RESUMO
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 MulherAssuntos
Conservadores da Densidade Óssea , Teriparatida , Densidade Óssea , Cosméticos , Humanos , OsteoporoseRESUMO
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: 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
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
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: 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.
Assuntos
Reabsorção Óssea/etiologia , Estradiol/sangue , Hormônio Foliculoestimulante Humano/sangue , Menopausa , Obesidade/fisiopatologia , Osteoporose Pós-Menopausa/etiologia , Sobrepeso/fisiopatologia , Adulto , Negro ou Afro-Americano , Asiático , Índice de Massa Corporal , Reabsorção Óssea/sangue , Reabsorção Óssea/etnologia , Reabsorção Óssea/urina , China/etnologia , Estudos de Coortes , Colágeno/urina , Feminino , Humanos , Japão/etnologia , Estudos Longitudinais , Menopausa/etnologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/etnologia , Osteoporose Pós-Menopausa/urina , Ovário/fisiopatologia , Estados Unidos , População BrancaRESUMO
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
African-American women have a lower risk of fracture than white women, and this difference is only partially explained by differences in dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro-finite element analysis (µFEA) in African-American (n = 100) and white (n = 173) women participating in the Study of Women's Health Across the Nation (SWAN). African-American women had larger and denser bones than whites, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p < 0.05 for all). African-Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African-Americans at both skeletal sites (p < 0.05 for all), and lower cortical porosity in African-Americans at the tibia (p < 0.05). African-American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African-American and white women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African-Americans and probably explain, at least in part, the lower fracture risk of African-American women.
Assuntos
Negro ou Afro-Americano , Osso e Ossos/anatomia & histologia , Osso e Ossos/fisiologia , População Branca , Absorciometria de Fóton , Adulto , Fenômenos Biomecânicos , Densidade Óssea/fisiologia , Osso e Ossos/diagnóstico por imagem , Estudos de Coortes , Feminino , Análise de Elementos Finitos , Humanos , Pessoa de Meia-Idade , Rádio (Anatomia)/anatomia & histologia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/fisiologia , Tíbia/anatomia & histologia , Tíbia/diagnóstico por imagem , Tíbia/fisiologia , Tomografia Computadorizada por Raios X , Suporte de CargaRESUMO
OBJECTIVE: Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women. METHODS: Women attended up to nine clinic visits for an average of 7.6 ± 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs. RESULTS: Women who experienced fractures (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.50; 95% CI, 1.28-1.68). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.46; 95% CI, 1.05-2.26). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61-6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08-2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD. CONCLUSIONS: A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.
Assuntos
Reabsorção Óssea/diagnóstico , Fraturas Ósseas/epidemiologia , Menopausa/fisiologia , Saúde da Mulher , Adulto , Reabsorção Óssea/complicações , Estudos de Coortes , Colágeno Tipo I/urina , Feminino , Fraturas Ósseas/etiologia , Fraturas Ósseas/urina , Humanos , Menopausa/urina , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose Pós-Menopausa/complicações , Peptídeos/urina , Fatores de RiscoRESUMO
CONTEXT: There has been considerable concern recently in the scientific and lay media regarding the benefits vs. the risks of bisphosphonates for the treatment of osteoporosis. Risks include possible associations with osteonecrosis of the jaw (ONJ) and atypical femur fractures. In this perspective, we review the use of bisphosphonates for the treatment of osteoporosis, including an objective assessment of the risks vs. the benefits of these drugs. EVIDENCE ACQUISITION: Authors' knowledge of the field and results of focused literature searches are presented. EVIDENCE SYNTHESIS: Bisphosphonates have proven efficacy in the prevention of bone loss and in the reduction of fractures in postmenopausal women and men with established osteoporosis. Although bisphosphonates, at doses used to treat osteoporosis, may be associated with an increased risk of ONJ and atypical femur fractures, many more fractures are prevented by the use of these drugs compared to the relatively low risk of these complications. Although oral bisphosphonates are associated with upper gastrointestinal side effects and iv bisphosphonates with acute phase reactions, the association of bisphosphonate use with esophageal cancer and atrial fibrillation is not well supported by current data. CONCLUSIONS: Bisphosphonates have been proven to prevent fractures in patients with established osteoporosis or those who are at high risk of fracture. In contrast, the incidence of major complications associated with bisphosphonate use, such as ONJ and atypical femur fractures, is very low.
Assuntos
Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/farmacologia , Feminino , Fraturas do Colo Femoral/induzido quimicamente , Fraturas do Colo Femoral/epidemiologia , Humanos , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/epidemiologia , Masculino , Modelos Biológicos , Osteonecrose/induzido quimicamente , Osteonecrose/epidemiologia , Medição de RiscoRESUMO
The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.
Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Dispositivos Lab-On-A-Chip , Teriparatida/administração & dosagem , Tecnologia sem Fio/instrumentação , Idoso , Biomarcadores/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Cálcio/metabolismo , Cápsulas , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/efeitos adversos , Feminino , Humanos , Teriparatida/efeitos adversos , Teriparatida/farmacocinética , Teriparatida/farmacologiaRESUMO
Once-daily injections of teriparatide initially increase biochemical markers of bone formation and resorption, but markers peak after 6-12 months and then decline despite continued treatment. We sought to determine whether increasing teriparatide doses in a stepwise fashion could prolong skeletal responsiveness. We randomized 52 postmenopausal women with low spine and/or hip bone mineral density (BMD) to either a constant or an escalating subcutaneous teriparatide dose (30 µg daily for 18months or 20 µg daily for 6 months, then 30 µg daily for 6 months, and then 40 µg daily for 6 months). Serum procollagen I N-terminal propeptide, osteocalcin, and C-terminal telopeptide of type I collagen were assessed frequently. BMD of the spine, hip, radius, and total body was measured every 6 months. Acute changes in urinary cyclic AMP in response to teriparatide were examined in a subset of women in the constant dose group. All bone markers differed significantly between the two treatment groups. During the final six months, bone markers declined in the constant dose group but remained stable or increased in the escalating dose group (all markers, p<0.017). Nonetheless, mean area under the curve did not differ between treatments for any bone marker, and BMD increases were equivalent in both treatment groups. Acute renal response to teriparatide, as assessed by urinary cyclic AMP, did not change over 18 months of teriparatide administration. In conclusion, stepwise increases in teriparatide prevented the decline in bone turnover markers that is observed with chronic administration without altering BMD increases. The time-dependent waning of the response to teriparatide appears to be bone-specific.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Conservadores da Densidade Óssea/administração & dosagem , AMP Cíclico/biossíntese , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente , Pós-Menopausa , Teriparatida/administração & dosagemRESUMO
The Study of Women's Health Across the Nation (SWAN) is an NIH-funded, multidisciplinary, longitudinal observational study of middle-aged U.S. women of multiple ethnicities in or near Boston, Newark, Pittsburgh, Detroit, Chicago, Oakland, and Los Angeles. SWAN measures multiple variables annually, including spine and hip areal bone mineral density (aBMD), serum and urine indices of bone remodeling, and pituitary, ovarian, and adrenal hormones. This chapter outlines the findings of the SWAN study so far.
Assuntos
Menopausa/fisiologia , Osteoporose Pós-Menopausa/epidemiologia , Biomarcadores/análise , Remodelação Óssea/fisiologia , Feminino , Humanos , Estudos Longitudinais , Menopausa/etnologia , Estudos Multicêntricos como Assunto , Osteoporose Pós-Menopausa/etnologia , Osteoporose Pós-Menopausa/etiologia , Saúde da MulherRESUMO
CONTEXT: Teriparatide increases both bone formation and bone resorption. OBJECTIVE: We sought to determine whether combining teriparatide with an antiresorptive agent would alter its anabolic action. DESIGN AND SETTING: This was a randomized controlled trial conducted in a single university hospital. PATIENTS AND INTERVENTION: We randomized 93 postmenopausal women with low bone mineral density (BMD) to alendronate 10 mg daily (group 1), teriparatide 40 microg sc daily (group 2), or both (group 3) for 30 months. Teriparatide was begun at month 6. MAIN OUTCOME MEASURES: BMD of the lumbar spine, proximal femur, proximal radius, and total body was measured by dual-energy x-ray absorptiometry (DXA) every 6 months. Lumbar spine trabecular BMD was measured at baseline and month 30 by quantitative computed tomography. Serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide levels were assessed frequently. Women who had at least one repeat DXA scan on therapy were included in the analyses (n = 69). RESULTS: DXA spine BMD increased more in women treated with teriparatide alone than with alendronate alone (18 +/- 11 vs. 7 +/- 4%; P < 0.001) or both (18+/-11 vs. 12 +/- 9%; P = 0.045). Similarly, femoral neck BMD increased more in women treated with teriparatide alone than with alendronate alone (11 +/- 5 vs. 4 +/- 4%; P < 0.001) or both (11 +/- 5 vs. 3 +/- 5%; P < 0.001). Quantitative computed tomography spine BMD increased 1 +/- 7, 61 +/- 31, and 24 +/- 24% in groups 1, 2, and 3 (P < 0.001 for all comparisons). Serum osteocalcin, N-terminal propeptide of type 1 collagen, and cross-linked N-telopeptides of type I collagen increased more with teriparatide alone than with both (P < 0.001 for each marker). CONCLUSION: Alendronate reduces the ability of teriparatide to increase BMD and bone turnover in women.
Assuntos
Alendronato/uso terapêutico , Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/prevenção & controle , Teriparatida/uso terapêutico , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Anabolizantes/administração & dosagem , Anabolizantes/efeitos adversos , Biomarcadores/sangue , Densidade Óssea , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente , Inquéritos e Questionários , Teriparatida/administração & dosagem , Teriparatida/efeitos adversosRESUMO
CONTEXT: In postmenopausal women, bone mineral density (BMD) declines after teriparatide therapy is stopped. The pattern of BMD loss after teriparatide therapy is stopped in men is less clear. OBJECTIVE: The aim of the study was to determine whether the pattern of teriparatide-induced bone accrual and post-teriparatide bone loss differs between postmenopausal women and eugonadal men. DESIGN: We conducted a prospective cohort substudy. PATIENTS: The study included 14 postmenopausal women and 17 eugonadal men, ages 46-85 yr, with lumbar spine or femoral neck BMD T-scores below -2. INTERVENTION: Teriparatide (37 microg sc daily) was administered for 24 months, followed by 12 months off therapy. MAIN OUTCOME MEASURES: We measured BMD at various anatomic sites by dual-energy x-ray absorptiometry, trabecular spine BMD by quantitative computed tomography, and bone turnover markers during the treatment and observation periods. The response to teriparatide administration and discontinuation was compared between females and males. RESULTS: BMD of the spine, femoral neck, total hip, and trabecular spine increased similarly during the treatment period in men and women, whereas BMD at the radius was stable in men but decreased by 8.1 +/- 3.3% in women (P < 0.0001). After teriparatide was stopped, BMD at the posterior-anterior spine decreased by 7.1 +/- 3.8% in women and by 4.1 +/- 3.5% in men (P = 0.036). BMD at the total hip and femoral neck decreased by 3.8 +/- 3.9 and 3.1 +/- 4.3%, respectively, in women but remained stable in men (P < 0.05 for both sites). BMD at the distal radius remained stable in men but increased in women by 1.6 +/- 3.1% (P = 0.069). CONCLUSIONS: Teriparatide appears to increase BMD similarly in postmenopausal women and eugonadal men with osteoporosis. After teriparatide is stopped, the decline in BMD is greater in women than in men. If confirmed in larger cohorts, these findings would suggest that the indication for immediate antiresorptive therapy after teriparatide may not be as urgent in men as in women.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
CONTEXT: The stimulatory effect of teriparatide on bone mineral density (BMD) and bone turnover is initially exuberant, but then diminishes. OBJECTIVE: Our objective was to determine whether retreating with teriparatide after a drug-free period can restore the initial exuberant response to teriparatide. DESIGN AND SETTING: This was a planned extension of a randomized controlled trial conducted in a single university hospital. PATIENTS AND INTERVENTION: Subjects previously participated in a 30-month randomized trial comparing the effects of alendronate (group 1), teriparatide (group 2), or both (group 3) on BMD and bone turnover in men and women with low BMD (phase 1). Subjects who completed phase 1 on their assigned therapy entered phase 2 (months 30-42), during which teriparatide was stopped in groups 2 and 3. Teriparatide was administered to all subjects during months 42 to 54 (phase 3). MAIN OUTCOME MEASURES: We compared changes in BMD and markers of bone turnover (serum osteocalcin, N-terminal propeptide of type 1 collagen, and N-telopeptide) between phase 1 and 3 in subjects receiving teriparatide alone. RESULTS: Posterior-anterior and lateral spine BMD increased 12.5 +/- 1.5 and 16.9 +/- 1.7%, respectively, during the first 12 months of teriparatide administration and 5.2 +/- 0.8 and 6.2 +/- 1.8%, respectively, during teriparatide retreatment (P < 0.001 and P = 0.001). Increases in osteocalcin (P < 0.001), N-terminal propeptide of type 1 collagen (P < 0.001), and N-telopeptide (P < 0.001) were greater during the first period of teriparatide administration. CONCLUSION: The response to teriparatide is attenuated when readministered after a 12-month hiatus.
Assuntos
Osteoporose/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Algoritmos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Retratamento , Teriparatida/administração & dosagem , Teriparatida/efeitos adversosRESUMO
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.