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Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Fe50(Pt1–xPdx)50 (at. %, x = 0, 0.25, 0.5, 0.75, 1) alloy thin films are prepared on MgO(001) substrates by using two methods, high-temperature deposition at 600 °C (one-step method) and low-temperature deposition at 200 °C followed by annealing at 600 °C (two-step method). The influence of formation method on the film structure is investigated. L10 crystals epitaxially grow on the substrates when films are deposited at 600 °C. Disordered crystals transform into L10 structure when films are annealed at 600 °C. The films with x > 0.5 consist of L10(001) crystals with the c-axis normal to the substrate surface, whereas the films with x < 0.25 involve small volumes of L10(100) crystals with the c-axis lying in the film plane. Similar final crystallographic orientation is realized for the Fe (Pt,Pd) films prepared by employing the two different methods. The films prepared by one-step method possess island-like surfaces involving side facets, while those prepared by two-step method have very flat surfaces with the arithmetical mean roughness lower than 0.2 nm. The two-step method is effective for preparation of Fe (Pt,Pd) films with flat surfaces.

L1 0 films formed on (001)-oriented underlayers or substrates may involve (100) crystal with the c-axis lying in the film plane in addition to (001) crystal with the c-axis normal to the film surface. In this paper, FePt, CoPt, and FePd alloy films with L1 0 structure are prepared on MgO(001) single-crystal substrates. The c-axis orientation is accurately controlled to be perpendicular by introducing a thin MgO cap layer on magnetic films with disordered structure prepared by low-temperature deposition at 200 °C and by annealing the bilayer films at 600 °C. The phase transformation preferentially occurs along the perpendicular direction in the MgO/(FePt, CoPt, FePd)/MgO sandwich structures. Furthermore, the cap layer promotes L1 0 ordering. The order degrees of FePt, CoPt, and FePd films with and without cap layers, (S w/ , S w/o ), are (0.82, 0.58), (0.36, 0.30), and (0.72, 0.62), respectively. The FePt film with cap layer shows a strong perpendicular magnetic anisotropy and a very low in-plane coercivity because of which the film does not include L1 0 (100) crystal and possesses a high-order degree.

This study examined whether the global clinical data for bazedoxifene could be extrapolated to a Japanese population by evaluating the results of a phase 2 study in postmenopausal Japanese women with osteoporosis as compared to those of a pivotal, phase 3 study. The efficacy of bazedoxifene 20 and 40 mg versus placebo on lumbar spine bone mineral density (BMD), bone turnover markers, lipid profile, incidence of fractures, and safety parameters was compared between the Japanese phase 2 study (N = 429) and the global phase 3 study (N = 7,492) during a 2-year period. In the primary population for assessment of bridging, differences in the mean percent change from baseline in lumbar spine BMD at 2 years relative to placebo were greater for women treated with bazedoxifene 20 and 40 mg in the phase 2 study than in the phase 3 study. BMD changes in the bazedoxifene groups were confirmed to be similar between the phase 2 study population and a subset of the phase 3 study population with similar baseline characteristics. The effects of bazedoxifene on incidence of fractures, bone turnover markers, and lipid metabolism were similar between studies. There were no major differences in safety parameters between studies. The greater improvement in lumbar spine BMD and similar results in bone turnover markers, fracture incidence, and safety profile observed with bazedoxifene in the phase 2 study compared with the phase 3 study confirmed the feasibility of extrapolating the global clinical data to a Japanese population.

FePd, FePt, and CoPt alloy thin films are deposited on (001) single-crystal substrates of MgO, SrTiO3, and LaAlO3 at 600°C by using an ultra-high vacuum radio-frequency magnetron sputtering system. The c-axis distribution and the order degree are carefully studied. The FePd films deposited on MgO and SrTiO3 substrates consist of L10(001) crystals with the c-axis perpendicular to the film surface. The FePd film deposited on LaAlO3 substrate and the FePt and the CoPt films deposited on all the substrates include L10(100) crystals with the c-axis lying in the film plane. The c-axis distribution is influenced by the combination of film and substrate materials. Higher order degrees are observed for the film material CoPt

The technique of body composition by dual-energy X-ray absorptiometry (DXA) has been used for several years in the research environment. Its ability to accurately and precisely measure lean, fat, and mineral composition in various body compartments has been well validated. Furthermore, the technique is widely available to clinical patients on existing DXA instruments throughout the world through the use of specific software packages and scanning algorithms. There have been few clear statements regarding the clinical indications for body composition measurement in patients outside the research setting. This is in part because of the lack of specific documented interventions that would be affected by body composition test results, beyond usual clinical advice. We have examined a few of the most common, specific scenarios (HIV therapy, sarcopenia, bariatric surgery, obesity) and proposed indications for body composition assessment. We have also discussed contraindications to body composition testing.

FePd, FePt, and CoPt alloy thin films are prepared on MgO(110) single-crystal substrates by using two different methods. One is one-step method consisting of deposition at an elevated substrate temperature of 600°C and the other is two-step method consisting of low-temperature deposition at 200°C followed by annealing at 600°C. The crystal structure, the crystallographic orientation, and the surface morphology are compared. L10 ordered FePd, FePt, and CoPt films epitaxially grow on the substrates with three variants, (110), (101), and (011), when deposited at 600°C. The c-axis of L10(110) variant is lying in the film plane, whereas those of L10(101) and L10(011) variants are 45° canted from the substrate surface. Disordered FePd, FePt, and CoPt single-crystal films of (110) orientation are formed by deposition at 200°C. An A1-L10 phase transformation occurs along A1[001], A1[010], and A1[001] by annealing the disordered films at 600°C. The annealed films thus consist of three L10 variants. Similar final crystal structure and orientation are realized in the FePd, the FePt, and the CoPt films prepared by employing the two different methods. The L10 ordered films prepared by one-step method have island-like surfaces involving facets, whereas those prepared by two-step method have very flat surfaces with the arithmetical mean roughness lower than 0.3 nm. The two-step method is useful for preparation of L10 ordered films with flat surfaces.

L10 ordered FePd alloy epitaxial thin films are prepared on MgO substrates of (001), (110), and (111) orientations by two different methods; by direct deposition at high temperature of 600°C and by preparation of film at a low temperature of 200°C followed by high temperature annealing at 600°C. The influence of preparation method on film structure, order degree, surface roughness, and magnetic property are investigated. Films with L10 ordered structure grow epitaxially on MgO substrates when deposited at 600°C. Epitaxial films with disordered A1 structure prepared at 200°C transform into L10 ordered structure by annealing at 600 °C. Although L10 order degree is similar between two kinds of FePd film prepared by different methods, the surface roughness and coercivity are different. The films prepared by annealing have very flat continuous surfaces as well as lower coercivities which results from easy movement of domain walls. The two step process employing low temperature film deposition followed by high temperature annealing is very effective in the preparation of L10 ordered alloy films with very flat surfaces, which are important for practical device applications.

This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (−0.65%, p

The aim of osteoporosis treatment is to prevent future fractures. Although concurrent treatment has been used very frequently for osteoporosis in clinical practice, there are no data on accurate and verified effectiveness of concurrent treatment for fracture prevention in patients with osteoporosis. To clarify the clinical usefulness of concurrent treatment, the Japan Osteoporosis Society has authorized the establishment of the A-TOP (Adequate Treatment of Osteoporosis) research group. The objective of this research is to establish a design for a clinical trial to prove whether concurrent treatment using both alfacalcidol (1-alpha-hydroxycholecalciferol) and alendronate is more effective as compared to treatment using alendronate alone in terms of fracture prevention. The present study was named JOINT (Japanese Osteoporosis Intervention Trial) and is based on a method using national, prospective, randomized, open-labeled, blinded endpoints focusing on postmenopausal osteoporosis with a high risk for fracture. The patients were mainly selected by practitioners and allocated randomly by a central registration system into two groups, of which one received 5 mg/day of alendronate alone, and the other received 1 μg/day of 1-alpha-hydroxycholecalciferol (alfacalcidol) in addition to the alendronate. The endpoints focused primarily on fracture prevention, and the patients' quality of life (QOL) and change in body height, as well as adherence and the adverse events of the treatments were evaluated secondarily. To obtain sufficient statistical power in the events during a 2-year observation period, the patients who are expected to have higher risk were selected to participate in this study, and it was decided that the final plan would involve 890 patients per group (two-sided alpha = 0.05, power = 0.8). Data collection began in November 2003. Correspondence regarding the registration of the investigator and the progress of the study was conducted through a web system from the Public Health Research Foundation to practitioners.

Introduction In a randomized, active-controlled, double-blinded, multicenter study, the efficacy and safety of minodronate were examined and compared to that of alendronate. Methods A total of 270 postmenopausal osteoporotic women ≥ 45 years of age were randomized into the minodronate group ( n = 135) or alendronate group ( n = 135). Each subject received 1 mg minodronate or 5 mg alendronate once a day for 12 months. Results Both treatment groups showed similar changes in BMD after 12 months. After 1 year of treatment, the lumbar spine BMD increased by 5.86% and 6.29% in the minodronate and alendronate groups, respectively, and the total hip BMD increased by 3.47% and 3.27%, respectively. Bone turnover markers were rapidly reduced within 1 month in both treatment groups. Urine DPD was significantly lower in the minodronate group than in the alendronate group at 6 months, and urine NTX was significantly lower in the minodronate group than in the alendronate group at 1 and 9 months. Both completion rates for the 12-month study and the overall incidence of clinical adverse events, including gastrointestinal events, were similar between the two groups. Conclusions The effects on lumbar and hip BMD and the safety profile of minodronate are comparable to those of alendronate. Minodronate is a promising new potent bisphosphonate for the treatment of osteoporosis.

The effect of vitamin K2 (menatetrenone) on bone turnover was investigated in postmenopausal patients with osteoporosis. A 6-month open-label, randomized prospective study was conducted in 109 patients. The control group (n = 53) received calcium aspartate (133.8 mg of elemental calcium daily), while the menatetrenone group (n = 56) received 45 mg of menatetrenone daily for 6 months. Serum and urinary levels of bone turnover markers were monitored. The serum level of undercarboxylated osteocalcin (uc-OC) was significantly lower (P

FePd alloy films of 1 to 500 nm thicknesses are prepared on MgO(001) single-crystal substrates by employing a two-step method consisting of low-temperature deposition at 200 °C followed by high-temperature annealing at 600 °C. The influences of film thickness on the crystallographic orientation, the degree of L 10 ordering, the magnetic property, and the surface roughness are systematically investigated. FePd(001) single-crystal films with disordered structure grow epitaxially on the substrates at 200 °C. The in-plane lattice is expanded to accommodate the lattice misfit between the film and the substrate (−9%). The distortion is decreased with increasing the thickness. When the films are annealed at 600 °C, transformation to L 10 phase occurs. The films thinner than 40 nm consist of L 10(001) variant with the c-axis normal to the substrate surface, where the transformation along the perpendicular direction is preferentially taking place. On the contrary, the films thicker than 100 nm involve L 10(100) and L 10(010) variants whose c-axes lie in the film plane and are rotated around the film normal by 90° of each other. The volume ratio of L 10(001) variant decreases to 0.22, as the thickness increases up to 500 nm. The order degrees of films thinner than 40 nm are 0.6–0.7. With further increasing the thickness, the order degree decreases. The lattice deformation in the disordered FePd film before annealing is effective in enhancing L 10 ordering and aligning the c-axis perpendicular to the substrate surface. The easy magnetization direction varies from perpendicular to in-plane, as the thickness increases from 100 to 500 nm. The magnetic anisotropy is affected by the crystal orientation and the order degree. The films thinner than 2 nm have island-like surfaces, where condensation of deposited atoms on substrate is taking place during the annealing process. When the thickness is increased beyond 10 nm, a flat surface is kept before and after annealing.

Milk has more beneficial effects on bone health than other food sources. Recent in vitro and in vivo studies have shown that milk whey protein, especially its basic protein fraction (milk basic protein, MBP), contains several components capable of promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effect of MBP on the bone metabolism of healthy menopausal women. Thirty-two healthy menopausal women were randomly assigned to treatment with either placebo or MBP (40 mg per day) for 6 months. The bone mineral density (BMD) of the lumbar vertebrae L2-L4 of each subject was measured by dual-energy X-ray absorptiometry (DXA) at 0 and 6 months of treatment. Serum and urine indices of bone metabolism were measured at 0, 3 and 6 months. Twenty-seven subjects who completed the study in accordance with the protocol were included in the analysis. The mean rate of gain of lumbar BMD in the MBP group (1.21%) was significantly higher than in the placebo group (-0.66%, P=0.046). When compared with the placebo group, urinary cross-linked N-telopeptides of type-I collagen (NTx) were significantly decreased in the MBP group at 6 months, but no significant difference in serum osteocalcin was observed between the two groups. The urinary NTx excretion was found to be related to serum osteocalcin in the MBP group at 3 and 6 months, indicating that MBP maintained the balance of bone remodeling. These results suggested that MBP supplementation was effective in preventing bone loss in menopausal women and that this improvement in BMD may be primarily mediated through the inhibition of bone resorption while maintaining the balance of bone remodeling by MBP supplementation.

The safety and efficacy of raloxifene, a selective estrogen receptor modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p

Fe50 Pt50–x Pdx (at. %, x = 0, 12.5, 25, 37.5, 50) alloy epitaxial films are prepared on MgO(001) substrates at temperatures ranging from room temperature to 600 °C by radio-frequency magnetron sputtering. The effects of substrate temperature and Pd/Pt composition on the order degree, c -axis distribution, and magnetic property are investigated. With increasing the substrate temperature, L 10 ordering is enhanced for all the compositions. The order degree of film deposited at 600 °C decreases from 0.37 to 0.23 as the x value increases from 0 to 12.5 at. %. With further increasing the x value, the order degree increases up to 0.69. The Fe50 Pt50–x Pdx films with x ≥ 25 consist of only an L 10 (001) single-crystal with the c -axis perpendicular to the substrate surface, whereas the films with x 10 (100) variant with the c -axis lying in the film plane in addition to L 10 (001) variant. The c -axis distribution is influenced by the Pd/Pt composition. The magnetic anisotropy is reflecting the c -axis distribution and the order degree.

Magnetic relaxation of FePd alloy epitaxial thin films with very flat surfaces prepared on MgO(001) substrate are measured by in-plane broadband ferromagnetic resonance (FMR). Magnetic relaxation is investigated as Δω for FMR absorption peak by frequency sweep measurements. ΔH is calculated by using the measured Δω. Gilbert damping constant, α, is estimated by employing a straight line fitting of the resonant frequency dependence of ΔH. The α value for an FePd film deposited at 200 ˚C, which shows disordered A1 structure, is 0.010 and ΔH0, which is frequency independent part of ΔH, is 10 Oe. The α value for a film annealed at 400 ˚C, which shows partially L10 ordered structure (S=0.32), is 0.013, which is slightly larger than that for the disorder A1 structure film. However, ΔH0 for the annealed film is 85 Oe, which is much larger than that for the film with disordered structure. The results show that the magnetic relaxation of the 400 ˚C annealed film is mainly dominated by ΔH0, which is related with magnetic in-homogeneity caused by the appearance of perpendicular anisotropy of partially ordered phase.

The fracture risk assessment tool ( FRAX® ) has been developed for the identification of individuals with high risk of fracture in whom treatment to prevent fractures would be appropriate. FRAX models are not yet available for all countries or ethnicities, but surrogate models can be used within regions with similar fracture risk. The International Society for Clinical Densitometry ( ISCD ) and International Osteoporosis Foundation ( IOF ) are nonprofit multidisciplinary international professional organizations. Their visions are to advance the awareness, education, prevention, and treatment of osteoporosis. In November 2010, the IOF/ISCD FRAX initiative was held in Bucharest, bringing together international experts to review and create evidence-based official positions guiding clinicians for the practical use of FRAX. A consensus meeting of the Asia-Pacific ( AP ) Panel of the ISCD recently reviewed the most current Official Positions of the Joint Official Positions of ISCD and IOF on FRAX in view of the different population characteristics and health standards in the AP regions. The reviewed position statements included not only the key spectrum of positions but also unique concerns in AP regions.

Anterior cruciate ligament (ACL) is continuously exposed to tensile load, which is generally recognized to be an essential factor in maintaining the physiological homeostasis of the ACL fibers during daily activities. Although this kind of mechanical stimulation is clearly known to play an important role in quickening repair of ACL injury, responses of ACL cells to mechanical stimulation still remain unclear. We have investigated whether extracellular signal-regulated kinase 1/2 (ERK1/2) in human ruptured ACL-derived cells are phosphorylated and involved in type I collagen (Col I) and decorin gene expression by mechanical stimulation. Mechanical stretch stimulates time-dependent phosphorylation of ERK1/2 in human ruptured ACL-derived cells. While Col I gene expression levels were increased in 48-h continuous mechanical stretch, decorin gene expression levels were decreased for 24-h continuous stimulation. Decorin gene expression levels were increased, however, in mechanical stretch+PD98059, which is an inhibitor of ERK pathway, treated cells as compared with control cells at 24 h. Our results show that ERK pathway is stimulated by mechanical stretch, and may be involved in regulation of Col I and decorin gene expression in ACL-derived cells.

Milk contains several components effective for bone health. In the previous in vitro and in vivo studies, we have shown that milk whey protein, especially its basic protein fraction (milk basic protein [MBP]), promoted bone formation and suppressed bone resorption. This present study examines the effect of MBP on the biochemical markers of bone metabolism in healthy adult men. Experimental beverages containing MBP (300 mg of MBP a day) were given to 30 normal healthy adult men for 16 days. The serum osteocalcin concentration had increased significantly after 16 days of ingesting the experimental beverage containing MBP. Urinary cross-linked N-teleopeptides of type-I collagen (NTx) excretion had decreased significantly after 16 days of ingesting MBP. The urinary NTx excretion was related to the serum osteocalcin concentration after 16 days of ingestion. These results suggest that MBP promoted bone formation and suppressed bone resorption, while maintaining the balance of bone remodeling.

We studied the effects of milk basic protein (MBP) on bone metabolism in ovariectomized (OVX) rats. Five-week-old female Sprague-Dawley rats were ovariectomized and fed a low-calcium diet (0.009% Ca) for 5 weeks. The OVX rats were divided into three experimental groups: Control group (20% casein), MBP-L group (19.9% casein, 0.1% MBP), and MBP-H (19% casein, 1% MBP) of six animals. The rats were fed each experimental diet for 3 weeks. The bone breaking strength and energy of femur in the MBP-H group were significantly higher than those in the control group. The bone breaking energy of femur in the MBP-L group was also significantly higher than those in the control group. There were no differences in the amount of femoral calcium and phosphorus among the three groups, however, the amounts of femoral proline, hydroxyproline and hydroxylysine (typical amino acids of collagen) in the MBP groups were significantly higher than those in the control group. These data indicate that MBP in the whey protein increases the amount of the bone collagen and enhances the bone strength.

We previously reported that fibroblast growth factor-2 (FGF-2) acts not only on osteoblasts to stimulate osteoclastic bone resorption indirectly but also on mature osteoclasts directly. In this study, we investigated the mechanism of this direct action of FGF-2 on mature osteoclasts using mouse and rabbit osteoclast culture systems. FGF-2 stimulated pit formation resorbed by isolated rabbit osteoclasts moderately from low concentrations (>/=10(-12) m), whereas at high concentrations (>/=10(-9) m) it showed stimulation on pit formation resorbed by unfractionated bone cells very potently. FGF-2 (>/=10(-12) m) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. Among FGF receptors (FGFR1 to 4) only FGFR1 was detected on isolated mouse osteoclasts, whereas all FGFRs were identified on mouse osteoblasts. FGF-2 (>/=10(-12) m) up-regulated the phosphorylation of cellular proteins, including p42/p44 mitogen-activated protein (MAP) kinase, and increased the kinase activity of immunoprecipitated FGFR1 in mouse osteoclasts. The stimulation of FGF-2 on mouse and rabbit osteoclast functions was abrogated by PD-98059, a specific inhibitor of p42/p44 MAP kinase. These results strongly suggest that FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.

We present here a case of prominent hypercalcemia accompanied by hypothalamic tumor and Graves' disease. A 24-year-old man with hypothalamic tumor showed hypopituitarism, central diabetes inspidus (DI) and hyperthyroidism. Nausea, loss of thirst and appetite, and general fatigue were found with the unveiling of hypercalcemia and hypernatremia. Parathyroid hormone (PTH) and 1alpha-dihydroxyvitamin D levels were suppressed with a normal range of PTH-related protein values. One-desamino-(8-D-arginine)-vasopressin (DDAVP) and half-saline administration normalized hypernatremia, while hypercalcemia was still sustained. Administration of cortisone acetate and thiamazole reduced the elevated serum Ca level. In the present case, concurrent hyperthyroidism was assumed to accelerate skeletal mobilization of calcium into the circulation. Hypocortisolism and central DI was also considered to contribute, to some extent, to the hypercalcemia through renal handling of Ca.

Body fat, fat mass, and fat free mass as a percentage of body composition were estimated by two methods: underwater weighing and skinfold thicknesses (skinfolds) at the triceps and subscapular regions. This study compares the results of the two different methods among 126 healthy women aged 19 – 20 years. The values of percent body fat as estimated by underwater weighing and by skinfolds of the Nagamine and Suzuki model were correlated; however, the estimates by skinfolds were significantly (p 2 = 0.501 and RMSE=0.007018) While there was no difference between the average of body fat percent as estimated by underwater weighing and the Nagamine and Suzuki model, there was a difference between underwater weighing and this new model in a cross-validation study. However this new model was more closely correlated with underwater weighing than the Nagamine and Suzuki model and this new model was a more accurate estimate of obesity than the Nagamine and Suzuki model. We therefore speculate that this new model is more suitable for current Japanese young women in general surveys. © 1997 Elsevier Science Inc.

In addition to obesity, abnormalities in glucose and lipid metabolism are common in hypertensives, indicating a possible link between hypertension and hyperinsulinemia. Since the frequency of obesity in Japanese is lower than that in Caucasians, the present study was designed to clarify the frequencies of hyperinsulinemia, glucose and lipid abnormalities, and obesity. We surveyed consecutively 470 men without a history of gastrectomy who visited a health clinic after excluding previously known hypertensives receiving hypotensive agents (4.2%) and diabetics (6.1%). Hypertensives with a blood pressure exceeding 150 and/or 90 mmHg (n = 62) had a significantly higher frequency of diabetes mellitus (6.5%) associated with hypercholesterolemia (24.2%) and mild obesity with a body mass index (BMI) of more than 25 (24.2%) than those of normotensives. When reanalyzed according to the presence or absence of hyperinsulinemia after 75 g oral glucose loading, hyperinsulinemic men demonstrated a higher blood pressure. The incidences of impaired glucose tolerance (67.1%), hypertriglyceridemia (64.4%), low HDL-cholesterol (53.4%), hypercholesterolemia (21.9%) and mild obesity (37.0%) were also significantly higher than those of normoinsulinemic subjects. Subjects with either hypertension and/or hyperinsulinemia had a significantly higher incidence of coexistence of these risk factors. Multiple regression analysis revealed that not only BMI, but also the plasma glucose and insulin response during the 75 g glucose loading test independently correlated with mean blood pressure. These results suggest that hypertensive and/or hyperinsulinemic subjects may be associated with excess cardiovascular risk and should be managed more carefully.

A massive outbreak of cryptosporidiosis occurred at a local town of Saitama Prefecture, in 1996. During this outbreak, we investigated the clinical features of children seen at Saitama Medical School. Cryptosporidium parvum (C. parvum) was detected from 10 out of 28 (36%) children with diarrhea during June and August, 1996. The average ages of the children who were positive and negative for C. parvum were 6.5 and 5 year old, respectively. Among the children infected with C. parvum, colic pain was observed in 3 children and 4 children had vomiting. However, none of the children showed fever over 38.0 degrees C nor bloody stools. Family members of children infected with C. parvum also had diarrhea and/or vomiting (5/6). C. parvum was repeatedly detected from 2 out of 3 children. All infected children had an improvement of abdominal symptoms in 4 to 10 days. C. parvum should be included as a pathogen which causes enterocolitis in Japanese children.

We conducted a randomized, double-blind trial to assess the effect of 28.2 μg teriparatide versus placebo (1.4 μg teriparatide) on reduction of the incidence of vertebral fractures. Individuals enrolled in this study included patients with primary osteoporosis with one to five vertebral fractures and capable of self-supported walking. Attention was focused on incident vertebral fractures, change in bone mineral density (BMD) of the lumbar spine, and safety. A total of 316 subjects participated in the study, which lasted up to 131 weeks. Incident vertebral fractures occurred in 3.3 % of subjects in the 28.2 μg teriparatide-treated group and 12.6 % of subjects in the placebo group during the 78-weeks study period. Kaplan–Meier estimates of risk after 78 weeks were 7.5 and 22.2 % in the teriparatide and placebo groups, respectively, with a relative risk reduction of 66.4 % by teriparatide (P = 0.008). Lumbar BMD in the 28.2 μg teriparatide group increased significantly by 4.4 ± 4.7 % at 78 weeks, which was significantly higher than the corresponding data in the placebo group (P = 0.001). Adverse events were observed in 86.7 % of individuals in the teriparatide group and 86.1 % of those in the placebo group. In conclusion, weekly injection of a low-dose of teriparatide (28.2 μg) reduced the risk of incident vertebral fractures and increased lumbar BMD.

With iodinated vasopressin analogue, d(CH2)5[Tyr(Me)2, Tyr(NH2)9] AVP, at position 9, followed by purification by HPLC (specific activity 473-543Ci/mmol), a specific binding was observed in the rat liver plasma membrane fraction. Scatchard analysis indicated a single class of high-affinity binding sites with a Kd of 0.23nM and Bmax of 142fmol/mg protein. V2-agonist, DDAVP, did not displace 125I-vasopressin analogue. These results suggest that 125I-d(CH2)5[Tyr(Me)2, Tyr(NH2)9] AVP with a high specific activity is a useful tool to investigate V1-receptors.

エイコサペンタエン酸(EPA)負荷による末梢血リンパ球表面マーカーに及ぼす影響について検討した.健常女性(n=12)に鶏肉中心の食事を摂取させた後, EPAに富んだ食事を負荷したfish群(n=6)とさらにEPA剤を追加したfish+EPA群(n=6)の2群に分け,末梢血リンパ球表面マーカーを負荷前後で測定した.血中EPAはfish群で17.5±7.2μg/ml(mean±SD)から195.0±53.9に, fish+EPA群では19.5±4.2から277.2±24.8へと著増した.末梢血表面マーカーについての検討では,いずれの群においてもIL-2レセプターおよびDR陽性のCD 4陽性細胞は有意に増加し, T細胞レセプター陽性のCD 8陽性細胞は有意に減少した. fish群では, DR陽性のCD 8陽性細胞は有意に増加した. EPA負荷は末梢血リンパ球表面マーカーに変化を及ぼすので,免疫系に影響を及ぼす可能性がある.

The International Society for Clinical Densitometry (lSCD) is a nonprofit multidisciplinary international professional organization. The ISCD mission is to advance excellence in the assessment of skeletal health. To achieve this mission, the ISCD has conducted a number of Position Development Conferences over the past 10 yr, bringing together international experts to review and create evidence-based position statements guiding clinicians involved in the area. The Asia-Pacific (AP) Panel of the ISCD was formed to give regional input to the ISCD from the AP Region and to oversee ISCD education and certification programs in the region. An AP Panel consensus meeting recently reviewed the most current Official Positions of the ISCD in view of the different population characteristics and health standards in the region. The reviewed position statements included those for bone testing by central and peripheral devices but did not include ISCD Official Positions on Vertebral Fracture Assessment or pediatric bone mineral density.

Beta-blockers without intrinsic sympathomimetic action have been reported to produce an increase in peripheral vascular resistance. The present study was designed to determine the effects of a new beta-blocker, nipradilol (3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran), on forearm blood flow (FBF) in seven patients (mean age, 51.6 ± 6.7 years) with essential hypertension. After overnight fasting, FBF was determined using venous occlusion strain-gauge plethysmography before and two hours after oral administration of 6 mg nipradilol or 20 mg propranolol. Both beta-blokers produced a significant decrease in blood pressure, and heart rate also tended to decrease. As a result, the product obtained by multiplying systolic blood pressure by heart rate was reduced after both nipradilol and propranolol. Nipradilol increased FBF from 0.78 ± 0.10 ml/100 ml/min to 1.72 ± 0.28 ml/100 ml/min ( P P 1 -blocking activity.

In the management of acute ischemic stroke, a diagnostic procedure is critically important. However, till date, no guideline or consensus regarding a standard diagnosis procedure has been established. We hereby report an institutional manual for the consistent diagnosis of acute ischemic stroke.The institutional manual was based on the National Institute of Neurological Disorders and Stroke III classification; however, the criteria for each stroke subtype were clearly defined using a rating system that included the representative observations specific to each subtype. The present manual was prepared in order to clearly define the characteristics of the stroke subtypes, which are often ambiguous in the clinical settings, and to design a diagnostic procedure within the institute with more emphasis on standardization rather than achieving complete accuracy. Several characteristic points were considered while doing this: lacunar infarctions should be clearly differentiated from other small infarctions, subtypes of "suspicious cardioembolism," "atherothrombotic infarction (embolic mechanism)," and "infarction due to arterial dissection" should be determined separately in order to identify the causal mechanism to the extent possible. For a final diagnosis, the patients were examined 3 time points during: at admission, during the subacute stage (day 4-7), and at discharge or more than 2 weeks after the onset of stroke. The current version of the manual has been used since 2006 after a transitional phase from 2004 to 2005. Retrospective comparisons on stroke diagnoses and clinical outcomes were performed between the periods during which the present manual was used and those during which it was not.The present manual was retrospectively applied for diagnosing 311 consecutive ischemic stroke patients who were admitted to our institute within 7 days after the onset in 2003; in the case of 85 patients (29%), the diagnosis was different from that made in 2003. Of all the lacunar infections reported in 2003, 17 were diagnosed as other conditions when the manual was used. Similarly, 45% of the cases of atherothrombotic infarction (thrombotic mechanism) and 24% of those of cardiac embolism in 2003 were diagnosed differently when the present manual was applied. The mean modified Rankin scale at discharge was 2.63 +/- 0.07 (mean +/- standard error of the mean) in patients in 2002 and 2003 (n=491), which was significantly different from 2.32 +/- 0.06 in patients in 2006 through March of 2008 (n=903; p=0.01).The present manual appears to be helpful to improve the uniformity of the diagnoses and the clinical results. It may also assist residents and their mentors in the educational field. The manual will require periodical evaluation and version upgrade in order to maintain its efficacy.

An increased risk of atherosclerotic disease has been reported in patients with diabetes mellitus. The present study was therefore designed to determine forearm blood flow (FBF) in patients with essential hypertension or those with diabetes mellitus with or without hypertension. FBF determined by venous occlusion plethysmography decreased with age in controls as well as in patients with essential hypertension, whereas FBF in diabetics was significantly lower irrespective of age or blood pressure. As a result, vascular resistance was significantly higher in diabetics than in controls or patients with essential hypertension. Glycemic control in normotensive diabetics during 3 weeks significantly augmented a diminished FBF. α 1 -Blockade by oral administration of 1 mg of prazosin also augmented the diminished FBF in diabetics, in association with a significant decrease in mean blood pressure and vascular resistance. These results suggest that FBF may be a simple and useful index for determining arterial and/or venous distensibility, and that α 1 -blocker therapy, in addition to glycemic control, may be a first-line antihypertensive treatment for diabetics with associated hypertension.

The role of arginine vasopressin (AVP) in blood pressure regulation in humans and animals is still controversial. The present study was designed to investigate the effects of AVP on blood pressure and the excretion of sodium and prostaglandin (PG) E2 in rabbits. AVP dissolved in 0.01 M acetic acid was infused subcutaneously at a rate of 0.86 ng/kg/min with a miniosmotic pump into 12 New Zealand white rabbits (2.7-3.4 kg), while 10 controls were given vehicle alone. AVP infusion resulted in a 3.5-fold rise in the level of plasma AVP (21.8 +/- 4.4 (SEM) pg/ml) as compared with controls, associated with a significant decrease in the urine volume and urinary excretion of sodium. The PGE2 excretion was increased 1.8-fold after AVP infusion. In the chronic AVP-infused group, blood pressure was not significantly increased, but the acute vascular response to AVP was significantly attenuated without any changes in the vasopressor response to angiotensin II. Preadministration of V1-antagonist completely abolished the vasopressor action of AVP, but not that of angiotensin II, in either group. These results suggest that circulating AVP within physiological range of concentrations may stimulate renal PGE2 synthesis and attenuate the vascular response through vascular V1 receptors without affecting the baroreflex, which may be attenuated through V2 receptors.

With the advent of long-acting or slow-release antihypertensive drugs, we should be aware of a fall in nighttime blood pressure (BP) as well as daytime blood pressure. In the present study, casual BPs at the physician's office as well as ambulatory BP was recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device in 24 essential hypertensives treated with slow-release nifedipine. Administration of slow-release nifedipine (20-40 mg, b.i.d.) decreased not only casual BPs but also ambulatory mean BP during the whole day or daytime (6 am to 10 pm). Slow-release nifedipine at 10 mg in the morning did not affect casual BPs at the office. However, mean BP obtained by ambulatory BP monitoring during the daytime was significantly attenuated. In addition, a profound fall in mean BP amounting to more than 20 mmHg during the night in some of the patients was observed during treatment with slow-release nifedipine not only at 20-40 mg (b.i.d.) but also at 10 mg once a day. These results suggest that we have to take into consideration the possibility that long-acting hypotensive agents may cause a great fall in nighttime BP during sleep, especially in the elderly.

Blood pressure (BP) obtained by the physician in his office and ambulatory BP recorded every hour throughout 24 hours with a noninvasive automated BP monitoring device were compared in 10 normotensives and 162 hypertensives. Casual BPs significantly correlated with averages in ambulatory BPs (ABPs) throughout the whole day, day (7 am - 10 pm) and night (0-5 am). However, it was noted that 6 of 10 normotensives and all of the moderate to severe hypertensives had ABPs of more than 150/90 mmHg at least once during the 24-hour period. The incidence of ABPs greater than 150/90 mmHg among all readings was higher in untreated and treated hypertensives with diastolic BPs in the office of more than 105 mmHg, and, when checked along with the clock time, higher not only in the morning but also in the evening. On the other hand, one-third or one-fifth of treated hypertensives with diastolic office BPs less than 90 mmHg or between 90 and 105 mmHg respectively had ABPs less than 150/90 mmHg throughout the whole day. When the effect of nicardipine (60 mg, t.i.d.) or slow-release nifedipine (27.3 +/- 3.0 mg, b.i.d.) on minimum BP during the night was analyzed, long-acting nifedipine decreased BP throughout the night to levels not significantly different from normotensive controls, whereas short-acting nicardipine did not affect nighttime BPs. These results suggest that simple ABP monitoring throughout the day gives us useful information to evaluate the severity of hypertension and the efficacy of antihypertensive medication as well as to avoid overtreatment with long-acting hypotensive agents resulting in a great fall in BP during sleep.

Peripheral assessment of bone density using photon absorptiometry techniques has been available for over 40 yr. The initial use of radio-isotopes as the photon source has been replaced by the use of X-ray technology. A wide variety of models of single- or dual-energy X-ray measurement tools have been made available for purchase, although not all are still commercially available. The Official Positions of the International Society for Clinical Densitometry (ISCD) have been developed following a systematic review of the literature by an ISCD task force and a subsequent Position Development Conference. These cover the technological diversity among peripheral dual-energy X-ray absorptiometry (pDXA) devices; define whether pDXA can be used for fracture risk assessment and/or to diagnose osteoporosis; examine whether pDXA can be used to initiate treatment and/or monitor treatment; provide recommendations for pDXA reporting; and review quality assurance and quality control necessary for effective use of pDXA.

Milk has beneficial effects on bone health than other food sources. Recent in vitro and in vivo studies have shown that milk whey protein, especially its basic protein fraction (milk basic protein: MBP), contains components capable of promoting bone formation and inhibiting bone resorption. We tried to examine the effect of MBP on bone mineral density (BMD) and markers of bone metabolism in healthy young adult women and perimenopausal women. In the healthy young women study, we found that MBP increased BMD, by promoting bone formation and inhibiting bone resorption. In the healthy perimenopausal women study, we also found that MBP increased BMD, primarily by inhibiting bone resorption, while maintaining bone formation. Thus, bone remodeling balances become positive that leads to maintenance or increase of bone formation. MBP supplementation could be effective for bone health in a wide range of generation especially those who hate to drink milk.

Effect of milk basic protein on bone metabolism in healthy young women.Milk has more beneficial effects on bone health than other food sources. Recent in vitro and in vivo studies have shown that milk whey protein, especially its basic protein fraction (milk basic protein, MBP), contains several components capable of promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effect of MBP on the bone mineral density and bone metabolism of healthy young women.Thirty-five healthy young women were randomly assigned to treatment with either placebo or MBP (40 mg per day) for 6 months. The bone mineral density (BMD) of the lumbar vertebrae L2-L4 of each subject was measured by dual-energy X-ray absorptiometry (DXA) at 0 and 6 months of treatment. Serum and urine indexes of bone metabolism were measured at 0, 3 and 6 months. All subjects completed the study in accordance with the protocol.The mean rate of gain of lumbar BMD in the MBP group (1.57%) was significantly higher than in the placebo group (0.13%, P=0.042). When compared with the placebo group, urinary cross-linked N-telopeptides of type-I collagen (NTx) were significantly decreased, and serum osteocalcin was significantly increased in the MBP group at 6 months.These results suggested that MBP supplementation was effective in increasing BMD in young women and that this increase in BMD may be primarily mediated through the promotion of bone formation and inhibition of bone resorption by MBP supplementation.

We investigated the usefullness of Binax NOW urine antigen test, an immunochromatographic assay that binds any soluble Streptococcus pneumoniae antigen (C polysaccharide) for the diagnosis of penumoniae form September 2003 to March 2005. We used 372 samples form the patinets with pneumoniae diagnosed for blood or sputum cultuter or gram-stained sputum smear. Out of 24 culture positive specimens, Binax NOW urine antigen test, showed positive in 18 (75%) specimens. The sensitivity of sputum and blood culture was 71.7% and 83.3%, respectively. Binax NOW urine antigen test was seemed false positives in 55 samples, false negatives in 6 samples. The specificity of Binax NOW urine antigen test was evaluated 84.1%. Overall agreement among tests was 83.6%. When compared to culture, false negative urine antigen may be the result of colonizing S. pneumoniae in sputum or pneumonia caused by an agent other than S. pneumoniae. CRP values for cases were both urine antigen and culture were positive ranged from 40 mg/dl to 10 mg/dl while urine antigen and culture negative cases were predominantly less than 10 mg/dl. Positive blood and pleural fluid culture cases were consistently associated with strongly positive urine antigen tests. Non-agreement between urine antigen, culture, and microscopy may be the result of specimen quality, labile nature of S. pneumoniae and antimicrobial therapy.

In this multicenter, randomized, double-blind controlled trial, the efficacy and safety of once-weekly dosing with 17.5 mg risedronate was compared with once-daily dosing with 2.5 mg risedronate in Japanese patients with involutional osteoporosis. A total of 496 patients were randomized to receive either once-weekly (n = 249) or once-daily (n = 247) treatment. All patients were supplemented with 200 mg/day calcium. Following 48 weeks of treatment, the mean (+/-SD) percent changes, from baseline, in the bone mineral density of the lumbar spine (L2-L4 BMD) in the once-weekly and once-daily treatment groups were 5.36 +/- 4.27% and 5.87 +/- 4.47%, respectively. The difference between the groups was -0.5% (95% confidence interval: -1.35% to 0.35%), demonstrating that the effect on BMD of once-weekly treatment was not inferior to that of once-daily treatment. The time-course reductions in biochemical markers of bone resorption (urinary N- and C-telopeptide of type I collagen) and bone formation (bone-specific alkaline phosphatase) were similar for the two dosing regimens. There were no differences in the incidence of new vertebral fractures or the worsening of existing fractures between the once-weekly (2.2%) and once-daily (2.7%) dosing regimens. No significant differences were observed between the two dosing regimens in the incidence or the type of adverse events. However, 10.1% of the patients in the once-daily group withdrew due to adverse events as compared to 5.2% in the once-weekly group. Moreover, drug-related adverse events, including upper gastrointestinal disorders and abnormal changes in laboratory parameters, tended to be less in the once-weekly dosing regimen than in the once-daily dosing regimen. In conclusion, once-weekly oral dosing with 17.5 mg risedronate was well tolerated in Japanese osteoporotic patients, and showed equivalent efficacy to once-daily oral dosing with 2.5 mg risedronate. This once-weekly regimen is expected to provide a more convenient therapeutic option as an alternative to daily dosing and to enhance patient compliance in long-term therapy for osteoporosis.

Selective estrogen receptor modulator (SERM) is a kind of drug that has agonistic and antagonistic effects of estrogen in different tissues. MORE study has shown that raloxyfene reduces osteoporotic vertebral fractures and serum cholesterol levels in postmenopausal women, while it does not stimulate the endometrium and decreases the breast cancer occurrence. There are more to be investigated like developing newer SERMs, a combination therapy with estrogen or the elucidation of mechanisms of estrogen effects.

Fourteen pediatric patients diagnosed as bacterial meningitis between August 1997 and April 2002 were enrolled in this study. Both rapid antigen detection test, Slidex Meningite 5 Kit (Biomerieux) and culture were performed using cerebrospinal fluids (CSF). H. influenzae was isolated from 11 samples and was the most frequently isolated bacteria, followed by S. pneumoniae from 4 samples and enteric bacteriae from 2 samples. Five out of six samples with positive result by culture were also positive by the rapid antigen test. Gram-negative rod was identified in smear specimens of CSF from all these 5 samples. Significance of the rapid antigen test should be recognized under drug resistance of those bacteriae are increasing.

The in vitro activity of antimicrobial agents against Streptococcus pneumoniae was determined using 16 strains of penicillin-susceptible S. pneumoniae (PSSP) and 26 strains of penicillin intermediately resistant S. pneumoniae (PISP) + penicillin-resistant S. pneumoniae (PRSP) in Japan. The minimum inhibitory concentrations (MICs) of potent antibiotics, including eight beta-lactams (benzylpenicillin, ampicillin, cefotiam, cefepime, cefditoren, faropenem, panipenem, and biapenem), three macrolides (erythromycin, clarithromycin, and azithromycin), telithromycin, and three fluoroquinolones (ciprofloxacin, levofloxacin, and gatifloxacin), were determined. Twenty-three strains exhibited genetic variations at pbp1a + pbp2x + pbp2b, which are genetic-PRSP (g-PRSP). g-PISP strains accounted for 62.5% (10/16) of the PSSP strains. The existence of an abnormal pbp gene conferred not only penicillin resistance but resistance to cephems; however, panipenem and biapenem had potent in vitro efficacy against alterations. Regarding the macrolide resistance mechanisms (mefA or ermB): 16 isolates had only mefA, 18 isolates had ermB, and 2 isolates had both mefA and ermB. There was no correlation between the existence of an abnormal pbp gene and the existence of the mefA gene or the ermB gene.