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BACKGROUND: Romosozumab, a fully humanized anti-sclerostin-antibody, is a bone-builder stimulating osteoblasts and inhibiting osteoclast by activation of the canonical Wnt-beta catenin signaling. This unique mechanism of action has the potential to address unmet needs in osteoporosis management. METHODS: The multifaceted practical clinical issues related to romosozumab are discussed, especially focusing on the rationale of employing a sclerostin inhibitor to target bone fragility as first line or second line treatment in post-menopausal osteoporosis and in males at increased risk of fractures. RESULTS: Four randomized clinical trials with several post-hoc analyses and more than ten observational studies have consistently demonstrated that romosozumab is effective in rapidly increasing bone mineral density (BMD) and decreasing risk of vertebral, non-vertebral and hip fractures in post-menopausal women at very-high risk of fractures. In male osteoporosis, only data on BMD are available. Noteworthy, romosozumab was shown to be more effective and rapid than teriparatide in improving BMD, bone structure and strength at the hip, especially in women already treated with anti-resorptive drugs. Interestingly, even if romosozumab displays best results in treatment-naïve patients, its favourable effects on BMD were observed even in women previously treated with teriparatide or denosumab, although to a lesser extent. CONCLUSIONS: Based on the available evidence, romosozumab could be proposed as ideal drug in several clinical settings, such as non-fractured post-menopausal women at very-high risk of fractures, patients with recent hip fracture, patients non responder to bisphosphonates and short-term denosumab therapy.
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PURPOSE: Since vertebral fragility fractures (VFFs) might increase the risk of subsequent fractures, we evaluated the incidence rate and the refracture risk of subsequent vertebral and non-vertebral fragility fractures (nVFFs) in untreated patients with a previous VFF. METHODS: We systematically searched PubMed, Embase, and Cochrane Library up to February 2022 for randomized clinical trials (RCTs) that analyzed the occurrence of subsequent fractures in untreated patients with prior VFFs. Two authors independently extracted data and appraised the risk of bias in the selected studies. Primary outcomes were subsequent VFFs, while secondary outcomes were further nVFFs. The outcome of refracture within ≥ 2 years after the index fracture was measured as (i) rate, expressed per 100 person-years (PYs), and (ii) risk, expressed in percentage. RESULTS: Forty RCTs met our inclusion criteria, ranging from medium to high quality. Among untreated patients with prior VFFs, the rate of subsequent VFFs and nVFFs was 12 [95% confidence interval (CI) 9-16] and 6 (95% CI 5-8%) per 100 PYs, respectively. The higher the number of previous VFFs, the higher the incidence. Moreover, the risk of VFFs and nVFFs increased within 2 (16.6% and 8%) and 4 years (35.1% and 17.4%) based on the index VFF. CONCLUSION: The highest risk of subsequent VFFs or nVFFs was already detected within 2 years following the initial VFF. Thus, prompt interventions should be designed to improve the detection and treatment of VFFs, aiming to reduce the risk of future FFs and properly implement secondary preventive measures.
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Fraturas Ósseas , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fraturas da Coluna Vertebral/etiologia , Coluna VertebralRESUMO
INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.
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Osteíte Deformante , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/terapia , Osteíte Deformante/epidemiologia , Osteíte Deformante/tratamento farmacológico , Itália/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Sociedades Médicas/normas , Difosfonatos/uso terapêuticoRESUMO
PURPOSE: Bone is one of the main targets of hormones and endocrine diseases are frequent causes of secondary osteoporosis and fractures in real-world clinical practice. However, diagnosis of skeletal fragility and prediction of fractures in this setting could be a challenge, since the skeletal alterations induced by endocrine disorders are not generally captured by dual-energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD), that is the gold standard for diagnosis of osteoporosis in the general population. The aim of this paper is to review the existing evidence related to bone quality features in endocrine diseases, proposing assessment with new techniques in the future. METHODS: A comprehensive search within electronic databases was performed to collect reports of bone quality in primary hyperparathyroidism, hypoparathyroidism, hyperthyroidism, hypercortisolism, growth hormone deficiency, acromegaly, male hypogonadism and diabetes mellitus. RESULTS: Using invasive and non-invasive techniques, such as high-resolution peripheral quantitative computed tomography or DXA measurement of trabecular bone score (TBS), several studies consistently reported altered bone quality as predominant determinant of fragility fractures in subjects affected by chronic endocrine disorders. CONCLUSIONS: Assessment of skeletal fragility in endocrine diseases might take advantage from the use of techniques to detect perturbation in bone architecture with the aim of best identifying patients at high risk of fractures.
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Acromegalia , Osteoporose , Fraturas por Osteoporose , Humanos , Masculino , Fraturas por Osteoporose/epidemiologia , Relevância Clínica , Osteoporose/complicações , Osso e Ossos , Densidade Óssea , Absorciometria de Fóton/métodos , Acromegalia/complicações , Vértebras LombaresRESUMO
PURPOSE: Preventing fragility fractures by treating osteoporosis may reduce disability and mortality worldwide. Algorithms combining clinical risk factors with bone mineral density have been developed to better estimate fracture risk and possible treatment thresholds. This systematic review supported panel members of the Italian Fragility Fracture Guidelines in recommending the use of best-performant tool. The clinical performance of the three most used fracture risk assessment tools (DeFRA, FRAX, and FRA-HS) was assessed in at-risk patients. METHODS: PubMed, Embase, and Cochrane Library were searched till December 2020 for studies investigating risk assessment tools for predicting major osteoporotic or hip fractures in patients with osteoporosis or fragility fractures. Sensitivity (Sn), specificity (Sp), and areas under the curve (AUCs) were evaluated for all tools at different thresholds. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2; certainty of evidence (CoE) was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Forty-three articles were considered (40, 1, and 2 for FRAX, FRA-HS, and DeFRA, respectively), with the CoE ranging from very low to high quality. A reduction of Sn and increase of Sp for major osteoporotic fractures were observed among women and the entire population with cut-off augmentation. No significant differences were found on comparing FRAX to DeFRA in women (AUC 59-88% vs. 74%) and diabetics (AUC 73% vs. 89%). FRAX demonstrated non-significantly better discriminatory power than FRA-HS among men. CONCLUSION: The task force formulated appropriate recommendations on the use of any fracture risk assessment tools in patients with or at risk of fragility fractures, since no statistically significant differences emerged across different prediction tools.
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Osteoporose , Fraturas por Osteoporose , Masculino , Humanos , Feminino , Osteoporose/diagnóstico , Fraturas por Osteoporose/diagnóstico , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Densidade Óssea , Fatores de Risco , Medição de RiscoRESUMO
BACKGROUND: Hypoparathyroidism (HypoP) is a rare endocrine condition characterized by hypocalcaemia and hyperphosphatemia, as a consequence of absent or improperly low parathyroid hormone (PTH) levels. Patients affected by HypoP have a clinical condition often characterized by paresthesias and muscle spasms, as well as long-term consequences as nephrolithiasis, extraskeletal calcification, and fractures. In the literature, likely due to these symptoms, few data exist regarding the appropriate physical activity (PA) in subjects suffering from HypoP. PURPOSE: This review evaluates the literature on exercise-based approaches to the management of individuals affected by HypoP and evaluates: (1) the effects of physical exercise on muscle cramps and other clinical symptoms; (2) the effects of exercise on PTH and calcium level; (3) the most suitable clinical exercise testing; and (4) the most suitable exercise combination. METHODS AND RESULTS: A systematic search was conducted using the databases MEDLINE, Google Scholar using "hypoparathyroidism AND Physical Activity", "Training AND hypoparathyroidism", "Exercise AND muscle cramps", "Exercise AND Fatigue" as keywords. In addition, references list from the included articles were searched and cross-checked to identify any further potentially eligible studies. A total of 50 manuscripts were found among which 39 manuscripts were selected. A few clinical studies have been performed in HypoP patients to evaluate PA training protocols. CONCLUSION: Although further research is needed to draw solid conclusions regarding best PA protocols in subjects affected by HypoP, a PA protocol has been proposed within the manuscript to encourage patients to attempt exercise to improve their clinical conditions and their quality of life.
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Hipoparatireoidismo , Hormônio Paratireóideo , Exercício Físico , Humanos , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/terapia , Cãibra Muscular , Qualidade de VidaRESUMO
PURPOSE: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar®) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. METHODS: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations. RESULTS: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described. CONCLUSIONS: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.
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Cálcio , Hipoparatireoidismo , Adulto , Humanos , Hormônio Paratireóideo , Fosfatos/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
We analyzed polymorphism of the ALPL gene in patients with low serum levels of tissue-nonspecific alkaline phosphatase (TNAP). The presence of three or more of the less frequent alleles of ALPL polymorphisms was associated with significantly lower TNAP serum level and higher frequencies of metatarsal fractures, which may help confirm a clinical suspicion of adult hypophosphatasia. INTRODUCTION: Alkaline phosphatases (ALPs) are membrane-bound enzymes that hydrolyze monophosphate esters at a high pH (pH 8-10). Inorganic pyrophosphate, pyridoxal 5-phosphate, the activated form of vitamin B6 (PLP), and phosphoethanolamine (PEA), are natural substrates of ALPs. Hypophosphatasia (HPP, OMIM 146300, 241500, 241510) is a heterogeneous rare metabolic bone disease caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL; MIM 171760) with a deficiency of TNAP. Clinical presentation of HPP in adults demonstrated a wide range of manifestations, many of which are nonspecific. In the present study, we screened the polymorphic genetic variants of ALPL in 56 subjects presenting low serum levels of TNAP and/or other clinical signs of adult HPP in order to evaluate a possible role of polymorphic variants in the diagnosis and management of HPP in adults. METHODS: Genomic DNA was extracted from peripheral blood and ALPL gene was sequenced by PCR-based Sanger technique. RESULTS: Fourteen different polymorphic variants were found in the study population. A lower serum level of TNAP and higher frequencies of metatarsal fractures were observed in patients bearing three or more of the minor frequency alleles (MFAs) of the ALPL polymorphic variants. The presence of some MFAs, mostly as a contemporary presence of three or more of them, was found to be mainly represented in patients having both a significantly lower level of TNAP and a higher level of vitamin B6. CONCLUSION: The genetic analysis and presence of some polymorphic variants may be an instrument to confirm clinical and biochemical data, consider adult HPP, and help clinicians be cautious in the administration of anti-reabsorption drugs.
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Hipofosfatasia , Adulto , Fosfatase Alcalina/genética , Alelos , Humanos , Hipofosfatasia/genética , Mutação , Fosfato de PiridoxalRESUMO
An innovative, non-ionizing technique to diagnose osteoporosis on lumbar spine and femoral neck was evaluated through a multicenter study involving 1914 women. The proposed method showed significant agreement with reference gold standard method and, therefore, a potential for early osteoporosis diagnoses and possibly improved patient management. INTRODUCTION: To assess precision (i.e., short term intra-operator precision) and diagnostic accuracy of an innovative non-ionizing technique, REMS (Radiofrequency Echographic Multi Spectrometry), in comparison with the clinical gold standard reference DXA (dual X-ray absorptiometry), through an observational multicenter clinical study. METHODS: In a multicenter cross-sectional observational study, a total of 1914 postmenopausal women (51-70 years) underwent spinal (n = 1553) and/or femoral (n = 1637) DXA, according to their medical prescription, and echographic scan of the same anatomical sites performed with the REMS approach. All the medical reports (DXA and REMS) were carefully checked to identify possible errors that could have caused inaccurate measurements: erroneous REMS reports were excluded, whereas erroneous DXA reports were re-analyzed where possible and otherwise excluded before assessing REMS accuracy. REMS precision was independently assessed. RESULTS: In the spinal group, quality assessment on medical reports produced the exclusion of 280 patients because of REMS errors and 78 patients because of DXA errors, whereas 296 DXA reports were re-analyzed and corrected. Analogously, in the femoral group there were 205 exclusions for REMS errors, 59 exclusions for DXA errors, and 217 re-analyzed DXA reports. In the resulting dataset (n = 1195 for spine, n = 1373 for femur) REMS outcome showed a good agreement with DXA: the average difference in bone mineral density (BMD, bias ± 2SD) was -0.004 ± 0.088 g/cm2 for spine and - 0.006 ± 0.076 g/cm2 for femur. Linear regression showed also that the two methods were well correlated: standard error of the estimate (SEE) was 5.3% for spine and 5.8% for femur. REMS precision, expressed as RMS-CV, was 0.38% for spine and 0.32% for femur. CONCLUSIONS: The REMS approach can be used for non-ionizing osteoporosis diagnosis directly on lumbar spine and femoral neck with a good level of accuracy and precision. However, a more rigorous operator training is needed to limit the erroneous acquisitions and to ensure the full clinical practicability.
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Colo do Fêmur/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Osteoporose Pós-Menopausa/diagnóstico por imagem , Absorciometria de Fóton/métodos , Idoso , Densidade Óssea/fisiologia , Estudos Transversais , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Reprodutibilidade dos Testes , Ultrassonografia/métodosRESUMO
PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13 years), the remaining 38 (6.3%, age 41 ± 17 years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.
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Cálcio/sangue , Hiperparatireoidismo Primário/diagnóstico , Glândulas Paratireoides/diagnóstico por imagem , Hormônio Paratireóideo/sangue , Idoso , Feminino , Seguimentos , Humanos , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/cirurgia , Itália , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/cirurgia , Paratireoidectomia , Estudos Prospectivos , UltrassonografiaRESUMO
This study investigates the relationship between cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality among 514 hip fracture hospitalized older persons. Patients with early cognitive dysfunction or delirium experienced a 2-fold increased mortality risk. Early post-operative cognitive dysfunction and delirium are negative prognostic factors for mortality. BACKGROUND AND PURPOSE: Premorbid cognitive impairment and dementia in older individuals negatively affect functional recovery after hip fracture. Additionally, post-operative delirium is an established risk factor for negative outcomes among hip fracture patients. While the majority of hip fracture patients experience minor post-surgical cognitive dysfunction, the prognostic value of this phenomenon is unknown. Therefore, we investigated the relationship between minor cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality after index hip fracture. SUBJECTS AND METHODS: We enrolled 514 patients with hip fracture (77.4 % women), aged 65 years or older (mean age 83.1 ± 7.3 years), who underwent surgical hip fracture repair. Patients were assessed daily from the second to the fourth post-operative day and at 3, 6, and 12 months thereafter. All participants underwent comprehensive assessment, including detection of delirium by using the confusion assessment method and evaluation of cognitive function by using mini-mental state examination (MMSE; score range 0 to 30, with lower scores indicating poorer performance). In the absence of delirium, post-surgical cognitive dysfunction was defined as having low performance on MMSE. Vital status of 1 year after the index fracture and date of death were gathered from local registries. RESULTS: The observed 1-year mortality rate was 14.8 %. Men were more likely to die than women within 1 year of the index fracture (p < 0.01). Compared to participants with better cognitive performance, those with MMSE < 24, as well as those with delirium in the post-operative phase, showed a significantly higher 1-year mortality rate (23.3 versus 17.9 and 8.1 %, respectively). Independent of age and sex, post-operative cognitive dysfunction as well as delirium was both associated with a 2-fold increased mortality risk. CONCLUSIONS: The presence of minor cognitive dysfunction in the early post-surgical phase is a negative prognostic factor for mortality among elderly hip fracture patients. The burden of minor cognitive dysfunction is likely superimposed on that of delirium in subgroups of frail patients.
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Disfunção Cognitiva/etiologia , Fixação de Fratura/efeitos adversos , Fraturas do Quadril/cirurgia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/epidemiologia , Delírio/epidemiologia , Delírio/etiologia , Feminino , Avaliação Geriátrica , Fraturas do Quadril/mortalidade , Fraturas do Quadril/psicologia , Hospitalização , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Fatores de RiscoRESUMO
RATIONALE: Calcidiol can be employed to correct vitamin D deficiency. MAIN RESULTS: Calcidiol administered at daily and weekly regimens over a period of 3 months was able to successfully raise 25-hydroxyvitamin D levels without altering other markers related to bone and mineral metabolism. SIGNIFICANCE: Calcidiol supplementation is effective and safe. INTRODUCTION: The correction of vitamin D status is necessary to maintain an optimal mineral and skeletal homeostasis. Despite cholecalciferol (vitamin D3) is the most commonly used drug for vitamin D supplementation, the more hydrophilic compound calcidiol (25-hydroxyvitamin D3) can be employed at daily, weekly, and monthly regimens to reach in the short term the target levels of serum 25-hydroxyvitamin D [25(OH)D]. In the administration of different doses of calcidiol pharmacokinetic study (ADDI-D study), the efficacy and safety of daily and weekly dosages of calcidiol were tested. METHODS: A total of 87 Caucasian, community-dwelling, postmenopausal women, aged 55 years or older, with vitamin D inadequacy (serum 25(OH)D levels <30 ng/ml, with mean 25(OH)D below 20 ng/ml, namely 16.5 ± 7.5 ng/ml) were randomized to receive three different dosages of calcidiol: 20 µg/day, 40 µg/day, and 125 µg/week for 3 months. The attained level of serum 25(OH)D was selected as primary endpoint to assess efficacy, while other parameters of mineral metabolism, (serum calcium, parathyroid hormone, phosphate, FGF23, urinary calcium, and markers of bone turnover) were assessed as secondary endpoints to establish safety. RESULTS: In all the three groups, serum 25(OH)D values significantly and promptly rose and plateaued above the 30 ng/ml threshold remaining within safety interval after 14 days of treatment, with similar efficacy for the similar daily and weekly dose regimens. The different dosages were also equally effective in controlling secondary hyperparathyroidism. No significant changes in calcium and phosphate metabolism and in bone turnover markers were observed for any of the treatments, confirming the safety of this compound. CONCLUSIONS: The results of this study demonstrate the short- and mid-term efficacy and safety on core parameters of mineral metabolism of different daily or weekly dosages of calcidiol when used to treat vitamin D inadequacy or deficiency in postmenopausal women. Further studies are needed to assess falls as primary outcome of calcidiol supplementation.
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Conservadores da Densidade Óssea/administração & dosagem , Calcifediol/administração & dosagem , Deficiência de Vitamina D/tratamento farmacológico , Biomarcadores/sangue , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcifediol/efeitos adversos , Calcifediol/uso terapêutico , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Pessoa de Meia-Idade , Fosfatos/sangue , Pós-Menopausa/metabolismo , Pós-Menopausa/fisiologia , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/fisiopatologiaRESUMO
UNLABELLED: The calcium-sensing receptor (CaSR), a key player in the maintenance of calcium homeostasis, can influence bone modeling and remodeling by directly acting on bone cells, as demonstrated by in vivo and in vitro evidence. The modulation of CaSR signaling can play a role in bone anabolism. INTRODUCTION: The calcium-sensing receptor (CaSR) is a key player in the maintenance of calcium homeostasis through the regulation of PTH secretion and calcium homeostasis, thus indirectly influencing bone metabolism. In addition to this role, in vitro and in vivo evidence points to direct effects of CaSR in bone modeling and remodeling. In addition, the activation of the CaSR is one of the anabolic mechanisms implicated in the action of strontium ranelate, to reduce fracture risk. METHODS: This review is based upon the acquisition of data from a PubMed enquiry using the terms "calcium sensing receptor," "CaSR" AND "bone remodeling," "bone modeling," "bone turnover," "osteoblast," "osteoclast," "osteocyte," "chondrocyte," "bone marrow," "calcilytics," "calcimimetics," "strontium," "osteoporosis," "skeletal homeostasis," and "bone metabolism." RESULTS: A fully functional CaSR is expressed in osteoblasts and osteoclasts, so that these cells are able to sense changes in the extracellular calcium and as a result modulate their behavior. CaSR agonists (calcimimetics) or antagonists (calcilytics) have the potential to indirectly influence skeletal homeostasis through the modulation of PTH secretion by the parathyroid glands. The bone anabolic effect of strontium ranelate, a divalent cation used as a treatment for postmenopausal and male osteoporosis, might be explained, at least in part, by the activation of CaSR in bone cells. CONCLUSIONS: Calcium released in the bone microenvironment during remodeling is a major factor in regulating bone cells. Osteoblast and osteoclast proliferation, differentiation, and apoptosis are influenced by local extracellular calcium concentration. Thus, the calcium-sensing properties of skeletal cells can be exploited in order to modulate bone turnover and can explain the bone anabolic effects of agents developed and employed to revert osteoporosis.
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Osso e Ossos/metabolismo , Receptores de Detecção de Cálcio/fisiologia , Animais , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/fisiologia , Cálcio/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/deficiência , Pesquisa Translacional Biomédica/métodosRESUMO
UNLABELLED: Scientific interest in vitamin D has greatly risen during the last 10 years. The analysis of the changes in vitamin D prescriptions and related costs in a regional prescription dataset has revealed a profound increase in the period 2006-2013. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed. INTRODUCTION: The aim of this study was to analyze the changes in population-based prescription patterns of vitamin D supplements in the general population in an Italian regional setting during an 8-year period (2006-2013). METHODS: Data have been retrieved from the database of reimbursed prescriptions of the Region of Tuscany containing all of the medical reimbursements for the whole regional population (total of 3,619,872 and 3,692,828 inhabitants in 2006 and 2013, respectively). Data referring to adult population (age 20-90+ years) have been considered for this analysis (3,033,530 in 2006 and 3,066,741 in 2013). Two different flows (pharmaceutical distribution dataset and general data flow) were taken into account, using the ATC5 coding system for vitamin D supplements alone or in combination with calcium or alendronate. The number of boxes dispensed was retrieved, the number of patients receiving a specific treatment was calculated, and a cost analysis was performed. RESULTS: An upsurge in the prescriptions of vitamin D compounds was disclosed, mainly sustained by a 75.3-fold increase in cholecalciferol, in all age groups and both sexes. This occurred in parallel to a 4.3-fold rise in prescriptions of oral alendronate in combination with cholecalciferol, a slight decrease in dispensed alendronate alone, and a modest increase in the prescription of the combination of calcium salts and cholecalciferol, and calcium alone. The total cost for reimbursement by the Regional Health System for vitamin D-related compounds rose from 3,242,100 euros in 2006 to 8,155,778 in 2013. CONCLUSION: The huge increase in vitamin D prescriptions and related costs in the last decade, as revealed by the analysis of a regional pharmaceutical dataset, reflects the increased awareness of the possible consequences of a poor vitamin D status. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed.
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Conservadores da Densidade Óssea/uso terapêutico , Suplementos Nutricionais , Padrões de Prática Médica/tendências , Vitamina D/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/uso terapêutico , Colecalciferol/uso terapêutico , Bases de Dados Factuais , Custos de Medicamentos/estatística & dados numéricos , Custos de Medicamentos/tendências , Prescrições de Medicamentos/estatística & dados numéricos , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Estudos Retrospectivos , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia , Adulto JovemRESUMO
UNLABELLED: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. INTRODUCTION: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. METHODS: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. RESULTS: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. CONCLUSIONS: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.
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Doenças do Desenvolvimento Ósseo/classificação , Doenças do Desenvolvimento Ósseo/genética , Doenças Ósseas Metabólicas/classificação , Doenças Ósseas Metabólicas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/metabolismo , Humanos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Osteócitos/fisiologia , Fenótipo , Proteoglicanas/metabolismo , Doenças Raras/classificação , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/metabolismoRESUMO
PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.
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Doenças do Sistema Endócrino/classificação , Endocrinologia/classificação , Doenças Raras/classificação , Relatório de Pesquisa , Adulto , Classificação , Doenças do Sistema Endócrino/diagnóstico , Endocrinologia/métodos , Feminino , Humanos , Masculino , Doenças Raras/diagnósticoRESUMO
Randomized clinical trials and observational studies on the implementation of clinical governance models, in patients who had experienced a fragility fracture, were examined. Literature was systematically reviewed and summarized by a panel of experts who formulated recommendations for the Italian guideline. PURPOSE: After experiencing a fracture, several strategies may be adopted to reduce the risk of recurrent fragility fractures and associated morbidity and mortality. Clinical governance models, such as the fracture liaison service (FLS), have been introduced for the identification, treatment, and monitoring of patients with secondary fragility fractures. A systematic review was conducted to evaluate the association between multidisciplinary care systems and several outcomes in patients with a fragility fracture in the context of the development of the Italian Guidelines. METHODS: PubMed, Embase, and the Cochrane Library were investigated up to December 2020 to update the search of the Scottish Intercollegiate Guidelines Network. Randomized clinical trials (RCTs) and observational studies that analyzed clinical governance models in patients who had experienced a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random-effects models. Primary outcomes were bone mineral density values, antiosteoporotic therapy initiation, adherence to antiosteoporotic medications, subsequent fracture, and mortality risk, while secondary outcomes were quality of life and physical performance. RESULTS: Fifteen RCTs and 62 observational studies, ranging from very low to low quality for bone mineral density values, antiosteoporotic initiation, adherence to antiosteoporotic medications, subsequent fracture, mortality, met our inclusion criteria. The implementation of clinical governance models compared to their pre-implementation or standard care/non-attenders significantly improved BMD testing rate, and increased the number of patients who initiated antiosteoporotic therapy and enhanced their adherence to the medications. Moreover, the treatment by clinical governance model respect to standard care/non-attenders significantly reduced the risk of subsequent fracture and mortality. The integrated structure of care enhanced the quality of life and physical function among patients with fragility fractures. CONCLUSIONS: Based on our findings, clinicians should promote the management of patients experiencing a fragility fracture through structured and integrated models of care. The task force has formulated appropriate recommendations on the implementation of multidisciplinary care systems in patients with, or at risk of, fragility fractures.
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Governança Clínica , Fraturas Ósseas , Humanos , Pessoa de Meia-Idade , Fraturas Ósseas/prevenção & controle , Densidade Óssea , Comitês Consultivos , Desempenho Físico FuncionalRESUMO
BACKGROUND: Patients with primary hyperparathyroidism (PHPT) with contraindications to parathyroidectomy (PTx) or persistent PHPT have few non surgical options. AIM: The aim of the study was to investigate the efficacy of cinacalcet in reducing serum calcium in patients with PHPT, for whom PTx would be indicated according to serum calcium levels, but in whom PTx is not clinically appropriate or is contraindicated [European Medicines Agency (EMA) prescription labeling]. SUBJECTS AND METHODS: The study (open-label prospective, conducted in a single tertiary center) included 12 sporadic and 2 multiple endocrine neoplasia type 1 PHPT patients with serum calcium greater than 11.2 mg/dl. Cinacalcet was administered in increasing doses until normal serum calcium was reached or side effects preventing a further increase occurred. Serum calcium, PTH, phosphate, 25OHD, markers of bone turnover, 24h-urinary calcium and areal bone mineral density (BMD) were measured. Safety biochemical indices and adverse events were monitored. RESULTS: The maintenance cinacalcet dose [median 30 mg twice daily (range 30 daily-60 mg twice daily)] was maintained constant during follow-up (median 12 months). Mean±SE baseline serum calcium was 12.2±0.3 mg/dl. Serum calcium decreased by at least 1 mg/dl in all patients and normalized in 10. Serum calcium at the last observation was 9.9±0.2 mg/dl (p<0.0001 vs baseline). PTH decreased by 17.1% compared to baseline (p=0.13), and never reached a normal value. BMD was unchanged. Adverse events occurred in 6 patients (43%) and required treatment withdrawal in 2. CONCLUSIONS: Cinacalcet reduced and often normalized serum calcium in PHPT patients who met the EMA labeling.
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Hipercalcemia/prevenção & controle , Hiperparatireoidismo Primário/tratamento farmacológico , Moduladores de Transporte de Membrana/uso terapêutico , Naftalenos/uso terapêutico , Receptores de Detecção de Cálcio/agonistas , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cinacalcete , Contraindicações , Rotulagem de Medicamentos , União Europeia , Feminino , Seguimentos , Humanos , Hipercalcemia/etiologia , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/etiologia , Hiperparatireoidismo Primário/fisiopatologia , Quimioterapia de Manutenção , Moduladores de Transporte de Membrana/efeitos adversos , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/fisiopatologia , Naftalenos/efeitos adversos , Paratireoidectomia , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Surgery is the therapy of choice in primary hyperparathyroidism (PHPT), although other less invasive techniques have been used in the attempt to cure the disease. Recently, high-intensity focused ultrasound (HIFU), a totally non-invasive technique, has become available to cure solid tumors. AIM: The aim of this pilot study has been to assess the safety and efficacy of HIFU in symptomatic patients with PHPT. MATERIAL AND METHODS: Four out of 31 patients with surgical indications within a cohort of 47-screened patients with PHPT were considered eligible for the study. All patients accepted to participate and were submitted to HIFU treatment in a single session. One patient was submitted to surgery after HIFU treatment. Patients were followed-up for 12 months after the procedure. RESULTS: A persistent or a partial remission of the disease, respectively, were obtained in 2 patients (50%), including the one who underwent surgery after HIFU treatment. Safety was assessed performing laryngoscopy in all patients after HIFU procedure. A transient vocal cord paralysis was observed in all patients treated by HIFU only. No permanent side effects were observed in the long term. CONCLUSIONS: HIFU might be a promising technique in treating PHPT, provided that further development of the software decreases the rate of side effects and improves the short- and long-term efficacy.