In subjects older than 50 years, the presence of clinical risk factors (CRFs) for fractures or a recent fracture is the cornerstone for case finding. In patients who are clinically at high short... Show moreIn subjects older than 50 years, the presence of clinical risk factors (CRFs) for fractures or a recent fracture is the cornerstone for case finding. In patients who are clinically at high short-and long-term risk of fractures (those with a recent clinical fracture or with multiple CRFs), further assessment with bone mineral density (BMD) measurement using dual-energy absorptiometry (DXA), imaging of the spine, fall risk evaluation and laboratory exami-nation contributes to treatment decisions according to the height and modifiability of fracture risk. Treatment is available with anti-resorptive and anabolic drugs, and from the start of treatment a lifelong strategy is needed to decide about continuous, intermit-tent, and sequential therapy. Implementation of guidelines re-quires further initiatives for improving case finding, public awareness about osteoporosis and national policies on reim-bursement of assessment and therapy. Show less
Objectives To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease... Show moreObjectives To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS). Methods ASSERT and GO-RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model. Results Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population. Conclusion Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice. Show less
Vastesaeger, N.; Heijde, D. van der; Inman, R.; Wang, Y.X.; Deodhar, A.; Hsu, B.; ... ; Braun, J. 2011
RANK (receptor activator of nuclear factor-kappa B), encoded by TNFRSF11A, is a key protein in osteoclastogenesis TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial... Show moreRANK (receptor activator of nuclear factor-kappa B), encoded by TNFRSF11A, is a key protein in osteoclastogenesis TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between 036 and 317 x 10(-4), with the major effect coming from females Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < 002) Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort Interestingly, both SNPs resulted in p values ranging from 013 to 838 x 10(-5) in both populations Meta-analysis over three populations resulted in p = 002 for rs35211496 and p = 1 27 x 10(-8) for rs1805034, again mainly coming from the female subgroups In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A (C) 2010 American Society for Bone and Mineral Research Show less
Chung, P.Y.J.; Beyens, G.; Boonen, S.; Papapoulos, S.; Geusens, P.; Karperien, M.; ... ; Hul, W. van 2010
Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the... Show morePaget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 x 10(-4) to 3.8 x 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 x 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 x 10(-4) and 8.8 x 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes. Show less
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force... Show moreReports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis A case definition was developed so that subsequent studies report on the same condition The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features including their location in the subtrochantenc region and femoral shaft transverse or short oblique orientation minimal or no associated trauma a medial spike when the fracture is complete and absence of comminution be present to designate a femoral fracture as atypical Minor features include their association with cortical thickening a periosteal reaction of the lateral cortex prodromal pain bilaterality delayed healing, comorbid conditions and concomitant drug exposures including BPs other antiresorptive agents, glucocorticoids, and proton pump inhibitors Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation accumulation of microdamage and advanced glycation end products mineralization remodeling vascularity and angiogenesis lend biologic plausibility to a potential association with long-term BP use Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low particularly compared with the number of vertebral hip and other fractures that are prevented by BPs Moreover a causal association between BPs and atypical fractures has not been established However recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem Given the relative rarity of atypical femoral fractures the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs Research directions should include development of animal models, increased surveillance and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management (C) 2010 American Society for Bone and Mineral Research Show less
Vastesaeoer, N.; Heijde, D. van der; Inman, R.; Wang, Y.; Deodhar, A.; Hsu, B.; ... ; GO-RAISE Investigators 2010
