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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).

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.

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.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).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.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.

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. 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. 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 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.

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

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.

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.

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. 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. 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. 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.

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.

Introduction Denosumab inhibits bone resorption by binding to and inactivating RANK ligand (RANKL), a key mediator of osteoclast formation, maturation and activation. As in the pivotal phase 3 study, FREEDOM, in predominantly postmenopausal Caucasian women with osteoporosis the efficacy of denosumab was evaluated by the phase 3 study, DIRECT, in Japanese osteoporosis patients. The study showed that 2-year treatment of denosumab significantly reduced risk of new vertebral fracture by 74.0% compared to placebo. However, there have been no data showing actions on Japanese bone architecture. Objectives Here we evaluate the effect of denosumab to hip geometry by hip structural analysis using dual-energy X-ray absorptiometry (DXA) data in Japanese. Methods The images for 687 patients derived from DIRECT study were evaluable for HSA. DIRECT study consisted of a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase, in which all subjects received denosumab. Hip geometry was analyzed using Hologic Apex DXA software version 13.5 (Madison, WI). Measurements include: BMD as average pixel value in the profile, bone outer diameter, endocortical diameter, mineralized bone cross-sectional area, average cortical thickness, cross-sectional moment of inertia (CSMI) as BMD times square of the distance from the center of mass, section modulus as CSMI divided by Dmax (maximum distance between the center of the mass and the outer cortex), buckling ratio as the ratio of bone diameter to average cortical thickness, and Dmax. Percent changes from baseline in HSA parameters at each time point were analyzed using one-sample t-test. Comparisons between the treatment groups for the percent changes in HSA parameters at each time point were performed using a two-sample t-test. Results The images for 687 patients applicable to HSA were used in the present study. The baseline characteristics were similar to those in the total 952 participants. Compared to placebo, denosumab significantly increased BMD, 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. Conclusions The present study reveals 3-year effect of denosumab on the geometrical parameters of hip bone structure. The improving effects suggest underlying mechanism for anti-fracture effect of denosumab in Japanese.

BackgroundDeteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis.ObjectiveOur aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk.MethodsPatients 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.ResultsA 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 may be required to maintain patients’ QOL in osteoporosis.

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.

Eldecalcitol, a vitamin D3 analogue, significantly reduces the risk of new vertebral fractures and increases bone mineral density (BMD) more than does alfacalcidol. To determine the effect of eldecalcitol on the incidence of all fragility fractures caused by osteoporosis, we conducted post hoc analyses of the phase III clinical trial to evaluate the incidence of the osteoporotic fractures defined in the World Health Organization (WHO) Technical Report, and, also, the incidence of the major osteoporotic fractures utilized in the WHO Fracture Risk Assessment Tool (FRAX), and compared those in the eldecalcitol group with those in the alfacalcidol group. We also analyzed the incidence of osteoporotic fractures stratified by prespecified risk factors for fractures. Eldecalcitol treatment reduced the incidence of osteoporotic fractures defined by the WHO more than alfacalcidol treatment (18.6 % vs. 25.2 %; hazard ratio, 0.70; 95 % CI, 0.54-0.93). Prevalent vertebral fractures, two or more prevalent vertebral fractures, and total hip BMD T score less than -2.5 were the risk factors for new osteoporotic fractures with significant differences between the two treatments. Eldecalcitol also decreased the incidence of major osteoporotic fractures in the FRAX more than alfacalcidol (11.1 % vs. 16.3 %; hazard ratio, 0.66; 95 % CI, 0.46-0.94). In conclusion, treatment with eldecalcitol reduced the risk of fragility fractures caused by osteoporosis compared with alfacalcidol administration, which may result from a potent effect of eldecalcitol on BMD, bone structure, and bone turnover.

In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.

The present study aimed to evaluate the prevalence and clinical presentation of Paget's disease of bone (PDB) in Japan. As PDB is a very rare disease in Japan, a nationwide mail survey was conducted targeting doctors in the specialty most frequently diagnosing and treating PDB patients in Japan. First, the literature for all case reports in Japan published between January 1990 and December 2002 was reviewed to determine who was diagnosing and treating PDB in Japan. This literature review for all case reports in Japan revealed that 72.1% of cases in Japan were reported from departments of orthopedic surgery. A nationwide two-phase mail survey was conducted for the departments of orthopedic surgery of 2,320 general hospitals accredited by the Japanese Orthopaedic Association. Phase 1 involved determining how many patients with PDB were followed at each hospital. If the answer was one or more, phase 2 of the survey gathered information on the clinical presentation of current patients. The mail survey yielded a final response rate of 75.4% for phase 1 and 87.6% for phase 2. Phase 1 indicated that the prevalence of PDB in Japan is about 2.8 cases per million capita. Phase 2 revealed a slight female predominance, lower frequency of familial clustering, higher frequency of femoral fracture in the affected femur, and a higher ratio of symptomatic PDB in Japan compared with findings in countries displaying a higher prevalence of PDB. The present epidemiological study revealed that the disorder is extremely rare in Japanese individuals, and that some differences exist with regard to the clinical features of PDB between Japanese patients and patients from high-prevalence countries.

Summary In a 2-year randomized, placebo-controlled study of 665 Japanese patients with primary osteoporosis, once-yearly administration of zoledronic acid (5 mg) reduced the risk of new morphometric vertebral fractures. Introduction The purpose of this study was to determine the efficacy and safety of once-yearly intravenous infusion of ZOL in Japanese patients with primary osteoporosis. Methods This was a two-year multicenter, randomized, placebo-controlled, double-blind, parallel-group comparative study (ZONE Study). Subjects were 665 Japanese patients between the ages of 65 and 89 years who had prevalent vertebral fracture. Subjects were randomly assigned to receive once-yearly intravenous infusion of 5 mg of ZOL or placebo at baseline and 12 months. Results The 2-year incidence of new morphometric vertebral fracture was 3.0 % (10/330 subjects) in the ZOL group and 8.9 % (29/327) in the placebo group (p = 0.0016). The 24-month cumulative incidence of new morphometric vertebral fracture was 3.3 % in the ZOL group versus 9.7 % in the placebo group (log-rank test: p = 0.0029; hazard ratio: 0.35; 95 % confidence interval: 0.17–0.72). The cumulative incidence of any clinical fracture, clinical vertebral fracture, and non-vertebral fracture was significantly reduced in the ZOL group by 54, 70, and 45 %, respectively, compared to the placebo group. At 24 months, ZOL administration increased bone mineral density in the lumbar spine, femoral neck, and total hip (t test: p

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K

Context: Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density. Objective: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. Design and Setting: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. Patients: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. Intervention: Subjects were randomly assigned to receive once-weekly sc injections of teriparatide (56.5 μg) or placebo for 72 wk. Main Outcome Measure: The primary endpoint was the incidence of new vertebral fracture. Results: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. Conclusion: Weekly sc administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk., The Journal of clinical endocrinology & metabolism, 97(9), pp.3097-3106; 2012

The aim of this study was to evaluate the efficacy and safety of intravenous alendronate (ALN) 900 µg every 4 weeks compared to oral ALN 35 mg once weekly.A 52-week, multicenter, randomized, double-masked, active-controlled, parallel-group, non-inferiority study was conducted in a total of 325 Japanese patients aged 48-87 years with osteoporosis. Patients were randomly assigned to an intravenous ALN (iv, n = 162) group or oral ALN (po, n = 163) group. The efficacy of the both formulations was assessed primarily by bone mineral density (BMD) measurement.The percentage BMD change from baseline in lumbar spine (L2-L4) after 52 weeks of treatment was 6.4 ± 0.3% in the iv group and 6.0 ± 0.3% in the po group (least-squares mean ± SE). The inter-group difference in least-squares mean of percentage change from baseline in BMD was 0.37%, and its 95% confidence interval was -0.47% to 1.20%. The non-inferiority of the iv group was established against the po group with a prespecified non-inferiority margin (Δ) of 1.5%. In addition, the four bone turnover markers were reduced to a similar level by either treatment throughout the treatment period. The safety profile was also similar between the two treatment groups. Because of the limitations presented in this study, the results of the iv group may not apply to non-Japanese patients with osteoporosis.The efficacy and safety of the intravenous ALN 900 µg once every 4 weeks were similar to those of the oral ALN 35 mg once weekly, indicating that intravenous administration of ALN is an effective treatment for osteoporosis and will provide a useful alternative to oral dosing.

The objective of this study was to determine the safety and efficacy of long-term minodronate treatment in women with postmenopausal osteoporosis based on re-analysis of a phase III 2-year clinical trial with a 1-year extension. Women aged 55–80 years old with fragility fractures were enrolled and randomized to take 1 mg minodronate or placebo once a day in the original 2-year study. The subjects who completed the 2-year study were invited to participate in an additional 1-year extension in which all subjects were to receive minodronate. Finally, a total 380 subjects completed the extension study (186 from the placebo group and 194 from the minodronate group). Fracture results observed in the extension study were consistent with those observed in the first 2 years in minodronate group. In contrast, the placebo/minodronate group showed a decreased incidence of new vertebral fractures during year 3 compared to that in year 2. In the patients who received minodronate in the original 2-year study, lumbar bone mineral density (BMD) increased consistently during year 3 and bone turnover markers decreased within the first 6 months and remained constant thereafter over 3 years. Similar positive effects of minodronate on BMD and bone turnover markers occurred when therapy was initiated in the placebo/minodronate group. No new safety concerns observed during the extension period compared to the safety observations made during the 2-year study. It was concluded that daily administration of 1 mg oral minodronate is safe and well tolerated, and that the efficacy of this dose in reducing vertebral fracture risk in postmenopausal women over 2 years is sustained with continuing treatment.

BackgroundEldecalcitol is an analog of 1,25-dihydroxyvitamin D3 that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456.Methods and resultsThis 3year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75μg eldecalcitol versus 1.0μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (

Summary Monthly minodronate at 30 or 50 mg had similar efficacy as 1 mg daily in terms of change in bone mineral density (BMD) and bone turnover markers with similar safety profiles. This new regimen provides patients with a new option for taking minodronate. Introduction Minodronate at a daily oral dose of 1 mg has been proven to have antivertebral fracture efficacy. In the present study, the efficacy and safety of oral minodronate at monthly doses of either 30 mg or 50 mg were compared with a daily dose of 1 mg. Methods A total of 692 patients with involutional osteoporosis were randomized to receive minodronate at either 30 or 50 mg monthly or a daily dose of 1 mg. The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at 12 months. Total hip BMD, bone turnover markers, serum calcium (Ca), and parathyroid hormone (PTH) levels were also evaluated. Results Minodronate at monthly doses of 30 or 50 mg were noninferior to the 1 mg daily dose in terms of change in LS-BMD. Changes in total hip BMD were also comparable. Although a transient decrease in serum Ca and increase in PTH levels were observed in all three groups at slightly different magnitudes and time courses, changes in bone turnover markers were comparable among the differentdosage groups with a similar time course. Safety profiles were also comparable. Conclusion Minodronate at monthly doses of 30 or 50 mg has similar efficacy to the daily 1 mg dose in terms of BMD and bone turnover markers with similar tolerability., Osteoporosis International, 23(6), pp.1737-1745; 2012

Fibroblast growth factor 2 (FGF-2) is a potent mitogen for mesenchymal cells, and a local application of recombinant human FGF-2 (rhFGF-2) in a gelatin hydrogel has been reported to accelerate bone union in our animal studies and preparatory dose-escalation trial on patients with surgical osteotomy. We have performed a randomized, double-blind, placebo-controlled trial in which patients with fresh tibial shaft fractures of transverse or short oblique type were randomly assigned to three groups receiving a single injection of the gelatin hydrogel containing either placebo or 0.8 mg (low-dosage group) or 2.4 mg (high-dosage group) of rhFGF-2 into the fracture gap at the end of an intramedullary nailing surgery. Of 194 consecutive patients over 2 years, 85 met the eligibility criteria, and 70 (24 in the placebo group and 23 each in low- and high-dosage groups) completed the 24-week study. The cumulative percentages of patients with radiographic bone union were higher in the rhFGF-2-treated groups (p = .031 and .009 in low- and high-dosage group, respectively) compared with the placebo group, although there was no significant difference between low- and high-dosage groups (p = .776). At 24 weeks, 4, 1, and 0 patients in the placebo, low-dosage, and high-dosage groups, respectively, continued to show delayed union. No patient underwent a secondary intervention, and the time to full weight bearing without pain was not significantly different among the three groups (p = .567). There also was no significant difference in the profiles of adverse events among the groups. In conclusion, a local application of the rhFGF-2 hydrogel accelerated healing of tibial shaft fractures with a safety profile. © 2010 American Society for Bone and Mineral Research.

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

Dual-energy X-ray absorptiometry-based hip structural analysis was performed to evaluate the effect of a bisphosphonate, minodronic acid hydrate, on the geometry of the proximal femur in Japanese patients with osteoporosis. The subjects were 103 postmenopausal patients (average age 63.9 +/- 6.4 years) with primary osteoporosis. Minodronic acid hydrate was administered orally at a dose of 1 mg/day for 12 months. Significant early responses at 3-6 months after the start of administration were observed in all three regions of the proximal femur (narrow neck, intertrochanter, and shaft) in terms of bone density, geometry, and bone strength indices. The outcomes of therapy included a reduction of the internal diameter of the cortical bone (-0.1, -0.6, and -0.2% in the neck, intertrochanter, and shaft, respectively, at 12 months; not significant) and a significant increase in cortical thickness (3.1, 3.7, and 2.0% in the respective regions at 12 months). Furthermore, minodronic acid hydrate induced a significant enlargement of the cross-sectional bone area, which is related to compressive strength; a significant increase in cross-sectional moment of inertia and section modulus (SM 4.9, 5.8, and 2.9% in the neck, intertrochanter, and shaft, respectively, at 12 months; P < 0.001), which are related to the bending strength; and a significant reduction in buckling ratio (BR -3.0% (P < 0.001), -4.2% (P < 0.001), and -1.4% (P < 0.05) in the respective regions at 12 months), which reflects improved cortical stability. These findings show that minodronic acid hydrate reduces age-related endocortical bone resorption, leading to increased cortical thickness and sustained or enhanced bone strength., Journal of bone and mineral metabolism, 28(3), pp.334-341; 2010

人間が積極的に生きる能力を高めるためには，環境の変化に対応して，生きるための新たな知識を発見し，知識を進化させ続けることが肝要である．脳の情報処理の機能を維持し向上させて，新たな知識をまとめ上げ，知識を進化させるためには，『既存の領域的な知識をベースにして，新たな領域的な知識を探索し，それらを広域的な知識に組み換える』ことがポイントになる．

Many types of bone densitometry equipment are available in Japan, but the numbers of such machines and the numbers of institutions that offer bone densitometry have not been clarified. We analyzed the data from annual surveys conducted by the Japan Osteoporosis Foundation from 1996 to 2006, and we obtained the following results on the use of densitometry equipment: (1) In 1996 there were 6,687 units of bone densitometry equipment in 6,483 institutions in Japan; in 2006 there were 16,371 units in 15,020 institutions. (2) In 2006, of the types of institutions with bone densitometry equipment, the number of clinics was the highest, followed in order by general hospitals, other types of institutions, screening institutions and university hospitals. Rates of increase in the installation of equipment in clinics and other types of institutions were high during the 11-year period from 1996. (3) From 1996 to 2006 the region of interest most frequently used for bone densitometry was the radius. However, during the 11-year period, the proportion of radial densitometry equipment in all institutions with bone densitometry equipment decreased, whereas the proportion of calcaneal densitometry equipment increased. (4) The number of dual-energy X-ray absorptiometry (DXA) units was the highest from 1996 to 2006. However, the proportion of DXA machines in all institutions with bone densitometry equipment decreased over the 11-year period, whereas the proportion of quantitative ultrasound (QUS) machines increased. (5) In 2006, bone densitometry equipment was available in 118 institutions per million Japanese people. Central DXA (spine/hip) equipment was available in 15 per million, radial DXA equipment in 63 per million, and calcaneal QUS equipment in 44 per million. (6) In 2006, among those places with bone densitometry equipment, 46% of university hospitals, 14% of general hospitals, 12% of screening institutions, 5% of clinics, and 6% of other types of institutions possessed more than one type of densitometry equipment. (7) In 2006, central DXA (spine/hip) was frequently available in university hospitals, radial densitometry equipment in general hospitals and clinics, and calcaneal densitometry equipment in screening institutions and other types of institutions.

To retrospectively evaluate the influence of postbiopsy hemorrhage on the accuracy of tumor detection at T2-weighted magnetic resonance (MR) imaging, dynamic contrast material-enhanced MR imaging, and diffusion-weighted (DW) MR imaging of prostate cancer, with histologic findings as the reference standard.The institutional review board approved this study and waived the requirement for informed consent. Forty male patients aged 62-84 years (mean age, 71 years) who had prostate cancer underwent MR imaging of the prostate gland after ultrasonographically (US) guided systematic 12-core-specimen biopsy. The mean time between biopsy and MR imaging was 24 days (range, 6-54 days). T1-weighted, T2-weighted, dynamic contrast-enhanced, and DW imaging examinations were performed at 1.5 T. The prostate was divided, according to the biopsy sites, into eight regions on the MR images. Three reviewers in consensus evaluated each region for hemorrhage and prostate cancer. Statistical evaluations were performed with Mann-Whitney U, Ryan, and Spearman rank correlation tests.Intraglandular hemorrhage was observed in 38 (95%) patients and significantly more often in the peripheral zone (PZ) than in the transition zone (TZ) (P.001). Degree of hemorrhage did not correlate significantly (P = .536) with time between biopsy and MR imaging. The sensitivity, specificity, and accuracy of combined T2-weighted, dynamic contrast-enhanced, and DW imaging in the diagnosis of prostate cancer were 69%, 85%, and 78%, respectively. Sensitivity and specificity were lower for the TZ than for the PZ. Degree of hemorrhage was significantly lower in regions of positive biopsy findings than in regions of negative biopsy findings (P = .001) and correlated negatively with tumor size (P = .043).Interpretation of combined T2-weighted, dynamic contrast-enhanced, and DW MR image findings can yield reasonable diagnostic accuracy in both the PZ (80% [191 of 240 regions]) and the TZ (74% [59 of 80 regions]).

人間の営みが依存している科学という『知』の探究には、必然的な推論の観点に重きを置くところの分析的な『貫く知』のプロセスの研究と蓋然的・構成的な推論の観点に重きを置くところの統合的な『連ねる知』のプロセスの研究がある。サステイナブルな生存には、それらが対立し相克しないでバランスよく進展しなければならない。『知』の部分への分析と全体への統合を調和させる『融合学』ともいうべき、科学の知の構造化を目差して探求し続けなければならない。

Purpose To identify age-related changes and differences in the diffusion of water molecules within the prostate, through diffusion-weighted imaging (DWI) of the prostate gland in healthy adult Japanese men. Materials and Methods A total of 114 healthy male volunteers (mean age, 55 years; range, 24–81 years) underwent DWI of the prostate with a single-shot echo-planar imaging (EPI) sequence using b-factors of 0 and 1000 seconds/mm2. Apparent diffusion coefficient (ADC) values of six locations in the peripheral zone (PZ) and two locations in the central gland (CG) were measured and correlations between region and age were examined. Results ADC values measured within both PZ and CG regions of the prostate showed a uniform distribution, and no significant differences were found between evaluated regions. However, mean ADC values were 1.64 ± 0.27 ×10−3 mm2/second for PZ and 1.26 ± 0.12 ×10−3 mm2/second for CG, representing a significant difference. In addition, significant positive correlations were identified between ADC values for both PZ and CG regions and subject age (r = 0.526, P < 0.0001; r = 0.190, P = 0.0431, respectively). Conclusion ADC values within both PZ and CG regions of the prostate increase with age, and this must be taken into consideration when using DWI in the diagnosis of prostate cancer. J. Magn. Reson. Imaging 2008. © 2008 Wiley-Liss, Inc.

Advanced glycation end products (AGE) in collagen have been reported to decrease the mechanical property of bone. However, there are no available data on the relation between fracture risk and levels of glycoxidative (nonenzymatic) cross-links of collagen in clinical samples. A total of 432 Japanese elderly women who were not receiving any drug treatment for osteoporosis were selected and followed for 5.2 +/- 3.3 (mean +/- SD) years for this observational study. Vertebral fractures and bone mineral density were assessed at baseline and then at 1- to 2-year intervals or at indication of any symptom. Two types of collagen metabolites were measured at baseline: urinary N-terminal telopeptide of type I collagen (NTX), a marker of pyridinium cross-link, and urinary pentosidine, a nonenzymatic collagen cross-link produced by AGEs. A total of 97 incident vertebral fractures on 72 subjects were observed. Simple regression analysis using Cox's hazards model showed that log-transformed urinary NTX and pentosidine are significant risk factors for time-dependent incidence of vertebral fractures, in addition to the traditional risk factors (age, lumbar bone mineral density, and number of prevalent vertebral fractures). However, urinary excretion of pentosidine (hazard ratio, 1.33; 95% CI, 1.01-1.76, P = 0.04) was a significant predictor of incident vertebral fracture after adjustment for other traditional risk factors. The present data suggest that AGE-related collagen cross-link is a novel risk for vertebral fracture.

地球規模の問題群に真に対処するためには、自己や人間などの＜この部分域＞を最適にすることと、他者や環境などの＜あの部分域＞をも含む、＜全体域＞を最適にすることを、矛盾なく両立させるような広域的な知を発見して、より高次の領域的な知を確立し、営みと営みの間にLatticeという融合の構造を作ることが必要である。そのために、人間の経験や学習の深さと広さを拡充して、アブダクションAbductionを実現する能力を進化させなければならない。

We here propose guidelines for the diagnosis and management of Paget's disease of bone (PDB) in Japan. These guidelines provide basic information on the epidemiology, pathophysiology, clinical signs and symptoms, diagnosis, indications for treatment, and available therapy, including orthopedic surgery. PDB is a chronic disorder characterized by focal abnormalities of bone turnover. The characteristic feature of PDB is excessive osteoclastic bone resorption coupled to increased and disorganized bone formation. The most common symptom of PDB is pain in involved bones. The most serious complication of PDB is malignant bone or soft-tissue tumor. PDB is uncommon in Japan; our survey in 2003 found 169 patients with PDB. The prevalence of PDB in Japan is 0.15/100 000; in patients aged 55 years or more, the proportion reaches 0.41/100 000. A careful medical history and physical examination are essential for the diagnosis. The diagnosis of PDB is based on finding the typical features on radiographs. Bone scintigraphy and measurement of serum alkaline phosphatase are sensitive means of screening for PDB. Since PDB is a rare disease in Japan, bone biopsy is quite often used to exclude bone metastases. The only evidence-based indication for treatment of PDB is pain in involved bones. In Japan, etidronate and calcitonin are approved by the Ministry of Health, Labour and Welfare for treating PDB, but currently risedronate is also under development for treating PDB in Japan. Indications for surgical intervention in PDB include unstable fractures, osteoarthritis, malignant soft-tissue tumor, osteosarcoma, and bone deformity.

The effects of dietary lactosucrose on calcium absorption from the intestine and calcium accumulation in bones were investigated in growing female rats. The apparent calcium-45 ((45)Ca) absorption, residual (45)Ca ratio in the body, and (45)Ca accumulation in the femur and tibia of lactosucrose-supplemented rats were significantly higher than in control rats 24 h after the administration of a (45)CaCl(2) solution.

The importance of physical activity in the development and maintenance of bone mineral density (BMD) is widely accepted. However, the effects on cortical BMD have not been clarified in detail. The present study examined bilateral asymmetries in cortical BMD of the tibia using peripheral quantitative computed tomography. Subjects comprised 37 young male athletes and 57 controls (age range, 18-28 years). BMD and geometrical indices were determined in bilateral tibiae. Cortical and trabecular BMD were calculated at the diaphysis and distal metaphysis, respectively. Cortical width, periosteal cross-sectional area, and cross-sectional moment of inertia were calculated using tomographic data of the tibial diaphysis. In athletes, the non-dominant leg showed greater cortical BMD than the dominant leg (mean difference, 5.42%; P < 0.0001). Cortical width and moment of inertia were also greater in the non-dominant leg. Periosteal area displayed no significant difference between legs. The control group exhibited similar results except for cortical BMD. No differences in trabecular BMD were noted between legs in either athletes or controls. These results implies the existence of mechanisms for the mechanical adaptation of cortical BMD. Dominant leg is used for mobility or manipulation whereas the non-dominant leg contributes to support the actions of the dominant leg. Loading differences in bilateral legs in young athletes might affect the remodeling rate leading to the side-to-side differences in cortical BMD.

In drug developments for osteoporosis, large-scale and longterm fracture prevention studies have been required. We investigated whether or not it was possible to reduce the sample size and observation period under new selection criteria for an osteoporotic fracture-prevention study. A Poisson regression model was used to identify independent risks for incident vertebral fracture in 515 postmenopausal women who had had no intervention for osteoporosis; this group was a subset of Nagano Cohort participants. The total observation period for this group was 2,577 person-years, and a total of 146 new vertebral fractures were observed. Risk assessment for incident vertebral fracture among numerical covariates revealed that the following items showed significant independent risks for incident fractures; namely, baseline age (hazard ratio [HR]; 1.84; 95% confidence interval (CI), 1.44-2.35; P < 0.001), number of preexisting vertebral fractures (HR, 1.28; 95% CI, 1.17-1.40; P < 0.001), baseline lumbar bone mineral density (LBMD) (HR, 0.79; 95% CI, 0.71-0.88; P < 0.001), and urinary excretion of deoxypyridinoline (DPD) (HR, 1.18; 95% CI, 1.03-1.35; P = 0.016). Because the initial urinary excretion of DPD was found to be a risk for incident vertebral fracture, in addition to the conventional risks, we assessed whether or not the sample size or observation period could be reduced by the incorporation of the urinary excretion of DPD into the selection criteria of a fracture-prevention study. The assessment of sample size was calculated, using the log rank test, at a two-tailed significance level of 5% and with a power of 80%. When osteoporotic patients with preexisting fracture were selected (conventional criteria), the 3-year probability of vertebral fracture was estimated as 14.3% in the present population. On the other hand, the new vertebral fracture rate during 3 years in the osteoporotic patients with preexisting fracture plus high urinary DPD (HR, above 1.0); (new selection criteria) was estimated as 23.2%. When the HR between test drug and placebo was changed from 0.4 to 0.8, the required sample size for any level of HR showed a 40% reduction for the new selection criteria compared to the conventional criteria. Therefore, the addition of urinary DPD level to the selection criteria is useful to reduce sample size in an osteoporosis fracture-prevention study.

This study determined the effect of long-term administration of 4(G)-beta-D-galactosylsucrose (lactosucrose; LS) on intestinal calcium absorption. In a randomized, single-blind, parallel-group study, LS (n=9, 6.0 g twice daily) or a placebo (maltose; n=8, 6.0 g twice daily) was administered to healthy young women for 92 wk: the study also included a 4-wk post-administration period. All participants completed the study. Dietary nutrient intake; fecal weight, pH, and moisture content; fecal concentrations of short-chain fatty acids (SCFA), putrefactive products, ammonia, and minerals (calcium, magnesium, phosphorus, and iron); and serum calcium and osteocalcin concentrations were measured every 24 wk. Urinary pyridinoline (PYR) and deoxypyridinoline (DPD), and urinary calcium excretion were measured every 12 wk. Significant effects of oligosaccharide treatment, time, and the interaction between oligosaccharide treatment and time were observed for fecal pH, SCFA, ammonia, and putrefactive product values (p0.05). Fecal pH, ammonia, and putrefactive product values decreased in the LS group, and the fecal SCFA concentration significantly increased during the administration period; these changes were not observed 4 wk post-administration. To examine the mineral balance of calcium, magnesium, and phosphorus in detail, all the participants completed a 6-d mineral balance study, sometime between week 56 and 60 of the longer study. During the mineral balance study, the daily calcium intake was set at 400 mg; all feces and urine were collected each day for 6 d after an 8-d acclimation period. In the balance study, fecal calcium excretion was significantly lower in the LS group than in the placebo group (p0.05), and apparent calcium absorption and retention, apparent magnesium and phosphorus absorption, and magnesium retention were significantly higher in the LS group than in the placebo group (p0.05). Our results suggest that the administration of LS produces a long-term enhancement of intestinal calcium absorption in healthy young women with lower than recommended calcium intakes.

To recover the damaged environment and ecosystem of the earth, we should search and discover broader domain knowledge which is common among different domain knowledges, and through it, we should maintain continuity between every diverse activities of human beings to live, that is, we have to let those activities not be inconsistent with each other to economize the amount of resource and energy.The characteristic of brain's information processing function is maintaining continual understanding and practice to the living environment by the process to realize concurrent optimization of each part and the whole between plural diverse and different domain knowledges in order to discover common broader domain knowledge to put it into practice.

Purpose: In this study, we investigated the usefulness of T1-weighted sagittal MR images at the lumbar vertebrae in the vertebral morphometry, in comparison with lateral radiographs. Subjects and methods: The subjects were 42 men (mean age: 53.0 years) and 41 women (mean age: 57.9 years). Both MRI and radiography of the lumbar spine were performed within 1 month. The vertebral body heights and their ratios were measured by the semi-automatic measuring system. The frequency of a vertebral fracture and the absolute value of vertebral body height in both morphometry were compared. Results: Based on the criteria for prevalent vertebral fracture using vertebral height ratios, the vertebrae were classified into four groups. Group 1 was defined as the vertebrae without fracture (n = 347 vertebrae). Groups 2–4 were defined as the vertebrae with fracture; Group 2 by both MRI and X-ray morphometry (n = 17), Group 3 by MRI morphometry alone (n = 17), and Group 4 by X-ray morphometry alone (n = 4). The rate of prevalent vertebral fracture diagnosed by MRI morphometry (8.8%) was higher than that by X-ray morphometry (5.5%). In Group 1, the values of anterior and posterior vertebral height obtained by MRI morphometry were greater than those obtained by X-ray morphometry. On the other hand, the values of central vertebral height obtained by MRI morphometry were smaller than those obtained by X-ray morphometry. Conclusion: Severe biconcave deformity of vertebra can be detected by both MRI and X-ray morphometry, although mild biconcave deformity can be detected only by MRI morphometry.

A number of prospective studies in the USA and Europe have demonstrated that quantitative ultrasound (QUS) measurements predict fracture risk. To our knowledge, there has been no such study in a Japanese population, and very few studies have measured the prognostic value of QUS measurements among men, even in the USA and Europe. We performed a three-center prospective study to investigate the relationship between baseline heel QUS measurements and non-spine fracture risk. There were 4,028 subjects (1,004 men and 3,024 women), 67.5+/-8.9 years [mean +/- standard deviation (SD)] of age), who underwent heel QUS (Achilles device) at three centers between 1993 and 2000. In 2002, the subjects were mailed a standardized questionnaire that asked about their history of fracture. The mean follow-up period was approximately 5 years. The Achilles measured speed of sound (SOS) and broadband ultrasound attenuation (BUA). We used Cox regression analysis to determine the hazard ratio (HR), using weighted coefficients. SOS, BUA, and stiffness index (SI) predicted self-reported hip, wrist, and total non-spine fractures. After we had adjusted for age, gender, and weight, the HRs of total non-spine fracture were 1.54 [95% confidence interval (CI) 1.39-1.69], 1.53 (1.37-1.70), and 1.80 (1.62-1.98) for 1 SD decrease in SOS, BUA, and SI, respectively. In men, SOS and SI also predicted total non-spine fractures with HRs similar to those in women. The HR of prediction for hip fracture by SOS and SI was better in the short term than in the long term, and the prediction for hip, wrist, and non-spine fracture remained significant between 5 to 10 years of follow-up. Measurements obtained from heel QUS predicted non-spine fracture in Japanese men and women, and the HRs of Japanese of both genders was similar to the risk ratio (RR) of Caucasian men and women. QUS parameters can predict hip, wrist, and non-spine fracture up to 10 years.

Many analyses of bone microarchitecture using three-dimensional images of micro CT (microCT) have been reported recently. However, as extirpated bone is the subject of measurement on microCT, various kinds of information are not available clinically. Our aim is to evaluate usefulness of fractal dimension as an index of bone strength different from bone mineral density in in-vivo, to which microCT could not be applied. In this fundamental study, the relation between pixel size and the slice thickness of images was examined when fractal analysis was applied to clinical images. We examined 40 lumbar spine specimens extirpated from 16 male cadavers (30-88 years; mean age, 60.8 years). Three-dimensional images of the trabeculae of 150 slices were obtained by a microCT system under the following conditions: matrix size, 512 x 512; slice thickness, 23.2 em; and pixel size, 18.6 em. Based on images of 150 slices, images of four different matrix sizes and nine different slice thicknesses were made using public domain software (NIH Image). The threshold value for image binarization, and the relation between pixel size and the slice thickness of an image used for two-dimensional and three-dimensional fractal analyses were studied. In addition, the box counting method was used for fractal analysis. One hundred forty-five in box counting was most suitable as the threshold value for image binarization on the 256 gray levels. The correlation coefficients between two-dimensional fractal dimensions of processed images and three-dimensional fractal dimensions of original images were more than 0.9 for pixel sizes < or =148.8 microm at a slice thickness of 1 mm, and < or =74.4 microm at one of 2 mm. In terms of the relation between the three-dimensional fractal dimension of processed images and three-dimensional fractal dimension of original images, when pixel size was less than 74.4 microm, a correlation coefficient of more than 0.9 was obtained even for the maximal slice thickness (1.74 mm) examined in this study.

Bone strength depends on bone quality (architecture, turnover, damage accumulation, and mineralization) as well as bone mass. In this study, human bone architecture was analyzed using fractal image analysis, and the clinical relevance of this method was evaluated. The subjects were 12 healthy female controls and 16 female patients suspected of having osteoporosis (age range, 22-70 years; mean age, 49.1 years). High-resolution CT images of the distal radius were acquired and analyzed using a peripheral quantitative computed tomography (pQCT) system. On the same day, bone mineral densities of the lumbar spine (L-BMD), proximal femur (F-BMD), and distal radius (R-BMD) were measured by dual-energy X-ray absorptiometry (DXA). We examined the correlation between the fractal dimension and six bone mass indices. Subjects diagnosed with osteopenia or osteoporosis were divided into two groups (with and without vertebral fracture), and we compared measured values between these two groups. The fractal dimension correlated most closely with L-BMD (r=0.744). The coefficient of correlation between the fractal dimension and L-BMD was very similar to the coefficient of correlation between L-BMD and F-BMD (r=0.783) and the coefficient of correlation between L-BMD and R-BMD (r=0.742). The fractal dimension was the only measured value that differed significantly between both the osteopenic and the osteoporotic subjects with and without vertebral fracture. The present results suggest that the fractal dimension of the distal radius can be reliably used as a bone strength index that reflects bone architecture as well as bone mass.