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1.
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.

2.
J Clin Endocrinol Metab ; 104(6): 2443-2452, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759221

RESUMO

CONTEXT: Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event. OBJECTIVE: To assess information on invasive oral procedures and events (OPEs)-dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery-during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases. DESIGN: Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension. SETTING: Multicenter, multinational clinical trial. PATIENTS: Postmenopausal women with osteoporosis. INTERVENTIONS: Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab. MAIN OUTCOME MEASURES: Self-reports of OPEs and adjudicated cases of ONJ. RESULTS: Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%). CONCLUSIONS: Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment.

3.
J Bone Miner Res ; 34(4): 626-631, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30601581

RESUMO

Denosumab, a RANKL inhibitor, reduced the risk of vertebral, hip, and nonvertebral fractures in the Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial of postmenopausal women with osteoporosis compared with placebo. Previous bone histomorphometric analysis in FREEDOM showed decreased bone resorption and turnover in cancellous bone after 2 and 3 years. The purpose of the present study was to evaluate the effects of denosumab compared with placebo in the cortical compartment from transiliac bone biopsies obtained during FREEDOM. A total of 112 specimens were evaluable for cortical histomorphometry, including 67 obtained at month 24 (37 placebo, 30 denosumab) and 45 at month 36 (25 placebo, 20 denosumab). Eroded surface, osteoclast surface, erosion depth, and wall thickness were measured on the endocortical surface. Cortical thickness and cortical porosity were also measured. Dynamic parameters of bone formation were assessed for endocortical, periosteal, and intracortical envelopes. Endocortical osteoclast surface, eroded surface, and mean and maximum erosion depth were significantly lower in the denosumab group versus placebo at months 24 and 36 (p < 0.0001 to p = 0.04). Endocortical wall thickness and intracortical measures (cortical porosity and cortical thickness) were not different between the two groups. Dynamic parameters were low with tetracycline labels in cortical bone observed in 13 (43%) and 10 (50%) of denosumab biopsies at months 24 and 36, respectively, reflecting a marked decrease in bone turnover. In conclusion, our data reveal the mechanism of action of denosumab on cortical bone: inhibition of osteoclastic resorption and reduced activation of new remodeling sites. In addition, reduced endocortical erosion depth with no change of wall thickness may contribute to increased bone strength by reducing the bone loss and fragility associated with deep resorption cavities and may likely contribute to the greater BMD gain with denosumab than with other antiresorptive agents. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

4.
Lancet Diabetes Endocrinol ; 6(6): 445-454, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29631782

RESUMO

BACKGROUND: Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis. METHODS: We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (≥7·5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2·0 or less, or -1·0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0·7 and -1·1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. FINDINGS: Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4·4% [95% CI 3·8-5·0] vs 2·3% [1·7-2·9]; p<0·0001) and glucocorticoid-initiating (3·8% [3·1-4·5] vs 0·8% [0·2-1·5]; p<0·0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group. INTERPRETATION: Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures. FUNDING: Amgen.

5.
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.

7.
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
8.
BMC Musculoskelet Disord ; 18(1): 174, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28449657

RESUMO

BACKGROUND: Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. METHODS: To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. RESULTS: Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (-1.9 and -2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). CONCLUSION: The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. TRIAL REGISTRATION: ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Fraturas do Quadril/tratamento farmacológico , Fraturas por Osteoporose/tratamento farmacológico , Pacientes Desistentes do Tratamento , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Resultado do Tratamento
9.
J Bone Miner Res ; 32(7): 1481-1485, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28277603

RESUMO

Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.


Assuntos
Denosumab/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Denosumab/efeitos adversos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/epidemiologia , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Estados Unidos/epidemiologia
12.
J Bone Miner Res ; 30(7): 1280-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25684625

RESUMO

Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formation-a hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual-energy X-ray absorptiometry (DXA) BMD continued to rise in DMAb-treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling-based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling-based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling-based bone formation and eroded surface. This conservation of modeling-based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling-based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long-term DMAb administration.


Assuntos
Envelhecimento/fisiologia , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Denosumab/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Feminino , Colo do Fêmur/efeitos dos fármacos , Colo do Fêmur/fisiologia , Corantes Fluorescentes/metabolismo , Macaca fascicularis , Ovariectomia , Coloração e Rotulagem
13.
J Clin Endocrinol Metab ; 100(4): 1335-42, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25607608

RESUMO

CONTEXT: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. OBJECTIVE: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). DESIGN: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. SETTING: This was a multicenter study conducted in North America and Europe. PARTICIPANTS: A total of 228 men entered the open-label phase and 219 completed the study. INTERVENTION: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. MAIN OUTCOME MEASURES: BMD, serum collagen type I C-telopeptide, and safety were measured. RESULTS: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. CONCLUSIONS: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Denosumab , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/efeitos dos fármacos , Fraturas Ósseas/epidemiologia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Radiografia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/efeitos dos fármacos , Resultado do Tratamento
14.
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
15.
Menopause ; 21(1): 25-32, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23676636

RESUMO

OBJECTIVE: This study aims to evaluate patient perceptions of subcutaneous denosumab or oral alendronate in postmenopausal women with or at risk for osteoporosis and how these perceptions influence adherence. METHODS: Postmenopausal women with low bone mass were randomized to denosumab 60 mg every 6 months for 1 year (treatment period 1 [TP1]) followed by alendronate 70 mg once weekly for 1 year (treatment period 2 [TP2]), or vice versa. Beliefs about Medicines Questionnaire data were collected at baseline and at 6, 12, 18, and 24 months; a necessity-concerns differential (NCD) was calculated for each time point. Logistic regression analyses were performed to evaluate the influences of baseline characteristics on nonadherence. RESULTS: Participants included 250 women (alendronate/denosumab, n = 124; denosumab/alendronate, n = 126). During TP1, the NCD at month 6 was higher with denosumab than with alendronate (P = 0.0076). In TP2, the NCD was higher for women switched to denosumab than for women switched to alendronate at 6 months (P = 0.0126) and 12 months (P = 0.4605). Denosumab was preferred to alendronate regardless of treatment sequence (P < 0.0001). Covariate analysis revealed that higher TP2 baseline necessity scores were associated with lower odds of nonadherence (P = 0.0055), whereas higher concerns about medication scores were associated with higher odds of nonadherence (P = 0.0247). Higher NCD scores were also associated with lower odds of nonadherence (P = 0.0015). CONCLUSIONS: Participants preferred denosumab to alendronate while on treatment and had more positive perceptions of denosumab than alendronate. These perceptions were associated with better adherence.


Assuntos
Alendronato/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Conhecimentos, Atitudes e Prática em Saúde , Adesão à Medicação , Osteoporose/tratamento farmacológico , Administração Oral , Idoso , Estudos Cross-Over , Denosumab , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Preferência do Paciente , Percepção , Inquéritos e Questionários
16.
J Clin Endocrinol Metab ; 98(11): 4483-92, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23979955

RESUMO

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fraturas Ósseas/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Estudos Cross-Over , Denosumab , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Incidência , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/epidemiologia , Placebos , Fatores de Risco , Tempo
17.
Pharmacoepidemiol Drug Saf ; 22(10): 1107-14, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23857864

RESUMO

PURPOSE: To describe the rationale and methods for a prospective, open-cohort study assessing the long-term safety of Prolia(®) for treatment of postmenopausal osteoporosis (PMO) in postmarketing settings. METHODS: Data will be derived from United States Medicare, United Healthcare, and Nordic (Denmark, Sweden, Norway) national registries. Observation will begin on the date of first Prolia(®) regulatory approval (May 26, 2010) and continue for 10 years. Women with PMO will be identified by postmenopausal age, osteoporosis diagnosis, osteoporotic fracture, or osteoporosis treatment. Exposure to Prolia(®) and bisphosphonates will be updated during follow-up; exposure cohorts will be defined based on patient-years during which patients are on- or post-treatment. Nine adverse events (AEs) will be assessed based on diagnosis codes: osteonecrosis of the jaw (ONJ), atypical femoral fracture (AFF), fracture healing complications, hypocalcemia, infection, dermatologic AEs, acute pancreatitis, hypersensitivity, and new primary malignancy. Medical review will confirm selected potential cases of ONJ and AFF. Incidence rates (IRs) of AEs will be described overall and for exposure cohorts; multivariate Cox proportional hazard regression models will compare IRs of AEs across exposure cohorts. Utilization patterns of Prolia(®) for approved, and unapproved indications will be described. CONCLUSION: This study is based on comprehensive preliminary research and considers methodological challenges specific to the study population. The integrated data systems used in this regulatory committed program can serve as a powerful data resource to assess diverse and rare AEs over time.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Coortes , Dinamarca/epidemiologia , Denosumab , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/epidemiologia , Fatores de Risco , Segurança , Resultado do Tratamento , Estados Unidos/epidemiologia
18.
Obstet Gynecol ; 121(6): 1291-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23812464

RESUMO

OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Difosfonatos/uso terapêutico , Fraturas Ósseas/prevenção & controle , Osteoporose/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Conservadores da Densidade Óssea/farmacologia , Denosumab , Difosfonatos/farmacologia , Feminino , Humanos , Ácido Ibandrônico , Pessoa de Meia-Idade , Ligante RANK/antagonistas & inibidores
19.
J Bone Miner Res ; 28(4): 746-52, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23109251

RESUMO

Osteoporosis is a chronic disease and requires long-term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off-treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off-treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During treatment, more placebo-treated subjects as compared with denosumab-treated subjects sustained a fracture and had significant decreases in BMD. During the off-treatment period (median 0.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49-1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off-treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months.


Assuntos
Denosumab/uso terapêutico , Osteoporose/complicações , Fraturas por Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Suspensão de Tratamento , Idoso , Demografia , Relação Dose-Resposta a Droga , Feminino , Humanos , Incidência , Fraturas por Osteoporose/etiologia
20.
Ann N Y Acad Sci ; 1263: 29-40, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22831177

RESUMO

Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), an essential cytokine for the formation, function, and survival of osteoclasts. The role of excessive RANKL as a contributor to conditions characterized by bone loss or bone destruction has been well studied. With its novel mechanism of action, denosumab offers a significant advance in the treatment of postmenopausal osteoporosis; bone loss associated with hormone ablation therapy in women with breast cancer and men with prostate cancer; and the prevention of skeletal-related events in patients with bone metastases from solid tumors by offering clinical benefit to these patients in need.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Descoberta de Drogas , Ligante RANK/antagonistas & inibidores , Animais , Antineoplásicos Hormonais/efeitos adversos , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/imunologia , Reabsorção Óssea/epidemiologia , Reabsorção Óssea/etiologia , Reabsorção Óssea/imunologia , Denosumab , Humanos , Osteoporose/epidemiologia , Osteoporose/etiologia , Osteoporose/imunologia , Ligante RANK/efeitos adversos , Resultado do Tratamento
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