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.

Distinct dietary risk factors for incident osteoporotic fractures in early and late postmenopausal phase women.

INTRODUCTION: Available evidence on favorable nutritional factors for preventing osteoporosis remains controversial. Considering the recent increases in life expectancy, we investigated the relationship between incident osteoporotic fractures and dietary habits in early and late postmenopausal phase women. MATERIALS AND METHODS: Subjects were Japanese postmenopausal outpatients recruited at a primary care institution in Nagano Prefecture (Nagano Cohort Study). Patients with critical or acute illness or secondary osteoporosis were not included in this study. In total, 1,071 participants were prospectively followed for a mean of 5.8 years. The cohort was divided into early (≤ 70 years) and late (> 70 years) postmenopausal phases based on median age. Dietary nutrient intake was estimated by the food frequency questionnaire method. According to baseline nutrient intake characteristics, we focused on protein/energy and Ca/NaCl intake ratios, which were also divided by the median values. RESULTS: Kaplan-Meier plots revealed a significantly higher occurrence of fractures for the high protein/energy intake group in early postmenopausal subjects (P = 0.009), whereas the low Ca/NaCl intake group in late postmenopausal subjects exhibited a significantly earlier occurrence of fractures (P = 0.002). Multivariate Cox regression uncovered significant independent risks of higher protein/energy (HR 1.35; 95% CI 1.04-1.74) and lower Ca/NaCl (HR 0.79; 95% CI 0.63-0.99) intake ratios for incident osteoporotic fractures in the early and late postmenopausal cohorts, respectively. CONCLUSION: Distinct dietary risk factors for osteoporotic fractures were identified in early and late postmenopausal phase women. Appropriate nutritional guidance according to patient age will be important for maintaining bone health and quality of life.

Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks. MATERIALS AND METHODS: Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups. RESULTS: Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13-0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40-2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study. CONCLUSION: Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

Relationship Between Changes in Serum Levels of Intact Parathyroid Hormone and Sclerostin After a Single Dose of Zoledronic Acid: Results of a Phase 1 Pharmacokinetic Study.

Although changes in serum sclerostin levels at 12 months after infusion of zoledronic acid have been reported, the changes in sclerostin levels at earlier time points are poorly understood. We reanalyzed the study data of a previous phase 1 pharmacokinetic study and investigated the correlation between changes in sclerostin levels and relevant factors in calcium metabolism. A total of 24 Japanese female subjects with primary postmenopausal osteoporosis were administered a single 4- or 5-mg dose of zoledronic acid. Serum and urine samples were collected on days 15, 29, 90, 180, and 365 after administration. Serum levels of calcium, phosphate, intact parathyroid hormone (iPTH), and sclerostin were measured. Levels of serum sclerostin were unchanged from baseline on days 15 and 29, but increased significantly on day 90, subsequently decreased significantly on day 180, and returned to baseline levels on day 365. A significant negative correlation was observed between changes in iPTH levels at early time points and sclerostin levels at later time points. This suggests that sclerostin was negatively regulated by iPTH, and the decrease in sclerostin may indicate the start of bone formation during later time points after zoledronic acid injection.

Association of pentosidine and homocysteine levels with number of teeth present in Japanese postmenopausal women.

INTRODUCTION: Little is known about whether substances inducing tissue protein degeneration in the oral cavity are associated with the number of teeth present in postmenopausal women. We sought to investigate the association of urinary pentosidine and serum homocysteine levels with the number of teeth and subsequent tooth loss in Japanese postmenopausal women. MATERIALS AND METHODS: Among participants in the Nagano Cohort Study, 785 postmenopausal women (mean age, 68.1 years) participated in the present study. The number of teeth was re-counted at the time of follow-up in 610 women. Poisson regression analysis was used to investigate differences in the number of teeth among quartiles of pentosidine or homocysteine, adjusting for covariates that correlated with the number of teeth. A Cox proportional hazard model was used to evaluate the association of subsequent tooth loss with pentosidine or homocysteine levels. RESULTS: Pentosidine quartiles were not associated with the number of teeth at baseline. Participants in the highest homocysteine quartile had significantly fewer teeth at baseline than those in the third and lowest quartiles (p < 0.001 for both). Those in the second quartile had fewer teeth than those in the third (p = 0.001) and lowest (p < 0.001) quartiles. An increased risk of tooth loss during follow-up was significantly associated with higher urinary pentosidine (hazard ratio = 1.073 for 10 pmol/mgCre; p = 0.001). CONCLUSION: Postmenopausal women with higher homocysteine levels had fewer teeth at baseline. A higher pentosidine concentration increased the risk of subsequent tooth loss. High pentosidine or homocysteine concentrations may be associated with tooth loss in postmenopausal women.

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study.

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

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.

Relationship Between Bone Mineral Density and Risk of Vertebral Fractures with Denosumab Treatment in Japanese Postmenopausal Women and Men with Osteoporosis.

In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment.ClinicalTrials.gov identifier: NCT00680953.

Correction to: The association of urinary pentosidine levels with the prevalence of osteoporotic fractures in postmenopausal women.

In the original publication of the article, the following sentence under the abstract section was published incorrectly as "A multivariable logistic regression analysis revealed that urinary pentosidine was significantly associated with the prevalence of fracture after adjustment for known risk factors for fracture (odds ratio 1.92, 95% CI 1.09-3.37, P = 0.023)."

Efficacy of denosumab co-administered with vitamin D and Ca by baseline vitamin D status.

INTRODUCTION: In anti-osteoporosis drug trials, vitamin D and calcium (Ca) are common supplements; however, the optimal dose of each is unclear. Using data from the randomized, double-blind, placebo-controlled DIRECT trial, we assessed whether baseline serum 25-hydroxy vitamin D (25[OH]D) level influences the efficacy of denosumab co-administered with vitamin D and Ca. MATERIALS AND METHODS: In this prespecified sub-analysis, subjects with primary osteoporosis who received denosumab or placebo, plus vitamin D (≥ 400 IU/day) and Ca (≥ 600 mg/day), were classified as 25(OH)D deficient (< 20 ng/mL), insufficient (≥ 20 to < 30 ng/mL), and sufficient (≥ 30 ng/mL). Study endpoints included absolute serum 25(OH)D level at baseline, 12 months, and 24 months; change in serum 25(OH)D and bone mineral density (BMD) status from baseline; and incidence of new vertebral fractures at 24 months. RESULTS: In 475 denosumab-treated and 481 placebo-treated subjects, proportions with deficient/insufficient/sufficient 25(OH)D at baseline were 53.1%/37.1%/9.9% and 50.9%/42.0%/7.1%, respectively. Supplementation significantly increased mean serum 25(OH)D levels; at 24 months, mean levels were > 30 ng/mL (sufficient) in both treatment groups. Increase in BMD over time was higher in the denosumab group vs. placebo group in all three vitamin D status groups. At month 24, denosumab-treated subjects with deficient/insufficient baseline 25(OH)D had a significantly lower risk of new vertebral fracture vs. placebo-treated subjects. CONCLUSION: Among DIRECT trial subjects supplemented with ≥ 400 IU/day of vitamin D and ≥ 600 mg/day of Ca, baseline 25(OH)D sufficiency may not influence the efficacy of denosumab in increasing BMD or preventing vertebral fractures.

Executive summary of clinical practice guide on fracture risk in lifestyle diseases.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

The association of urinary pentosidine levels with the prevalence of osteoporotic fractures in postmenopausal women.

To evaluate whether or not the urinary pentosidine level has clinical value in the assessment of the osteoporotic fracture risk, a novel ELISA for pentosidine was used in clinical samples. This study employed a cross-sectional design to analyze a subset of postmenopausal women in the Nagano Cohort Study. A total of 517 urine samples were analyzed using an ELISA system, which can measure urinary pentosidine without hydrolysis. Patients were asked about their history of non-vertebral osteoporotic fracture and the prevalence of vertebral fracture was semi-quantitatively assessed on X-ray films. A 10-year increase in age was related to a 1.09-fold increase in the urinary pentosidine level (95% CI 1.05-1.13, P < 0.001), prevalent fracture (+) was related to a 1.10-fold increase in the urinary pentosidine level (95% CI 1.03-1.18, P = 0.006). Patients with prevalent fracture who had a normal bone mineral density (BMD) showed higher pentosidine levels (median 34.3 pM/mg Cr) than patients with a low BMD without fracture (median 31.4 pM/mg Cr). A multivariable logistic regression analysis revealed that urinary pentosidine was significantly associated with the prevalence of fracture after adjustment for known risk factors for fracture (odds ratio 1.92, 95% CI 1.09-3.37, P = 0.023). The present results indicated a significant association between urinary pentosidine and fracture after adjustment for age and BMD, suggesting that urinary pentosidine may be useful for assessing the fracture risk in postmenopausal women.

Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid.

Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy is a rare but severe side effect in osteoporosis patients. Recently, the number of osteoporosis patients with ONJ has dramatically increased in Japan. This has contributed to an increase in the number of patients avoiding extractions. However, there has been no prospective study providing definitive incidence data for ONJ in Japanese patients. The purpose of this study was to elucidate the true as well as suspected incidence of ONJ. A total of 3229 subjects (1612 subjects in the minodronic acid group and 1617 subjects in the raloxifene group) in the Japanese Osteoporosis Intervention Trial protocol number 4 participated in this study. ONJ was diagnosed by experienced dentists. Suspected Stage 0 and 1 (bone exposure of the jaw) ONJ was assessed by a structured questionnaire at baseline and at 6, 12, 18, and 24 months. No established ONJ cases were diagnosed during the study. The incidence of suspected Stage 0 and/or Stage 1 ONJ was 6.14 per 1000 patient-years in the minodronic acid group and 3.38 per 1000 patient-years in the raloxifene group [hazard ratio (95% confidence interval) = 1.82 (0.84-3.93), P = 0.13]. Approximately 50-60% of bone exposures that appeared during the study had disappeared at the next observation. Although the subjects in this study may have developed a greater interest in the health of the oral cavity, the incidence of ONJ after minodronic acid treatment would be lower than the expected incident rate.

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.

Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

Increasing evidence suggests that osteocalcin is involved in the regulation of glucose homeostasis. However, the relationship between serum osteocalcin levels and risk of incident type 2 diabetes mellitus is not clear. The objective of this study is to investigate whether serum osteocalcin levels are associated with the risk of incident type 2 diabetes mellitus. This study included 1691 Japanese postmenopausal women, 61 incident diabetes cases, and 1630 non-diabetic control subjects in the observation period. Baseline concentrations of intact osteocalcin, HbA1c, bone-specific alkaline phosphatase, adiponectin, leptin, urinary N-telopeptides were assessed. Serum osteocalcin levels were significantly correlated with HbA1c levels among 1691 Japanese postmenopausal women (R = -0.12, P < 0.0001). In receiver operating characteristic curve analysis, the optimal cut-off levels for serum osteocalcin to predict the development of type 2 diabetes mellitus was 6.1 ng/mL. The group with baseline osteocalcin levels <6.1 ng/mL showed a significantly higher risk for developing diabetes than the group with baseline osteocalcin levels >6.1 ng/mL (log-rank test, P  <  0.0001) during the mean observation period (7.6 ± 6.1 years; mean ± SD). In multiple Cox proportional hazard analysis, osteocalcin levels were significantly associated with development of type 2 diabetes mellitus during the observation period. Our results indicate that a decrease in serum osteocalcin levels is associated with future development of type 2 diabetes mellitus independent of conventional risk factors in Japanese postmenopausal women.

Optimal vitamin D intake for preventing serum 25-hydroxyvitamin D insufficiency in young Japanese women.

Populations of East Asian countries have been known to have low calcium intakes and low serum 25(OH)D concentrations, suggesting that Ca and vitamin D (VitD)-deficiencies are commonly observed. These nutritional imbalances may lead to low peak bone mass (PBM). The low PBM seen in Ca/VitD-deficient individuals may lead to osteoporosis, as well as an increased risk of fracture. A survey was conducted in young Japanese women (n = 296, 21.2 ± 2.3 years old) on their Ca/VitD intakes and serum 25(OH)D levels, which demonstrated a significant positive correlation between VitD intake and serum 25(OH)D levels (R 2 = 0.020, P = 0.016), and the proportion with serum 25(OH)D over 20 ng/mL was significantly increased with VitD intake (P = 0.013). Serum 25(OH)D was negatively correlated to serum intact parathyroid hormone (R 2 = 0.053, P < 0.001). On receiver operating characteristic curve analysis, the VitD intake threshold for maintaining 25(OH)D levels at 20 ng/mL or higher was 11.6 µg/day or greater. It was suggested that the recommended VitD intake allowance, defined in the Adequate Intakes as 5.5 µg/day, may not be sufficient to maintain serum 25(OH)D levels for bone health.

Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women.

Decline of body weight with aging is a major risk factor for frailty, osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. Recently, we have shown that 5-year treatment with raloxifene prevented age-related weight loss, suggesting some other drugs for osteoporosis may also prevent a decrease in body weight with aging. The present study aimed to identify the relationship between bisphosphonate treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 551 Japanese postmenopausal women with bisphosphonate treatment, which included risedronate or alendronate treatment (BP-treatment group; N = 193) and without treatment by any osteoporosis drug (no-treatment group; N = 358) for 4-7 years (mean observation periods; 5.5 years) and analyzed the relationship of these with BMD, body mass index (BMI), body weight, and biochemical markers. The mean (SD) age of the participants was 68.6 (9.8) years in the BP-treatment group and 63.7 (10.6) years in the no-treatment group. Percent changes in body weight and BMI were significantly different between the BP-treatment and no-treatment groups (P < 0.01 and P < 0.01, respectively). In multiple linear regression analysis, bisphosphonate treatment was a significant independent determinant of percent changes in body weight and BMI (P < 0.01 and P = 0.01, respectively). Long-term use of bisphosphonates prevented reductions in BMI and body weight, usually observed in elderly women. Our results suggest that bisphosphonate treatment not only reduces the risk for incident osteoporotic fractures but also for frailty in the elderly.

Safety, pharmacokinetics, and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis.

Although once-yearly intravenous administration of zoledronic acid has been reported to inhibit bone resorption and increase bone mineral density, no studies have evaluated its effectiveness in treating osteoporosis in Japanese patients. Therefore, the purpose of this study was to investigate the pharmacokinetics and assess the safety of and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. This was a single-administration study with a single-blind parallel-group design. The study participants were 24 Japanese patients with primary osteoporosis. The patients were divided into two groups, with each group receiving a single injection of zoledronic acid (4 or 5 mg). Pharmacokinetics and urinary excretion were then compared, and drug-related adverse events and changes in the levels of bone turnover markers were assessed at 12 months. Mean plasma concentrations of zoledronic acid peaked in both groups immediately after administration, and decreased to 1% or less of peak levels after 24 h. Noncompartmental analysis revealed that C max and the area under the curve from time zero to infinity increased in proportion to the dose. The levels of bone resorption and formation markers decreased from day 15 and from 3 months after administration respectively, and suppression of these markers remained constant for the entire study period. No serious adverse events were reported. There was no large difference between the 4- and 5-mg groups in terms of pharmacokinetics, changes in the levels of bone turnover markers, and safety profiles. This study demonstrated acceptable pharmacokinetics and changes in bone metabolism associated with zoledronic acid treatment in female Japanese osteoporosis patients. Both the 4-mg dose and the 5-mg dose demonstrated acceptable safety and sustained antiresorptive effects for the duration of the study.

Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal women.

Decline of body weight and body mass index (BMI) with aging is a major risk factor for osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. However, the effects of treatment for osteoporosis on body composition are not well known. The present study aimed to identify the relationship between raloxifene treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 236 Japanese postmenopausal women with raloxifene treatment (N = 50) and without treatment by any osteoporosis drug (N = 186) for 5 years and analyzed the relationship of these with BMD, BMI, body weight, and biochemical markers. The mean (SD) age of the participants was 65.5 (9.3) years. Percent-changes in body weight and BMI were significantly different between women taking raloxifene and those not taking any osteoporosis drugs (P = 0.03 and 0.048, respectively). Raloxifene treatment was a significant independent determinant of body weight and BMI. Long-term treatment with raloxifene prevents age-related weight loss.

Decreased rate of hip fracture and consequent reduction in estimated medical costs in Japan.

The frequency of hip fractures associated with aging of the population is declining in many countries. Even in Japan, where this frequency has been increasing continually, a shift to decreasing frequency has been noted in recent reports. The objective of this study was to investigate the effects of this decrease and to estimate the number of hip fracture patients and the resulting reduction in national medical care expenditures. The differences in the number of patients were estimated by multiplying the population for each sex and each age group by the fracture rates before the decrease (2007) and after the decrease (2012). Total reduced cost was calculated by multiplying the treatment cost required for hip fracture and the annual medical cost of nursing care. The estimated number of hip fracture patients decreased by approximately 4000 in the elderly female population, and the resulting reduction in medical costs was approximately US$280 million. The number of patients with hip fractures has decreased in elderly Japanese women; as a result, the medical costs for treatment and nursing care might decrease.