RESUMO
Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.
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Conservadores da Densidade Óssea , Densidade Óssea , Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Fraturas por Osteoporose/prevenção & controle , Anabolizantes/uso terapêutico , Teriparatida/uso terapêutico , Análise Custo-BenefícioRESUMO
Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.
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Calcâneo , Fraturas Ósseas , Osteoporose , Adulto , Humanos , Densidade Óssea/genética , Estudo de Associação Genômica Ampla , Calcanhar , Fraturas Ósseas/genética , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Calcâneo/diagnóstico por imagem , Calcâneo/fisiologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular , Canais de Cálcio/genética , Proteínas Wnt/genéticaRESUMO
OBJECTIVES: Oestrogen deficiency is a rare disease and leads inter alia to arthralgia and osteoporosis in men. The clinical relevance of aromatase to a functioning male metabolism has become evident since 1991, when cases of patients with oestrogen deficiency caused by aromatase mutation were first described. Only few cases are known so far, which will now be presented in a case report and review of the literature. METHODS: All available publications since the first description in 1991 dealing with loss-of-function aromatase mutation in men were summarised and our case report was added. RESULTS: The mutations that cause the aromatase protein to lose function leads to a rather heterogeneous clinical picture. It is, however, clear that oestrogens play a central role in male patients, especially in bone metabolism. Most frequently, tall stature, unclosed epiphyseal joints, and osteoporosis are detected in affected individuals as a consequence of the change in hormonal status. CONCLUSIONS: As low oestrogen is associated with arthralgia, patients with aromatase mutation may be referred to a rheumatologist. Despite aromatase deficiency being a rare disease, the study of the effects of oestrogen on male bone development provides important insights for endocrine bone regulation. It has been demonstrated that androgens alone are not sufficient for adequate skeletal development in males. The described effects of loss of oestrogens are known from the aromatase inhibitor therapy in breast cancer treatment. This work highlights the important role of oestrogens in individual health and disease in men. Molecular effects of oestrogens on bone metabolism are summarised.
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Aromatase , Osteoporose , Humanos , Masculino , Aromatase/genética , Aromatase/metabolismo , Doenças Raras , Estrogênios , Osteoporose/tratamento farmacológico , Osteoporose/genética , MutaçãoRESUMO
CONTEXT: Hypoparathyroidism (hypoPT) is a rare endocrine disorder. Little is known about what factors are associated with potential quality of life (QOL) impairments. DESIGN: HypoPT patients at a minimum of 6 months' post diagnosis were invited to participate in an online survey through their treating physician or through self-help organisations METHODS: Impairments of clinical importance in QOL were considered present if the score of the respective functioning scale of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 exceeded a pre-defined threshold. Symptom burden was assessed using the HPQ-28. Multivariate logistic regression was used to identify factors associated with impairments in QOL. RESULTS: Data were available for 264 hypoPT patients. Impairments of clinical importance in QOL were reported for 40.4% in role functioning (RF), 40.6% in social functioning (SF), 60.8% in physical functioning (PF), 65.5% in cognitive functioning (CF) and 76.0% in emotional functioning (EF). Higher odds for reporting impaired QOL were seen for higher symptom burden (for almost all domains) and for being unable to work (for PF, RF and SF). Surgery for thyroid cancer being the cause of hypoPT was associated with lower odds in PF for patients and in PF and CF for patients with surgery for other thyroid-related diseases being the hypoPT cause. CONCLUSIONS: HypoPT needs to be recognised as a disease which might be associated with impaired QOL and affect daily living. Symptom management is crucial for improving QOL in hypoPT patients but socioeconomic factors like work-ability need to be considered when treating hypoPT patients.
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Hipoparatireoidismo , Neoplasias da Glândula Tireoide , Cognição , Humanos , Hipoparatireoidismo/etiologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
Indolent systemic mastocytosis (ISM) is a group of heterogenous diseases characterized by abnormal accumulation of mast cells in at least one organ. ISM can be a cause of osteoporosis. The aim of this study is to determine the prevalence, and the prognosis of ISM in a cohort of patients with osteoporosis. In this monocentric and retrospective study, patients with osteoporosis who did not receive a bone biopsy (cohort 1) and patients that subsequently received a diagnostic bone biopsy for differential diagnosis (cohort 2) are compared with patients who are diagnosed with ISM (cohort 3). A total of 8392 patients are diagnosed with osteoporosis. Out of these patients 1374 underwent a diagnostic bone biopsy resulting in 43 patients with ISM. These figures indicate that ISM is diagnosed in 0.5% of patients with osteoporosis and in 3.1% (men 5.8%) of patients who underwent bone biopsies. Patients with ISM sustained significantly more vertebral fractures in comparison to patients in cohort 2 (4.4 ± 3.6 versus 2.4 ± 2.5 vertebral fractures, p < 0.001) and women were significantly younger compared to cohort 2 (57.3 ± 12 versus 63.6 ± 12 years, p < 0.05). Only 33% showed an involvement of the skin (urticaria pigmentosa). ISM is a rare cause of osteoporosis (0.5%). However, in a subgroup of rather young male patients with osteoporosis the prevalence is more than 5%. Thus, ISM should be considered in premenopausal women and men presenting with vertebral fractures even if urticaria pigmentosa is not present.
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Mastocitose Sistêmica , Osteoporose , Estudos de Coortes , Feminino , Humanos , Masculino , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/epidemiologia , Osteoporose/epidemiologia , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND: In many cases primary hyperparathyroidism (PHPT) remains asymptomatic for years and is only detected by abnormalities in routine diagnostics. While symptomatic disease almost always requires surgical treatment, in symptom-free patients the question of whether and in what form treatment should be carried out is particularly important. OBJECTIVE: The aim of this review is to summarize the current recommendations regarding the diagnostics and treatment of asymptomatic PHPT, taking the existing evidence into account. RESULTS AND CONCLUSION: The diagnostics of asymptomatic PHPT is the same as for symptomatic disease. The diagnosis is made in the presence of elevated parathyroid hormone and balanced vitamin D levels when a combination of hypercalcemia, hypophosphatemia and hypercalciuria is present. Borderline laboratory findings occur especially in asymptomatic PHPT and the differential diagnosis of familial hypocalciuric hypercalcemia must be considered. Once the diagnosis is made sonography, radiography or computed tomography (CT) is used to search for nephrolithiasis or nephrocalcinosis. Regarding bone mineral density (BMD) measurements, in addition to routine measurements at the lumbar spine and femur, measurement at the distal radius is important as it is the most sensitive site for detecting osteoporosis in PHPT. An indication for parathyroidectomy is confirmed in the case of hypercalcemia >â¯1.0â¯mg/dl (>0.25â¯mmol/l) above the upper limit of normal, hypercalciuria >â¯400â¯mg/day (>10â¯mmol/day), renal insufficiency, proven osteoporosis or age <â¯50 years. If none of these criteria are fulfilled and surgery is not desired by the patient, annual laboratory check-ups and assessment of BMD every 1-2 years are recommended.
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Hipercalcemia , Hiperparatireoidismo Primário , Osteoporose , Densidade Óssea , Cálcio , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/cirurgia , Pessoa de Meia-Idade , ParatireoidectomiaRESUMO
OBJECTIVE: To address knowledge gaps regarding burdens associated with not adequately controlled chronic hypoparathyroidism. DESIGN: Global patient and caregiver survey. STUDY POPULATIONS: Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy and their caregivers. MEASUREMENTS: Health-related quality of life (HRQoL) and health status were evaluated using the 36-item Short Form version 2 (SF-36 v2.0) and Five-Level EuroQoL 5 Dimensions (EQ-5D-5L) instruments, respectively. Hypoparathyroidism-associated symptoms were assessed by a disease-specific Hypoparathyroidism Symptom Diary and caregiver burden via the Modified Caregiver Strain Index (MCSI). RESULTS: Data were obtained from 398 patients and 207 caregivers. Patients' self-rated hypoparathyroidism-related symptom severity was none (3%), mild (32%), moderate (53%) or severe (12%). Per the Hypoparathyroidism Symptom Diary, patients reported moderate, severe or very severe symptoms of physical fatigue (73%), muscle cramps (55%), heaviness in limbs (55%) and tingling (51%) over a 7-day recall period. Impacts (rated 'somewhat' or 'very much') were reported by 84% of patients for ability to exercise, 78% for sleep, 75% for ability to work and 63% for family relationships. Inverse relationships were observed between patient self-rated overall symptom severity and HRQoL and health status assessment scores-the greater the symptom severity, the lower the SF-36 and EQ-5D-5L scores. Caregiver burden increased with patient self-rated symptom severity: none, 1.7 MCSI; mild, 5.4 MCSI; moderate, 9.5 MCSI; and severe, 12.5 MCSI. CONCLUSION: Patients with not adequately controlled hypoparathyroidism reported substantial symptoms and impacts. Greater patient symptom severity was associated with decreased patient HRQoL and health status assessments and increased caregiver burden.
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Cuidadores , Efeitos Psicossociais da Doença , Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/terapia , Qualidade de Vida , Adulto , Idoso , Sobrecarga do Cuidador/epidemiologia , Sobrecarga do Cuidador/etiologia , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Doença Crônica , Feminino , Nível de Saúde , Humanos , Hipoparatireoidismo/sangue , Hipoparatireoidismo/psicologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Inquéritos e QuestionáriosRESUMO
In September 2023, the guideline on the prophylaxis, diagnosis, and treatment of osteoporosis in postmenopausal women and men was published as a completely revised guideline. The implications for practice include a change in the justifying indication for performing a bone density measurement, the time interval over which the fracture risk is determined, the level and number of therapy thresholds, and the recommendations for the therapeutic approach that are adapted to the individual fracture risk present. Risk assessment for the prediction of spine and hip fractures is essential in the context of osteoporosis diagnostics. In addition to age and gender, there are a total of 33 risk factors to determine the individual risk of fracture. Much more attention is paid to the assessment of the risk of falls and, depending on the result, combined with recommendations for muscle training and protein intake from the age of 65. Risk indicators must also be taken into account when determining the indication for osteoporosis diagnosis, as well as the risk factors of the imminent risk of fracture. The indication for baseline diagnostics has changed from the >20% 10-year fracture risk to diagnostics in postmenopausal women and in men aged 50 years and older, depending on the fracture risk factor profile. This eliminates a specific fracture risk threshold for basic diagnostics. Thus, in the young patient group (50-60 years), the risk factors considered medically relevant for the indication for osteoporosis diagnosis must be taken into account. New thresholds as an indication for initiating therapy is the determination of fracture risk using a risk calculator over 3 years instead of 10 years. The indication for drug therapy should be based on the threshold values of the DVO risk model. The data clearly suggests a significantly faster and more effective fracture risk-reducing effect of anabolic therapy. This is recommended in the first sequence in cases of a very high risk of fracture from 10%/3 years with osteoanabolic active substances (teriparatide or romosozumab). Such a therapy sequence should be initiated directly and not delayed due to upcoming dental procedures. Follow-up therapy to consolidate the reduction of fracture risk should be chosen individually.
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Densidade Óssea , Osteoporose , Guias de Prática Clínica como Assunto , Humanos , Osteoporose/terapia , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Medição de Risco , Fraturas por Osteoporose/prevenção & controle , Conservadores da Densidade Óssea/uso terapêuticoRESUMO
Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
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Osteoclastos , Osteopetrose , Osteopetrose/genética , Osteopetrose/patologia , Humanos , Osteoclastos/patologia , Adulto , Canais de Cloreto/genética , MutaçãoRESUMO
PURPOSE: To investigate the quality of life (QoL) in patients with hypoparathyroidism (hypoPT) compared to the general population and to identify sociodemographic and clinical factors that are associated with symptom burden. METHODS: Patients with a diagnosis of hypoPT participated in an online survey. Information regarding the survey was distributed by treating physicians or a self-help organization. Quality of life was assessed using the EORTC QLQ-C30 and symptom burden using the Hypoparathyroid Patient Questionnaire (HPQ28). Multivariate linear regression analysis was used to compare QoL of hypoPT patients with the general population (adjusted for age, sex, education)and to identify factors associated with symptom burden. RESULTS: Altogether, 264 hypoPT patients provided information on QoL and symptom burden. HypoPT was associated with worse cognitive (ß = -15.9; p < 0.01) and emotional functioning (ß = -12.3; p = 0.04) compared to the general population. The highest symptom burden in hypoPT patients was observed for the domains loss of vitality (mean: 61.4; SD: 21.9), pain and cramps (mean: 43.7; SD: 26.5), and numbness and tingling sensations (mean: 38.9; SD: 30.0). Female gender was associated with a higher symptom burden across all nine domains of the HPQ28, while longer disease duration was associated with a lower symptom burden in neurovegetative symptoms, loss of vitality, depression and anxiety, and depressive symptoms. CONCLUSION: HypoPT patients have impaired QoL compared to the general population. Being female is strongly associated with high symptom burden.
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Hipoparatireoidismo , Qualidade de Vida , Humanos , Feminino , Masculino , Qualidade de Vida/psicologia , Hipoparatireoidismo/epidemiologia , Inquéritos e Questionários , Dor , Ansiedade/epidemiologiaRESUMO
Background: Klinefelter syndrome (KS) may be associated with a wide spectrum of phenotypic changes including endocrine, metabolic, cognitive, psychiatric and cardiorespiratory pathologies in adults. However, in adolescence the clinical phenotype of KS is not well described, especially regarding physical fitness. The present study reports on cardiorespiratory function in adolescents and young adults with KS. Methods: Adolescents and young adults with KS were recruited in a cross-sectional pilot study. Biochemical parameters of fitness including hormonal status, a body impedance analysis, the grip strength, the amount of physical activity at home for 5 days via trackbands and anamnestic parameters were assessed. In addition, participants underwent an incremental symptom-limited cardiopulmonary exercise test (CPET) on a bicycle ergometer. Results: Nineteen participants with KS aged 15.90 ± 4.12 years (range: 9.00 - 25.00) participated in the study. Pubertal status was Tanner 1 (n = 2), Tanner 2 - 4 (n = 7) and Tanner 5 (n = 10). Seven participants received testosterone replacement therapy. Mean BMI z-score was 0.45 ± 1.36 and mean fat mass was 22.93% ± 9.09. Grip strength was age-appropriate or above normal. 18 participants underwent CPET with subnormal results for maximum heart rate (z-score -2.84 ± 2.04); maximum workload (Wattmax; z score -1.28 ± 1.15) and maximum oxygen uptake per minute (z- score -2.25 ± 2.46). Eight participants (42.1%) met the criteria for chronotropic insufficiency (CI). Data from track-bands showed sedentary behavior for 81.15% ± 6.72 of the wear time. Conclusion: A substantial impairment of cardiopulmonary function can be detected in this group of boys to young adults with KS, including chronotropic insufficiency in 40%. The track-band data suggest a predominantly sedentary lifestyle, despite normal muscular strength as assessed via grip strength. Future studies need to investigate the cardiorespiratory system and its adaption to physical stress in a larger cohort and in more detail. It is feasible that the observed impairments contribute to the avoidance of sports in individuals with KS and may contribute to the development of obesity and the unfavorable metabolic phenotype.
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Aptidão Cardiorrespiratória , Síndrome de Klinefelter , Humanos , Projetos Piloto , Consumo de Oxigênio , Estudos Transversais , OxigênioRESUMO
PURPOSE: Hypoparathyriodism (hypoPT) is a rare endocrine disorder. It is not known how hypoPT is managed in Germany or whether patients have unmet information needs or impairments in their daily living. METHODS: HypoPT patients at a minimum of 6 months' post-diagnosis were invited to participate in an online survey through their treating physician or through patient organizations. An extensive questionnaire, which was developed and pilot-tested with hypoPT patients, was administered. RESULTS: A total of 264 patients with a mean age of 54.5 years (SD: 13.3), 85.2% female and 92% with postsurgical hypoPT, participated in the study. In total, 74% of the patients reported regular monitoring of serum calcium at least every 6 months, with lower control frequencies for phosphate (47%), magnesium (36%), creatinine (54%), and parathyroid hormone (50%), and 24-h urine calcium excretion (36%) on a yearly basis. Information on symptoms of hypo- and hypercalcemia was available in 72 and 45% of the patients. Information needs were related to the disease and its treatment as well as to nutrition, physical activities/sports, and support opportunities. Statistically significant differences for all information needs in association with symptom burden were observed. Hospitalization for hypocalcemia was reported by 32%, nutritional impairments (38%) or impact on work ability (52%) was available among patients with hypoPT. CONCLUSION: HypoPT patients experience impairments in daily living and report unmet information needs. Patient and physician education regarding hypoPT is one of the key concepts for improving the management of patients with hypoPT.
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Cálcio , Hipoparatireoidismo , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Complicações Pós-Operatórias , Hipoparatireoidismo/epidemiologia , Hipoparatireoidismo/terapia , Hormônio Paratireóideo , Gestão da InformaçãoRESUMO
Hypercalcemia as a laboratory result is often diagnosed during evaluation for osteoporosis. Any form of hypercalcemia should be evaluated further. Owing to fluctuating calcium levels, the measurement should be repeated and corrected for elevated albumin levels by calculation or by measuring ionized calcium. In the diagnosis of primary hyperparathyroidism, measurement of parathyroid hormone, creatinine/glomerular filtration rate, phosphate, 25-OH vitamin D3 and 24-hour urine values are essential for differential diagnosis. Kidney ultrasound is used to detect nephrocalcinosis or kidney stones, and dual-energy X-ray absorptiometry (DXA) to determine bone mineral density (BMD) at the lumbar spine, femoral neck, total femur, and distal forearm. Complete cure is only possible through surgical resection of the adenoma(s). The indication for surgery is dependent on the age of the patient, existing complications, and the patient's preference. Diagnostic imaging should only be performed if surgery is planned. Typically, neck ultrasound and 99mTc MIBI scintigraphy are sufficient to localize the parathyroid adenoma. Presurgical diagnostic evaluation of the thyroid is reasonable for surgical planning. Vitamin-D deficiency should be normalized before surgery. Postsurgical calcium and vitamin-D administration will prevent postsurgical hypocalcemia and hungry-bone disease, and may optimize the outcome of BMD. Treatment of osteoporosis without fractures might not be necessary, owing to normalization of BMD several years after parathyroid surgery. The continuation of specific anti-osteoporotic treatment with bisphosphonates post-surgery did not have any advantage and hence cannot be recommended.
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Hipercalcemia , Osteoporose , Absorciometria de Fóton/efeitos adversos , Densidade Óssea , Cálcio , Colo do Fêmur , Humanos , Hipercalcemia/diagnóstico , Hormônio Paratireóideo , VitaminasRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a common yet little recognized health problem in women with polycystic ovary syndrome (PCOS). In a retrospective setting, we investigated the effects of metformin treatment on the hepatic steatosis index (HSI) as a readily available biomarker panel for NAFLD. HSI values of >36 are considered to be highly suggestive for NAFLD. In our cohort, HSI values indicating NAFLD were found in 60/81 (74.1%) women at baseline. The mean HSI improved significantly after the metformin treatment from 43.2 ± 1.0 to 41.0 ± 1.1. Subgroup analyses of non-obese (body mass index (BMI) < 30 kg/m2), obese (BMI 30−35 kg/m2) and very obese (BMI > 35 kg/m2) women yielded mean baseline HSI values of 35.5 ± 4.5, 41.2 ± 2.7 and 51.2 ± 4.7, respectively. A significant improvement in the HSI of 1.5 ± 2.1 was observed after metformin treatment in non-obese women but not in the obese subgroups. The data suggest a new aspect of metformin treatment in non-obese PCOS patients, namely, a possible improvement in NAFLD. This study highlighted hepatic steatosis as a common comorbidity in PCOS patients that can severely affect their long-term health, and therefore, deserves more attention in the management of PCOS patients.
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Exogenous glucocorticoids increase the risk for osteoporosis, but the role of endogenous glucocorticoids remains elusive. Here, we describe the generation and validation of a loss- and a gain-of-function model of the cortisol producing enzyme 11ß-HSD1 (HSD11B1) to modulate the endogenous glucocorticoid conversion in SCP-1 cells - a model for human mesenchymal stem cells capable of adipogenic and osteogenic differentiation. CRISPR-Cas9 was successfully used to generate a cell line carrying a single base duplication and a 5 bp deletion in exon 5, leading to missense amino acid sequences after codon 146. These inactivating genomic alterations were validated by deep sequencing and by cloning with subsequent capillary sequencing. 11ß-HSD1 protein levels were reduced by 70% in the knockout cells and cortisol production was not detectable. Targeted chromosomal integration was used to stably overexpress HSD11B1. Compared to wildtype cells, HSD11B1 overexpression resulted in a 7.9-fold increase in HSD11B1 mRNA expression, a 5-fold increase in 11ß-HSD1 protein expression and 3.3-fold increase in extracellular cortisol levels under adipogenic differentiation. The generated cells were used to address the effects of 11ß-HSD1 expression on adipogenic and osteogenic differentiation. Compared to the wildtype, HSD11B1 overexpression led to a 3.7-fold increase in mRNA expression of lipoprotein lipase (LPL) and 2.5-fold increase in lipid production under adipogenic differentiation. Under osteogenic differentiation, HSD11B1 knockout led to enhanced alkaline phosphatase (ALP) activity and mRNA expression, and HSD11B1 overexpression resulted in a 4.6-fold and 11.7-fold increase in mRNA expression of Dickkopf-related protein 1 (DKK1) and LPL, respectively. Here we describe a HSD11B1 loss- and gain-of-function model in SCP-1 cells at genetic, molecular and functional levels. We used these models to study the effects of endogenous cortisol production on mesenchymal stem cell differentiation and demonstrate an 11ß-HSD1 dependent switch from osteogenic to adipogenic differentiation. These results might help to better understand the role of endogenous cortisol production in osteoporosis on a molecular and cellular level.
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Quality of life (QoL) is impaired in patients with chronic hypoparathyroidism (HypoPT). With a recently developed specific patient questionnaire, the 28-item Hypoparathyroid Patient Questionnaire (HPQ 28), we were able to demonstrate an effect of laboratory parameters on symptoms and complaints identified by scales and items of the HPQ 28. Here, we evaluated the effect of conventional treatment modalities on QoL using this specific questionnaire. In this cross-sectional study, we included 49 HypoPT (41 female and 8 male) patients. Laboratory values of total serum calcium, magnesium, phosphate, calcium-phosphate product (CPP), and 24-hour urine for calcium and phosphate were analyzed. Patients completed the HPQ 28 questionnaire during the corresponding visit. Mean age was 57.3 ± 10.5 years and duration of disease 12.6 ± 9.8 years. Most patients (86%, n = 42) were treated with the active vitamin D analogs calcitriol, alfacalcidol, or dihydrotachysterol (DHT). The use of calcium and magnesium supplements influenced scales on HPQ 28 in a dose-dependent manner. We detected a dose-dependent increase on the HPQ 28 scales "depression and anxiety" and "pain and cramps," and the item "numbness and tingling" related to calcitriol. This effect was independent of gender, age, underlying disease, kind of surgery, serum 25-hydroxyvitamin D3, calcium, or phosphate values. This study presents the first data on specific symptoms of HypoPT patients dependent on different treatment modalities. Our data suggest that in part the reduced QoL in these patients might be caused by conventional treatment. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Osteomalacia , Adolescente , Adulto , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Osteomalacia/tratamento farmacológico , Fosfatos , Qualidade de VidaRESUMO
Chronic hypoparathyroidism (HypoPT) is associated with significant morbidity and impaired quality of life (QoL). The goals of management for chronic HypoPT include improvement in QoL and the prevention of both hypo- and hypercalcemia symptoms and long-term complications. Several groups have provided consensus statements and guidelines on the management of HypoPT; however, due to limited evidence, these recommendations have largely been based on literature reviews, expert opinion, and consensus statements. The objective of this study was to use a systematic approach to describe current practice for the initial assessment and follow-up of patients with chronic HypoPT. We developed a survey asking experts in the field to select the responses that best reflect their current practice. The survey found no differences in responses between nonsurgical and postsurgical patient assessment. For new patients, respondents usually performed an assessment of serum lab profile (calcium [either albumin-adjusted or ionized], magnesium, creatinine, phosphate, 25-hydroxyvitamin D), 24-hour urine (creatinine, calcium), and a renal ultrasound to evaluate for the presence of nephrocalcinosis or nephrolithiasis. For follow-up patients, most respondents perform blood tests and urine tests every 6 months or less frequently. The reported clinical practice patterns for monitoring for complications of chronic HypoPT vary considerably among respondents. Based on the responses in this systematic expert practice survey, we provide practice suggestions for initial assessment and follow-up of patients with chronic HypoPT. In addition, we highlight areas with significant variation in practice and identify important areas for future research. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Hipoparatireoidismo , Qualidade de Vida , Humanos , Cálcio , Creatinina , Hipoparatireoidismo/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta-analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Cálcio , Hipoparatireoidismo , Feminino , Humanos , Cálcio da Dieta , Hipoparatireoidismo/tratamento farmacológico , Hormônio Paratireóideo , Qualidade de Vida , Vitamina D , Guias de Prática Clínica como AssuntoRESUMO
This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.