Hyperparathyrodism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder. Loss of function of the cell division cycle protein 73 homolog (CDC73) gene is responsible for the syndrome. This ...gene encodes an ubiquitously expressed 531 amino acid protein, parafibromin, that acts as a tumor suppressor. Loss of heterozygosity (LOH) of the CDC73 locus in many HPT-JT associated parathyroid tumors from patients with germline mutation is in accordance with Knudson’s “two-hit” model for hereditary cancer. A 41-year-old man with mandible ossifying fibroma suffered from severe hypercalcemia due to parathyroid carcinoma (PC). Genetic analysis was performed to evaluate germinal and somatic CDC73 gene mutation as well as real-time qRT-PCR to quantify CDC73 mRNA, miR-155 and miR-664 expression levels. Immunohistochemistry and Western blotting (WB) assay were carried out to evaluate parafibromin protein expression. A novel heterozygous nonsense mutation, c.191-192 delT, was identified in the CDC73 gene. No CDC73 LOH was found in PC tissue, nor any differences in expression levels for CDC73 gene, miR-155 and miR-664 between PC and parathyroid adenoma control tissues. On the contrary, both immunohistochemistry and WB assay showed an approximate 90% reduction of parafibromin protein expression in PC. In conclusion, this study describes a novel germinal mutation, c.191-192 delT, in the CDC73 gene. Despite normal CDC73 gene expression, we found a significant decrease in parafibromin. We hypothesize that a gene silencing mechanism, possibly induced by microRNA, could play a role in determining somatic post-transcriptional inactivation of the wild type CDC73 allele.
Background
The Italian Society for Orthopaedics and Traumatology conceived this guidance—which is primarily addressed to Italian orthopedic surgeons, but should also prove useful to other bone ...specialists and to general practitioners—in order to improve the diagnosis, prevention, and treatment of osteoporosis and its consequences.
Materials and methods
Literature reviews by a multidisciplinary team.
Results
The following topics are covered: the role of instrumental, metabolic, and genetic evaluations in the diagnosis of osteoporosis; appraisal of the risk of fracture and thresholds for intervention; general strategies for the prevention and treatment of osteoporosis (primary and secondary prevention); the pharmacologic treatment of osteoporosis; the setting and implementation of fracture liaison services for tertiary prevention. Grade A, B, and C recommendations are provided based on the main levels of evidence (1–3). Toolboxes for everyday clinical practice are provided.
Conclusions
The first up-to-date Italian guidelines for the primary, secondary, and tertiary prevention of osteoporosis and osteoporotic fractures are presented.
Hip fractures are a major health issue considerably impacting patients’ quality of life and well-being. This is particularly evident in elderly subjects, in which the decline in bone and muscle mass ...coexists and predisposes individuals to fall and fracture. Among interventions to be implemented in hip fractured patients, the assessment and management of nutritional status is pivotal, particularly in subjects older than 65. Nutrition plays a central role in both primary and secondary preventions of fracture. An adequate protein intake improves muscle mass and strength and the intestinal absorption of calcium. Other nutrients with recognized beneficial effects on bone health are calcium, vitamins D, K, and C, potassium, magnesium, folate, and carotenoids. With reference to calcium, results from longitudinal studies showed that the consumption of dairy foods has a protective role against fractures. Moreover, the most recent systematic reviews and meta-analyses and one umbrella review demonstrated that the combination of calcium and vitamin D supplementation significantly reduces hip fracture risk, with presumed higher efficacy in older and institutionalized subjects. Owing to these reasons, the adequate intake of calcium, vitamin D, protein, and other macro and micronutrients has been successfully implemented in the Fracture Liaison Services (FLSs) that represent the most reliable model of management for hip fracture patients. In this narrative review, papers (randomized controlled trials, prospective and intervention studies, and systematic reviews) retrieved by records from three different databases (PubMed, Embase, and Medline) have been analyzed, and the available information on the screening, assessment, and management of nutritional and vitamin D status and calcium intake in patients with hip fractures is presented along with specific prevention and treatment measures.
Context: It is unclear whether patients with asymptomatic primary hyperparathyroidism (PHPT) do better with parathyroidectomy (PTx) as compared with conservative medical management.
Objective: The ...aim of the study was to evaluate the beneficial effect of PTx vs. conservative management in patients with mild asymptomatic PHPT.
Design: We conducted a prospective, randomized study.
Setting: The study took place at a referral center.
Patients: We studied 50 patients who did not meet any guidelines for parathyroid surgery as recommended by the National Institutes of Health Consensus Development Conference on Asymptomatic PHPT.
Intervention: Patients were randomly assigned to PTx or no PTx and were evaluated at 6 months and at 1 yr.
Main Outcome Measures: We compared changes (percentage of basal) of lumbar spine bone mineral density (BMD) between the two groups at 1 yr.
Results: The change in BMD at lumbar spine was greater after PTx (+4.16 ± 1.13 for PTx vs. −1.12 ± 0.71 for no PTx; P = 0.0002). The change in BMD at the total hip was also significantly greater in the PTx group (+2.61 ± 0.71 for PTx vs. −1.88 ± 0.60 for no PTx; P = 0.0001). There was no difference in BMD after 1 yr between both groups at the one-third radius site. In comparison with those who did not undergo surgery, the PTx subjects, after 1 yr, showed significant differences in four quality of life measures as determined by the 36-item short form health survey scale: bodily pain (P = 0.001), general health (P = 0.008), vitality (P = 0.003), and mental health (P = 0.017).
Conclusions: In patients with mild asymptomatic PHPT, successful PTx is followed by an improvement in BMD and quality of life. Most patients followed without surgery did not show evidence of progression.
The major physiological role of the vitamin D receptor (VDR) is the maintenance of mineral ion homeostasis. Mutation of the VDR, in humans and mice, results in alopecia. Unlike the effects of the VDR ...on mineral ion homeostasis, the actions of the VDR that prevent alopecia are ligand-independent. Although absence of the VDR does not prevent the development of a keratinocyte stem cell niche in the bulge region of the hair follicle, it results in an inability of these stem cells to regenerate the lower portion of the hair follicle in vivo and impairs keratinocyte stem cell colony formation in vitro. VDR ablation is associated with a gradual decrease in keratinocyte stem cells, accompanied by an increase in sebaceous activity, a phenotype analogous to that seen with impaired canonical Wnt signaling. Transient gene expression assays demonstrate that the cooperative transcriptional effects of β-catenin and Lef1 are abolished in keratinocytes isolated from VDR-null mice, revealing a role for the unliganded VDR in canonical Wnt signaling. Thus, absence of the VDR impairs canonical Wnt signaling in keratinocytes and leads to the development of alopecia due to a defect in keratinocyte stem cells.
Both osteoporosis with related fragility fractures and cardiovascular diseases are rapidly outspreading worldwide. Since they are often coexistent in elderly patients and may be related to possible ...common pathogenetic mechanisms, the possible reciprocal effects of drugs employed to treat these diseases have to be considered in clinical practice. Bisphosphonates, the agents most largely employed to decrease bone fragility, have been shown to be overall safe with respect to cardiovascular diseases and even capable of reducing cardiovascular morbidity in some settings, as mainly shown by real life studies. No randomized controlled trials with cardiovascular outcomes as primary endpoints are available. While contradictory results have emerged about a possible BSP-mediated reduction of overall mortality, it is undeniable that these drugs can be employed safely in patients with high fracture risk, since no increased mortality has ever been demonstrated. Although partial reassurance has emerged from meta-analysis assessing the risk of cardiac arrhythmias during bisphosphonates treatment, caution is warranted in administering this class of drugs to patients at risk for atrial fibrillation, possibly preferring other antiresorptives or anabolics, according to osteoporosis guidelines. This paper focuses on the complex relationship between bisphosphonates use and cardiovascular disease and possible co-management issues.
Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of ...postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS®) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.
Subclinical vitamin D deficiency Cianferotti, Luisella, MD, PhD; Marcocci, Claudio, MD
Best Practice & Research Clinical Endocrinology & Metabolism,
08/2012, Letnik:
26, Številka:
4
Journal Article
Recenzirano
The optimal vitamin D status, as defined by serum 25-hydroxyvitamin D 25(OH)D, is still controversial. Some individuals are at risk for subclinical vitamin D deficiency, as defined by serum 25(OH)D ...levels between 25 and 75 nmol/L, and up to 80–100% of the entire population can display inadequate serum 25(OH)D values depending on latitude and seasonality. The clinical manifestation of extreme vitamin D deficiency, i.e. rickets and osteomalacia, are rare. Levels of 25(OH)D ≥ 50 nmol/L are required for optimal musculoskeletal health. However, levels of 25(OH)D above 75 nmol/L may be necessary to maximize musculoskeletal benefits and take advantage of the extraskeletal actions of vitamin D. This review will summarize the actual positions on the boundaries of subclinical vitamin D deficiency, the main available evidence on the effects of inadequate vitamin D status on skeletal and extraskeletal targets and supplementation strategies.
Purpose
Tumor induced osteomalacia (TIO) is a rare disease of mineral metabolism, whose clinical picture is dominated by hypophosphatemia usually due to an excess of circulating FGF23 produced by ...small mesenchymal tumors. Data on the real prevalence of the disease are lacking, with the knowledge of the disease mainly relying on case reports and small case series. No estimate is available on the prevalence of uncured TIO.
Methods
National multi-center, cross-sectional and retrospective study on persistent or recurrent cases of TIO followed in referral centers for bone diseases
;
systematic review of the published persistent and recurrent cases of TIO. Data from patients consecutively evaluated in referral Italian centers for bone diseases were collected; a PubMed search on persistent, recurrent and unoperable cases of TIO was carried out.
Results
Sixteen patients (mean age at diagnosis 52.5 ± 10.6 years) with persistent (
n
= 6, 37,5%), recurrent (
n
= 7, 43.7%) or not operable (
n
= 3, 18.8%) TIO were described. Delay in diagnosis (2.5 ± 1.3 years) was demonstrated. All patients experienced fragility fractures or pseudofractures and disabling bone and muscle pain. BMD was significantly reduced (mean T-score −2.7 ± 1.7 and −2.7 ± 0.9 at lumbar spine and femoral neck, respectively). Fourteen patients were maintained under therapy with phosphate salts and calcitriol, while in 2 patients therapy with burosumab, an anti-FGF23 antibody, was commenced.
Conclusion
A significant number of patients with TIO remain either undiagnosed for tumor localization or tumor recur or persist after surgery. These patients with active disease represent possible candidates for burosumab treatment.
Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks ...of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.
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