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1.
J Clin Endocrinol Metab ; 103(7): 2498-2509, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29672714

RESUMO

Context: Denosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis. Objective: Determine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics. Design and Setting: International, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension. Patients: Postmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points. Interventions: FREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years. Outcomes: Bone histology, histomorphometry, matrix mineralization. Results: Ten-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter. Conclusions: Denosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

2.
BMC Musculoskelet Disord ; 19(1): 17, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343266

RESUMO

BACKGROUND: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). METHODS: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. RESULTS: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. CONCLUSIONS: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. TRIAL REGISTRATION: NCT00486434 (trial 1) and NCT00704847 (trial 2).


Assuntos
Artralgia/diagnóstico , Artralgia/terapia , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/terapia , Medição da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Artralgia/epidemiologia , Ensaios Clínicos Fase III como Assunto/métodos , Humanos , Osteoartrite do Joelho/epidemiologia , Efeito Placebo
3.
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.

4.
Mayo Clin Proc ; 92(2): 200-210, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28160873

RESUMO

OBJECTIVE: To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis). PATIENTS AND METHODS: ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients. RESULTS: Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P<.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95% CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95% CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95% CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P<.001). CONCLUSION: Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01657162.


Assuntos
Alendronato/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/administração & dosagem , Fraturas da Coluna Vertebral/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Fraturas por Osteoporose/etiologia , Proteína Relacionada ao Hormônio Paratireóideo/efeitos adversos , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Modelos de Riscos Proporcionais , Fraturas da Coluna Vertebral/etiologia
5.
Bone ; 91: 122-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27462009

RESUMO

This randomized, double-blind, placebo-controlled phase III study was conducted to assess the efficacy and safety of oral calcitonin (SMC021) for the treatment of postmenopausal osteoporosis. A total of 4665 postmenopausal women with osteoporosis were randomized 1:1 to receive calcium and vitamin D plus either SMC021 tablets (0.8mg/d) or placebo for 36months. The primary endpoint was the proportion of patients with a new vertebral fracture. The two groups were well balanced at baseline with regards to demographic and clinical data. No effect of SMC021 on preventing new vertebral fractures was observed, nor was any effect seen on new hip or non-vertebral fractures. Women receiving SMC021 had a mean 1.02% (±0.12%) increase in lumbar spine bone mineral density (BMD) compared with a mean 0.18% (±0.12%) increase in the placebo group by the end of the study (p<0.0001). Similarly, small increases in BMD were observed at the femoral neck and hip in both groups. Levels of the biomarkers of bone turnover, urinary CTX-I and CTX-II, were 15% lower in the SMC021 group than in the placebo arm at 12 and 24months, but not at 36months. No change in quality of life between groups, assessed by the Qualeffo-14 questionnaire, was observed in either group between baseline and month 36. Pharmacokinetics analysis confirmed exposure to SMC021, but the drug levels were markedly lower than expected. Approximately 92% of subjects in each treatment group experienced an adverse event (AE), the majority of which were mild or moderate in intensity. AEs associated with SMC021 were primarily of gastrointestinal origin and included nausea, vomiting and abdominal pain, as well as hot flushes which were the reason for the slightly higher drop-out rate in the active treatment arm compared to placebo. The number of severe AEs was low in both groups. Thirty-five deaths were reported but none were considered treatment-related. Due to the lack of efficacy in preventing fractures, the development of the orally formulated calcitonin was terminated despite the promising results in earlier studies.


Assuntos
Calcitonina/efeitos adversos , Calcitonina/uso terapêutico , Cálcio/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Vitamina D/uso terapêutico , Administração Oral , Idoso , Biomarcadores/metabolismo , Densidade Óssea , Remodelação Óssea/efeitos dos fármacos , Calcitonina/administração & dosagem , Calcitonina/farmacocinética , Demografia , Método Duplo-Cego , Feminino , Humanos , Incidência , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/complicações , Fraturas por Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/fisiopatologia , Placebos , Qualidade de Vida , Fatores de Risco , Resultado do Tratamento
6.
J Bone Miner Res ; 29(9): 2051-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24692050

RESUMO

Denosumab reduced bone resorption, increased bone mineral density (BMD), and decreased new vertebral, hip, and nonvertebral fracture risk in postmenopausal women with osteoporosis in the FREEDOM trial. Consistent with its mechanism of action, transiliac crest bone biopsies from subjects treated with denosumab for 1 to 3 years demonstrated reduced bone turnover that was reversible upon treatment cessation. Long-term denosumab treatment for up to 6 years in the FREEDOM extension provides sustained bone turnover reduction and continued low fracture incidence. Here, we evaluate 5 years of denosumab treatment on bone remodeling at the tissue level. Transiliac crest bone biopsies were obtained from 41 subjects (13 cross-over and 28 long-term from the FREEDOM placebo and denosumab groups, respectively) at year 2 of the FREEDOM extension, representing up to 5 years of denosumab treatment. Demographics for this subset were comparable to the overall extension cohort. The mean (SD) duration from the last denosumab dose to the first dose of tetracycline was 5.7 (0.5) months. Qualitative bone histology assessed in all biopsy samples was unremarkable, showing normally mineralized lamellar bone. Structural indices, including trabecular bone volume, number, and surface, were similar between cross-over and long-term groups. Bone resorption was decreased as reflected by eroded surface in cross-over and long-term subjects. A total of 11 of 13 (85%) cross-over subjects and 20 of 28 (71%) long-term subjects had specimens with double or single tetracycline label in trabecular and/or cortical compartments; specimens from 5 cross-over subjects and 10 long-term subjects were evaluable for dynamic trabecular bone parameters. Dynamic remodeling indices were low for both groups and consistent with reduced bone turnover with denosumab. In conclusion, denosumab treatment through 5 years resulted in normal bone quality with reduced bone turnover. These observations are consistent with its mechanism of action and associated with continued BMD increases and low fracture incidence.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/patologia , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Biópsia , Conservadores da Densidade Óssea/farmacologia , Osso e Ossos/efeitos dos fármacos , Demografia , Denosumab , Feminino , Humanos , Coloração e Rotulagem , Tetraciclina , Fatores de Tempo
7.
J Bone Miner Res ; 25(10): 2256-65, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20533525

RESUMO

Denosumab, a human monoclonal antibody against RANKL, reversibly inhibits osteoclast-mediated bone resorption and has been developed for use in osteoporosis. Its effects on bone histomorphometry have not been described previously. Iliac crest bone biopsies were collected at 24 and/or 36 months from osteoporotic postmenopausal women in the FREEDOM study (45 women receiving placebo and 47 denosumab) and at 12 months from postmenopausal women previously treated with alendronate in the STAND study (21 continuing alendronate and 15 changed to denosumab at trial entry). Qualitative histologic evaluation of biopsies was unremarkable. In the FREEDOM study, median eroded surface was reduced by more than 80% and osteoclasts were absent from more than 50% of biopsies in the denosumab group. Double labeling in trabecular bone was observed in 94% of placebo bones and in 19% of those treated with denosumab. Median bone-formation rate was reduced by 97%. Among denosumab-treated subjects, those with double labels and those with absent labels had similar levels of biochemical markers of bone turnover. In the STAND trial, indices of bone turnover tended to be lower in the denosumab group than in the alendronate group. Double labeling in trabecular bone was seen in 20% of the denosumab biopsies and in 90% of the alendronate samples. Denosumab markedly reduces bone turnover and also reduces fracture numbers. Longer follow-up is necessary to determine how long such low turnover is safe.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Ligante RANK/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados , Denosumab , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Placebos , Tomografia Computadorizada por Raios X
8.
J Strength Cond Res ; 24(4): 1074-81, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20300017

RESUMO

The purpose of the study was to investigate simultaneous effects of energy balance, caloric intake, and the hormonal anabolic-catabolic balance in bodybuilders prior to competition. Fourteen male bodybuilders took part in an 11-week energy-restricted period to reduce body fat. The subjects were divided into the energy-restricted group (ERG) (n = 7), who were preparing for the competition, or the control group (CG) (n = 7) who continued to train regularly and did not change their dietary or training pattern. Participants were tested at 11 weeks (T1), 5 weeks (T2), and 3 days (T3) before competition for diet, body composition, and fasting hormonal assessment. Body mass and body fat percentage of ERG were significantly (p < 0.05) decreased during the study period. In ERG, insulinlike growth factor-1 (IGF-1) and insulin decreased significantly during the 11-week weight-reduction period (p < 0.05). Testosterone was decreased only from week 11 to week 5 (from 20.3 +/- 6.0 to 18.0 +/- 6.8 nmol/L). Changes in IGF-I concentration were significantly related to changes in insulin (r = 0.741), fat mass (r = 0.705), lean body mass (r = 0.696), and body mass (r = 0.652). Changes in insulin concentrations were significantly related to changes in fat mass (r = 0.630) and lean body mass (r = 0.725). These data indicate that severe energy restriction to extremely low body energy reserves decreases significantly the concentrations of 3 anabolic pathways despite high protein intake. Monitoring of insulin and IGF-1 concentration is suggested to prevent losses in muscle mass in energy-restricted conditions. Other nutritional strategies might be needed to prevent possible catabolic effect during preparation of bodybuilders to competition.


Assuntos
Desempenho Atlético/fisiologia , Ingestão de Energia , Metabolismo Energético/fisiologia , Educação Física e Treinamento/métodos , Treinamento de Resistência , Levantamento de Peso/fisiologia , Perda de Peso/fisiologia , Tecido Adiposo/metabolismo , Adulto , Atletas , Glicemia/análise , Índice de Massa Corporal , Restrição Calórica , Estudos de Casos e Controles , Comportamento Competitivo , Proteínas na Dieta/administração & dosagem , Hormônio do Crescimento Humano/sangue , Humanos , Hidrocortisona/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Estatísticas não Paramétricas , Testosterona/sangue , Adulto Jovem
9.
Arthritis Res Ther ; 12(2): R42, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20226018

RESUMO

INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.


Assuntos
Artrite Reumatoide/fisiopatologia , Avaliação da Deficiência , Pessoas com Deficiência , Emprego/estatística & dados numéricos , Bases de Dados Factuais , Fadiga , Feminino , Saúde Global , Nível de Saúde , Humanos , Seguro por Invalidez/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Medicina do Trabalho/estatística & dados numéricos , Dor , Índice de Gravidade de Doença , Inquéritos e Questionários , Avaliação da Capacidade de Trabalho
10.
Metabolism ; 57(2): 221-5, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18191052

RESUMO

The aim of this study was to investigate responses of ghrelin, leptin, and adiponectin to a weight reduction period of 10 weeks in male subjects with high lean body mass and low body fat values. Fourteen male bodybuilders (7 competitors: 28.3 +/- 10.3 years, 175.3 +/- 5.4 cm, 82.2 +/- 9.3 kg; 7 controls: 22.4 +/- 3.0 years, 182.4 +/- 6.9 cm, 85.3 +/- 10.5 kg) participated in this study. The subjects were tested 3 times: 11 weeks (TEST1), 5 weeks (TEST2), and 3 days (TEST3) before the national championships. Testing procedure included dual-energy x-ray absorptiometry scan; calculation of daily energy intake and expenditure; and venous blood sampling for fasting ghrelin, leptin, and adiponectin. In the competitors' group, a significant (P < .05) 4.1-kg loss of body fat was observed that resulted in 6.5% +/- 1.5% of the body fat at the end of the study. Ghrelin increased significantly by 20.4% by TEST2. By TEST3, ghrelin was further increased by 6% (P > .05). The pattern of leptin was opposite, with a significant 27.7% decrease at TEST2 and no further decrease at TEST3 (P > .05). No significant change was observed in adiponectin concentration during the study. In the control group, no significant changes in biochemical parameters were observed. In conclusion, ghrelin concentration significantly increases, but is suppressed in conditions of limited energy availability that is accompanied by significant body mass loss in male subjects with initial low body fat values.


Assuntos
Composição Corporal/fisiologia , Grelina/sangue , Leptina/sangue , Perda de Peso/fisiologia , Absorciometria de Fóton , Adiponectina/sangue , Adulto , Dieta Redutora , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Humanos , Masculino , Esportes , Estatísticas não Paramétricas
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