Inactivating PTH/PTHrP Signaling Disorders.

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network.

OBJECTIVE: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. DESIGN AND METHODS: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. RESULTS AND CONCLUSIONS: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.

Classification of Disorders of Bone and Calcium Metabolism.

Classification is a natural human trait that enables us to put what may otherwise be very complex subjects into some order. However, classification should be seen not as an end in itself but rather as a means to help us understand certain topics. In the case of medicine, classification helps to provide information about the causes underlying many of the conditions encountered and, in some cases, provides a rationale for developing new treatments. This chapter aims to provide a helpful (if complex) classification of diseases of bone and calcium and, where known, to describe the underlying genetic mechanisms.

Taxonomy of rare genetic metabolic bone disorders.

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.

Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference.

A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Association of bone mineral density with periodontal status in postmenopausal women.

AIM: Menopausal changes expose an individual towards risk of various pathologies during midlife transition. This study aimed to investigate the possible association of bone mineral density (BMD) with periodontal parameters in early postmenopausal Indian women. METHODS: In 78 dentate postmenopausal female patients periodontal examination was performed including clinical attachment loss, pocket depth, plaque index and sulcular bleeding index. Alveolar crestal height was measured on proximal surfaces of all posterior teeth except third molars with the help of bitewing radiographs. Patient's BMD was assessed with dual energy X-ray absorptiometry. Statistical analysis was performed to assess the correlation between BMD and periodontal parameters. RESULTS: Pocket depth, clinical attachment loss and alveolar crestal height were found to have negative and statistically significant (P = -0.000 each) correlation with T-score, with the value of Pearson's correlation coefficient being -0.474, -0.426, and -0.419 respectively. Number of teeth lost due to periodontitis was not significantly correlated with T-score (P > 0.05). Results of anova and the post-hoc Tukey test revealed a statistically significant difference of mean clinical attachment loss, pocket depth and alveolar crestal height for the osteoporotic versus osteopenic group and the osteoporotic versus normal group. However, between the osteopenic and normal group, the differences of mean were statistically nonsignificant (P > 0.05). Body mass index was found to have a weakly positive (r = 0.376) and statistically significant (P = 0.001) correlation with T-score. CONCLUSIONS: Bone mineral density is an important risk indicator for periodontitis in postmenopausal women. Number of teeth lost due to periodontitis is not significantly affected by the BMD of the early postmenopausal phase.

A capacidade reacional do osso e os nomes das doenças ósseas inflamatórias / The bone reactional capability and thenames of inflammatory bone diseases

As reações ósseas frente às demandas funcionais e agressões são diferentes de acordo com a morfologia do local, intensidade e duração da irritação e do estado sistêmico do paciente. Nesse trabalho, inicialmente procurou-se correlacionar esses três importantes fatores para compreender o resultado final na estrutura óssea, especialmente do ponto de vista imaginológico. Em seguida, são apresentados os conceitos dos nomes universalmente aceitos para identificar as doenças ósseas inflamatórias, de forma a facilitar a comunicação científica e clínica entre os profissionais.

The bone reactions before functional demands and aggressions are different according to the local morphology,intensity and duration of the irritation and systemic state of the patient. In this work, initially it was sought to correlate these three important factors to comprehend the final result on the bone structure, especially from the imaging point of view. Then, it was presented the concepts of universally accepted names to identify inflammatory bone diseases, in order to facilitate the scientific and clinical communication between professionals.

Correlation of tooth mobility with systemic bone mineral density and periodontal status in Indian women.

Imbalanced bone remodelling associated with osteopaenic or osteoporotic conditions can lead to a net bone loss throughout the skeleton, including the oral cavity, possibly leading to tooth mobility. This study investigated possible associations between systemic bone mineral density and both tooth mobility and periodontal status in peri-menopausal women. Subjects comprised 119 dentate, peri-menopausal Indian women between 40 and 54 years old. Clinical parameters recorded were systemic bone mineral density (BMD), tooth mobility in terms of Periotest value (PTV score), clinical attachment loss (CAL), pocket depth (PD), plaque index (PI) and sulcular bleeding index (SBI). Statistical analysis was performed to assess correlations between PTV score and T-score. PTV score correlated significantly (P < 0.05) with T-score, PD and CAL. The partial correlation coefficient between PTV score and T-score after adjusting for confounders was -0.3676 (P < 0.05). Results of one-way analysis of variance showed a significant difference between mean PTV scores for osteoporotic, osteopaenic and normal patients. In this population of peri-menopausal women, systemic bone mineral density represented an independent factor associated with tooth mobility.

Correlation of periodontal status and bone mineral density in postmenopausal women: a digital radiographic and quantitative ultrasound study.

BACKGROUND: Data suggest that postmenopausal women with osteoporosis are at an increased risk for periodontal attachment loss and tooth loss; however, the extent of relationship between these two diseases is still not clear. AIM: The aim of the study was to evaluate the correlation of periodontal status and bone mineral density (BMD) in postmenopausal women. MATERIALS AND METHODS: The study population included 60 postmenopausal women aged 50-60 years (mean±SD: 55.5±3.4 years). Periodontal status was examined by plaque index, bleeding index, probing depth, and clinical attachment level (CAL). Digital panoramic radiograph was taken to measure the maxillary and mandibular alveolar bone density values. Skeletal (calcaneal) BMD was measured by quantitative ultrasound technique for T-score values. The recorded data for T-score, maxillary and mandibular alveolar bone densities, and periodontal status were subjected to statistical analysis for correlation and regression procedures. RESULTS: The results showed that mandibular alveolar (r=0.907, P<0.001) and maxillary alveolar bone density (r=0.898, P<0.001) had significant positive correlation with calcaneal T-score. Probing depth (r=-0.316, P<0.05), bleeding index (r=-0.277, P<0.05), and plaque index (r=-0.285, P<0.05) showed weak but significant negative correlation with calcaneal T-score and alveolar bone density of both the jaws, whereas CAL showed weak correlation with T-score which could not reach to a statistically significance level (r=-0.221, P>0.05). CONCLUSION: Calcaneal BMD was related to alveolar bone loss and, to a lesser extent, to clinical attachment loss, implicating postmenopausal bone loss as a risk indicator for periodontal disease in postmenopausal women.

Bone histology in chronic kidney disease-related mineral and bone disorder.

A quantitative histological analysis of biopsied bone samples is currently regarded as the gold standard for a diagnosing procedure for bone diseases associated with chronic kidney disease-related mineral and bone disorder. Conventionally, "bone cell activities" and "bone mineralization" are applied as two independent assessment axes, and the histology results are classified into five categories according to these axes. Recently, a new bone histology classification system called the Turnover-Mineralization-Volume system, which applied "cancellous bone volume" as another major assessing axis, was advocated; however, both classification systems have many unsolved problems. Clinicians must realize the limitations in evaluating bone metabolism by bone histology. We will need to establish a new classification method for renal bone diseases independent of histological findings.

[Morphological analysis of bone dynamics and metabolic bone disease. Renal Osteodystrophy and New KDIGO CKD-MBD classification].

Global Kidney Disease Guideline Organization ; KDIGO has decided to express the abnormality in bone and mineral metabolism associated with chronic kidney disease (CKD) as CKD-Mineral Bone Disorder (CKD-MBD) . The term "renal osteodystrophy" is now only used for expressing bone pathological abnormality diagnosed by biopsy. The classical classification of bone pathology in CKD is superseded by new T (Turnover) M (mineralization) V (Volume) classification.

[Diagnostic approach to osteoporosis]. / Diagnostik der Osteoporose.

The diagnostic approach to osteoporosis usually involves an ample risk assessment, a physical examination, a radiograph of the thoracic and lumbar spine, a bone densitometry using dual X-ray absorptiometry, and a basic blood test. The aim of this approach is to assign a person to one of the WHO-based diagnostic categories, and to estimate the ten-year fracture risk of this individual. In countries where available, the individual ten-year fracture risk can now easily be calculated for men and women of forty years of age and above, by using a computer-driven calculation tool, called FRAX, which has been developed by WHO recently.

Chronic kidney disease-mineral-bone disorder: a new paradigm.

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD-mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory-abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone-changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification-vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease.

The effect of measurement of the contralateral hip if the spine is not included in the bone mineral density analysis.

The aim of this study was to determine if measurement of the contralateral femora has an effect on osteoporosis diagnosis and treatment classification if the spine is not included in the bone mineral density (BMD) scan. The method used was the T-score discordance from the dual femur BMD scans of 537 women (mean age: 61.2 yr; standard deviation: 10.5; age range: 32-90 yr) who were evaluated to determine if inclusion of the contralateral hip in the BMD study made a difference in clinical diagnosis and treatment classification when the spine was not included in the BMD scan. Clinical diagnosis and treatment classification was based on the lowest T-score at each hip of three femur sites: the neck, the trochanter, and the total femur. The results of the diagnosis classification (i.e., normal, osteopenia, and osteoporosis) differed in the right versus the left femora in 28% of subjects at one or more sites, and in 14%, 15%, and 10% of subjects at the neck, trochanter, and total femur, respectively. Diagnosis discordance increased in subjects who were aged 65 yr and older. Treatment classification (T>or=-1.5; T<-1.5; T<-2.0) differed in the right versus the left femora in 33% of subjects at one or more sites, and in 18%, 14%, and 12% of subjects at the neck, trochanter, and total femur, respectively. Treatment discordance increased in subjects age 65 yr and older. Using the lowest T-score for clinical diagnosis classification, when the contralateral hip was considered, a clinical difference in diagnosis from normal-->osteopenia occurred in 3.9% of subjects, and from osteopenia-->osteoporosis in 1.3% of subjects. A clinical difference in treatment category from T>or=-1.5-->T<-1.5 occurred in 2.7% of subjects, and from T>or=-2-->T<-2 in 2.7% of subjects. In conclusion, inclusion of the bilateral hip in the BMD study made a clinical difference in diagnosis classification in 5.2% of subjects and in treatment classification in 5.4% of subjects. T-score differences between the contralateral hips increased with age. In the subgroup of subjects age 65 yr and older, a clinical difference in classification to a more severe diagnosis or treatment category occurred in 5.35% and 7.25% of subjects, respectively.

Quantitative evaluation of bone density using the Hounsfield index.

PURPOSE: The primary aims of this retrospective study were to: (1) evaluate bone quality in different segments of the edentulous jaw and correlate it with demographic data and (2) establish a quantitative and objective assessment of bone quality based on the Hounsfield scale. MATERIALS AND METHODS: One hundred one randomly selected computerized tomographic (CT) scans were used for the analysis. Edentulous segments ranging from 10 to 30 mm were selected for evaluation, and the findings were analyzed and correlated to demographics. Implant recipient sites were evaluated visually for bone classification by 2 independent examiners. The same sites were subsequently evaluated digitally using the Hounsfield scale, and the results were correlated with the visual classification. RESULTS: The 4 quadrants of the mouth displayed Hounsfield unit (HU) values ranging from -240 HU to 1,159 HU. The highest unit/mean density value (559 +/- 208 HU) was found in the anterior mandible, followed by 517 +/- 177 HU for the anterior maxilla, 333 +/- 199 HU for the posterior maxilla, and 321 +/- 132 HU for the posterior mandible. There was no association between the Hounsfield value and density and age or gender. When subjective bone quality was correlated to Hounsfield index findings, only the relationship between HU and type 4 bone was found to be significant. CONCLUSIONS: Knowledge of the Hounsfield value as a quantitative measurement of bone density can be helpful as a diagnostic tool. It can provide the implant surgeon with an objective assessment of bone density, which could result in modification of surgical techniques or extended healing time, especially in situations where poor bone quality is suspected.

Construction of two instruments for the presumptive detection of post-menopausal women with low spinal bone mass by means of clinical risk factors.

The objective of this investigation was the design of two instruments based on clinical risk factors for the presumptive detection of post-menopausal women with spinal BMD<2.5 S.D. below average (LBMD). We investigated the association of 20 risk factors (RF) with LBMD in a series of 131 women. According to current densitometric criteria, subjects were classified as normals (N=33); osteopenics (N=53) and osteoporotics (N=45). Normals and osteopenics were taken as a single group because only 'nulliparity' and 'personal fractures' exhibited significant differences between these groups. A logistic regression attempting to identify which factors were associated with osteopenia showed a poor fit (pseudo R(2)=0.289). Univariate unconditional logistic regression analysis was used to calculate odd ratios (ORs) and their 95% CI for all RF. Those with associated P-values <0.100 were included in a multivariate logistic regression analysis to obtain the odds ratios (OR) adjusted by the effects of the others. The variables with not significant beta coefficients were eliminated, producing a reduced model. BMI (<25 kg/m(2)), calcium intake (<1.2g/day), menopause (>10 years), and the simultaneous occurrence of kyphosis and personal fractures showed significant association with low bone mass at the lumbar spine and their effect was additive. Fitting of the data to the model was assessed with the Hosmer-Lemeshow test (P=0.926) The area under the ROC curve is 0.833 (95% CI=0.757-0.909). The following equation calculates the probability of having low spinal bone mass: The sensitivity, specificity and area under the ROC curve were defined. The point of maximum specificity and sensitivity derived from the ROC curve, has a probability of 0.409. With such a cut-off point, the equation has a sensitivity of 73%, specificity 79%, positive predictive value 65% and negative predictive value 85%. The second instrument associates very low lumbar bone mass with the number of risk factors accumulated per patient. At baseline, all subjects had four RFs: they were, women, white, post-menopausal, and with no previous exposure to estrogens. With six additional RFs the presumptive diagnosis of LBMD has a specificity of 99%, positive predicting value 94% and false positives 6.5%. The area under the curve in a ROC graph was 0.826 (95% CI=0.747-0.914). Comparing present instruments with others in the literature, it is concluded that each population require its own algorithm for the presumptive detection of subjects with low bone mass. The algorithm should be reassessed periodically if the characteristics of the population or its social-economic conditions change.