Bisphosphonate Drugs Research Articles

Synthesis, characterization and in vitro evaluation of a bone targeting delivery system for salmon Calcitonin

Synthetic salmon Calcitonin (sCT) is currently used to treat and manage conditions associated with low bone mass, and elicits its antiresorptive effect by acting upon Calcitonin receptors (CTRs) located on bone-resorbing osteoclast cells. However, CTRs are also widely distributed in many non-skeletal tissues (such as kidney, brain, and lung), and the competitive uptake of available sCT amongst such CTRs likely reduces sCT availability for bone resident osteoclast cells, particularly if the drug is administered systemically and not specifically targeted to bone. Hence, the objective of this study was to synthesize and characterize a bisphosphonate (BP)-mediated bone targeting delivery system for sCT and to determine whether the bioactivity of sCT was retained after BP conjugation. BP–sCT conjugates were synthesized by initially reacting sCT with sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate (sulfo-SMCC) in dimethyl formamide in the presence of triethylamine (TEA) at room temperature. Thiolated (Thiol)-BP was then reacted with the sCT–sulfo-SMCC conjugates to generate sCT–BP conjugates, which were purified by dialysis and assayed using the micro-BCA protein assay. Non-BP containing control sCT–Cysteine conjugates were also synthesized using the same procedure. Reactions were monitored and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF) analysis and Tris–Tricine SDS-PAGE. Conjugates were evaluated for in vitro bone mineral affinity using a hydroxyapatite binding test, for bone mineral specificity using different calcium salt binding affinity assays, and for continued sCT bioactivity after conjugation using an intracellular cAMP stimulation in human T47D breast cancer cells. Our results confirmed that BP-conjugated sCT exhibited significantly greater affinity and specificity for bone mineral over unmodified sCT, and that sCT–BP conjugates retained strong CT bioactivity after conjugation. Our conjugation strategy holds the promise of facilitating the delivery of sCT preferentially to skeletal bony tissues, thereby increasing its local concentration to bone surfaces. This peptide hormone–bisphosphonate drug system represents a new class of antiresorptive drug that has not previously been attempted, nor has a bone targeting formulation of sCT been reported.

Medical Therapy and Multilevel Vertebroplasty in Osteoporosis: When and Why

Vertebroplasty (VP) is a mini-invasive percutaneous technique for the treatment of symptomatic, vertebral body fracture (VBF) caused by porotic or other diseases and its outcome has now been demonstrated by many trials. Beyond the results of these trials on the efficacy and safety of VP, the real problem for patients with osteoporotic and non-osteoporotic vertebral fractures is the risk of new fractures to adjacent or distant vertebra following VP that is reported to range from 10% to 30%. It is still unclear whether this is related to the natural history of the underlying disease (osteoporotic and non-osteoporotic diseases) or to the treatment, especially when a single vertebral fracture in an osteoporotic patient is highly predictive of future fractures. To prevent new fractures to adjacent or distant vertebra following VP in porotic patients multiple non-pharmacologic interventions are recommended (diet with vitamin D or calcium supplements, smoking cessation, exercise) in addition to a specific medical therapy to block the activation of osteoclast cells responsible for bone resorption, and to re-establish correct bone remodeling. These drugs include anti-catabolic drugs: bisphosphonate, oestrogen hormone, and anabolic drugs: PTH analogues and strontium ranelate. Bisphosphonate are the most commonly used compounds to treat postmenopausal osteoporosis. However, medical treatment appears to be too slow to prevent the natural history of patients with VBF. One session multilevel VP could be performed to prevent vertebral refracture risk in porotic or non-porotic patients with recurrent VBFs also after the first VP even if there is not a true vertebral collapse. Even if there are no limits to how many body levels can be treated in one session, European and American guidelines suggest doing no more than three body levels in the same session to reduce patient discomfort, and to prevent peri-procedural anesthesiologic problems, like uncontrolled fat-embolism, cement leakage, and pulmonary embolism, that could be increased. How many vertebrae could be treated in same session could be analyzed beforehand based on MDCT vertebral morphology and trabecular structure, or on MRI-signal changes. Added to medical therapy, multilevel VP can be performed in selected cases to treat VBF related to osteoporosis, preventing fractures or refracture without any further thrombo-embolic or fat uncontrolled embolism peri or post-procedural complications.

Characteristics of Implant Failures in Patients With a History of Oral Bisphosphonate Therapy

This study examines the pattern of implant failures reported in a large cohort of patients who received oral bisphosphonate therapy. A total of 8,572 individuals who received oral bisphosphonate drugs returned a dental survey that obtained information pertaining to implant placement and related complications. Among the 589 individuals reporting dental implants, 16 reported implant failures that were verified by dental records. Implant placement, timing of failure, and bisphosphonate duration were ascertained to determine the characteristics of implant loss in the setting of oral bisphosphonate exposure. Among the 16 patients (all women, aged 70.2 +/- 7.6 yrs) there were 26 implant failures; 8 had failure of 12 implants in the maxilla and 9 had failure of 14 implants in the mandible. Early failure (<or=1 yr after placement) was experienced by 8 patients (8 implants), whereas late failures (>1 yr after placement) occurred in 10 patients (18 implants); 2 patients had both early and late failures. Overall, few patients reported implant failures. However, among these, there were more late than early failures and a slightly higher proportion of failures in the mandible versus the maxilla. Further studies should investigate the role of chronic bisphosphonate therapy in implant survival and long-term implant osseointegration.

Lipophilic pyridinium bisphosphonates: potent gammadelta T cell stimulators.

Bisphosphonates such as risedronate and ibandronate are widely used to treat a variety of bone resorption diseases, preventing protein prenylation and disrupting osteoclast function[1]. Bisphosphonates also activate human γδ T cells (expressing the Vγ2Vδ2 T cell receptor), and these activated γδ T cells kill tumor cells[2, 3]. There has thus been interest in using bisphosphonates in cancer immunotherapy, with promising results against B-cell malignancies[4] and hormone refractory prostate cancer[5]. And in a very recent clinical trial, it was shown that zoledronate offered a significant anticancer benefit when added to hormone therapy, reducing the risk of cancer returning by 36%[6]. The bisphosphonates used in these trials are, however, extremely polar and are rapidly removed from the circulation by binding to bone. We reasoned that it might be possible to develop more lipophilic bisphosphonates[7] as γδ T cell stimulators that would have increased cell uptake properties, as well as decreased bone binding affinity[8]. Here, we report the discovery that novel, lipophilic, pyridinium bisphosphonates are ~250x more effective in γδ T cell activation than any other bisphosphonate drugs.

Synthesis of an analogue of the bisphosphonate drug Ibandronate for targeted drug-delivery therapeutic strategies

An analogue of the bisphosphonate drug Ibandronate was prepared and coupled via a cleavable ester function to a bromoacetyl linker with specific reactivity for thiol groups. This compound should find useful applications in therapeutic strategies aiming to deliver bisphosphonate drugs specifically to cancer cells making use of proteins as vectors. The specific delivery of bisphosphonates to cancer cells instead of bone, the usual site of accumulation of these cytotoxic drugs, could greatly widen their therapeutic applications.

Dual Roles for Perivascular Macrophages in Immune-to-Brain Signaling

Cytokines produced during infection/inflammation activate adaptive central nervous system (CNS) responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular cell types, endothelial cells (ECs) versus perivascular cells (PVCs; a subset of brain-resident macrophages), participate in this response remains unsettled. We exploited the phagocytic activity of PVCs to deplete them in rats by central injection of a liposome-encapsulated proapoptotic drug. This manipulation abrogated CNS and hormonal indices of HPA activation under immune challenge conditions (interleukin-1) that activated prostanoid synthesis only in PVCs, while enhancing these responses to stimuli (lipopolysaccharide) that engaged prostanoid production by ECs as well. Thus, PVCs provide both prostanoid-mediated drive to the HPA axis and an anti-inflammatory action that constrains endothelial and overall CNS responses to inflammatory insults.

Electrooxidation and determination of etidronate using copper nanoparticles and microparticles-modified carbon paste electrodes

The electrochemical behavior and determination of a bisphosphonate drug, sodium etidronate, on three different copper-based electrodes: polycrystalline copper electrode (CE) and copper microparticles- (m-CPE) and copper nanoparticles (n-CPE)-modified carbon paste electrodes was investigated. In the voltammograms recorded using CE, one anodic peak was appeared while, both m-CPE and n-CPE represented two anodic oxidation peaks. The anodic current density at 610 mV for n-CPE is >5 times higher that of m-CPE. This was related to the nanosize effect of copper nanoparticles. The anodic currents were related to the electrocatalytic oxidation of etidronate via the electrogenerated active species of Cu(III) in an EC' mechanism. The catalytic rate constant for the oxidation process and the diffusion coefficient of etidronate were obtained as 8.9×10³ cm³ mol-1 s-1 and 1.55×10-6 cm² s-1, respectively. A sensitive and time-saving sensing procedure was developed for the analysis of etidronate, and the corresponding analytical parameters were reported. Etidronate was determined with a limit of detection of 10.57 μmol L-1 with a linear range of 200-2538 μmol L-1. Accuracy was also checked by recovery test on spiked samples. The proposed amperometric method was applied to the analysis of commercial pharmaceutical tablets and the results were in good agreement with the declared values.

Renal Safety of Ibandronate in the Treatment of Myeloma Patients.

Abstract 4943 IntroductionTreatment of myeloma bone disease with bisphosphonates is standard of care. But renal toxicity due to bisphosphonate treatment tends to be a major problem in myeloma patients, especially. Patients with reduced kidney function and patients who have switched bisphosphonate drugs are at highest risk. Toxicity appears typically after few months of treatment. In patients with myeloma and impaired renal function with GFR < 30 ml/min no bisphosphonate is approved for treatment of myeloma bone disease in Germany. In breast cancer patients ibandronate dosage should be reduced from 6 to 2 mg in advanced kidney failure (GFR < 30 ml/min).We evaluated safety data about renal function from myeloma patients, who were treated with ibandronate. The patients were stratified according to pre-treatment and kidney function. MethodsIn a prospective non-interventional study (NIS) about safety and efficacy of ibandronate in breast cancer patients it turned out that unintentionally myeloma patients were also included. Out of 3528 documented patients 93 myeloma patients were identified. We evaluated the data from these myeloma patients separately.The myeloma patients were subdivided in 4 groups according to their renal function: GFR > 90 (stage 1), 60 – 90 (stage 2), 30 – 59 (stage 3) and < 30 (stage 4-5) ml/min. Since pre-treatment with or without bisphosphonates could be of influence, patients were analysed according to former pre-treatment: no bisphosphonate (I), ibandronate (II), and other bisphosphonates (III). The kidney function was calculated every month over a period of six months. ResultsNinety-three (93) patients with multiple myeloma were available for evaluation. In 87 patients renal function was documented over a minimum of 5 months. Eleven (11) patients had stage 1, 34 patients had stage 2, 36 patients stage 3 and 12 patients stage 4-5 of renal impairment, respectively. There were no differences in renal function according to their pre-treatment. There were also no differences in the three groups (I-III) regarding the prevalence of diabetes, hypertension and kidney function. A total number of 620 infusions were documented. The ibandronate dosage was 6 mg in 89% of all infusions, 4 mg in 4%, 3 mg in 2% and 2 mg in 5%, respectively. In the subgroups (stages) renal function was stable over time (mean GFR+/-SD ; difference over the time [ml/min]: stage 1: 116,8+/- 20,9; - 3,38; stage 2: 74,7 +/- 8.4; +2,04; stage 3: 46,1 +/- 8,1; +3,7; stage 4-5: 20,4 +/- 7; + 13,37; all changes n. s.), but there was a trend for improved renal function in patients with renal function stage 4-5. The mean changes were similar in all groups irrespectively of the pre-treatment. In 8 patients the treatment was terminated prematurely. Three patients had disease progression, and two patients died due to myeloma during study period. Two patients were lost by follow up and one patient declined further treatment. DiscussionThe data of this non-interventional study suggest that there is no evidence for renal toxicity of ibandronate in myeloma patients in all stages of renal function. This applies also for patients who received higher dosages of ibandronate as recommended. Patients with worse kidney function (stage 4-5) had a trend of improvement of renal function over the study period, however the changes were not significant due to the limited number of patients. There were also no differences in renal function irrespectively of the pre-treatment. DisclosuresBergner:Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ibandronate is not approved for use in myeloma bone disease.

Dental management of patients at risk of osteochemonecrosis of the jaws: a critical review

Osteonecrosis of the jaw bones is a complication of bisphosphonate (BP) drug usage characterised by trans-mucosal exposure of necrotic bone, often followed by infection and pain. Osteonecrosis is observed in cancer patients on high-potency intravenous BP more frequently than in osteoporotic individuals using low-potency oral BP. The management of osteonecrosis caused by BP is often unsatisfactory and control of risk factors is considered the most effective means of prevention. Surgical manipulation and dental infection of the jawbone are the major risk factors, hence it is suggested that careful management of oral health and relevant dental procedures may decrease the risk of osteonecrosis in individuals on BP. Recommendations for dentists and oral surgeons have been suggested by different groups of clinicians but they are often controversial and there is no clear evidence for their efficacy in reducing the likelihood of osteonecrosis development. This report critically reviews current dental recommendations for individuals using BP with the aim of helping the reader to transfer them into practice as part of pragmatic and non-detrimental clinical decisions making.

Risks Associated with Oral Bisphosphonates

Among large case series of bisphosphonate related osteonecrosis of the jaw (BRONJ), up to 5-10% have occurred in the setting of oral bisphosphonate (BP) therapy. Although rare, this is a concern given the widespread use of oral BPs for prevention of osteoporotic fractures. While numerous studies have examined BRONJ risk with chronic intravenous BP therapy, few have examined BRONJ risk with oral bisphosphonate drugs. Early data from a German case registry suggested a prevalence of 0.0004% among 780,000 oral BP users, while a large Australian provider survey found a much higher prevalence of 0.01-0.04% across the Australian States. The frequency was higher if extractions were performed (prevalence 0.09-0.34%). These findings contrast with data from a single dental center where ONJ occurred in 4.3% of 208 patients who self-reported alendronate use and 6.1% in the subset of 66 who also underwent extraction.

Nanostructured polyelectrolyte multilayer drug delivery systems for bone metastasis prevention

Polyelectrolyte multilayers (PEM) are well established nanoarchitectures with numerous potential applications, in particular as biomaterial coatings. They may exhibit specific biological properties in terms of controlled cell activation or local drug delivery. Here, in a new approach for bone metastasis prevention, we employed poly- l-lysine covalently grafted with β-cyclodextrin as a polycationic vector (PLL–CD) for the antitumor bisphosphonate drug risedronate (RIS). Molar ratio for maximum loading of the PLL–CD vector with RIS was determined by Raman microspectroscopy. The efficacy of RIS at inhibiting cancer cell invasion in vitro was strongly enhanced upon complexation, whatever PLL–CD:RIS complexes were in solution or embedded into PEM nanoarchitectures. Complexes in solution also clearly prevented cancer-induced bone metastasis in animals. Incorporation of the complexes into PEM nanoarchitectures covering bone implants appears of interest for in situ prevention of bone metastasis after ablation.

Bioavailability and bioequivalence of two oral formulations of alendronate sodium 70 mg: An open-label, randomized, two-period crossover comparison in healthy Korean adult male volunteers

Background: Alendronate sodium is a Bisphosphonate drug used to treat and prevent osteoporosis and several other bone diseases. A new formulation has been developed and is currently awaiting regulatory approval, pending findings on bioequivalence. Objectives: The aims of the present study were to compare the bioavailability and pharmacokinetic (PK) properties, and to determine the bioequivalence, of a test and reference formulation of alendronate sodium 70 mg in a healthy Korean adult male population. Methods: This open-label, randomized, 2-sequence, 2-period crossover study was carried out at Hanyang University Medical Center (Seoul, Republic of Korea). Healthy Korean adult male volunteers were randomly assigned to receive a single 70-mg dose of the test or reference formulation of alendronate sodium, administered with 240 mL of water, followed by a 7-day washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Serial blood samples were collected and adverse events were monitored by a clinical investigator via observation, personal interview, and vital signs (blood pressure, heart rate, and body temperature) over a 7-hour period (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, and 7 hours) after drug administration. Plasma alendronate sodium concentrations were determined using a validated high-performance liquid chromatographic-postcolumn fluorescence derivatization method, with visible detection in the range of 2 to 100 ng/mL and lower limit of quantification set at 2 ng/mL. PK properties, including AUC 0−t, AUC 0−∞, C max, T max, t 1/2, and the elimination constant (k e), were determined using noncompart-mental analysis. The formulations were considered bioequivalent if the 90% CI ratios for C max and AUC were within the predetermined interval of 80% to 125%, the regulatory definition set by the US Food and Drug Administration (FDA). Results: Twenty-three healthy male volunteers (mean [SD] age, 23.5 [2.0] years [range, 19–28 years]; height, 175.9 [5.4] cm [range, 162.0–185.0 cm]; and weight, 71.2 [9.5] kg [range, 61–96 kg]) were included in the study. No period or sequence effects were detected. The 90% CIs for the corresponding ratios of AUC 0−t, AUC 0−∞ and C max were 84.97 to 114.47, 86.09 to 115.59, and 82.37 to 110.71, respectively. Additionally, the mean (range) of T max was 1.09 hours (0.5–2.0 hours), and the mean (SD) of t 1/2 and k e were 2.04 (0.97) hours and 0.34 (0.71) hour, respectively. The values for the test and reference formulations were within the FDA bioequivalence definition interval of 80% to 125%. No adverse events were reported in this study. Conclusions: Single doses of these formulations of alendronate sodium 70 mg met the criteria for bio-equivalence. No statistically significant differences in AUC 0−t, AUC 0−∞, and C max were found in this healthy Korean adult male population.

Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

Zoledronic acid and interleukin-2 treatment improves immunocompetence in HIV-infected persons by activating Vγ9Vδ2 T cells

gammadelta T cells bearing the Vgamma9Vdelta2 T-cell receptor exert many antiviral effector functions in humans, including release of anti-HIV factors and direct cytotoxicity against virus-infected cells. Moreover, they are known to activate dendritic cells, improving antigen presentation function. After HIV infection, Vgamma9Vdelta2 T-cell number and reactivity are rapidly affected and they decrease upon disease progression. Bisphosphonate drugs such as zoledronic acid (Zol), used to treat bone diseases, have been shown to induce in vivo, in combination with interleukin-2, Vgamma9Vdelta2 T-cells' activation. The aim of this work was to verify whether the administration of Zol in combination with interleukin-2 in HIV-infected patients might improve Vgamma9Vdelta2 T-cell function, including immune adjuvancy mediated by gammadelta-dendritic cell cross-talk. In HIV patients naive to antiretroviral therapy, we analyzed the effect of combined Zol and interleukin-2 treatment, in comparison to Zol alone, on Vgamma9Vdelta2 T-cell number, maturation and function, on dendritic cell activation and on HIV-specific CD8 T-cell response. Zol and interleukin-2-combined treatment induced in-vivo Vgamma9Vdelta2 T-cell expansion and maturation. Paralleling Vgamma9Vdelta2 T-cell activation, increased dendritic cell maturation and HIV-specific CD8 T-cell responses were found. The specific modulation of Vgamma9Vdelta2 T-cell number and responsiveness after HIV infection may be at least transiently restored in vivo by Zol and interleukin-2 treatment. In this way, the immune effector mechanisms, secondary to Vgamma9Vdelta2 T-cell activation, were improved, suggesting a possible adjuvancy role of Zol and interleukin-2 treatment in restoring innate and specific competence in HIV-infected persons.

Osteonecrosis: prevention is key

Bisphosphonate drugs have widespread use in the treatment of certain cancers and for osteoporosis. However, their use is associated with a troubling dental condition as a side-effect. Caroline Holland explains.

Spectrophotometric Determination of Risedronate in Pharmaceutical Formulations via Complex Formation with Cu (II) Ions: Application to Content Uniformity Testing

A simple, sensitive, rapid and accurate spectrophotometric method was developed for the determination of risedronate, a bisphosphonate drug important for the treatment of a variety of bone diseases, in raw material and pharmaceutical formulations. The proposed method is based on complex formation between risedronate and Cu (II) ions in acetate buffer of pH5.5. The optimum conditions for this reaction were ascertained and a spectrophotometric method was developed for the determination of risedronate in concentration range of 2-40 µg/mL with detection limit of 0.03 µg/mL (9.51 × 10-8 mol/L). The molar absorbtivity was 8.00 × 103 l/mol/cm. The method was successfully applied for the determination of risedronate in tablet dosage form with mean percentage recovery of 101.04 ± 0.32. The results obtained were favorably compared with those obtained by the comparison method. Furthermore, the proposed method was applied for content uniformity testing of risedronate tablets.

Positive mode electrospray ionization mass spectrometry of bisphosphonates using dicationic and tricationic ion-pairing agents

A general method for detecting bisphosphonate drugs by ESI-MS and LC–ESI-MS as positive ions has been developed. Bisphosphonates can have multiple negative charges in solution. Tricationic ion-pairing reagents were paired with bisphosphonates to form a positively charged complex. It was clear that this facile pairing method worked. However, an appreciable presence of −1 bisphosphonate species were observed in positive mode ESI-MS (i.e. as the +2 complex with tricationic reagents). This led to an extended investigation on the use of dicationic pairing agents. The use of dicationic reagents improved the detection sensitivity for all of the bisphosphonates. Tandem mass spectrometry also improved the limits of detection for most of the bisphosphonates using both the tricationic and dicationic pairing reagents. A tricationic reagent also was used as an ion-pairing reagent in chromatography experiments. Thus the addition of a single reagent produced benefits in that it increased chromatographic retention and enhanced the ESI-MS detection of bisphosphonates.

Persistence with calcium and vitamin D in elderly patients after hip fracture

All hip fracture (HF) subjects are candidates for calcium and vitamin D (CaD) supplementation. Up to 50% of HF older adults present with secondary hyperparathyroidism (HPTH) resulting from hypovitaminosis D on hospital admission. To investigate the patterns and predictors of persistence with CaD supplementation in the elderly after HF, we considered all patients aged 70 years or older who were discharged alive after surgical repair of HF in the period of 1 year from an Orthopaedic Unit. Baseline characteristics of the subjects and osteoporosis treatment prescribed at discharge were retrieved from medical record review. A telephone interview at 6 months evaluated whether patients were currently taking CaD supplementation. Nonpersistence was defined when subjects ceased therapy within 6 months. Univariate and multivariate models were applied to determine the relationship between 6 months persistence with CaD and the variables collected: age, living situation, prescription of a bisphosphonate, baseline walking ability, number of drugs used, presence of dementia, number of active clinical issues at discharge (ACIs), discharge location, and being referred to a center for metabolic bone diseases (preplanned visit) at discharge. Of 428 subjects enrolled, 117 were excluded for different reasons (incomplete data, no therapy, death). A total of 311 subjects were discharged with a prescription of CaD (calcium 1,000 mg, cholecalciferol 800 UI, once daily) and were considered for the analysis. At 6 months, only 114 patients (36.7%) were currently taking CaD supplementation. In a univariate analysis, the following variables were significantly related with persistence: absence of dementia, prescription of a bisphosphonate, six or fewer drugs being used (drugs used <or=6), two or less ACIs (<or=2 ACIs) at discharge, ability to walk without aid at baseline, being discharged home, and being referred to a preplanned visit. In a multivariate model, the prescription of a bisphosphonate at discharge (OR 3.178, 95% CI 1.477-6.836, P = 0.003), a preplanned visit (OR 1.953, 95% CI 1.066-3.514, P = 0.03), the absence of dementia (OR 1.877, 95% CI 1.021-3.451, P = 0.043), and <or=6 drugs used (OR 1.842, 95% CI 1.066-3.182, P = 0.029) remained the most significant predictors of persistence with CaD. In HF elderly, who are at high risk of hypovitaminosis D and HPTH, persistence with CaD supplementation is very low. The enrolment in a postsurgical program for the management of bone disease can significantly increase persistence. Moreover, factors related to the complexity of older adult patients (polypharmacotherapy, dementia) seem to be particularly important in compliance with prescribed drugs.

Use of Alendronate and Risk of Incident Atrial Fibrillation in Women

ABSTRACT Recent trials have suggested an increased risk of serious atrial fibrillation (AF) in osteoporotic women taking alendronate or zoledronic acid—an unanticipated side-effect that had not been recognized previously. The present trial is an ongoing population-based case-control study of risk factors for incident AF taking place in a clinical practice setting. The case group of 719 women confirmed as having AF in the years 2001–2004 was compared with 966 women without AF who were matched with case women for age, calendar year, and the presence or absence of treated hypertension. More case patients than control women had used alendronate at some time (6.5% versus 4.1%). The odds ratio (OR) for AF in women taking alendronate at any time, compared to those never taking any bisphosphonate drug, was 1.86, with a 95% confidence interval (CI) of 1.09–3.15 after adjusting for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease. Further adjustment for numerous possible confounding factors yielded an OR of 1.83 (95% CI, 1.04–3.24). The OR was slightly but not significantly higher for past users than for current users. Neither the total cumulative dose of alendronate dispensed nor the time since first use significantly influenced the risk of AF. AF was transient in approximately 42% of cases, intermittent or persistent in 46%, and sustained in 11.5%. Based on the population-attributable fraction, it was estimated that 3% of incident cases of AF in this population might be explained by the use of alendronate. The risk of AF associated with alendronate therapy was higher in diabetic patients and in those currently taking statins. These findings demonstrate the need to weigh the benefits of alendronate therapy against the possibly increased risk of AF in 2 groups of women: those with no more than a modest increase in risk of fracture, and those having risk factors for AF such as coronary disease, heart failure, or diabetes.

Direct hospital resource utilization and costs of treating patients with multiple myeloma in Southwest Sweden: A 5-year retrospective analysis

Background: Approximately 570 patients are diagnosed with multiple myeloma (MM) in Sweden each year. Few studies have estimated the cost of treatment for these patients. Objective: The purpose of this study was to retrospectively investigate the direct hospital resource utilization and costs associated with the treatment of patients with MM in southwest Sweden. Methods: Patients aged ≥18 years who initiated first-line chemotherapy in the year 2001 at hospitals in southwestern Sweden were included in this retrospective chart review. Direct hospital-based resources and their corresponding costs (year-2006 euros) for each patient were calculated until the patient's death, or until December 31, 2005. Costs for outpatient and terminal stage care related to MM were not included. Results: Ninety-four patients were included; 20 were still alive at study completion. Mean age at diagnosis was 76 years and patients were followed for a mean of 32.7 months; 55% were males and 74% had at least 1 comorbidity. First-, second-, and third-line treatment lasted a mean of 24.3, 5.8, and 2.6 months, and included 2.8, 2.6, and 3.1 chemotherapy drugs per patient, respectively. Of the 80 patients who received first-line chemotherapy, 72 were prescribed melphalan and 55 patients received a combination of melphalan and prednisone, as recommended by Swedish treatment guidelines. The mean total cost per patient was €88,199, or €2770 per patient-month. Therapy-induced and comorbidity-related events constituted 42% of total costs, as much as autologous stem-cell transplantation and inpatient care together. Chemotherapy, bisphosphonate, and blood cell-enhancement drugs each amounted to only 2% of total costs, but chemotherapy drugs increased from €29/month in first-line therapy to €453/month in third-line therapy. Conclusions: The cost of treating Swedish patients with MM varied greatly between individuals but, overall, chemotherapy drugs constituted only a minor part of the total monthly cost (2%), whereas costs for inpatient stays and therapy-induced adverse events or comorbidity-related events accounted for 35% and42%, respectively. There was no significant differencein monthly cost between treatment lines.