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Abstract  Smad6 plays pivotal roles in the negative regulation of transforming growth factor β (TGFβ) family signaling as one of the feedback molecules. Here, we analyzed whether the human Smad6 gene is involved in the regulation of bone mass, using association analysis between bone mineral density (BMD) and single-nucleotide polymorphism (SNP) in the Smad6 gene. Association of an SNP at IVS3+26115A>C (intron 3, rs755451) in the Smad6 gene with BMD was examined in 721 Japanese postmenopausal Japanese women (age 65.2 ± 9.6 years; mean ± SD). The subjects bearing at least one variant C allele (CC ± AC; n = 387) had significantly lower Z-scores for total body and lumbar BMD than the subjects with no C allele (AA; n = 334) (total body, 0.23 ± 0.98 versus 0.50 ± 1.07; P = 0.0004; lumbar spine, −0.20 ± 1.38 versus 0.10 ± 1.48; P = 0.0050). These findings suggest that the Smad6 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis. [ABSTRACT FROM AUTHOR]

Abstract  The effect of vitamin K2 (menatetrenone) on bone turnover was investigated in postmenopausal patients with osteoporosis. A 6-month open-label, randomized prospective study was conducted in 109 patients. The control group (n = 53) received calcium aspartate (133.8 mg of elemental calcium daily), while the menatetrenone group (n = 56) received 45 mg of menatetrenone daily for 6 months. Serum and urinary levels of bone turnover markers were monitored. The serum level of undercarboxylated osteocalcin (uc-OC) was significantly lower (P P = 0.018). Significant differences of uc-OC and Gla-OC between the two groups were observed from 1 month onward. In addition, a higher level of intact osteocalcin was found in the menatetrenone group compared with the control group after 6 months (P = 0.006). Assessment of bone resorption markers showed that menatetrenone therapy was associated with significantly higher urinary N-telopeptide of type I collagen (NTX) excretion compared with the control group after 6 months, while there was no significant difference of urinary deoxypyridinoline excretion between the two groups. In conclusion, one month of menatetrenone therapy enhanced the secretion and gamma-carboxylation of osteocalcin, while urinary NTX excretion was increased after 6 months of treatment. Further investigations are required to determine whether the effects of menatetrenone on bone turnover are associated with fracture prevention. [ABSTRACT FROM AUTHOR]

Abstract  A functional polymorphism in methylenetetrahydrofolate reductase (MTHFR) has been identified at codon 677 (C677T). The T-allele variant (valine type) has lower enzyme activity than the wild type (C-allele or alanine type), resulting in a slightly elevated homocysteine level, which has been recently recognized as a risk factor for fracture. However, whether subjects bearing the T allele have higher susceptibility to fractures is still controversial. We have investigated the effects of MTHFR polymorphism on fracture susceptibility in Japanese postmenopausal women. A total of 502 postmenopausal ambulatory Japanese women were followed up for 5.1 ± 3.4 (mean ± SD) years, and a total of 155 patients with incident fractures (121 patients with vertebral fractures and 34 cases with fractures at other sites) were recorded. When compared with the patients without any fractures, the patients with incident fractures were older, had more prevalent fractures, had higher urinary levels of bone turnover markers as well as plasma homocysteine level, but were shorter in body height and had lower bone mineral density. The prevalence of the TT genotype of MTHFR was significantly higher in the patients with incident fractures compared to the other genotypes. The subjects with the TT genotype had a higher incidence rate of fracture and higher plasma level of homocysteine than the subjects bearing the non-TT genotype. This relationship was observed in both osteoporotic and nonosteoporotic groups. The hazard ratio for TT genotype without osteoporosis, non-TT genotype with osteoporosis, and TT genotype with osteoporosis was 1.49 (0.91–2.45), 3.64 (2.50–5.29), and 7.21 (4.34–11.97), respectively, compared to the non-TT genotype without osteoporosis. A higher hazard ratio for the TT genotype with osteoporosis was still apparent after adjustment for age, body size, and number of prevalent vertebral fractures. These results indicate that the TT genotype of MTHFR may be a risk factor for future fracture in addition to the traditional risk factors. [ABSTRACT FROM AUTHOR]

Abstract  It has been reported that vitamin K supplementation effectively prevents fractures and sustains bone mineral density in osteoporosis. However, there are only limited reported data concerning the association between vitamin K nutritional status and bone mineral density (BMD) or fractures in Japan. The objectives were to evaluate the association between plasma phylloquinone (K1) or menaquinone (MK-4 and MK-7) concentration and BMD or fracture in Japanese women prospectively. A total of 379 healthy women aged 30–88 years (mean age, 63.0 years) were consecutively enrolled. Plasma K1, MK-4, MK-7, and serum undercarboxylated osteocalcin (ucOC) concentrations, BMD, and incidence of vertebral fractures were evaluated. In stepwise multiple linear regression analyses, L2–4 BMD and a bone turnover marker, log K1, concentrations were independently correlated with vertebral fracture incidence. When subjects were divided into low and high K1 groups by plasma K1 concentration, the incidence of vertebral fracture in the low K1 group (14.4%) was significantly higher than that in the high K1 group (4.2%), and its age-adjusted RR was 3.58 (95% CI, 3.26–3.93). L2–4 BMD was not different between the two groups. These results suggest that subjects with vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD. [ABSTRACT FROM AUTHOR]

Abstract  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. [ABSTRACT FROM AUTHOR]

Abstract  The Wnt-β-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-β-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by β-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3′-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34–6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-β-catenin-regulated gene in bone and cartilage metabolism. [ABSTRACT FROM AUTHOR]

Background: Alendronate, a potent antiresorptive agent, effectively reduces fracture risk. Alendronate increases bone mineral density (BMD) and decreases bone turnover markers to a similar extent in white and Asian people, including Japanese. However, no large trials of this drug have been conducted specifically in the Japanese population.Objective: This study examined the antifracture efficacy of alendronate in Japanese patients.Methods: We conducted a 2-year, multicenter, randomized, double-blind, active-controlled, double-dummy trial of women and men with osteoporosis in Japan, with radiographically diagnosed vertebral fracture being the primary end point. Patients were randomized to receive alendronate 5 mg/d or alfacalcidol 1 gmg/d.Results: A total of 365 patients (349 women, 16 men; mean age, 73 years) were enrolled in the study. At the end of 24 months, spinal BMD was significantly increased versus baseline by a mean of 6.9% in the alendronate-treated group (P < 0.001) and 1.5% in the alfacalcidol-treated group; the median increases in BMD at 24 months versus baseline were 8.3% and 1.4%, respectively. The incidence of vertebral fracture >6 months after randomization (the primary end point) was significantly reduced by 66% (relative risk [RR], 0.34; 95% CI, 0.15–0.74) in the alendronate group (4.3% vs 12.7% incidence). When all fractures during the 24 months were considered, the incidence of multiple (≥2) vertebral fractures also was reduced significantly by 67% (RR, 0.33; 95% CI, 0.11–0.96; 2.4% vs 7.3% incidence). The difference in overall incidence (≥1 vertebral fracture during all 24 months) was not significant (12.2% vs 16.7%), implying that risk reductions (relative to the active control) improved after 6 months. This is consistent with bone biology theory, which predicts that several months are required to refill existing resorption sites and increase bone strength more than the active control. Thus, theory predicts that several months would be required to increase bone strength and reduce fracture risk relative to the active control. This study was limited to Japanese participants, but the findings are consistent with results reported from similar studies among white people. Furthermore, because this was an active-controlled trial, it may have underestimated the antifracture efficacy of alendronate relative to a true placebo.Conclusions: The effectiveness of alendronate in reducing the risk of radiographically defined vertebral fracture in Japanese women and men with osteoporosis is similar to that reported previously in white people. As a consequence, the benefits of alendronate in reducing vertebral and hip fractures can be expected to be substantial and early (beginning at month 6). [Copyright &y& Elsevier]

Study Design: Retrospective observational study from the Nagano Cohort Study.Objective: Clarify the association between spinal osteoarthritis and loss of stature in postmenopausal women.Summary Of Background Data: Loss of stature with aging is known to deteriorate health-related quality of life and has been implicated with increased mortality. Although the association of vertebral fracture with height loss has been well documented, the relationship between stature loss and spinal osteoarthritis remains unclear.Methods: We retrospectively investigated Japanese postmenopausal women recruited from the Nagano Cohort Study. The participants were outpatients at a primary care institute in Nagano prefecture, Japan. A total of 977 postmenopausal patients (mean age: 65.8 yr) completed a minimum of 1 year of follow-up, with an average observation period of 7.6 years. Quartile analysis on the prevalence of spinal osteoarthritis and occurrence of incident fracture was performed based on the rate of stature change per year (Δ cm/yr). Multiple regression analysis was also conducted to identify the determinants of stature change.Results: The lower quartiles of stature change rate (i.e., more rapid stature loss) displayed a significantly higher prevalence of spinal osteoarthritis (P < 0.001) and incident vertebral fracture (P < 0.001). A statistically significant independent negative association for spinal osteoarthritis prevalence with change in stature was revealed by multiple regression analysis after adjusting for confounders including incident vertebral fracture. The partial regression coefficient for spinal osteoarthritis was -0.18 (95% confidence interval -0.33 to -0.03; P = 0.016).Conclusion: This study demonstrated an independent association of spinal osteoarthritis with stature loss in postmenopausal women. Adequate understanding of this relationship and appropriate treatment approaches will help improve health-related quality of life in elderly patients.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

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

AbstractObjectives:The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting.Research design and methods:Eligible patients were postmenopausal women with severe osteoporosis who were aged 70 years or older and had several risk factors for incident fractures. The primary endpoint was prevention of incident fractures, and the anti-fracture efficacy was evaluated in relation to the baseline serum 25(OH)D level.Results:A total of 2164 patients were randomized to alendronate plus alfacalcidol (combination therapy) or alendronate alone (monotherapy). Although the overall difference in the incidence of vertebral fracture between the two groups was not significant, the combination therapy group had a significantly reduced risk of vertebral fractures after the first 6 months (HR, 0.53). In subgroup analyses, the combination therapy group was superior in the strata of number of prevalent vertebral fractures of ≥2 (HR, 0.51) and grade 3 of prevalent vertebral fractures (HR, 0.55). The rate of non-vertebral weight-bearing bone fractures was significantly lower in the combination therapy group than in the monotherapy group during the follow-up period (HR, 0.31). A lower baseline 25(OH)D level was associated with a higher incidence of non-vertebral weight-bearing bone fractures (HR, 3.42) despite alendronate use. Although one patient given the combination therapy had mild hypercalcemia, serious hypercalcemia and unknown adverse events were not encountered. Because of the limitations presented in this study, these results may not apply to female patients with longer than 2 years of treatments, and to male osteoporosis patients.Conclusions:The combination therapy was no more effective for overall vertebral fracture prevention. However, subgroup analysis has shown that it was more effective for fracture prevention in patients with severe vertebral deformity, multiple prevalent vertebral fractures, and for non-vertebral weight-bearing bone fracture prevention. [ABSTRACT FROM AUTHOR]

Objectives:The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting.Research design and methods:Eligible patients were postmenopausal women with severe osteoporosis who were aged 70 years or older and had several risk factors for incident fractures. The primary endpoint was prevention of incident fractures, and the anti-fracture efficacy was evaluated in relation to the baseline serum 25(OH)D level.Results:A total of 2164 patients were randomized to alendronate plus alfacalcidol (combination therapy) or alendronate alone (monotherapy). Although the overall difference in the incidence of vertebral fracture between the two groups was not significant, the combination therapy group had a significantly reduced risk of vertebral fractures after the first 6 months (HR, 0.53). In subgroup analyses, the combination therapy group was superior in the strata of number of prevalent vertebral fractures of ≥2 (HR, 0.51) and grade 3 of prevalent vertebral fractures (HR, 0.55). The rate of non-vertebral weight-bearing bone fractures was significantly lower in the combination therapy group than in the monotherapy group during the follow-up period (HR, 0.31). A lower baseline 25(OH)D level was associated with a higher incidence of non-vertebral weight-bearing bone fractures (HR, 3.42) despite alendronate use. Although one patient given the combination therapy had mild hypercalcemia, serious hypercalcemia and unknown adverse events were not encountered. Because of the limitations presented in this study, these results may not apply to female patients with longer than 2 years of treatments, and to male osteoporosis patients.Conclusions:The combination therapy was no more effective for overall vertebral fracture prevention. However, subgroup analysis has shown that it was more effective for fracture prevention in patients with severe vertebral deformity, multiple prevalent vertebral fractures, and for non-vertebral weight-bearing bone fracture prevention. [ABSTRACT FROM AUTHOR]

Abstract  The Japanese Society for Bone and Mineral Research developed the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL) to evaluate the disease-specific Health-Related QOL, which is specific for osteoporosis of Japanese patients. JOQOL was revised in 2000; it consisted of 38 items with the scale graded from 0 to 4 and a total full score of 152. To elucidate the reliability and validity of the revised JOQOL, we enrolled 193 postmenopausal women as subjects and diagnosed them as having osteoporosis or osteopenia. The mean age of the subjects was 68.2 ± 8 years; 58 subjects (30.1%) had at least one vertebral fracture. Among them, 83 patients were retested for reliability. The mean lapse from the time of test to that of retest was 23.7(±9.5) days. The subjects were questioned using the JOQOL, Medical Outcomes Study Short Form 36 (SF-36), along with questions on subjects’ characteristics and their ADL. The JOQOL scores at the test and the retest were significantly correlated (r = 0.973) without significant difference between their mean scores. All the JOQOL items showed significant correlations at the test and the retest (Kendall’s τ = 0.599–0.947). Cronbach’s alpha coefficient of JOQOL was 0.918. These results proved the high reliability of JOQOL. The JOQOL score showed negative correlation with age (r = −0.183). The subjects with vertebral fractures had significantly lower JOQOL scores than the subjects without fractures. The JOQOL showed a significant correlation with all the scores in each domain of eight of SF-36 (r = 0.350–0.839). These results were consistent with that of the preceding study. It is concluded that the reliability and the validity of JOQOL were demonstrated in this study. [ABSTRACT FROM AUTHOR]