Circulating α-Klotho Counteracts Transforming Growth Factor-ß-Induced Sarcopenia.

α-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. α-Klotho has two forms: membrane α-Klotho and circulating α-Klotho (c-α-Klotho). Loss of membrane α-Klotho impairs a phosphaturic effect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-α-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-α-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-ß effector, became activated in skeletal muscle. Moreover, c-α-Klotho suppressed muscle-wasting TGF-ß molecules, including myostatin, growth and differentiation factor 11, activin, and TGF-ß1, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-α-Klotho reversed impaired in vitro myogenesis caused by these TGF-ßs. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-ßs, restored muscle atrophy and weakness in α-Klotho (-/-) mice and in elderly wild-type mice by suppression of activated Smad2 and up-regulated Cdkn1a (p21) transcript, a target of phosphorylated Smad2. Ki26894 also induced the slow to fast myofiber switch. These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-ß-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-ß blockade to prevent sarcopenia.

Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Impact of bone mineral density in reducing fracture risk in patients receiving alendronate plus alfacalcidol therapy.

BACKGROUD: Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. METHODS: We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. RESULTS: The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. CONCLUSIONS: The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

Randomized head-to-head comparison of minodronic acid and raloxifene for fracture incidence in postmenopausal Japanese women: the Japanese Osteoporosis Intervention Trial (JOINT)-04.

AIMS: We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. METHODS: The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients' quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. RESULTS: A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78-1.13, p = .494), 0.86 (95% CI: 0.70-1.05, p = .147), and 1.22 (95% CI: 0.86-1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p<.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively. CONCLUSIONS: Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

Executive summary of the Japan Osteoporosis Society Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

With the aging of society, the number of osteoporosis-related fractures is increasing. Prevention of osteoporosis and maintenance of the quality of life of osteoporosis patients require early diagnosis, effective treatment, and highly precise treatment monitoring. Although bone biopsy is clinically one of the essential techniques for diagnosis of osteoporosis, it is invasive and difficult to perform in general clinical practice. Bone mineral density measurement is another essential technique available in clinical practice that provides good precision. However, it is not effective for determining the appropriate treatment options or evaluating short-term treatment efficacy. On the other hand, bone turnover markers (BTMs) have gained attention because they provide information that is valuable for both the selection of treatment and short-term monitoring. BTMs are now positioned to become a tool for clinically assessing bone turnover outcomes. Since the Japan Osteoporosis Society issued its Guidelines for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis in 2012, new drugs, drug formulations, and combination drug therapies have been approved; therefore, we updated the 2012 guidelines in the Guide for the Use of Bone Turnover Markers in the Diagnosis and Treatment of Osteoporosis (2018 Edition).

Study design of multi-center, open-label randomized controlled, head-to-head trial comparing minodronic acid and raloxifene: Japanese Osteoporosis Intervention Trial (JOINT)-04.

We planned to conduct multi-center, open-labeled, blinded-endpoints, head-to-head randomized trial of minodronate and raloxifene to compare incidences of vertebral and non-vertebral fractures. The study is the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-4). Here, we present the pre-fixed study design. The inclusion criteria are ambulatory older women with osteoporosis, aged > 60 years, and without pre-specified risk factors for secondary osteoporosis and dementia. The subjects who meet selection criteria will be randomly allocated to the raloxifene (60 mg/day) or minodronate (1 mg/day or 50 mg/4 weeks) groups using the central registry. The co-primary endpoints are osteoporotic (vertebral, humeral, femoral, and radial), vertebral, and major osteoporotic (clinical vertebral, humeral, femoral, and radial) fractures. Furthermore, we plan to use the Hochberg procedure to preserve an overall type 1 error rate. In addition, changes in bone mineral density (BMD), hip-structure analysis (HSA) variables, height, bone turnover markers, serum cholesterol and triglyceride concentrations, dental health questionnaire, fall frequency, fall risk index, nursing care level, physical function, quality of life (QOL), and safety profiles were assessed as secondary endpoints. To detect 24% reduction of major osteoporotic fractures with 80% power and a two-sided significance level of 5% with a 2-year observation period, 1734 patients/treatment arm would be required. Subgroup analysis stratified to the following factors age, body mass index, BMD, 25-hydroxyvitamin D concentration, estimated glomerular filtration rate (eGFR), prevalent vertebral fracture number, hypertension status, and diabetes mellitus is pre-specified. The protocol is registered in the trial registry system, and the trial identification number is UMIN000005433.

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.

Attempt at standardization of bone quantitative ultrasound in Japan.

Dual X-ray absorptiometry (DXA) is used to diagnose osteoporosis. On the other hand, quantitative ultrasound (QUS) is widely used to assess bone density as part of medical screening as it is relatively inexpensive and easy to perform. Current QUS devices do not share precise ultrasound-related parameters, such as frequency, waveform, beam pattern, transient response, definition of propagation time, definition of degree of attenuation, and precise measurement site, resulting in different measurements across models. The Japan Osteoporosis Society established a QUS Standardization Committee in 2007 to investigate standardization of speed of sound (SOS) and broadband ultrasonic attenuation (BUA) measurements to resolve this issue. The committee came up with a formula to convert SOS and BUA values yielded by each model available in Japan. This has made it possible to convert QUS measurements from different models into standardized values, greatly improving the effectiveness of QUS measurements.

Erratum to: Attempt at standardization of bone quantitative ultrasound in Japan.

In the original version of the article, the third author name was incorrectly published. The correct name is Kosei Yoh.

Effects of 3-year denosumab treatment on hip structure in Japanese postmenopausal women and men with osteoporosis.

Denosumab, a human monoclonal antibody against RANK ligand, is shown to have strong anti-fracture effects in Japanese osteoporosis patients. However, there have been no data showing actions on Japanese bone architecture. Here we show that denosumab continuously improves several geometrical parameters calculated by hip structural analysis for 3 years. Compared to placebo, denosumab significantly increased bone mineral density, cortical thickness and cross sectional area in all of the three analyzed areas: the narrow neck, intertrochanter and femoral shaft. The subsequent derived mechanical parameters, cross-sectional moment of inertia, section modulus and buckling ratio, were also improved by denosumab. In addition, the improvement of these parameters was also observed in the patients that had switched from placebo to denosumab treatment. The present study suggests the structural evidence explaining the strong anti-fracture efficacy of denosumab and its significant effects on cortical bone in Japanese.

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.

Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p < 0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K2 group than in the risedronate alone group (10.0 % vs 6.7 %). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention.

Effect of swimming exercise on three-dimensional trabecular bone microarchitecture in ovariectomized rats.

Swimming is generally considered ineffective for increasing bone mass in humans, at least compared with weight-bearing sports. However, swimming exercise has sometimes been shown to have a strong positive effect on bone mass in small animals. This study investigated the effects of swimming on bone mass, strength, and microarchitecture in ovariectomized (OVX) rats. OVX or sham operations were performed on 18-wk-old female Fisher 344 rats. Rats were randomly divided into four groups: sham sedentary (Sham-CON), sham swimming exercised (Sham-SWI), OVX sedentary (OVX-CON), and OVX swimming exercised (OVX-SWI). Rats in exercise groups performed swimming in a water bath for 60 min/day, 5 days/wk, for 12 wk. Bone mineral density (BMD) in right femurs was analyzed using dual-energy X-ray absorptiometry. Three-dimensional trabecular architecture at the distal femoral metaphysis was analyzed using microcomputed tomography (µCT). Geometrical properties of diaphyseal cortical bone were evaluated in the midfemoral region using µCT. The biomechanical properties of femurs were analyzed using three-point bending. Femoral BMD was significantly decreased following ovariectomy. This change was suppressed by swimming. Trabecular bone thickness, number, and connectivity were decreased by ovariectomy, whereas structure model index (i.e., ratio of rod-like to plate-like trabeculae) increased. These changes were also suppressed by swimming exercise. Femurs displayed greater cortical width and maximum load in SWI groups than in CON groups. Together, these results demonstrate that swimming exercise drastically alleviated both OVX-induced decreases in bone mass and mechanical strength and the deterioration of trabecular microarchitecture in rat models of osteoporosis.

Effects of different types of jump impact on trabecular bone mass and microarchitecture in growing rats.

Substantial evidence from animal studies indicates that jumping increases bone mass and strength. However, most studies have focused on the take-off, rather than the landing phase of jumps. Thus, we compared the effects of landing and upward jump impact on trabecular bone mass and microarchitecture. Male Wistar rats aged 10 weeks were randomly assigned to the following groups: sedentary control (CON), 40-cm upward jumps (40UJ); 40-cm drop jumps (40DJ); and 60-cm drop jumps (60DJ) (n = 10 each). The upward jump protocol comprised 10 upward jumps/day, 5 days/week for 8 weeks to a height of 40 cm. The drop jump protocol comprised dropping rats from a height of 40 or 60 cm at the same frequency and time period as the 40UJ group. Trabecular bone mass, architecture, and mineralization at the distal femoral metaphysis were evaluated using microcomputed tomography. Ground reaction force (GRF) was measured using a force platform. Bone mass was significantly higher in the 40UJ group compared with the DJ groups (+49.1% and +28.3%, respectively), although peak GRF (-57.8% and -122.7%, respectively) and unit time force (-21.6% and -36.2%, respectively) were significantly lower in the 40UJ group. These results showed that trabecular bone mass in growing rats is increased more effectively by the take-off than by the landing phases of jumps and suggest that mechanical stress accompanied by muscle contraction would be more important than GRF as an osteogenic stimulus. However, the relevance of these findings to human bone physiology is unclear and requires further study.

The effects of once-weekly teriparatide on hip geometry assessed by hip structural analysis in postmenopausal osteoporotic women with high fracture risk.

Weekly administration of teriparatide has been shown to reduce the risk of vertebral and non-vertebral fractures in patients with osteoporosis at higher fracture risk in Japan. However, its efficacy for hip fracture has not been established. To gain insight into the effect of weekly teriparatide on the hip, hip structural analysis (HSA) based on dual-energy X-ray absorptiometry (DXA) was performed using the data of 209 postmenopausal osteoporotic women who had participated in the original randomized, multicenter, double-blind, placebo-controlled trial assessing the effects of once-weekly 56.5 µg teriparatide for 72 weeks. The DXA scans, obtained at baseline, 48 weeks and 72 weeks, were analyzed to extract bone mineral density (BMD) and cross-sectional geometrical indices at the narrowest point on the neck (NN), the intertrochanteric region (IT), and the proximal shaft. Compared with placebo after 72 weeks, the teriparatide group showed significantly higher BMD, average cortical thickness, bone cross-sectional area, and section modulus, and lower buckling ratio at both the NN and IT regions. No significant expansion of periosteal diameter was observed at these regions. There were no significant differences in BMD and HSA indices at the shaft region. The results indicate that overall structural strength in the proximal femur increased compared to placebo, suggesting that once-weekly teriparatide effectively reverses changes in hip geometry and strength with aging.

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.

Serum 25-hydroxyvitamin D level as an independent determinant of quality of life in osteoporosis with a high risk for fracture.

BACKGROUND: Deteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis. OBJECTIVE: Our aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk. METHODS: Patients were osteoporotic women aged ≥70 years and with ≥1 risk factor for incident fracture, namely prevalent osteoporotic fracture, bone mineral density (BMD) >-3.0 SD of young adult mean, or high bone turnover marker. Health-related QOL was assessed using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL). When patients were classified into quartiles by total QOL score). Serum 25-hydroxyvitamin D (25[OH]D) level was measured by immunoassay. RESULTS: A total of 1585 osteoporotic women were included in the study (age range, 70-95 years). Age, body mass index, serum 25(OH)D status (low, normal, or high), bone mineral density, number of prevalent vertebral fractures, presence of hypertension, presence of osteoarthritis, and history of falls were significantly correlated with QOL quartile. Multivariate liner regression analysis indicated that low serum 25(OH)D level (<20 ng/mL) was an independent determinant of total QOL score quartile (P = 0.0055). The conventional determinants of QOL-age (P < 0.0001), body mass index (P = 0.0060), number of prevalent vertebral fractures (P < 0.0001), presence of osteoarthritis (P = 0.0074), and history of fall (P = 0.0098)-were also independent determinants of total QOL score. CONCLUSIONS: These results strongly suggest that low serum 25(OH)D level was a significant determinant of QOL in these osteoporotic women, independently of the conventional factors that reduce QOL. Maintenance of serum 25(OH)D levels >20 ng/mL may be required to maintain patients' QOL in 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.

Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03).

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

Once-Weekly Injection of Low-Dose Teriparatide (28.2 µg) Reduced the Risk of Vertebral Fracture in Patients with Primary Osteoporosis.

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.