Akira Itabashi

Milk basic protein: a novel protective function of milk against osteoporosis

Milk is recommended as an excellent calcium source for bone health. Moreover, milk is considered to contain other components effective for bone health. In our previous studies, using an unfractionated bone cell culture system, we found that milk whey protein, especially its basic fraction (milk basic protein [MBP]), suppressed bone resorption. In this present study, we investigated whether MBP could prevent bone loss in aged ovariectomized rats. Twenty-one 51-week-old female Sprague-Dawley rats were ovariectomized (ovx), and another seven rats received a sham operation (sham). After a 4-week recovery period, the ovx rats were separated into three groups, and they were then fed a control diet, a 0.01% MBP diet (0. 01% casein of the control diet replaced with MBP), or a 0.1% MBP diet for 17 weeks. The sham rats were fed the control diet. Bone mineral density (BMD) of the femur was measured by dual-energy X-ray absorptiometry in vivo. The BMD in the ovx-control group noticeably decreased during the experimental period in comparison with that in the sham group. However, the BMD in the OVX-0.1% MBP group was significantly higher than that in ovx-control group at weeks 12 and 16 (p < 0.05). After the 17-week feeding period, the breaking energy of the excised femur of all groups was determined by use of a three-point bending rheolometer. The breaking energy in the ovx-control group was significantly lower than that in the sham group (p < 0.05). However, the breaking energy in the ovx-0.1% MBP group was significantly higher than that of the ovx-control group (p < 0.05). Urinary deoxypyridinoline (D-Pyr) level of the ovx-control group was higher than that of the sham group, whereas the level of D-Pyr excretion in the ovx-0.01% MBP and ovx-0.1% MBP groups was significantly lower than that of the ovx-control group (p < 0.05). These results suggest that MBP suppresses the osteoclast-mediated bone resorption and prevents bone loss caused by ovariectomy. Moreover, we performed an in vitro study using isolated osteoclasts from rabbit bone to investigate the possible mechanism. MBP dose-dependently suppressed the number of pits formed by these osteoclasts. This result indicates that MBP suppresses bone resorption by its direct effects on osteoclasts. To our knowledge, this study provides the first evidence that MBP directly suppresses osteoclast-mediated bone resorption, resulting in the prevention of the bone loss that occurs in ovx rats.

Effect of Captopril on Glucose Concentration: Possible Role of Augmented Postprandial Forearm Blood Flow

The goal of this study was to evaluate the effects of captopril on plasma glucose concentration. The daily profiles of the plasma glucose levels were determined in 12 non-insulin-dependent diabetic normotensive subjects, treated with or without captopril at a dose of 25 mg 3 times/day. Forearm blood flow was also measured by strain-gauge plethysmography. Administration of captopril improved the daily profile of the plasma glucose level. Postprandial forearm blood flow was also augmented 2 h after a meal. These results suggest that angiotensin-converting enzyme inhibitors may improve glucose metabolism in diabetic subjects, possibly through enhancement of blood flow to skeletal muscle.

Fibroblast Growth Factor (FGF)-2 Directly Stimulates Mature Osteoclast Function through Activation of FGF Receptor 1 and p42/p44 MAP Kinase

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.

Peripheral dual-energy X-ray absorptiometry in the management of osteoporosis: the 2007 ISCD Official Positions

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.

A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial

To demonstrate the clinical benefit of risedronate at 2.5 mg daily in the treatment of involutional osteoporosis, the effect of risedronate on incidence of vertebral fracture was compared with that of etidronate. A total of 547 patients with one to four vertebral fractures were randomized to receive either treatment with 2.5 mg/day of risedronate or intermittent treatment (treatment of 2 weeks and off period of 10 weeks) with 200 mg/day of etidronate for 96 weeks in a double-masked fashion. All patients received 200 mg calcium supplement daily. Lateral and anteroposterior thoracic and lumbar spine radiographs were obtained at baseline and at 24, 48, 72, and 96 weeks. Cumulative incidence rates of patients who had at least one new or worsening vertebral fracture during the 96-week period were 12.3% for risedronate and 14.2% for etidronate, and it was verified that the fracture prevention effect of risedronate was not inferior to that of etidronate. The incidence rates of fracture during the initial 24-week period were 8.8% for risedronate and 6.0% for etidronate, but the cumulative incidence rate of fracture from 24 to 96 weeks was lower in the risedronate group (3.9%) as compared to the etidronate group (8.7%). Height loss was significantly less in the risedronate group (−0.28 cm) than in the etidronate group (−0.70 cm) after 96 weeks. Decreases in bone resorption markers including urinary total deoxypyridinoline and NTX were significantly greater in the risedronate group than in the etidronate group throughout the treatment period. An improvement of patient QOL was observed in both groups. No significant difference in the incidence of adverse events was observed between the two treatments. Daily oral risedronate (2.5 mg) was shown to provide an effective therapy for involutional osteoporosis in Japanese patients with good tolerability.

Milk Basic Protein (MBP) Increases Radial Bone Mineral Density in Healthy Adult Women

We studied the effects of daily intake of milk basic protein (MBP) on radial bone mineral density (BMD) in healthy adult women. Thirty-three healthy women were randomly assigned to a 6-month trial with either placebo or MBP (40 mg per day). The radial BMD of each volunteer was measured at the beginning of and at six months after the trial. The mean BMD value at the 6th month in the MBP group increased significantly at both 1/6 and 1/10 portion from the distal end of the radius, whereas that in the control group did not. The BMD gain of each volunteer in the MBP group was significantly higher than that in the placebo group. Thus a daily MBP supplementation of 40 mg in healthy adult women can significantly increase radial BMD.

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, Liver Glycogen synthase activity, and β-oxidation in fructose-fed rats

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Efficacy and tolerability of once-weekly administration of 17.5 mg risedronate in Japanese patients with involutional osteoporosis: a comparison with 2.5-mg once-daily dosage regimen.

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.

A double-blinded head-to-head trial of minodronate and alendronate in women with postmenopausal osteoporosis

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 >or=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 Official Positions of the International Society for Clinical Densitometry: Indications of Use and Reporting of DXA for Body Composition

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.