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1.
J Bone Miner Res ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31348548

RESUMO

Pregnancy and lactation-associated osteoporosis (PLO) is a rare, severe, early form of osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. In studies of idiopathic osteoporosis (IOP) in premenopausal women, we enrolled 78 women with low-trauma fractures and 40 healthy controls, all with normal menses and no secondary cause of bone loss. In 15 of the affected women, the PLO subgroup, fractures had occurred during late pregnancy or lactation. We hypothesized that clinical, bone structural, and metabolic characteristics would differ between women with PLO and those with (non-PLO) IOP and controls. All were evaluated > 12 months postpartum, when structural and remodeling characteristics would be expected to reflect baseline premenopausal status rather than transient postpartum changes. As previously reported, affected subjects (PLO and IOP) had BMD and microarchitectural deficiencies compared to controls. Women with PLO did not differ from those with IOP in terms of age, BMI, body fat, menarcheal age, parity, or age at first pregnancy. However, women with PLO had a more severe clinical presentation than those with IOP: more fractures (5.5 ± 3.3 versus 2.6 ± 2.1; p = 0.005); more vertebral fractures (80% versus 17%; p < 0.001); and higher prevalence of multiple fractures. BMD deficits were more profound and cortical width tended to be lower in PLO. PLO subjects also had significantly lower tissue-level mineral apposition rate and bone formation rates (0.005 ± 0.005 versus 0.011 ± 0.010 mm2 /mm/year; p = 0.006), as well as lower serum P1NP (33 ± 12 versus 44 ± 18 µg/L; p = 0.02) and CTX (257 ± 102 versus 355 ± 193 pg/mL; p = 0.01) than IOP. The finding that women with PLO have a low bone remodeling state assessed more than a year postpartum increases our understanding of the pathogenic mechanism of PLO. We conclude that women with PLO may have underlying osteoblast functional deficits which could affect their therapeutic response to osteoanabolic medications. © 2019 American Society for Bone and Mineral Research.

2.
Bone ; 111: 109-115, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29555310

RESUMO

Investigators and clinicians use bone histomorphometry data from iliac bone biopsies to study bone abnormalities in diseased patients, and to understand the safety and effectiveness of pharmaceutical interventions. This requires access to a high quality normal data-set to be used for comparisons, a resource that has not been adequate to date. The objective of this work is to present static and dynamic bone histomorphometry data from transilial bone biopsies performed on 48 healthy males, evenly distributed between ages 45 and 75. In addition, we compared these results with results from our earlier study in normal postmenopausal women (Recker et al., 1988 [1]). The data include bone density and anthropometric measurements, micro-CT, and a collection of serum biochemical measurements. We found that several of the histomorphometry variables were correlated with serum measurements, i.e. serum testosterone and sex hormone-binding globulin (SHBG). Micro-CT variables were correlated with the static histomorphometry variables, and were very similar. Age-related changes were observed for both histomorphometry and Micro-CT, but were surprisingly small in most cases. Comparisons with our previously reported histomorphometry data from normal women were surprisingly similar, but there was a significant age by gender interaction in the wall thickness (W.Th) measurements, i.e. there was a small increase in this variable with age in men, and a significant decline with age in women. The population selected for this study, and the prior study in normal women, were carefully chosen so as to rule out the presence of clinical, life-style or other confounding factors. While the cohort chosen herein was a convenience sample, and not a population-based sample, we believe it can be used as a reference standard with proper precautions in its interpretation and in its comparisons with diseased populations.

3.
J Bone Miner Res ; 33(2): 298-306, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29024120

RESUMO

There has been renewed interest of late in the role of modeling-based formation (MBF) during osteoporosis therapy. Here we describe early effects of an established anabolic (teriparatide) versus antiresorptive (denosumab) agent on remodeling-based formation (RBF), MBF, and overflow MBF (oMBF) in human transiliac bone biopsies. Postmenopausal women with osteoporosis received subcutaneous teriparatide (n = 33, 20 µg/d) or denosumab (n = 36, 60 mg once/6 months), open-label for 6 months at 7 US and Canadian sites. Subjects received double fluorochrome labeling at baseline and before biopsy at 3 months. Sites of bone formation were designated as MBF if the underlying cement line was smooth, RBF if scalloped, and oMBF if formed over smooth cement lines adjacent to scalloped reversal lines. At baseline, mean RBF/bone surface (BS), MBF/BS, and oMBF/BS were similar between the teriparatide and denosumab groups in each bone envelope assessed (cancellous, endocortical, periosteal). All types of formation significantly increased from baseline in the cancellous and endocortical envelopes (differences p < 0.001) with teriparatide (range of changes 2.9- to 21.9-fold), as did MBF in the periosteum (p < 0.001). In contrast, all types of formation were decreased or not significantly changed with denosumab, except MBF/BS in the cancellous envelope, which increased 2.5-fold (difference p = 0.048). These data highlight mechanistic differences between these agents: all 3 types of bone formation increased significantly with teriparatide, whereas formation was predominantly decreased or not significantly changed with denosumab, except for a slight increase in MBF/BS in the cancellous envelope. © 2017 American Society for Bone and Mineral Research.

4.
Bone ; 108: 55-61, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29258873

RESUMO

Investigators and clinicians have had few normal bone histomorphometry data available to compare with those found in diseased patients, or in the results of treatments. The Goals and Objectives of this work are two-fold: 1. to present static and dynamic bone histomorphometry data from transilial bone biopsies performed on 76 healthy, premenopausal women. 2. To present paired static and dynamic bone histomorphometry data from bone biopsies on a subset (N=51 pairs) of these same healthy women whose biopsies were repeated 12months after their last menses. Statistical comparisons between the pre- and postmenopausal data are presented. These data will shrink this important gap, both for clinicians and investigators. We enrolled 76 healthy, premenopausal women over age 46, performed transilial bone biopsies after tetracycline labeling, and during a period of 9.5years, we re-biopsied 51 of them who passed through menopause and remained healthy the entire time. We also obtained serum biochemical measurements, and serial DXA exams during the period of observation. The dynamic bone histomorphometry demonstrated a doubling of bone remodeling, and increases in serum bone markers at the time of the second biopsy. Lumbar spine bone density also declined, and there were significant correlations between serum markers and histomorphometry variables. The data demonstrate that healthy menopause results in an important increase in bone remodeling, and a loss of bone density. We do not fully understand the mechanisms of these transmenopausal changes, but the data provide some clues that are helpful.

5.
Curr Osteoporos Rep ; 15(3): 153-161, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28432596

RESUMO

PURPOSE OF REVIEW: The goal of this paper is to evaluate critically the literature published over the past 3 years regarding the Wnt signaling pathway. The Wnt pathway was found to be involved in bone biology in 2001-2002 with the discovery of a (G171V) mutation in the lipoprotein receptor-related protein 5 (LRP5) that resulted in high bone mass and another mutation that completely inactivated Lrp5 function and resulted in osteoporosis pseudoglioma syndrome (OPPG). The molecular biology has been complex, and very interesting. It has provided many opportunities for exploitation to develop new clinical treatments, particularly for osteoporosis. More clinical possibilities include: treatments for fracture healing, corticosteroid osteoporosis, osteogenesis imperfecta, and others. In addition, we wish to provide historical information coming from distant publications (~350 years ago) regarding bone biology that have been confirmed by study of Wnt signaling. RECENT FINDINGS: A recent finding is the development of an antibody to sclerostin that is under study as a treatment for osteoporosis. Development of treatments for other forms of osteoporosis, such as corticosteroid osteoporosis, is also underway. The full range of the applications of the work is not yet been achieved.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Osteogênese Imperfeita/genética , Osteoporose/tratamento farmacológico , Via de Sinalização Wnt/genética , Humanos , Terapia de Alvo Molecular
6.
J Bone Miner Res ; 32(6): 1267-1273, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28218468

RESUMO

We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations. © 2017 American Society for Bone and Mineral Research.


Assuntos
Osteoblastos/metabolismo , Osteogênese , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Pré-Menopausa/fisiologia , Receptor IGF Tipo 1/metabolismo , Células-Tronco/metabolismo , Teriparatida/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Adolescente , Adulto , Biópsia , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pré-Menopausa/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Teriparatida/farmacologia , Adulto Jovem
7.
Sci Rep ; 7: 40593, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28079136

RESUMO

The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose-response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose-response. Five SNPs, rs10500804 (P = 4.93 × 10-7), rs2060793 (P = 6.63 × 10-7), rs10741657 (P = 1.49 × 10-6), rs10766197 (P = 1.05 × 10-5) and rs11023380 (P = 7.67 × 10-5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 × 10-7), rs2298850 (P = 1.94 × 10-6), rs1155563 (P = 6.39 × 10-6), rs705119 (P = 2.80 × 10-5), rs705120 (P = 1.08 × 10-4) and rs222040 (P = 1.59 × 10-4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 × 10-4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women.


Assuntos
Colecalciferol/uso terapêutico , Suplementos Nutricionais , Polimorfismo de Nucleotídeo Único/genética , Receptor X Retinoide alfa/genética , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/genética , Vitamina D/análogos & derivados , Vitamina D/sangue
8.
Bone ; 97: 314-319, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27826127

RESUMO

There are a number of effective treatments for osteoporosis but most are in the antiresorptive class of compounds. Abaloparatide-SC is a new osteoanabolic agent, which increased bone mineral density and lowered the risk of osteoporosis-related fractures in the phase 3 ACTIVE trial. The objective of this report is to describe the effects of abaloparatide-SC 80µg on bone histology and histomorphometry in iliac crest bone biopsies from this trial in which participants were randomized to receive blinded daily subcutaneous injections of placebo or abaloparatide-SC 80µg/d or open-label teriparatide 20µg/d for 18months. Iliac crest bone biopsies were obtained between 12 and 18months. Qualitative histological analysis of biopsies from abaloparatide-SC-treated patients revealed normal bone microarchitecture without evidence of adverse effects on mineralization or on the formation of normal lamellar bone. There were no bone marrow abnormalities, marrow fibrosis nor was there presence of excess osteoid or woven bone. There were few significant differences among the three treatment groups in a standard panel of static and dynamic histomorphometric indices. The mineral apposition rate was higher in the teriparatide-treated group than in the placebo-treated group. The eroded surface was lower in the abaloparatide-SC-treated group than in the placebo-treated group. Cortical porosity was higher in both the abaloparatide-SC- and the teriparatide-treated groups than in the placebo-treated group. We conclude that histological and histomorphometric analysis of iliac crest bone biopsies from subjects who were treated for up to 18months with abaloparatide-SC showed no evidence of concern for bone safety. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01343004.


Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Densidade Óssea , Estudos de Coortes , Demografia , Feminino , Humanos , Pessoa de Meia-Idade
9.
Arch Osteoporos ; 11: 22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27229335

RESUMO

The methods and processes described in this manuscript have been approved and adopted by the NOF Board of Trustees on November 11, 2015. This manuscript has been peer-reviewed by the NOF Research Committee and Osteoporosis International. The National Osteoporosis Foundation frequently publishes position statements for the benefit of educating healthcare professionals and the general public on a particular issue and/or concern related to preventing osteoporosis and/or promoting strong bones throughout the lifespan. This manuscript represents the official methods and processes adopted by the NOF Board of Trustees for the purpose developing future position statements in a transparent and unbiased manner.


Assuntos
Conferências de Consenso como Assunto , Fundações/normas , Processos Grupais , Osteoporose , Guias de Prática Clínica como Assunto/normas , Fundações/organização & administração , Humanos
11.
J Bone Miner Res ; 31(7): 1429-39, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26841258

RESUMO

Previously, we reported the effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone formation based on biochemical markers and bone histomorphometry of the cancellous envelope at month 6 in postmenopausal women with osteoporosis who participated in the 12-month primary Skeletal Histomorphometry in Subjects on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study. Patients were eligible to enter a 12-month extension on their original treatment regimen: TPTD 20 µg/day (s.c. injection) or ZOL 5 mg/year (i.v. infusion). A second biopsy was performed at month 24. Here we report longitudinal changes between and within each treatment group in the cancellous, endocortical, intracortical, and periosteal bone envelopes in patients with evaluable biopsies at months 6 and 24 (paired data set: TPTD, n = 10; ZOL, n = 9). Between-group differences are also reported in the larger set of patients with evaluable biopsies at month 6 (TPTD, n = 28; ZOL, n = 30). Data from the cancellous envelope at month 6 or month 24 provided a reference to compare differences across envelopes within each treatment group. The 24-month results extend our earlier report that TPTD and ZOL possess different tissue-level mechanisms of action. Moreover, these differences persisted for at least 2 years in all four bone envelopes. Few longitudinal differences were observed within or across bone envelopes in ZOL-treated patients, suggesting that the low bone formation indices at month 6 persisted to month 24. Conversely, the magnitude of the effect of TPTD on bone formation varied across individual envelopes: median values for mineralizing surface (MS/BS) and bone formation rate (BFR/BS) at month 6 were approximately 3-fold to 5-fold higher in the endocortical and intracortical envelopes compared to the cancellous envelope. Although MS/BS and BFR/BS declined in these envelopes at month 24, median values continued to exceed, or were not significantly different from, those in the cancellous envelope. This study demonstrates for the first time that bone formation indices are higher with TPTD treatment than with ZOL in all four bone envelopes and the difference persists for at least 2 years. Moreover, the magnitude of the effect of TPTD in cortical bone remains robust at 24 months. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Osso Esponjoso , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Osteoporose Pós-Menopausa , Periósteo , Pós-Menopausa/metabolismo , Teriparatida/administração & dosagem , Idoso , Densidade Óssea/efeitos dos fármacos , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Periósteo/metabolismo , Periósteo/patologia , Fatores de Tempo , Ácido Zoledrônico
12.
J Bone Miner Res ; 31(5): 1070-81, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26636271

RESUMO

Fourier transform infrared imaging (FTIRI) provides information on spatial distribution of the chemical composition of thin tissue specimens at ∼7 µm spatial resolution. This study of 120 age- and bone mineral density (BMD)-matched patients was designed to investigate the association of FTIRI variables, measured in iliac crest biopsies, with fragility fractures at any site. An earlier study of 54 women found hip BMD to be a significant explanatory variable of fracture risk for cortical bone but not for cancellous bone. In the current study, where age and BMD were controlled through matching, no such association was observed, validating the pairing scheme. Our first study of unmatched iliac crest biopsies found increases in collagen maturity (cancellous and cortical bone) and mineral crystal size (cortical bone only) to be a significant explanatory variable of fracture when combined with other covariates. The ratio for collagen maturity has been correlated to the amount of enzymatic collagen cross-links. To assess the impact of other FTIRI variables (acid phosphate substitution, carbonate-to-phosphate ratio, and the pixel distribution [heterogeneity] of all relevant FTIRI variables), we examined biopsies from a matched case-controlled study, in which 60 women with fractures were each paired with an age- and BMD-matched female control. With the matched data set of 120 women, conditional logistic regression analyses revealed that significant explanatory variables of fracture were decreased carbonate-to-phosphate ratio in both cancellous (odds ratio [OR] = 0.580, 95% confidence interval [CI] 0.37-0.909, p = 0.0176) and cortical bone (OR = 0.519, 95% CI 0.325-0.829, p = 0.0061), and increased heterogeneity (broadened pixel distribution) of collagen maturity for cancellous bone (OR = 1.549, 95% CI 1.002-2.396, p = 0.0491). The observation that collagen maturity was no longer linked to fracture in age- and BMD-matched samples suggests that age-dependent variation in collagen maturity may be a more important contributory factor to fragility fractures than previously thought. © 2015 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea , Osso Esponjoso , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/metabolismo , Ílio , Idoso , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Estudos de Casos e Controles , Colágeno/metabolismo , Feminino , Humanos , Ílio/diagnóstico por imagem , Ílio/metabolismo , Pessoa de Meia-Idade , Espectroscopia de Infravermelho com Transformada de Fourier
13.
J Bone Miner Res ; 31(1): 190-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26234180

RESUMO

Low-energy fractures are frequent complications in type 1 diabetes mellitus patients (T1DM). Modifications of bone intrinsic composition might be a potential cause of fragility observed in diabetic subjects. Advanced glycation end products (AGEs) were found in numerous connective tissues from T1DM patients. However, whether AGEs are present at high levels in bone matrix from diabetic subjects is unknown. Moreover, whether elevated AGEs in the bone matrix impair mineralization has not been addressed in humans. The purposes of this study were 1) to determine whether bone matrix from fracturing and nonfracturing T1DM contained more AGEs than bone from healthy patients (CTL), and 2) to compare the degree of mineralization of bone and hardness between fracturing and nonfracturing T1DM versus CTL. We analyzed iliac crest bone biopsies from 5 fracturing T1DM patients, 5 nonfracturing T1DM patients, and 5 healthy subjects, all age- and sex-matched. AGEs (pentosidine) in bone matrix was measured by high-performance liquid chromatography separately in trabecular and cortical bone. The degree of mineralization of bone (DMB) was assessed by digitized microradiography, and mechanical properties by micro- and nanohardness tests. Trabecular bone from fracturing T1DM exhibited significantly higher levels of pentosidine than CTL (p = 0.04) and was more mineralized than nonfracturing T1DM (p = 0.04) and CTL (p = 0.04). Trabecular bone was not significantly different in pentosidine between nonfracturing T1DM and CTL. Cortical bone from nonfracturing T1DM was not significantly different from CTL. Positive correlations were found between HbA1c and pentosidine (r' = 0.79, p < 0.003) and between HbA1c and DMB (r' = 0.64, p < 0.02). Both modifications could lead to less flexible bone (reduced modulus of elasticity) and a tendency toward low-energy fractures in T1DM patients.


Assuntos
Densidade Óssea , Calcificação Fisiológica , Diabetes Mellitus Tipo 1 , Fraturas Ósseas , Produtos Finais de Glicação Avançada , Adulto , Complicações do Diabetes/diagnóstico por imagem , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/etiologia , Fraturas Ósseas/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia
14.
J Clin Endocrinol Metab ; 100(11): 4208-14, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26358172

RESUMO

CONTEXT: Without antiresorptive therapy, postmenopausal women lose bone mass after teriparatide (TPTD) discontinuation; estrogen treatment prevents bone loss in this setting. It is not known whether premenopausal women with regular menses lose bone mass after teriparatide discontinuation. OBJECTIVE: This study aimed to test the hypothesis that normally menstruating premenopausal women with idiopathic osteoporosis (IOP) will maintain teriparatide-associated bone mineral density (BMD) gains after medication cessation. DESIGN: Twenty-one premenopausal IOP women previously enrolled in an open-label pilot study of teriparatide (20 mcg for 18-24 mo), had substantial BMD increases at the lumbar spine (LS; 10.8 ± 8.3%), total hip (TH; 6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%). For this study, BMD was remeasured 2.0 ± 0.6 years after teriparatide cessation. PARTICIPANTS: Fifteen women, who had gained 11.1 ± 7.2% at LS and 6.1 ± 6.5% at TH and were premenopausal at teriparatide completion, were followed without antiresorptive treatment. RESULTS: Two years after completing teriparatide, BMD declined by 4.8 ± 4.3% (P = .0007) at the LS. In contrast, BMD remained stable at the femoral neck (-1.5 ± 4.2%) and TH (-1.1 ± 3.7%). Those who sustained LS bone loss >3% (-7.3 ± 2.9%; n = 10), did not differ from those with stable LS BMD (0.1 ± 1.1%; n=5) with regard to baseline body mass index, BMD at any site, or duration of followup, but were significantly older at re-evaluation (46 ± 3 vs 38 ± 7; P = .046), had larger increases in LS BMD during teriparatide treatment and higher cancellous bone remodeling on transiliac biopsy at baseline and completion of teriparatide treatment. Serum bone turnover markers did not differ at baseline or teriparatide completion, but tended to be higher at the re-evaluation timepoint in those with post-teriparatide bone loss. CONCLUSIONS: These findings lead us to conclude that premenopausal women with IOP, particularly those over 40, may require antiresorptive treatment to prevent bone loss after teriparatide.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/patologia , Teriparatida/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Conservadores da Densidade Óssea/efeitos adversos , Desenvolvimento Ósseo/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Minerais/metabolismo , Projetos Piloto , Pré-Menopausa , Coluna Vertebral/patologia , Teriparatida/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
J Bone Miner Res ; 30(9): 1717-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25707611

RESUMO

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Densidade Óssea , Proteínas Morfogenéticas Ósseas/sangue , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Idoso , Anticorpos Monoclonais/química , Anticorpos Monoclonais Humanizados/sangue , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/sangue , Proteínas Morfogenéticas Ósseas/imunologia , Reabsorção Óssea , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Marcadores Genéticos/imunologia , Humanos , Pessoa de Meia-Idade , Osteogênese , Esteroides/química , Fatores de Tempo
16.
J Bone Miner Res ; 30(2): 216-24, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25196993

RESUMO

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Densidade Óssea/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/imunologia , Marcadores Genéticos/imunologia , Pós-Menopausa , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Osteoporose Pós-Menopausa/tratamento farmacológico , Placebos , Pós-Menopausa/efeitos dos fármacos , Resultado do Tratamento
17.
PLoS One ; 9(5): e97098, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24820117

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. METHODOLOGY/PRINCIPAL FINDINGS: We used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression. CONCLUSIONS/SIGNIFICANCE: Our study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis.


Assuntos
MicroRNAs/genética , Osteoporose Pós-Menopausa/genética , Idoso , Sequência de Bases , Biomarcadores/metabolismo , Densidade Óssea , Biologia Computacional , Feminino , Regulação da Expressão Gênica , Humanos , MicroRNAs/sangue , Pessoa de Meia-Idade , Monócitos/metabolismo , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/fisiopatologia
18.
J Clin Endocrinol Metab ; 99(7): 2418-25, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24684466

RESUMO

CONTEXT: In premenopausal women with idiopathic osteoporosis (IOP), treatment with teriparatide leads to substantial improvement in bone density and quality at central skeletal sites. The effects of teriparatide may differ on cortical and trabecular bone and also at the central and the peripheral skeleton. OBJECTIVE: The objective of the study was to determine whether teriparatide was associated with improvements in compartmental volumetric bone mineral density (BMD), bone microarchitecture, and estimated bone strength of the distal radius and tibia as assessed by high-resolution peripheral quantitative computed tomography. DESIGN, SETTING, AND PARTICIPANTS: Premenopausal women (n = 20, age 41 ± 5 y) with IOP (low trauma fractures and/or Z-scores ≤ -2.0) were scanned with high-resolution peripheral quantitative computed tomography at baseline and after 18 months of teriparatide treatment. Cortical and trabecular volumetric BMD and microarchitecture were measured by both standard and advanced techniques, including individual trabecula segmentation, and bone strength was estimated by finite element analysis. MAIN OUTCOME MEASURES: The total volumetric BMD and homogeneous bone stiffness were measured. RESULTS: Trabecular volumetric BMD increased significantly by 2.6% (1.8, 6.2) [median (interquartile range)] at the radius and 2.5% (1.1, 3.6) at the tibia. In addition, trabecular plate bone volume fraction increased by 9.1% (2.1, 17.1) at the radius and 7.6% (1.0, 9.7) at the tibia. Cortical thickness and volumetric density did not change; however, cortical porosity increased at the radius but not at the tibia. Despite these changes, whole-bone stiffness and failure load estimated by finite element analysis increased at both the radius and tibia. CONCLUSIONS: In premenopausal women with IOP, 18 months of teriparatide was associated with increases in trabecular volumetric BMD, improved trabecular microarchitecture, and estimated bone strength at both the radius and tibia.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Teriparatida/administração & dosagem , Adulto , Osso e Ossos/diagnóstico por imagem , Feminino , Fraturas Ósseas/prevenção & controle , Humanos , Fenômenos Mecânicos/efeitos dos fármacos , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Projetos Piloto , Pré-Menopausa/efeitos dos fármacos , Tomografia Computadorizada por Raios X/métodos
19.
JPEN J Parenter Enteral Nutr ; 38(6): 728-35, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23765064

RESUMO

BACKGROUND: Aluminum (Al) contamination of parenteral nutrition (PN) solutions remains a concern for long-term PN patients. Al accumulates particularly in bone. Excessive exposure to Al may result in increased Al body burden and impaired bone formation and mineralization, leading to bone disease. Although the U.S. Food and Drug Administration (FDA) has limited Al contamination in large-volume parenteral solutions, small-volume parenterals may still contribute considerable amounts of Al to PN solutions. The goal of this study is to determine whether or not long-term adult PN patients remain at risk for increased bone Al accumulation. METHODS: We measured Al accumulation in autopsy bones from 7 patients who had received PN for 2-21 years and compared bone Al levels with those in living control patients undergoing hip or knee replacement. Electrothermal atomic absorption spectrometry was used for bone Al measurements. RESULTS: When compared with bone Al content in controls, markedly elevated Al levels (P < .0001) were found in the bones of all but 1 patient, who received PN for only 2 years before death. Even greater Al accumulation was found for PN patients who developed late renal impairment (P = .0159). CONCLUSIONS: We conclude that long-term adult PN patients continue to be at risk for Al toxicity.


Assuntos
Alumínio/química , Autopsia/métodos , Osso e Ossos/química , Nutrição Parenteral/efeitos adversos , Adulto , Idoso , Contaminação de Medicamentos , Humanos , Pessoa de Meia-Idade , Soluções de Nutrição Parenteral/química , Reprodutibilidade dos Testes , Espectrofotometria Atômica , Estados Unidos , United States Food and Drug Administration
20.
J Steroid Biochem Mol Biol ; 144 Pt A: 207-14, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24128439

RESUMO

Factors contributing to the variability of serum 25-hydroxyvitamin D [25(OH)D] in response to a given dose of vitamin D supplementation are largely unknown. We examined whether DNA methylation levels of Cytochrome P450 (CYP) enzymes (CYP2R1, CYP24A1, CYP27A1, and CYP27B1) are potential biomarkers predicting vitamin D response variation. We randomized 446 white postmenopausal women to a calcium and vitamin D (1100IU/day) intervention for at least 12 months. From these subjects, 18 with the highest 12-month increase in serum 25(OH)D were selected as "responders." Another 18 with the lowest 12-month increase in serum 25(OH)D were selected as "non-responders." DNA methylation levels between the groups were compared. To validate findings in the first study, association between DNA methylation levels and vitamin D response variation was studied in another 145 extended independent white postmenopausal women. In the first study, compared to non-responders, responders had significantly lower baseline DNA methylation levels in the promoter region of CYP2R1 (8% in the responders vs. 30% in the non-responders, P=0.004), and CYP24A1 (13% in the responders vs. 32% in the non-responders, P=0.001). In the validation study, for CYP2R1, baseline DNA methylation levels at eight CpG sites were negatively associated with 12-month increases in serum 25(OH)D (P<0.05). For CYP24A1, baseline DNA methylation levels at two CpG sites were also negatively associated with vitamin D response variation (r=-0.151, P=0.011; r=-0.131, P=0.025). These negative associations were consistent with the first study's results. Our findings indicate that baseline DNA methylation levels of CYP2R1 and CYP24A1 may predict vitamin D response variation. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Metilação de DNA , Variação Genética , Esteroide Hidroxilases/genética , Vitamina D/análogos & derivados , Vitaminas/sangue , Família 2 do Citocromo P450 , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/administração & dosagem , Vitamina D/sangue , Vitamina D3 24-Hidroxilase , Vitaminas/administração & dosagem
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