Characterizing Bone Phenotypes Related to Skeletal Fragility Using Advanced Medical Imaging.

PURPOSE OF REVIEW: Summarize the recent literature that investigates how advanced medical imaging has contributed to our understanding of skeletal phenotypes and fracture risk across the lifespan. RECENT FINDINGS: Characterization of bone phenotypes on the macro-scale using advanced imaging has shown that while wide bones are generally stronger than narrow bones, they may be more susceptible to age-related declines in bone strength. On the micro-scale, HR-pQCT has been used to identify bone microarchitecture phenotypes that improve stratification of fracture risk based on phenotype-specific risk factors. Adolescence is a key phase for bone development, with distinct sex-specific growth patterns and significant within-sex bone property variability. However, longitudinal studies are needed to evaluate how early skeletal growth impacts adult bone phenotypes and fracture risk. Metabolic and rare bone diseases amplify fracture risk, but the interplay between bone phenotypes and disease remains unclear. Although bone phenotyping is a promising approach to improve fracture risk assessment, the clinical availability of advanced imaging is still limited. Consequently, alternative strategies for assessing and managing fracture risk include vertebral fracture assessment from clinically available medical imaging modalities/techniques or from fracture risk assessment tools based on clinical risk factors. Bone fragility is not solely determined by its density but by a combination of bone geometry, distribution of bone mass, microarchitecture, and the intrinsic material properties of bone tissue. As such, different individuals can exhibit distinct bone phenotypes, which may predispose them to be more vulnerable or resilient to certain perturbations that influence bone strength.

The contribution of lower-mineralized tissue to the healing of distal radius fractures assessed using HR-pQCT.

High-resolution peripheral quantitative CT (HR-pQCT) enables quantitative assessment of distal radius fracture healing. In previous studies, lower-mineralized tissue formation was observed on HR-pQCT scans, starting early during healing, but the contribution of this tissue to the stiffness of distal radius fractures is unknown. Therefore, the aim of this study was to investigate the contribution of lower-mineralized tissue to the stiffness of fractured distal radii during the first twelve weeks of healing. We did so by combining the results from two series of micro-finite element (µFE-) models obtained using different density thresholds for bone segmentation. Forty-five postmenopausal women with a conservatively-treated distal radius fracture had HR-pQCT scans of their fractured radius at baseline (BL; 1-2 weeks post-fracture), 3-4 weeks, 6-8 weeks, and 12 weeks post-fracture. Compression stiffness (S) was computed using two series of µFE-models from the scans: one series (Msingle) included only higher-mineralized tissue (>320 mg HA/cm3), and one series (Mdual) differentiated between lower-mineralized tissue (200-320 mg HA/cm3) and higher-mineralized tissue. µFE-elements were assigned a Young's Modulus of 10 GPa (higher-mineralized tissue) or 5 GPa (lower-mineralized tissue), and an axial compression test to 1 % strain was simulated. The contribution of the lower-mineralized tissue to S was quantified as the ratio Sdual/Ssingle. Changes during healing were quantified using linear mixed effects models and expressed as estimated marginal means (EMMs) with 95 %-confidence intervals (95 %-CI). Median time to cast removal was 5.0 (IQR: 1.1) weeks. Sdual and Ssingle gradually increased during healing to a significantly higher value than BL at 12 weeks post-fracture (both p < 0.0001). In contrast, Sdual/Ssingle was significantly higher than BL at 3-4 weeks post-fracture (p = 0.0010), remained significantly higher at 6-8 weeks post-fracture (p < 0.0001), and then decreased to BL-values at the 12-week visit. EMMs ranged between 1.05 (95 %-CI: 1.04-1.06) and 1.08 (95 %-CI: 1.07-1.10). To conclude, combining stiffness results from two series of µFE-models obtained using single- and dual-threshold segmentation enables quantification of the contribution of lower-mineralized tissue to the stiffness of distal radius fractures during healing. This contribution is minor but changes significantly around the time of cast removal. Its course and timing during healing may be clinically relevant. Quantification of the contribution of lower-mineralized tissue to stiffness gives a more complete impression of strength recovery post-fracture than the evaluation of stiffness using a single series of µFE-models.

What Is the Diagnostic Performance of Conventional Radiographs and Clinical Reassessment Compared With HR-pQCT Scaphoid Fracture Diagnosis?

BACKGROUND: Conventional radiographs and clinical reassessment are considered guides in managing clinically suspected scaphoid fractures. This is a unique study as it assessed the value of conventional radiographs and clinical reassessment in a cohort of patients, all of whom underwent additional imaging, regardless of the outcome of conventional radiographs and clinical reassessment. QUESTIONS/PURPOSES: (1) What is the diagnostic performance of conventional radiographs in patients with a clinically suspected scaphoid fracture compared with high-resolution peripheral quantitative CT (HR-pQCT)? (2) What is the diagnostic performance of clinical reassessment in patients with a clinically suspected scaphoid fracture compared with HR-pQCT? (3) What is the diagnostic performance of conventional radiographs and clinical reassessment combined compared with HR-pQCT? METHODS: Between December 2017 and October 2018, 162 patients with a clinically suspected scaphoid fracture presented to the emergency department (ED). Forty-six patients were excluded and another 25 were not willing or able to participate, which resulted in 91 included patients. All patients underwent conventional radiography in the ED and clinical reassessment 7 to 14 days later, together with CT and HR-pQCT. The diagnostic performance characteristics and accuracy of conventional radiographs and clinical reassessment were compared with those of HR-pQCT for the diagnosis of fractures since this was proven to be superior to CT scaphoid fracture detection. The cohort included 45 men and 46 women with a median (IQR) age of 52 years (29 to 67). Twenty-four patients with a median age of 44 years (35 to 65) were diagnosed with a scaphoid fracture on HR-pQCT. RESULTS: When compared with HR-pQCT, conventional radiographs alone had a sensitivity of 67% (95% CI 45% to 84%), specificity of 85% (95% CI 74% to 93%), positive predictive value (PPV) of 62% (95% CI 46% to 75%), negative predictive value (NPV) of 88% (95% CI 80% to 93%), and a positive and negative likelihood ratio (LR) of 4.5 (95% CI 2.4 to 8.5) and 0.4 (95% CI 0.2 to 0.7), respectively. Compared with HR-pQCT, clinical reassessment alone resulted in a sensitivity of 58% (95% CI 37% to 78%), specificity of 42% (95% CI 30% to 54%), PPV of 26% (95% CI 19% to 35%), NPV of 74% (95% CI 62% to 83%), as well as a positive and negative LR of 1.0 (95% CI 0.7 to 1.5) and 1.0 (95% CI 0.6 to 1.7), respectively. Combining clinical examination with conventional radiography produced a sensitivity of 50% (95% CI 29% to 71%), specificity of 91% (95% CI 82% to 97%), PPV of 67% (95% CI 46% to 83%), NPV of 84% (95% CI 77% to 88%), as well as a positive and negative LR of 5.6 (95% CI 2.4 to 13.2) and 0.6 (95% CI 0.4 to 0.8), respectively. CONCLUSION: The accuracy of conventional radiographs (80% compared with HR-pQCT) and clinical reassessment (46% compared with HR-pQCT) indicate that the value of clinical reassessment is limited in diagnosing scaphoid fractures and cannot be considered directive in managing scaphoid fractures. The combination of conventional radiographs and clinical reassessment does not increase the accuracy of these diagnostic tests compared with the accuracy of conventional radiographs alone and is therefore also limited in diagnosing scaphoid fractures. LEVEL OF EVIDENCE: Level II, diagnostic study.

Decreased Mortality and Subsequent Fracture Risk in Patients With a Major and Hip Fracture After the Introduction of a Fracture Liaison Service: A 3-Year Follow-Up Survey.

Fracture liaison services (FLS) are considered to be the most effective organizational approach for secondary fracture prevention. In this study, we evaluated whether FLS care was associated with reduced subsequent fracture and mortality risk over 3 years of follow-up. In total, 8682 consecutive patients aged 50-90 years with a recent fracture were included. Before FLS introduction, regular fracture treatment procedures were followed (pre-FLS). After FLS introduction, patients were invited to the FLS and FLS attenders were assessed for osteoporosis, prevalent vertebral fractures, metabolic bone disorders, medication use, and fall risk, and treatment for fracture prevention was initiated according to Dutch guidelines. All fractures were radiographically confirmed and categorized into major/hip (pelvis, proximal humerus or tibia, vertebral, multiple rib, distal femur) and non-major/non-hip (all other fractures). Mortality risk was examined using age and sex adjusted Cox proportional hazard models. For subsequent fracture risk, Cox proportional hazard models were adjusted for age, sex, and competing mortality risk (subdistribution hazard [SHR] approach). The pre-FLS group consisted of 2530 patients (72% women), of whom 1188 (46.9%) had major/hip index fractures, the post-FLS group consisted of 6152 patients (69% women), of whom 2973 (48.3%) had major/hip index fractures. In patients with a non-major/non-hip fracture there was no difference in subsequent non-major/non-hip fracture risk or mortality between pre-FLS and post-FLS. In patients with a major/hip index fracture, mortality risk was lower post-FLS (hazard ratio [HR] 0.84; 95% confidence interval [CI], 0.73-0.96) and subsequent major/hip fracture risk was lower in the first 360 days after index fracture post-FLS compared to pre-FLS (SHR 0.67; 95% CI, 0.52-0.87). In conclusion, FLS care was associated with a lower mortality risk in the first 3 years and a lower subsequent major/hip fracture risk in the first year in patients with a major/hip index fracture but not in patients with a non-major/non-hip fracture. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Prevalent Morphometrically Assessed Vertebral Fractures in Individuals With Type 2 Diabetes, Prediabetes and Normal Glucose Metabolism: The Maastricht Study.

BACKGROUND: Type 2 diabetes (T2D) is frequently reported to be associated with an increased fracture risk. Epidemiological data on prevalent morphometric vertebral fractures (VFs) in T2D are sparse and even less is known in the prediabetic state. PURPOSE: To determine the association between prevalence and severity of morphometric VFs and glucose metabolism state: normal glucose metabolism (NGM), impaired glucose metabolism (prediabetes) or T2D. METHODS: This study included cross-sectional data from 3625 participants of the Maastricht Study who had a vertebral fracture assessment on lateral Dual Energy X-Ray Absorptiometry images. VFs were classified based on morphometric assessment into mild, moderate and severe VFs (respectively 20-24%, 25-39% or ≥40% reduction in expected vertebral body height). Logistic regression models were used to investigate the association between glucose metabolism status and the prevalence and severity of VFs. Analyses were adjusted for subject characteristics and life-style factors. RESULTS: T2D individuals were older (62.8 ± 7.5 years old) and less often female (30.5%) compared to the NGM group (57.7 ± 8.5 years old, and 58.8% female, respectively). At least one mild, moderate or severe prevalent VF was found in 8.6% of the men and 2.2% of the women in the T2D group, in 9.4% and 8.4% in the prediabetes group and in 9.1% and 4.8% in the NGM group, respectively. After adjustment T2D in women was associated with a lower probability of having a prevalent VF compared to NGM [adjusted OR 0.25 (95% CI 0.09-0.65)], while this was not the case for prediabetes. Furthermore, women with T2D had a significantly lower probability of a prevalent moderate or severe VF [adjusted OR 0.32 (95% CI 0.11-0.96)]. In men there was no significant association between T2D or prediabetes and prevalent VFs. CONCLUSION: Women with T2D had a lower probability of prevalent VFs compared to women with a normal glucose metabolism, while this was not the case for men with T2D and participants with prediabetes.

Association between bone shape and the presence of a fracture in patients with a clinically suspected scaphoid fracture.

Scaphoid fractures are difficult to diagnose with current imaging modalities. It is unknown whether the shape of the scaphoid bone, assessed by statistical shape modeling, can be used to differentiate between fractured and non-fractured bones. Therefore, the aim of this study was to investigate whether the presence of a scaphoid fracture is associated with shape modes of a statistical shape model (SSM). Forty-one high-resolution peripheral quantitative computed tomography (HR-pQCT) scans were available from patients with a clinically suspected scaphoid fracture of whom 15 patients had a scaphoid fracture. The scans showed no motion artefacts affecting bone shape. The scaphoid bones were semi-automatically contoured, and the contours were converted to triangular meshes. The meshes were registered, followed by principal component analysis to determine mean shape and shape modes describing shape variance. The first five out of the forty shape modes cumulatively explained 87.8% of the shape variance. Logistic regression analysis was used to study the association between shape modes and fracture presence. The regression models were used to classify the 41 scaphoid bones as fractured or non-fractured using a cut-off value that maximized the sum of sensitivity and specificity. The classification of the models was compared with fracture diagnosis on HR-pQCT. A regression model with four shape modes had an area under the ROC-curve of 72.3% and correctly classified 75.6% of the scaphoid bones (fractured: 60.0%, non-fractured: 84.6%). To conclude, fracture presence in patients with a clinically suspected scaphoid fracture appears to be associated with the shape of the scaphoid bone.

The Prevalence of Celiac Disease in a Fracture Liaison Service Population.

Celiac disease (CD) is a known risk factor for osteoporosis and fractures. The prevalence of CD in patients with a recent fracture is unknown. We therefore systematically screened patients at a fracture liaison service (FLS) to study the prevalence of CD. Patients with a recent fracture aged ≥ 50 years were invited to VieCuri Medical Center's FLS. In FLS attendees, bone mineral density (BMD) and laboratory evaluation for metabolic bone disorders and serological screening for CD was systematically evaluated. If serologic testing for CD was positive, duodenal biopsies were performed to confirm the diagnosis CD. Data were collected in 1042 consecutive FLS attendees. Median age was 66 years (Interquartile range (IQR) 15), 27.6% had a major and 6.9% a hip fracture, 26.4% had osteoporosis and 50.8% osteopenia. Prevalent vertebral fractures were found in 29.1%. CD was already diagnosed in two patients (0.19%), one still had a positive serology. Three other patients (0.29%) had a positive serology for CD (one with gastro-intestinal complaints). In two of them, CD was confirmed by duodenal histology (0.19%) and one refused further evaluation. The prevalence of biopsy-proven CD was therefore 0.38% (4/1042) of which 0.19% (2/1042) was newly diagnosed. The prevalence of CD in patients with a recent fracture at the FLS was 0.38% and within the range of reported prevalences in the Western-European population (0.33-1.5%). Newly diagnosed CD was only found in 0.19%. Therefore, standard screening for CD in FLS patients is not recommended.

Bone Microarchitecture and Distal Radius Fracture Pattern Complexity.

Distal radius fractures (DRFs) occur in various complexity patterns among patients differing in age, gender, and bone mineral density (BMD). Our aim was to investigate the association of patient characteristics, BMD, bone microarchitecture, and bone strength with the pattern complexity of DRFs. In this study, 251 patients aged 50-90 years with a radiologically confirmed DRF who attended the Fracture Liaison Service of VieCuri Medical Centre, the Netherlands, between November 2013 and June 2016 were included. In all patients fracture risk factors and underling metabolic disorders were evaluated and BMD measurement with vertebral fractures assessment by dual-energy X-ray absorptiometry was performed. Radiographs of all DRFs were reviewed by two independent investigators to assess fracture pattern complexity according to the AO/OTA classification in extra-articular (A), partially articular (B), and complete articular (C) fractures. For this study, patients with A and C fractures were compared. Seventy-one patients were additionally assessed by high-resolution peripheral quantitative computed tomography. Compared to group A, mean age, the proportion of males, and current smokers were higher in group C, but BMD and prevalent vertebral fractures were not different. In univariate analyses, age, male gender, trabecular area, volumetric BMD (vBMD), and stiffness were associated with type C fractures. In multivariate analyses, only male gender (odds ratio (OR) 8.48 95% confidence interval (CI) 1.75-41.18, p = 0.008]) and age (OR 1.11 [95% CI 1.03-1.19, p = 0.007]) were significantly associated with DRF pattern complexity. In conclusion, our data demonstrate that age and gender, but not body mass index, BMD, bone microarchitecture, or strength were associated with pattern complexity of DRFs.© 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:1690-1697, 2019.

Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study.

OBJECTIVE: Osteoporotic fragility fractures, that are common in men and women, signal increased risk of future fractures and of premature mortality. Less than one-third of postmenopausal women and fewer men are prescribed active treatments to reduce fracture risk. Therefore, in this study the association of oral bisphosphonate recommendation with subsequent fracture and mortality over eight years in a fracture liaison service setting was analysed. MATERIALS AND METHODS: In this prospective cohort study, 5011 men and women aged >50 years, who sustained a clinical fracture, accepted the invitation to attend the fracture liaison service of the West Glasgow health service between 1999 and 2007. These patients were fully assessed and all were recommended calcium and vitamin D. Based on pre-defined fracture risk criteria, 2534 (50.7%) patients were additionally also recommended oral bisphosphonates. Mortality and subsequent fracture risk were the pre-defined outcomes analysed using Cox proportional hazard models. RESULTS: Those recommended bisphosphonates were more often female (82.9 vs. 72.4%), were older (73.4 vs. 64.4 years), had lower bone mineral density T-score (-3.1 vs. -1.5) and more had sustained hip fractures (21.7 vs. 6.2%; p < 0.001). After adjustments, patients recommended bisphosphonates had lower subsequent fracture risk (Hazard Ratio (HR): 0.60; 95% confidence interval (CI): 0.49-0.73) and lower mortality risk (HR: 0.79, 95%CI: 0.64-0.97). CONCLUSION: Of the patients, who are fully assessed after a fracture at the fracture liaison service, those with higher fracture risk and a recommendation for bisphosphonates had worse baseline characteristics. However, after adjusting for these differences, those recommended bisphosphonate treatment had a substantially lower risk for subsequent fragility fracture and lower risk for mortality. These community-based data indicate the adverse public health outcomes and mortality impacts of the current low treatment levels post fracture could be improved by bisphosphonate recommendation for both subsequent fracture and mortality.

Reliability of HR-pQCT Derived Cortical Bone Structural Parameters When Using Uncorrected Instead of Corrected Automatically Generated Endocortical Contours in a Cross-Sectional Study: The Maastricht Study.

Most HR-pQCT studies examining cortical bone use an automatically generated endocortical contour (AUTO), which is manually corrected if it visually deviates from the apparent endocortical margin (semi-automatic method, S-AUTO). This technique may be prone to operator-related variability and is time consuming. We examined whether the AUTO instead of the S-AUTO method can be used for cortical bone analysis. Fifty scans of the distal radius and tibia from participants of The Maastricht Study were evaluated with AUTO, and subsequently with S-AUTO by three independent operators. AUTO cortical bone parameters were compared to the average parameters obtained by the three operators (S-AUTOmean). All differences in mean cortical bone parameters between AUTO and S-AUTOmean were < 5%, except for lower AUTO cortical porosity of the radius (- 16%) and tibia (- 6%), and cortical pore volume (Ct.Po.V) of the radius (- 7%). The ICC of S-AUTOmean and AUTO was > 0.90 for all parameters, except for cortical pore diameter of the radius (0.79) and tibia (0.74) and Ct.Po.V of the tibia (0.89), without systematic errors on the Bland-Altman plots. The precision errors (RMS-CV%) of the radius parameters between S-AUTOmean and AUTO were comparable to those between the individual operators, whereas the tibia RMS-CV% between S-AUTOmean and AUTO were higher than those of the individual operators. Comparison of the three operators revealed clear inter-operator variability. This study suggests that the AUTO method can be used for cortical bone analysis in a cross-sectional study, but that the absolute values-particularly of the porosity-related parameters-will be lower.

Fracture liaison services: do they reduce fracture rates?

The fracture liaison service (FLS) care is considered the most appropriate organizational approach for secondary fracture prevention. We performed a literature search to evaluate to what extent the introduction of a FLS reduced subsequent fracture rates. We identified five studies that compared subsequent fracture rates. These studies varied in study design, proportion of women, baseline and subsequent fracture type [vertebral fracture (VF), non-VF (NVF) or hip fractures], duration of follow-up, response rates of attending the FLS, as well as variables included in adjusted analyses (age, sex, baseline fracture, time dependency). In two studies comparing hospitals with and without a FLS, the adjusted hazard ratio (HR) for subsequent fractures was significantly lower in the FLS hospitals (HR: 0.84 during the first year, 0.44 during the second year for subsequent NVFs after baseline NVF, and 0.67 during the third year for subsequent VFs + NVFs after baseline VFs + NVFs). When comparing fracture rates before (pre-FLS) and after (post-FLS) introduction of a FLS, the adjusted HR for subsequent NVFs after baseline NVF was significantly lower in the post-FLS group after 2 years in one study (HR = 0.65) and nonsignificant in another study for subsequent hip fractures after baseline hip fracture. One study comparing pre-FLS and post-FLS with a follow-up of less than a year did not demonstrate a significant difference in subsequent fracture risk. In conclusion, only five FLS studies with heterogeneous study designs are available, three of them reported a lower subsequent fracture rate related to FLS care. Larger and long-term studies will be needed to further quantify the effect of FLS care on subsequent fracture risk.

The Phenotype of Patients with a Recent Fracture: A Literature Survey of the Fracture Liaison Service.

The aetiology of fractures in patients aged 50 years and older is multifactorial, and includes bone- and fall-related risks. The Fracture Liaison Service (FLS) is recommended to identify patients with a recent fracture and to evaluate their subsequent fracture risk, in order to take measures to decrease the risk of subsequent fractures in patients with a high risk phenotype. A literature survey was conducted to describe components of the bone- and fall-related phenotype of patients attending the FLS. Components of the patient phenotype at the FLS have been reported in 33 studies. Patient selection varied widely in terms of patient identification, selection, and FLS attendance. Consequently, there was a high variability in FLS patient characteristics, such as mean age (64-80 years), proportion of men (13-30%), and fracture locations (2-51% hip, <1-41% vertebral, and 49-95% non-hip, non-vertebral fractures). The studies also varied in the risk evaluation performed. When reported, there was a highly variability in the percentage of patients with osteoporosis (12-54%), prevalent vertebral fractures (20-57%), newly diagnosed contributors to secondary osteoporosis and metabolic bone disorders (3-70%), and fall-related risk factors (60-84%). In FLS literature, we found a high variability in patient selection and risk evaluation, resulting in a highly variable phenotype. In order to specify the bone- and fall related phenotypes at the FLS, systematic studies on the presence and combinations of these risks are needed.

Replacement Effects of Sedentary Time on Metabolic Outcomes: The Maastricht Study.

INTRODUCTION: Sedentary time has been associated with detrimental health effects, so in some countries, guidelines to reduce sedentary time have been developed. As reducing sedentary time inevitably results in more nonsedentary time, effects of this reduction may depend on the activity with which it is replaced. PURPOSE: This study aimed to examine associations of theoretical reallocations of sedentary time to standing or stepping with cardiometabolic outcomes and type 2 diabetes. METHODS: We included 2213 participants (51% men, mean ± SD age = 60.0 ± 8.1 yr) of the Maastricht Study who were asked to wear an accelerometer 24 h·d for a week. We calculated daily sedentary, standing, and stepping time. An isotemporal substitution modeling approach was applied to examine effects on waist circumference; body mass index; cholesterol, triacylglycerol, glucose, and insulin levels; metabolic syndrome; and type 2 diabetes. RESULTS: Replacement of sedentary time (30 min·d) with stepping was associated with lower odds for metabolic syndrome (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.66-0.78) and type 2 diabetes (OR = 0.79, 95% CI = 0.72-0.87), more favorable waist circumference (B = -1.42, 95% CI = -1.78 to -1.06), and body mass index (B = -0.48, 95% CI = -0.62 to -0.35) and improved cholesterol, triacylglycerol, glucose, and insulin levels. Replacing sedentary time with standing was associated with lower odds for metabolic syndrome and type 2 diabetes and favorable outcomes in waist circumference, cholesterol, triacylglycerol, and insulin levels. CONCLUSION: Theoretical replacements of sedentary time with nonsedentary time (both standing and stepping) were associated with lower odds for metabolic syndrome, type 2 diabetes, and beneficial metabolic outcomes. These results could be important for the general population, including those who cannot meet physical activity guidelines. Consideration should be given to developing recommendations for daily reallocating sedentary time.

Cardiovascular risk factor analysis in patients with a recent clinical fracture at the fracture liaison service.

Patients with a low bone mineral density have an increased risk of cardiovascular diseases (CVD) and venous thromboembolic events (VTE). The aim of our retrospective chart review was to investigate the prevalence of CVD, VTE, hypertension (HT), and diabetes mellitus type 2 (DM2) in patients with a recent clinical fracture visiting the Fracture Liaison Service (FLS). Out of 3057 patients aged 50-90 years, 1359 consecutive patients, who agreed and were able to visit the FLS for fracture risk evaluation, were included (71.7% women; mean age 65.2 yrs). Based on medical history, 29.9% had a history of CVD (13.7%), VTE (1.7%), HT (14.9%), and DM2 (7.1%) or a combination. Their prevalence increased with age (21% in patients aged 50-59 years to 48% in patients aged >80 years) and was higher in men than in women (36% versus 27%), but independent of bone mineral density and fracture type. Careful evaluation of medical history with respect to these risk factors should be performed in patients with a recent clinical fracture before starting treatment with medications that increase the risk of VTE or cardiovascular events, such as raloxifene, strontium ranelate, or NSAIDs.

Increased fracture risk in patients with type 2 diabetes mellitus: an overview of the underlying mechanisms and the usefulness of imaging modalities and fracture risk assessment tools.

Type 2 diabetes mellitus has recently been linked to an increased fracture risk. Since bone mass seems to be normal to elevated in patient with type 2 diabetes, the increased fracture risk is thought to be due to both an increased falling frequency and decreased bone quality. The increased falling frequency is mainly a result of complications of the disease such as a retinopathy and polyneuropathy. Bone quality is affected through changes in bone shape, bone micro-architecture, and in material properties such as bone mineralization and the quality of collagen. Commonly used methods for predicting fracture risk such as dual energy X-ray absorptiometry and fracture risk assessment tools are helpful in patients with type 2 diabetes mellitus, but underestimate the absolute fracture risk for a given score. New imaging modalities such as high resolution peripheral quantitative computed tomography are promising for giving insight in the complex etiology underlying the fragility of the diabetic bone, as they can give more insight into the microarchitecture and geometry of the bone. We present an overview of the contributing mechanisms to the increased fracture risk and the usefulness of imaging modalities and risk assessment tools in predicting fracture risk in patients with type 2 diabetes.

Serum 25(OH)D response to vitamin D3 supplementation: a meta-regression analysis.

OBJECTIVE: The aim of this study was to review factors that influence serum 25(OH)D when patients are given vitamin D supplements. METHODS: From a comprehensive search of all randomized controlled clinical trials with vitamin D3 supplementation available on PubMed up to November 2011, we selected 33 with 43 treatment arms that included at least 30 adult participants. The achieved pooled mean difference (PMD) and 95% confidence intervals (CIs) were calculated using the random-effects models. Meta-regression and subgroup analyses were performed for prespecified factors, including dose, duration, baseline serum 25(OH)D, and age. RESULTS: With a mean baseline serum 25(OH)D of 50.4 nmol/L, PMD was 37 nmol/L (95% CI, 33-41) with significant heterogeneity among studies. Dose (slope: 0.006; P < 0.001), trial duration (slope: 0.21; P < 0.001), baseline serum 25(OH)D (slope: -0.19; P < 0.001), and age (slope: 0.42; P < 0.001) independently influenced vitamin D response. Similar results were found in studies with a mean baseline serum 25(OH)D <50 nmol/L. In subgroup analyses, the PMD was higher with doses ≥800 IU/d (39.3 nmol/L) after 6 to 12 mo (41.7 nmol/L), with baseline 25(OH)D <50 nmol/L (39.6 nmol/L), and in adults aged >80 y (40.5 nmol/L). CONCLUSION: This meta regression indicates that a higher increase in serum levels of 25(OH)D in adults is found with a dose of ≥800 IU/d, after at least 6 to 12 mo, and even when baseline 25(OH)D is low and in adults >80 y.

Secondary osteoporosis and metabolic bone disease in patients 50 years and older with osteoporosis or with a recent clinical fracture: a clinical perspective.

PURPOSE OF REVIEW: The purpose of this review is to provide guidance to clinicians about which laboratory tests should be performed in patients with osteoporosis or with a recent fracture. RECENT FINDINGS: Newly diagnosed secondary osteoporosis and other metabolic bone diseases (SECOB) have been found in 5-48% of patients with osteoporosis. In patients with a recent fracture, new SECOB is found in 10-47% of patients with osteoporosis, and in 26-51% if all patients with a fracture regardless of bone mineral density (BMD) are screened. More than one SECOB can be found in the same patient, even when they have already known SECOB. In primary hyperparathyroidism, hyperthyroidism, hypercortisolism, and multiple myeloma, both SECOB and its treatment have an impact on BMD and fractures. For other SECOBs, no treatment is available, or there are no data about the effect of treatment of the SECOB on BMD and fractures. SUMMARY: We recommend performing the following tests in all patients with osteoporosis or a recent clinical fracture: calcium, phosphate, creatinine, albumin, erythrocyte sedimentation rate in all patients, 24 h urine calcium in men and serum testosterone in men less than 70 years. On indication, additional tests can be performed.

Suboptimal effect of different vitamin D3 supplementations and doses adapted to baseline serum 25(OH)D on achieved 25(OH)D levels in patients with a recent fracture: a prospective observational study.

OBJECTIVE: Guidelines on the need for dose adaptation of vitamin D3 supplementation according to baseline serum 25(OH)D are inconclusive. The effects of increasing doses of vitamin D3 at lower baseline serum 25(OH)D values on the serum 25(OH)D after 4.2 and 11 months were determined in an observational study. DESIGN: A prospective observational study. METHODS: Out of 1481 consecutive women and men with a recent clinical fracture, 707 had a baseline 25(OH)D level <50 nmol/l and were supplemented with increasing doses of vitamin D3 (400, 800, 1700, and ≥3500 IU/day) according to the lower baseline 25(OH)D. Final analysis was restricted to the 221 participants who had full follow-up data available for 11 months. RESULTS: Serum 25(OH)D ≥50 nmol/l was achieved in 57-76% of patients after 4.2 months and in 73-79% after 11 months. These percentages were similar for all doses (P=0.06 and P=0.91 respectively). The mean achieved 25(OH)D was similar for all dose groups (56.1-64.0 nmol/l after 4.2 months and 60.2-76.3 nmol/l after 11 months). With multivariate analysis, the increase in 25(OH)D (17±32.0 after 4.2 months and 24.3±34.0 nmol/l after 11 months) was dependent on the baseline 25(OH)D (P<0.001), not on supplementation dose, season, age, BMI, or gender. CONCLUSIONS: The increase in serum 25(OH)D was significantly larger with higher vitamin D3 supplementation doses. However, this dose-effect response was mainly explained by the baseline 25(OH)D, not the supplementation dose, with a greater magnitude of response at lower baseline 25(OH)D concentrations. In 21-27% of patients, serum 25(OH)D3 levels did not reach 50 nmol/l after 11 months, at any dose. Further studies are needed to identify possible causes of suboptimal response such as non-compliance, undiagnosed malabsorption syndromes, or variability in cholecalciferol content of the vitamin D supplements.