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Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.
Assuntos
Histiocitose de Células de Langerhans , Adulto , Criança , Cladribina/uso terapêutico , Consenso , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases , MutaçãoRESUMO
To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.
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Conservadores da Densidade Óssea , Reabsorção Óssea , Osteoporose Pós-Menopausa , Humanos , Feminino , Animais , Camundongos , Osteoporose Pós-Menopausa/tratamento farmacológico , Denosumab/farmacologia , Denosumab/uso terapêutico , Densidade ÓsseaRESUMO
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by hypercalcemia due to inappropriately high parathyroid hormone secretion. While in the typical, symptomatic form of the disease diagnosis is set easily and standard management is surgical removal of the hyperfunctioning parathyroid (HP), this may not be the case in more subtle forms of PHPT, such as the asymptomatic and the normocalcemic PHPT. Localization of the HP could also be challenging, especially in small-sized adenomas, ectopic lesions or multiglandular disease. An experienced surgical team is essential to achieve curative parathyroidectomy. In this article, we used illustrative clinical vignettes to dissect the approach to the patient with PHPT, from the diagnosis establishment to the suggested investigation to identify classical and non-classical PHPT features and the methodology to locate the abnormal tissue. Accordingly, we elaborated on appropriate management, both surgical and conservative.
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The long-term effects of zoledronate treatment in women with postmenopausal osteoporosis who stop denosumab therapy when they become osteopenic are not known. In a prospective, randomized, controlled clinical trial we previously reported that a single intravenous infusion of zoledronate 5 mg given to such patients 6 months after the last denosumab injection effectively prevents bone loss in the majority of them for up to 3 years. The study was extended for an additional 2 years and included all 19 patients from one Trial Site of the total 27 patients originally randomized in the zoledronate arm. Baseline characteristics of this cohort treated with denosumab for 2.4 ± 0.2 years were not different from those of the whole initial cohort or from the patients who did not participate in this extension. At the end of 5 years 7 patients had become again osteoporotic requiring additional treatment, 9 remained osteopenic while 3 did not complete the study extension. Thus, more than half of the osteoporotic women who became osteopenic with denosumab treatment and stopped it, maintained the BMD gains 5 years after a single zoledronate infusion with no additional treatment. Whether these results are also applicable to patients treated with denosumab for longer periods remains to be established.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Humanos , Feminino , Osteoporose Pós-Menopausa/tratamento farmacológico , Ácido Zoledrônico/uso terapêutico , Denosumab , Densidade Óssea , Estudos ProspectivosRESUMO
This phase IIb clinical trial evaluated the efficacy of a bimonthly treatment schedule (Q8W) with 4 subcutaneous doses of denosumab 120 mg among adults with Langerhans cell histiocytosis needing first-line systemic therapy for either multifocal single-system disease or multisystem disease without risk organ involvement. Two months after the last treatment administration, seven patients showed disease regression, one stable disease, one non-active disease, and one disease progression. One year after treatment, progression was evident in two patients, while the remaining exhibited either a regression (three patients) or non-active disease (five patients). No permanent sequalae developed during the study and no adverse events were adjudicated in treatment. In conclusion, four doses of denosumab 120 mg Q8W subcutaneously are an effective treatment option in Langerhans cell histiocytosis patients without risk organ involvement exhibiting a response rate of 80%. Further studies are needed to confirm its role as a disease modifying agent.
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Denosumab , Histiocitose de Células de Langerhans , Adulto , Humanos , Denosumab/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Screening and linkage to care (SLTC) for osteoporosis is suboptimal in several settings. In Greece, it is estimated that only up to 8.6% of postmenopausal women are SLTC for osteoporosis, despite having suffered a previous fracture. AIMS: This study aims to estimate the impact of comprehensive screening on future fracture burden amongst post-menopausal women aged 50-74, with one prior osteoporotic fracture, in Greece. METHODS: We developed a cohort stochastic model, based on published epidemiological and clinical data, to assess impact of screening on future fracture burden in two scenarios: a current, assuming an 8.6% background SLTC, and a completely hypothetical, assuming 100% SLTC. RESULTS: Amongst a cohort of 50,000 post-menopausal women aged 50-74, with one prior osteoporotic fracture, applying the hypothetical versus the current scenario would result in a reduction in deaths (-0.6%) and fractures (-4.3%) over 10 years. The hypothetical scenario leads to greater reductions in costs associated with vertebral (-8.1%) and hip (-5.5%) fractures, followed by other non-vertebral (-3.0%) and forearm (-2.5%) fractures. In the hypothetical scenario, treatment initiations and total screenings increased almost tenfold versus the current scenario, at an estimated direct incremental cost of 27.83 per woman per year in the cohort. DISCUSSION: Our study adds to the existing evidence on the impact of screening to prevent fractures amongst post-menopausal women. Despite being based on a stochastic model, our study confirms findings most recently published in the literature. CONCLUSIONS: Our study models the positive public health impact of increasing SLTC levels amongst post-menopausal women with a prior osteoporotic fracture.
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Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Feminino , Humanos , Fraturas por Osteoporose/diagnóstico , Fraturas por Osteoporose/epidemiologia , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/epidemiologia , Pós-Menopausa , Grécia/epidemiologia , Osteoporose/complicações , Osteoporose/diagnóstico , Osteoporose/epidemiologiaRESUMO
Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations. The activation of the MAP kinase pathway plays an integral role in its pathogenesis with genetic alterations found in the majority of cases that most frequently involve a somatic mutation of the oncogenic BRAFV600E variant. In this study we investigated the prevalence of the BRAFV600E mutation and its clinical relevance in adult Greek patients with LCH. Among 37 patients studied, the BRAFV600E mutation was identified in 12 out of 31 (38.7%), whereas in six patients (19.3%) the results were in conclusive. The presence of the mutation did not correlate with age at diagnosis, organ involvement, disease extent, response to initial treatment, development of diabetes insipidus and relapse risk. In our series the prevalence of the BRAFV600E mutation is at the lower range of the relative percentage found in children, but in line to that obtained in previous studies of adult patients with LCH that have found an up to 50% prevalence of the BRAFV600E mutation in these patients. Further studies with a larger number of adults are needed to identify the exact prevalence of mutations in the RAS-RAF-MEK-ERK pathway and their role on clinical parameters and disease outcomes.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2029988 .
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Histiocitose de Células de Langerhans , Proteínas Proto-Oncogênicas B-raf , Adulto , Criança , Grécia/epidemiologia , Histiocitose de Células de Langerhans/epidemiologia , Histiocitose de Células de Langerhans/genética , Humanos , Mutação , Prevalência , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
AIM: Bone remodelling can be followed through the bone turnover markers (BTMs). Aim of the present study was to record the fluctuation of an osteoclastic and an osteoblastic BTM [C-terminal telopeptide of type I collagen (CTX) and N-terminal pro-peptide of type I pro-collagen (PINP), respectively] in both the gingival crevicular fluid (GCF) and the serum of orthodontic patients before and after the initial application of orthodontic forces. MATERIALS AND METHODS: Twenty-one Caucasian patients were prospectively evaluated. GCF and blood samples were collected in order to measure the selected biomarkers by ELISA at three time-points: exactly before, 5 days, and 14 days after bonding of the appliances. Standardized sample handling and patient preparation procedures were adopted in order to reduce pre-analytical variability. RESULTS: GCF and serum CTX levels were found to be independent of age, although higher in the serum of female subjects. PINP levels were found higher in the serum of patients ≥25 years old, as well as in the GCF of males. A positive correlation between serum and GCF baseline PINP levels was observed. LIMITATIONS: The effect of orthodontic treatment on bone remodelling might not be absolutely representative of the local bone microenvironment as the levels of the specific BTMs where measured within the GCF of the lower front teeth. CONCLUSIONS: This is the first time PINP and CTX have been evaluated in the GCF and serum of orthodontic patients with fixed appliances. No statistically significant alterations of CTX and PINP levels in the GCF and the serum of patients were recorded over time during the initial stages of orthodontic treatment.
Assuntos
Líquido do Sulco Gengival , Soro , Adulto , Biomarcadores , Remodelação Óssea , Colágeno Tipo I/análise , Feminino , Humanos , Masculino , Aparelhos Ortodônticos , Aparelhos Ortodônticos Fixos , Soro/químicaRESUMO
Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.
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Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Densidade Óssea , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Feminino , Humanos , Osteoporose Pós-Menopausa/tratamento farmacológico , Ácido ZoledrônicoRESUMO
Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (nâ¯=â¯20), teriparatide (nâ¯=â¯8), zoledronate (nâ¯=â¯8) or teriparatide/denosumab combination (nâ¯=â¯3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Fraturas por Osteoporose/epidemiologia , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Feminino , Grécia , Humanos , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Estudos Retrospectivos , Teriparatida/uso terapêutico , Ácido Zoledrônico/uso terapêuticoRESUMO
Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.
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Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Fraturas da Coluna Vertebral , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea , Denosumab/uso terapêutico , Feminino , Humanos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/prevenção & controle , Suspensão de TratamentoRESUMO
Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a variable clinical course and outcome. Although there are some data regarding its incidence in children, such information in adults is lacking. To address the actual annual LCH incidence among adults, we prospectively recorded, during a 12-month period, any new case with a definitive histological diagnosis of LCH, among persons aged 18 and older living in Greece. Fourteen new cases were recorded corresponding to an annual incidence of 1.58 per million population. Female to male ratio was 1.34, and mean age at diagnosis was 43.5 years.
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Histiocitose de Células de Langerhans/epidemiologia , Adulto , Idoso , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of the disease show significant differences between genders, with the majority of cases being reported in postmenopausal women. Due to this gender predilection, several studies have investigated the role of sex hormones in the pathogenesis of the disease and their potential use as targets for optimal and gender-specific management. Epigenetic mechanisms that regulate gene transcription may also contribute to these differences between genders. In this review, we outline what is currently known regarding the role of sex hormones and the recent data on the role of non-coding RNAs in the differences between genders in primary hyperparathyroidism due to sporadic parathyroid adenomas.
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Neoplasias das Paratireoides/epidemiologia , Neoplasias das Paratireoides/etiologia , Suscetibilidade a Doenças , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/genética , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Hormônio Paratireóideo/biossíntese , Neoplasias das Paratireoides/metabolismo , Prevalência , Fatores SexuaisAssuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Humanos , Feminino , Alendronato/uso terapêutico , Denosumab/uso terapêutico , Osteoporose/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
Hungry Bone Syndrome (HBS) refers to rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia occurring in patients with increased bone turnover after successful management of the underlying disorder. We describe a male patient with primary hyperparathyroidism (PHPT), in whom HBS was diagnosed 6 months after parathyroidectomy. Histopathologic examination revealed an atypical parathyroid adenoma (APA), while immunohistochemistry showed cell proliferation index Ki-67 10% and overexpression of cyclin D1 (>90%). Preoperative treatment with vitamin D3 had normalized 25OHD and alkaline phosphatase levels, reflected in an improvement in bone turnover prior to surgery. Postoperative treatment for HBS with alfacalcidol, calcium, vitamin D3 and magnesium was administered for a long period. This treatment prevented severe postoperative hypocalcemia and he was discharged two days later. Preoperative cinacalcet treatment did not reduce hypercalcemia implying that the tumor had lack of calciumsensing receptors (CaSR). In conclusion, preoperative restoration of low 25OHD levels is essential for prevention of HBS. Postoperative treatment with active metabolites of vitamin D must be initiated as early as possible, in order to prevent or minimize the development of HBS, and to reduce the duration of hospitalization.
Assuntos
Hipocalcemia/etiologia , Hipofosfatemia/etiologia , Paratireoidectomia/efeitos adversos , Complicações Pós-Operatórias/etiologia , Adenoma/complicações , Adenoma/cirurgia , Adulto , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Colecalciferol/uso terapêutico , Cinacalcete/uso terapêutico , Humanos , Hidroxicolecalciferóis/uso terapêutico , Hiperparatireoidismo/tratamento farmacológico , Hiperparatireoidismo/etiologia , Hiperparatireoidismo/cirurgia , Hipocalcemia/tratamento farmacológico , Hipofosfatemia/tratamento farmacológico , Magnésio/uso terapêutico , Masculino , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/cirurgia , Complicações Pós-Operatórias/tratamento farmacológico , SíndromeRESUMO
OBJECTIVES: Noggin inactivates bone morphogenetic proteins (BMPs), possibly exerting negative effects on the skeleton.We aimed to compare the effect of agents with opposite impact on bone turnover on noggin circulating levels. METHODS: In this observational, open label, non-randomized clinical study postmenopausal women with low bone mass were treated with either denosumab (n=30) or teriparatide (n=30). Serum samples were obtained at baseline, three and twelve months after treatment initiation. Prevalent fractures were recorded at baseline and lumbar spine bone mineral density (LS BMD) was measured at baseline and twelve months. Measured parameters included noggin, BMP-2, BMP-4, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTx). RESULTS: Noggin levels remained unchanged after either denosumab or teriparatide treatment. Baseline noggin levels were not different between women with vs. without previous anti-osteoporotic treatment, or between those with vs. without vertebral or non-vertebral fractures and were not correlated with age or LS BMD. At twelve months, noggin levels were positively correlated with P1NP within the denosumab (rs= 0.47; p=0.014), whereas negatively within the teriparatide group (rs= -0.43; p=0.019). CONCLUSIONS: In postmenopausal women with low bone mass noggin levels were not correlated with bone parameters at any time point, except with P1NP at 12 months, and remained stable with both denosumab and teriparatide treatment.
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Conservadores da Densidade Óssea/uso terapêutico , Proteínas de Transporte/sangue , Denosumab/uso terapêutico , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Juvenile Paget's disease (JPD) is a rare, autosomal recessive disorder featuring markedly increased serum alkaline phosphatase activity, indicative of greatly accelerated bone turnover throughout the skeleton. The main aim of this study was to evaluate circulating periostin and sclerostin levels in two adult patients with mild JPD (due to "Balkan" mutation). We measured periostin and sclerostin levels in a previously described woman and a newly diagnosed man with JPD, and 10 apparently healthy individuals, matched (1:5) to JPD patients for gender, age and body mass index. Sclerostin levels were similar between JPD patients and controls. Periostin levels were about 2.5 times higher in JPD patients. Periostin and sclerostin levels were negatively correlated (rs= -0.63; p=0.03). In conclusion, a trend towards higher periostin levels was observed in JPD patients, whereas sclerostin levels were similar to controls.
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There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation.
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Proteínas Morfogenéticas Ósseas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Absorciometria de Fóton , Proteínas Adaptadoras de Transdução de Sinal , Estudos Transversais , Feminino , Marcadores Genéticos , Humanos , Região Lombossacral/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/metabolismoRESUMO
The activins-follistatins-inhibins (AFI) hormonal system affects bone metabolism. Treatments that alter bone metabolism may also alter the AFI molecules. In this non-randomized, open-label, head-to-head comparative study, circulating levels of the AFI system were evaluated in postmenopausal women with osteoporosis treated for 12 months with either teriparatide (n = 23) or denosumab (n = 22). Τeriparatide treatment increased activin B (p = 0.01) and activin AB (p = 0.004) and the ratios activin A/follistatin (p = 0.006), activin B/follistatin (p = 0.007), activin AB/follistatin (p < 0.001) and activin AB/FSTL3 (p = 0.034). The significant p for trend in group*time interactions of activins B and AB and of the ratio activin AB/FSTL3 remained robust after adjustment for body mass index (BMI) and lumbar spine bone mineral density (LS BMD) but it was lost for activin B after adjustment for previous antiresorptive treatment. The effect of teriparatide on BMD was attenuated when it was adjusted for baseline activins levels or their 12-month changes. No changes were observed after denosumab treatment. In conclusion, activins B and AB, as well as the ratios of all activins to follistatin and of activin AB to FSTL3 increased with teriparatide treatment, possibly in a compensatory manner. Future studies are needed to study the potentially important role activins may play in bone biology and any associations with the effect of teriparatide on BMD.
Bone and the muscle, comprise two tissues that are considered to interact with each other, not only through mechanical but also through endocrine signals. Several components of the activins-follistatins-inhibins (AFI) hormonal system have been shown to be secreted by the muscle and affect the bone possibly contributing to this interplay. We have previously investigated levels of the AFI molecules in casecontrol studies and reported differences between osteoporotic versus osteopenic versus postmenopausal and premenopausal women with normal bone mineral density (BMD). In this 12-month, non-randomized, open-labeled, head-to-head comparative study, we prospectively compared the effect of antiosteoporotic agents with opposite effect on bone metabolism, i.e., teriparatide versus denosumab, on the circulating concentrations of all known molecules of the AFI system in postmenopausal women with osteoporosis. We observed increases of activins after teriparatide treatment, but no effect after denosumab treatment on any of the AFI molecules studied. Since activins are mainly acting in an autocrine way and since activin B and AB have not been extensively studied, further studies in the basic research, preclinical and clinical research fields are required to expand these observations and fully elucidate physiology and any therapeutic potential.
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Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared with TPTD in treatment-naive women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Finally, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.