RESUMO
BACKGROUND: Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. METHODS: This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to teriparatide received denosumab (teriparatide to denosumab group), those originally assigned to denosumab received teriparatide (denosumab to teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00926380. FINDINGS: Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18·3% (95% CI 14·9-21·8) in 27 women in the teriparatide to denosumab group, 14·0% (10·9-17·2) in 27 women the denosumab to teriparatide group, and 16·0% (14·0-18·0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0·13 for the teriparatide to denosumab group vs the denosumab to teriparatide group, p=0·30 for the teriparatide to denosumab group vs the combination to denosumab group, and p=0·41 for the denosumab to teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the teriparatide to denosumab group (6·6% [95% CI 5·3-7·9]) than in the denosumab to teriparatide group (2·8% [1·3-4·2], p=0·0002), but had the greatest increase in the combination to denosumab group (8·6% [7·1-10·0]; p=0·0446 vs the teriparatide to denosumab group, p<0·0001 vs the denosumab to teriparatide group). Similarly, femoral neck bone mineral density increased more in the teriparatide to denosumab group (8·3% [95% CI 6·1-10·5]) and the combination to denosumab group (9·1% [6·1-12·0]) than in the denosumab to teriparatide group (4·9% [2·2-7·5]; p=0·0447 for teriparatide to denosumab vs denosumab to teriparatide, p=0·0336 for combination to denosumab vs denosumab to teriparatide). Differences between the combination to denosumab group and the teriparatide to denosumab group did not differ significantly (p=0·67). After 48 months, radius bone mineral density was unchanged in the teriparatide to denosumab group (0·0% [95% CI -1·3 to 1·4]), whereas it decreased by -1·8% (-5·0 to 1·3) in the denosumab to teriparatide group, and increased by 2·8% (1·2-4·4) in the combination to denosumab group (p=0·0075 for the teriparatide to denosumab group vs the combination to denosumab group; p=0·0099 for the denosumab to teriparatide group vs the combination to denosumab group). One participant in the denosumab to teriparatide group had nephrolithiasis, classified as being possibly related to treatment. INTERPRETATION: In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. FUNDING: Amgen, Eli Lilly, and National Institutes of Health.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Denosumab , Esquema de Medicação , Substituição de Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Método Simples-Cego , Teriparatida/efeitos adversos , Teriparatida/uso terapêuticoRESUMO
Both antiresorptive and anabolic osteoporosis medications increase bone mineral density (BMD), but no single agent can restore normal bone strength in most osteoporotic patients. Moreover, the magnitude and consistency of the patient response to each individual agent vary depending on the anatomic site. In the DATA study, we reported that in postmenopausal osteoporotic women, 2 years of combined denosumab and teriparatide increase mean BMD at the hip and spine more than either drug alone. In the current analysis, we wished to determine if the individual rates of BMD response were also greater among women treated with both drugs. In DATA, 94 postmenopausal osteoporotic women (ages 51-91) were randomized to receive teriparatide (20 mcg subcutaneously daily), denosumab (60 mg subcutaneously every 6 mo), or both medications for 24 mo. The BMD of the total hip (TH), femoral neck (FN), and lumbar spine (LS) were assessed by dual-energy X-ray absorptiometry. The 82 subjects who completed all 2-yr treatments were analyzed. Responders were defined as experiencing BMD increases of >3%. An "excellent response" was defined as an increase of >6%. Over 24 mo, TH BMD increased by >3% in 36%, 53%, and 92% of women in the teriparatide, denosumab, and combination groups, respectively, and by >6% in 11%, 17%, and 50% in the teriparatide, denosumab, and combination groups, respectively (p < 0.01 for all comparisons vs combination). FN response rates were similar to TH. In the LS, BMD increased by >3% in 85%, 93%, and 100% of women in the teriparatide, denosumab, and combination groups, respectively (p = nonsignificant for all comparisons) and by >6% in 63%, 78%, and 100% of women in the teriparatide, denosumab, and combination groups, respectively (combination vs teriparatide, p = 0.001; combination vs denosumab, p = 0.016). In summary, more women treated with 24 mo of combined denosumab and teriparatide achieved a significant response at the TH and FN than those treated with either drug alone. All women treated with both agents together experienced an excellent response at the LS. These results support the continued investigation of combined denosumab and teriparatide therapy in postmenopausal osteoporotic women utilizing clinical endpoints such as fracture reduction.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/uso terapêutico , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Quimioterapia Combinada , Feminino , Colo do Fêmur/diagnóstico por imagem , Quadril/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Resultado do TratamentoRESUMO
BACKGROUND: Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone. METHODS: From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 µg teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380. FINDINGS: 94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9·1%, [SD 3·9]) than in the teriparatide (6·2% [4·6], p=0·0139) or denosumab (5·5% [3·3], p=0·0005) groups. Femoral-neck BMD also increased more in the combination group (4·2% [3·0]) than in the teriparatide (0·8% [4·1], p=0·0007) and denosumab (2·1% [3·8], p=0·0238) groups, as did total-hip BMD (combination, 4·9% [2·9]; teriparatide, 0·7% [2·7], p<0·0001; denosumab 2·5% [2·6], p=0·0011). INTERPRETATION: Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture. FUNDING: Amgen, Eli Lilly, National Center for Research Resources.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Área Sob a Curva , Biomarcadores/metabolismo , Conservadores da Densidade Óssea/efeitos adversos , Terapia Combinada/métodos , Denosumab , Combinação de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Teriparatida/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: A test that helps predict the time to the final menstrual period (FMP) has been sought for many years. OBJECTIVE: To assess the ability of antimullerian hormone (AMH) measurements to predictions the time to FMP. DESIGN: Prospective longitudinal cohort study. SETTING: The Study of Women's Health Across the Nation. PARTICIPANTS AND MEASUREMENTS: AMH and FSH were measured in 1537 pre- or early perimenopausal women, mean age 47.5â ±â 2.6 years at baseline, then serially until 12 months of amenorrhea occurred. AMH was measured using a 2-site ELISA with a detection limit of 1.85 pg/mL. MAIN OUTCOME MEASURE: Areas under the receiver operating curves (AUC) for AMH-based and FSH-based predictions of time to FMP, stratified by age. Probabilities that women would undergo their FMP in the next 12, 24, or 36 months across a range of AMH values were assessed. RESULTS: AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for AMH-based than FSH-based models. The probability that a woman with an AMH <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an AMH >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old. CONCLUSIONS: AMH measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.
Assuntos
Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Menopausa , Ciclo Menstrual , Reprodução , Adulto , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estados Unidos , Saúde da MulherRESUMO
CONTEXT: Rates of bone loss across the menopause transition and factors associated with variation in menopausal bone loss are poorly understood. OBJECTIVE: Our objective was to assess rates of bone loss at each stage of the transition and examine major factors that modify those rates. DESIGN, SETTING, AND PARTICIPANTS: We conducted a longitudinal cohort study of 1902 African-American, Caucasian, Chinese, or Japanese women participating in The Study of Women's Health Across the Nation. Women were pre- or early perimenopausal at baseline. OUTCOME MEASURE: We assessed bone mineral density (BMD) of the lumbar spine and total hip across a maximum of six annual visits. RESULTS: There was little change in BMD during the pre- or early perimenopause. BMD declined substantially in the late perimenopause, with an average loss of 0.018 and 0.010 g/cm2.yr from the spine and hip, respectively (P<0.001 for both). In the postmenopause, rates of loss from the spine and hip were 0.022 and 0.013 g/cm2.yr, respectively (P<0.001 for both). During the late peri- and postmenopause, bone loss was approximately 35-55% slower in women in the top vs. the bottom tertile of body weight. Apparent ethnic differences in rates of spine bone loss were largely explained by differences in body weight. CONCLUSIONS: Bone loss accelerates substantially in the late perimenopause and continues at a similar pace in the first postmenopausal years. Body weight is a major determinant of the rate of menopausal BMD loss, whereas ethnicity, per se, is not. Healthcare providers should consider this information when deciding when to screen women for osteoporosis.
Assuntos
Densidade Óssea , Menopausa/etnologia , Negro ou Afro-Americano , Povo Asiático , Peso Corporal , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , População BrancaRESUMO
BACKGROUND: Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density. METHODS: We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. RESULTS: The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons). CONCLUSIONS: Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.
Assuntos
Alendronato/uso terapêutico , Osteoporose/tratamento farmacológico , Teriparatida/uso terapêutico , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Fosfatase Alcalina/sangue , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Cálcio/sangue , Cálcio/uso terapêutico , Cálcio/urina , Quimioterapia Combinada , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/patologia , Humanos , Injeções Subcutâneas , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Cooperação do Paciente , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/patologia , Teriparatida/efeitos adversos , Vitamina D/uso terapêuticoRESUMO
UNLABELLED: OBJECTIVE AND CONTEXT: Our objective was to examine predictability of reproductive hormone concentrations for bone mineral density (BMD) loss during the menopausal transition. DESIGN: We conducted a longitudinal (five annual examinations), multiple-site (n = 5) cohort study, the Study of Women's Health Across the Nation (SWAN). PARTICIPANTS: Participants included, at baseline, 2311 premenopausal or early perimenopausal African-American, Caucasian, Chinese, and Japanese women. MAIN OUTCOME MEASURES: We assessed annual dual-energy x-ray absorptiometry lumbar spine and total hip BMD measures, with endogenous estradiol (E2), FSH, androgens, and self-reported menstrual bleeding patterns. RESULTS: Over the 4-yr period, lumbar spine BMD loss was 5.6% in natural postmenopause, 3.9% in surgical postmenopause, or 3.2% in late perimenopause. Baseline FSH concentrations, subsequent FSH levels, and their interaction predicted 4-yr BMD loss. If baseline FSH was less than 25 mIU/ml, higher follow-up FSH (>70 mIU/ml) predicted a 4-yr spine BMD loss of -0.05 g/cm(2). If baseline FSH values were more than 35-45 mIU/ml, lower follow-up FSH (i.e. 40-50 mIU/ml) predicted a -0.05 g/cm(2) 4-yr spine BMD loss. Charts show amounts of predicted BMD losses with combinations of baseline FSH values and FSH levels over time. E2 concentrations less than 35 pg/ml were associated with lower BMD, but annual E2 measures and changes did not predict BMD loss. Testosterone, free androgen index, and dehydroepiandrosterone sulfate concentrations were not significantly associated with BMD loss. CONCLUSIONS: Spine and hip BMD losses during the menopause transition were most strongly related to the interaction between initial FSH levels and longitudinal FSH changes and not to E2 or androgen levels or changes.
Assuntos
Densidade Óssea/fisiologia , Hormônios/sangue , Menopausa/fisiologia , Absorciometria de Fóton , Adulto , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Interpretação Estatística de Dados , Terapia de Reposição de Estrogênios , Estrogênios/sangue , Feminino , Seguimentos , Hormônios Esteroides Gonadais/sangue , Humanos , Estudos Longitudinais , Pessoa de Meia-IdadeRESUMO
CONTEXT: We have previously demonstrated that alendronate reduces the ability of teriparatide to increase bone mineral density (BMD) in osteoporotic men. The underlying basis for this observation is poorly understood. OBJECTIVE: The primary aim of this study was to determine whether teriparatide increases osteoblast activity when the ability of teriparatide to increase osteoclast activity is suppressed by alendronate. DESIGN: This was a nonblinded, randomized, controlled trial. SETTING: The study was conducted at the General Clinical Research Center of a teaching hospital. PATIENTS: We studied 63 men, age 46-85, with low spine and/or hip BMD. INTERVENTIONS: Subjects received alendronate 10 mg daily (group 1), teriparatide 37 microg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6. MAIN OUTCOME MEASURES: The primary endpoint was the change in serum N-telopeptide, osteocalcin, and amino-terminal propeptide of type 1 procollagen. RESULTS: In men receiving teriparatide monotherapy (group 2), levels of all bone turnover markers increased markedly during the first 6 months of teriparatide administration and then declined toward baseline during the next 18 months. In men who received combination therapy (group 3), bone turnover marker levels declined in the first 6 months (while receiving alendronate alone) and then returned to baseline levels (N-telopeptide) or above (osteocalcin and amino-terminal propeptide of type 1 procollagen) after teriparatide was added. Changes in each marker were significantly different between groups 1 and 2 (all P values < 0.001), groups 1 and 3 (all P values < 0.001), and groups 2 and 3 (all P values < 0.03). CONCLUSIONS: As with BMD, alendronate impairs the action of teriparatide to increase bone turnover in men.
Assuntos
Alendronato/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Remodelação Óssea/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Teriparatida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Colágeno Tipo I/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose/fisiopatologia , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Pró-Colágeno/sangue , Resultado do TratamentoRESUMO
UNLABELLED: Prednisone 5 mg/day suppresses multiple indices of bone formation in a randomized placebo-controlled trial in healthy postmenopausal females. This suggests that even low doses of prednisone may reduce bone repair or renewal and may have adverse effects on bone mass and/or bone strength. INTRODUCTION: High doses of chronic glucocorticoids are known to have adverse effects on bone, and measures to prevent bone loss are well established for doses >7.5 mg daily, because these doses can cause premature or exaggerated osteoporosis. However, it is unclear if chronic prednisone doses of 5 mg daily have the same effects on bone. There are no established recommendations for preventing glucocorticoid-induced osteoporosis in people taking prednisone 5 mg daily, a dose used frequently in medical practice to treat diseases of the lungs, joints, skin, muscles, eyes, nerves, etc. Our primary objective was to test whether prednisone 5 mg daily affects serum and urine indices of bone metabolism in healthy postmenopausal women. Our secondary objectives were to determine if prednisone 5 mg affected systolic or diastolic blood pressure or causes side effects. MATERIALS AND METHODS: A double-blinded randomized placebo-controlled 8-week trial in 50 healthy postmenopausal women was conducted at the Massachusetts General Hospital Outpatient General Clinical Research Center. Patients were randomly assigned to prednisone 5 mg daily or matching placebo for 6 weeks, followed by a 2-week recovery phase. Markers of bone formation and resorption were determined at weeks 0, 2, 4, 6, and 8. Indices of osteoblast activity included serum propeptide of type I N-terminal procollagen (PINP), propeptide of type I C-terminal procollagen (PICP), osteocalcin, and bone-specific alkaline phosphatase (BSALP). Indices of osteoclast activity included urine and serum type I collagen N-telopeptide (NTX) and free urinary deoxypyridinoline (DPD). RESULTS AND CONCLUSIONS: Prednisone rapidly and significantly decreased serum PINP (p < 0.01), PICP (p < 0.01), and osteocalcin (p < 0.01) and free urinary deoxypyridinoline (p = 0.017). These changes were largely reversed during the recovery period. Side effects were indistinguishable in the two groups. Neither systolic nor diastolic blood pressure changed significantly throughout the study between the two groups. In conclusion, low-dose prednisone significantly decreases indices of bone formation and may decrease indices of bone resorption in postmenopausal women. Further studies are needed to assess the effects of low-dose prednisone on BMD and fracture risk.
Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Pós-Menopausa/efeitos dos fármacos , Prednisona/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Remodelação Óssea/fisiologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/sangueRESUMO
BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) reduces fracture risk in postmenopausal women with osteoporosis. We assessed the safety and incidence of new vertebral fractures after withdrawal of teriparatide. METHODS: This study is a follow-up to the Fracture Prevention Trial (FPT), a randomized, placebo-controlled study of postmenopausal women with osteoporosis treated with teriparatide (20 or 40 microg) once daily for a mean of 18 months. More than 90% of the women remaining at the end of the FPT continued into the follow-up study (n = 1262). Patients and investigators were unblinded to original treatment group assignment. Women were treated according to standard clinical practice, including elective use of osteoporosis drugs. New vertebral fractures were determined by semiquantitative scoring of lateral thoracic lumbar spine radiographs 18 months after the end of the FPT. RESULTS: During the follow-up study, the reduction in fracture risk associated with previous treatment with teriparatide, 20 and 40 microg, was 41% (P = .004) and 45% (P = .001), respectively, vs placebo. The absolute reduction from the FPT baseline to the 18-month follow-up visit was 13% for both doses. Osteoporosis drugs were used by 47% of women during follow-up, with greater use in the former placebo group (P = .04); nevertheless, persistent fracture protection of previous teriparatide therapy was evident. Post hoc analysis also suggests that teriparatide treatment substantially reduced the increased risk of subsequent fracture in women who sustained a fracture during the FPT (P = .05). CONCLUSION: Vertebral fracture risk reduction by teriparatide administration persists for at least 18 months after discontinuation of therapy.
Assuntos
Osteoporose Pós-Menopausa/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Comportamento de Redução do Risco , Fraturas da Coluna Vertebral/prevenção & controle , Teriparatida/uso terapêutico , Idoso , Densidade Óssea , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Fraturas da Coluna Vertebral/etiologia , Fatores de Tempo , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral quantitative computed tomography (HR-pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20 µg daily (n = 31), denosumab 60 mg every 6 months (n = 33), or both (n = 30) for 12 months. In the teriparatide group, total volumetric bone mineral density (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1 ± 2.2%) than both the denosumab (2.2 ± 1.9%) and teriparatide groups (-0.3 ± 1.9%) (p < 0.02 for both comparisons). Cortical vBMD decreased by 1.6 ± 1.9% at the tibia and by 0.9 ± 2.8% at the radius in the teriparatide group, whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5 ± 1.5%) than both monotherapy groups (p < 0.04 for both comparisons). Cortical thickness did not change in the teriparatide group but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4 ± 3.9%) than both monotherapy groups (p < 0.01 for both comparisons). In the teriparatide group, radial cortical porosity increased by 20.9 ± 37.6% and by 5.6 ± 9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and teriparatide in combination improves HR-pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa , Rádio (Anatomia) , Teriparatida/administração & dosagem , Tíbia , Idoso , Idoso de 80 Anos ou mais , Denosumab , Quimioterapia Combinada/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo , Radiografia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/metabolismo , Tíbia/diagnóstico por imagem , Tíbia/metabolismoRESUMO
CONTEXT: In postmenopausal osteoporotic women, denosumab fully inhibits teriparatide-induced bone resorption at approved doses. This property of denosumab is distinct from that of alendronate and likely contributes to the efficacy of combination denosumab and teriparatide therapy. Whether denosumab fully inhibits bone resorption when challenged by a higher dose of teriparatide is unknown. OBJECTIVE: We aimed to define the comparative ability of denosumab and alendronate to block the acute proresorptive effects of high-dose teriparatide. DESIGN, SETTING, AND PARTICIPANTS: In this randomized controlled trial, bone resorption (serum C-telopeptide [CTX]) was measured in 25 postmenopausal women prior to and 4 hours after a single 40-µg sc teriparatide injection. Subjects then received either a single injection of denosumab 60 mg or oral alendronate 70 mg weekly for 8 weeks. After 8 weeks, serum CTX was again measured before and 4 hours after a teriparatide a 40-µg injection. OUTCOMES: The primary outcome was the between-group difference in the teriparatide-induced change in CTX from baseline to week 8. RESULTS: At baseline, 40 µg of teriparatide induced similar 4-hour increases in mean CTX in both groups (alendronate 47% ± 14%, denosumab 46% ± 16%). After 8 weeks, teriparatide was still able to stimulate bone resorption in women treated with alendronate (mean CTX increase of 43% ± 29%) but not in women treated with denosumab (-7% ± 11%; P < .001 for between group comparison). CONCLUSIONS: Denosumab, but not alendronate, fully inhibits the ability of high-dose teriparatide to increase bone resorption acutely. These results suggest that combining denosumab with a more potent anabolic stimulus may result in greater separation between bone resorption and formation and hence greater increases in bone mass.
Assuntos
Alendronato/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/prevenção & controle , Resistência a Medicamentos , Teriparatida/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Alendronato/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Denosumab , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/epidemiologia , Teriparatida/administração & dosagemRESUMO
High-protein diets increase calciuria. No previous studies have examined the ad libitum U.S. diet's effect on calciuria or bone resorption.Thirty-nine healthy, premenopausal women consuming ad libitum diets [mean, 1.1 g/kg protein, 819 mg (20.5 mmol) Ca, 1152 mg (37 mmol) P, 129 mmol Na] were switched to isocaloric diets containing the U.S. recommended dietary allowance (RDA) of protein (0.8 g/kg) and similar amounts of calcium, phosphorus, and sodium. Bone resorption and related endpoints were assessed before and 1 wk after the switch. As dietary protein changed from ad libitum to RDA levels, mean urine nitrogen decreased 26% (2.4 g/d; P < 0.001) and mean blood urea nitrogen decreased 15% (1.9 mg/dl; P < 0.001). Mean urine pH increased from 6.3 to 6.8 (P < 0.001), and net renal acid excretion (NRAE = urine ammonium plus titratable acids minus bicarbonate) decreased 68% (21.4 mEq/d; P < 0.001). Mean urinary calcium decreased 32% [42 mg (1 mmol)/d; P < 0.001], and bone resorption urine N-telopeptides) decreased 17% (74 micromol bovine collagen equivalents/d; P < 0.001). Mean serum calcium, PTH, and 1,25 dihydroxy vitamin D remained unchanged. In this 2-wk study, decreasing dietary protein from ad libitum to RDA levels decreased NRAE, calciuria and estimates of bone resorption, suggesting that decreased U.S. protein consumption might reduce bone loss. Inasmuch as other dietary modifications, such as increasing vegetable and fruit intake, can result in sustained reductions in NRAE without reducing protein intake, the advisability of reducing protein intake for skeletal protection from acid attack requires further investigation.
Assuntos
Reabsorção Óssea/prevenção & controle , Cálcio/urina , Proteínas Alimentares/administração & dosagem , Política Nutricional , Ácidos/urina , Adulto , Nitrogênio da Ureia Sanguínea , Colágeno/urina , Colágeno Tipo I , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração de Íons de Hidrogênio , Nitrogênio/urina , Peptídeos/urina , Urina/químicaRESUMO
Bone mineral density (BMD) and fracture rates vary among women of differing ethnicities. Little is known, however, about ethnic variation in bone turnover. We measured serum osteocalcin (OC) and urinary N-telopeptide of type I collagen (NTX) levels in 2313 pre- or early perimenopausal women who were Caucasian (n = 1140), African-American (n = 651), Chinese (n = 247), or Japanese (n = 275) and were participating in the Study of Women's Health Across the Nation. Serum OC and urinary NTX levels were compared before and after adjustment for a series of lifestyle and anthropometric variables that can affect bone turnover. Unadjusted serum OC levels were highest in Caucasian women (P < 0.001 vs. all other groups), higher in African-American than Chinese women (P = 0.006), and similar in Chinese and Japanese women (P = 0.203) and African-American and Japanese women (P = 0.187). Unadjusted serum OC levels were 11-24% higher in Caucasians than in the other groups. Adjustment for covariates did not alter the ethnic pattern of serum OC levels. Unadjusted urinary NTX levels were statistically significantly higher in Caucasian and African-American women than in Chinese women (P < 0.001) for both comparisons). Unadjusted urinary NTX levels were higher in Caucasian than in Japanese women (P = 0.071) and higher in Japanese than in Chinese women (P = 0.055), but these differences were of borderline statistical significance. Unadjusted urinary NTX levels were 9-18% higher in African-Americans and Caucasians than in the other groups. Among Caucasians, there were significant geographic regional variations in both serum OC and urinary NTX levels, with higher levels in women from the Northeast and the Midwest than in women from California. These data demonstrate significant ethnic differences in bone turnover in pre- and early perimenopausal women. Although these differences in adult bone turnover may explain some of the known ethnic variation in BMD, ethnic patterns of adult bone turnover do not parallel patterns of BMD. Other factors, such as differences in bone accretion, are likely responsible for much of the ethnic variation in adult BMD.
Assuntos
Desenvolvimento Ósseo , Climatério/fisiologia , Pré-Menopausa/fisiologia , Grupos Raciais , Adulto , Antropometria , Estudos de Coortes , Colágeno/urina , Etnicidade , Feminino , Humanos , Estilo de Vida , Estudos Longitudinais , Pessoa de Meia-Idade , Osteocalcina/sangueRESUMO
Bone mineral density (BMD) and fracture rates vary among women of differing ethnicities. Most reports suggest that BMD is highest in African-Americans, lowest in Asians, and intermediate in Caucasians, yet Asians have lower fracture rates than Caucasians. To assess the contributions of anthropometric and lifestyle characteristics to ethnic differences in BMD, we assessed lumbar spine and femoral neck BMD by dual-energy x-ray absorptiometry in 2277 (for the lumbar spine) and 2330 (for the femoral neck) premenopausal or early perimenopausal women (mean age, 46.2 yr) participating in the Study of Women's Health Across the Nation. Forty-nine percent of the women were Caucasian, 28% were African-American, 12% were Japanese, and 11% were Chinese. BMDs were compared among ethnic groups before and after adjustment for covariates. Before adjustment, lumbar spine and femoral neck BMDs were highest in African-American women, next highest in Caucasian women, and lowest in Chinese and Japanese women. Unadjusted lumbar spine and femoral neck BMDs were 7-12% and 14-24% higher, respectively, in African-American women than in Caucasians, Japanese, or Chinese women. After adjustment, lumbar spine and femoral neck BMD remained highest in African-American women, and there were no significant differences between the remaining groups. When BMD was assessed in a subset of women weighing less than 70 kg and then adjusted for covariates, lumbar spine BMD became similar in African-American, Chinese, and Japanese women and was lowest in Caucasian women. Adjustment for bone size increased values for Chinese women to levels equal to or above those of Caucasian and Japanese women. Among women of comparable weights, there are no differences in lumbar spine BMD among African-American, Chinese, and Japanese women, all of whom have higher BMDs than Caucasians. Femoral neck BMD is highest in African-Americans and similar in Chinese, Japanese, and Caucasians. These findings may explain why Caucasian women have higher fracture rates than African-Americans and Asians.
Assuntos
Densidade Óssea , Climatério/fisiologia , Pré-Menopausa/fisiologia , Grupos Raciais , Antropometria , Estudos de Coortes , Etnicidade , Feminino , Colo do Fêmur/metabolismo , Humanos , Estilo de Vida , Estudos Longitudinais , Vértebras Lombares/metabolismo , Pessoa de Meia-IdadeRESUMO
PURPOSE: To examine the relationships between disordered eating, menstrual irregularity, and low bone mineral density (BMD) in young female runners. METHODS: Subjects were 91 competitive female distance runners aged 18-26 yr. Disordered eating was measured by the Eating Disorder Inventory (EDI). Menstrual irregularity was defined as oligo/amenorrhea (0-9 menses per year). BMD was measured by dual x-ray absorptiometry. RESULTS: An elevated score on the EDI (highest quartile) was associated with oligo/amenorrhea, after adjusting for percent body fat, age, miles run per week, age at menarche, and dietary fat, (OR [95% CI]: 4.6 [1.1-18.6]). Oligo/amenorrheic runners had lower BMD than eumenorrheic runners at the spine (-5%), hip (-6%), and whole body (-3%), even after accounting for weight, percent body fat, EDI score, and age at menarche. Eumenorrheic runners with elevated EDI scores had lower BMD than eumenorrheic runners with normal EDI scores at the spine (-11%), with trends at the hip (-5%), and whole body (-5%), after adjusting for differences in weight and percent body fat. Runners with both an elevated EDI score and oligo/amenorrhea had no further reduction in BMD than runners with only one of these risk factors. CONCLUSION: In young competitive female distance runners, (i) disordered eating is strongly related to menstrual irregularity, (ii) menstrual irregularity is associated with low BMD, and (iii) disordered eating is associated with low BMD in the absence of menstrual irregularity.
Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Distúrbios Menstruais/epidemiologia , Osteoporose/epidemiologia , Corrida/fisiologia , Absorciometria de Fóton , Adolescente , Adulto , Densidade Óssea/fisiologia , Comorbidade , Estudos Transversais , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Feminino , Seguimentos , Humanos , Modelos Lineares , Distúrbios Menstruais/diagnóstico , Análise Multivariada , Osteoporose/diagnóstico , Prevalência , Probabilidade , Medição de Risco , Estudos de AmostragemRESUMO
To test the hypothesis that parathyroid hormone (PTH) regulates interleukin-6 (IL-6) expression locally in bone, the expression of IL-6 mRNA was examined by in situ hybridization after a subcutaneous injection of human PTH [1-84] (225 microg/kg) in 4-week old rats. Whereas IL-6 mRNA was not detected at the basal status, it was transiently detected in a subpopulation of stromal cells in the intertrabecular region of the metaphyses from 1/2 to 1 hr after PTH injection. Contrastingly, IL-6 transcripts were not detected in other cell populations at any time points examined. Since IL-6 is a known activator of osteoclasts, these results are consistent with the hypothesis that PTH stimulates the local IL-6 synthesis in stromal cells to indirectly activate osteoclasts.
Assuntos
Osso e Ossos/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Hormônio Paratireóideo/farmacologia , Células Estromais/efeitos dos fármacos , Animais , Reabsorção Óssea , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Células Estromais/metabolismoRESUMO
CONTEXT: Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone. OBJECTIVE: The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent. DESIGN: Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 µg daily), denosumab (60 mg every 6 months), or both medications for 24 months. PARTICIPANTS: Participants were 94 postmenopausal women with osteoporosis. OUTCOME MEASURES: Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured. RESULTS: At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy. CONCLUSIONS: Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores/sangue , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Denosumab , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Pró-Colágeno/sangue , Teriparatida/administração & dosagem , Teriparatida/efeitos adversos , Resultado do TratamentoRESUMO
Several studies, using dual-energy X-ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux-en-Y gastric bypass surgery and 20 obese nonsurgical controls. At 1 year, subjects who underwent gastric bypass surgery lost 37 ± 2 kg compared with 3 ± 2 kg lost in the nonsurgical controls (p < 0.0001). Spine BMD declined more in the surgical group than in the nonsurgical group whether assessed by DXA (-3.3 versus -1.1%, p = 0.034) or by QCT (-3.4 versus 0.2%, p = 0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (-8.9 versus -1.1%, p < 0.0001 for the total hip and -6.1 versus -2.0%, p = 0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82% ± 10% and by 220% ± 22%, respectively, by 6 months and remained elevated over 12 months (p < 0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip.
Assuntos
Absorciometria de Fóton , Cirurgia Bariátrica/efeitos adversos , Osteoporose/etiologia , Tomografia Computadorizada por Raios X , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/diagnóstico por imagem , Obesidade Mórbida/cirurgia , Osteoporose/diagnóstico por imagemRESUMO
OBJECTIVE: Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. METHODS: Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. RESULTS: Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m² and smallest in women with BMI >30 kg/m². Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. SUMMARY: During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.