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1.
Osteoporos Int ; 35(5): 911-918, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38494549

RESUMO

This study evaluated the yield of routine laboratory examination in a large population of older women in primary care. The prevalence of laboratory abnormalities was low and the clinical consequences in follow-up were limited. There was a weak association of laboratory abnormalities with osteoporosis but no association with vertebral fractures and recent fractures. PURPOSE: Most osteoporosis guidelines advice routine laboratory examination. We have investigated the yield of laboratory examinations in facture risk evaluation of elderly women in primary care. METHODS: We assessed the prevalence of laboratory abnormalities and their association with risk factors for fractures, recent fractures, low bone mineral density (BMD), and prevalent vertebral fracture in 8996 women ≥ 65 years of age participating in a primary care fracture risk screening study. In a sample of 2208 of these participants, we also evaluated the medical consequences in the medical records during a follow-up period of ≥ 1 year. RESULTS: Vitamin D deficiency (< 30 nmol/L) was present in 13% and insufficiency (< 50 nmol/L) in 43% of the study sample. The prevalence of other laboratory abnormalities (ESR, calcium, creatinine, FT4) was 4.6% in women with risk factors for fractures, 6.1% in women with low BMD (T-score ≤ - 2.5), 6.0% after a prevalent vertebral fracture, 5.2% after a recent fracture and 2.6% in the absence of important risk factors for fractures. Laboratory abnormalities other than vitamin D were associated with low BMD (OR 1.4, 95%CI 1.1-1.8) but not with prevalent vertebral fractures nor recent fractures. Low BMD was associated with renal failure (OR 2.0, 95%CI 1.3-3.4), vitamin D insufficiency (OR 1.2, 95%CI 1.0-1.3) and deficiency (OR 1.3, 95%CI 1.1-.5). In the follow-up period, 82% of the laboratory abnormalities did not result in a new diagnosis or treatment reported in the medical records. CONCLUSIONS: We identified a low prevalence of laboratory abnormalities in a primary care population of older women and the majority of these findings had no medical consequences.


Assuntos
Fraturas Ósseas , Osteoporose , Fraturas da Coluna Vertebral , Feminino , Humanos , Idoso , Fraturas da Coluna Vertebral/diagnóstico , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/etiologia , Densidade Óssea , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/complicações , Fraturas Ósseas/epidemiologia , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Atenção Primária à Saúde
2.
Hum Gene Ther ; 33(15-16): 782-788, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35502479

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.


Assuntos
Miosite Ossificante , Ossificação Heterotópica , Receptores de Ativinas Tipo I/genética , Estudos de Viabilidade , Terapia Genética/efeitos adversos , Humanos , Miosite Ossificante/complicações , Miosite Ossificante/genética , Miosite Ossificante/terapia , Ossificação Heterotópica/genética
3.
Front Med (Lausanne) ; 9: 852678, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35391888

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by heterotopic ossification (HO) of the skeletal muscles, fascia, tendons and ligaments. Patients often experience limitations in jaw function due to HO formation in the maxillofacial region. However, no studies have yet analyzed the age of onset and location of HO and the type of restrictions it may yield in the maxillofacial region. The aim of this study was to evaluate all existing literature on the site of onset of HO and associated functional restrictions of the jaw. To this end, a scoping review was performed focusing on limitations of jaw movement in FOP patients. The literature search resulted in 725 articles, of which 30 articles were included for full study after applying the exclusion criteria. From these articles 94 FOP patients were evaluated for gender, age, presence and age at which HO started in the maxillofacial region, location of HO, whether HO was caused spontaneous or traumatic and maximum mouth opening. Formation of HO is slightly more common in female patients compared to male patients, but the age of HO onset or the maximum mouth opening does not differ between genders. Trauma-induced HO occurred at a significantly younger age than spontaneous HO. Interestingly, a difference in maximum mouth opening was observed between the different ossified locations in the maxillofacial region, with ossification of the masseter muscle resulting in the smallest and ossification of the zygomatic arch resulting in the largest maximum mouth opening. This review revealed that the location of the maxillofacial region affected by HO determines the degree of limitations of the maximum mouth opening. This finding may be important for establishing clinical guidelines for the dental management of FOP patients.

4.
Biomedicines ; 9(6)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205844

RESUMO

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFß, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32760351

RESUMO

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO) that occurs in muscle tissue, tendons, and ligaments. The disease is caused by mutations in the Activin receptor type I (ACVR1) gene resulting in enhanced responsiveness to Activin-A. Binding of this molecule to the mutated receptor induces HO. Bone metabolism normally requires the coupled action of osteoblasts and osteoclasts, which seems to be disturbed during HO. We hypothesize that Activin-A may also counteract the formation of osteoclasts in FOP patients. In this study we investigated the effect of Activin-A on osteoclast differentiation of CD14+ monocytes from FOP patients and healthy controls. The lymphocytic and monocytic cell populations were determined by FACS analysis. Expression of the mutated R206H receptor was assessed and confirmed by allele specific PCR. The effect of Activin-A on osteoclastogenesis was assessed by counting the number and size of multinucleated cells. Osteoclast activity was determined by culturing the cells on Osteo Assay plates. The influence of Activin-A on expression of various osteoclast related genes was studied with QPCR. Blood from FOP patients contained similar percentages of classical, intermediate, or non-classical monocytes as healthy controls. Addition of Activin-A to the osteoclastogenesis cultures resulted in fewer osteoclasts in both control and FOP cultures. The osteoclasts formed in the presence of Activin-A were, however, much larger and more active compared to the cultures without Activin-A. This effect was tempered when the Activin-A inhibitor follistatin was added to the Activin-A containing cultures. Expression of osteoclast specific genes Cathepsin K and TRAcP was upregulated, gene expression of osteoclastogenesis related genes M-CSF and DC-STAMP was downregulated by Activin-A. Since Activin-A is a promising target for inhibiting the formation of HO in FOP, it is important to know its effects on both osteoblasts and osteoclasts. Our study shows that Activin-A induces fewer, but larger and more active osteoclasts independent of the presence of the mutated ACVR1 receptor. When considering FOP as an Activin-A driven disease that acts locally, our findings suggest that Activin-A could cause a more pronounced local resorption by larger osteoclasts. Thus, when targeting Activin-A in patients with neutralizing antibodies, HO formation could potentially be inhibited, and osteoclastic activity could be slightly reduced, but then performed dispersedly by more and smaller osteoclasts.


Assuntos
Ativinas/metabolismo , Reabsorção Óssea/patologia , Monócitos/citologia , Miosite Ossificante/patologia , Osteoclastos/citologia , Osteogênese , Adulto , Idoso , Reabsorção Óssea/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Miosite Ossificante/metabolismo , Osteoclastos/metabolismo , Transdução de Sinais , Adulto Jovem
6.
Bone ; 124: 1-6, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30858149

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant disorder characterized by heterotopic ossification (HO) in muscles, ligaments and tendons. Flare-ups often precede the formation of HO, resulting in immobilization of joints. Due to progression of the disease without signs of a flare-up, co-existence of a chronic progression of HO has been postulated, but conclusive evidence is lacking. Recently, it has been shown that [18F]NaF PET/CT is able to identify early ossifying disease activity during flare-ups. Therefore, the purpose of the present study was to assess whether [18F]NaF PET/CT might also be able to identify the possible presence of chronic progressive HO in FOP. A total of thirteen [18F]NaF PET/CT scans from five FOP patients were analysed. Scans were acquired over a period of 0.5 to 2 years. Volumes of HO and standardized uptake values (SUV) were obtained based on manual segmentation of CT images. SUVpeak values, defined as the average SUV value of a 1 mL sphere containing the hottest voxel pixels, were obtained. Two out of five patients experienced ≥1 active clinical flare-ups at the time of the [18F]NaF PET/CT scan. In addition, in four out of five patients, serial scans showed radiological progression of HO (3 to 8 cm3), as assessed by CT volume, in the absence of a clinical flare-up. This volumetric increase was present in 6/47 (12.8%) of identified HO structures and, in all cases, was accompanied by increased [18F]NaF uptake, with SUVpeak ranging from 8.4 to 17.9. In conclusion, HO may progress without signs of a flare-up. [18F]NaF PET/CT is able to identify these asymptomatic, but progressive HO lesions, thereby demonstrating the presence of chronic activity in FOP. Consequently, future drugs should not only target new HO formation, but also this chronic HO progression.


Assuntos
Osso e Ossos/diagnóstico por imagem , Coristoma/diagnóstico por imagem , Miosite Ossificante/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluoreto de Sódio/química , Adolescente , Adulto , Osso e Ossos/patologia , Feminino , Humanos , Masculino , Adulto Jovem
7.
J Cell Physiol ; 234(7): 10238-10247, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30417373

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by heterotopic ossification (HO). The disease is caused by a mutation in the activin receptor type 1 (ACVR1) gene that enhances this receptor's responsiveness to Activin-A. Binding of Activin-A to the mutated ACVR1 receptor induces osteogenic differentiation. Whether Activin-A also affects osteoclast formation in FOP is not known. Therefore we investigated its effect on the osteoclastogenesis-inducing potential of periodontal ligament fibroblasts (PLF) from teeth of healthy controls and patients with FOP. We used western blot analysis of phosphorylated SMAD3 (pSMAD3) and quantitative polymerase chain reaction to assess the effect of Activin-A on the PLF. PLF-induced osteoclast formation and gene expression were studied by coculturing control and FOP PLF with CD14-positive osteoclast precursor cells from healthy donors. Osteoclast formation was also assessed in control CD14 cultures stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANK-L). Although Activin-A increased activation of the pSMAD3 pathway in both control and FOP PLF, it increased ACVR1, FK binding protein 12 (FKBP12), an inhibitor of DNA binding 1 protein (ID-1) expression only in FOP PLF. Activin-A inhibited PLF mediated osteoclast formation albeit only significantly when induced by FOP PLF. In these cocultures, it reduced M-CSF and dendritic cell-specific transmembrane protein (DC-STAMP) expression. Activin-A also inhibited osteoclast formation in M-CSF and RANK-L mediated monocultures of CD14+ cells by inhibiting their proliferation. This study brings new insight on the role of Activin A in osteoclast formation, which may further add to understanding FOP pathophysiology; in addition to the known Activin-A-mediated HO, this study shows that Activin-A may also inhibit osteoclast formation, thereby further promoting HO formation.


Assuntos
Ativinas/farmacologia , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Miosite Ossificante/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/efeitos dos fármacos , Receptores de Ativinas Tipo I/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Miosite Ossificante/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Ligamento Periodontal/metabolismo , Ligamento Periodontal/patologia , Fosforilação , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína 1A de Ligação a Tacrolimo/metabolismo , Adulto Jovem
8.
Br J Clin Pharmacol ; 85(6): 1199-1207, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30281842

RESUMO

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Ensaios Clínicos como Assunto/métodos , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Projetos de Pesquisa , Consenso , Humanos , Miosite Ossificante/diagnóstico , Miosite Ossificante/fisiopatologia , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/fisiopatologia , Segurança do Paciente , Seleção de Pacientes , Participação dos Interessados
9.
Bone ; 109: 168-177, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28705683

RESUMO

Fibrodysplasia Ossificans Progressiva (FOP) is a progressive disease characterized by periods of heterotopic ossification of soft connective tissues, including ligaments. Though progress has been made in recent years in unraveling the underlying mechanism, patient-derived cell models are necessary to test potential treatment options. Periodontal ligament fibroblasts (PLF) from extracted teeth can be used to study deviant bone modeling processes in vitro since these cells are derived from genuine ligaments. They further provide a tool to study the hitherto unknown role of the bone morphogenesis protein receptor type 1 (BMPR-1) Activin A type 1 receptor ACVR1-R206H mutation in osteoclastogenesis. To further validate this potential model, osteogenesis and osteoclastogenesis was studied in the presence of TGF-ß/activin receptor inhibitor GW788388. Control and FOP fibroblasts (n=6 of each) were used in osteogenesis and osteoclastogenesis assays in the absence or presence of TGF-ß/activin receptor inhibitor GW788388. For osteogenesis, alkaline phosphatase (ALP) activity, alizarin red staining for mineralization and qPCR for expression of osteogenic markers was assessed. TRACP staining, multinuclearity and expression of osteoclastogenesis markers were used as a measure of osteoclast formation. FOP fibroblasts cultured in osteogenic medium displayed a trend of higher ALP activity at 7days. Gene expression of ALP from FOP fibroblasts was significantly higher at 3days. Mineralization was similar at 21days for both groups. GW788388 did not influence mineral deposition in both groups. Osteoclast formation was inhibited by GW788388 on plastic for both controls and FOP. On cortical bone slices, however, osteoclast formation was significantly lowered by GW788388, only in FOP cultures. qPCR revealed strong expression of RANKL at 7days and a significant decline at 14 and 21days in both FOP and control cultures. In contrast to the osteoclastogenesis results, the RANKL/OPG ratio was higher in the presence of GW788388, only in FOP cultures. TGF-ß expression was significantly higher at 14 and 21days compared to 7days, possibly signifying a role in later stages of osteoclast formation. Addition of GW788388 strongly decreased TGF-ß expression. Our study shows that periodontal ligament fibroblasts from FOP patients displayed at most slightly enhanced in vitro osteogenesis and osteoclastogenesis. This model could be useful to elucidate molecular mechanisms leading to heterotopic ossification in FOP such as in the presence of specific ACVR1-R206H activators as Activin A.


Assuntos
Fibroblastos/citologia , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/citologia , Benzamidas/farmacologia , Western Blotting , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Feminino , Humanos , Pirazóis/farmacologia , Fator de Crescimento Transformador beta/metabolismo
10.
Bone ; 84: 169-180, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26769004

RESUMO

Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G>A; R206H) in the ACVR1-encoding gene which leads to dysregulated BMP signaling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression which indicates a strong contribution by environmental factors. Given the pro-inflammatory role of TGFß, we studied the role of TGFß in the progression of osteogenic differentiation in primary dermal fibroblasts from five classical FOP patients based on a novel method of platelet lysate-based osteogenic transdifferentiation. During the course of transdifferentiation the osteogenic properties of the cells were evaluated by the mRNA expression of Sp7/Osterix, Runx2, Alp, OC and the presence of mineralization. During transdifferentiation the expression of osteoblast markers Runx2 (p<0.05) and Alp were higher in patient cells compared to healthy controls. All cell lines exhibited increase in mineralisation. FOP fibroblasts also expressed higher baseline Sp7/Osterix levels (p<0.05) confirming their higher osteogenic potential. The pharmacological inhibition of TGFß signaling during osteogenic transdifferentiation resulted in the attenuation of osteogenic transdifferentiation in all cell lines as shown by the decrease in the expression of Runx2 (p<0.05), Alp and mineralization. We suggest that blocking of TGFß signaling can decrease the osteogenic transdifferentiation of FOP fibroblasts.


Assuntos
Transdiferenciação Celular , Modelos Biológicos , Miosite Ossificante/metabolismo , Miosite Ossificante/patologia , Osteogênese , Fator de Crescimento Transformador beta/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Adolescente , Adulto , Fosfatase Alcalina/metabolismo , Animais , Benzamidas/farmacologia , Plaquetas/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/genética , Transdiferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/genética , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Miosite Ossificante/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Pirazóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Smad/metabolismo , Adulto Jovem
11.
Ned Tijdschr Geneeskd ; 155: A3077, 2011.
Artigo em Holandês | MEDLINE | ID: mdl-21486510

RESUMO

Osteonecrosis of the jaw in association with long-term use of bisphosphonates (BRONJ) is a relatively rare but serious side effect that is difficult to treat. The incidence of BRONJ in patients treated for osteoporosis is low at 0.1%. The incidence in cancer patients treated with high doses of intravenous bisphosphonates is higher, ranging between 3% and 10%. Risk factors for BRONJ are invasive treatments such as tooth extractions, root canal procedures and the placement of dental implants, as well as trauma caused by pressure from poorly fitting dental prostheses. High-risk patients should be examined by a dentist or an oral surgeon and, if necessary, undergo dental treatment prior to treatment with bisphosphonates. All patients taking bisphosphonates should maintain good oral hygiene, receive regular dental examinations and see a dentist if any oral symptoms develop. Physicians who prescribe medication as well as the patient's dentist and oral surgeon should be aware of the use of bisphosphonates and BRONJ as a possible adverse reaction. This requires cooperation and the exchange of information between a patient's health care providers.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/induzido quimicamente , Osteonecrose/induzido quimicamente , Conservadores da Densidade Óssea/administração & dosagem , Odontologia , Difosfonatos/administração & dosagem , Humanos , Incidência , Comunicação Interdisciplinar , Doenças Maxilomandibulares/epidemiologia , Osteonecrose/epidemiologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Fatores de Risco
12.
Eur J Endocrinol ; 159 Suppl 1: S101-5, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18775977

RESUMO

In hypophosphatemic rickets, there are both inherited and acquired forms, where X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form and caused by mutations in the phosphate-regulating endopeptidase (PHEX) gene. XLH is associated with growth retardation and bone deformities. The renal tubular cells have an important role in calcium and phosphate metabolism, where the 1alpha-hydroxylase enzyme metabolizes the conversion of 25 (OH)-vitamin D to potent 1,25 (OH)2-vitamin D, whereas the sodium-phosphate transporter controls tubular phosphate reabsorption. The pathophysiological defect in XLH is speculated to cause an increase in a circulating phosphate regulating hormone termed phosphatonin (fibroblast growth factor 23 is the primary phosphatonin candidate), which leads to inhibition of 1alpha-hydroxylase, and simultaneously to inhibition of the sodium-phosphate transporter domain NPT2c leading to parathyroid hormone-independent phosphaturia. Hence, current treatment of XLH is 1,25 (OH)2-vitamin D or the vitamin D analog alfacalcidol and elementary phosphorus. Unfortunately, patients with XLH may develop nephrocalcinosis, secondary or tertiary hyperparathyroidism, and in some situations also hypertension and cardiovascular abnormalities. We describe a patient with XLH caused by a novel missense mutation in the PHEX gene, who on treatment with alfacalcidol and oral phosphate had normal growth and minimal bone deformities, but who subsequently developed moderate nephrocalcinosis, significant hyperparathyroidism, hypercalcemia, renal failure, and hypertension. We also report the use of the calcimimetic drug cinacalcet in the successful treatment of hypercalcemia and hyperparathyroidism.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X , Hipercalcemia/induzido quimicamente , Hipercalcemia/tratamento farmacológico , Hiperparatireoidismo/induzido quimicamente , Hiperparatireoidismo/tratamento farmacológico , Naftalenos/uso terapêutico , Administração Oral , Conservadores da Densidade Óssea/uso terapêutico , Cinacalcete , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Humanos , Hidroxicolecalciferóis/efeitos adversos , Hidroxicolecalciferóis/uso terapêutico , Hipertensão/induzido quimicamente , Lactente , Mutação de Sentido Incorreto , Nefrocalcinose/induzido quimicamente , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Fosfatos/uso terapêutico , Insuficiência Renal/induzido quimicamente
13.
Neuropsychopharmacology ; 31(7): 1508-18, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16292319

RESUMO

Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n=28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n=14) or placebo (n=14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z=3.9) and right inferior prefrontal cortex (Z=3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p=0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of context-dependency. The validity of these predictions can be tested in large-scale clinical trials.


Assuntos
Encéfalo , Antagonistas de Estrogênios/farmacologia , Imageamento por Ressonância Magnética , Rememoração Mental/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Idoso , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Mapeamento Encefálico , Método Duplo-Cego , Lateralidade Funcional/efeitos dos fármacos , Lateralidade Funcional/fisiologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Reconhecimento Visual de Modelos/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos
15.
Maturitas ; 51(3): 286-93, 2005 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-15978972

RESUMO

OBJECTIVE: In aging men serum levels of testosterone and insulin-like growth factor-1 (IGF-1) decline, potential factors in the reduced muscle strength, abdominal obesity, sexual dysfunction and impaired general well being of aging. The partial oestrogen agonist and antagonist raloxifene increase serum testosterone levels in aging men, but the effect of raloxifene on serum IGF-1 levels in men is unknown. In this study the effects of raloxifene on IGF-1 levels and the associated increase in serum testosterone were compared to the effects of oral testosterone supplementation. DESIGN AND PATIENTS: Thirty healthy elderly men between 60 and 70 years received raloxifene 120 mg/day or placebo in a randomised double blind fashion for 3 months. Secondly, seven female to male (F to M) transsexuals undergoing hormonal sex reassignment received testosterone undecanoate 160 mg/day. MEASUREMENT: At baseline and after three months serum levels of testosterone, IGF-1 and its most important binding protein, IFGBP-3 was measured. In the group transsexuals also serum gonadotrophins and 17beta-oestradiol was measured. RESULTS: Compared to placebo raloxifene increased serum testosterone by 20% but it decreased serum IGF-1 levels by 24.5% (95% confidence interval (CI): -13.0 to -36.1%). No significant change in serum IGFBP-3 levels was found. The effect of raloxifene on serum IGF-1 has been observed with other oral oestrogens, and, therefore, is likely to be ascribed to the partial oestrogen agonist activity of raloxifene. In the F to M transsexuals, serum testosterone levels increased from median <1.0 nmol/l to 6.2 nmol/l, without significant changes in serum gonadotrophins and 17beta-oestradiol levels. Serum IGF-1 levels increased by 12.1% (95% CI: 1.9-22.3%) versus baseline. No effect was observed on serum IGFBP-3 levels. CONCLUSION: Both raloxifene and oral testosterone increased serum testosterone, but raloxifene significantly decreased serum IGF-1 levels without affecting IGFBP-3. By contrast, oral testosterone supplementation in F to M transsexuals increased IGF-1 levels. In both treatment groups no significant change in serum IGFBP-3 was found.


Assuntos
Antagonistas de Estrogênios/farmacologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Testosterona/análogos & derivados , Testosterona/sangue , Administração Oral , Adolescente , Adulto , Idoso , Envelhecimento/fisiologia , Método Duplo-Cego , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cloridrato de Raloxifeno/administração & dosagem , Testosterona/administração & dosagem , Testosterona/biossíntese , Testosterona/farmacologia , Transexualidade/sangue , Transexualidade/tratamento farmacológico
16.
Blood Coagul Fibrinolysis ; 15(8): 649-55, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15613919

RESUMO

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n=17), 60 mg raloxifene (n=23), 150 mg raloxifene (n=20) or placebo (n=23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n=15) or placebo (n=15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P <0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.


Assuntos
Resistência à Proteína C Ativada/induzido quimicamente , Homocisteína/sangue , Pós-Menopausa/sangue , Cloridrato de Raloxifeno/efeitos adversos , Idoso , Método Duplo-Cego , Terapia de Reposição de Estrogênios , Estrogênios Conjugados (USP)/administração & dosagem , Fator V , Feminino , Humanos , Masculino , Acetato de Medroxiprogesterona/administração & dosagem , Pessoa de Meia-Idade , Placebos , Cloridrato de Raloxifeno/administração & dosagem
17.
Fertil Steril ; 82(2): 384-90, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15302288

RESUMO

OBJECTIVE: To assess and compare the effect of conjugated estrogen and of the selective estrogen receptor modulator raloxifene on serum levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) and on the IGF-I/IGFBP-3 ratio. DESIGN: A 2-year randomized, double-blind, placebo-controlled study. SETTING: Endocrinology outpatient department. PATIENT(S): Fifty-six postmenopausal, hysterectomized women. INTERVENTION(S): Women received raloxifene hydrochloride in doses of 60 mg/day (n = 15) or 150 mg/day (n = 13), conjugated equine estrogen (CEE) in doses of 0.625 mg/day (n = 15), or a placebo (n = 13) over the course of 2 years. MAIN OUTCOME MEASURE(S): At baseline and after 6, 12, and 24 months of treatment, serum levels of IGF-I, IGFBP-3, and insulin were measured, and an IGF-I/IFGBP-3 ratio was calculated. RESULT(S): Both raloxifene and CEE decreased serum IGF-I concentration. In contrast to CEE, which had no effect, both raloxifene doses of 60 and 150 mg/day significantly increased serum IGFBP-3 during the 2 years. Compared with placebo, the decrease in IGF-I/IGFBP-3 ratio was -32.5% (95% CI: -20.1; -44.8%) for CEE; -16.4% (95% CI: -3.6; -29.2%) for raloxifene at 150 mg/day; and -15.4% (95% CI: -1.0; -29.8%) for raloxifene at 60 mg/day. No effect of CEE or raloxifene was found on insulin concentration at any time point. CONCLUSION(S): Long-term use of both CEE and raloxifene decreases serum IGF-I and the IGF-I/IGFBP-3 ratio, but, unlike CEE, raloxifene produced a significant yet small increase in IGFBP-3.


Assuntos
Estrogênios Conjugados (USP)/farmacologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Cloridrato de Raloxifeno/farmacologia , Método Duplo-Cego , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacologia , Feminino , Humanos , Histerectomia , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Pessoa de Meia-Idade , Placebos , Pós-Menopausa , Fatores de Tempo
18.
Arch Intern Med ; 164(8): 871-9, 2004 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15111373

RESUMO

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Colesterol/sangue , Antagonistas de Estrogênios/farmacologia , Estrogênios Conjugados (USP)/farmacologia , Estrogênios/farmacologia , Lipídeos/sangue , Cloridrato de Raloxifeno/farmacologia , Fosfatase Alcalina/sangue , HDL-Colesterol/sangue , Colágeno/urina , Colágeno Tipo I , Método Duplo-Cego , Feminino , Humanos , Histerectomia , Lipoproteínas , Pessoa de Meia-Idade , Osteocalcina/sangue , Peptídeos/urina
19.
Eur J Endocrinol ; 150(4): 539-46, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15080785

RESUMO

OBJECTIVE: To explore effects on serum lipids, pituitary-gonadal axis, prostate and bone turnover of the administration of the mixed oestrogen agonist/antagonist raloxifene in healthy elderly men. PARTICIPANTS: Thirty healthy men aged 60-70 years randomly received raloxifene 120 mg/day (n=15) or placebo (n=15) for 3 months. MEASUREMENTS: In this double-blind, placebo-controlled study, serum gonadotrophins, sex hormones, prostate specific antigen (PSA), a marker of bone turnover, urinary hydroxyproline (OHPro) and cholesterol were measured at baseline and after 3 months. RESULTS: Raloxifene significantly increased serum concentrations of LH and FSH (by 29% and 21%), total testosterone (20%), free testosterone (16%) and bioavailable testosterone (not bound to sex hormone-binding globulin (SHBG; 20%). In parallel with testosterone, 17 beta-oestradiol also increased by 21%. SHBG increased by 7%. Total cholesterol (TChol) decreased significantly, from 5.7 to 5.5 mmol/l (P=0.03). Low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) showed a trend to decrease. Overall, there was no change in urinary OHPro/creatinine ratio as a marker for bone resorption. However, the raloxifene-induced increases in both serum testosterone and 17 beta-oestradiol were significantly related to a lower OHPro/creatinine ratio. Total PSA increased by 17% without significant changes in free PSA or free/total PSA ratio. Participants reported no side effects and raloxifene was well tolerated. CONCLUSION: In healthy elderly man, raloxifene 120 mg/day for 3 months increased LH, FSH and sex steroid hormones. Potentially beneficial effects were the small but significant decrease in TChol and the trend towards a decrease in LDL-c. Negative effects were the trend towards a decrease in HDL-c and the significant increase in serum PSA. A decrease in markers of bone resorption during raloxifene treatment was found only in men with relatively high increases in serum testosterone and 17 beta-oestradiol. Overall, there were no clear beneficial effects of administration of raloxifene to ageing men in this preliminary investigation.


Assuntos
Osso e Ossos/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Gonadotropinas/sangue , Cloridrato de Raloxifeno/administração & dosagem , Testosterona/sangue , Adulto , Idoso , Osso e Ossos/efeitos dos fármacos , Estradiol/sangue , Antagonistas de Estrogênios/efeitos adversos , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Cloridrato de Raloxifeno/efeitos adversos , Globulina de Ligação a Hormônio Sexual/metabolismo
20.
Fertil Steril ; 77(6): 1110-7, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12057714

RESUMO

OBJECTIVE: To evaluate the effect of the selective estrogen receptor modulator raloxifene hydrochloride (Evista, Eli Lilly and Company, Indianapolis, IN) on plasma levels of beta-endorphin, and to determine whether beta-endorphin levels and menopausal symptoms are related. DESIGN: A randomized, double-blind, placebo-controlled pilot study. SETTING: Endocrinology outpatient department. PATIENT(S): Forty postmenopausal women. INTERVENTION(S): The women received raloxifene, 60 mg/d, or placebo for 3 months. A questionnaire on climacteric symptoms was administered before and after treatment. MAIN OUTCOME MEASURE(S): Circulating levels of beta-endorphin, climacteric symptom score, and correlation with beta-endorphin levels. RESULT(S): Raloxifene treatment significantly increased levels of beta-endorphin and did not significantly affect climacteric symptoms, with the exception of worsening vasomotor symptoms. No significant relation was seen between plasma levels of beta-endorphin and climacteric symptoms. CONCLUSION(S): Raloxifene modulates plasma levels of beta-endorphin without concomitantly relieving climacteric symptoms, as seen with hormone replacement therapy.


Assuntos
Pós-Menopausa/sangue , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , beta-Endorfina/sangue , Idoso , Climatério/efeitos dos fármacos , Climatério/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Placebos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologia
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