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Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22-2.07; P < 0.001), but not with lumbar BMD. In contrast, a significant negative correlation was found between CML and lumbar BMD (r =  - 0.180; P < 0.001), and this relationship was significant after adjustment for confounders (OR 0.84, 95% CI 0.76-0.93; P < 0.01). Although patients with prevalent vertebral fracture had significantly higher CML levels, the association between CML and prevalent vertebral fracture did not reach significance in the multivariate regression model. Both PEN and CML may play important roles in bone health for postmenopausal women, possibly via different mechanisms.

Introduction: Because aging is a predictor of renal insufficiency in the general population, renal function is a concern in postmenopausal patients undergoing treatment for osteoporosis. Although high serum phosphate concentration is a predictor of renal insufficiency, the effect of selective estrogen receptor modulator (SERM) on renal function and phosphate homeostasis remains to be established., Materials and Methods: We administered 20 mg/day bazedoxifene to 48 postmenopausal osteoporotic women who had been taking alfacalcidol for ≥ 6 months, and assessed lumbar spine bone mineral density (LS-BMD), renal function (by calculating estimated glomerular filtration rate using serum cystatin-C levels [eGFRcys] [range 38.0-98.2 mL/min/1.73 m 2 ]), and phosphate homeostasis., Results: LS-BMD was significantly higher 6 months after the initiation of bazedoxifene administration. eGFRcys had increased by 3 months after initiation and was stable until 12 months. Serum phosphate gradually decreased after initiation, reaching statistical significance at 6 months. The changes in serum phosphate were also significant when the maximum tubular reabsorption rate of phosphate was normalized to glomerular filtration rate (TmP/GFR), indicating that bazedoxifene treatment reduces serum phosphate by increasing the urinary excretion of phosphate. The change in eGFRcys after the initiation of bazedoxifene was significantly negatively correlated with the change in serum phosphate, suggesting that a reduction in serum phosphate improves renal function., Conclusion: Bazedoxifene improves renal function, possibly by increasing renal phosphate excretion, in postmenopausal osteoporotic women without severe renal insufficiency.

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.

Purpose : The correlation between serum levels of homocysteine and bone mineral density remains controversial. The aim of this study was to identify the potential factors associated with the levels of serum total homocysteine (S-Hcy) and urinary N-terminal telopeptide of type I collagen (U-NTX) in female osteoporotic patients. Materials and Methods : This cross-sectional study included 163 female osteoporotic patients, aged between 48 and 91 years, who had never been treated with anti-osteoporosis therapy. Background data including spine and hip bone mineral density, ongoing therapy for the metabolic disease, aortic calcification score as evaluated by lateral lumbar X-ray film, and recent fragility fracture history were obtained. S-Hcy, U-NTX levels, and creatinine clearance were measured. Results : Multiple linear regression analysis revealed a significant correlation between S-Hcy levels and aortic calcification score ( p = 0.022), creatinine clearance ( p = 0.004), and recent fracture history (within 1 year after fracture) ( p = 0.028); conversely, U-NTX levels correlated significantly with total hip bone mineral density ( p < 0.0001) and recent fracture history (p = 0.0007). Conclusions : S-Hcy levels had no correlation with bone mineral density, but were associated with the degree of aortic calcification, renal function, and fracture events. These confounding factors should be taken into consideration when the relationship between S-Hcy and bone mineral density is discussed.

Background/aim: This study was designed to evaluate the relationship between urinary phytate concentration and risk of fracture at 10 years, determined by using the FRAX model, in women who had undergone menopause within 5 years of the time of enrollment., Materials and Methods: Of the 212 postmenopausal women evaluated, 69 were excluded because they had urinary phytate concentrations between 0.51 and 0.99 mg/L. Of the remaining 143 women, 91 had low (≤0.50 mg/L) and 52 had high (≥1.0 mg/L) urinary phytate concentrations. The 10-year risk of fracture was calculated by using the FRAX model., Results: The risks of major osteoporotic fracture and hip fracture were higher in women with low urinary phytate levels (P < 0.001 in both cases). Evaluation of the risk of hip fracture in women with and without risk factors for osteoporosis (e.g., tobacco, alcohol, and drug consumption) and according to urinary phytate concentrations indicated that, among women with no risk factors, those with low and high urinary phytate levels had a range of risks of 0%–0.6% and 0%–0.3%, respectively (P = 0.098). Moreover, among women with at least one risk factor, those with low and high urinary phytate had a range of risks of 0.1%–0.8% and 0.1%–0.4%, respectively (P = 0.002). Similar results were observed when the risks of major osteoporotic fracture were analyzed., Conclusion: These results indicate the relationship of phytate with the risks of major osteoporotic fracture and hip fracture, with these differences being more marked in women with risk factors for osteoporosis. From this study follows the importance of the consumption of phytate-rich products (nuts, legumes, whole cereals) to protect against the risk of fracture in 10 years, mainly in women with risk factors for osteoporosis.

Objective: In the present study, we aimed to characterize the pathological development of menopausal osteoporosis, as well as to explore potential biomarkers and metabolic pathways involved in osteoporosis., Methods: Urine samples from 322 female participants categorized by menopause status and different bone conditions were collected and analyzed based on a gas chromatography-mass spectrometry (GC-MS) approach. Multivariate and univariate statistical analyses were carried out for urinary metabolomic profile characterization and comparison., Results: Seventeen metabolites in the low bone mineral density (BMD) groups were clearly differentiated from those in normal BMD groups. Among these 17 differentiating metabolites, taurine, β-alanine, and 5-hydroxycaproic acid were found to be potential biomarkers of osteoporosis. The taurine metabolic pathway and the β-alanine metabolic pathway were found to be related to menopause and bone loss., Conclusions: Based on the GC-MS metabolomic platform, four typical pathological phases during the progression of postmenopausal osteoporosis were described. Several differentiating metabolites and metabolic pathways were found to be closely related to the pathology of postmenopausal osteoporosis. Our results provided a solid foundation for further studies on early diagnosis and pathomechanistic evaluation.

The relationship between daily boron intake and osteocalcin-mediated osteoporosis was studied in boron-exposed postmenopausal women. It is known that boron and osteocalcin are important in bone metabolism, however the effect of boron in bone metabolism has not been fully discovered. The study was performed on 53 postmenopausal women aged 55-60 living in parts of Balikesir, Turkey, where the subjects are naturally exposed to high (≥1 mg/L) or low (<1 mg/L) boron concentration in drinking water. 24-h urine samples were collected from all participants and creatinine clearance was detected. Boron intake levels of the subjects whose clearance levels were between 80-124 mL/min were measured by inductively coupled plasma-optical emission spectrometry (ICP-OES) in urine samples. Serum osteocalcin levels of the subjects were measured by osteocalcin enzyme-linked immunosorbent assay (ELISA) kit. Osteocalcin polymorphism rs1800247 was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Serum osteocalcin levels in boron-exposed postmenopausal women were significantly higher than that of control group (P ≤ 0.05) and the correlation between the serum osteocalcin level and rs1800247 polymorphism was not significant in both groups (P > 0.05). The differences in the distribution of osteocalcin genotypes and alleles in postmenopausal women were not significant between the boron exposed and the control groups (P > 0.05). Serum osteocalcin level in the CC genotype was significantly higher compared to the TC genotype in boron-exposed group (P ≤ 0.05). Our study suggests that daily boron intake of 1 mg/L may affect bone metabolism in postmenopausal women positively., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objective: Postmenopausal osteoporosis is a frequent cause of morbidity and can negatively impact life expectancy; iodine is an essential element for bone mineralization, and iodine deficiency is frequently observed. The aim of the present study was to understand the connection between postmenopausal osteoporosis and the level of iodine in the body., Methods: A total of 132 participants were divided into three groups: group 1 consisted of healthy postmenopausal women (n = 34), group 2 comprised osteopenic women (n = 38), and group 3 included women with postmenopausal osteoporosis (n = 60). The three groups were compared according to demographic, clinical, and laboratory findings., Results: The urinary iodine levels were recorded as 216.1 ± 125.2 in the control group, 154.6 ± 76.6 in the osteopenic group, and 137.5 ± 64.9 in the postmenopausal osteoporosis group (P < 0.001). These differences were maintained after adjustment for body mass index (P < 0.001). The urinary iodine level accurately correlated with the total T-score for the lumbar spine (r = 0.236, P = 0.008). Multiple regression analysis showed that corrected for body mass index, alkaline phosphatase isoenzyme, and urinary deoxypyridinoline, the urinary iodine level was significantly associated with total T-score (beta coefficient = 0.270, P = 0.006)., Conclusions: The urinary iodine level was significantly lower in women with postmenopausal osteoporosis, and iodine replacement may be important in preventing osteoporosis in areas where iodine deficiency is endemic.

Association between lung function and bone metabolism remains controversial. We found that impaired lung function was associated with vertebral fractures and bone loss in Japanese postmenopausal women. While vertebral deformities would impair lung function, respiratory dysfunction might in turn increase fracture risk, suggesting a complex bidirectional interaction., Introduction: Association between bone metabolism and pulmonary function in the general population is controversial. The aim of this study was to investigate relationship between lung and bone parameters in elderly postmenopausal women., Methods: One hundred and six postmenopausal women (75.6 ± 8.0 years old) who underwent spirometric tests were examined for prevalent vertebral fractures, bone mineral density (BMD), bone metabolic markers, and other metabolic indices such as urinary pentosidine., Results: Multivariable logistic regression analyses revealed that forced vital capacity (FVC) (OR = 0.063, 95% CI: 0.011-0.352, p = 0.002) and urinary pentosidine (OR = 1.067, 95% CI: 1.020-1.117, p = 0.005) were associated with the presence of vertebral fractures after adjustment for height loss, age, and BMD at femoral neck. Moreover, vital capacity (VC) or FVC as well as body mass index and age was among independent determinants of BMD after adjustment for height loss and the number and grade of vertebral fractures in forced multiple linear regression analysis (VC: β = 0.212, p = 0.021, FVC: β = 0.217, p = 0.031). Urinary pentosidine was negatively correlated with pulmonary function parameters such as FVC and forced expiratory volume in 1 s (FEV 1.0 ), although these correlations appeared dependent on age., Conclusions: Diminished FVC was associated with prevalent vertebral fractures and decreased BMD in Japanese postmenopausal women without apparent pulmonary diseases. Mechanism of such association between pulmonary function and bone status remains to be determined.

Objective: Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates., Methods: The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment., Results: The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment., Conclusion: In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers., Abbreviations: BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Since the in vitro and in vivo anti-osteoporotic effects of Pueraria mirifica (PM) in rodents have been verified, its activity in menopausal monkeys was evaluated as required before it can be applicable for human use. In this study, postmenopausal osteoporotic monkeys were divided into two groups (five per group), and fed daily with standard diet alone (PMP0 group) or diet mixed with 1000 mg/kg body weight (BW) of PM powder (PMP1000 group) for 16 months. Every 2 months, the bone mineral density (BMD), bone mineral content (BMC) and bone geometry parameters (cortical area and thickness and periosteal and endosteal circumference) at the distal radius and proximal tibia were determined using peripheral quantitative computed tomography together with plasma and urinary bone markers. Compared with the baseline (month 0) values, the cortical, but not trabecular, BMDs and BMCs and the cortical area and thickness at the metaphysis and diaphysis of the radius and tibia of the PMP0 group continuously decreased during the 16-month study period. In contrast, PMP1000 treatment ameliorated the bone loss mainly at the cortical diaphysis by decreasing bone turnover, as indicated by the lowered plasma bone-specific alkaline phosphatase and osteocalcin levels. Generally, changes in the cortical bone geometry were in the opposite direction to the cortical bone mass after PMP1000 treatment. This study indicated that postmenopausal monkeys continuously lose their cortical bone compartment, and they have a higher possibility for long bone fractures. Oral PMP treatment could improve both the bone quantity (BMC and BMD) and quality (bone geometry)., (© 2016 Society for Endocrinology.)

Background: Dietary soluble corn fiber (SCF) significantly improves calcium absorption in adolescents and the bone strength and architecture in rodent models., Objective: In this study, we aimed to determine the skeletal benefits of SCF in postmenopausal women., Design: We used our novel technology of determining bone calcium retention by following the urinary appearance of (41)Ca, a rare long-lived radioisotope, from prelabeled bone to rapidly and sensitively evaluate the effectiveness of SCF in reducing bone loss. A randomized-order, crossover, double-blinded trial was performed in 14 healthy postmenopausal women to compare doses of 0, 10, and 20 g fiber from SCF/d for 50 d., Results: A dose-response effect was shown with 10 and 20 g fiber from SCF/d, whereby bone calcium retention was improved by 4.8% (P < 0.05) and 7% (P < 0.04), respectively. The bone turnover biomarkers N-terminal telopeptide and osteocalcin were not changed by the interventions; however, a significant increase in bone-specific alkaline phosphatase, which is a bone-formation marker, was detected between 0 and 20 g fiber from SCF/d (8%; P = 0.035)., Conclusion: Daily SCF consumption significantly increased bone calcium retention in postmenopausal women, which improved the bone calcium balance by an estimated 50 mg/d. This study was registered at clinicaltrials.gov as NCT02416947., (© 2016 American Society for Nutrition.)

Dietary supplementation with dried plum (DP) has been shown to protect against and reverse established osteopenia in ovariectomized rodents. Based on in vitro studies, we hypothesized that DP polyphenols may be responsible for that bone-sparing effect. This study was designed to (1) analyze whether the main phenolic acids of DP control preosteoblast proliferation and activity in vitro; (2) determine if the polyphenolic content of DP or DP juice concentrate is the main component improving bone health in vivo; and (3) analyze whether DP metabolites directly modulate preosteoblast physiology ex vivo. In vitro, we found that neochlorogenic, chlorogenic, and caffeic acids induce the proliferation and repress the alkaline phosphatase activity of primary preosteoblasts in a dose-dependent manner. In vivo, low-chlorogenic acid Agen prunes (AP) enriched with a high-fiber diet and low-chlorogenic acid AP juice concentrate prevented the decrease of total femoral bone mineral density induced by estrogen deficiency in 5-month-old female rats and positively restored the variations of the bone markers osteocalcin and deoxypyridinoline. Ex vivo, we demonstrated that serum from rats fed with low-chlorogenic acid AP enriched with a high-fiber diet showed repressed proliferation and stimulated alkaline phosphatase activity of primary preosteoblasts. Overall, the beneficial action of AP on bone health was not dependent on its polyphenolic content., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: High salt intake is a well-known risk factor for osteoporosis, but the association between bone mass and urinary sodium excretion has not been studied as yet. This study investigates the hypothesis that urinary sodium excretion is negatively associated with bone mass and the risk of osteoporosis., Methods: This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, 2008-2011. Participants (n = 16,279) were divided into age groups; men were categorized as younger than 50 years of age or 50 years or greater, women were categorized as pre- or post-menopausal., Results: Multivariate linear regression analysis showed that urinary sodium excretion was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in premenopausal and postmenopausal women. Sodium excretion was negatively associated with BMC and BMD of the lumbar spine in women with normal bone health, osteopenia and osteoporosis, but there was no association in men. Increased sodium excretion was significantly associated with risk for osteoporosis/osteopenia in premenopausal women., Conclusions: This study demonstrates that urinary sodium excretion is negatively associated with bone health, suggesting that high salt intake could be a possible risk factor for osteoporosis in Korean women, but not in men., (© 2016 S. Karger AG, Basel.)

Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emerging in vitro evidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-κb ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a sample (n = 124), including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449, p = 0.004, and R(2) = 0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications.

Objective: This study measured the differences in bone mineral density and content in relation to changes in serum hormone and bone marker levels during the perimenopausal transition in naturally menopausal cynomolgus monkeys., Methods: The bone mineral density and content of premenopausal, perimenopausal, and early (0-< 5 y), mid (5-10 y), and late (> 10 y) postmenopausal monkeys were measured at the distal radius and proximal tibia in both metaphysis and diaphysis. Hormonal and bone marker levels were also measured., Results: The serum 17β-estradiol level significantly decreased during late postmenopause, whereas the serum follicle-stimulating hormone levels significantly increased from early postmenopause before declining at late postmenopause. Trabecular bone loss at metaphysis occurred once the animals entered into the perimenopausal period, whereas cortical bone loss gradually and continuously decreased, dependent on the time-course after perimenopause, and was greatest in the late postmenopausal period. Serum bone-specific alkaline phosphatase and urinary N-telopeptide of bone type-1 collagen levels were negatively correlated with the trabecular bone mineral content at metaphysis, whereas serum osteocalcin levels showed a negative correlation with the cortical bone mineral density at the diaphysis. The only positive linear correlation observed was between serum follicle-stimulating hormone and urinary N-telopeptide of bone type-1 collagen levels., Conclusions: Unlike the ovariectomized monkey models that do not retain the perimenopausal transition, naturally menopausal monkeys elicit different patterns of bone loss during the transition-an abrupt decline in the trabecular metaphysis and a gradual decline in the cortical diaphysis. Naturally menopausal cynomolgus monkeys offer an alternative model for osteoporosis research for postmenopausal women.

Accumulating evidence shows that high sodium chloride intake increases urinary calcium excretion and may be a risk factor for osteoporosis. However, the effect of oral sodium chloride intake on bone mineral density (BMD) and risk of osteoporosis has been inadequately researched. The aim of the present study was to determine whether urinary sodium excretion (reflecting oral sodium chloride intake) associates with BMD and prevalence of osteoporosis in postmenopausal women. This cross-sectional study involved a nationally representative sample consisting of 2,779 postmenopausal women who participated in the Korea National Health and Nutritional Examination Surveys in 2008-2011. The association of urinary sodium/creatinine ratio with BMD and other osteoporosis risk factors was assessed. In addition, the prevalence of osteoporosis was assessed in four groups with different urinary sodium/creatinine ratios. Participants with osteoporosis had significantly higher urinary sodium/creatinine ratios than the participants without osteoporosis. After adjusting for multiple confounding factors, urinary sodium/creatinine ratio correlated inversely with lumbar spine BMD (P = 0.001). Similarly, when participants were divided into quartile groups according to urinary sodium/creatinine ratio, the average BMD dropped as the urinary sodium/creatinine ratio increased. Multiple logistic regression analysis revealed that compared to quartile 1, quartile 4 had a significantly increased prevalence of lumbar spine osteoporosis (odds ratios 1.346, P for trend = 0.044). High urinary sodium excretion was significantly associated with low BMD and high prevalence of osteoporosis in lumbar spine. These results suggest that high sodium chloride intake decreases lumbar spine BMD and increases the risk of osteoporosis in postmenopausal women.

Osteoporosis is the most important metabolic bone disease in patients with diabetes mellitus. Several studies have documented that metformin is osteogenic in vitro. In contrast, others showed no effect of metformin on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Incretin hormones have received much attention because of their beneficial effects beyond glycemia, including on bone health. The study evaluated the anti-osteoporotic effect of metformin and sitagliptin in postmenopausal diabetic women. Forty postmenopausal diabetic women were randomly divided into two equal groups. Group 1 received metformin (Glucophage(®) 500 mg) 1 tablet twice daily, and group 2 received sitagliptin (Januvia(®) 100 mg) 1 tablet/day, for 12 weeks. Fasting blood and urine samples were collected for measurement of serum total alkaline phosphatase (ALP), osteocalcin, and urinary deoxypyridinoline (DPD). Laboratory tests were measured at baseline, after 4 and 8 weeks, and at the end of the study. Bone mineral density of the anterior posterior lumbar spine was measured by dual energy X-ray absorptiometry at baseline and after 12 weeks of the intervention. In the metformin-treated group, the mean values for all markers of bone turnover at 12 weeks of treatment were not significantly different from baseline. In group 2, the mean serum total ALP was significantly decreased, serum osteocalcin levels were non-significantly decreased gradually by 10% at 12 weeks, while urinary DPD decreased significantly and was then maintained at 28% decrease at 12 weeks. In conclusion, metformin is neither osteogenic nor has anti-osteoporotic effect, while sitagliptin could positively regulate bone metabolism.

Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.

Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T-score > -1) and established OP (BMD T-score < -2.5, with at least one low-energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age-adjusted and BMI-adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population-based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation., (© 2014 American Society for Bone and Mineral Research.)

Objective: The aim of this study was to examine the level of compliance and persistence in patients with postmenopausal osteoporosis (OP) receiving daily risedronate (5 mg) with either fixed dosing of three different timing regimens (A: before breakfast; B: in-between meals; C: before bedtime) or with flexible dosing and the effect on urinary N-terminal telopeptide of Type 1 collagen (NTX-1)., Methods: The study included 448 patients with postmenopausal OP. Patients were randomly assigned into six treatment groups each with a permutation of the treatment sequence (ABC, BCA, etc.) in the crossover phase (3 x 1 week) and randomized to 23 weeks of either the daily flexible (either regimen A, B or C) or fixed timing (only regimen A, B, or C) in the patient's preference phase. Urinary NTX-1 was tested., Results: A total of 433 patients participated in the patient's preference phase (49.7% preferred flexible and 50.3% fixed timing). There was no significant difference between the proportion of responders who were both compliant and persistent in the flexible (54.4%) and fixed regimens (53.7%) (p=0.8803). A significant difference between the flexible and fixed regimens was seen in persistence in favor of the flexible regimen (p=0.0306). There was no significant difference between the flexible and fixed regimens in terms of compliance (p=0.4611). Change in urinary NTX-1 did not show any difference between the two regimens. At the final visit, 51% of patients in the flexible and 55% in the fixed regimen group considered the used risedronate regimen as excellent or very good (p=0.1440)., Conclusion: A flexible dosing with daily risedronate appears be a valuable option in terms of compliance and persistence for patients with postmenopausal OP.

Objective: The aim of this study was to determine whether calcium supplementation, compared with placebo, increases urine calcium concentrations to levels indicative of increased renal stone risk, and the role that fluid intake, as indicated by urine volume, may play in mitigating this risk., Methods: This is a secondary analysis of data from a randomized placebo-controlled trial of 500 mg/d calcium supplementation to prevent bone loss. Subjects were 240 white postmenopausal women age 40 to 70 years in good general health. Effects of supplementation on 1-year changes in 24h urine calcium concentration and urine volume were examined., Results: Both treatment group and urine volume were strong independent predictors of urine calcium concentration (p < 0.001). Among subjects with urine volume under 2 L/24 h, more than half of placebo subjects were at lowest risk for renal stones compared with less than 35% of calcium-supplemented subjects. Among those with higher urine volumes, all placebo subjects and more than 80% of calcium supplemented subjects were at lowest risk., Conclusions: The increased risk of renal stones with calcium supplement use may be largely eliminated with adequate fluid intake, but older adults may not spontaneously consume adequate fluids to minimize this risk and should be counseled to do so.

Background: In spite of several studies, the impact of homocysteine level and folic acid supplementation on bone metabolism is yet to be recognized. In this registered clinical trial (IRCT2014042217385N1), we aimed to find out the power of 6-month folic acid supplementation on homocysteine level and bone metabolism., Methods: Forty postmenopausal osteoporotic women (50 to 87 years) were enrolled in the study. All participants were randomized to receive folic acid 1 mg (n = 17) or placebo (n = 14). At baseline, 3 months, and finally 6 months post intervention, the level of homocysteine, vitamin B12, and bone biomarkers were measured., Results: Both groups were similar at baseline. The homocysteine decreased in both groups but statistically non-significant (P > 0.05). The changes of the serum level of vitamin B12, osteocalcin, and β cross laps were significant between groups after 6 months (P ≤ 0.05)., Conclusion: The trend of changes of bone biomarkers after 6 months folic acid supplementation shows that homocysteine concentration and/or folic acid supplementation have impact on the rate of bone metabolism. However, further investigations by larger sample size and differentiating age and gender are still needed to clarify the exact role of folate, homocysteine and vitamin B12.

Unlabelled: Response to therapy depends on patient compliance but accurate assessment is difficult and adequate levels of adherence are uncertain. Adherence to raloxifene treatment may be assessed more accurately by electronic monitoring than by counting returned tablets. The level of adherence is positively associated with the degree of bone response., Introduction: Adherence to study medication is usually estimated by counting returned tablets. This method relies on subjects' honesty and may be inaccurate. We aimed to assess adherence more accurately, and examine its effect on measures of bone response, by using electronic monitoring., Methods: Osteopenic women, ages 50 to 80, were prescribed daily raloxifene for 2 years. Electronic bottle caps (Medication Event Monitoring System (MEMS), Aardex) recorded the date and time on opening. Returned tablets were also counted. We measured bone mineral density (BMD) in duplicate at the spine and hip at baseline and 2 years. We also measured urinary N-terminal cross-linked telopeptide of type I collagen (NTX) at baseline, 1 and 2 years. We calculated the percentage changes in BMD and NTX from mean baseline to mean follow up measurements. Percentage adherence was assessed by both methods for 71 subjects that completed the study., Results: The two methods correlated significantly (p <0.001, Spearman's rho = 0.73) but the tablet count showed a higher median adherence than the MEMS caps (95.7 vs. 85.0%, p <0.001), with greater divergence at lower adherence levels. MEMS adherence in 65 subjects with complete data correlated with NTX response (p <0.01, rho = -0.33) but with BMD response only at the femoral neck. However, adherence in the lowest quartile was associated with poorer BMD response at all sites (p <0.05)., Conclusion: Tablet counts may give similar results overall but conceal substantial individual non-adherence. Monitoring caps may assess adherence more accurately than tablet counts and would be the preferred method in clinical trials. The degree of adherence is associated with both bone turnover and BMD responses to anti-resorptive therapy.

Aim: A lack of estrogen in postmenopausal women is an important factor causing the development of osteoporosis. Our purpose is to investigate the effects of Fibroblast Growth Factor 23 (FGF-23) on bone mineral metabolism and bone turnover., Methods: Twenty-eight patients with postmenopausal osteoporosis (PMO), 32 patients with postmenopausal osteopenia and 30 healthy control subjects (postmenopausal non-osteoporosis) were included in this study. In order to assess the bone mineral metabolism; FGF 23, parathyroid hormone, vitamin D, calcium, phosphate, osteocalcin, alkaline phosphatase and hydroxyproline levels were measured., Results: FGF 23 levels were found significantly higher in PMO group compared with postmenopausal osteopenia and control groups (P<0.01 and P<0.05 respectively). Urine hydroxyproline level was detected to be significantly lower in PMO patients compared with control group (P<0.01). Lomber and femur BMD levels were found to be significantly lower in PMO patients compared with postmenopausal osteopenia and control groups (P<0.001, P<0.001; P<0.001, P<0.001 respectively). On the other hand, when we categorized the PMO group subjects according to the age of menopause, the FGF 23 levels were found to be significantly higher in the group of menopausal age <5 years compared to the group of menopausal age >10 and to the group of menopausal age 5-10 years (P<0.05, P<0.05)., Conclusion: We think our findings indicate that serum FGF 23 level is a significant determinant of increased bone turnover at early periods in PMO patients.

Objective: Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity., Methods: Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women., Results: Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m² and smallest in women with BMI >30 kg/m². Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI., Summary: During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.

The purpose of the present study was to precisely compare both the efficacy and abdominal symptom-related quality of life after treatment with daily minodronate and weekly alendronate in patients with primary postmenopausal osteoporosis. The efficacy of the two drugs was assessed based on improvements in a bone turnover marker, back pain, and gastrointestinal symptoms that impair quality of life, which was assessed using the Izumo scale questionnaire. In the minodronate group, there were no significant changes during the treatment period in the specific scores for heartburn, epigastralgia and epigastric fullness, whereas all of the scores were significantly elevated at some time point after drug administration in the alendronate group. Urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, and bone-specific alkaline phosphatase, a bone formation marker, significantly decreased in both groups, but decreases in uNTX in the minodronate group was observed significantly earlier compared with those in the alendronate group. The back pain scores, which were obtained using a visual analog scale, were significantly reduced in both groups. However, analgesic effects were detected earlier in the minodronate group. In conclusion, compared with weekly alendronate, daily minodronate improved bone turnover and back pain more promptly without causing upper gastrointestinal symptoms.

Unlabelled: We measured urinary N-telopeptide of type I collagen (U-NTX) to monitor response to bisphosphonates for osteoporosis. Decrease in U-NTX was associated with increase in spine bone density. A lesser response in U-NTX was more likely in those with secondary osteoporosis or with poor compliance. U-NTX may be a useful early indicator of treatment non-compliance or secondary osteoporosis., Introduction: This study aims to determine the utility of the bone resorption marker, U-NTX, in the clinical setting, to monitor the response to bisphosphonate therapy (alendronate and risedronate) for osteoporosis., Methods: A retrospective evaluation of data collected as part of the bone turnover marker monitoring service in the Metabolic Bone Centre, Sheffield, UK. Treatment compliance, underlying causes of osteoporosis, change in U-NTX/creatinine (Cr) at 4 months and change in spine and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry were recorded. Treatment response was defined as either a change in U-NTX/Cr greater than a pre-defined least significant change (LSC) of 54 % or to within the lower half of a pre-defined pre-menopausal reference interval (≤ 30 nM BCE/mmol Cr)., Results: A greater decrease in U-NTX/Cr at 4 months was associated with a greater increase in spine BMD at 18 months (r = -0.33; P < 0.0001, Pearson's correlation). The mean U-NTX/Cr at 4 months was higher in patients with secondary osteoporosis compared with those with primary osteoporosis (P < 0.01, ANOVA). A lesser response in U-NTX/Cr increased the likelihood of secondary osteoporosis or poor treatment compliance (P = 0.04, Fisher's exact test). A lack of response in U-NTX/Cr to within the lower half of the reference interval was a better indicator of secondary osteoporosis and treatment non-compliance than a change in U-NTX/Cr greater than LSC., Conclusions: Treatment monitoring using U-NTX/Cr has a place in clinical practice for the early identification of non-compliance or presence of secondary osteoporosis.

Bone metabolism is assessed using biochemical bone turnover markers (BTM). BTM reflect the metabolic effect of drugs on bone turnover, help to establish the lowest dose inducing the largest change in the BTM, predict treatment-related reduction in fracture risk, and are helpful in bridging studies. Changes in BTM during anti-osteoporotic therapy depend on the cellular mechanism of action of the drug, degree of change in bone turnover rate and route of administration. BTM help to establish the optimal dose of anti-osteoporotic drugs because treatment-related changes in BTM are more rapid compared with change in BMD. A greater decrease in BTM levels during the first year of tantiresorptive treatment is associated with greater antifracture efficacy over 3 years. According to preliminary data, measurement of BTM can improve persistence with anti-resorptive treatment. The use of BTM to monitor anti-osteoporotic therapy in "real life" is limited at this stage., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Vitamin D insufficiency is prevalent in osteopenic and osteoporotic postmenopausal women. The persistent increase in circulating parathyroid hormone (PTH) caused by vitamin D insufficiency reduces bone density response to antiresorptive agents in these postmenopausal women. It is not well known whether administration of raloxifene might increase serum PTH secondary to the suppression of serum calcium in postmenopausal women with osteopenia or osteoporosis. We tried to assess whether raloxifene might affect serum PTH and whether the addition of alfacalcidol to raloxifene therapy could have favorable effects on bone mineral density (BMD) and bone turnover as compared to raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopenia (≤2.0 SD based on young Japanese women). A total of 169 subjects were randomly assigned to groups receiving 60 mg raloxifene (R), or 1 μg alfacalcidol (D), or a combination of both (R + D) for 2 years. Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured at randomization. The modified 'intention to treat' method was used. We compared the groups using a Tukey-Kramer test for changes in L- and TH-BMD and calcium metabolism when significant differences were found using one-way ANOVA. The parameters in each group during the experimental period were analyzed by means of paired t tests. Baseline 25(OH)D and i-PTH were 23.7 ng/ml and 38.4 pg/ml, respectively. At 6 months, i-PTH demonstrated a significant increase (+21.0%) in the R-group whereas significant decreases in i-PTH were observed in the D-group and combination-group (-15.9 and -8.9%, respectively). There were significant increases in L-BMD in the R + D-group (+4.1% at 1 year and +4.7% at 2 years, P < 0.0001) and in the R-group (+2.9% at 1 year and +2.8% at 2 years, P < 0.001), but the difference between the groups did not reach a significant level. Vitamin D status at randomization did not affect the subsequent BMD response in coadministration of alfacalcidol with raloxifene. Supplementation with alfacalcidol to raloxifene therapy demonstrates a greater bone-sparing effect by suppressing the secondary increment of serum PTH than when raloxifene is used alone.

In order to compare the possible relationship between urinary concentrations of boron, calcium, magnesium and phosphorus in serum and urine of postmenopausal women with and without osteoporosis, we selected 45 postmenopausal women over 47 years of age, divided into two groups: group I clinically healthy postmenopausal women and group II postmenopausal women with osteoporosis, without chronic kidney and hepatic diseases or diabetes mellitus. We determined the boron (B), phosphorus (P), total calcium (Ca) and total magnesium (Mg) in the urine of two hours, by atomic emission spectroscopy with induction-coupled plasma (ICPA-ES). Total calcium and total magnesium in serum were determined by atomic flame absorption spectroscopy (FAAS) and inorganic phosphorus in serum, and creatinine in serum and urine, by molecular absorption spectrometry. The preliminary results suggest the existence of a significant difference (p < 0.05) in boron and phosphorus concentrations in the urine of two hours between the groups. The model of linear regression analysis used showed a relationship between urinary concentrations of boron/creatinine index and calcium/ creatinine, magnesium/creatinine and phosphorus/creatinine indexes in the urine of postmenopausal women with osteoporosis.

Objective: To determine the prevalence of hypercalciuria (HC) in postmenopausal women with osteoporosis and its relationship with clinical data and bone mineral metabolism., Subjects and Methods: Calciuria was measured in 24-hour urine samples of 127 women. BMD was measured in the lumbar spine and femur by dual-energy X-ray absorptiometry (DXA)., Results: Mean age (±SD) was 64 (±8) years. According to urinary calcium excretion, patients were divided into normo- and hypercalciuric (HC). Of the 127 patients, 19 (15%) were classified as HC. The only difference between the groups was the age of onset of menopause (46 ± 6 vs. 50 ± 3 years HC, p < 0.0005). No association was found between calciuria and age, BMI, BMD, calcium, phosphorus, PTH, and alkaline phosphatase., Conclusion: HC is frequent in postmenopausal women with osteoporosis, and calciuria measurement should be included in the investigation of these patients.

Intramuscularly administered elcatonin (ECT) reduces pain via the central nervous system. A prospective study was performed to determine whether ECT has a beneficial effect on back pain and function in postmenopausal women with osteoporosis during bisphosphonate therapy. Sixty-one postmenopausal osteoporotic women with back pain (mean age: 73.7 years, range: 54-96 years) were divided into two groups: the control group (n=30) and the ECT (intramuscular, 20 units a week) group (n=31). All patients received treatment with risedronate (17.5 mg weekly). The duration of the study was 8 weeks. Urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX), visual analogue scale (VAS) for back pain at rest and movement, and Roland-Morris Disability Questionnaire (RDQ) score for function were assessed. Urinary NTX levels, VAS at rest and movement, and RDQ score markedly decreased during 8 weeks of treatment in both ECT and control groups. A significant reduction in VAS at movement, but not in VAS at rest and RDQ score, was noted in the ECT group than in the control group. This effect was observed from 2 weeks after the start of therapy. These results suggested that ECT in combination with risedronate was more effective than risedronate alone for reducing back pain in postmenopausal women with osteoporosis.

Objective: The aim of this study was to assess the factors associated with the effectiveness of treatment with alendronate (ALN) quantified by a reduction in urinary excretion of N-telopeptide (NTx)., Methods: The study is an observational, prospective, multicenter trial, with a 6-month follow-up. Postmenopausal osteoporotic women (densitometric criteria), who initiated treatment with ALN (70 mg/weekly) without previous treatment with antiresorptive agents (12 month) and calcitonin (6 month), were included. The assessment of NTx levels (nmol bone collagen equivalents/mmol creatinine) in the urine was performed at baseline and after completion of follow-up. A logistic regression model included "achieving a reduction in urinary NTx of at least 30% (minimal clinically significant change [MCSC])" as a dichotomous dependent variable and the following as independent variables: baseline urinary NTx levels, treatment compliance, years since diagnosis of menopause, ALN treatment duration, and treatment with calcium and vitamin D. Treatment compliance was assessed as the percentage of days of medication prescribed as a function of the time between the beginning and end of treatment. Good compliance was defined as a percentage between 80% and 120%., Results: The variables that reached statistical significance were baseline urinary NTx values (odds ratio, 1.052; 95% CI, 1.025-1.079) and compliance (odds ratio, 3.9; 95% CI, 1.5-10.1). Therefore, the women with good treatment compliance were almost 4 times more likely to achieve an MCSC in NTx levels, and the raise in one unit of urinary NTx baseline values increased by 5% of the probability of achieving MCSC., Conclusions: Treatment with ALN (70 mg/week) in women with postmenopausal osteoporosis effectively reduces the urinary excretion of the bone turnover biomarker NTx. The probability of achieving a clinically significant reduction is greater in those women with higher baseline levels of NTx and in women who comply with treatment.

Estrogen metabolites play important roles in the development of female-related disorders and homeostasis of the bone. To improve detectability, a validated gas chromatography-mass spectrometry (GC-MS) method was conducted with two-phase extractive ethoxycarbonlyation (EOC) and subsequent pentafluoropropionyl (PFP) derivatization was introduced. The resulting samples were separated through a high-temperature MXT-1 column within an 8 min run and were detected in the selected ion monitoring (SIM) mode. The optimized analytical conditions led to good separation with a symmetric peak shape for 19 estrogens as their EOC-PFP derivatives. The limit of quantification (LOQ) was from 0.02 to ∼0.1 ng/ml for most estrogens analyzed, except for 2-hydroxyestriol (0.5 ng/ml). The devised method was found to be linear (r² > 0.995) in the range from the LOQ to 40 ng/ml, whereas the precision (% CV) and accuracy (% bias) ranged from 1.4 to 10.5% and from 91.4 to 108.5%, respectively. The good sensitivity and selectivity of this method even allowed quantification of the estrogen metabolites in urine samples obtained from the postmenopausal female patients with osteoporosis. The present technique can be useful for clinical diagnosis as well as to better understand the pathogenesis of estrogen-related disorders in low-level quantification.

Menopause and increasing age are associated with a decrease in calcium absorption that can contribute to the pathogenesis of osteoporosis. We hypothesized that alendronate plus vitamin D(3) (ALN + D) would increase fractional calcium absorption (FCA). In this randomized, double-blind, placebo-controlled multicenter clinical trial, 56 postmenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations of 25 ng/mL or less and low bone mineral density (BMD) received 5 weekly doses of placebo or alendronate 70 mg plus vitamin D(3) 2800 IU (ALN + D). Calcium intake was stabilized to approximately 1200 mg/d prior to randomization. FCA was determined using a dual-tracer stable-calcium isotope method. FCA and 25(OH)D were similar between treatment groups at baseline (0.31 ± 0.12 ng/mL and 19.8 ± 4.7 ng/mL, respectively). After 1 month of treatment, subjects randomized to ALN + D experienced a significant least squares (LS) mean [95% confidence interval (CI)] increase in FCA [0.070 (0.042, 0.098)], whereas FCA did not change significantly in the placebo group [-0.016 (-0.044, 0.012)]. After ALN + D treatment, patients had higher 25(OH)D levels (LS mean difference 7.3 ng/mL, p < .001). The rise in serum 1,25-dihydroxyvitamin D(3) (p < .02) and parathyroid hormone (p < .001) were greater in the ALN + D group than in placebo-treated patients. ALN + D was associated with an increase in FCA of 0.07. To our knowledge, there is no other trial showing such a marked rise in calcium absorption owing to treatment with a bisphosphonate or owing to a small rise in 25(OH)D. This unique response of ALN + D is important for the treatment of osteoporosis, but the exact mechanism requires further study., (Copyright © 2011 American Society for Bone and Mineral Research.)

Objective: The aim of this study was to assess the effects of zoledronic acid and raloxifene on bone turnover markers., Methods: This multicenter, randomized, double-blind study involved 110 postmenopausal women with low bone mineral density who received either a single intravenous infusion of zoledronic acid 5 mg or 6 months of daily oral raloxifene 60 mg. The primary efficacy variable was change from baseline in the bone resorption marker urine N-telopeptide of type I collagen. The secondary efficacy variable was change from baseline in the bone formation marker serum bone-specific alkaline phosphatase. Analysis time points were at 2, 4, and 6 (primary) months., Results: At 6 months, zoledronic acid produced a significantly greater reduction than did raloxifene in urine N-telopeptide of type I collagen (P < 0.001). Zoledronic acid also yielded significantly greater decreases in urine N-telopeptide of type I collagen at 2 and 4 months and in serum bone-specific alkaline phosphatase at all time points (P < 0.001 vs raloxifene for all comparisons). Both treatments were well tolerated. More adverse events occurred in the zoledronic acid group; these were primarily transient postdose symptoms that occurred within the first 3 days after the infusion., Conclusions: Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass.

Unlabelled: Apparent failures of bone mineral density (BMD) response to teriparatide at spine or hip occur even in a high compliance context (15% spine and 55% hip). Apparent non-responders nevertheless show good biomarker response, suggesting that apparent BMD non-response is due to measurement imprecision. Calcium intake may be an important determinant of hip response., Introduction: Individuals vary in response to bone active agents, but that variability is poorly quantified and its basis is not well understood. The study included 203 postmenopausal women with moderately severe osteoporosis, all treated with teriparatide, calcium, and vitamin D. The study was performed at the Creighton University Medical Center, a single site., Methods: This is a prospective study of change in bone mineral density and resorption biomarkers over a 12-month treatment period. BMD response at spine and total hip was quantified by computing slopes for each participant's values, and biomarker change by the difference in values across the 12-month study period., Results: Of the total number of participants, 85.2% exhibited a significant spine BMD response, while only 44.8% had a significant change at the hip. However, mean biomarker response was marginally larger for the BMD non-responders at either site than for the responders, indicating biological, if not measurable densitometric, activity of teriparatide in essentially all participants., Conclusions: Occasional apparent failures of BMD response in patients receiving teriparatide are probably not due to failure of response at the level of the bone remodeling apparatus, but instead reflect a combination of measurement imprecision and variable bone remodeling balance. The reason for the latter remains unclear.

Osteoporosis occurs when there is an imbalance between resorption and formation of bone, with resorption predominating. Inhibitors of cathepsin K may rebalance this condition. This is the first efficacy study of a new cathepsin K inhibitor, ONO-5334. The objective of the study was to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double-blind, placebo- and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Subjects included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment arms: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg once weekly. Lumbar spine, total hip, and femoral neck BMD values were obtained along with biochemical markers of bone turnover and standard safety assessments. All ONO-5334 doses and alendronate showed a significant increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little or no suppression of ONO-5334 on bone-formation markers compared with alendronate, although the suppressive effects on bone-resorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. Further clinical studies are warranted to investigate long-term efficacy as well as safety of ONO-5334., (Copyright © 2011 American Society for Bone and Mineral Research.)

Our objective in this study was to determine the effects of a high-protein and high-potential renal acid load (PRAL) diet on calcium (Ca) absorption and retention and markers of bone metabolism. In a randomized crossover design, 16 postmenopausal women consumed 2 diets: 1 with low protein and low PRAL (LPLP; total protein: 61 g/d; PRAL: -48 mEq/d) and 1 with high protein and high PRAL (HPHP; total protein: 118 g/d; PRAL: 33 mEq/d) for 7 wk each separated by a 1-wk break. Ca absorption was measured by whole body scintillation counting of radio-labeled (47)Ca. Compared with the LPLP diet, the HPHP diet increased participants' serum IGF-I concentrations (P < 0.0001), decreased serum intact PTH concentrations (P < 0.001), and increased fractional (47)Ca absorption (mean ± pooled SD: 22.3 vs. 26.5 ± 5.4%; P < 0.05) and urinary Ca excretion (156 vs. 203 ± 63 mg/d; P = 0.005). The net difference between the amount of Ca absorbed and excreted in urine did not differ between 2 diet periods (55 vs. 28 ± 51 mg/d). The dietary treatments did not affect other markers of bone metabolism. In summary, a diet high in protein and PRAL increases the fractional absorption of dietary Ca, which partially compensates for increased urinary Ca, in postmenopausal women. The increased IGF-I and decreased PTH concentrations in serum, with no change in biomarkers of bone resorption or formation, indicate a high-protein diet has no adverse effects on bone health.

The aim of this study was to determine whether the bone-resorption response to anastrozole differed according to initial patient age in postmenopausal women with breast cancer in a cross-sectional study. Second-morning void urines were collected for measurement of urinary cross-linked N-telopeptide of type I collagen (uNTx, corrected for creatinine and log-transformed) from postmenopausal women, 99 with breast cancer on anastrozole (ABC), 88 with newly diagnosed breast cancer (NDBC), and 137 community-dwelling healthy control (HC) women. Bone mineral density (BMD) was also measured at the lumbar spine (LS, L2-L4) and the femoral neck (FN) in the ABC group. uNTx (nanomole bone collagen equivalents/millimole creatinine) levels increased with age in HC subjects. In patients <70 years, anastrozole treatment led to a significant increase in uNTx compared with age-related HC subjects (1.74 vs. 1.55, P < 0.005). Patients >70 years showed no such increase compared to HC (1.72 vs. 1.69, nonsignificant); however, NDBC women >70 years had uNTx levels significantly lower than HC women (1.59 vs. 1.69, P < 0.05). There was no difference in uNTx levels above and below the age of 70 years in NDBC women (1.56 vs. 1.59, nonsignificant). ABC women were more likely to have a positive LS BMD z score than age-matched controls. Anastrozole treatment increases bone turnover more in younger postmenopausal women with breast cancer than in older women compared to healthy controls. Higher LS BMD in ABC patients may help protect against fracture.

The aim was to evaluate the influence of dietary Ca-Mg-phytate consumption on the bone characteristics of ovariectomized rats, an animal model for postmenopausal osteoporosis. Twenty ovariectomized female Wistar rats were randomly assigned to two groups fed, respectively, with a non-phytate diet (AIN-76A) or the same diet enriched with 1% phytate (as the calcium magnesium salt, phytin). After 12 weeks of feeding the rats were sacrificed, and both femoral bones and L4 vertebra were removed from each rat. Bone mass, length, width, volume, and mineral density were measured, and the phosphorus, calcium, magnesium, and zinc contents of bones were determined. Deoxypyridinoline (a bone resorption marker) was measured in urine, and osteocalcin (a bone formation marker) was measured in serum. The calcium and phosphorus contents and bone mineral density were significantly higher in both femoral bones and L4 vertebra for phytate-treated rats in comparison to rats in the non-phytate group. Deoxypyridinoline was significantly increased in rats in the non-phytate treatment group. Ca-Mg-phytate consumption reduces bone mineral density loss due to estrogen deficiency. Thus, phytate exhibits effects similar to those of bisphosphonates on bone resorption and may be of use in the primary prevention of osteoporosis if larger studies in humans confirm these findings.

Summary: Urinary deoxypyridinoline (DPD) level was associated with prevalent vertebral fractures in glucocorticoid (GC)-treated postmenopausal women independently of lumbar spine bone mineral density (BMD)., Introduction: Bone metabolic indices are the potential predictors of bone fragility. However, their diagnostic efficiency for identifying the risk of GC-induced vertebral fractures is still unclear. We therefore evaluated whether bone metabolic indices would assess the risk of vertebral fractures in GC-treated women., Methods: One hundred seventy-five women treated with GC for more than 6 months were enrolled in this study., Results: Both premenopausal and postmenopausal women with vertebral fractures had significantly higher urinary DPD levels than those without vertebral fractures. When multivariable logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each of DPD or osteocalcin level adjusted for age, weight, height, current and maximum doses of GC, duration of GC treatment, as well as lumbar spine BMD as an independent variable, DPD level was identified as a factor associated with the presence of vertebral fractures in postmenopausal women but not in premenopausal women., Conclusion: Urinary DPD level was significantly associated with prevalent vertebral fractures in GC-treated postmenopausal women independently of lumbar spine BMD.

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.

Patients who are diagnosed with osteoporosis and beginning treatment often discontinue their osteoporosis medication relatively early after the start of treatment because of their poor recognition of fracture risk and the asymptomatic nature of osteoporosis. In this study we aimed to assess adherence to treatment with 1 microg alfacalcidol (D), 60 mg raloxifene (R) or a combination of both (D + R) for 1 year in postmenopausal Japanese women with osteoporosis or osteopenia. We defined persistence of D and R as continuing to take tablets for more than 7 of any 14 days immediately before the 1-year visit. A total of 137 subjects aged 49-81 years [64.9 +/- 7.0 years, 16.0 +/- 12.7 years since menopause (YSM)] were randomly assigned to each treatment group. The proportions persisting with each treatment group at 1 year were 61.4, 65.3, 55.1% for D, R and D + R groups, respectively whereas the compliance to each therapy as judged by the medical possession ratio (MPR) at 1 year were 77.5, 93.8, 78.4%, respectively. There were no significant differences in persistence, compliance and the number of subjects who discontinued treatment due to adverse events among each group. We found significant inverse correlations in percent changes at 1 year between compliance and serum BAP in R and D + R groups or urinary (u-) CTX in the R group. The changes in the level of serum BAP and u-CTX were significantly higher in high-compliance patients (MPR > 80%) treated with raloxifene alone or concomitantly with alfacalcidol compared to those in low-compliance patients.

Background: Increased body burden of environmental cadmium has been associated with greater risk of decreased bone mineral density (BMD) and osteoporosis in middle-aged and older women, and an inverse relationship has been reported between follicle-stimulating hormone (FSH) and BMD in middle-aged women; however, the relationships between cadmium and FSH are uncertain, and the associations of each with bone loss have not been analyzed in a single population., Objectives: The objective of this study was to evaluate the associations between creatinine-adjusted urinary cadmium (UCd) and FSH levels, and the associations between UCd and FSH with BMD and osteoporosis, in postmenopausal and perimenopausal women aged 42-60 years., Methods: Data were obtained from the Third National Health Examination and Nutrition Survey, 1988-1994 (NHANES III). Outcomes evaluated were serum FSH levels, femoral bone mineral density measured by dual energy X-ray absorptiometry, and osteoporosis indicated by femoral BMD cutoffs based on the international standard. Urinary cadmium levels were analyzed for association with these outcomes, and FSH levels analyzed for association with bone effects, using multiple regression. Subset analysis was conducted by a dichotomous measure of body mass index (BMI) to proxy higher and lower adipose-synthesized estrogen effects., Results: UCd was associated with increased serum FSH in perimenopausal women with high BMI (n=642; beta=0.45; p< or =0.05; R(2)=0.35) and low BMI (n=408; beta=0.61; p< or =0.01; R(2)=0.34). Among perimenopausal women with high BMI, BMD was inversely related to UCd (beta=-0.04; p< or =0.05) and FSH (beta=-0.03; p< or =0.05). In postmenopausal women with low BMI, an incremental increase in FSH was associated with 2.78 greater odds for osteoporosis (109 with and 706 without) (OR=2.78; 95% CI=1.43, 5.42; p< or =0.01)., Conclusion: Long-term cadmium exposure at environmental levels is associated with increased serum FSH, and both FSH and UCd are associated with bone loss, in US women aged 42-60 years.

Background: The role of bisphosphonates (BPs) in the management of patients with hypercalciuria (HC) associated with osteoporosis is still uncertain. The aim of the study was to evaluate the effect of alendronate and indapamide alone or in combination on bone mineral density (BMD) and 24-h urinary calcium excretion (24-CaU) in post-menopausal women with HC and low BMD., Methods: A total of 77 post-menopausal women with HC (24-CaU > 4 mg/kg/day) and low BMD [T-score < -2.0 at lumbar spine (LS), femoral neck (FN) or total hip (TH)] from two centres of Northern Italy were randomized to receive indapamide 2.5 mg daily alone (24 patients, IND group), alendronate 70 mg weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN + IND group). Throughout the study, all subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1000 mg. Patients were instructed to increase water intake up to 2000 mL daily. The percentage and absolute changes of BMD at LS, FN and TH, and the variation of 24-CaU from baseline at 1 year were the primary outcomes. Serum calcium, phosphate, parathyroid hormone and bone alkaline phosphatase were also measured., Results: Overall 67 women completed the study and were included in the final analysis. Patients in the three groups were similar with regard to baseline characteristics. BMD did not significantly change from baseline after 1 year of treatment with indapamide (LS: +1 +/- 3.1%; FN: -0.3 +/- 3.5%; TH: -0.4 +/- 3.1%), while it showed a significant increase from baseline in the other two groups (ALN; LS: +5.8 +/- 4.2%, P < 0.001; FN: +3.9 +/- 7.9%, P = 0.018; TH: +2 +/- 3.6%, P = 0.006) (ALN + IND; LS: +8.2 +/- 5.3%, P < 0.001; FN: +4.9 +/- 6.7%, P = 0.007; TH: +2.9 +/- 4.2%, P = 0.004). Patients in the combination group showed a significantly higher increase of BMD at LS compared to ALN (P = 0.04). After 1 year, 24-CaU values significantly decreased from baseline in all groups (IND, 239 +/- 78 versus 364 +/- 44, P < 0.001) (ALN, 279 +/- 68 versus 379 +/- 79, P < 0.001) (ALN + IND, 191 +/- 68 versus 390 +/- 55, P < 0.001). The mean percentage decrease of 24-CaU in ALN + IND group (-50%) was significantly greater compared to ALN (-24%, P < 0.001) and IND (-35%, P = 0.012)., Conclusions: These results show a benefit, in terms of BMD improvement and 24-CaU reduction, associated with BPs' therapy in combination with indapamide in HC associated with osteoporosis. The combination therapy demonstrated a reduction of 24-CaU and an increase in LS BMD superior to that observed with alendronate alone. Our results support a new potential approach with BPs associated with thiazide diuretics or indapamide in the management of post-menopausal women with HC and associated bone loss. Studies on the larger sample size are needed to demonstrate the efficacy on the fracture outcome.

Objectives: To review the clinical value of bone turnover markers (BTM), to initiate and/or monitor anti-resorptive treatment for osteoporosis compared with bone mineral density (BMD) and to evaluate suitable BTM and changes in BTM levels for significance of treatment efficiency., Methodology: Consensus meeting generating guidelines for clinical practice after review and discussion of the randomised controlled trials or meta-analyses on the management of osteoporosis in postmenopausal women., Results: Although the correlation between BMD and BTM is statistically significant, BTM cannot be used as predictive markers of BMD in an individual patient. Both are independent predictors of fracture risk, but BTM can only be used as an additional risk factor in the decision to treat. Current data do not support the use of BTM to select the optimal treatment. However, they can be used to monitor treatment efficiency before BMD changes can be evaluated. Early changes in BTM can be used to measure the clinical efficacy of an anti-resorptive treatment and to reinforce patient compliance., Discussion: Determining a threshold of BTM reflecting an optimal long-term effect is not obvious. The objective should be the return to the premenopausal range and/or a decrease at least equal to the least significant change (30%). Preanalytical and analytical variability of BTM is an important limitation to their use. Serum C-terminal cross-linked telopeptide of type I collagen (CTX), procollagen 1 N terminal extension peptide and bone specific alkaline phosphatase (BSALP) appear to be the most suitable., Conclusion: Consensus regarding the use of BTM resulted in guidelines for clinical practice. BMD determines the indication to treat osteoporosis. BTM reflect treatment efficiency and can be used to motivate patients to persist with their medication.

Purpose: Deoxypyridinoline (DPD) is a derivative of hydroxypyridinium, which is released during bone resorption into the blood stream and is eliminated unmodified with urine. A further collagen-derived marker of bone resorption is the C-terminal telopeptide of type I collagen (beta-CTX-I, here abbreviated as CTX), which is released in bone resorption and almost entirely excreted by the kidneys. The aim of our study was to investigate different well-described patient groups as well as normal probands in view of differences and expected correlations of these two parameters: patients with insulin-dependent diabetes mellitus, postmenopausal women with osteoporosis and healthy control persons., Materials and Methods: We used a solid-phase chemiluminescence enzyme immunoassay (Pyrilinks D-IMMULITE) for urinary DPD measurement and for the assessment of urinary CTX we used a quantitative ELISA (Osteometer Biotec A-S, CrossLaps ELISA)., Results: We found a highly significant correlation between both parameters in the group of healthy persons (r = 0.75, p < 0.05, n = 28) as well as in the group of patients with diabetes mellitus type I (r = 0.79, p < 0.05, n = 65). Also, a significant correlation was observed between DPD and CTX (r = 0.583, p < 0.05, n = 88) in the group of female osteoporotic patients., Conclusions: Despite good correlations between DPD and CTX in all of the investigated groups, these urinary markers were of limited diagnostic significance in the group of postmenopausal osteoporosis due to a wide spread (few patients showed concentrations above the range of healthy persons) in this newly diagnosed drug-naïve patient collective.

Objective: To study the relationship between bone markers and bone mineral density (BMD) in an effort to identify their utility in postmenopausal women with osteoporosis., Methods: Eighty-two consecutive postmenopausal women with untreated osteoporosis were included in the study. Forearm, spinal, and femoral BMD by dual-energy x-ray absorptiometry and markers of bone formation (serum osteocalcin and bone-specific alkaline phosphatase) and bone resorption (urinary free deoxypyridinoline) were measured in all patients. Patients with low serum vitamin D levels, secondary osteoporosis, or clinically significant systemic disease were excluded from the study. The patients were classified on the basis of BMD of the lumbar spine into the following 3 groups: mild (n = 23) (T score -2.5 through -3), moderate (n = 42) (T score -3.1 through -4), or severe (n = 17) (T score