From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Appelman-Dijkstra NM
PROVIDER: S-EPMC4879160 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.
Appelman-Dijkstra Natasha M NM Papapoulos Socrates E SE
Endocrine 20160218 3
During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we re ...[more]
Similar Datasets
Project description:Rare diseases are those which affect a small number of people compared to the general population. However, many patients with a rare disease remain undiagnosed, and a large majority of rare diseases still have no form of viable treatment. Approximately 40% of rare diseases include neurologic and neurodevelopmental disorders. In order to understand the characteristics of rare neurological disorders and identify causative genes, various model organisms have been utilized extensively. In this review, the characteristics of model organisms, such as roundworms, fruit flies, and zebrafish, are examined, with an emphasis on zebrafish disease modeling in rare neurological disorders.
| S-EPMC9000079 | biostudies-literature
Project description:ObjectiveCraniofacial disharmony in skeletal diseases is strongly associated with sleep-disordered breathing. This study was aimed at studying the sleep respiratory patterns in young children with rare skeletal disorders.DesignThis retrospective study included children with achondroplasia (ACH), osteogenesis imperfecta (OI) and Ellis van Creveld Syndrome. Our subjects underwent an in-laboratory overnight respiratory polygraph between January 2012 and April 2016. All medical records were reviewed and brain Magnetic Resonance Imaging was conducted on patients with ACH, nasopharynx, oropharynx and laryngopharynx spaces.PatientsTwenty-four children were enrolled, 13 with ACH, 2 with spondyloepiphyseal dysplasia, 1 with odontochondrodysplasia, 6 with OI and 2 with Ellis van Creveld Syndrome.ResultsChildren with ACH, who had adenotonsillectomy, showed fewer sleep respiratory involvement than untreated children. Among 13 patients with ACH, brain magnetic resonance imaging was available in 10 subjects and significant negative correlation was found between sleep respiratory patterns, nasopharynx and oropharynx space (p < 0.05). In 2 patients with spondyloepiphyseal dysplasia, mild-to-moderate sleep respiratory involvement was found. Both subjects had a history of adenotonsillectomy. Mild sleep respiratory involvement was also observed in 4 out of 6 patients with OI. One patient with Ellis van Creveld syndrome had mild sleep respiratory disturbance.ConclusionsSleep respiratory disturbances were detected in children with ACH, and with less severity also in OI and Ellis van Creveld syndrome. Adenotonsillectomy was successful in ACH in reducing symptoms. In light of our findings, multicenter studies are needed to obtain further information on these rare skeletal diseases.
| S-EPMC6244108 | biostudies-literature
Project description:In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular etiology of these diseases. Herein, we review three such disorders, impacted by debilitating deficits in bone mineralization or cartilage ossification, as well as the novel disease-modifying drugs that are now available to treat these conditions. Specifically, we discuss asfotase alfa, burosumab-twza, and vosoritide, for the treatment of hypophosphatasia, X-linked hypophosphatemia and achondroplasia, respectively. For each skeletal disorder, an overview of the clinical phenotype and natural history of disease is provided, along with a discussion of the clinical pharmacology, mechanism of action and FDA indication for the relevant medication. In each case, a brief review of clinical trial data supporting drug development for each medication is provided. Additionally, guidance as to drug dosing and long-term monitoring of adverse events and pediatric efficacy is presented, to aid the clinician seeking to utilize these novel therapies in their practice, or to become familiar with the healthcare expectations for children receiving these medications through specialized multidisciplinary clinics. The availability of these targeted therapies now significantly augments treatment options for conditions in which past therapy has relied upon less specific, symptomatic medical and orthopedic care.
| S-EPMC9592743 | biostudies-literature
Project description:Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for β-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent β-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for β-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.
| S-EPMC8171369 | biostudies-literature
Project description:This observational study assessed the impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany. Continued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.PurposeThe efficacy of osteoporosis medications has been demonstrated in clinical trials, but a lack of evidence exists of their real-world effectiveness. This real-world study assessed the treatment patterns and impact on the fracture incidence of osteoporosis medications in postmenopausal women in Germany.MethodsThis cohort study used data from the WIG2 benchmark database, a German anonymised healthcare claims database. All women ≥ 50 years of age with ≥ 1 prescription for osteoporosis medication between 1 January 2013 and 31 December 2017 were included. The primary outcome was treatment effectiveness, evaluated as the change in fracture incidence after initiating treatment. Fracture types included all fractures, clinical vertebral, hip and wrist/forearm. Fracture incidence was assessed during the early-treatment period (0-3 months) and the on-treatment period (4-12, 13-24, 25-36 and 37-48 months).ResultsBaseline covariates and treatment patterns were determined for 41,861 patients. The median duration of therapy was longer with denosumab (587 days) than with intravenous ibandronate (451 days), intravenous zoledronate (389 days) or oral bisphosphonates (258 days). The baseline incidence rate of all fractures was higher in patients receiving denosumab than in those receiving other treatments (87.6, 78.2, 56.6 and 66.0 per 1000 person-years for denosumab, oral bisphosphonates, intravenous ibandronate and intravenous zoledronate, respectively). Rates of all fractures declined with continued denosumab (by 38%, 50%, 56% and 67% at 12, 24, 36 and 48 months, respectively) and oral bisphosphonates (by 39%, 44%, 49% and 42%, respectively) treatment.ConclusionContinued treatment with osteoporosis medications was associated with reductions of fracture rates in a real-world setting.
| S-EPMC9512727 | biostudies-literature
Project description:Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.
| S-EPMC8037620 | biostudies-literature
Project description:Family-based designs are increasingly being used for identification of rare variants in complex disorders. This paper addresses two questions related to the utility of these designs. First, under what circumstances are rare disease-related variants expected to cosegregate with disease in families? Second, under what circumstances is a disease-variant association expected to be greater in studies restricted to familial cases than in studies of unselected cases? To investigate these questions, we developed a probability model of disease causation involving two loci. To address cosegregation, we examined the probability that an affected first-degree relative of a variant-carrying proband would also carry the variant. We find that this probability increases with increasing odds ratio (OR) for the variant, but declines with increasing sibling recurrence risk ratio (λs). For example, under reasonable assumptions, the 15q13.3 microdeletion in idiopathic generalized epilepsy, with an OR estimate of 68 in large case-control studies, is expected to be present in >95% of affected first-degree relatives of variant-carrying probands. However, for a variant with OR=5, the probability an affected relative has the variant ranges from 82% (when λs=2) to 58% (when λs=50). We also find that restriction of a study to familial cases does not necessarily increase a rare variant's association with disease, especially if λs is high and the variant contributes little to overall disease familial aggregation. These findings provide guidance for the design of family-based studies of rare variants in complex disorders.
| S-EPMC3598309 | biostudies-other
Project description:We describe a 79-year-old man with spondylodiscitis and unknown pathogen, treated with cefazolin and rifampicin. He developed a massive digestive hemorrhage. Prothrombin time was prolonged with severe vitamin-K-dependent clotting-factor deficiency. Severe bleeding can occur during cefazolin and rifampicin use. This deficiency should be assessed before prescribing cefazolin-rifampicin and prothrombin time monitored.
| S-EPMC8131959 | biostudies-literature
Project description:The available literature on the orthodontic treatment of patients with rare disorders is extremely scarce. The aim of this study was to analyze the diagnosis and orthodontic treatment of a group of 94 individuals with rare diseases, referred for orthodontic evaluation to a university special care dentistry center (University of Santiago de Compostela, Spain). We created a control group of 94 systemically healthy individuals, paired by sex and age range. For all participants, we recorded their dental and skeletal abnormalities, oromotor dysfunctions and the characteristics of their orthodontic treatment. Some of the morphological and functional abnormalities were more prevalent in the rare disorders group than in the control group, including dental agenesis, microdontia, enamel defects, maxillary hypoplasia, overbite, cleft lip/palate, mouth breathing, atypical swallowing, lingual/labial interposition, labial incompetence, modified consistency diet, bruxism, and muscle tone abnormalities. Compared with the control group, the 56 patients with rare disorders who underwent orthodontic treatment required more desensitization sessions, used mixed appliances (fixed and removable) more often and for longer periods and had more frequent complications, such as gingivitis, caries, mucosal ulcers and recurrent debonding of the device. In conclusion, for selected patients with rare disorders, it is feasible to perform orthodontic treatment, whose planning will be determined by the dental-skeletal abnormalities and oromotor dysfunctions. Although complications are more frequent, they can typically be solved without having to stop treatment.
| S-EPMC8954363 | biostudies-literature
Project description:The last decade has seen a dramatic increase in innovative ideas for the treatment of genetic disorders for which no curative therapies exist. Gene and protein replacement therapies stand out as novel approaches to treat a select group of these diseases, such as certain tissue fragility disorders. Further, the advent of stem cell approaches, such as induced pluripotent stem cells (iPSC) technology, has led to the development of new methods of creating replacement tissues for regenerative medicine. This coincided with the discovery of genome editing techniques, which allow for the correction of disease-causing mutations. The culmination of these discoveries suggests that new and innovative therapies for monogenetic disorders affecting single organs or tissues are on the horizon. Challenges remain, however, especially with diseases that simultaneously affect several tissues and organs during development. Examples of this group of diseases include ectodermal dysplasias, genetic disorders affecting the development of tissues and organs such as the skin, cornea, and epithelial appendages. Gene or protein replacement strategies are unlikely to be successful in addressing the multiorgan phenotype of these diseases. Instead, we believe that a more effective approach will be to focus on correcting phenotypes in the most severely affected tissues. This could include the generation of replacement tissues or the identification of pharmaceutical compounds that correct disease pathways in specific tissues.
| S-EPMC8378213 | biostudies-literature