Prevention of COVID-19 with oral vitamin D supplemental therapy in essential healthcare teams (PROTECT): protocol for a multicentre, triple-blind, randomised, placebo-controlled trial.

INTRODUCTION: In the COVID-19 pandemic, healthcare workers (HCWs) were at high risk of infection due to their exposure to COVID infections. HCWs were the backbone of our healthcare response to this pandemic; every HCW withdrawn or lost due to infection had a substantial impact on our capacity to deliver care. Primary prevention was a key approach to reduce infection. Vitamin D insufficiency is highly prevalent in Canadians and worldwide. Vitamin D supplementation has been shown to significantly decrease the risk of respiratory infections. Whether this risk reduction would apply to COVID-19 infections remained to be determined. This study aimed to determine the impact of high-dose vitamin D supplementation on incidence of laboratory-confirmed COVID-19 infection rate and severity in HCWs working in high COVID incidence areas. METHODS AND ANALYSIS: PROTECT was a triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D supplementation in HCWs. Participants were randomly allocated in a 1:1 ratio in variable block size to intervention (one oral loading dose of 100 000 IU vitamin D3+10 000 IU weekly vitamin D3) or control (identical placebo loading dose+weekly placebo). The primary outcome was the incidence of laboratory-confirmed COVID-19 infection, documented by RT-qPCR on salivary (or nasopharyngeal) specimens obtained for screening or diagnostic purposes, as well as self-obtained salivary specimens and COVID-19 seroconversion at endpoint. Secondary outcomes included disease severity; duration of COVID-19-related symptoms; COVID-19 seroconversion documented at endpoint; duration of work absenteeism; duration of unemployment support; and adverse health events. The trial was terminated prematurely, due to recruitment difficulty. ETHICS AND DISSEMINATION: This study involves human participants and was approved by the Research Ethics Board (REB) of the Centre hospitalier universitaire (CHU) Sainte-Justine serving as central committee for participating institutions (#MP-21-2021-3044). Participants provided written informed consent to participate in the study before taking part. Results are being disseminated to the medical community via national/international conferences and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT04483635.

Increased Imminent Fracture Risk in Liver Transplant Recipients Despite Bisphosphonate Therapy.

BACKGROUND: Bone loss is significant after orthotopic liver transplant (OLT) and is associated with increased fracture risk and decreased quality of life. In post-transplant fracture prevention, the cornerstone of therapeutic management is bisphosphonates. METHODS: We conducted a retrospective study in a cohort of 155 OLT recipients who received a bisphosphonate prescription at hospital discharge between 2012 and 2016 to investigate post-OLT fragility fracture incidence and predictive risk factors. RESULTS: Before OLT, 14 patients presented a T score < -2.5 SD, and 23 patients (14.8%) had a history of fracture. During follow-up, the cumulative incidence of fractures on bisphosphonates (99.4% risedronate/alendronate) was 9.7% at 12 months and 13.1% at 24 months. The median time to first fragility fracture was 10 months (IQR, 3-22 months) and thus within the first 2 years of follow-up. Predictive factors of fragility fractures in multivariate Cox regression analyses included age 60 years or older (hazard ratio [HR], 2.61; 95% CI, 1.14-6.01; P = .02), post-transplant diabetes mellitus (HR, 3.82; 95% CI, 1.55-9.44; P = .004), and cholestatic disease (HR, 5.93; 95% CI, 2.30-15.26; P = .0002). Additionally, the female sex was associated with a strong trend toward increased fracture risk in univariate analysis (HR, 2.27; 95% CI, 1.00-5.15; P = .05), as well as a post-transplant absolute decrease in bone mineral density at the femoral neck and total hip (P = .08). CONCLUSIONS: This real-world study reports a high incidence of fractures post-OLT despite bisphosphonate therapy. Age 60 years or older, post-transplant diabetes mellitus, cholestatic disease, female sex, and femoral neck and/or total hip bone mineral density loss contribute to increased imminent fracture risk in liver transplant recipients.

Oral vitamin D supplemental therapy to attain a desired serum 25-hydroxyvitamin D concentration in essential healthcare teams.

BACKGROUND: The study objectives were to ascertain the efficacy of vitamin D supplementation in rapidly increasing serum vitamin D and of implementation of a hybrid (virtual and in-person) trial. METHODS: In a randomized triple-blind controlled trial, healthcare workers were allocated to receive an oral bolus of 100,000 IU with 10,000 IU/week of vitamin D3 or placebo. The co-primary outcomes were the change from baseline in serum 25-hydroxyvitamin D [(Δ) 25(OH)D] and proportion with vitamin D sufficiency (25(OH)D ≥ 75 nmol/L), at endpoint. Adherence to supplements and procedures as well as adverse event rates were documented. RESULTS: Thirty-four (19 intervention, 15 control) subjects were randomized, with 28 (41%) virtual visits. After 44.78 ± 11.00 days from baseline, a significant adjusted group difference of 44.2 (34.7, 53.8) nmol/L was observed in the Δ 25(OH)D (95% CI) in favor of supplementation; 77.8% of intervention, and 13.3% of control, patients were vitamin D sufficient (OR:6.11, 95% CI:1.6, 22.9). The adherence to intervention was 94.7% in the intervention and 100% in the control groups. Irrespective of visit type, high adherence was observed in sampling procedures and completion of fortnightly online questionnaire. No adverse events attributable to vitamin D were reported. CONCLUSION: The vitamin D supplementation rapidly and safely raised 25(OH)D levels to sufficient levels for a biological effect. Similarly high adherence to study procedures was observed with virtual and in-person participation. TRIAL REGISTRATION: This trial was registered at https://clinicaltrials.gov on July 23, 2020 (# NCT04483635 ).

Lenvatinib Therapy for Advanced Thyroid Cancer: Real-Life Data on Safety, Efficacy, and Some Rare Side Effects.

Context: The SELECT trial led to the approval of lenvatinib for the treatment of advanced radioiodine-refractory differentiated thyroid carcinomas (DTCs) but also revealed an important adverse event (AE) profile which may limit its use in clinical practice. Objective: We aim to describe the efficacy and toxicity profiles of lenvatinib in real life. Methods: We included all patients who received lenvatinib for an advanced DTC at our institution, enrolling 27 patients. We reviewed retrospectively electronic medical records to assess efficacy and AEs. Results: Among the 24 patients with evaluation of tumor response during treatment, overall response rate (ORR) was 37.0% (95% CI, 19.4%-57.6%), and disease control rate was 85.2% (95% CI, 66.3%-95.8%). The median progression-free survival (PFS) was 12 months (95% CI, 7.5-16.5]. The most prevalent AEs were hypertension (77.8%), fatigue (55.6%), and weight loss (51.9%). At least one grade ≥ 3 AE was experienced by 25/27 patients (92.6%), mostly hypertension (59.3%). Lenvatinib was discontinued due to AEs in 13/27 patients (48.1%). Interestingly, 1 patient experienced a grade 4 posterior reversible encephalopathy syndrome, and another developed a Takotsubo cardiomyopathy. Conclusion: The safety profile of lenvatinib in our cohort was similar to that reported in the literature, with a predominance of hypertension. Rigorous blood pressure control is therefore essential to avoid discontinuing therapy. We also report 2 severe and rarely described AEs that physicians should watch for. As for efficacy, although less than in the SELECT trial, ORR and PFS were similar to other real-life studies.

Prediction of Osteoporotic Fractures in Elderly Individuals: A Derivation and Internal Validation Study Using Healthcare Administrative Data.

In Canada and other countries, osteoporosis is monitored as part of chronic disease population surveillance programs. Although fractures are the principal manifestation of osteoporosis, very few algorithms are available to identify individuals at high risk of osteoporotic fractures in current surveillance systems. The objective of this study was to derive and validate predictive models to accurately identify individuals at high risk of osteoporotic fracture using information available in healthcare administrative data. More than 270,000 men and women aged ≥66 years were randomly selected from the Quebec Integrated Chronic Disease Surveillance System. Selected individuals were followed between fiscal years 2006-2007 and 2015-2016. Models were constructed for prediction of hip/femur and major osteoporotic fractures for follow-up periods of 5 and 10 years. A total of 62 potential predictors measurable in healthcare administrative databases were identified. Predictor selection was performed using a manual backward algorithm. The predictive performance of the final models was assessed using measures of discrimination, calibration, and overall performance. Between 20 and 25 predictors were retained in the final prediction models (eg, age, sex, social deprivation index, most of the major and minor risk factors for osteoporosis, diabetes, Parkinson's disease, cognitive impairment, anemia, anxio-depressive disorders). Discrimination of the final models was higher for the prediction of hip/femur fracture than major osteoporotic fracture and higher for prediction for a 5-year than a 10-year period (hip/femur fracture for 5 years: c-index = 0.77; major osteoporotic fracture for 5 years: c-index = 0.71; hip/femur fracture for 10 years: c-index = 0.73; major osteoporotic fracture for 10 years: c-index = 0.68). The predicted probabilities globally agreed with the observed probabilities. In conclusion, the derived models had adequate predictive performance in internal validation. As a final step, these models should be validated in an external cohort and used to develop indicators for surveillance of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture.

Bisphosphonates (BPs) are the most widely used drugs for the treatment of osteoporosis but prolonged use of BPs might increase the risk of atypical femur fracture (AFF). There are only a few studies that address the bone material quality in patients on long-term BP treatment with or without AFFs. We analyzed 52 trans-iliac bone biopsies from patients on long-term BP therapy with (n = 26) and without (n = 26) AFF. At the microscopic level, the degree of mineralization of bone (DMB) was assessed on whole bone by X-ray digitized microradiography while microhardness by Vickers microindentation, and bone matrix characteristics by Fourier transform infrared microspectroscopy (FTIRM) (mineral/organic ratio, mineral maturity and crystallinity, and collagen maturity) were measured at random focal areas. The AFF patients were treated longer than non-AFF patients (9.7 ± 3.3 years versus 7.9 ± 2.7 years). As expected, bone remodeling was low in both groups, without difference between them. The AFF group had significantly higher DMB in cortical bone (+2.9%, p = .001), which remained so after adjusting for treatment duration (p = .007), and showed a trend in cancellous bone (+1.6%, p = .05). Consistent with higher DMB, heterogeneity index (HI) was lower in the AFF than in the non-AFF group, illustrating lower heterogeneity of mineralization in the AFF group. A significant positive correlation between the duration of treatment and DMB in cortical bone was found in AFF, and not in the non-AFF group. Microhardness and bone matrix characteristics were similar between groups. We conclude that the AFF group had a duration-dependent increase in DMB leading to a significantly higher DMB than the non-AFF. Because BPs have high affinity to bone mineral and lining the walls of the osteocyte lacunae, the accumulation of matrix-bound BPs in AFF could lead to inhibition of the osteocyte cytoskeleton blunting their response to mechanical strains, a hypothesis to be further investigated. © 2021 American Society for Bone and Mineral Research (ASBMR).

Number, Location, and Time Since Prior Fracture as Predictors of Future Fracture in the Elderly From the General Population.

Prognostic tools are available to identify individuals at high risk of osteoporotic fracture and to assist physicians in management decisions. Some authors have suggested improving the predictive ability of these tools by integrating characteristics of prior fractures (number, location, and time since prior fracture). The objectives of this study were: (1) to evaluate the sex- and age-specific associations between characteristics of prior fractures and the occurrence of a future osteoporotic fracture; and (2) to assess whether the characteristics of prior fractures could increase the discriminative ability of fracture risk prediction tools. A retrospective cohort study was conducted using administrative data. Men and women aged ≥66 years were selected and grouped into two cohorts. In cohort #1 (N = 759,500), history of fractures was measured between fiscal years 1997-1998 and 2003-2004, and future fractures were identified between 2004-2005 and 2013-2014. In cohort #2 (N = 807,245), history of fractures was measured between 1997-1998 and 2008-2009, and future fractures were identified between 2009-2010 and 2013-2014. Time until a first hip/femur and major osteoporotic fracture were the outcomes of interest. Adjusted HRs and c-indices were calculated. The association between history of prior fractures and future fracture was stronger in men and younger individuals. The locations of prior fractures associated with the lowest and highest risks were foot/ankle/tibia/fibula (maximal HR = 1.64) and hip/femur (maximal HR = 9.02), respectively. The association was stronger for recent fractures (maximal HR = 4.93), but was still significant for fractures occurring 10 to 12 years prior to the beginning of follow-up (maximal HR = 1.99). Characteristics of prior fractures did not increase model discrimination. Our study confirms that the risk of future fracture increases with the number of prior fractures, varies according to prior fracture location, and decreases with time since prior fracture. However, the integration of these characteristics in current fracture risk prediction tools is not required because it does not improve predictive ability. © 2018 American Society for Bone and Mineral Research.

Hypomagnesemia During Teriparatide Treatment in Osteoporosis: Incidence and Determinants.

In our clinical experience, we have encountered patients who developed hypomagnesemia after the introduction of teriparatide. Some trials have reported hypomagnesemia as an adverse event during teriparatide treatment, but this issue had never been studied specifically. Our objective was twofold: 1) determine the incidence of hypomagnesemia (serum magnesium <0.7 mmol/L) associated with teriparatide in a retrospective cohort and 2) identify the predisposing factors to hypomagnesemia in this cohort. We reviewed the files of 53 patients treated for severe osteoporosis with teriparatide for 6 to 24 months between May 2008 and January 2016. Serum magnesium levels were measured at 0, 3, 6, 12, 18, and 24 months. In the full cohort, we observed an average decrease of serum magnesium of 0.075 mmol/L, 0.069 mmol/L, 0.085 mmol/L, 0.086 mmol/L (p < 0.001) at 3, 6, 12 months, and at the end of the treatment, respectively. The cumulative incidence of hypomagnesemia during treatment with teriparatide was 35.9% (19 patients). Patients' older age (71.1 versus 65.1 years; p = 0.05) and lower baseline level of magnesium before teriparatide treatment (0.81 mmol/L versus 0.85 mmol/L; p = 0.03) were significant risk factors for teriparatide-induced hypomagnesemia. The average decrease of serum magnesium was greater in the patients who developed hypomagnesemia compared with normomagnesemic patients at 3 months (0.110 mmol/L versus 0.054 mmol/L; p = 0.02), 6 months (0.139 mmol/L versus 0.036 mmol/L; p < 0.001), and 12 months (0.156 mmol/L versus 0.048 mmol/L; p < 0.001). Serum calcium, creatinine, and parathyroid hormone remained normal throughout the treatment period. We observed a statistically significant decrease in the serum magnesium levels in patients treated with teriparatide for severe osteoporosis. Older age and lower baseline magnesium were significant determinants of hypomagnesemia. Closer monitoring of serum magnesium level should be considered in these patients. © 2018 American Society for Bone and Mineral Research.

Impaired rib bone mass and quality in end-stage cystic fibrosis patients.

BACKGROUND: Advancements in research and clinical care have considerably extended the life expectancy of cystic fibrosis (CF) patients. However, with this extended survival come comorbidities. One of the leading co-morbidities is CF-related bone disease (CFBD), which progresses with disease severity and places patients at high risk for fractures, particularly of the ribs and vertebrae. Evidence that CF patients with vertebral fractures had higher bone mineral density (BMD) than the nonfracture group led us to postulate that bone quality is impaired in these patients. We therefore examined rib specimens resected at the time of lung transplant in CF patients to measure parameters of bone quantity and quality. METHODS: In this exploratory study, we analysed 19 end-stage CF and 13 control rib specimens resected from otherwise healthy lung donors. BMD, bone microarchitecture, static parameters of bone formation and resorption and microcrack density of rib specimens were quantified by imaging, histomorphometric and histological methods. Variables reflecting the mineralization of ribs were assessed by digitized microradiography. The degree of bone mineralization (g/cm3) and the heterogeneity index of the mineralization (g/cm3) were calculated for trabecular and cortical bone. RESULTS: Compared to controls, CF ribs exhibited lower areal and trabecular volumetric BMD, decreased trabecular thickness and osteoid parameters, and increased microcrack density, that was particularly pronounced in specimens from patients with CF-related diabetes. Static parameters of bone resorption were similar in both groups. Degree of mineralization of total bone, but not heterogeneity index, was increased in CF specimens. CONCLUSION: The combination of reduced bone mass, altered microarchitecture, imbalanced bone remodeling (maintained bone resorption but decreased formation), increased microdamage and a small increase of the degree of mineralization, may lead to decreased bone strength, which, when coupled with chronic coughing and chest physical therapy, may provide an explanation for the increased incidence of rib fractures previously reported in this population.

Assessment of femur geometrical parameters using EOS™ imaging technology in patients with atypical femur fractures; preliminary results.

Atypical femur fractures (AFF) arise in the subtrochanteric and diaphyseal regions. Because of this unique distribution, we hypothesized that patients with AFF demonstrate specific geometrical variations of their lower limb whereby baseline tensile forces applied to the lateral cortex are higher and might favor the appearance of these rare stress fractures, when exposed to bisphosphonates. Using the low irradiation 2D-3D X-ray scanner EOS™ imaging technology we aimed to characterize and compare femur geometric parameters between women who sustained bisphosphonate-associated AFF and those who had experienced similar duration of exposure to bisphosphonates but did not sustain fractures. Conditional logistic regression models were constructed to estimate the association between selected geometric parameters and the occurrence of AFF. We identified 16 Caucasian women with AFF and recruited 16 ethnicity-, sex-, age-, height- and cumulative bisphosphonate exposure-matched controls from local osteoporosis clinics. Compared to controls, those with AFF had more lateral femur bowing (-3.2° SD [3.4] versus -0.8° SD [1.9] p=0.02). In regression analysis, lateral femur bowing was associated with the risk of AFF (aOR 1.54; 95% CI 1.04-2.28, p=0.03). Women who sustained a subtrochanteric AFF demonstrated a lesser femoral neck shaft angle (varus geometry) than those with a fracture at a diaphyseal site (121.9 [3.6]° versus 127.6 [7.2]°, p=0.07), whereas femur bowing was more prominent in those with a diaphyseal fracture compared to those with a subtrochanteric fracture (-4.3 [3.2]° versus -0.9 [2.7]°, p=0.07). Our analyses support that subjects with AFF exhibit femoral geometry parameters that result in higher tensile mechanical load on the lateral femur. This may play a critical role in the pathogenesis of AFF and requires further evaluation in a larger size population.

Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals.

OBJECTIVE: Hypertension and osteoporosis are age-related health risks differentially expressed in men and women. Here we have analysed their prevalence in a randomly selected cross-sectional cohort [CARTaGENE (CaG) of Quebec, Canada and explored their existing relationships along with height, arterial stiffness and bone fractures. METHODS: The principal cohort CaG included 20 007 individuals of age 40-70 years. Participants were subjected to an extensive phenotyping and a questionnaire of medical history and habits. RESULTS: We determined the differences in height of participants and their relation to hypertension status and sex in this cohort and validated it in two other cohorts (The Canadian Heart Health Study and a family cohort from the Saguenay Lac Saint-Jean, a region of Quebec). In all three cohorts, we found that at younger age individuals with hypertension are taller than normotensive individuals, but they have a shorter stature at an older age compared with normotensive individuals. In CaG, we observed that hypertension, low bone mineral density (BMD) and arterial stiffness are strongly associated with height when adjusted for antihypertensive medications (P < 0.0001). Fractures are the net outcome of low BMD, and a significant association is observed (odds ratio = 2.34, confidence interval = 2.12-2.57); this relation was stronger in hypertensive individuals compared with normotensive individuals particularly in younger hypertensive individuals. In addition, we observed that increased arterial stiffness was significantly correlated with a low BMD in both men and women at all ages. CONCLUSION: Shorter stature in elderly, low BMD and fractures correlated with increased arterial stiffness and hypertension. We propose that hypertension and osteoporosis share components of accelerated aging.

Teriparatide and bone turnover and formation in a hemodialysis patient with low-turnover bone disease: a case report.

Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20µg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population.

Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays.

OBJECTIVE: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday." QUALITY OF EVIDENCE: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials). MAIN MESSAGE: The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy. CONCLUSION: When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.

Pasireotide monotherapy in Cushing's disease: a single-centre experience with 5-year extension of phase III Trial.

PURPOSE: A recent phase III randomized controlled trial (NCT00434148) showed efficacy of pasireotide in the treatment of patients with Cushing's disease (CD). Patients were invited to participate in an extension phase of the protocol and a subgroup had a sustained response. We report the experience with 4 patients in our center of which 2 full responders have completed 5.5 and 4.25 years of treatment with disease control. METHODS: The trial protocol was described previously. The extension phase consisted of 3-monthly visits with clinical, biochemical, and imaging evaluation and investigator-driven pasireotide titration. Research charts were retrospectively analyzed. RESULTS: Four patients with persistent CD following pituitary surgery completed the first 6 months of the trial and 3 continued in the next 6 month open-label phase. Two patients with baseline urinary free cortisol (UFC) 5.3-6.7 times the upper limit of normal had a rapid sustained response to pasireotide and entered the extension phase after 12 months. They remain in clinical and biochemical disease remission and 1 patient now only requires 300 µg daily of pasireotide. All 4 patients developed glucose intolerance; however, the two patients in the extension phase were eventually able to discontinue all diabetes pharmacotherapy. Adverse events included second degree atrioventicular block type 1 without QT prolongation in a patient with pre-existing sinus bradycardia, and symptomatic cholelithiasis requiring cholecystectomy in a second patient. CONCLUSIONS: Pasireotide therapy can provide normalization of UFC and of clinical symptoms and signs of CD during up to 5 years of follow-up. This study demonstrates the possible recuperation of normoglycemia after continued use of pasireotide and control of underlying hypercortisolemia. Longer-term monitoring for potential adverse events related to continued use of pasireotide is indicated.

High-resolution peripheral quantitative computed tomography for the assessment of bone strength and structure: a review by the Canadian Bone Strength Working Group.

Bone structure is an integral determinant of bone strength. The availability of high resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure three-dimensional bone microarchitecture and volumetric bone mineral density in vivo, with accuracy previously unachievable and with relatively low-dose radiation. Recent studies using this novel imaging tool have increased our understanding of age-related changes and sex differences in bone microarchitecture, as well as the effect of different pharmacological therapies. One advantage of this novel tool is the use of finite element analysis modelling to non-invasively estimate bone strength and predict fractures using reconstructed three-dimensional images. In this paper, we describe the strengths and limitations of HR-pQCT and review the clinical studies using this tool.

Varying conceptions of competence: an analysis of how health sciences educators define competence.

CONTEXT: Current debate in medical education focuses on the nature of 'competency-based medical education' (CBME) and whether or not it should be adopted. Many medical schools claim to run 'competency-based' curricula, but the structure of their programmes can differ radically. A review of the existing CBME literature reveals that little attention has been paid to defining the concept of competence. A straightforward examination of what is meant by the term 'competence' is noticeably missing from the literature, despite its impact on medical training. OBJECTIVES: This paper aims to illustrate the varying conceptions of 'competence' by comparing and contrasting definitions provided in the health sciences education literature and discussing their respective impacts on medical education. METHODS: A systematic review of recent publications in medical education journals published in English and French was conducted to extract definitions of competence or, if definitions were not explicitly stated, to derive the authors' implicit conception of competence. A sample of 14 definitions from articles in the health sciences education field was studied using thematic analysis. RESULTS: There is agreement that competence is composed of knowledge, skills and other components. Although agreement about the nature of these other components is lacking, attitudes and values are suggested to be essential ingredients of competence. Furthermore, a clear divergence in conceptions of how a competent person utilises these components is apparent. One view specifies that competence involves selecting components according to specific situations, as required. A second view places greater emphasis on the synergy that results from the use of a combination of components in a given situation. CONCLUSIONS: These conceptual distinctions have many implications for the way CBME is implemented. A conception of competence as the selection of components may lead to a greater emphasis, in a training setting, on the mastery of each component separately. A conception of competence as the use of a combination of components leads to greater emphasis on the synergy that results as they are deployed in clinical situations.

Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis.

Role of zoledronic acid in the prevention and treatment of osteoporosis.

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced osteoporosis. Given that Zol is generally well tolerated and very convenient, it is an interesting therapeutic option for aging patients who take multiple oral drugs, who have adherence or gastrointestinal tolerance issues, and who have an indication for oral bisphosphonates. Zol is not recommended for patients with severe renal impairment. Vitamin D deficiency should be corrected before the administration of Zol.

Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice.

Interferon γ (IFN-γ) is a cytokine produced locally in the bone microenvironment by cells of immune origin as well as mesenchymal stem cells. However, its role in normal bone remodeling is still poorly understood. In this study we first examined the consequences of IFN-γ ablation in vivo in C57BL/6 mice expressing the IFN-γ receptor knockout phenotype (IFNγR1(-/-)). Compared with their wild-type littermates (IFNγR1(+/+)), IFNγR1(-/-) mice exhibit a reduction in bone volume associated with significant changes in cortical and trabecular structural parameters characteristic of an osteoporotic phenotype. Bone histomorphometry of IFNγR1(-/-) mice showed a low-bone-turnover pattern with a decrease in bone formation, a significant reduction in osteoblast and osteoclast numbers, and a reduction in circulating levels of bone-formation and bone-resorption markers. Furthermore, administration of IFN-γ (2000 and 10,000 units) to wild-type C57BL/6 sham-operated (SHAM) and ovariectomized (OVX) female mice significantly improved bone mass and microarchitecture, mechanical properties of bone, and the ratio between bone formation and bone resorption in SHAM mice and rescued osteoporosis in OVX mice. These data therefore support an important physiologic role for IFN-γ signaling as a potential new anabolic therapeutic target for osteoporosis.