Double-Stranded Structure of the Polyinosinic-Polycytidylic Acid Molecule to Elicit TLR3 Signaling and Adjuvant Activity in Murine Intranasal A(H1N1)pdm09 Influenza Vaccination.

Polyinosinic-polycytidylic acid (PIC) is a potent double-stranded RNA (dsRNA) adjuvant useful in intranasal influenza vaccination. In mice, the intensity and duration of immune responses to PIC correlated with the double-stranded chain length. A rational method to avoid PIC chain extension in PIC production is to use multiple short poly(I) molecules and one long poly(C) molecule for PIC assembly. In this study, we elucidate that a newly developed uPIC100-400 molecule comprising multiple 0.1 kb poly(I) molecules and one 0.4 kb poly(C) molecule effectively enhanced the immune responses in mice, by preventing the challenged viral propagation and inducing hemagglutinin-specific IgA, after intranasal A(H1N1)pdm09 influenza vaccination. Reduced intraperitoneal toxicity of PIC prepared with multiple short poly(I) molecules in mice indicates the widened effective range of uPIC100-400 as an adjuvant. In contrast to uPIC100-400, the PIC molecule comprising multiple 0.05 kb poly(I) molecules failed to elicit mouse mucosal immunity. These results were consistent with TLR3 response but not retinoic acid inducible gene I (RIG-I)-like receptor response in the cell assays, which suggests that the adjuvant effect of PIC in mouse intranasal immunization depends on TLR3 signaling. In conclusion, the double-stranded PIC with reduced toxicity developed in this study would contribute to the development of PIC-adjuvanted vaccines.

Eldecalcitol is superior to alfacalcidol in maintaining bone mineral density in glucocorticoid-induced osteoporosis patients (e-GLORIA).

INTRODUCTION: Eldecalcitol increases bone mineral density (BMD) and reduces vertebral fracture in patients with primary osteoporosis. However, the effect of eldecalcitol on BMD and fracture in glucocorticoid-induced osteoporosis (GIO) patients is unknown. This study was undertaken to compare the effect of eldecalcitol on BMD and fracture with that of alfacalcidol in GIO patients. MATERIALS AND METHODS: A randomized, open-label, parallel group study was conducted to identify the effectiveness and safety of monotherapy with 0.75 µg eldecalcitol compared with 1.0 µg alfacalcidol in GIO patients. RESULTS: Lumbar spine BMD increased with eldecalcitol, but decreased with alfacalcidol at 12 and 24 months (between group difference 1.29%, p < 0.01, and 1.10%, p < 0.05, respectively). Total hip and femoral neck BMD were maintained until 24 months by eldecalcitol, but decreased by alfacalcidol (between group difference 0.97%, p < 0.05 and 1.22%, p < 0.05, respectively). Both bone formation and resorption markers were more strongly suppressed by eldecalcitol than by alfacalcidol. Eldecalcitol showed better effect on BMD than alfacalcidol in patients with no prevalent fracture and BMD > 70% of the young adult mean, and with ≤ 3 months of previous glucocorticoid treatment. No significant difference in the incidence of vertebral fracture was found, and the incidence of adverse events was similar between the two groups. CONCLUSIONS: Eldecalcitol was more effective than alfacalcidol in maintaining BMD in GIO patients. Because eldecalcitol was effective in patients with no or short-term previous glucocorticoid treatment, as well as those without prevalent fracture or low BMD, eldecalcitol can be a good candidate for primary prevention of GIO. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000011700.

Minodronate combined with alfacalcidol versus alfacalcidol alone for glucocorticoid-induced osteoporosis: a multicenter, randomized, comparative study.

INTRODUCTION: This study compared the clinical usefulness of minodronate (50 mg/4 weeks) plus alfacalcidol (1 µg/day) (Group M) with that of alfacalcidol alone (1 µg/day) (Group A) for treating glucocorticoid-induced osteoporosis. MATERIALS AND METHODS: The primary endpoints were the changes from baseline in lumbar spine (LS) bone mineral density (BMD) and the cumulative incidence of vertebral fracture at 24 months; secondary endpoints included the changes from baseline in total hip (TH) BMD and bone turnover markers. RESULTS: Of 164 patients enrolled, 152 (Group M, n = 75; Group A, n = 77) were included in the analysis of efficacy. At each time point and at 24 months, LS BMD and TH BMD were significantly higher in Group M than in Group A. The 152 patients were divided into two subgroups that were previously treated with glucocorticoids for ≤ 3 months or > 3 months. In both subgroups, the changes from baseline in LS BMD and TH BMD from baseline at 24 months had increased more in Group M than in Group A. There were no differences found in the incidence of vertebral fracture between the groups, because the number of enrolled patients was lesser than that initially expected. In Group M, both bone formation and resorption markers significantly decreased from baseline at 3 months and maintained at 6, 12, and 24 months. CONCLUSIONS: Minodronate plus alfacalcidol was more effective than alfacalcidol alone in increasing BMD and was effective in increasing BMD for both prevention and treatment. Therefore, minodronate can be a good candidate drug for the treatment of glucocorticoid-induced osteoporosis.

Polarization envelope helicity dependent photovoltage in GaAs/Al0.3Ga0.7As modulation-doped quantum well.

In this study, we demonstrate the switching of the direction of the photocurrent in an n-type GaAs/Al0.3Ga0.7As modulation-doped quantum well using a polarization pulse-shaping apparatus containing a 4f setup. The right- and left-polarization-twisting pulses with a polarization rotation frequency in the THz-regime are incident on a modulation-doped quantum well. The results show that the sign of the photovoltage is dependent on the direction of rotation of the polarization-twisting pulses, which can be explained by the circular photogalvanic effect combined with the production of a classical edge photocurrent from the acceleration of free electrons in the vicinity of the sample edge by the incident optical electric field. The wide range over which the polarization-rotation frequency may be tuned makes this method a powerful tool to investigate the response of an extensive variety of materials in the THz-regime.

A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.

Novel methods for nucleotide length control in double-stranded polyinosinic-polycytidylic acid production using uneven length components.

Polyinosinic-polycytidylic acid (PIC), a double-stranded RNA that induces innate immunity in mammals, is a candidate immunopotentiator for pharmaceuticals. The potency and adverse effects of PIC are strongly correlated with the nucleotide length, and the inability to precisely control the length in PIC production limits its practical use. Length extension during the annealing process is the major factor underlying the lack of control, but tuning the annealing conditions is insufficient to resolve this issue. In this study, we developed a novel method to produce accurate nucleotide length PIC at an industrial scale. The length extension was significantly suppressed by the assembly of multiple short polyinosinic acid molecules with one long polycytidylic acid molecule. A newly developed PIC, uPIC100-400, demonstrated a reproducible length and better storage stability than that of corresponding evenly structured PIC. Human dsRNA receptors exhibited equivalent responsiveness to uPIC100-400 and the evenly structured PIC with the same length.

Shape-dependent adjuvanticity of nanoparticle-conjugated RNA adjuvants for intranasal inactivated influenza vaccines.

Intranasal inactivated influenza vaccines can elicit mucosal immune responses that protect against virus infection. For the development of intranasal inactivated influenza vaccines, effective adjuvants inducing minimal adverse reactions are required. Generally, however, lower toxicity adjuvants have lower adjuvanticity. In this research, we fabricated nanoparticle-based adjuvants to enhance its adjuvanticity. Herein, we focused on low-molecular-weight polyinosinic-polycytidylic acid, referred to as uPIC(40:400), as a weak and less toxic RNA adjuvant. We conjugated uPIC(40:400) with different shaped gold nanoparticles (AuNPs) electrostatically. Conjugation with gold nanorods, but not spherical AuNPs, markedly enhanced the adjuvanticity of uPIC(40:400), leading to the suppression of viral infection in mice. Notably, conjugation with gold nanorods did not increase the inflammatory cytokine production in dendritic cells. These data indicated that gold nanorods can provide a good platform for enhancing the weak adjuvanticity of uPIC(40:400) while maintaining low inflammatory cytokine production toward the development of intranasal inactivated influenza vaccines.

Monthly oral ibandronate 100 mg is as effective as monthly intravenous ibandronate 1 mg in patients with various pathologies in the MOVEST study.

The non-inferiority of oral ibandronate 100 mg to intravenous (i.v.) ibandronate 1 mg in increasing lumbar spine (LS) bone mineral density (BMD) after 12 months of treatment was demonstrated in the randomized, phase III MOVEST study. We conducted subgroup analyses in the per-protocol set of the study (n = 183 oral ibandronate; n = 189 i.v. ibandronate). In patients with LS BMD T score ≥ -3.0 or < -3.0 at screening, LS BMD gains from baseline were 4.42 and 5.79%, respectively, with oral ibandronate, and 4.60 and 5.83%, respectively, with i.v. ibandronate. LS BMD gains in patients with or without prevalent vertebral fractures were 5.21 and 5.23%, respectively, with oral ibandronate, and 5.01 and 5.49%, respectively, with i.v. ibandronate. In patients aged <75 or ≥75 years, LS BMD gains were 5.46 and 4.51%, respectively, with oral ibandronate, and 5.25 and 5.77%, respectively, with i.v. ibandronate. LS BMD gains in patients with baseline 25-hydroxyvitamin D levels ≥20 or <20 ng/mL were 5.35 and 4.76%, respectively, with oral ibandronate, and 5.05 and 6.57%, respectively, with i.v. ibandronate. Similar results were obtained in patients with or without prior bisphosphonate (BP) treatment, and in those receiving osteoporosis drug treatment other than BPs. In conclusion, oral ibandronate 100 mg demonstrated comparable BMD gains with monthly i.v. ibandronate, and thus shows high utility in the lifestyle and disease conditions associated with osteoporosis in Japanese patients.

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk.

INTRODUCTION: To clarify the additional efficacy and safety benefits of 24 months' treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks. METHODS: This was a multicenter, open-label, single-arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 µg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2-L4) BMD measured by dual-energy X-ray absorptiometry. RESULTS: A total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks. CONCLUSION: The once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. FUNDING: Asahi Kasei Pharma Corporation. CLINICAL TRIAL REGISTRATION: JapicCTI-132276.

Associations between serum 25-hydroxyvitamin D3 level and skeletal muscle mass and lower limb muscle strength in Japanese middle-aged subjects.

OBJECTIVES: One of the important risk factors of falling is decreased muscle mass and muscle strength. Recently, there has been an increasing concern on the role of vitamin D in muscle strength and physical activity. Aim of our study is to examine the relationships between vitamin D status and muscle mass and muscle strength in middle-aged healthy adults. METHODS: Subjects were 40 healthy volunteers aged 42.0 ± 10.6 years old. Evaluation was made for serum vitamin D3 metabolites including 25-hydroxyvitamin D3 [25(OH)D3] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] concentrations, lower limb muscle strength, and dietary intake by food frequency questionnaire. Body composition was measured by dual-energy X-ray absorptiometry (DXA), and appendicular skeletal mass index (ASMI) was calculated as skeletal muscle mass/squared height. RESULTS: 70% of the subjects had vitamin D insufficiency/deficiency (serum total 25(OH)D < 20 ng/mL), and female subjects had significantly lower serum total 25(OH)D level compared with males. Vitamin D insufficiency/deficiency group had significantly higher body fat, lower SMI and muscle strength, probably reflecting higher percentage of female subjects. Serum vitamin D3 metabolites levels were significantly correlated with whole and site-specific ASMI, and lower limb muscle strength, except for the correlation between serum 24,25(OH)2D3 concentration and lower limb muscle strength. In addition, serum 25(OH)D3 level was a positive significant predictor for both ASMI and lower limb muscle strength, while serum 24,25(OH)2D3 level was not their significant predictor. CONCLUSIONS: Serum 25(OH)D3 level was significantly correlated with both skeletal muscle mass and lower limb muscle strength.

Effect of elcatonin versus nonsteroidal anti-inflammatory medications for acute back pain in patients with osteoporotic vertebral fracture: a multiclinic randomized controlled trial.

The aim of this study was to compare the efficacy of elcatonin injections and oral nonsteroidal anti-inflammatory drugs (NSAIDs) for patients with osteoporosis who have acute lumbar pain after experiencing new vertebral compression fractures. Two hundred twenty-eight Japanese female patients (mean age 77.3 years) with acute lumbar pain from osteoporotic vertebral fractures were randomly divided into two groups. Patients in one group were given an NSAID (NSAIDs group) and patients in the other group were given weekly intramuscular injections of 20 units of elcatonin (elcatonin group). All patients underwent follow-up examinations up to 6 weeks from the start of the trial. Outcome measures were the level of functional impairment according to the Japan Questionnaire for Osteoporotic Pain (JQ22), the Roland-Morris Disability Questionnaire (RDQ), and a visual analog scale (VAS) of pain intensity. Statistical analyses focused on (1) the time course of pain and functional level using linear mixed effects models to analyze the longitudinal data and (2) the effectiveness of elcatonin injection with mean difference values and 95 % confidence intervals. Significant differences were seen over time between the initial values and the postintervention values (4 and 6 weeks) in JQ22, RDQ, and VAS scores (effect size d > 0.4) in each group. The mean differences between the elcatonin group and the NSAIDs group in each measure at 4 and 6 weeks were -4.8 and -8.3 for the JQ22, -1.3 and -2.6 for the RDQ, and -11.3 and -11.5 for the VAS, shifted to elcatonin. Once weekly elcatonin injection was more effective than NSAIDs for treating acute lumbar pain and improving mobility in Japanese women with osteoporotic vertebral fractures.

A case of hepatitis C-associated osteosclerosis: accelerated bone turnover controlled by pulse steroid therapy.

Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient's symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis. LEARNING POINTS: HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.

Contribution of hypoalbuminemia and decreased renal function to the increased mortality after newly diagnosed vertebral fracture in Japanese subjects.

BACKGROUND AND OBJECTIVES: Reports on the mortality and its contributing factors after vertebral fracture (VFx) has been scarce, and limited to prevalent VFx. In this paper, we have studied the factors influencing mortality after freshly diagnosed VFx. METHODS AND STUDY DESIGN: 759 subjects aged 78.8±8.5 years old with back or lumbar pain, and diagnosed as fresh VFx by MRI were studied for their age, gender, number of prevalent fracture (s), survival or the date of death, circulating concentrations of Hb, albumin, C reactive protein, and estimated glomerular filtration rate (eGFR). Cox's proportional hazard analysis was performed to assess the significant predictors for mortality. The cut-off concentrations of the variables for mortality were analyzed using the receiver operator characteristic (ROC) curve. RESULTS: The median observation duration was 3.8 years, and 3-year survival rate was 78.8%. Cox's proportional hazard analysis has shown that serum albumin concentration (hazard ratio (HR) =0.355) and eGFR (HR=0.993) were significant predictors for mortality. The cut-off concentrations were 3.6 g/dL and 60 mL/min/1.73m2, respectively. Kaplan-Meier curves revealed that survival rates were significantly decreased in patients with both serum albumin concentration and eGFR below these cut-off concentrations. CONCLUSIONS: The present study has revealed that malnutrition and impaired renal function were significant predictors for mortality after VFx.

Higher response with bone mineral density increase with monthly injectable ibandronate 1 mg compared with oral risedronate in the MOVER study.

We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.

Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT).

CONTEXT: Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis. OBJECTIVE: The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted. PATIENTS: Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures. INTERVENTION: Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D. MAIN OUTCOME MEASURE: The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo. RESULTS: Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194-0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study. CONCLUSION: These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis.

Once-weekly teriparatide reduces the risk of vertebral fracture in patients with various fracture risks: subgroup analysis of the Teriparatide Once-Weekly Efficacy Research (TOWER) trial.

Once-weekly teriparatide (human parathyroid hormone [1-34]) (56.5 µg for 72 weeks) injections provided a vertebral fracture risk reduction in Japanese osteoporotic patients evaluated in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial. Using data from the TOWER trial, a subgroup analysis was performed to study the efficacy of once-weekly teriparatide for a variety of baseline clinical risk factors in placebo (n = 281) and teriparatide (n = 261) groups. Significant fracture risk reductions were observed in the subgroups of individuals aged <75 years [relative risk (RR) 0.06, p = 0.007] and ≥75 years (RR 0.32, p = 0.015). A significant risk reduction was observed among patients with prevalent vertebral fracture in the subgroup with 1 (RR 0.08, p = 0.015) or ≥2 (RR 0.29, p = 0.009) prevalent vertebral fractures, and in those with grade 3 deformity (RR 0.26, p = 0.003). Significant risk reduction was observed in the subgroup with lumbar bone mineral density (BMD) < -2.5 SD (RR 0.25, p = 0.035). In the teriparatide group, no incident fracture was observed in the subgroups with a prevalent vertebral fracture number of 0, with grade 0-2 vertebral deformity, or with lumbar BMD ≥2.5 SD. Significant risk reduction was observed in all of the bone turnover marker and estimated glomerular filtration rate subgroups. In conclusion, once-weekly 56.5 µg teriparatide injection reduced the vertebral fracture risk in patients with varying degrees of fracture risk, age, vertebral fracture number and grade, bone turnover level, and renal function.

[Once-weekly teriparatide treatment on osteoporosis].

Teriparatide (human PTH 1-34) transiently stimulate both bone formation and bone resorption and subsequently bone formation markers increased. The changes in bone turnover markers 24 h after each injection of once-weekly 56.5µg teriparatide were constant for 24 weeks. Once-weekly injections of teriparatide increased bone mineral density by 8.1% at the lumbar spine and reduced the risk of new vertebral fracture with a relative risk reduction of 80% compared to placebo for the patients with osteoporosis. Significant vertebral fracture risk reductions were also observed in the patients with high risk for fracture such as higher age, low bone mineral density, or sever vertebral fracture grade. Once-weekly teriparatide improved cortical bone parameters at proximal femur, may have the potential to prevent hip fracture. The duration of teriparatide treatment was limited. Therefore subsequent treatment for osteoporosis should be need. Bisphosphonates seem to be a useful choice as a subsequent treatment to once-weekly teriparatide.

Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis.

This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77-1.54]; 1 mg, HR 0.88 (95 % CI 0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8-20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2-15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6-16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis.

Justification criteria for vertebral fractures: year 2012 revision.

Justification Criteria for Vertebral Fractures 2012 version was made based on new clinical findings. Major differences in this version compared to the 1996 version are inclusion of the semiquantitative method (SQ), statements to improve considerations during radiographic analysis, and the need for more detailed evaluation by MRI.

Number and severity of prevalent vertebral fractures and the risk of subsequent vertebral fractures in Japanese women with osteoporosis: results from the minodronate trial.

The aim was to evaluate the risk of new vertebral fractures with the increasing number and severity of prevalent vertebral fractures in women who received placebo or minodronate in a post hoc analysis of a 2-year randomized, double-blind, placebo-controlled study. The subjects were women aged 55-80 years old with 1-5 fragility fractures between the T4 and L4 vertebrae and bone mineral density <80 % of the young adult mean. A total of 704 subjects were randomized to take minodronate 1 mg (n = 359) or placebo (n = 345) once a day for 24 months. In the placebo group, the risk of incident vertebral fractures during the 2-year observational period was significantly related to the number and severity of prevalent vertebral fractures at baseline. The number of prevalent vertebral fractures was an independent risk factor for incident vertebral fracture in multivariate analysis. The relative risk reductions of vertebral fractures by minodronate treatment were 45.2, 61.1, and 64.2 % for patients with 1, 2, and ≥3 prevalent vertebral fractures, respectively, and 87.8, 64.6, and 50.1 % for patients with mild, moderate, and severe prevalent vertebral fractures, respectively. In conclusion, the number of prevalent vertebral fractures is an independent risk factor for incident vertebral fracture and minodronate reduces the fracture risk even in patients at a higher risk for fracture.