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1.
Clin Exp Rheumatol ; 37 Suppl 117(2): 130-136, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31162033

RESUMO

OBJECTIVES: Cardiovascular (CV) events are highly prevalent in systemic necrotising vasculitides (SNV). Visceral/subcutaneous adipose tissue (VAT/SAT) ratio has been shown to be associated with CV events in various diseases. We aimed to assess the relevance of abdominal adipose tissue measurement to predict major CV events (MCVEs) in SNV. METHODS: Patients with SNV were successively included in a longitudinal study assessing MCVEs and other sequelae. Dual x-ray absorptiometry was performed to evaluate abdominal adipose tissue. Patients were prospectively followed for MCVEs, defined as myocardial infarction, unstable angina, stroke, arterial revascularisation and/or hospitalisation for or death from CV causes. RESULTS: One hundred and twenty consecutive SNV patients were included and analysed (54 males, mean age 53±18 years). High CV risk was found in 28 (23.3%) patients. In univariate analysis, age, male gender, VDI, VAT/SAT ratio and serum troponin level were significantly associated with high CV risk, whereas age and VAT/SAT ratio remained independently associated with high CV risk. Variables associated with high tertile of VAT/SAT ratio included age and metabolic risk factors. After median follow-up of 42 months, 19 (16%) patients experienced MCVEs. Hazard ratios for incident MCVEs compared with 1st tertile of VAT/SAT ratio were 7.22 (1.02-51.3; p=0.048) and 9.90 (3.15-31.2; p=0.0002) in the 2nd and 3rd tertile, respectively. CONCLUSIONS: Abdominal visceral adipose tissue is a reliable surrogate marker of CV risk and predicts incident MCVEs in SNV patients. Abdominal adipose tissue should be probably evaluated routinely in these patients to assess CV risk.


Assuntos
Gordura Abdominal/metabolismo , Doenças Cardiovasculares , Vasculite Sistêmica/complicações , Tecido Adiposo/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Gordura Intra-Abdominal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vasculite Sistêmica/metabolismo
2.
J Clin Endocrinol Metab ; 104(8): 3450-3461, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125092

RESUMO

CONTEXT: Evidence for further nonvertebral fracture (NVF) reductions with long-term antiresorptive therapy in osteoporosis is lacking. OBJECTIVE: To evaluate NVF risk reduction in subjects receiving ≤10 years of denosumab treatment. DESIGN: Phase 3, randomized, placebo-controlled, 3-year Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (NCT00089791) and its open-label 7-year extension (NCT00523341). SETTING: One hundred seventy-two study centers worldwide. PATIENTS: Women 60 to 90 years, lumbar spine or total hip bone mineral density T-scores <-2.5 (≥-4.0 at both). INTERVENTIONS: Subjects randomly assigned 1:1 denosumab 60 mg SC Q6M (long-term) or placebo (crossover) in FREEDOM; eligible subjects could enroll in the extension to receive denosumab 60 mg SC Q6M. MAIN OUTCOME MEASURES: NVF Exposure-adjusted subject incidence (per 100 subject-years) during denosumab treatment years 1 to 3 and 4 to 7 (all subjects) and years 4 to 10 (long-term only), and rate ratios (RRs) for years 4 to 7 or 4 to 10 vs 1 to 3. RESULTS: Among 4074 subjects (2343 long-term, 1731 crossover), NVF rates (95% CI) in all subjects were 2.15 (1.90 to 2.43) during years 1 to 3 and 1.53 (1.34 to 1.75) during years 4 to 7 of denosumab treatment [RR (95% CI) = 0.72 (0.61 to 0.86); P < 0.001]; in long-term only were 1.98 (1.67 to 2.34) during years 1 to 3 and 1.44 (1.24 to 1.66) during years 4 to 10 [RR = 0.74 (0.60 to 0.93); P = 0.008]. combined osteonecrosis of the jaw and atypical femoral fracture rate was 0.06. CONCLUSIONS: Long-term denosumab treatment, >3 and ≤10 years, was associated with further reductions in NVF rates compared with the first 3 years.

3.
Joint Bone Spine ; 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30978416

RESUMO

OBJECTIVE: To evaluate the prevalence of biological abnormalities leading to secondary osteoporosis in recently fractured patients. METHODS: Adults older than 50, hospitalized for a non-vertebral fracture from July 2015 to October 2016, were assessed for bone fragility contributors in the orthopedics department. Bone mineral density (BMD) measurements and vertebral fracture assessment (VFA) were performed within 3 months. We assessed the prevalence of biological abnormalities in all the patients with recent fracture and in subgroups. RESULTS: Among 439 hospitalized patients for non-vertebral low trauma fracture, 372 had biological tests (285 women, mean age 77.5 ± 13 years) and 353 (94.6%) had at least ≥ 1 biological abnormality, most frequently vitamin D insufficiency (< 75 nmol/L) (80%). Hypercalcemia was found in 22 (7.7%) patients, explained by possible primary hyperparathyroidism in 6 cases, and by the other causes of hypercalcemia including postoperative low albumin. A high PTH level was observed in 64 (20.8%) patients. We found 3 monoclonal bands. Results were similar in patients with and without vertebral fracture or osteoporosis. Finally, many biological abnormalities can be explained by the postoperative context (low TSH, hypogammaglobulinemia, low albumin, low alkaline phosphatase) and need a control. CONCLUSION: This study performed in patient with recent low trauma non-vertebral fractures showed that 94.6% of patients had at least one contributor to bone fragility, which was the vitamin D insufficiency in most of cases. We found a high proportion of biological abnormalities which require additional explorations but most of them can be explained by the postoperative context.

5.
Ann Rheum Dis ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389692

RESUMO

OBJECTIVES: An increased risk of vertebral fractures (VFs) has been reported in spondyloarthritis (SpA). Our hypothesis is that the prevalence of VFs is lower than reported in previous studies, especially in early SpA. This study aimed at assessing the incidence of radiographical VFs over 5 years in early axial SpA. METHODS: The DESIR (DEvenir des Spondylarthropathies Indifférenciées Récentes) cohort, which included patients with inflammatory back pain highly suggestive of axial SpA, is the basis of this study. All radiographs of the DESIR cohort had been assessed at a central facility, by one investigator specialised in the field of the diagnosis of VFs according to Genant's method. We assessed the prevalence and incidence of VFs and vertebral deformities at baseline and over 5 years. RESULTS: Five-year X-rays were available for 432 patients (mean age 34.3±8.7 years, 53% women). Diagnosis of VF was doubtful and needed adjudication for 19 patients (4.4%). 13 patients had prevalent VFs (3.0%) which were located at the thoracic spine (12 were grade 1). At 5 years, five patients had an incident VF (1.15%); seven vertebrae were fractured, mostly located at the thoracic spine (n=6/7), and of grade 1 (n=6/7). CONCLUSION: In the DESIR cohort, a population of early SpA, we found a low prevalence and incidence of VFs (3.0% and 1.15 %), respectively. This confirms our hypothesis that the actual prevalence and incidence of VFvertebral fracture in SpA is lower than that reported in the previous studies.

7.
J Mech Behav Biomed Mater ; 87: 190-196, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30077078

RESUMO

Finite element models (FEM) derived from qCT-scans were developed as a clinical tool to evaluate vertebral strength. However, the high dose, time and cost of qCT-scanner are limitations for routine osteoporotic diagnosis. A new approach considers using bi-planar dual energy (BP2E) X-rays absorptiometry to build vertebral FEM using synchronized sagittal and frontal plane radiographs. The purpose of this study was to compare the performance of the areal bone mineral density (aBMD) measured from DXA, qCT-based FEM and BP2E-based FEM in predicting experimental vertebral strength. Twenty eight vertebrae from eleven lumbar spine segments were imaged with qCT, DXA and BP2E X-rays before destructively tested in anterior compression. FEM were built based on qCT and BP2E images for each vertebra. Subject-specific FEM were built based on 1) the BP2E images using 3D reconstruction and volumetric BMD distribution estimation and 2) the qCT scans using slice by slice segmentation and voxel based calibration. Linear regression analysis was performed to find the best predictor for experimental vertebral strength (Fexpe); aBMD, modeled vertebral strength and vertebral stiffness. Areal BMD was moderately correlated with Fexpe (R2 = 0.74). FEM calculations of vertebral strength were highly to strongly correlated with Fexpe (R2 = 0.84, p < 0.001 for BP2E model and R2 = 0.95, p < 0.001 for qCT model). The results of this study suggest that aBMD accounted for only 74% of Fexpe variability while FE models accounted for at least 84%. For anterior compressive loading on isolated vertebral bodies, simplistic loading condition aimed to replicate anterior wedge fractures, both FEM were good predictors of Fexpe. Therefore FEM based on BP2E X-rays absorptiometry could be a good alternative to replace qCT-based models in the prediction of vertebral strength. However future work should investigate the performance of the BP2E-based model in vivo in discriminating patients with and without vertebral fracture in a prospective study.

8.
PLoS One ; 13(6): e0196536, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29958270

RESUMO

OBJECTIVE: We aimed to compare bone mineral density (BMD) and bone remodeling markers in chronic low back pain (cLBP) patients with and without active discopathy (Modic 1 changes). DESIGN: We conducted a single center case-control exploratory study. For 18 months, all patients referred to a tertiary care physical medicine and rehabilitation department in France were consecutively screened. Patients fulfilling the inclusion criteria were prospectively enrolled. Cases were defined as cLBP patients with lumbar active discopathy detected on MRI and controls as cLBP patients without active discopathy. Bone mineral density (BMD) at the spine, femoral neck and total femur was assessed by dual-energy X-ray absorptiometry, and bone remodeling markers were assessed in fasting serum samples. Overall, 37 cLBP patients (13 cases and 24 controls) fulfilled inclusion criteria and were included. RESULTS: The median age was 42.0 years (Q1-Q3: 36.0-51.0) and mean (SD) LBP duration 72.3 (57.4) months. We found that BMD and levels of bone remodeling markers in cLBP patients did not differ with and without active discopathy. CONCLUSION: Our results do not support the association between active discopathy and systemic bone fragility.


Assuntos
Densidade Óssea , Remodelação Óssea , Dor Crônica/metabolismo , Colo do Fêmur/metabolismo , Doenças da Coluna Vertebral/metabolismo , Coluna Vertebral/metabolismo , Absorciometria de Fóton , Adulto , Estudos de Casos e Controles , Dor Crônica/diagnóstico por imagem , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Dor Lombar/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Doenças da Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem
9.
Sci Rep ; 8(1): 7731, 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769586

RESUMO

In spondyloarthritis, little is known about the relation between circulating cytokines and patient phenotype. We have quantified serum levels of T helper type 1 cell (Th1), Th2 and Th17 cytokines in patients with recent-onset axial spondyloarthritis (AxSpA) from the DESIR cohort, a prospective, multicenter French cohort consisting of 708 patients with recent-onset inflammatory back pain (duration >3 months but <3 years) suggestive of AxSpA. Serum levels of Th1, Th2, and Th17 cytokines were assessed at baseline in patients from the DESIR cohort fulfilling the ASAS criteria (ASAS+) and were compared with age- and sex-matched healthy controls. At baseline, ASAS+ patients (n = 443) and healthy controls (n = 79) did not differ in levels of most of the Th1, Th2 and Th17 cytokines except for IL-31, and sCD40L, which were significantly higher for ASAS+ patients than controls (p < 0.001 and p = 0.012, respectively). On multivariable analysis of ASAS+ patients, IL-31 level was associated with sCD40L level (p < 0.0001), modified Stoke AS Spine Score (mSASSS) < 1 (p = 0.035). The multivariable analyses showed that IL-31 was an independent factor associated with mSASSS < 1 (p = 0.001) and low bone mineral density (p = 0.01). Increased level of IL-31 might protect against structural damage but is also related to low BMD.

10.
Joint Bone Spine ; 85(5): 519-530, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29654947

RESUMO

OBJECTIVES: To update the 2012 recommendations on pharmacotherapy for postmenopausal osteoporosis, under the aegis of the Bone Task Force of the French Society for Rheumatology (SFR) and of the Osteoporosis Research and Information Group (GRIO), in collaboration with scientific societies (Collège national des généralistes enseignants, Collège national des gynécologues et obstétriciens français, Fédération nationale des collèges de gynécologie médicale, Groupe d'étude de la ménopause et du vieillissement hormonal, Société française de chirurgie orthopédique, Société française d'endocrinologie, and Société française de gériatrie et de gérontologie). METHODS: Updated recommendations were developed by a task force whose members represented the medical specialties involved in the management of postmenopausal osteoporosis. The update was based on a literature review and developed using the method advocated by the French National Authority for Health (HAS). DISCUSSION AND CONCLUSION: The updated recommendations place strong emphasis on the treatment of women with severe fractures, in whom the use of osteoporosis medications is recommended. All the available osteoporosis medications are suitable in patients with severe fractures; zoledronic acid deserves preference as the fist-line drug after a hip fracture. In patients with or without non-severe fractures, the decision to use osteoporosis medications is based on bone mineral density values and in challenging cases, on probabilities supplied by prediction tools such as FRAX®. All osteoporosis medications are suitable; raloxifene should be reserved for patients at low risk for peripheral fractures. The fracture risk should be reevaluated every 2 to 3 years to decide on the best follow-up treatment. These updated recommendations discuss the selection of first-line osteoporosis medications and treatment sequences.

11.
Bone ; 111: 44-48, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29551751

RESUMO

Bone turnover increases at the menopause and is associated with accelerated bone loss. However, it is not known to what extent there is an imbalance between the processes of bone resorption and bone formation, nor whether it is the rate of bone turnover or the bone balance that is most closely associated with the rate of bone loss. We studied 657 healthy women ages 20 to 79 from five European cities (the OPUS Study) and divided them into two premenopausal age groups, 20 to 29 (n=129), 30 to 39years (n=183), and three postmenopausal groups 1 to 10years (n=91), 11 to 20years (n=131) and 21+ years since menopause (n=123). We measured collagen type I C-telopeptide (CTX, a marker of bone resorption) and procollagen I N-propeptide (PINP, a marker of bone formation). We used these two markers to calculate the overall bone turnover and the difference between bone formation and resorption (bone balance) using the results from the women ages 30 to 39years to calculate a standardised score (T-score). We found that the CTX and PINP levels were higher in the women ages 20 to 29 and in the women in the three menopausal groups as compared to women ages 30 to 39years (p<0.001). For example, the CTX and PINP levels were 80 and 33% higher in women 1 to 10years since menopause as compared to women ages 30 to 39years. In this group of postmenopausal women, the bone turnover expressed as a T-score was 0.72 (0.57 to 0.88, 95%CI) and the bone balance was -0.37 (-0.59 to -0.16). There was greater rate of bone loss from the total hip in all the groups of women after the menopause compared to women before the menopause. We conclude that the bone loss after the menopause is associated with both an increase in bone turnover and a negative bone balance and that bone loss was most clearly associated with overall bone turnover.

12.
Eur J Nucl Med Mol Imaging ; 45(10): 1710-1720, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29532101

RESUMO

PURPOSE: Oncogenic osteomalacia is an endocrine disorder induced by small benign tumours (TIO) producing excessive fibroblast growth factor-23 (FGF23). The only way of curing oncogenic osteomalacia is surgical resection of the culprit TIO, which is extremely difficult to detect using conventional imaging modalities due to its small size and variable location in the body. Since TIO frequently overexpress somatostatin receptors, a clinical utility of SPECT or PET with radiolabelled somatostatin analogues has been reported. Among them, 68Ga-DOTA-TOC has recently been granted a marketing authorization, facilitating its routine application. We report here the results of the first series evaluating the diagnostic performance of 68Ga-DOTA-TOC PET/CT in detecting TIO and its impact on patient management. METHODS: 68Ga-DOTA-TOC PET/CT and clinical and imaging data from 15 patients with clinical and biochemical signs of oncogenic osteomalacia were retrospectively reviewed. The 68Ga-DOTA-TOC PET/CT findings were compared with the results of post-surgical pathology and clinical and biochemical follow-up. RESULTS: 68Ga-DOTA-TOC PET/CT resulted in the detection of one focus suspicious for TIO in nine of 15 patients (60%), and a tumour was surgically removed in eight. Post-operative pathology confirmed a TIO in those eight patients whose symptoms diminished promptly and biochemical anomalies resolved. 68Ga-DOTA-TOC PET/CT sensitivity, specificity and accuracy were 73%, 67% and 71%, respectively. 68Ga-DOTA-TOC PET/CT findings affected patient management in 67% of cases. In particular, 68Ga-DOTA-TOC PET/CT was able to detect the TIO with a negative or a false-positive result of a previous 111In-pentetreotide SPECT/CT in 5/8 patients (63%) or a previous FDG PET/CT in 7/11 patients (64%). No close relationship was found between the positivity of 68Ga-DOTA-TOC PET/CT and the serum level of a biochemical marker. However, a true-positive result of 68Ga-DOTA-TOC PET/CT was obtained in only one patient with a non-elevated serum level of FGF23. CONCLUSION: 68Ga-DOTA-TOC PET/CT is an accurate imaging modality in the detection of TIO; in particular, it is worthwhile after failure of somatostatin receptor SPECT(/CT) or FDG PET/CT.


Assuntos
Neoplasias/complicações , Neoplasias/diagnóstico por imagem , Compostos Organometálicos , Osteomalacia/complicações , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
14.
J Bone Miner Res ; 33(2): 190-198, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29105841

RESUMO

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above-baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant-years). Among participants with ≥1 off-treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3-1.9) times higher with each additional year of off-treatment follow-up; among participants with available off-treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1-1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant-years) of nonvertebral fractures during the off-treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov: NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.

15.
Semin Arthritis Rheum ; 47(5): 741-748, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29102156

RESUMO

OBJECTIVE: To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors. METHODS: In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored. RESULTS: A total of 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n = 47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.94 ± 2.20 vs. 3.18 ± 2.21, P = 0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was re-established in 47/59 patients (80%). CONCLUSION: No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Espondilartrite/tratamento farmacológico , Adulto , Substituição de Medicamentos , Feminino , França , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento
16.
J Bone Miner Metab ; 36(6): 723-733, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29236161

RESUMO

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

18.
Bone ; 105: 287-291, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28842362

RESUMO

Low-trauma fractures tend to cluster in time, and subsequent fractures have a role in increased morbidity and mortality in osteoporotic patients. The aim of this study was to identify the risk factors of short-term subsequent non-vertebral fracture (NVF). Patients were included from the Fracture Liaison Service (FLS) which provides assessment for osteoporosis to all in-hospital patients admitted for a low-trauma NVF in the Orthopaedics department. Location and date of occurrence of previous fractures, risk factors for osteoporosis and falls were collected. Bone mineral density was measured at the lumbar spine and total hip; presence of vertebral fractures was evaluated using vertebral fracture assessment (VFA). Nine hundred and fifty patients were included (84% women; 75±12years), with a mean T-score at the femoral neck of -2.3±1.0. Four hundred and sixty eight (49%) patients were in the FLS because of a hip fracture. Using multivariable analysis, the risk of being in the FLS with a previous fracture ≤3years before was associated with: history of fall in the year before the admission (OR=2.75, CI 95% 1.55-4.93), history of severe low-trauma NVF (OR=2.54; CI 95% 1.45-4.52), and BMI lower than 20kg/m2 (OR=2.45, CI 95% 1.25-4.87); age older than 78years-old was protective to the risk of re-fracture (OR=0.44, CI 95% 0.24-0.80). Some risk factors (age, history of fall and of previous severe non-vertebral fracture) can help in the selection of patients at high risk of refracture, who should receive the highest priority for a treatment.


Assuntos
Fraturas por Osteoporose/epidemiologia , Feminino , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Fatores de Tempo
20.
Lancet Diabetes Endocrinol ; 5(7): 513-523, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28546097

RESUMO

BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Denosumab/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo
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