Using 3D image registration to maximize the reproducibility of longitudinal bone strength assessment by HR-pQCT and finite element analysis.

We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D image registration to account for misalignment between images. This reduced variability in longitudinal FE estimates and improved our ability to measure in vivo changes in HR-pQCT studies of bone strength. INTRODUCTION: We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D rigid-body registration (3DR) to maximize reproducibility by accounting for misalignment between images. METHODS: In our proposed approach, we used the full common bone volume defined by 3DR to estimate standard FE parameters. Using standard HR-pQCT imaging protocols, we validated the 3DR approach with ex vivo samples of the distal radius (n = 10, four repeat scans) by assessing whether 3DR can reduce measurement variability from repositioning error. We used in vivo data (n = 40, five longitudinal scans) to assess the sensitivity of 3DR to detect changes in bone strength at the distal radius by the standard deviation of the rate of change (σ), where the ideal value of σ is minimized to define true change. FE estimates by 3DR were compared to estimates by no registration (NR) and slice-matching (SM). RESULTS: Group-wise comparisons of ex vivo variation (CVRMS, %) found that FE measurement precision was improved by SM (CVRMS < 0.80%) and 3DR (CVRMS < 0.62%) compared to NR (CVRMS~2%), and 3DR was advantageous as repositioning error increased. Longitudinal in vivo reproducibility was minimized by 3DR for failure load estimates (σ = 0.008 kN/month). CONCLUSION: Although 3D registration cannot negate motion artifacts, it plays an important role in detecting and reducing variability in FE estimates for longitudinal HR-pQCT data and is well suited for estimating effects of interventions in in vivo longitudinal studies of bone strength.

Longitudinal bone microarchitectural changes are best detected using image registration.

Longitudinal studies of bone using high-resolution medical imaging may result in non-physiological measurements of longitudinal changes. In this study, we determined that three-dimensional image processing techniques best capture realistic longitudinal changes in bone density and should therefore be used with high-resolution imaging when studying bone changes over time. INTRODUCTION: The purpose of this study was to determine which longitudinal analysis technique (no registration (NR), slice-match (SM) registration, or three-dimensional registration (3DR)) produced the most realistic longitudinal changes in a 3-year study of bone density and structure using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: We assessed HR-pQCT scans of the distal radius and tibia for men and women (N = 40) aged 55-70 years at baseline and 6, 12, 24, and 36 months. To evaluate which longitudinal analysis technique (NR, SM, or 3DR) best captured physiologically reasonable 3-year changes, we calculated the standard deviation of the absolute rate of change in each bone parameter. The data were compared between longitudinal analysis techniques using repeated measures ANOVA and post hoc analysis. RESULTS: As expected, both SM and 3DR better captured physiological longitudinal changes than NR. At the tibia, there were no differences between SM and 3DR; however, at the radius where precision was lower, 3DR produced better results for total bone mineral density. CONCLUSIONS: At least SM or 3DR should be implemented in longitudinal studies using HR-pQCT. 3DR is preferable, particularly at the radius, to ensure that physiological changes in bone density are observed.

Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial.

Although high-dose vitamin D supplementation is common, effects on arterial calcification remain unexplored. Tibial artery calcification was identified and quantified over 3 years in participants randomized to 400, 4000, or 10,000 IU vitamin D3 daily. High-dose vitamin D supplementation did not affect the development or progression of arterial calcification. INTRODUCTION: To determine whether vitamin D supplementation has a dose-dependent effect on development and progression of arterial calcification. METHODS: This was a secondary analysis of the Calgary Vitamin D Study, a 3-year, double-blind, randomized controlled trial conducted at a single-center in Calgary, Canada. Participants were community-dwelling adults aged 55-70 years with serum 25-hydroxyvitamin D 30-125 nmol/L. Participants were randomized 1:1:1 to receive vitamin D3 400, 4000, or 10,000 IU/day for 3 years. Tibial artery calcification was identified and quantified (in milligrams of hydroxyapatite, mgHA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6, 12, 24, and 36 months. Changes in calcification over time and treatment group interaction were evaluated using a constrained linear mixed effects model. RESULTS: Of 311 randomized participants, 302 (400: 105, 4000: 96, 10,000: 101) were eligible for analysis of arterial calcification (54% male, mean (SD) age 62 (4) years, mean (SD) 25-hydroxyvitamin D 78.9 (19.9) nmol/L). At baseline, 85 (28%) had tibial artery calcification, and mean (95% CI) calcification quantity was 2.8 mgHA (95% CI 1.7-3.9). In these 85 participants, calcification quantity increased linearly by 0.020 mgHA/month (95% CI 0.012-0.029) throughout the study, with no evidence of a treatment-group effect (p = 0.645 for interaction). No participants developed new arterial calcifications during the study. CONCLUSIONS: In this population of community-dwelling adults who were vitamin D replete at baseline, supplementation with vitamin D 400, 4000, or 10,000 IU/day did not have differential effects on the development or progression of arterial calcification over 3 years. TRIAL REGISTRATION: clinicaltrials.gov (NCT01900860).

Testing a theoretical model of imminent fracture risk in elderly women: an observational cohort analysis of the Canadian Multicentre Osteoporosis Study.

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health. INTRODUCTION: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk. METHODS: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI). RESULTS: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ2(172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001). CONCLUSIONS: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

Longitudinal assessment of health-related quality of life in osteoporosis: data from the population-based Canadian Multicentre Osteoporosis Study.

Little is known about the association between health-related quality of life (HRQOL) and osteoporosis in the absence of fracture, and how HRQOL may change over time. This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. INTRODUCTION: Fragility fractures have a detrimental effect on the health-related quality of life (HRQOL) of those with osteoporosis. Less is known about the association between HRQOL and osteoporosis in the absence of fracture. METHODS: Canadian Multicentre Osteoporosis Study participants completed the SF-36, a detailed health questionnaire and measures of bone mineral density (BMD) at baseline and follow-up. We report the results of participants ≥ 50 years with 10-year follow-up. Self-reported osteoporosis at baseline and BMD-based osteoporosis at follow-up were ascertained. Multivariable linear regression models were developed for baseline SF-36 domains, component summaries, and change over time, adjusting for relevant baseline information. RESULTS: Baseline data were available for 5266 women and 2112 men. Women in the osteoporosis group had substantially lower SF-36 baseline scores, particularly in the physically oriented domains, than those without osteoporosis. A similar but attenuated pattern was evident for the men. After 10-year follow-up (2797 women and 1023 men), most domain scores dropped for women and men regardless of osteoporosis status, with the exception of mentally-oriented ones. In general, a fragility fracture was associated with lower SF-36 scores and larger declines over time. CONCLUSIONS: This study provides evidence of substantially reduced HRQOL in women and men with self-reported and/or BMD-confirmed osteoporosis, even in the absence of fragility fracture. HRQOL should be thoroughly investigated even prior to fracture, to develop appropriate interventions for all stages of the disease.

Mortality risk reduction differs according to bisphosphonate class: a 15-year observational study.

In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. INTRODUCTION: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. METHODS: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. RESULTS: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48-0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66-1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031-0.70)] for n-BP vs. etidronate]. CONCLUSION: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Cortical porosity exhibits accelerated rate of change in peri- compared with post-menopausal women.

The rate of change in bone density was not different between peri- and post-menopausal women. Differences in rate of change were observed in bone microarchitecture, specifically cortical porosity (Ct.Po), where peri-menopausal women increased +9% per year compared with the +6% per year for post-menopausal women. INTRODUCTION: The purpose of this study was to compare changes in bone density and microarchitecture in peri- and post-menopausal women over 6 years. METHODS: Peri- (n = 26) and post- (n = 65) menopausal women were selected from the Canadian Multicenter Osteoporosis Study. Caucasian women were scanned on dual x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and follow-up, an average 6 years later. To compare repeat scans, automated 3D image registration was conducted. At the radius and tibia, total volumetric BMD (Tt.BMD), total bone area (Tt.Ar) and cortical porosity (Ct.Po) were assessed, and finite element analysis estimated apparent bone strength. RESULTS: At the tibia, the rate of change for Ct.Po and Tt.Ar was different between groups. Peri-menopausal women had a + 9% per year increase in Ct.Po, but this increase was slower for post-menopausal women at +6% per year (p = 0.049). In addition, post-menopausal women had an increase in Tt.Ar of +0.13% per year compared with a slower increase of +0.06% per year for peri-menopausal women (p = 0.017). The rate of change of density between groups was not significantly different and was approximately -1% per year at the hip by DXA, and -1% per year at the radius and -0.5% per year tibia by HR-pQCT. CONCLUSION: This is a 6-year prospective HR-pQCT study exploring rate of change in Caucasian peri- and post-menopausal women. The microarchitectural features represented by Ct.Po and Tt.Ar changed at a significantly different rate between groups, but group differences were not detected by density measures.

Economic evaluation of a population-based osteoporosis intervention for outpatients with non-traumatic non-hip fractures: the "Catch a Break" 1i [type C] FLS.

Fracture liaison services (FLS) are advocated to improve osteoporosis treatment after fragility fracture, but there are few economic analyses of different models. A population-based 1i [=type C] FLS for non-hip fractures was implemented and it costs $44 per patient and it was very cost-effective ($9200 per QALY gained). Small operational changes would convert it from cost-effective to cost-saving. INTRODUCTION: After fragility fracture, <20% of patients receive osteoporosis treatment. FLS are recommended to address this deficit but there are very few economic analyses of different FLS models. Therefore, we conducted an economic analysis of a 1i (=type C) FLS called "Catch a Break (CaB)." METHODS: CaB is a population-based FLS in Alberta, Canada, that case-finds older outpatients with non-traumatic upper extremity, spine, pelvis, or "other" non-hip fractures and provides telephonic outreach and printed educational materials to patients and their physicians. Cost-effectiveness was assessed using Markov decision-analytic models. Costs were expressed in 2014 Canadian dollars and effectiveness based on model simulations of recurrent fractures and quality-adjusted life years (QALYs). Perspective was healthcare payer; horizon was lifetime; and costs and benefits were discounted 3%. RESULTS: Over 1 year, CaB enrolled 7323 outpatients (mean age 67 years, 75% female, 69% upper extremity) at average cost of $44 per patient. Compared with usual care, CaB increased rates of bisphosphonate treatment by 4.3 to 17.5% (p < 0.001). Over their lifetime, for every 10,000 patients enrolled in CaB, 4 hip fractures (14 fractures total) would be avoided and 12 QALYs gained. Compared with usual care, incremental cost-effectiveness of CaB was estimated at $9200 per QALY. CaB was cost-effective in 85% of 10,000 probabilistic simulations. Sensitivity analyses showed if "other" fractures were excluded and intervention costs reduced 25% that CaB would become cost-saving. CONCLUSIONS: A relatively inexpensive population-based 1i (=type C) FLS was implemented in Alberta and it was very cost-effective. If CaB excluded "other" fractures and decreased intervention costs by 25%, it would be cost-saving, as would any FLS that was more effective and less expensive.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Pollinator adaptation and the evolution of floral nectar sugar composition.

A long-standing debate concerns whether nectar sugar composition evolves as an adaptation to pollinator dietary requirements or whether it is 'phylogenetically constrained'. Here, we use a modelling approach to evaluate the hypothesis that nectar sucrose proportion (NSP) is an adaptation to pollinators. We analyse ~ 2100 species of asterids, spanning several plant families and pollinator groups (PGs), and show that the hypothesis of adaptation cannot be rejected: NSP evolves towards two optimal values, high NSP for specialist-pollinated and low NSP for generalist-pollinated plants. However, the inferred adaptive process is weak, suggesting that adaptation to PG only provides a partial explanation for how nectar evolves. Additional factors are therefore needed to fully explain nectar evolution, and we suggest that future studies might incorporate floral shape and size and the abiotic environment into the analytical framework. Further, we show that NSP and PG evolution are correlated - in a manner dictated by pollinator behaviour. This contrasts with the view that a plant necessarily has to adapt its nectar composition to ensure pollination but rather suggests that pollinators adapt their foraging behaviour or dietary requirements to the nectar sugar composition presented by the plants. Finally, we document unexpectedly sucrose-poor nectar in some specialized nectarivorous bird-pollinated plants from the Old World, which might represent an overlooked form of pollinator deception. Thus, our broad study provides several new insights into how nectar evolves and we conclude by discussing why maintaining the conceptual dichotomy between adaptation and constraint might be unhelpful for advancing this field.

Characteristics of hyperparathyroid states in the Canadian multicentre osteoporosis study (CaMos) and relationship to skeletal markers.

CONTEXT: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism. OBJECTIVE: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD). DESIGN AND PARTICIPANTS: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay. OUTCOME MEASURES: L1-L4, femoral neck and total hip BMD. RESULTS: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively. CONCLUSION: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels.

Bone quality in osteopenic postmenopausal women is not improved after 12 months of whole-body vibration training.

UNLABELLED: Whole-body vibration training may improve bone quality through structural adaptation. We tested if 12 months of training affects bone structure in osteopenic postmenopausal women by using advanced 3-dimensional high-resolution imaging techniques. We found that whole-body vibration training did not improve bone structure compared to inactive controls. INTRODUCTION: Whole-body vibration training (WBVT) has been suggested as a preventive measure against bone loss. Contradicting results of previous studies may be confounded by insufficiently sensitive bone density measures to detect relevant bone changes. WBVT may improve bone quality through structural adaptations, without increasing bone mineral density (BMD). We hypothesized that 12 months of WBVT will improve or maintain bone microarchitecture and bone strength in osteopenic postmenopausal women. METHODS: Twenty-two women received WBVT for 2-3 sessions/week and were compared with 20 controls. Bone outcomes were measured by high-resolution peripheral quantitative CT (HR-pQCT, XtremeCT, Scanco Medical) and finite element estimated bone strength. Balance and jump performance and maximum voluntary contraction (MVC) of knee flexor and extensor muscles were recorded. All measurements were taken at baseline, 4, 8, and 12 months and a reduced data set at 4 and 8 months follow-up and compared using a mixed model repeated measures ANOVA. RESULTS: Thirty-one women completed the study with 90 % compliance (WBVT: n = 17, control n = 14). Total BMD (p < 0.001), cortical area*(p = 0.004), cortical thickness (p = 0.011), and cortical porosity (p = 0.024) all significantly decreased over time in both groups; WBVT did not affect the response. All other bone outcomes were not affected by WBVT or time. No difference in measures of balance, jump height, and MVC due to WBVT were detected. CONCLUSION: In our cohort, WBVT did not lead to improved bone quality in postmenopausal osteopenic women after 12 months of training compared to controls, and there were no detected benefits related to balance and muscle strength outcomes.

The relationship between serum 25(OH)D and bone density and microarchitecture as measured by HR-pQCT.

UNLABELLED: The relation between serum 25-hydroxy vitamin D [25(OH)D] and bone quality is not well understood, particularly for high levels. We measured bone microarchitecture in three groups of people stratified by their serum 25(OH)D. There was a weak association of serum 25(OH)D and microarchitecture for this cross-sectional population, suggesting possible benefits to bone quality. INTRODUCTION: Vitamin D plays an important role in bone and mineral metabolism, but the relation between serum 25(OH)D and bone quality is not well understood. Here, we present a cross-sectional study that investigated a convenience group of participants from an ongoing health initiative in Alberta, Canada, who have been receiving daily vitamin D supplementation. METHODS: A total of 105 participants were organized into three groups based on their serum 25(OH)D levels: low (<75 nmol/L), medium (75-175 nmol/L), and high (>175 nmol/L). They were also assessed with 25(OH)D as a continuous variable. Average daily supplementation was 7670 ± 438 IU, and the change in 25(OH)D ranged from 22 to 33 % during the period of receiving supplements. We used high-resolution peripheral quantitative computed tomography measurements at the radius and tibia to assess bone microarchitecture. RESULTS: Microarchitectural parameters were not strongly associated with serum 25(OH)D. In the tibia, there were fewer trabeculae (TbN; p = 0.015) and a non-significant trend toward thicker trabeculae (p = 0.067) of the high group. Body mass index (BMI) was negatively associated with serum 25(OH)D levels (p < 0.001) and PTH levels (p < 0.001). There was no clinically significant relationship detected between high serum 25(OH)D and high serum calcium. CONCLUSION: These data suggest a weak relationship between serum 25(OH)D and bone microarchitecture in this population of mostly vitamin-D-sufficient participants, and there were no indications of negative effects related to the high supplementation levels. These data provided a basis to design and implement our 3-year dose-dependent randomized controlled trial investigating the effects of vitamin D supplementation on bone health outcomes.

Critical impact of patient knowledge and bone density testing on starting osteoporosis treatment after fragility fracture: secondary analyses from two controlled trials.

UNLABELLED: Most patients are not treated for osteoporosis after their fragility fracture "teachable moment." Among almost 400 consecutive wrist fracture patients, we determined that better-than-average osteoporosis knowledge (adjusted odds = 2.6) and BMD testing (adjusted odds = 6.5) were significant modifiable facilitators of bisphosphonate treatment while male sex, working outside the home, and depression were major barriers. INTRODUCTION: In the year following fragility fracture, fewer than one quarter of patients are treated for osteoporosis. Although much is known regarding health system and provider barriers and facilitators to osteoporosis treatment, much less is understood about modifiable patient-related factors. METHODS: Older patients with wrist fracture not treated for osteoporosis were enrolled in trials that compared a multifaceted intervention with usual care controls. Baseline data included a test of patient osteoporosis knowledge. We then determined baseline factors that independently predicted starting bisphosphonate treatment within 1 year. RESULTS: Three hundred seventy-four patients were enrolled; mean age 64 years, 78 % women, 90 % white, and 54 % with prior fracture. Within 1 year, 86 of 374 (23 %) patients were treated with bisphosphonates. Patients who were treated had better osteoporosis knowledge at baseline (70 % correct vs 57 % for untreated, p < 0.001) than patients who remained untreated; conversely, untreated patients were more likely to be male, still working, and report depression. In fully adjusted models, osteoporosis knowledge was independently associated with starting bisphosphonates (adjusted OR 2.6, 95 %CI 1.3-5.3). Obtaining a BMD test (aOR 6.5, 95 %CI 3.4-12.2) and abnormal BMD results (aOR 34.5, 95 %CI 16.8-70.9) were strongly associated with starting treatment. CONCLUSIONS: The most important modifiable facilitators of osteoporosis treatment in patients with fracture were knowledge and BMD testing. Specifically targeting these two patient-level factors should improve post-fracture treatment rates.

Women with previous fragility fractures can be classified based on bone microarchitecture and finite element analysis measured with HR-pQCT.

UNLABELLED: High-resolution peripheral quantitative computed tomography (HR-pQCT) measurements of distal radius and tibia bone microarchitecture and finite element (FE) estimates of bone strength performed well at classifying postmenopausal women with and without previous fracture. The HR-pQCT measurements outperformed dual energy x-ray absorptiometry (DXA) at classifying forearm fractures and fractures at other skeletal sites. INTRODUCTION: Areal bone mineral density (aBMD) is the primary measurement used to assess osteoporosis and fracture risk; however, it does not take into account bone microarchitecture, which also contributes to bone strength. Thus, our objective was to determine if bone microarchitecture measured with HR-pQCT and FE estimates of bone strength could classify women with and without low-trauma fractures. METHODS: We used HR-pQCT to assess bone microarchitecture at the distal radius and tibia in 44 postmenopausal women with a history of low-trauma fracture and 88 age-matched controls from the Calgary cohort of the Canadian Multicentre Osteoporosis Study (CaMos) study. We estimated bone strength using FE analysis and simulated distal radius aBMD from the HR-pQCT scans. Femoral neck (FN) and lumbar spine (LS) aBMD were measured with DXA. We used support vector machines (SVM) and a tenfold cross-validation to classify the fracture cases and controls and to determine accuracy. RESULTS: The combination of HR-pQCT measures of microarchitecture and FE estimates of bone strength had the highest area under the receiver operating characteristic (ROC) curve of 0.82 when classifying forearm fractures compared to an area under the curve (AUC) of 0.71 from DXA-derived aBMD of the forearm and 0.63 from FN and spine DXA. For all fracture types, FE estimates of bone strength at the forearm alone resulted in an AUC of 0.69. CONCLUSION: Models based on HR-pQCT measurements of bone microarchitecture and estimates of bone strength performed better than DXA-derived aBMD at classifying women with and without prior fracture. In future, these models may improve prediction of individuals at risk of low-trauma fracture.

Improved adherence with PTH(1-84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis.

UNLABELLED: The purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy. INTRODUCTION: There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy. METHODS: Seven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers. RESULTS: PTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p<0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2% above baseline. Larger increases in spine BMD were observed in participants with ≥80% adherence to daily injections of PTH(1-84) (8.3% in adherent vs 4.9% in poorly adherent patients). Total hip BMD gains were 1.7% in adherent vs 0.6% in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1-84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1-84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group. CONCLUSIONS: PTH(1-84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1-84) for up to 24 months is also associated with greater efficacy.

Longitudinal changes in calcium and vitamin D intakes and relationship to bone mineral density in a prospective population-based study: the Canadian Multicentre Osteoporosis Study (CaMos).

OBJECTIVES: Our objective was to study changes in calcium and vitamin D intakes over time, and their cross-sectional and longitudinal associations with bone mineral density (BMD). METHODS: We followed 9382 women and men aged ≥25 and 899 aged 16-24, for 10 and 2 years respectively. RESULTS: Calcium and vitamin D intakes increased over time in adults, but decreased in women aged 16-18. The increased intakes in adults were largely attributable to the increased use of calcium and/or vitamin D supplements. Both the percentage of supplement users and average dose among users increased over time. There was nevertheless a high prevalence of calcium and vitamin D intake below the estimated average requirement. At baseline, higher calcium and vitamin D intakes were associated with higher total hip and femoral neck BMD in young men, and cumulatively high levels of calcium and vitamin D intakes over time contributed to better BMD maintenance at lumbar spine and hip sites in adult women. CONCLUSIONS: Although total intakes, particularly of vitamin D, frequently fell below the Institute of Medicine recommendations despite an increase over time in supplement use, we found some positive associations between total calcium and vitamin D intake and bone health.

Novel requirements for HAP2-mediated gamete fusion in Tetrahymena.

The ancestral gamete fusion protein, HAP2, catalyzes sperm-egg fusion in a broad range of taxa dating to the last eukaryotic common ancestor. Remarkably, HAP2 orthologs are structurally related to the class II fusogens of modern-day viruses, and recent studies make clear that these proteins utilize similar mechanisms to achieve membrane merger. To identify factors that may regulate HAP2 activity, we screened mutants of the ciliate Tetrahymena thermophila for behaviors that mimic Δhap2 knockout phenotypes in this species. Using this approach, we identified two new genes, GFU1 and GFU2, whose products are necessary for the formation of membrane pores during fertilization and show that the product of a third gene, namely ZFR1, may be involved in pore maintenance and/or expansion. Finally, we propose a model that explains cooperativity between the fusion machinery on apposed membranes of mating cells and accounts for successful fertilization in T. thermophila's multiple mating type system.

Denosumab: mechanism of action and clinical outcomes.

AIMS: To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments. METHODS: Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches. FINDINGS: Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high-risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment. DISCUSSION: Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first-line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options.