Methods for estimating causal relationships of adverse events with dietary supplements.

OBJECTIVE: Dietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports. DESIGN: Causal relationship assessment using prospectively collected data. SETTING AND PARTICIPANTS: 4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm. PRIMARY OUTCOME MEASURES: The distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss' κ. RESULTS: Using these two methods, most of the 200 case reports were categorised as 'lack of information' or 'possible' adverse events. Inter-rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss' κ, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss' κ (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss' κ (95% CI) 0.622 (0.622 to 0.622). CONCLUSIONS: These methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods.

The bioassay-guided isolation of growth inhibitors of adult T-cell leukemia (ATL), from the Jamaican plant Hyptis verticillata, and NMR characterization of hyptoside.

Through bioassay-guided isolation, five compounds with growth inhibitory activity on S1T, an adult T-cell leukemia (ATL) cell line, were isolated from the crude methanol extract of the aerial parts of Hyptis verticillata.

Novel cytotoxic isolated from Jamaican Hyptis verticillata jacq induces apoptosis and overcomes multidrug resistance.

BACKGROUND: Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid. MATERIALS AND METHODS: Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated. RESULTS: The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone. CONCLUSION: The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.

Antipyretic and analgesic effects of zaltoprofen for the treatment of acute upper respiratory tract infection: verification of a noninferiority hypothesis using loxoprofen sodium.

A multicenter, placebo-controlled, double-dummy, randomized, parallel-group, double-blind study was conducted to verify the hypothesis of noninferiority for single-dose administration of zaltoprofen 160 mg, a nonsteroidal anti-inflammatory drug, compared with loxoprofen sodium 60 mg (loxoprofen), in terms of antipyretic and analgesic effects in patients with acute upper respiratory tract infection. The eligible 330 patients were assigned to one of 3 groups: zaltoprofen 160 mg, loxoprofen 60 mg and placebo. The analysis set consisted of 322 patients. Antipyretic effects were assessed by measuring body temperature, and analgesic effects were evaluated using a visual analog scale (VAS) for 4 h under the control of study staff. A detection kit for influenza virus A and B antigens was used to determine the presence of influenza virus infection. Compared with immediately before administration and with the placebo group, significant decreases in body temperature and summary VAS pain scores were noted in both the zaltoprofen and loxoprofen groups at 4 h after drug administration. Based on the degree of decrease in body temperature and the summary VAS pain scores up to 4 h after administration, noninferiority in terms of antipyretic and analgesic effects of zaltoprofen compared with those of loxoprofen was confirmed after single administration. Similar antipyretic and analgesic effects were also confirmed in influenza virus antigen-positive patients (73 patients). No clinical concerns were identified regarding safety. Zaltoprofen and loxoprofen are confirmed to be safe and useful for patients with acute upper respiratory tract infection, including those with influenza infection.

Acute effects of intravenous nicorandil on hemodynamics in patients hospitalized with acute decompensated heart failure.

BACKGROUND: Nicorandil injection, a potent vasodilator with K(ATP) channel opening action and nitrate-like action, has been used for treatment of unstable angina. In the present investigation, we examined the effect of intravenous nicorandil on hemodynamics in patients with acute decompensated heart failure (ADHF). METHODS: ADHF patients admitted to hospital with pulmonary artery wedge pressure (PAWP)≥18 mm Hg were enrolled. Patients received nicorandil by an intravenous bolus injection of 0.2mg/kg/5 min followed by continuous infusion at a rate of 0.05, 0.10, or 0.20mg/kg/h for 6h. RESULTS: Nicorandil administration caused a significant decrease in PAWP and increase in the cardiac index (CI) that began immediately after the injection and were maintained during the continuous infusion. After 6h, nicorandil administration at 0.2mg/kg/5 min followed by 0.20mg/kg/h resulted in a decrease in PAWP (26.5%, p<0.01), an increase in CI (15.8%, p<0.05), and a decrease in total peripheral resistance (13.8%, p<0.01) in a dose-dependent manner. Nicorandil decreased blood pressure significantly, without an excessive decrease or negative impact even in patients with lower systolic blood pressure. CONCLUSION: Intravenous administration of nicorandil, by bolus injection followed by continuous infusion, improves PAWP and CI in ADHF patients immediately and continuously as a potent vasodilator with combined preload and afterload reduction. These results demonstrate that nicorandil is a safe and effective new medication for the treatment of ADHF.

Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug. OBJECTIVE: This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans. METHODS: This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests. RESULTS: Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C(max)) increased in a manner that was less than dose proportional. T(max) ranged from 1.50 to 6.00 hours, and elimination t((1/2)) ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V(d) (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t((1/2)) ranged from approximately 10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (approximately 1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was >or=80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study. CONCLUSIONS: In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.

A double-blind study of zaltoprofen for the treatment of upper respiratory tract infection.

We conducted a double-blind study to evaluate the antipyretic and analgesic effects of a single administration of zaltoprofen, a nonsteroidal anti-inflammatory drug, in patients with acute upper respiratory tract infection. 170 patients were assigned to one of the 3 treatment groups (80, 160 mg, placebo). Changes over time of body temperature and the visual analog scale score of pain were measured under the supervision of the study staff at the participating medical institutions. A significant decrease in body temperature from the baseline value was noted at all measurement points from 0.5 to 6 h after drug administration in the zaltoprofen groups. The lowest temperature during the observation period was recorded between 3 and 4 h, and the body temperature tended to rise at 6 h. No significant decrease in body temperature was noted at any time during the observation period in the placebo group. A significant decrease in pain scores from the baseline was noted at all measurement points in the zaltoprofen groups, and the decrease was maintained even at 6 h. An analgesic effect but no antipyretic effect was observed in the placebo group.

[Effect of diet on the pharmacokinetics of tebipenem pivoxil fine granules in healthy male volunteers].

Tebipenem pivoxil (TBPM-PI), a novel oral carbapenem antibiotic, is a prodrug of tebipenem (TBPM). We assessed the pharmacokinetics of TBPM-PI fine granules at 250 mg as potency in healthy male volunteers in fasting and non-fasting states. Cmax of TBPM in the non-fasting state was lowered to approximately 60% of that in the fasting state, however AUC(0-infinity) and urinary excretion of TBPM in the non-fasting state were almost equivalent to those in the fasting state when TBPM-PI fine granules were administered. In conclusion, the absorption rate of TBPM-PI was reduced in the non-fasting state after the administration of TBPM-PI fine granules, but intake of food had little influence on the absorption amount of TBPM. Thus the effect of diets on the pharmacokinetics of TBPM-PI would raise no problem in clinical use of TBPM-PI.

A zinc-containing compound, Polaprezinc, is effective for patients with taste disorders: randomized, double-blind, placebo-controlled, multi-center study.

CONCLUSIONS: The effect of a zinc-containing compound, Polaprezinc, was shown to clinically improve the disease conditions of idiopathic taste disorders with no serious side effects in a well controlled double-blinded clinical study. OBJECTIVES: The purpose of the present study was to evaluate the efficacy and safety of a zinc-containing compound in the treatment of patients with idiopathic taste disorders, including patients with low serum zinc, by a Good Clinical Practice (GCP)-compliant, randomized, placebo-controlled, double-blind, multi-center clinical study. SUBJECTS AND METHODS: A group of 109 patients suffering from taste disorders was assigned into placebo and three treatment groups. Each group of patients was given either placebo (n=28), or 17 mg (n=27), 34 mg (n=26) or 68 mg (n=28) of oral zinc, Polaprezinc preparations, daily for 12 weeks. RESULTS: The group of patients given 68 mg zinc showed a significant improvement in their gustatory sensitivity compared with the placebo group. The most common side effects observed were increase in serum triglyceride and serum alkaline phosphatase, decrease in serum iron, and some gastrointestinal incidents, although they were not serious.

Comparison of fluticasone furoate and fluticasone propionate for the treatment of Japanese cedar pollinosis.

Fluticasone furoate nasal spray (FFNS) is a novel, enhanced-affinity glucocorticoid administered in a unique side-actuated device for the treatment of allergic rhinitis. No previous clinical studies have compared the efficacy of FFNS with another intranasal steroid. The purpose of this study was to compare the efficacy and safety of FFNS, 110 microg/day, once daily with fluticasone propionate nasal spray (FPNS), 200 microg/day, twice daily in patients with Japanese cedar pollinosis to support the regulatory filing in Japan. In this multicenter, randomized, placebo-controlled, double-blind, parallel-group study, patients (>or=16 years old) were randomized to receive 2 weeks of treatment with FFNS (n = 151), FFNS placebo (n = 72), FPNS (n = 148), or FPNS placebo (n = 75). FFNS once daily was noninferior to FPNS twice daily in mean change from baseline in three total nasal symptom scores (3TNSS; sneezing, rhinorrhea, and nasal congestion; -1.23 +/- 0.140 and -1.06 +/- 0.142, respectively). Compared with placebo, FFNS was superior in reducing 3TNSS (p < 0.001). Both FFNS and FPNS showed similar mean changes from baseline in 4TNSS (3TNSS and nasal itching) and individual nasal symptom scores. The onset of action for FFNS was observed from the 1st day of treatment, whereas in the FPNS group it was observed on the 2nd day. There were similar improvements in rhinoscopy findings, activity of daily life interference, and patient-rated overall evaluation to therapy in the FFNS and FPNS groups. FFNS was well tolerated. Treatment with once-daily FFNS was effective and noninferior to twice-daily FPNS in reducing nasal symptoms. Faster onset of action for FFNS was observed.

Comparison of salmeterol/fluticasone propionate (FP) combination with FP+sustained release theophylline in moderate asthma patients.

OBJECTIVES: To compare the efficacy and safety of the salmeterol/fluticasone propionate combination product with concurrent sustained release theophylline plus fluticasone propionate in adult Japanese patients with persistent asthma. DESIGN: Multicentre, randomised, double-blind, double-dummy, parallel-group study. PATIENTS AND INTERVENTIONS: Three hundred and eighty-three asthmatic patients receiving sustained release theophylline 200-400mg/day entered the study and were randomised to receive either salmeterol/fluticasone propionate combination (SFC) 50microg/250microg+1 placebo tablet, fluticasone propionate 250microg+1 sustained release theophylline 200mg (SR-T+FP), twice daily for 8 weeks. RESULTS: The adjusted mean change morning peak expiratory flow (PEF) over 8 weeks was 29.8L/min in the SFC group and 16.3L/min in the SR-T+FP group, with a treatment difference of 13.4L/min (p=0.0004). SFC improved evening PEF, FEV1, V50 and V25 at the completion of treatment to a greater extent than SR-T+FP (all p<0.05). A higher percentage of patients on SFC were symptom free (p=0.0286) and rescue free (ns) than those on SR-T+FP. There was not a statistically significant difference between treatments in symptom scores. Both treatments were well tolerated. CONCLUSIONS: The finding that SFC was associated with greater improvements in lung function than SR-T+FP, a commonly employed treatment for asthmatic patients in Japan, suggests that SFC should be the preferred therapeutic option in these patients.

Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkinson's disease: STRONG study.

We report the results of a randomized, double-blind, placebo-controlled, 16-week study to evaluate the efficacy and safety of ropinirole, 0.75 to 15.0 mg/day, as an adjunct to levodopa. A total of 243 patients were randomly assigned into placebo or ropinirole groups. The mean (standard deviation) dose of ropinirole at endpoint was 7.12 (2.88) mg/day. The primary endpoint-the mean reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) total motor score-was significantly greater for the ropinirole group than the placebo group (-9.5 vs. -4.5, P = 0.00001). The mean reduction in the UPDRS total activities of daily living (ADL) score was also significantly greater for ropinirole than for placebo (-2.7 vs. -1.0, P = 0.0002). The percentage of patients showing at least a 20% reduction in the percentage of time spent "off" was significantly greater for the ropinirole group than for the placebo group (58.7% vs. 38.6%, P = 0.030). A total of 84.3 and 65.6% of the patients experienced adverse events while receiving ropinirole or placebo, respectively. The results showed that ropinirole was more effective than placebo in improving motor function and ADL when used as an adjunct to levodopa in patients with advanced Parkinson's disease.

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

OBJECTIVE: We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

Sulfatides, L- and P-selectin ligands, exacerbate the intimal hyperplasia occurring after endothelial injury.

Leukocytes may be important in the development of intimal hyperplasia, but little is known about the participation of sulfatides (3-sulfated galactosyl ceramides) which are native ligands of L- and P-selectin. This study was designed to determine whether sulfatides affect the development of intimal hyperplasia. ICR mice were randomized to receive vehicle or sulfatides intravenously either at 1, 3, or 10 mg/kg/day for 7 days, or at 10 mg/kg/day for 1, 3, or 7 days. Endothelial damage was inflicted on the femoral artery via the photochemical reaction between rose bengal and green light. Scanning electron and light microscopic observations 3 days after the injury indicated that sulfatides-treated animals had more neutrophils adhering to the injury site than vehicle-treated controls. At 21 days, sulfatides-treated animals had a greater neointimal area than controls. In in vitro studies, sulfatides (i) increased cytosolic free calcium in mouse neutrophils, (ii) caused increases in expression of Mac-1 (CD 11 b/CD 18) on the neutrophil membrane surface in mouse whole blood. These findings suggest that neutrophil accumulation on the subendothelial matrix or adherence of platelets mediated by adhesive interactions between L- or P-selectin and sulfatides may contribute to the development of intimal hyperplasia. The neutrophil accumulation may be mediated by an increase in Mac-1 caused by the agonistic effects of sulfatides on the neutrophil membrane surface, or by an increase in L- and P-selectin ligands resulting from the binding of sulfatides onto the exposed subendothelial matrix.

Neutrophil accumulation promotes intimal hyperplasia after photochemically induced arterial injury in mice.

The role of leukocytes in the pathogenesis of coronary arterial disease has become a focus for clinical research. The aim of this study was to determine whether neutrophil accumulation would participate in the development of intimal hyperplasia after endothelial injury in mice, and whether d-myo-inositol hexakisphosphate (phytic acid) which inhibits the binding of L- and P-selectin to sialyl Lewis(X) could inhibit the development of intimal hyperplasia. Endothelial injury was inflicted in one femoral artery via the photochemical reaction between systemically injected rose bengal and transillumination with green light (wavelength: 540 nm). Scanning electron microscopic observation at 3 days after the injury showed an increase in the number of leukocytes adhering to the injury site. Histological observation at 21 days showed that in the neutropenia group administered anti-neutrophil antibody and in the phytic acid-treated group the progression of intimal hyperplasia was significantly attenuated by comparison with the corresponding control groups. These results suggest that neutrophil accumulation contributes to the initiation and/or development of intimal hyperplasia and L- and/or P-selectin may participate in their mechanisms.

Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy?

Inflammatory and/or autoimmune diseases like ulcerative colitis (UC) or Crohn's disease (CD) are debilitating chronic disorders that poorly respond to pharmacological interventions. Further, drug therapy has adverse effects that add to disease complications. The current thinking is that disorders like inflammatory bowel disease (IBD) reflect an over exuberant immune activation driven by cytokines including TNF-alpha. Major sources of cytokines include myeloid leukocytes (granulocytes, monocytes/macrophages), which in IBD are elevated with activation behavior and are found in vast numbers within the inflamed intestinal mucosa. Accordingly, myeloid cells should be the targets of therapy. Adacolumn is filled with cellulose acetate beads that selectively adsorb and deplete myeloid cells and a small fraction of lymphocytes (FcgammaR and complement receptors bearing cells). In one study, 20 steroid naive patients with moderate (n = 14) or severe (n = 6) UC according to Rachmilewitz despite 1.5-2.25 g/day of 5-aminosalicylic acid received 6 to 10 Adacolumn sessions at 2 sessions/week. Efficacy was assessed 1 week after the last session. The majority of patients responded to 6 sessions, 17 (85%) achieved remission. In 2 of the 3 non-responders, CAI was 8 and 12 in 1; all 3 had deep colonic ulcers at study initiation. Decreases were seen in total leukocytes (P = 0.003), % neutrophils (P = 0.003), % monocytes (P = 0.004), an increase in lymphocytes (P = 0.001), decreases in C-reactive protein (P = 0.0002), and rises in blood levels of soluble TNF-alpha receptors I (P = 0.0007), II (P = 0.0045). In a separate study, a case with very severe steroid refractory UC who received up to 11 sessions responded well and avoided colectomy. Further, myeloid cell purging with Adacolumn has been associated with the release of IL-1 receptor antagonist, suppression of TNF-alpha, IL-1beta, IL-6, IL-8, down-modulation of L-selectin and the chemokine receptor CXCR3. In conclusion, selective depletion of myeloid cells appears to induce anti-inflammatory effects and represents a non-pharmacological treatment for patients with active IBD. The treatment has a clear drug-sparing role. Changes in blood levels of inflammatory and anti-inflammatory factors are thought to contribute to the efficacy of this procedure.

[Comparison of myocardial perfusion imaging by thallium-201 single-photon emission computed tomography with SUNY4001 (adenosine) and exercise--crossover clinical trial at multi-center].

We compared the ischemic diagnosis ability and adverse events of 201Tl myocardial perfusion imaging with SUNY4001 (adenosine) stress to that with exercise (ergometer) stress both on random crossover trial. Thirty one known or suspected chronic stable angina patients who are able to exercise and 10 healthy volunteers were enrolled for the trial. The early and delayed images were obtained by SPECT imaging. The concordance of diagnoses [ischemia vs. no ischemia] between the two types of stresses was 97.3% (36/37) [Kappa: 0.9068]. The sensitivity and specificity based on the exercise test were 100% (6/6) and 96.8% (30/31) respectively. The incidence of adverse events caused by SUNY4001 and the exercise were 44.7% (17/38) and 52.6% (20/38), respectively. Major adverse events caused by SUNY4001 were BP decrease, flushing and headache. And those by exercise were ST decrease, dyspnea and chest pain. None of the adverse events required the intervention or caused life-threatening complication in the trial. The trial showed that the ischemic diagnosis ability and safety of 201Tl scintigraphy with SUNY4001 stress are almost equal to those of the exercise stress that is considered as the standard stress method. We concluded that 201Tl imaging with SUNY4001 is safe and useful for detecting ischemic heart disease, especially for patients unable to exercise adequately.

Alendronate reduced vertebral fracture risk in postmenopausal Japanese women with osteoporosis: a 3-year follow-up study.

The risk-reducing effect of alendronate on vertebral fractures has been consistently reported. In a 2-year, randomized, double-blind, active drug-controlled (1 microg alfacalcidol) double-dummy study, we also reported that alendronate (5.0 mg) had a fracture-reducing effect in Japanese patients with preexisting vertebral fractures. The present report describes the risk-reducing effect of alendronate (5.0 mg) for 3 years in postmenopausal osteoporotic patients. The 3-year treatment period consisted of the original 2-year double-blind study followed by a 1-year extension. A total of 170 postmenopausal female patients were involved in the third year; 90 received alendronate and 80 received alfacalcidol. Both efficacy and safety were analyzed in these 170 patients. Vertebral fracture was determined by quantitative morphometry, and vertebral bone mineral density (BMD) was measured by the DXA method (dual-energy X-ray absorptiometry). The primary efficacy endpoint was the incidence of vertebral fracture, excluding fracture cases that occurred in the first 6 months after treatment initiation. The cumulative incidence of vertebral fracture at 3 years was 7.8% (7/90) in the alendronate group and 18.8% (15/80) in the alfacalcidol group, indicating a significantly reduced risk of fractures in the alendronate group (relative risk = 0.41, 95% CI = 0.18-0.97). Lumbar spine BMD increased by 9.2% in the alendronate group (n = 26) and by 1.4% in the alfacalcidol group (n = 22) at 3 years. The safety profile of alendronate during 3 years of treatment was similar to that of alfacalcidol. The present study thus demonstrated that treatment with alendronate 5.0 mg for 3 years increased vertebral BMD and reduced the risk of vertebral fractures in Japanese, postmenopausal women with osteoporosis.