Safety and effectiveness of risedronate in Paget's disease of bone: postmarketing surveillance study in Japan.

INTRODUCTION: We conducted an all-case postmarketing surveillance study between 2008 and 2017 to evaluate the safety and effectiveness of risedronate for Paget's disease of bone (PDB) in Japan. MATERIAL AND METHODS: This study registered all patients who received once-daily risedronate 17.5 mg for the treatment of PDB and collected data over a 48-week follow-up period per treatment cycle for each patient. RESULTS: The safety analysis set included 184 patients (mean age, 63.7 years), 81 (44.0%) of whom previously received a bisphosphonate. Of them, 41 (22.3%) experienced 72 adverse drug reactions (ADRs), and 8 (4.3%) experienced 14 serious ADRs. Common ADRs included gastrointestinal disorders (20 patients, 10.9%) and hypocalcemia (6 patients, 3.3%). The effectiveness analysis set included 182 patients, 124 of whom completed only one treatment cycle and 58 of whom completed multiple treatment cycles. The proportions of patients who normalized serum alkaline phosphatase (ALP) concentration were 71.1% (113/159 patients) and 67.3% (33/49 patients) for the first and second treatment cycles, respectively. The relapse rate according to ALP levels after the end of treatment for the first cycle was 5.0% (95% confidence interval [CI] = 2.1-11.5) at 24 weeks and 12.9% (95% CI = 7.5-21.7) at 40 weeks. Regarding pain relief, the achievement rates were 70.0% (49/70 patients) and 30.8% (4/13 patients) for the first and second treatment cycles, respectively. CONCLUSION: To conclude, risedronate 17.5 mg/day is safe and effective for treating patients with PDB in daily practice.

Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high). OBJECTIVES: To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively. SEARCH METHODS: We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023. SELECTION CRITERIA: We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study. MAIN RESULTS: Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies. AUTHORS' CONCLUSIONS: This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.

Comparative effects of 17% ethylenediaminetetraacetic acid and 9% etidronic acid applied with different irrigant activation techniques on the release of growth factors from dentin: in vitro study.

BACKGROUND: Growth factors embedded in the extracellular matrix of the dentin play an important role in the migration, proliferation, and differentiation of dental pulp stem cells in regenerative endodontics. In regenerative endodontic treatments, the type of irrigation solution used is crucial for the release of growth factors (GFs) from the dentin matrix. This study evaluated the effectiveness of different irrigant activation techniques (IAT) using two different chelating agents, 17% ethylenediaminetetraacetic acid (EDTA) and 9% etidronic acid (HEDP), in terms of their GF release. METHODS: Seventy-two mandibular premolar teeth were prepared to simulate an open apex. The root fragments were irrigated with 20 ml of 1.5% sodium hypochlorite and 20 ml of saline solution. Eight root fragments were randomly separated for the control group, and the remaining 64 fragments were randomly separated into eight groups based on two different chelating agents (17% EDTA and 9% HEDP) and four different IAT ((conventional needle irrigation (CNI), passive ultrasonic irrigation (PUI), sonic activation with EDDY, and XP-endo Finisher (XPF)). TGF-ß1, VEGF-A, BMP-7 and IGF-1 release levels were determined using an ELISA, and statistical analysis was performed using the Kolmogorov-Smirnov test, ANOVA, and the Tukey test (p < .05). RESULTS: Compared to the control group, the experimental groups showed significantly higher GF release when using EDTA or HEDP. Among the activation groups, the EDDY group triggered the highest GF release, and the CNI group triggered the lowest. CONCLUSIONS: IAT with EDTA and HEDP can increase GF release, with EDDY being the most effective IAT method. Using chelating agents with IAT may be beneficial in regenerative endodontic treatments.

Fracture risk in women with osteoporosis initiated on gastro-resistant risedronate versus immediate release risedronate or alendronate: a claims data analysis in the USA.

The study results indicate that women with osteoporosis initiated on gastro-resistant risedronate have a lower risk of fracture than those initiated on immediate release risedronate or alendronate. A large proportion of women discontinued all oral bisphosphonate therapies within 1 year of treatment start. PURPOSE: Using a US claims database (2009-2019), we compared risk of fractures between women with osteoporosis initiated on gastro-resistant (GR) risedronate and those initiated on (a) immediate release (IR) risedronate or (b) immediate release alendronate. METHODS: Women aged ≥ 60 years with osteoporosis who had ≥ 2 oral bisphosphonate prescription fills were followed for ≥ 1 year after the first observed bisphosphonates dispensing (index date). Fracture risk was compared between the GR risedronate and IR risedronate/alendronate cohorts using adjusted incidence rate ratios (aIRRs), both overall and in subgroups with high fracture risk due to older age or comorbidity/medications. Site-specific fractures were identified based on diagnosis codes recorded on medical claims using a claims-based algorithm. Persistence on bisphosphonate therapy was evaluated for all groups. RESULTS: aIRRs generally indicated lower fracture risk for GR risedronate than IR risedronate and alendronate. When comparing GR risedronate to IR risedronate, statistically significant aIRRs (p < 0.05) were observed for pelvic fractures in the full cohorts (aIRRs = 0.37), for any fracture and pelvic fractures among women aged ≥ 65 years (aIRRs = 0.63 and 0.41), for any fracture and pelvic fractures among women aged ≥ 70 years (aIRRs = 0.69 and 0.24), and for pelvic fracture among high-risk women due to comorbidity/medications (aIRR = 0.34). When comparing GR risedronate to alendronate, statistically significant aIRRs were observed for pelvic fractures in the full cohorts (aIRR = 0.54), for any fracture and wrist/arm fractures among women aged ≥ 65 years (aIRRs = 0.73 and 0.63), and for any fracture, pelvic, and wrist/arm fractures among women aged ≥ 70 years (aIRRs = 0.72, 0.36, and 0.58). In all cohorts, ~ 40% completely discontinued oral bisphosphonates within 1 year. CONCLUSIONS: Discontinuation rates of oral bisphosphonate therapy were high. However, women initiated on GR risedronate had a significantly lower risk of fracture for several skeletal sites than women initiated on IR risedronate/alendronate, particularly those aged ≥ 70 years.

Enhanced inhibition of HEDP on SRB-mediated corrosion with D-phenylalanine.

Microbiologically influenced corrosion (MIC) caused by biofilm is a serious problem in many industries. D-amino acids could be a potential strategy to enhance traditional corrosion inhibitors due to their roles in biofilm reduction. However, the synergistic mechanism of D-amino acids and inhibitors remains unknown. In this study, D-Phenylalanine (D-Phe) and 1-hydroxyethane-1,1-diphosphonic acid (HEDP) were selected as the typical D-amino acid and corrosion inhibitor to evaluate their effect on the corrosion caused by Desulfovibrio vulgaris. The combination of HEDP and D-Phe obviously slowed down the corrosion process by 32.25%, decreased the corrosion pit depth and retarded cathodic reaction. SEM and CLSM analysis indicated that D-Phe reduced the content of extracellular protein and thus inhibited the biofilm formation. The molecular mechanism of D-Phe and HEDP on corrosion inhibition was further explored via transcriptome. The combination of HEDP and D-Phe down-regulated the gene expression of peptidoglycan, flagellum, electron transfer, ferredoxin and quorum sensing (QS) molecules, leading to less peptidoglycan synthesis, weaker electron transfer and stronger QS factor inhibition. This work provides a new strategy for improving traditional corrosion inhibitors, retarding MIC and mitigating subsequent water eutrophication.

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification.

Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease.

Real-Time Impedance-Based Monitoring of the Growth and Inhibition of Osteomyelitis Biofilm Pathogen Staphylococcus aureus Treated with Novel Bisphosphonate-Fluoroquinolone Antimicrobial Conjugates.

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis.

Fluorescent-Tagged Antiscalants-The New Materials for Scale Inhibition Mechanism Studies, Antiscalant Traceability and Antiscaling Efficacy Optimization during CaCO3 and CaSO4·2H2O Scale Formation.

Equipment scaling leads to reduced production efficiency in a wide range of industrial applications worldwide. Various antiscaling agents are currently commonly used to mitigate this problem. However, irrespective of their long and successful application in water treatment technologies, little is known about the mechanisms of scale inhibition, particularly the localization of scale inhibitors on scale deposits. The lack of such knowledge is a limiting factor in the development of applications for antiscalants. Meanwhile, fluorescent fragments integrated into scale inhibitor molecules have provided a successful solution to the problem. The focus of this study is, therefore, on the synthesis and investigation of a novel fluorescent antiscalant: (2-(6-morpholino-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)yl)ethylazanediyl)bis(methylenephosphonic acid) (ADMP-F) which is an analog of the commercial antiscalant: aminotris(methylenephosphonic acid) (ATMP). ADMP-F has been found to effectively control the precipitation of CaCO3 and CaSO4 in solution and is a promising tracer for organophosphonate scale inhibitors. ADMP-F was compared with two other fluorescent antiscalants-polyacrylate (PAA-F1) and bisphosphonate (HEDP-F)-and was found to be highly effective: PAA-F1 > ADMP-F >> HEDP-F (CaCO3) and PAA-F1 > ADMP-F > HEDP-F (CaSO4·2H2O). The visualization of the antiscalants on the deposits provides unique information on their location and reveals differences in the "antiscalant-deposit" interactions for scale inhibitors of different natures. For these reasons, a number of important refinements to the mechanisms of scale inhibition are proposed.

Europium(III) Meets Etidronic Acid (HEDP): A Coordination Study Combining Spectroscopic, Spectrometric, and Quantum Chemical Methods.

Etidronic acid (1-Hydroxyethylidene-1,1-diphosphonic acid, HEDP, H4L) is a proposed decorporation agent for U(VI). This paper studied its complex formation with Eu(III), an inactive analog of trivalent actinides, over a wide pH range, at varying metal-to-ligand ratios (M:L) and total concentrations. Combining spectroscopic, spectrometric, and quantum chemical methods, five distinct Eu(III)-HEDP complexes were found, four of which were characterized. The readily soluble EuH2L+ and Eu(H2L)2- species with log ß values of 23.7 ± 0.1 and 45.1 ± 0.9 are formed at acidic pH. At near-neutral pH, EuHL0s forms with a log ß of ~23.6 and, additionally, a most probably polynuclear complex. The readily dissolved EuL- species with a log ß of ~11.2 is formed at alkaline pH. A six-membered chelate ring is the key motif in all solution structures. The equilibrium between the Eu(III)-HEDP species is influenced by several parameters, i.e., pH, M:L, total Eu(III) and HEDP concentrations, and time. Overall, the present work sheds light on the very complex speciation in the HEDP-Eu(III) system and indicates that, for risk assessment of potential decorporation scenarios, side reactions of HEDP with trivalent actinides and lanthanides should also be taken into account.

Decomplexation of Cu-1-hydroxyethylidene-1,1-diphosphonic acid by a three-dimensional electrolysis system with activated biochar as particle electrodes.

The feasibility of decomplexation removal of typical contaminants in electroplating wastewater, complexed Cu(II) with 1-hydroxyethylidene-1,1-diphosphonic acid (Cu-HEDP), was first performed by a three-dimensional electrode reactor with activated biochar as particle electrodes. For the case of 50 mg/L Cu-HEDP, Cu(II) removal (90.7%) and PO43- conversion (34.9%) were achieved under the conditions of electric current 40 mA, initial pH 7, acid-treated almond shell biochar (AASB) addition 20 g/L, and reaction time 180 min, with second-order rate constants of 1.10 × 10-3 and 1.94 × 10-5 min-1 respectively. The growing chelating effect between Cu(II) and HEDP and the comprehensive actions of adsorptive accumulation, direct and indirect oxidation given by particle electrodes accounted for the enhanced removal of Cu-HEDP, even though the mineralization of HEDP was mainly dependent on anode oxidation. The performance attenuation of AASB particle electrodes was ascribed to the excessive consumption of oxygen-containing functionalities during the reaction, especially acidic carboxylic groups and quinones on particle electrodes, which decreased from 446.74 to 291.48 µmol/g, and 377.55 to 247.71 µmol/g, respectively. Based on the determination of adsorption behavior and indirect electrochemical oxidation mediated by in situ electrogenerated H2O2 and reactive oxygen species (e.g., •OH), a possible removal mechanism of Cu-HEDP by three-dimensional electrolysis was further proposed.

Antiresorptive treatments for corticosteroid-induced osteoporosis: a Bayesian network meta-analysis.

INTRODUCTION: Corticosteroid-induced osteoporosis (CIO) is the most common type of secondary osteoporosis, leading to fractures, and increased morbidity and mortality. SOURCE OF DATA: Pubmed, EMBASE, Scopus and Google Scholar databases. AREAS OF AGREEMENT: Prolonged glucocorticoids administration leads to secondary osteoporosis. AREAS OF CONTROVERSY: The optimal management for CIO is controversial. GROWING POINTS: The present study compared bone mineral density, fractures and adverse events in patients undergoing treatment with risedronate, alendronate, zoledronate, denosumab or etidronate for CIO. AREAS TIMELY FOR DEVELOPING RESEARCH: For selected patients with CIO, alendronate performed better overall. These results must be interpreted within the limitations of the present study. LEVEL OF EVIDENCE: I, Bayesian network meta-analysis of randomized clinical trials.

Bone-loading exercises versus risedronate for the prevention of osteoporosis in postmenopausal women with low bone mass: a randomized controlled trial.

PURPOSE: This randomized controlled trial compared changes in bone mineral density (BMD) and bone turnover in postmenopausal women with low bone mass randomized to 12 months of either risedronate, exercise, or a control group. METHODS: Two hundred seventy-six women with low bone mass, within 6 years of menopause, were included in analysis. Treatment groups were 12 months of (a) calcium and vitamin D supplements (CaD) (control), (b) risedronate + CaD (risedronate), or (c) bone-loading exercises + CaD (exercise). BMD and serum markers for bone formation (Alkphase B) and resorption (Serum Ntx) were analyzed at baseline, 6, and 12 months. RESULTS: Using hierarchical linear modeling, a group by time interaction was found for BMD at the spine, indicating a greater improvement in the risedronate group compared to exercise (p ≤ .010) or control groups (p ≤ .001). At 12 months, for women prescribed risedronate, changes in BMD at the spine, hip, and femoral neck from baseline were + 1.9%, + 0.9%, and + .09%; in exercise group women, + 0.2%, + 0.5%, and - 0.4%; and in control group women, - 0.7%, + 0.5%, and - 0.5%. There were also significant differences in reductions in Alkphase B (RvsE, p < .001, RvsC, p < .001) and Serum Ntx (RvsE, p = .004, RvsC, p = .007) in risedronate women compared to exercise and control groups. For risedronate, 12-month changes in Alkphase B and Serum Ntx were - 20.3% and - 19.0%; for exercise, - 6.7% and - 7.0%; and for control, - 6.3% and - 9.0%. CONCLUSION: Postmenopausal women with low bone mass should obtain adequate calcium and vitamin D and participate in bone-loading exercises. Additional use of BPs will increase BMD, especially at the spine.

Fracture rates and economic outcomes in patients with osteoporosis prescribed risedronate gastro-resistant versus other oral bisphosphonates: a claims data analysis.

Patients with osteoporosis prescribed risedronate gastro-resistant had a lower incidence of fractures versus those prescribed other oral bisphosphonates. Administration of risedronate gastric-resistant does not require fasting, and this more convenient dosing administration may explain its improved efficacy. PURPOSE: Up to half of patients do not follow complex dosing instructions of immediate-release bisphosphonates used for the prevention of osteoporotic fractures, which can result in suboptimal effectiveness. Risedronate gastro-resistant (GR) offers a more convenient dosing option by eliminating the need for fasting. This study compares fracture rates and outcomes between osteoporosis women treated with risedronate GR (GR cohort) versus other oral bisphosphonates (other cohort). METHODS: Claims from women with osteoporosis in the USA were analyzed. Patients were classified into the two cohorts based on the first oral bisphosphonate observed (index date) and matched 1:1 based on patient characteristics. Patients were observed for ≥ 2 years following the index date. Fracture rates, health care resource utilization and costs, and treatment persistence were compared. RESULTS: In total, 2,726 patients were selected in each cohort (median age: 60.0 years). The incidence of fractures was lower in the GR versus the other cohort for any fracture sites (incidence rate ratio, 95% CI: 0.83, 0.70-0.97) and spine fractures (0.71, 0.54-0.95), although the respective rate of medication discontinuation at 2 years was 80.5% and 74.4%. Time to first fracture was delayed for the GR cohort, reaching statistical significance after 36 months. The GR cohort incurred fewer hospitalizations (incidence rate per 1,000 patient-years: GR = 106.74; other = 124.20, p < 0.05) translating into lower hospitalization costs per patient per year (GR = $3,611; other = $4,603, p < 0.05). CONCLUSIONS: Patients prescribed risedronate GR versus other bisphosphonates had a lower incidence of fractures, which may be explained by the fact that the GR formulation is absorbed even when taken with food.

Treatment of Temporomandibular Joint Heterotopic Ossification: A Novel Protocol With Multimodal Therapy Based on Literature Review and Presentation of a Unique Case Report.

PURPOSE: The purpose of this study was to create a treatment protocol for cases of heterotopic ossification (HO) of the temporomandibular joint (TMJ), particularly those refractory to current TMJ HO protocols. In addition, we demonstrate the success of this protocol on a unique case of recurrent HO that failed multiple TMJ HO protocols in the setting of an improvised explosive device (IED) blast in a wounded warrior. METHODS: An electronic literature review was conducted via PubMed and Web of Science. Twenty-five studies were identified to provide supporting evidence for a proposed, up-to-date protocol for the treatment of refractory TMJ HO. The authors present a case report of a wounded warrior with HO ankylosis of bilateral TMJs in the setting of IED blast and demonstrate successful use of our surgical and pharmacotherapeutic protocol. RESULTS: Based on the literature review, our proposed protocol consists of pharmacotherapy with celecoxib and etidronate, with weekly forced dilation (brisement) and home physical therapy with the TheraBite Jaw Motion Rehab System. Surgically, the TMJ should be treated with two-stage reconstruction using initial polymethyl methacrylate spacers and subsequent total joint replacement with custom prostheses, fat grafting, and 3-dimensional-navigated total resection of HO. This protocol was successfully utilized in our patient's refractory HO ankylosed TMJ secondary to IED blast, and the patient's maximal incisal opening was regained and has remained stable 2 years after surgery without recurrent HO. CONCLUSIONS: Our method for treatment in this case deviated from the standard TMJ Concepts HO protocol in that it included multimodal pharmacotherapy with celecoxib and etidronate. Based on our literature review and experience, we advise that clinicians utilize our protocol for the management of all craniofacial HO cases, particularly in cases of recurrent HO that fail conventional therapies and/or involving high-order blast trauma.

The response of dual-species bacterial biofilm to 2% and 5% NaOCl mixed with etidronic acid: A laboratory real-time evaluation using optical coherence tomography.

AIM: The addition of etidronic acid (HEDP) to sodium hypochlorite (NaOCl) could increase the antibiofilm potency of the irrigant, whilst maintaining the benefits of continuous chelation. Studies conducted so far have shown that mixing HEDP with NaOCl solutions of relatively low concentration does not compromise the antibiofilm efficacy of the irrigant. However, the working lifespan of NaOCl may decrease resulting in a reduction of its antibiofilm efficacy over time (efficiency). In this regard, continuous irrigant replenishment needs to be examined. This study investigated the response of a dual-species biofilm when challenged with 2% and 5% NaOCl mixed with HEDP for a prolonged timespan and under steady laminar flow. METHODOLOGY: Dual-species biofilms comprised of Streptococcus oralis J22 and Actinomyces naeslundii T14V-J1 were grown on human dentine discs in a constant depth film fermenter (CDFF) for 96 h. Biofilms were treated with 2% and 5% NaOCl, alone or mixed with HEDP. Irrigants were applied under steady laminar flow for 8 min. Biofilm response was evaluated by means of optical coherence tomography (OCT). Biofilm removal, biofilm disruption, rate of biofilm loss and disruption as well as bubble formation were assessed. One-way anova, Wilcoxon's signed-rank test and Kruskal-Wallis H test were performed for statistical analysis of the data. The level of significance was set at a ≤.05. RESULTS: Increasing NaOCl concentration resulted in increased biofilm removal and disruption, higher rate of biofilm loss and disruption and increased bubble formation. Mixing HEDP with NaOCl caused a delay in the antibiofilm action of the latter, without compromising its antibiofilm efficacy. CONCLUSIONS: NaOCl concentration dictates the biofilm response irrespective of the presence of HEDP. The addition of HEDP resulted in a delay in the antibiofilm action of NaOCl. This delay affects the efficiency, but not the efficacy of the irrigant over time.

Impact of agitation/activation strategies on the antibiofilm potential of sodium hypochlorite/etidronate mixture in vitro.

BACKGROUND: To investigate the effect of a rotary agitation method or ultrasonically activated irrigation on the antibiofilm effect of a mixture of sodium hypochlorite (NaOCl) and etidronate (1-hydroxyethylidene-1,1-bisphosphonate, HEBP) using a dual-species biofilm model in root canal system. METHODS: Mature dual-species biofilms of Enterococcus faecalis and Streptococcus gordonii were formed in root canals of mandibular premolars. Teeth were randomly allotted (n = 12) to group 1, XP-endo Finisher (XPF); group 2, ultrasonically activated irrigation (UAI); group 3, syringe-and-needle irrigation (SNI). In all groups, canals were instrumented with a rotary instrument (XP-endo Shaper) prior to irrigant agitation/activation. A mixture containing 2.5% NaOCl and 9% HEBP was used throughout the experiment. Bacterial counts from the canal were determined using qPCR before preparation (S1), after preparation (S2), and after final irrigation agitation/activation (S3). Bacterial viability within the dentinal tubules in the coronal, middle and apical root-thirds was quantified using confocal microscopy after Live/Dead staining. The bacterial counts and viability were compared between groups using one-way ANOVA and post-hoc Tukey's tests. Paired t-test was used to compare the bacterial counts within groups. RESULTS: Instrumentation alone could significantly reduce the microbial counts in all the groups (P < 0.0001). Subsequent agitation/activation resulted in significant microbial reduction only in XPF and UAI (P < 0.05), both of which reduced significantly more microbial counts than SNI (P < 0.05). Live/Dead staining revealed that XPF and UAI showed significantly greater percentage of dead bacteria within the dentinal tubules than SNI in the coronal third (P < 0.05); UAI resulted in the significantly highest percentage of dead bacteria in the middle third (P < 0.05); while there was no significant difference between the groups in the apical third (P > 0.05). CONCLUSIONS: When using the sodium hypochlorite/etidronate mixture for irrigation, final irrigant agitation/activation with XP-endo Finisher or ultrasonic can improve disinfection of the main root canal space and the dentinal tubules in the coronal third, while ultrasonically activated irrigation appears to exhibit better disinfection within dentinal tubules in the middle third.

Investigation of Physical Properties of Disodium Etidronate Tetrahydrate and Application of Phosphorus K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy.

PURPOSE: Disodium etidronate is a bisphosphonate, compounds that are widely used in the treatment of bone disorders such as osteoporosis and Paget's disease. We investigated the physical properties of disodium etidronate tetrahydrate crystal, form I. METHODS: We used X-ray powder diffraction (XRPD), thermal analysis, dynamic vapor sorption (DVS), X-ray single crystal structure analysis, and phosphorus K-edge X-ray absorption near-edge structure (XANES) spectroscopy for the first time. RESULTS: XRPD and thermal analyses demonstrated that form I was dehydrated and transformed to an amorphous form, to a crystalline form II, and finally to a form III by heating. DVS measurements revealed that the amorphous form, form II, and form III were rehydrated to form I by humidification, and form I was stable even at 0% relative humidity. These results indicate that form I is the most stable solid-state under ambient conditions and is suitable as an API for manufacture in solid formulations. The phosphorus K-edge XANES spectra differed among form I, the amorphous form, and form II, which may be ascribed to the difference in the coordinate bond schemes between the phosphate moieties and sodium ions. The results demonstrated that the phosphorus K-edge XANES spectroscopy could be applied to the identification or the discrimination of crystal forms of the APIs containing phosphate moieties. CONCLUSIONS: Acquired information about physical properties are crucial for manufacturing of solid formulations of disodium etidronate. XANES spectroscopy is a promising alternative method for evaluating the solid-state forms of APIs.

Efficacy of bisphosphonates in detection of early enamel caries using NIR fluorescence imaging and inhibition of caries progression.

NIR fluorescence imaging using bisphosphonate-Indocyanine green has been indicated for early interproximal caries detection. This study assessed diagnostic accuracy of caries detection by NIR fluorescence imaging with OsteoSense 750® (OS750) in vitro and ex vivo, and to analyze the therapeutic efficacy of a bisphosphonate (Etidronate) in inhibiting enamel caries progression in vitro. Methods: Four experiments were conducted using extracted human teeth; 1) to calculate the infiltration rate of OS750 into interproximal white spot lesions using fluorescence microscope, 2) to assess diagnostic accuracy of interproximal natural white spot lesions using desktop NIR fluorescence imaging device in vitro setting, 3) to assess diagnostic accuracy of artificially created deeper enamel carious lesion (0.5 mm~1.0 mm) using NIR fluorescence image through the head-mount display in ex vivo setting, 4) to compare the progression on the enamel caries lesions treated by Etidronate, NaF and distilled-water. Diagnostic accuracy was analyzed using sensitivity, specificity and receiver operating curves (ROC). The caries progression was calculated with micro-CT and was statistically analyzed using a two-way ANOVA and the Tukey HDS post-hoc test. Results: 1) The infiltration rate of OS750 was 101.83% ± 8.66 (Min: 90.10%, Max: 133.94%). 2) The average of sensitivity and specificity in vitro setting experiments were 86.7% ± 4.4% and 70% ± 11%, respectively. The average of area under the ROC curves (AUC) was 0.883 ± 0.059 indicating excellent performance. 3) The mean sensitivity and specificity in ex vivo setting was 82.97% ± 15% and 76.78% ± 13.27% respectively. 4) The carious lesion volume treated by Etidronate was significantly smaller at post treatment-1 (p<0.05) and treatment-2 (p<0.01) than the control. There was no significant difference in lesion volume in the Etidronate and NaF group at the time point of post treatment-1. Conclusion: This study suggests that bisphosphonates contribute to both early diagnosis of enamel caries and inhibition of caries progression.

Efficacy and safety of 188Re-HEDP in lung cancer patients with bone metastases: a randomized, multicenter, multiple-dose phase IIa study.

PURPOSE: To investigate the pain-relieving effect and safety of three different doses of 188Re-hydroxyethylidine diphosphonate (HEDP) in patients with lung cancer and bone metastases. METHODS: For this randomised, phase 2 and multicenter trial, we enrolled patients with lung carcinoma and multifocal bone metastases and excluded patients who had received bisphosphonates or external-beam radiotherapy within the previous 4 weeks. Fifty-four patients were randomized to receive a single injection of 188Re-HEDP, at doses of 30, 40 or 50 MBq/kg (interval, 12 weeks). Patients were followed-up by assessment of numerical rating scale (NRS) score, global quality of life (QOL) score and adverse events (AEs). ANOVA analysis, Chi-Squared test and LSD-t test were used in this study. RESULTS: Significantly decreased NRS scores relative to baseline were observed in 40 MBq/kg group (Week 0 vs. Week 12: 6.0 ± 1.4 vs. 4.8 ± 2.5, P = 0.033) and 50 MBq/kg group (Week 0 vs. Week 12: 5.5 ± 1.5 vs. 4.5 ± 2.9, P = 0.046). Significant change of global QOL score from baseline was observed in 40 MBq/kg group at week 8 (global QOL score: P = 0.024, pain score: P = 0.041) and 50 MBq/kg group (pain score: P = 0.021) at week 12. No patients withdrew trial because of AEs in three groups. CONCLUSIONS: 188Re-HEDP at dose of 40 and 50 MBq/kg was generally effective to alleviate pain and improve QOL in lung cancer patients with painful bone metastases. 188Re-HEDP was safe and well-tolerated.