Summary
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.
The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota ...contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.
In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. ...After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.
Bone Disease in the Common Marmoset Olson, E. J.; Shaw, G. C.; Hutchinson, E. K. ...
Veterinary pathology,
09/2015, Volume:
52, Issue:
5
Journal Article
Peer reviewed
The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone ...disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses.
Pharmacology of bisphosphonates Cremers, Serge; Drake, Matthew T.; Ebetino, F. Hal ...
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
June 2019, Volume:
85, Issue:
6
Journal Article
Peer reviewed
Open access
The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs ...have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from “bench to bedside and back again”. Several of the leading BPs achieved “blockbuster” status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.
Context:
Although mild to moderate chronic kidney disease (CKD) and vitamin D deficiency are prevalent in the elderly population worldwide and are associated with sarcopenia, their influence on bone ...mineral density (BMD) has not been determined.
Objective:
The objective of the study was to determine the combined effects of vitamin D deficiency and CKD on BMD in the elderly population and their relationships with sarcopenia and PTH levels.
Design, Setting, and Subjects:
This was a cross-sectional study with nationally representative samples of 6949 subjects aged 55 years or older from the Korea National Health and Nutrition Examination Surveys conducted between 2008 and 2011.
Main Outcome Measures:
The study population was divided into four groups according to vitamin D and CKD status. The combined association of CKD and vitamin D deficiency 25(OH)D<20 ng/mL with osteopenia or osteoporosis was assessed, and the status of PTH and the sarcopenic index (appendicular skeletal muscle mass as a percentage of body weight or appendicular skeletal muscle mass per weight) as a measure of sarcopenia were evaluated.
Results:
BMD in the total hip and femoral neck as well as femoral bone geometry was markedly deteriorated in stage 3 and 4 CKD subjects with vitamin D deficiency compared with other groups. Regardless of gender, these subjects also had higher levels of PTH and increased prevalence of sarcopenia. Multivariable logistic regression analyses demonstrated that CKD subjects with vitamin D deficiency showed a significantly increased risk of osteoporosis or osteopenia odds ratios 1.49 and 2.06 (1.81 and 2.65) at the femur neck and total hip, respectively, in women (men), which was mainly associated with elevated levels of PTH and sarcopenia in these groups.
Conclusions:
The combination of mild to moderate CKD and vitamin D deficiency was significantly associated with low BMD in a geriatric population, linked with hyperparathyroidism and sarcopenia.
Thalassemia bone disease is a common and severe complication of thalassemia—an inherited blood disorder due to mutations in the α or β hemoglobin gene. In its more severe form, severe anemia is ...present, and treatment with frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incomplete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant complication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thalassemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and the clinical implications for monitoring and treating this disorder.
Bone Disease after Kidney Transplantation Bouquegneau, Antoine; Salam, Syrazah; Delanaye, Pierre ...
Clinical journal of the American Society of Nephrology,
07/2016, Volume:
11, Issue:
7
Journal Article, Web Resource
Peer reviewed
Open access
Bone and mineral disorders occur frequently in kidney transplant recipients and are associated with a high risk of fracture, morbidity, and mortality. There is a broad spectrum of often overlapping ...bone diseases seen after transplantation, including osteoporosis as well as persisting high- or low-turnover bone disease. The pathophysiology underlying bone disorders after transplantation results from a complex interplay of factors, including preexisting renal osteodystrophy and bone loss related to a variety of causes, such as immunosuppression and alterations in the parathyroid hormone-vitamin D-fibroblast growth factor 23 axis as well as changes in mineral metabolism. Management is complex, because noninvasive tools, such as imaging and bone biomarkers, do not have sufficient sensitivity and specificity to detect these abnormalities in bone structure and function, whereas bone biopsy is not a widely available diagnostic tool. In this review, we focus on recent data that highlight improvements in our understanding of the prevalence, pathophysiology, and diagnostic and therapeutic strategies of mineral and bone disorders in kidney transplant recipients.
Skeletal fluorosis resulting from high fluoride level in drinking water is a major public health problem. The present study evaluated the association between exposures to drinking water fluoride and ...skeletal fluorosis in 5 villages of Poldasht County, Iran. All the data and information on the prevalence of bone diseases were obtained from the Health Record Department, Poldasht Health Centre. To obtain the odds ratio of bone disease problem in different risk factors, when considering the cluster effect of rural area, logistic regression in a multilevel model was used. Results showed that skeletal fluorosis of people who live in areas with high fluoride concentration is 18.1% higher than that of individuals who live in areas with low fluoride concentration. Skeletal fluorosis (54.5%) was observed in the age group of 71 years and above, and was more commonly found in females than males. According to Unadjusted, individuals who consume ≤3 unit milk and dairy products per week have almost the same level of bone diseases as compared to those that consume more than 3 units. This study indicated that, skeletal fluorosis is a general health problem in these rural areas because the results revealed that high percentage of the studied population had symptoms of skeletal fluorosis.
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