analysis counted the number of osteoclasts, inflammatory cells, blood vessels and fibroblasts (n/104  m2 ) in periodontal ligament (PDL) of the distobuccal root. RESULTS: A reduction of 58.3% of OTM was found in Group OTM+A and 99.6% in Group OTM+Z, when compared with Group OTM. There was a significant decrease of osteoclasts and inflammatory cells in BP-treated groups. Blood vessels and fibroblastic cells decreased mainly in Group OTM+Z. CONCLUSION: Alendronate sodium and zoledronic acid have similar effects on the periodontal tissue during orthodontic treatment in rats. Especially, zoledronic acid can affect orthodontic tooth movement.

Mass spectrometry and molecular modeling studies on the inclusion complexes between alendronate and ß-cyclodextrin.

Complexation of alendronate sodium (AlnNa) with ß-cyclodextrin (ß-CD) was studied by means of ESI-mass spectrometry. The experimental results show that stable 1:1 inclusion complexes between selected bisphosphonates and ß-CD were formed. In addition, complexes with different stoichiometry were observed. DFT/B3LYP calculations were performed to elucidate the different inclusion behavior between alendronate and ß-CD. Molecular modeling showed that the inclusion complex of Aln-ß-CD where the two phosphonate groups bound to the central carbon atom of bisphosphonate were inserted into the cavity of ß-CD from its "top" side was thermodynamically more favorable than when they were inserted from its "bottom" side; the complexation energy was -74.05 versus -60.85 kcal/mol. The calculations indicated that the formation of conventional hydrogen bonds was the main factor for non-covalent ß-CD:Aln complex formation and stabilization in the gas phase.

Study of Injectable Hydrogel Based on ALN/nHA Promoting Osteogenesis and Inhibiting Osteoclasts in Osteoporotic Bone Defects Repair.

Osteoporotic bone defects cannot withstand surgery with more significant trauma due to bone fragility, while systemic drug therapy has formidable adverse effects. Consequently, the present study introduces an innovatively devised injectable double-crosslinked hydrogel, as a potential therapeutic avenue for addressing varied shapes of osteoporotic bone defects via a minimally invasive approach. The injectable hydrogel is formed by the formation of Schiff base bonds between oxidized sodium alginate (OSA) and carboxymethyl chitosan, and the polymerization of gelatin methacrylate by UV light crosslinking. Additionally, alendronate sodium (ALN) is loaded into the hydrogel through Schiff base formation with OSA, and nanohydroxyapatite (nHA) is incorporated into the hydrogel via blending. The hydrogel demonstrates excellent injectability, and the nHA improves the mechanical properties of hydrogel and can promote bone formation. In addition, the hydrogel can sustain the release of ALN, which has the effect of inhibiting osteoclasts. Cell studies indicate that the hydrogel can promote the differentiation of osteoblasts and inhibit the activity of osteoclast, so as to obtain better osteogenic effect. Therefore, the injectable hydrogel can be used to repair osteoporotic bone defects through a minimally invasive, simple treatment modality.

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.

Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis.

Low bone mass, degeneration of bone tissue, and disruption of bone microarchitecture are all symptoms of the disease osteoporosis, which can decrease bone strength and increase the risk of fractures. The main objective of the current study was to use a phospholipid-based phase separation in-situ gel (PPSG) in combination with an alendronate sodium nanoemulsion (ALS-NE) to help prevent bone resorption in rats. The effect of factors such as concentrations of the ALS aqueous solution, surfactant Plurol Oleique CC 497, and Maisine CC oil on nanoemulsion characteristics such as stability index and globular size was investigated using an l-optimal coordinate exchange statistical design. Injectable PPSG with the best nanoemulsion formulation was tested for viscosity, gel strength, water absorption, and in-vitro ALS release. ALS retention in the rats' muscles was measured after 30 days. The droplet size and stability index of the optimal nanoemulsion were 90 ± 2.0 nm and 85 ± 1.9%, respectively. When mixed with water, the optimal ALS-NE-loaded PPSG became viscous and achieved 36 seconds of gel strength, which was adequate for an injectable in-situ formulation. In comparison with the ALS solution-loaded in-situ gel, the newly created optimal ALS-NE-loaded PPSG produced the sustained and regulated release of ALS; hence, a higher percentage of ALS remained in rats' muscles after 30 days. PPSG that has been loaded with an ALS-NE may therefore be a more auspicious, productive, and effective platform for osteoporosis treatment than conventional oral forms.

Supplement of exogenous inorganic pyrophosphate inhibits atheromatous calcification in Apolipoprotein E knockout mice.

Inorganic pyrophosphate (PPi) is the endogenous inhibitor for vascular calcification (VC). The present study was to investigate the effects of adenosine disodium triphosphate (ADTP) and alendronate sodium (AL), two exogenous PPi sources, on the atheromatous calcification (AC) in Apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were randomly divided into five groups: ApoE KO group, ApoE KO + ADTP (Low) group, ApoE KO + ADTP (High) group, ApoE KO + AL (Low) group and ApoE KO + AL (High) group. The mice in ApoE KO + ADTP (Low) group and ApoE KO + ADTP (High) group were intraperitoneally injected with ADTP with dose of 0.5 and 1.0 mg/kg/day for 2 months respectively. The mice in ApoE KO + AL (Low) group and ApoE KO + AL (High) group were intraperitoneally injected with AL with dose of 0.6 and 1.2 mg/kg/day for 2 months respectively. The age matched C57 mice were used as control group. All ApoE KO and C57 mice were fed with normal chow throughout the experiment. The calcification was evaluated using von Kossa method. The contents of PPi, triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ) and interleukin-10 (IL-10) as well as the activity of alkaline phosphatase (ALP) in serum were measured. The results showed that compared with C57 mice, ApoE KO mice developed severe AC accompanied with high levels of TC, TG, LDL, IL-6, TNF-α and IFN-γ in serum and with low levels of PPi and IL-10 in serum. Both ADTP and AL dose-dependently reduced the AC in ApoE KO mice compared with that of ApoE mice, without affecting the contents of lipid profiles. In addition, ADTP and AL increased the contents of PPi and IL-10 while decreased the contents of TNF-α, IL-6 and IFN-γ in serum of ApoE KO mice, having no affection on ALP activity. The results suggested that ADTP and AL reduced AC in ApoE KO mice by increasing the PPi level and regulating the inflammation.

Formulation and Evaluation of Niosomal Alendronate Sodium Encapsulated in Polymeric Microneedles: In Vitro Studies, Stability Study and Cytotoxicity Study.

The aim of this study is to design and evaluate a transdermal delivery system for alendronate sodium (ALS) loaded with nanocarrier to improve its permeability and prolong its release. This is due to its low bioavailability, potential gastrointestinal side effects, and the special administration needed for the oral dosage form of ALS. When using the ether injection method, various niosomal formulations were produced. Size of the particles, polydispersity index (PDI), surface charge (ZP), drug entrapment efficiency (EE), and in vitro release were used to characterize the resulting niosomes. The size of niosomes ranged between 99.6 ± 0.9 and 464.3 ± 67.6 nm, and ZP was from −27.6 to −42.27 mV. The niosomal formulation was then loaded to aqueous polymer solution of 30% polyvinyl pyrrolidone (PVP) (MN-1), 30% PVP with 15% poly(vinyl alcohol) (PVA) (2:1) (MN-2), and 30% PVP with 15% PVA (1:1) (MN-3). The cumulative amount of ALS (Q) was in the following order: MN-1 > MN-2 > MN-3. All formulations in this study were stable at room temperature over two months, in terms of moisture content and drug content. In conclusion, a transdermal delivery of ALS niosomes combined in microneedles (MNs) was successfully prepared to provide sustained release of ALS.

Myricetin Loaded Nano-micelles Delivery System Reduces Bone Loss Induced by Ovariectomy in Rats Through Inhibition of Osteoclast Formation.

In recent years, much attention has been paid to the therapeutic effects of phytochemicals on osteoporosis. Other studies have shown that myricetin (MY) could promote osteogenic activity and inhibit osteoclastic effect, albeit little is known about effect of MY micellar system on osteoporosis. Therefore, we sought to discuss the therapeutic effect and mechanism of MY-loaded bone-targeting micelles on osteoporosis induced by ovariectomy (OVA) in rats. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles were prepared via ethanol injection method, while in vitro release study, bone targeting, pharmacokinetic studies, and the effect on proliferation of osteoblasts were investigated. Further, the therapeutic effect on osteoporosis was studied through ovariectomized rats. Compared with free MY, oral bioavailability of AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles in rats was increased by 3.54 times. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles exhibited bone targeting potential, and could significantly increase the activity of alkaline phosphatase and promote the proliferation of osteoblasts. Importantly, AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles mainly regulated bone metabolism by inhibiting bone resorption, thereby improving the symptoms of osteoporosis in OVA rats. The AL-P(LLA-CL)-PEG-P(LLA-CL)-MY micelles substantially enhanced the oral bioavailability of MY and demonstrated good bone targeting capability, thereby suggesting its prospect as carrier for osteoporotic improvement in OVA rats.

NH2-MIL-101(Fe) nanozyme-based dual-modality sensor for determination of alendronate sodium and study of two-dimensional correlation spectroscopy.

We developed a dual-modality sensing platform for ratiometric fluorescence and colorimetric determination of alendronate sodium (ALDS). This platform was performed by using a NH2- MIL-101(Fe) as a peroxidase mimic. Since preferential complexing between Fe3+ (active site for peroxidase) and ALDS, the production of 2,3-diaminophenazine (DAP, oxidized product of OPD) has been inhibited in the presence of H2O2. As a result, the ratiometric fluorescence value of F556/F456 and absorbance at 450 nm exhibited significant changes, which could be used as the dual-modality sensing platform. In addition, Two-dimensional correlation spectroscopy (2D-COS) analysis on Fourier-transform infrared (FTIR), ultraviolet visible and ratiometric fluorescence spectra were applied to investigate the binding features. Synchronous and asynchronous maps of these spectra confirmed our above hypothesis, in which Fe3+-ALDS complex was the critical factor that regulated dual-modality signals. To our knowledge, the 2D-COS method was applied to study the catalytic and sensing mechanism of nanozyme as NH2- MIL-101(Fe) for the first time. This technique was helpful to understand interaction of substrates on nanozyme and develop more sensitive sensors for assaying.

Effects of alendronate sodium combined with InterTan on osteoporotic femoral intertrochanteric fractures and fracture recurrence.

BACKGROUND: Osteoporosis is a global disease affecting 6.6% of the total population. Osteoporosis complications include fractures, increased bone fragility, and reduced bone strength. The most commonly affected parts are the vertebral body, hip, and wrist. AIM: To examine the effect of alendronate sodium combined with InterTan for osteoporotic femoral intertrochanteric fractures on bone and fracture recurrence. METHODS: In total, 126 cases of osteoporotic femoral intertrochanteric fractures were selected and divided into two groups according to the 1:1 principle by the simple random method. They were admitted to the Department of Orthopedics, First Affiliated Hospital of Xingtai Medical College, from January 2018 to September 2020. The control group was treated with InterTan fixation combined with placebo, and the observation group with alendronate sodium based on InterTan fixation. Operation-related indicators, complications, and recurrent fractures were compared between the groups. Changes in bone metabolism markers, t value for hip bone mineral density, and Harris Hip Score were observed. RESULTS: Operation time, intraoperative blood loss, postoperative ambulation time, and complications were compared between the groups, and no significant difference was found. The fracture healing time was significantly shorter in the observation group than in the control group. ß-Collagen-specific sequence (ß-CTX) and total aminoterminal propeptide of type I procollagen (T-PINP) in the control group at 3 mo after operation were compared with those before operation, and the difference was not significant. Six months after the operation, the ß-CTX level decreased and T-PINP level increased. ß-CTX level at 3 and 6 mo in the observation group after operation was lower, and T-PINP level was higher, than that before operation. Compared with the control group, T-PINP level of the observation group was significantly higher and ß-CTX level was significantly lower at 3 and 6 mo after operation. The t value of hip bone mineral density was compared in the control group before and 1 mo after operation, and significant difference was not found. Compared with the control group, the t value of hip bone mineral density in the observation group was significantly higher at 1, 3, 6, and 12 mo after operation. Compared with the control group, the Harris score of the observation group was significantly higher at 1, 3, 6, and 12 mo after operation. The recurrence rate of fractures in the observation group within 12 mo was 0.00%, which was significantly lower than 6.35% in the control group. CONCLUSION: Alendronate sodium combined with InterTan in the treatment of osteoporotic femoral intertrochanteric fractures can increase bone mineral density, improve hip joint function, promote fracture healing, and reduce fracture recurrence.

Monostotic Fibrous Dysplasia in the Femur Strongly Expressing RANKL With Concomitant Osteoporotic Vertebral Compression Fracture: A Case Report.

Background/Aim: This study aimed to present a rare case of fibrous dysplasia (FD) in a healthy young adult man with a concomitant osteoporotic vertebral compression fracture. FD is a benign lesion of the bone characterized by replacement of the medullary component with fibro-osseous tissue that contains abnormally arranged trabeculae of immature woven bone. Recently it has been reported that several bone tumors including FD express the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL). Therefore, we hypothesized that FD contributed to osteoporosis, linked by the RANK-RANKL pathway of osteoclastogenesis. Case Report: We report the case of a healthy man with monostotic femoral fibrous dysplasia (FD) with concomitant 7 th thoracic vertebra compression fracture due to osteoporosis [young adult mean (YAM) was 79% in bone mineral density (BMD)]. After curettage of the FD, artificial bone grafting in the cavity, and administration of alendronate sodium, BMD improved considerably within 9 months. FD is a benign bone condition in which abnormal fibrous tissue replaces normal bone. The axis of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been implicated in osteoporosis pathogenesis. RANKL immunohistochemical staining was performed, and strong staining of stromal cells was observed compared to other FD cases that showed weak to moderate staining. Conclusion: The presence of FD might have contributed to the low BMD due to the RANK-RANKL axis acting as osteoclastogenesis stimulator.

Apamin-Conjugated Alendronate Sodium Nanocomplex for Management of Pancreatic Cancer.

Pancreatic cancer has a low survival rate and has limited therapeutic options due to the peculiarity of the tumor tissue. Cancer nanotechnology provides several opportunities to resolve such difficulties as a result of the high surface-to-volume ratio of nanostructures. Peptide-drug nanocomplexes have proved to have immense potential in anticancer activity against pancreatic cancer cells. Thus, in the present study apamin (APA) and alendronate sodium (ALS) were combined to form nanocomplexes (APA-ALS-NC) against pancreatic cancer cells. Optimization of ALS, incubation time, and sonication time in terms of particle size of the nanocomplex was carried out. The optimized formulation was evaluated for anticancer activities in pancreatic cancer cells (PANC-1 cells). A Box-Behnken design using ALS, incubation time, and sonication time as independent factors and particle size as the response was chosen to optimize the APA-ALS-NC formulation. The optimized APA-ALS-NC had a particle size of 161.52 ± 8.4 nm. The evaluation of APA-ALS-NC in PANC-1 cells was carried out using various in vitro tests. The IC50 values were determined by MTT assay and found to be 37.6 ± 1.65, 13.4 ± 0.59, and 1.01 ± 0.04 µg/mL for ALS, APA, and APA-ALS-NC, respectively. The higher cytotoxicity activity of APA-ALS-NC was confirmed from the higher percentage of cells in the necrosis phase (apoptosis study) and the G2-M phase (cell cycle study) compared to that of ALS and APA. While the loss of mitochondrial membrane potential was less for APA-ALS-NC, the levels of IL-1ß, TNF-α, caspase-3, ROS, IL-6, and NF-kB showed that APA-ALS-NC can significantly enhance apoptosis and cytotoxicity in PANC-1 cells. Moreover, Bax (10.87 ± 1.36), Bcl-2 (0.27 ± 0.02), and p53 (9.16 ± 1.22) gene expressions confirmed that APA-ALS-NC had a significant apoptotic effect compared to ALS and APA. In summary, the APA-ALS-NC had a more significant cytotoxic effect than ALS and APA. The results of the present study are promising for further evaluation in pre-clinical and clinical trials for arriving at a successful therapeutic strategy against pancreatic cancer.

Oral administration of alendronate and vitamin D3 for the treatment of chronic non-bacterial osteomyelitis of the jaw.

Chronic non-bacterial osteomyelitis (CNO) is a rare and difficult-to-diagnose disease, especially when limited to the jaws. We report the case of a 5-year-old girl with spontaneous jaw pain and a large pre-auricular facial swelling overlying the angle of the mandible that was non-responsive to previous antibiotic and non-steroidal anti-inflammatory treatment. The diagnosis was confirmed as CNO following evaluation and workup by a multidisciplinary team. The patient exhibited a favourable response to oral alendronate sodium plus vitamin D3 combination treatment. We believe that alendronate sodium is an effective second-line drug for CNO.

A New Insight into Coating's Formation Mechanism Between TiO2 and Alendronate on Titanium Dental Implant.

Organophosphorus compounds, like bisphosphonates, drugs for treatment and prevention of bone diseases, have been successfully applied in recent years as bioactive and osseoinductive coatings on dental implants. An integrated experimental-theoretical approach was utilized in this study to clarify the mechanism of bisphosphonate-based coating formation on dental implant surfaces. Experimental validation of the alendronate coating formation on the titanium dental implant surface was carried out by X-ray photoelectron spectroscopy and contact angle measurements. Detailed theoretical simulations of all probable molecular implant surface/alendronate interactions were performed employing quantum chemical calculations at the density functional theory level. The calculated Gibbs free energies of (TiO2)10-alendronate interaction indicate a more spontaneous exergonic process when alendronate molecules interact directly with the titanium surface via two strong bonds, Ti-N and Ti-O, through simultaneous participation common to both phosphonate and amine branches. Additionally, the stability of the alendronate-modified implant during 7 day-immersion in a simulated saliva solution has been investigated by using electrochemical impedance spectroscopy. The alendronate coating was stable during immersion in the artificial saliva solution and acted as an additional barrier on the implant with overall resistivity, R ~ 5.9 MΩ cm2.

Guided bone regeneration by the development of alendronate sodium loaded in-situ gel and membrane formulations.

Biocompatible materials applied in guided bone regeneration are needed to prevent leakage caused by the invasion of peripheral epithelium. (2.1) The aim of this study is to develop a thermosensitive in situ gel system containing alendronate sodium loaded PLGA nanoparticles and alendronate sodium loaded membranes for guided bone regeneration. Thermosensitive Pluronic F127 gel system was preferred to prevent soft tissue migration to the defect site and prolong the residence time of the nanoparticles in this region. In situ gel system was combined with membrane formulation to enhance bone regenaration activity. Efficacy of combination system was investigated by implanting in 0.5 × 0.5 cm critical size defect in tibia of New Zealand female rabbits. According to the histopathological results, fibroblast formations were found at defect area after 6 weeks of post implantation. In contrast, treatment with the combination of in-situ gel containing nanoparticles with membrane provided woven bone formation with mature bone after 4 weeks of post implantation. As a results, the combination of in-situ gel formulation containing alendronate sodium-loaded nanoparticles with membrane formulation could be effectively applided for guided bone regeneration.

Hantzsch pre-column derivatization for simultaneous determination of alendronate sodium and its pharmacopoeial related impurity: Comparative study with synchronous fluorometry using fluorescamine.

High performance liquid chromatographic (HPLC) method with a pre-column derivatization based on Hantzsch condensation reaction was applied for simultaneous determination of alendronate sodium (ALN) and its main related impurity, 4-Aminobutanoic acid (ABA) at its pharmacopeial limit. The separation of colored condensation products of ALN and ABA were achieved on Agilent Zobrax Eclipse SB-C18 analytical column (250 × 4.6 mm, 5 µm) using a mobile phase composed of acetonitrile-0.1 M acetate buffer, pH 5.0 (15:85, v/v). The flow rate was 1 mL min-1. The detection was carried out at 340 nm using photo-diode array detector. Peak areas were used for the linear regression line in the range of 10-500 and 0.2-40 µg mL-1 for ALN and ABA, respectively. Different conditions for the optimization of the derivatization reactions as well as for the HPLC measurement were studied. The proposed method was validated for linearity, precision, accuracy, specificity and robustness. This method was used to check the purity of ALN in the presence of ABA (related impurity) at the pharmacopeial limit (0.5%). For comparison purpose, another method was proposed which involves synchronous fluorescence measurement after ALN reaction with fluorescamine. In this method, the third derivative synchronous spectra were estimated as peak to peak measurement from 339 to 370 nm for ALN determination with LOD and LOQ of 24 and 73 ng mL-1, respectively, showing very high sensitivity. Both methods have been applied for determination of the alendronate sodium (ALN) in bulk and pharmaceutical preparations without interference of additives in tablets or oral solution.

Rapid magnetic solid-phase extraction based on alendronate sodium grafted mesoporous magnetic nanoparticle for the determination of trans-resveratrol in peanut oils.

In the present study, a rapid and effective method based on alendronate sodium grafted mesoporous magnetic nanoparticle (Fe3O4@ANDS) extraction for the determination of trans-resveratrol (TRA) in peanut oils was developed by coupling with HPLC-UV detection. The Fe3O4@ANDS was prepared via Lewis acid/base interaction which was simply carried out in mild aqueous condition without the using of organic solvent. The resultant Fe3O4@ANDS encompassed amino group on its surface, and it was employed as magnetic solid-phase extraction adsorbent for purification and enrichment of TRA from peanut oils through hydrogen bond interaction. Under the optimized conditions, the whole pretreatment process could be accomplished within 10 min without time-consuming concentrated and reconstituted process. The linearity range of the proposed method was 1-10,000 ng/g with satisfactory correlation coefficient (R2) of 0.9992. The recoveries in spiked oil samples were in the range of 78.6-118.9% with the RSDs less than 3.3% (intra-day) and 15.2% (inter-day). The limit of detection for TRA in peanut oils was 0.3 ng/g which was comparative to the reported methods by using LC-MS/MS detection. Finally, the established method was successfully applied to the analysis of TRA in several peanut oils with different brands from local market as well as other kinds of vegetable oils.

Analyses of the efficacy of percutaneous kyphoplasty and alendronate sodium on thoracolumbar vertebral fracture and the risk factors of fracture.

The present study investigated the efficacy of percutaneous kyphoplasty and alendronate sodium on thoracolumbar vertebral fracture, and the risk factors leading to the recurrence of fracture. In the present study, a total of 80 patients with thoracolumbar vertebral fracture who were admitted to the Affiliated Jiangyin Hospital of Southeast University Medical College between January 2014 and March 2016 for combination treatment of percutaneous kyphoplasty and alendronate sodium were enrolled. According to the recurrence of fracture, the patients were divided into two groups, the observation group (patients with fracture recurrence, n=40) and control group (patients with no fracture recurrence, n=40). All patients participated in a 1-year follow-up. The recurrence of fracture and the site of fracture were identified through the clinical symptoms and examination of the spine using magnetic resonance imaging. In addition, comparisons of the time of alleviation in numbness of lower limb and that in pains in waist and legs were carried out. Furthermore, statistics on the adverse reactions during intervention in the two groups were also collected; changes in visual analogue scale (VAS) and Oswestry Disability Index (ODI) of pains at different time points in two groups were also observed. One-way analysis and multivariate analysis were performed to identify the relevant risk factors. Alleviation time in numbness of lower legs in patients of the control group was significantly earlier than that in the observation group (P<0.05) and the alleviation time in pains of the waist and legs of patients in the control group was also significantly earlier than that in the observation group (P<0.05). Furthermore, the incidence rates of abdominal pain, diarrhea, constipation and hypocalcemiain in the control group were also significantly lower compared with those in the observation group (P<0.05). One week, one month and one year after operation, the scores of VAS of pains and ODI in the control group were significantly lower compared with those in the observation group in the same period (P<0.05). Lower preoperative bone density and exosmosis of bone cement in treatment were the independent risk factors leading to the recurrence of fracture. For patients with thoracolumbar vertebral fracture who received the combination treatment of percutaneous kyphoplasty and alendronate sodium, there underlies an important correlation between the recurrence rate of fracture and the preoperative bone density as well as the exosmosis of bone cement in operation.