Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contains some typos in Figs. 2, 3, 4, and Supplemental Fig. 1. The corrected figures are given below.

Correction to: Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

The original version of this article, published on 21 March 2019, unfortunately contained a mistake.

Osteoporotic fracture trends in a population of US managed care enrollees from 2007 to 2017.

This study expands on previous findings that hip fracture rates may no longer be declining. We found that age- and sex-adjusted fracture rates in the US plateaued or increased through mid-2017 in a population of commercially insured and Medicare Advantage health plan enrollees, in contrast to a decline from 2007 to 2013. INTRODUCTION: The purpose of this study was to evaluate fracture trends in US commercial and Medicare Advantage health plan members aged ≥ 50 years between 2007 and 2017. METHODS: Retrospective analysis of the Optum Research Database from January 1, 2007, to May 31, 2017. RESULTS: Of 1,841,263 patients identified with an index fracture, 930,690 were case-qualifying and included in this analysis. The overall age- and sex-adjusted fracture rate decreased from 14.67/1000 person-years (py) in 2007 to 11.79/1000 py in 2013, followed by a plateau for the next 3 years and then an increase to 12.50/1000 py in mid-2017. In females aged ≥ 65 years, fracture rates declined from 27.49/1000 py in 2007 to 22.08/1000 py in 2013, then increased to 24.92/1000 py in mid-2017. Likewise, fracture rates in males aged ≥ 65 years declined from 2007 (12.00/1000 py) to 2013 (10.72/1000 py), then increased to 12.04/1000 py in mid-2017. The age- and sex-adjusted fracture rates for most fracture sites declined from 2007 to 2013 by 3.7% per year (P = 0.310). CONCLUSIONS: Following a consistent decline in fracture rate from 2007 to 2013, trends from 2014 to 2017 indicate fracture rates are no longer declining and, for some fracture types, rates are rising.

Abaloparatide for risk reduction of nonvertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis.

This network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options. INTRODUCTION: This network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO). METHODS: PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches. RESULTS: A total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04-0.34), the NVF network (RR = 0.50; 95% CrI 0.28-0.85), and the wrist fracture network (RR = 0.39; CrI 0.15-0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons. CONCLUSIONS: This NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA.

Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

PURPOSE: Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. METHODS: Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). RESULTS: After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p < 0.001) and 1.54 percentage points greater for abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p < 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for abaloparatide compared with placebo (-0.42; 95% CI -1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (-1.66%; 95% CI -2.27, -1.06; p < 0.001). The decline with abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p < 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11). CONCLUSIONS: Compared with teriparatide, abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with abaloparatide.

Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability.

We evaluated the efficacy of abaloparatide in women who were at increased risk for fracture, based on CHMP recommended risk thresholds, at the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) study baseline. Among patients at high risk based on FRAX probabilities, 18 months of abaloparatide significantly decreased risk for all fracture endpoints compared with placebo. PURPOSE: Abaloparatide, a novel anabolic agent for the treatment of postmenopausal osteoporosis, significantly reduced the risk of vertebral and nonvertebral fractures in the ACTIVE study compared with placebo. In this post hoc analysis, we evaluated abaloparatide's efficacy in a subset of women in the study at an increased risk of fracture at baseline, based on the Committee for Medicinal Products for Human Use (CHMP) recommended risk thresholds for inclusion in clinical trials. METHODS: Women with a baseline 10-year risk of major osteoporotic fracture ≥ 10% or hip fracture ≥ 5%, assessed using the FRAX® tool (including femoral neck bone mineral density), were included in the analysis. The proportion with one or more events of new morphometric vertebral fractures was calculated. Event rates for nonvertebral, major osteoporotic, and all clinical fractures were estimated using Kaplan-Meier analysis. RESULTS: Following 18 months of treatment, abaloparatide significantly reduced incident vertebral fractures compared with placebo (relative risk reduction = 91%; 0.5% versus 5.6%; p < 0.001). Abaloparatide treatment was also associated with significantly fewer nonvertebral, major osteoporotic, and clinical fractures compared with placebo: 2.7% versus 5.8%, p = 0.036; 1.3% versus 6.0%, p < 0.001; and 3.5% versus 8.2%, p = 0.006, respectively. The effect of abaloparatide on major osteoporotic fractures (78% reduction) was significantly greater than that seen with teriparatide (23% reduction, p = 0.007). CONCLUSION: In a subset of postmenopausal women at increased risk of fracture as judged by CHMP guidance, abaloparatide significantly decreased the risk of all fracture endpoints compared with placebo.

Bone turnover markers to explain changes in lumbar spine BMD with abaloparatide and teriparatide: results from ACTIVE.

Early PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents. INTRODUCTION: We evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an "uncoupling index" (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups. METHODS: Blood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient. RESULTS: Early BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P < 0.0001) with abaloparatide (r = 0.561) than teriparatide (r = 0.198). The mean UI at 1 month was greater for abaloparatide versus teriparatide (1.743 and 1.493, respectively; P = 0.03) but was similar at 3 months or later time points. CONCLUSIONS: Early s-PINP changes correlate with percentage change in lumbar spine BMD 18 months after treatment with both abaloparatide and teriparatide, though the correlation with abaloparatide was greater. The UI was similar between abaloparatide and teriparatide suggesting that the balance between formation and resorption markers was similar.

Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial.

BACKGROUND: Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE. METHODS: Proportions of patients experiencing BMD gains from baseline of >0%, >3%, and >6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites. RESULTS: At months 6, 12, and 18, there were significantly more >3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P < 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the >0% and >6% responder thresholds. CONCLUSIONS: In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.

Characteristics of recurrent fractures.

The present study, drawn from a sample of the Icelandic population, quantified high immediate risk and utility loss of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) that attenuated with time. INTRODUCTION: The risk of a subsequent osteoporotic fracture is particularly acute immediately after an index fracture and wanes progressively with time. The aim of this study was to quantify the risk and utility consequences of subsequent fracture after a sentinel fracture (at the hip, spine, distal forearm and humerus) with an emphasis on the time course of recurrent fracture. METHODS: The Reykjavik Study fracture registration, drawn from a sample of the Icelandic population (n = 18,872), recorded all fractures of the participants from their entry into the study until December 31, 2012. Medical records for the participants were manually examined and verified. First sentinel fractures were identified. Subsequent fractures, deaths, 10-year probability of fracture and cumulative disutility using multipliers derived from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) were examined as a function of time after fracture, age and sex. RESULTS: Over 10 years, subsequent fractures were sustained in 28% of 1498 individuals with a sentinel hip fracture. For other sentinel fractures, the proportion ranged from 35 to 38%. After each sentinel fracture, the risk of subsequent fracture was highest in the immediate post fracture interval and decreased markedly with time. Thus, amongst individuals who sustained a recurrent fracture, 31-45% did so within 1 year of the sentinel fracture. Hazard ratios for fracture recurrence (population relative risks) were accordingly highest immediately after the sentinel fracture (2.6-5.3, depending on the site of fracture) and fell progressively over 10 years (1.5-2.2). Population relative risks also decreased progressively with age. The utility loss during the first 10 years after a sentinel fracture varied by age (less with age) and sex (greater in women). In women at the age of 70 years, the mean utility loss due to fractures in the whole cohort was 0.081 whereas this was 12-fold greater in women with a sentinel hip fracture, and was increased 15-fold for spine fracture, 4-fold for forearm fracture and 8-fold for humeral fracture. CONCLUSION: High fracture risks and utility loss immediately after fracture suggest that treatment given as soon as possible after fracture would avoid a higher number of new fractures compared with treatment given later. This provides the rationale for very early intervention immediately after a sentinel fracture.

Feed and water deprivation has a negative but transient effect on the rumen kinetics of Bos indicus steers.

The effects on rumen kinetics after feed and water had been deprived for 72 hr were studied using four fistulated Bos indicus steers. The animals were assigned in a 2 × 4 crossover design with two treatments: feed and water ad libitum (control) and no feed and water for 72 hr (deprived) with four steers per treatment over two time periods. Feed and water deprivation caused decreases in the numbers of cellulolytic bacteria (1.4 vs. 0.4 cfu × 106 /ml; p = .001), live (23.7 vs. 0.8 × 109 /ml; p = .001), dead (12.7 vs. 0.5 × 109 /ml; p = .001) and total bacterial counts (36.4 vs. 1.4 × 109 /ml; p = .001) at day 0, compared with the control treatment. However, the deprived group had greater numbers of cellulolytic bacteria (2.7 vs. 50.1 cfu × 106 /ml; p = .001), live (18.3 vs. 42.2 × 109 /ml; p = .001), dead (6. 5 vs. 19.1 × 109 /ml; p = .001) and total bacterial counts (24.8 vs. 61.3 × 109 /ml; p = .001) from rumen fluid on day 4, compared with the control treatment. The numbers of protozoa in rumen fluid from the deprived group were less than (551.2 vs. 2.4 × 103 /ml; p = .001) the control group on day 0. However, the deprived treatment had fewer protozoa in rumen fluid than the control treatment on day 4 (p = .001) and day 9 (p = .001). Volatile fatty acids and in vitro gas production as functional measurements of rumen fluid followed the same trend as the bacterial and protozoa populations. These results indicate that feed and water deprivation would have a negative but transient effect on the rumen kinetics of Bos indicus steers.

Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial.

In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. INTRODUCTION: Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). METHODS: This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 µg), subcutaneous teriparatide (20 µg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. RESULTS: After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 µg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p < 0.05 for each). The TBS in the placebo group declined by 1.08%. The TBS increase in each treatment group was significantly higher than placebo at 24 weeks (p < 0.0001 for each) after adjustment for age, BMI, and baseline TBS. A dose-response was observed at 24 weeks across the three doses of abaloparatide-SC and placebo (p = 0.02). The increase in TBS in the abaloparatide-SC 80 µg group was significantly greater than TPTD (p < 0.03). CONCLUSIONS: These results are consistent with an effect of abaloparatide-SC to improve lumbar spine skeletal microarchitecture, as assessed by TBS.

Effect of hormonal synchronisation and/or short-term supplementation with maize on follicular dynamics and hormone profiles in goats during the non-breeding season.

This study aimed to evaluate the reproductive response of anoestrous goats that were either hormonally treated and/or supplemented with maize for 9days to determine which treatment combination was the most effective in enhancing follicular development and ovulation rate, and whether these responses were associated with increases in metabolic hormones. The experiment was carried out using 28 does, using a 2×2 factorial design with seven does in each group to test the effect of synchronisation of oestrus, supplementation with maize and their interactions. Synchronisation of oestrous cycles (P<0.001) but not supplementation with maize or the interaction between the two (P>0.05) increased the number of codominant follicles, the diameter of the largest follicle on Day 9 and growth rate of follicles during the period of supplementation. Compared with non-supplemented animals, supplementation with maize increased the total number of follicles observed between Days 7 and 9 (P=0.039). In addition, nutritional supplementation with maize in combination with synchronisation of oestrus increased the ovulation rate by 43% (P=0.074). Interactions between time and supplementation with maize showed that plasma concentrations of insulin, leptin and IGF-1 were greater in does supplemented with maize compared with non-supplemented does (P<0.001). The findings show that hormonal synchronisation had the most influence on modifying follicular development and ovulation in anoestrous goats. Supplementation with maize increased the concentrations of insulin, leptin and IGF-1, which could potentially modify the sensitivity of follicles to gonadotrophins and reduce rates of atresia.

Bos indicus cattle possess greater basal concentrations of HSP27, alpha B-crystallin, and HSP70 in skeletal muscle in vivo compared with cattle.

The objectives of the present study were to evaluate the basal concentrations of heat shock proteins (HSP) between and cattle and to determine if HSP basal concentrations change as an animal matures. A total of 40 cattle were used in a 2 × 2 factorial design to evaluate the effects of genotype and age (heifers and mature cows) on basal concentrations of heat shock protein 27 (HSP27), α B-crystallin (Cryab), and heat shock protein 70 (HSP70). Each experimental group of 10 animals was sampled on a separate day over a period of 4 wk during July 2014. A muscle sample was collected from the longissimus thoracis (LT) and concentrations of HSP were quantified using ELISA. There were no significant differences in HSP concentration for the interaction between age and genotype or for age alone. cattle had greater ( < 0.05) basal concentrations of HSP27, Cryab, and HSP70 in the LT than cattle. The results of this study show that basal in vivo HSP concentrations differ between and cattle. However, further studies are needed to investigate the relationship between HSP concentrations and meat tenderness with respect to genotypes to see if HSP concentrations account for at least some variability in tenderness differences.

Effects of rosiglitazone vs metformin on circulating osteoclast and osteogenic precursor cells in postmenopausal women with type 2 diabetes mellitus.

CONTEXT: Thiazolidinediones are associated with increased fractures in type 2 diabetes mellitus (T2D). One explanation is that activation of peroxisome proliferator-activated receptor-γ expression alters bone remodeling cells. OBJECTIVE: To investigate whether osteoclast and osteogenic precursor cells are altered by rosiglitazone (RSG) treatment in T2D as compared to metformin (MET) treatment. DESIGN: A randomized controlled trial of RSG or MET for 52 weeks, followed by 24 weeks of MET. SETTING: Data were generated at a tertiary care center. PATIENTS: Seventy-three T2D postmenopausal women participated. MAIN OUTCOME MEASURES: Peripheral blood mononuclear cells were isolated and cultured with receptor activator of nuclear factor κB ligand and stained for tartrate-resistant acid phosphatase to measure circulating osteoclast precursors. Peripheral blood mononuclear cells were also characterized for osteogenic, endothelial, and calcification markers by flow cytometry with the ligands osteocalcin (OCN), CD34, and CD 146. RESULTS: Tartrate-resistant acid phosphatase-positive cells increased between weeks 0 and 52 (RSG, 2.9 ± 2 to 14.0 ± 3 U/L, P = .001; MET, 3.3 ± 2 to 16.7 ± 2 U/L, P = .001), increasing further in the RSG group after changing to MET (to 26.5 ± 5 U/L, P = .05 vs wk 52). With RSG, OCN+ cells with CD34 but without CD146 fell from weeks 0 to 52 (20.1 ± 1% to 15.5 ± 2%; P = .03), remaining stable through week 76. The OCN+ cells lacking both CD34 and CD146 increased from weeks 0 to 52 (67.3 ± 2 to 74.4 ± 2%; P = .02), but returned to baseline after switching to MET. CONCLUSION: In postmenopausal women with T2D, circulating osteoclast precursor cells increase with both RSG and MET, and increase further when switching from RSG to MET. Subpopulations of cells that may be involved in the osteogenic lineage pathway are also altered with RSG. Further work is necessary to elucidate how these changes may relate to fracture risk.

Estimating prevalence of osteoporosis: examples from industrialized countries.

UNLABELLED: In nine industrialized countries in North America, Europe, Japan, and Australia, country-specific osteoporosis prevalence (estimated from published data) at the total hip or hip/spine ranged from 9 to 38 % for women and 1 to 8 % for men. In these countries, osteoporosis affects up to 49 million individuals. PURPOSE: Standardized country-specific prevalence estimates are scarce, limiting our ability to anticipate the potential global impact of osteoporosis. This study estimated the prevalence of osteoporosis in several industrialized countries (USA, Canada, five European countries, Australia, and Japan) using the World Health Organization (WHO) bone mineral density (BMD)-based definition of osteoporosis: BMD T-score assessed by dual-energy x-ray absorptiometry ≤-2.5. METHODS: Osteoporosis prevalence was estimated for males and females aged 50 years and above using total hip BMD and then either total hip or spine BMD. We compiled published location-specific data, using the National Health and Nutrition Examination Survey (NHANES) III age and BMD reference groups, and adjusted for differences in disease definitions across sources. Relevant NHANES III ratios (e.g., male to female osteoporosis at the total hip) were applied where data were missing for countries outside the USA. Data were extrapolated from geographically similar countries as needed. Population counts for 2010 were used to estimate the number of individuals with osteoporosis in each country. RESULTS: For females, osteoporosis prevalence ranged from 9 % (UK) to 15 % (France and Germany) based on total hip BMD and from 16 % (USA) to 38 % (Japan) when spine BMD data were included. For males, prevalence ranged from 1 % (UK) to 4 % (Japan) based on total hip BMD and from 3 % (Canada) to 8 % (France, Germany, Italy, and Spain) when spine BMD data were included. CONCLUSIONS: Up to 49 million individuals met the WHO osteoporosis criteria in a number of industrialized countries in North America, Europe, Japan, and Australia.

Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance. OBJECTIVE: The UGL-OR1001 trial aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. DESIGN: 24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide. PATIENTS OR OTHER PARTICIPANTS: Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents. INTERVENTION(S): Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control. MAIN OUTCOME MEASURE(S): The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1-L4 axial lumbar spine after 24 weeks in the rhPTH(1-31)NH(2) arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723. RESULTS: The oral tablet formulation of rhPTH(1-31)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline (p<0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p<0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1. CONCLUSIONS: In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1-31)NH(2) leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development.

Sex- and age-specific incidence of non-traumatic fractures in selected industrialized countries.

UNLABELLED: Various methodological approaches have estimated the incidence of osteoporosis-related fractures, making comparisons difficult. This study estimated the incidence rates of non-traumatic fractures in 12 countries using standard definitions. Applying these rates to the 2010 population figures of these countries, a total of 5.2 million non-traumatic fractures were estimated, mostly in women. PURPOSE: The purpose of this study was to estimate annual country-, sex-, and age-specific incidence of non-traumatic hip, vertebral, and other fractures for women aged ≥50 and men ≥60 years and the number of fractures expected in 12 countries based on these incidence rates. METHODS: Electronically indexed medical literature and relevant web sites were reviewed to identify studies reporting age- and sex-specific fracture incidence rates to obtain estimates of the proportion of fractures considered to be non-traumatic and to gather relevant census data. From these data, we extrapolated to estimate the number of fractures in 12 countries in North America, Europe, Japan, and Australia. RESULTS: Annual non-traumatic hip fracture incidence rates were highest for women in Sweden, Denmark, and Finland. In women, vertebral fractures were more common than hip fractures. The incidence of vertebral fractures was highest among Scandinavian and Canadian women. In men, Scandinavians had the highest incidence of hip fractures, while Australian men had the highest incidence of vertebral fractures. Hip and vertebral fracture incidence increased steeply with age for both women and men. Age appears to exert less influence on the incidence of fractures at sites other than hip and vertebrae. In 2010, 5.2 million non-traumatic fractures were expected in the 12 countries studied, of which 2.8 million were at the hip or spine. Women accounted for most of the total non-traumatic fracture burden (77 %). CONCLUSIONS: Non-traumatic fractures pose a significant burden, affecting millions of women and men in countries around the world each year.

A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients.

AIM: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet® (rosiglitazone/metformin/AVM) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. METHODS: This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naÏve, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. RESULTS: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < 0.0001) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < 0.0012 and p = 0.0005, respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD. CONCLUSION: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip.

Meteorological effects on the daily activity patterns of tabanid biting flies in northern Queensland, Australia.

Information on the daily activity patterns of tabanid flies is important in the development of strategies that decrease the risk of pathogens transmitted by them. In addition, this information is useful to maximize numbers of tabanids trapped during short-term studies and to target feeding behavior studies of certain tabanid species to their times of peak activity. The current study examined the effects of various meteorological factors on the daily activity patterns of common tropical species of tabanids in north Queensland. Each species studied responded differently to weather factors. Tabanus townsvilli Ricardo (Diptera: Tabanidae) was most active during late morning and early afternoon, whereas Pseudotabanus silvester (Bergroth) and Tabanus pallipennis Macquart were most active in the late afternoon. Tabanus dorsobimaculatus Macquart was most active in the morning and early afternoon. Data on daily activity patterns of tabanid flies indicates that in an area such as Townsville, North Queensland, where several species of tabanid are present concurrently in high numbers, the overlapping periods of high activity for these species indicate a high risk of pathogen transmission for most of the day (10.00-19.00 hours). Similarly, because each species responds differently to weather variables, only extreme weather conditions are likely to inhibit activity of all species. These data also indicate that for maximal results, trapping and feeding behavior studies should be tailored to the preferred activity period of the species under investigation.