Comparison of once-weekly teriparatide and alendronate against new osteoporotic vertebral fractures at week 12.

The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.

Zoledronic acid sequential therapy could avoid disadvantages due to the discontinuation of less than 3-year denosumab treatment.

INTRODUCTION: Rapid descent in bone mineral density (BMD) and ascent in bone turnover marker (BTM) occur within the short period following denosumab (Dmab) discontinuation. In addition, the incidence of vertebral fracture also rises within the short period. The purpose of this study is to investigate the effects of sequential therapy using zoledronic acid (ZOL) on any adverse events after Dmab discontinuation. MATERIALS AND METHODS: This study was a multicenter retrospective observational study, and the subjects were osteoporosis patients who visited our institutions between 2013 and 2018. We performed sequential therapy using ZOL for 30 patients who had difficulty continuing Dmab, due to physical or social reasons, and investigated the fracture incidence and BMD/BTM changes at 4 time points (at the start of Dmab, the start of ZOL, 6 months after ZOL and 12 months after ZOL). RESULTS: No new vertebral/nonvertebral fractures were observed at each time point after switching from Dmab to ZOL in any of the 30 patients. The BMD/BTM changes were evaluated in 18 of the 30 cases, since all data of lumbar/femoral neck BMDs and TRACP-5b at 4 time points was only available in 18 cases. BMDs significantly increased at each time point compared with that at the start of Dmab. Serum TRACP-5b significantly decreased at each time point compared with that at the start of Dmab. CONCLUSION: It was suggested that sequential therapy using ZOL could suppress the decrease of BMD, and increase of BTM, if the period of Dmab administration was less than 3 years.

Efficacy of non-steroidal anti-inflammatory drugs on zoledronic acid-induced acute-phase reactions: randomized, open-label, Japanese OZ study.

INTRODUCTION: Zoledronic acid infusion is used to treat osteoporosis but patients, especially Japanese patients, often experience acute-phase reactions (APRs). In this multicenter, randomized, open-label, parallel-group study, we examined the efficacy of the most commonly used non-steroidal anti-inflammatory drug loxoprofen in Japan in reducing the incidence rate of zoledronic acid-induced APRs and body temperature, and investigated risk/protective factors for APRs in this population. MATERIALS AND METHODS: Patients aged ≥ 60 years with primary osteoporosis (n = 368) were allocated randomly to zoledronic acid plus loxoprofen (ZOL + LOX) or zoledronic acid alone (ZOL). All patients received 5-mg zoledronic acid infusion on day 1, and patients in the ZOL + LOX group also received 120 mg and 180 mg of oral loxoprofen on days 1 and 2, respectively. Adverse events and body temperature were recorded during the 7-day observation period. RESULTS: The incidence rates of APRs were 34.4% (64/186 patients) and 47.8% (87/182 patients) in the ZOL + LOX and ZOL groups, respectively (P = 0.0109). The proportions of patients with increased body temperature (≥ 1 °C and ≥ 37.5 °C) were similar in both groups (P = 0.1186). Past bisphosphonate users had a significantly lower incidence rate of APRs than treatment-naïve patients (odds ratio 0.444, 95% confidence interval 0.285-0.692, P = 0.0003). CONCLUSIONS: Zoledronic acid-induced APRs appeared to be suppressed by loxoprofen. Known risk/protective factors, including prior osteoporosis treatment, were applicable to Japanese patients.

In-vivo postoperative motion analysis of metal and ceramic bipolar hip hemiarthroplasty.

BACKGROUND: We hypothesized that ceramic bipolar shows less impingement between stem neck and outer head compared to metal bipolar, because of its low coefficient of friction with the acetabulum cartilage. In this paper, a three dimensional (3D) postoperative motion analysis has been used to assess the different motion characteristics of metal and ceramic bipolar hip hemiarthroplasty systems. METHODS: This study was conducted on 40 patients divided in two matched cohorts: 20 patients with metal bipolar and 20 patients with the ceramic bipolar. We obtained motion pictures from standing position to maximum abduction in flexion by fluoroscopy then analyzed by 2D-3D image matching method. The motion range of the "Outer head angle", "Stem neck angle" and the "Stem neck and outer head angle" was compared between the metal bipolar group and the ceramic bipolar group. RESULTS: The metal bipolar group's inner head's range of movement was greater than the ceramic bipolar group. Impingement between stem neck and outer head occurred in 30% of metal group patients. There were no impingement cases for the ceramic bipolar group. CONCLUSIONS: The ceramic bipolar shows less impingement between stem neck and outer head compared to the metal bipolar. Ceramic bipolar may reduce the typical bipolar related complication and exert less effect on the acetabular cartilage due to less surface coefficient of friction.

Reliability and validity in measurement of true humeral retroversion by a three-dimensional cylinder fitting method.

HYPOTHESIS AND BACKGROUND: Humeral retroversion is defined as the orientation of the humeral head relative to the distal humerus. Because none of the previous methods used to measure humeral retroversion strictly follow this definition, values obtained by these techniques vary and may be biased by morphologic variations of the humerus. The purpose of this study was 2-fold: to validate a method to define the axis of the distal humerus with a virtual cylinder and to establish the reliability of 3-dimensional (3D) measurement of humeral retroversion by this cylinder fitting method. METHODS: Humeral retroversion in 14 baseball players (28 humeri) was measured by the 3D cylinder fitting method. The root mean square error was calculated to compare values obtained by a single tester and by 2 different testers using the embedded coordinate system. To establish the reliability, intraclass correlation coefficient (ICC) and precision (standard error of measurement [SEM]) were calculated. RESULTS: The root mean square errors for the humeral coordinate system were <1.0 mm/1.0° for comparison of all translations/rotations obtained by a single tester and <1.0 mm/2.0° for comparison obtained by 2 different testers. Assessment of reliability and precision of the 3D measurement of retroversion yielded an intratester ICC of 0.99 (SEM, 1.0°) and intertester ICC of 0.96 (SEM, 2.8°). DISCUSSION AND CONCLUSION: The error in measurements obtained by a distal humerus cylinder fitting method was small enough not to affect retroversion measurement. The 3D measurement of retroversion by this method provides excellent intratester and intertester reliability.

Scapular Kinematics During Late Cocking of a Simulated Throwing Activity in Baseball Players With Shoulder Injury: A Cross-Sectional Study Using a 3D-to-2D Registration Technique.

CONTEXT: Abnormal scapular kinematics during throwing motion in baseball players with shoulder disorders has not yet been clarified, although altered scapular position has been suggested to be associated with shoulder disorder. OBJECTIVE: To determine if the shoulders of baseball players with throwing disorders demonstrate abnormal scapular kinematics during the simulated arm-cocking phase of throwing activity. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Eleven baseball players (age 21.1 ± 1.2 y) with a unilateral shoulder disorder volunteered to participate, including 9 players at the college level and 2 at the adult level. The mean playing experience was 12.1 ± 2.7 y. MAIN OUTCOME MEASURES: Scapular upward/downward rotation, anteroposterior tilting, and external/internal rotation during simulated arm-cocking motion were analyzed using a 3-to-2-dimensional registration technique. RESULTS: Scapular external rotation in the throwing shoulder was significantly smaller by 2.0-6.0° than that of the contralateral shoulder. There were no detectable differences in scapular upward/downward rotation or anteroposterior tilting between the throwing and contralateral shoulders. CONCLUSIONS: Compared with that in the contralateral shoulder, scapular external rotation was smaller in the throwing shoulder, which would increase glenohumeral horizontal abduction during the arm-cocking phase and be related to the throwing-shoulder disorder.

Approximation of Glomerular Filtration Rate after 1 Year Using Annual Medical Examination Data.

Background: This cohort study was conducted to devise an approximation formula for predicting the glomerular filtration rate (GFR) after 1 year using annual medical examination data from the general population. Methods: Consecutive annual medical examination data were obtained for 41,337 inhabitants. Machine learning with the random forest method was used to assess the importance of each clinical parameter in terms of its association with estimated GFR (eGFR) after 1 year. An approximation formula was developed by multiple linear regression analysis based on the four most important clinical parameters. The relationship between the GFR after 1 year approximated by our formula and the eGFR after 1 year was analyzed using Pearson's correlation coefficient. Results: The following approximation formula was obtained by multiple linear regression analysis: approximate GFR after 1 year (mL/min/1.73 m2) = -0.054 × age + 0.162 × hemoglobin - 0.085 × uric acid + 0.849 × eGFR + 11.5. The approximate GFR after 1 year was significantly and strongly correlated with the eGFR at that time (r = 0.884; p < 0.001). Conclusions: An approximation formula including age, hemoglobin, uric acid, and eGFR may be useful for predicting GFR after 1 year among members of the general population.

A comparative study of the effects of daily minodronate and weekly alendronate on upper gastrointestinal symptoms, bone resorption, and back pain in postmenopausal osteoporosis patients.

The purpose of the present study was to precisely compare both the efficacy and abdominal symptom-related quality of life after treatment with daily minodronate and weekly alendronate in patients with primary postmenopausal osteoporosis. The efficacy of the two drugs was assessed based on improvements in a bone turnover marker, back pain, and gastrointestinal symptoms that impair quality of life, which was assessed using the Izumo scale questionnaire. In the minodronate group, there were no significant changes during the treatment period in the specific scores for heartburn, epigastralgia and epigastric fullness, whereas all of the scores were significantly elevated at some time point after drug administration in the alendronate group. Urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, and bone-specific alkaline phosphatase, a bone formation marker, significantly decreased in both groups, but decreases in uNTX in the minodronate group was observed significantly earlier compared with those in the alendronate group. The back pain scores, which were obtained using a visual analog scale, were significantly reduced in both groups. However, analgesic effects were detected earlier in the minodronate group. In conclusion, compared with weekly alendronate, daily minodronate improved bone turnover and back pain more promptly without causing upper gastrointestinal symptoms.

In Vivo Postoperative Motion of Fixed and Mobile Medial Pivot Knees Under Weight-Bearing Conditions after Cruciate-Sacrificing Total Knee Arthroplasty.

BACKGROUND: In vivo three-dimensional (3D) motion under weight-bearing conditions was analyzed postoperatively in medial pivot cruciate-substituting (CS) knee systems with fixed and mobile inserts. METHODS: Tibiofemoral knee kinematics during squatting were captured with X-ray fluoroscopy for 4 patients in each cohort. The 3D motion of implants was analyzed with KneeMotion motion analysis software (LEXI Corporation; Tokyo, Japan). In addition, anterior-posterior (AP) movement of the distal-most points and the angle of axial rotation of the femoral component on the tibial component were assessed in both cohorts. RESULTS: Mean AP movement of the femoral component on the tibial component was 3.8±0.5 mm on the medial side and 9.5±0.5 mm on the lateral side in the cohort with fixed prostheses and 5.9±2.1 mm on the medial side and 10.0±2.5 mm on the lateral side in the cohort with mobile prostheses. The mean angle of axial rotation of the femoral component on the tibial component was 14.4±1.1 degrees and 8.2±2.7 degrees of external rotation for fixed knees and mobile knees, respectively. CONCLUSIONS: Postoperative motion analysis confirmed that fixed and mobile CS implants, which have a similar design, guided medial pivot motion under weight-bearing conditions. However, motion differed between these implant types after mid-flexion: bicondylar rollback after medial pivot motion was noted in the mobile cohort.

Biomechanical comparison of lag screw and non-spiral blade fixation of a novel femoral trochanteric nail in an osteoporotic bone model.

There is no consensus regarding the advantages of the lag screw type over the blade type for treating femoral trochanteric fractures. We aimed to investigate whether non-spiral blade (Conventional-Blade, Fid-Blade) nails provide better biomechanical fixation than lag screws in a severe osteoporotic bone model. Different severities of osteoporotic cancellous bone were modelled using polyurethane foam blocks of three densities (0.24, 0.16, and 0.08 g/cm3). Three torsional tests were performed using each component for each density of the polyurethane block, and the maximum torque was recorded; subsequently, the energy required to achieve 30° rotation was calculated. Using a push-in test, the maximum force was recorded, and the energy required to achieve 4-mm displacement was calculated. For 0.08-g/cm3 density, the peak torques to achieve 30° rotation, energy required to achieve 30° rotation, peak force to achieve 4-mm displacement, and energy required to achieve 4-mm displacement were significantly greater for Conventional-Blade and Fid-Blade than those for Lag Screw. The fixation stability of the blade-type Magnum nail component is better than that of the lag screw type under any test condition. The blade-type nail component may have better fixation stability than the lag screw type in a severe osteoporotic bone model.

Bone microstructure changes due to once-/twice-weekly teriparatide administration: A report of five cases using high-resolution peripheral quantitative computed tomography.

This study was conducted with the aim of presenting cases in which high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to investigate changes in the bone microstructure due to once-weekly/twice-weekly administration of teriparatide (TPTD). Of osteoporosis patients who participated in a non-inferiority trial (TWICE study: once-weekly vs twice-weekly TPTD) with lumbar bone mineral density as the primary endpoint, five cases scanned by HR-pQCT before TPTD administration were analysed. Two cases were given once-weekly TPTD, three were given twice-weekly TPD, and HR-pQCT was repeated after 48 weeks. A sufficient anabolic effect of once-weekly/twice-weekly TPTD on the trabecular and cortical bone at the tibia was obtained. In addition, the average change in cortical porosity (Ct.Po) was only 0.3% in the tibia and 0.2% in the radius. These findings indicate that once-weekly and twice-weekly TPTD can be expected to improve the bone microstructure, and the increase in Ct.Po may be suppressed.

Close Association of Matrix Metalloproteinase-9 Levels With the Presence of Thin-Cap Fibroatheroma in Acute Coronary Syndrome Patients: Assessment by Optical Coherence Tomography and Intravascular Ultrasonography.

BACKGROUND: Thin-cap fibroatheroma (TCFA) has been suggested as a precursor lesion of coronary plaque rupture. As elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been documented in patients with acute coronary syndrome (ACS), we sought to determine whether the presence of TCFA is linked to MMP-9 levels in these patients. METHODS: We evaluated 51 ACS patients with de novo culprit lesions who were examined via optical coherence tomography and intravascular ultrasound. Blood samples were obtained from the peripheral vein (PV) and the ostium and culprit lesion of the infarct-related coronary artery (CA) in the acute phase of ACS and from the PV in the chronic phase (8 months after ACS). RESULTS: The plasma MMP-9 level in the acute phase was significantly higher than that in the chronic phase. Plasma MMP-9 levels at the culprit lesion of the infarct-related CA were significantly higher than, but positively correlated with those in the PV (10.9 (5.9-16.1) ng/mL and 8.9 (5.6-13.0) ng/mL, p < 0.0001, respectively; Spearman ρ = 0.84, p < 0.0001). Significantly higher PV plasma MMP-9 levels were observed in patients with TCFA than in patients without TCFA (12.1 (7.0-13.5) and 5.7 (4.0-8.2) ng/ml, p<0.0001, respectively). Further, plasma MMP-9 levels in the PV were positively correlated with the remodeling index (Spearman ρ = 0.29, p = 0.039) and negatively correlated with fibrous cap thickness (Spearman ρ = -0.42, p = 0.0021). Receiver operating characteristic curve analysis showed that the plasma MMP-9 levels in the PV could predict the presence of TCFA at a cut-off value of 9.9 ng/mL. CONCLUSIONS: Plasma MMP-9 levels were closely associated with MMP-9 levels in the CA and were further linked with TCFA in patients with ACS.

Component gap control during posterior-stabilised total knee arthroplasty using the posterior condylar pre-cut technique.

PURPOSE: Adjusting the gap lengths to ensure equal lengths in both extension and flexion during total knee arthroplasty (TKA) is important for achieving successful outcomes. We designed a new pre-cut trial component (PCT) for posterior-stabilised (PS) TKA and aimed to determine whether the pre-cut technique is useful for component gap (CG) control in PS TKA. METHODS: A total of 70 knees were included. The PS PCT for PS TKA is composed of a 9-mm-thick distal part and 5-mm-thick posterior part with a cam structure. First, the distal femur and proximal tibia were cut to create an extension gap. Next, a 4-mm pre-cut was made from the posterior femoral condylar line; then, the PS PCT was attached, and the CGs were checked and compared at 0° and 90° knee flexion. Final CGs with the trial femoral components were compared with gaps in PS PCT at 0° and 90° knee flexion. RESULTS: CGs using PS PCTs were 10.2 mm at 0° and 13.6 mm at 90° knee flexion. According to the release of the posterior capsule at intercondylar notch and the adjustment of the cutting level of posterior femoral condyle, the final CG on knee extension was 11.3 mm; it did not significantly differ from CGs with PS PCT. The final CG at 90° knee flexion was 12.7 mm; it did not significantly differ from the estimated gap (12.4 mm) in PS PCT after flexion gap control. CONCLUSION: CG control using PS PCT is a useful technique during PS TKA. LEVEL OF EVIDENCE: Level IV: Case series.

Daily activity relates to not only femoral bone mineral density, but also hip structural analysis parameters: A cross-sectional observational study.

OBJECTIVES: Physical activity to maintain bone mass and strength is important for hip fracture prevention. We aim to investigate the relationship between physical performance/activity status and bone mineral density (BMD)/hip structural analysis (HSA) parameters among postmenopausal women in Japan. METHODS: Sixty-two postmenopausal women diagnosed with osteoporosis (mean age: 72.61 ± 7.43 years) were enrolled in this cross-sectional observational study. They were evaluated for BMD and HSA in the proximal femur by dual-energy X-ray absorptiometry and underwent several physical performance tests, the Geriatric Locomotive Function Scale of 25 questions (GLFS-25). Principal component analysis (PCA) was used to summarize data on the BMD/HSA parameters. Partial correlation analysis, multiple regression analysis, and structural equation modeling (SEM) were performed to investigate the relationship between physical performance/activity status and BMD/HSA parameters of the proximal femur. RESULTS: In a partial correlation analysis adjusted for age and body mass index (BMI), GLFS-25 scores were correlated with HSA parameter (|r| = 0.260-0.396, P < 0.05). Principal component 1 (PC1) calculated by PCA was interpreted as more reflective of bone strength based on the value of BMD/HSA parameters. The SEM results showed that the model created by the 3 questions (Q13, brisk walking; Q15, keep walking without rest; Q20, load-bearing tasks and housework) of the GLFS-25 had the best fit and was associated with the PC1 score (ß = -0.444, P = 0.001). CONCLUSIONS: The GLFS-25 score was associated with the BMD/HSA parameter, which may reflect the bone strength of the proximal femur as calculated by PCA.

Differences in the effects of BMI on bone microstructure between loaded and unloaded bones assessed by HR-pQCT in Japanese postmenopausal women.

OBJECTIVES: The relationship between weight-related load and bone mineral density (BMD)/bone microstructure under normal load conditions using high-resolution peripheral quantitative computed tomography (HR-pQCT) remains unconfirmed. The study aims to investigate the differences in effect of body mass index (BMI) on BMD/bone microstructure of loaded and unloaded bones, respectively, in Japanese postmenopausal women. METHODS: Fifty-seven postmenopausal women underwent HR-pQCT on the tibia and radius. Correlation analysis, principal component (PC) analysis, and hierarchical multiple regression were performed to examine the relationship between BMI and HR-pQCT parameters. RESULTS: Several microstructural parameters of the tibia and radius correlated with BMI through a simple correlation analysis, and these relationships remained unchanged even with an age-adjusted partial correlation analysis. PC analysis was conducted using seven bone microstructure parameters. The first PC (PC1) reflected all parameters of trabecular and cortical bone microstructures, except for cortical porosity, whereas the second PC (PC2) reflected only cortical bone microstructure. Hierarchical multiple regression analysis indicated that BMI was more strongly related to BMD/bone microstructure in the tibia than in the radius. Furthermore, BMI was associated with trabecular/cortical BMD, and PC1 (not PC2) of the tibia and radius. Thus, BMI was strongly related to the trabecular bone microstructure rather than the cortical bone microstructure. CONCLUSIONS: Our data confirmed that BMI is associated with volumetric BMD and trabecular bone microstructure parameters in the tibia and radius. However, although BMI may be more related to HR-pQCT parameters in the tibia than in the radius, the magnitude of association is modest.

Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice.

Calcium balance is important in bone homeostasis. The transient receptor potential vanilloid (TRPV) channel is a nonselective cation channel permeable to calcium and is activated by various physiological and pharmacological stimuli. TRPV1 and TRPV4, in particular, have important roles in intracellular Ca2+ signaling and extracellular calcium homeostasis in bone cells. TRPV1 and TRPV4 separately mediate osteoclast and osteoblast differentiation, and deficiency in any of these channels leads to increased bone mass. However, it remains unknown whether bone mass increases in the absence of both TRPV1 and TRPV4. In this study, we used TRPV1 and TRPV4 double knockout (DKO) mice to evaluate their bone mass in vivo, and osteoclast and osteoblast differentiation in vitro. Our results showed that DKO mice and wild type (WT) mice had no significant difference in body weight and femur length. However, the results of dual-energy X-ray absorption, microcomputed tomography, and bone histomorphometry clearly showed that DKO mice had higher bone mass than WT mice. Furthermore, DKO mice had less multinucleated osteoclasts and had lower bone resorption. In addition, the results of cell culture using flushed bone marrow from mouse femurs and tibias showed that osteoclast differentiation was suppressed, whereas osteoblast differentiation was promoted in DKO mice. In conclusion, our results suggest that the increase in bone mass in DKO mice was induced not only by the suppression of osteoclast differentiation and activity but also by the augmentation of osteoblast differentiation and activity. Our findings reveal that both the single deficiency of TRPVs and the concurrent deficiency of TRPVs result in an increase in bone mass. Furthermore, our data showed that DKO mice and single KO mice had varying approaches to osteoclast and osteoblast differentiation in vitro, and therefore, it is important to conduct further studies on TRPVs regarding the increase in bone mass to explore not only individual but also a combination of TRPVs.

Treatment with once-weekly alendronate oral jelly compared with once-weekly alendronate oral tablet for Japanese patients with primary osteoporosis: An open-label, prospective, observational study.

BACKGROUND AND AIMS: Clinical data regarding alendronate jelly are limited. We compared the efficacy and safety of once-weekly alendronate oral jelly with once-weekly alendronate tablet formulations in the context of primary osteoporosis. METHODS: In this 6-month, open-label, prospective, observational study, Japanese patients aged ≥60 years with primary osteoporosis were included from 14 primary care centres in Japan. The effects of once-weekly alendronate oral jelly and tablet formulations on bone mineral density (BMD), bone turnover markers, and quality of life related to gastrointestinal symptoms were assessed at baseline and 6 months. Treatment was allocated by patient preference. This potentially confounding factor was adjusted for statistically. RESULTS: In total, 170 patients were enrolled (jelly, n = 97; tablet, n = 73). Mean percent changes in radius, lumbar spine, femoral neck, and hip BMD were similar in both treatment groups at 6 months. Both formulations decreased tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen 1 N-terminal peptide (P1NP) between baseline and 6 months (by about 50% and 60%, respectively); no significant differences in mean changes were noted in these markers between groups. At 6 months, no significant differences were noted in visual analogue scale or EuroQOL five-dimension questionnaire scores between groups. The jelly group had significantly lower scores than the tablet group in the Izumo scale domains of heartburn (-0.81, P = 0.0040), epigastralgia (-0.94, P = 0.0003), and epigastric fullness (-0.49, P = 0.044). During treatment, more patients discontinued for upper gastrointestinal symptoms in the tablet group (n = 4) than the jelly group (n = 1). CONCLUSIONS: Once-weekly alendronate oral jelly 35 mg may be a suitable alternative therapeutic agent for primary osteoporosis in Japan.

Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats.

BACKGROUND: Inflammation plays an important role in the pathogenesis of hypertension and hypertensive organ damage. Interleukin (IL)-10, a pleiotropic anti-inflammatory cytokine, exerts vasculoprotective effects in many animal models. In the present study, we examined the preventive effects of adeno-associated virus (AAV) vector-mediated sustained IL-10 expression against hypertensive heart disease and renal dysfunction in Dahl salt-sensitive rats. METHODS: We injected the rats intramuscularly with an AAV type 1-based vector encoding rat IL-10 or enhanced green fluorescent protein (EGFP) at 5 weeks of age; subsequently, the rats were fed a high-sodium diet from 6 weeks of age. RESULTS: Sustained IL-10 expression significantly improved survival rate of Dahl salt-sensitive rats compared with EGFP expression (62.5% versus 0%, p < 0.001); it also caused 26.0% reduction in systolic blood pressure at 15 weeks (p < 0.0001). Echocardiography exhibited a 22.0% reduction in hypertrophy (p < 0.0001) and a 26.3% improvement in fractional shortening (p < 0.0001) of the rat left ventricle in the IL-10 group compared to the EGFP group. IL-10 expression also caused a 21.7% decrease in the heart weight/body weight index and cardiac atrial natriuretic peptide levels. Histopathological studies revealed that IL-10 decreased inflammatory cell infiltration, fibrosis, and transforming growth factor-beta(1) levels in the failing heart. Furthermore, IL-10 expression significantly reduced urine protein excretion with increased glomerular filtration rates. CONCLUSIONS: This is the first study to demonstrate that the anti-inflammatory cytokine IL-10 has a significant anti-hypertensive effect. AAV vector-mediated IL-10 expression potentially prevents the progression of refractory hypertension and hypertensive organ damage in humans.

M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system.

OBJECTIVE: Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 microg/(kg x day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. CONCLUSIONS: These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

Influence on the bone mineral density and bone metabolism marker after the interruption and reinitiation of monthly minodronate therapy in postmenopausal women with osteoporosis.

OBJECTIVES: The purpose of this study was to investigate the influences of interruption and reinitiation of monthly minodronate therapy on the bone mineral density (BMD) and bone metabolism markers in postmenopausal women with osteoporosis. METHODS: Study patients were included if they had been administered monthly minodronate therapy for ≥6 months, interrupted the therapy, and reinitiated the therapy for ≥12 months. The BMD and bone metabolism markers were assessed at 4 time points: initiation, interruption, reinitiation and 1 year after reinitiation of therapy. RESULTS: A total of 23 patients were enrolled. The mean monthly minodronate treatment period was 23.8 ±â€¯12.9 months following a mean interruption period of 11.9 ±â€¯5.4 months. Once increased by monthly minodronate treatment for 2 years on average, the BMD of lumbar spine and radius did not significantly decrease even after an interruption for 1 year on average. However, the BMD of the femoral neck did decrease after interruption. The BMD of the lumbar spine and radius increased further after 1 year of monthly minodronate retreatment. The BMD of the femoral neck did not change. Once decreased after the treatment for an average of 2 years followed by an interruption for 1 year, bone metabolism markers increased gradually but did not recover to baseline levels. A potent suppressive effect on bone resorption was noted. The change rate was greater for the bone formation marker procollagen 1 N-terminal propeptide. CONCLUSIONS: Monthly minodronate treatment increases BMD and reduces bone metabolism markers. The effect lessens after treatment interruptions, and can be restored by retreatment.