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Context Severe osteodystrophy is common in patients with liver dysfunction. Markers of bone metabolism may help in early diagnosis of osteodystrophy and in understanding underlying pathophysiological mechanisms. Objective To elucidate changes in bone metabolism associated with cirrhosis and to determine the route of elimination for the markers. Methods Case–control study at a public university hospital. Fifty-nine patients with cirrhosis (47 alcoholic and 12 nonalcoholic cirrhosis) and 20 controls were included. Participants underwent catheterization of the femoral artery, and the hepatic, renal, and femoral veins with collection of blood from all 4 sites. Regional arteriovenous differences in concentrations of bone metabolism markers were determined: procollagen of type I collagen propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX), osteocalcin, tartrate-resistant acid phosphatase isoform 5b (TRAcP5b), osteoprotegerin (OPG), and sclerostin and correlated with degree of disease (Child–Pugh classification). Results PINP concentration was higher (median: 87.9 µg/L) in patients with cirrhosis than in controls (52.6 µg/L) (P = .001), while hepatic extraction was lower (4.3% vs 14.5%) (P < .001). Both CTX and TRAcP5b were higher in patients with cirrhosis (340 ng/L and 3.20 U/L) than in controls (215 ng/L and 1.60 U/L) (P < .001 and P < .0001). Hepatic sclerostin extraction was lower in patients with cirrhosis (14.6%) than in controls (28.7%) (P < .0001). In both groups OPG showed a hepatic release rate (production) of 6%. Conclusion Patients with cirrhosis have increased bone resorption, but unaltered bone formation. Sclerostin is eliminated through the liver while OPG is produced in the liver. Bone markers may prove useful in evaluating bone turnover in patients with cirrhosis.

Background Pseudohypoparathyroidism is a rare genetic disease characterized by hypocalcaemia and hyperphosphataemia due to the defect to the guanine nucleotide-binding protein alpha subunit (GNAS) gene. Patients with pseudoparathyroidism type 1a and 1c could manifest Albright’s hereditary osteodystrophy and multiple hormone resistance including gonadotropin and thyroid stimulating hormone. Case presentation Here we report a Chinese man who presented with fatigue, recurrent seizure and Albright’s hereditary osteodystrophy. His genetic study revealed a heterozygote mutation in the GNAS gene [NM_000516.4(GNAS): c2787_2788del (p.Val930AspfsTer12)]. After calcium and calcitriol supplement, his seizures achieved partially remission. Conclusions We report a case of PHP1a or 1c with a novel frameshift mutation in GNAS gene in a patient presenting with AHO, as well as TSH and partial gonadotropin resistance. This mutation in this case has not been reported in literature and adds to the spectrum of genetic mutations related to PHP.

International audience; Active vitamin D analogs and calcimimetics are the main therapies used for treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Peripheral blood mononuclear cells of 19 pediatric patients with CKD1-5D and 6 healthy donors (HD) were differentiated into mature osteoclasts with receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of single or combined treatment with active vitamin D (1.25-D) and/or calcimimetic KP2326 were evaluated on osteoclastic differentiation and osteoclastic-mediated bone resorption. Although 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when glomerular filtration rate decreased. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through a putative activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited osteoclast-mediated bone resorption. Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however, to a different extent. There is a progressive resistance to 1.25-D in advanced CKD that is not found with KP2326. KP2326 also inhibits bone resorption. Given that 1.25-D has no effect on osteoclastic resorption activity and that calcimimetics also have direct anabolic effects on osteoblasts, there is an experimental rationale that could favor the use of decreased doses of 1.25-D with low doses of calcimimetics in SHPT in dialysis to improve the underlying osteodystrophy. However, this last point deserves confirmatory clinical studies. © 2020 American Society for Bone and Mineral Research.

Anonychia refers to the absence of nail plates owing to an autosomal dominant or recessive inheritance. Congenital anonychia is a rare condition that may be associated with other ectodermal or mesodermal malformations like epidermolysis bullosa, (deafness, onychodystrophy, osteodystrophy, and mental retardation) syndrome and Iso-Kikuchi syndrome. Here, we report 3 cases with anonychia congenita appearing in different generations of a single family in Kingdom of Saudi Arabia.

Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright’s hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as “inactivating PTH/PTHrP signaling disorder type 2” (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype–phenotype correlation of this disease. An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features. The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband’s mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1–7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described. We report a kindred harboring a large GNAS deletion. A genotype–phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother.

Reports on the prevalence of torus mandibularis among dialysis patients have been limited and inconclusive. A wide variety of oral manifestations has been found in patients with hyperparathyroidism. Furthermore, uremia-related changes in facial bone structures have been described in the literature. This prospective observational study examined 322 hemodialysis patients treated at the Chang Gung Memorial Hospital from 1 August to 31 December 2016. Two subgroups were identified: patients with torus mandibularis (n = 25) and those without (n = 297). Clinical oral examinations including inspection and palpation were employed. Our study found that most mandibular tori were symmetric (84.0%), nodular (96.0%), less than 2 cm in size (96.0%), and located in the premolar area (92.0%). Poor oral hygiene was observed among these patients, with 49.7% and 24.5% scoring 3 and 4, respectively, on the Quigley-Hein plaque index. More than half (55.0%) of patients lost their first molars. Multivariate logistic regression analysis revealed that blood phosphate level (odds ratio = 1.494, p = 0.029) and younger age (odds ratio = 0.954, p = 0.009) correlated significantly with torus mandibularis. The prevalence of torus mandibularis in patients receiving hemodialysis in this study was 7.8%. Younger age and a higher blood phosphate level were predictors for torus mandibularis in these patients.

Background The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright’s hereditary osteodystrophy (AHO), and ectopic ossification. Methods This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively. Results Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR. Conclusions Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

Osteogenesis imperfecta (OI) is a rare congenital osteodystrophy. Patients with OI present with osteoporosis, extreme bone fragility and severe deformities of the lower limbs, which predispose them to frequent fractures. The aim of our study is to describe the minimally invasive osteotomy technique to correct the tibial deformities in patients with OI type III, using the Fassier-Duval (FD) intramedullary nailing, which is considered the gold standard in this kind of surgery. We analyzed the results obtained from 14 patients with OI type III, treated for tibial deformities with the minimally invasive percutaneous osteotomy technique and osteosynthesis with the FD telescopic nail. The results were compared with that of a control group composed of 18 patients with OI type III, treated for tibial deformities with open technique osteotomies and osteosynthesis with FD telescopic nail. The follow-up was set at 18 months postoperatively. The data concerning the following were collected from the two groups: duration of surgery, number of osteotomies performed, postoperative pain, time required for functional recovery, and for the formation of bone callus. To analyze the variations in the quality of life, all the patients were given the Pediatric Outcomes Data Collection Instrument questionnaire, before surgery and at the end of the follow-up. In patients who underwent corrective surgery with the percutaneous technique, the average duration of surgery was inferior, the postoperative pain was significantly lower, the recovery of 90° range of motion of knee flexion was reached at an average of 37.8 days, and they ambulated bearing full weight on the leg without auxiliary aids on average 45 days after surgery. The Pediatric Outcomes Data Collection Instrument questionnaire values were satisfactory in both groups. The osteosynthesis with the FD telescopic nail, performed with the minimally invasive surgical technique, has improved the management of deformities in OI. The minimally invasive technique, however, requires the maturation of three distinct learning curves: surgery on patients with OI, open technique with the FD nail, and percutaneous technique with the FD nail.

Publisher Copyright: © 2021, The Author(s). Bone histomorphometric analysis is the most accurate method for the evaluation of bone turnover, but non-invasive tools are also required. We studied whether bone biomarkers can predict high bone turnover determined by bone histomorphometry after kidney transplantation. We retrospectively evaluated the results of bone biopsy specimens obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover between 2000 and 2015. Bone biomarkers were acquired concurrently. Of 813 kidney transplant recipients, 154 (19%) biopsies were taken at a median of 28 (interquartile range, 18–70) months after engraftment. Of 114 patients included in the statistical analysis, 80 (70%) presented with high bone turnover. Normal or low bone turnover was detected in 34 patients (30%). For discriminating high bone turnover from non-high, alkaline phosphatase, parathyroid hormone, and ionized calcium had the areas under the receiver operating characteristic curve (AUCs) of 0.704, 0.661, and 0.619, respectively. The combination of these markers performed better with an AUC of 0.775. The positive predictive value for high turnover at a predicted probability cutoff of 90% was 95% while the negative predictive value was 35%. This study concurs with previous observations that hyperparathyroidism with or without hypercalcemia does not necessarily imply high bone turnover in kidney transplant recipients. The prediction of high bone turnover can be improved by considering alkaline phosphatase levels, as presented in the logistic regression model. If bone biopsy is not readily available, this model may serve as clinically available tool in recognizing high turnover after engraftment.

Purpose: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS­-inactivating mutations are classified as “inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2.” This study reports a case of mild POH overlap syndrome to improve understanding of genotype–phenotype correlations.Methods: A 13-year-and-6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies.Results: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation.Conclusion: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

Objectives: To study computed tomography findings in Paget's disease of temporal bone (PDTB) and analyze the relations between otic capsule bone mineral density values measured in Hounsfield Units (HU) and hearing loss (HL). Study Design: Observational case-control study. Setting: Tertiary referral center. Patients: Radiographically confirmed PDTB cases and control group. Intervention: Diagnostic. Main Outcome Measures: Hearing thresholds and computed tomography bone density values. Results: Twenty-three ears in the case group (PDTB) and 27 control ears were included. In the PDTB group, HL was found in 87% of the ears (43% mixed) and an air-conduction threshold of 50.7 dB (SD = 19.8). In the control group, 48% of the ears showed HL (7% mixed) and an air-conduction threshold of 34.5 dB (SD = 20.6) was found; the difference was statistically significant (p < 0.05). Measurements of bone density (HU) in the otic capsule (regions of interest [ROI] 1 and 2) and in the petrous bone (ROI 3) were significantly lower (p < 0.05) in the PDTB group than in controls. The PDTB group presented a significant association between otic capsule bone density in ROI 1 and mean otic capsule density with air and bone-conduction thresholds (p < 0.05). In controls, no association was observed between any density value and audiometric thresholds. Conclusion: PDTB patients showed more frequent HL, lower thresholds, and a higher proportion of mixed HL than controls. Bone density (HU) was decreased in all ROIs in PDTB patients in comparison with controls. Bone density in the otic capsule was associated with HL in PDTB patients, but no association was observed between bone density and HL in controls.

Background DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures; MIM 220500) is a rare multisystem genetic disorder, mainly characterized by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficit, and seizures. The disease is caused by homozygous or compound heterozygous mutation in the TBC1 domain family member 24 (TBC1D24) gene (gene locus/MIM 613577) on chromosome 16p13. Objectives We report the first case of DOORS syndrome from Indonesia. Materials and methods A review of the literature was conducted and cases compared. Results A 27-day-old baby girl was brought to us with a history of recurrent seizures and absence of all finger- and toenails since birth. In addition, physical examination revealed left eye strabismus and a single transverse palmar crease on both hands. X-rays of the hands and feet showed absence of the distal phalanx of her right and left fingers II-V and the distal phalanx of her right and left toes I-V, respectively. Brainstem-evoked response audiometry test revealed profound bilateral sensorineural deafness. Pentalogy of Fallot was diagnosed by echocardiography, while an abnormal diffuse epileptiform pattern was found on electroencephalography. Conclusion This is the first report of an association between pentalogy of Fallot and single transverse palmar crease in DOORS syndrome.

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.

Objectives The objective of this paper is to report a peculiar case of a patient with pseudohypoparathyroidism type 1b (PHP1B). Pseudohypoparathyroidism (PHP) refers to a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) concentrations as the result of end-organ unresponsiveness to PTH. Case presentation We present a 14-year-old boy, who was admitted with severe symptomatic hypocalcaemia, absence of dysmorphic features and Albright's hereditary osteodystrophy features. Laboratory investigations revealed markedly low serum calcium, high phosphate, markedly elevated PTH levels and vitamin D insufficiency, while magnesium, albumin, ALP and TSH were normal. The clinical and laboratory findings were consistent with PHP1B. Molecular analysis revealed loss of methylation at the AB DMR of the GNAS locus, confirming the diagnosis. Yet no STX16 deletion was detected. Conclusions It is possible that delSTX16- patients carry a defect in an element that controls the methylation both at the GNAS-A/B DMR and at the GNAS-AS2. This rare case emphasizes the need of individualized molecular analysis in PHP1B patients in order to elucidate the possible molecular defect.

Current multifactorial age estimation methods are based on radiography, however, in the forensic field there is growing interest in using magnetic resonance imaging (MRI). With regard to the carpal region, MRI provides more information for defining the individual ossification nuclei and the cartilage surrounding single bones. During the phase of bone growth, the progressive reduction of the cartilage layer is accompanied by the development of a cartilage-bone interface. The aim of our study was to create a new model for age estimation, based on the ratio between the area occupied by the nucleus of ossification (NO) and the surface of growth (SG) of each carpal bone, the latter derived by adding NO to the area of cartilage-bone interface. We analyzed 57 MRI scans of Italian subjects aged between 12 and 20 years, without growth diseases, endocrine disorders or osteodystrophy. Measurements of NO and SG areas were extracted using ImageJ software, and the ratio between the NO and SG of each bone (NOSG) was calculated. A multiple linear regression model was used to estimate the individual's age as a function of the variables: gender and wrist bone measurements. The results showed that the best model was obtained with 6 predictors (nvmax=6): Gender, and the NOSG of the Trapezoid, Trapezium, Scaphoid, Pisiform, and Capitate. The median of the residuals (observed age minus predicted age) was -0.025 years, with an IQR of 0.19 years. Thus a new forensic approach to age assessment using MRI is introduced in this paper, which gives the preliminary results.

The clinical phenotype of pseudohypoparathyroidism (PHP) is caused by Albright's Hereditary Osteodystrophy (AHO). Often, "round face" the only facial clinical sign reported in the literature. The aim of this study was to highlight various cranio-maxillofacial clinical findings associated with AHO.Four patients presented with PHP type 1a. Only one patient exhibited the classical round face. All patients exhibited dental anomalies, class III malocclusion with maxillary retrusion, and a copper beaten appearance of the skull. One suffered from craniosynostosis.The frequency of craniofacial and dental features associated with malocclusion should prompt careful follow-up, particularly during facial growth, in patients with AHO.

Otosclerosis/otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to progressive hearing loss. Diagnosis is usually clinical, based on the findings of anamnesis, physical examination, and audiometric evaluation. However, high-resolution computed tomography scan and MRI have played an important role in the diagnosis and therapeutic approach of otosclerosis and in assisting in the differential diagnosis. The therapeutic approach is aimed at preventing, or at least minimizing, disease progression while attempting to restore hearing. The use of sodium fluoride and bisphosphonates can be an important adjunct, perhaps even primary treatment, in managing active lesions.

INTRODUCTION Factors associated with osteodystrophy in predialysis patients are poorly understood. In the present study, we attempted to evaluate the impact of body composition and hormonal regulatory factors on the bone microstructure in a group of men with chronic kidney disease (CKD) stages 3 and 4. MATERIALS AND METHODS 46 men, aged 50 - 75 years, with previously unrecognized CKD were evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT), and dual-energy X-ray absorptiometry (DXA). HR-pQCT parameters were correlated with estimated glomerular filtration rate (eGFR), age, body mass index (BMI), muscle mass index (MMI), and biochemistry. RESULTS As compared to patients in stage 3 CKD, those with stage 4 CKD showed lower serum 25-hydroxyvitamin D (25(OH)D) and bicarbonate levels, and higher serum fibroblast growth factor 23 (FGF-23) and parathyroid hormone (PTH) levels. They also exhibited lower total, trabecular, and cortical volumetric bone mineral density, lower trabecular bone volume/tissue volume, trabecular number, trabecular and cortical thickness, and increased heterogeneity of the trabecular network. In the whole cohort, cortical bone density and thickness were negatively associated with age, PTH, and FGF-23, and positively with BMI. Trabecular bone parameters were positively associated with MMI and 25(OH)D. After simultaneously adjusting for age and eGFR, BMI, and MMI remained significantly associated with bone microstructural variables. CONCLUSION HR-pQCT showed significant differences in bone microstructure in stage 4 vs. stage 3 CKD patients. Increased BMI, probably due to increased muscle mass, may favorably affect bone architecture in predialysis CKD patients. .

Aim: To assess the cost-effectiveness of nutrition education by dedicated dietitians (DD) for hyperphosphatemia management among hemodialysis patients.Materials and methods: This was a trial-based economic evaluation in 12 Lebanese hospital-based units. In total, 545 prevalent patients were cluster randomized to DD, trained hospital dietitian (THD), and existing practice (EP) groups. During Phase I (6 months), DD (n=116) received intensive education by DD trained on renal nutrition, THD (n=299) received care from trained hospital dietitians, and EP (n=130) received usual care from untrained hospital dietitians. Patients were followed-up during Phase II (6 months).Results: At baseline, EP had the lowest weekly hemodialysis time, and DD had the highest serum phosphorus and malnutrition-inflammation score. The additional costs of the intervention were low compared with the societal costs (DD: $76.7, $21,007.7; EP: $4.6, $18,675.4; THD: $17.4, $20,078.6, respectively). Between Phases I and II, DD showed the greatest decline in services use and societal costs (DD: -$2,364.0; EP: -$1,727.7; THD: -$1,105.7). At endline, DD experienced the highest decrease in adjusted serum phosphorus (DD: -0.32; EP: +0.16; THD: +0.04mg/dL), no difference in quality-adjusted life-years (QALY), and the highest societal costs. DD had a cost-effectiveness ratio of $7,853.6 per 1mg decrease in phosphorus, compared with EP; and was dominated by THD. Regarding QALY, DD was dominated by EP and THD. The results were sensitive to changes in key parameters.Limitations: The analysis depended on numerous assumptions. Interpreting the results is limited by the significant baseline differences in key parameters, suggestive of higher baseline societal costs in DD.Conclusions: DD yielded the greatest effectiveness and decrease in societal costs, but did not affect QALY. Regarding serum phosphorus, DD was likely to be cost-effective compared with EP, but had a low cost-effectiveness probability compared with THD. Regarding QALY, DD was not likely to be cost-effective. Assessing the long-term cost-effectiveness of DD, on similar groups, is recommended.

Pseudohypoparathyroidism (PHP) is an extremely rare group of disorders. It is a spectrum of disorders caused by end organ resistance to parathyroid hormone (PTH) and is represented by impaired signalling that activates cAMP dependent pathways via alpha subunit of G-protein (GS). It is characterised by hypocalcemia, hyperphosphatemia, raised PTH levels due to insensitivity to biological activity of PTH, and normal renal function tests. We describe a case of 10-year girl who presented with fear of falling down from heights. Her laboratory evaluation and skeletal survey showed evidence of PHP along with features of Albright's hereditary osteodystrophy (AHO) pointing towards the diagnosis of PHP type 1a.

Hyperphosphatemia is common in chronic kidney disease (CKD). Often seen as the "silent killer" because of its dramatic effect on vascular calcifications, hyperphosphatemia explains, at least partly, the onset of the complex mineral and bone disorders associated with CKD (CKD-MBD), together with hypocalcemia and decreased 1-25(OH)2 vitamin D levels. The impact of CKD-MBD may be immediate with abnormalities of bone and mineral metabolism with secondary hyperparathyroidism and increased FGF23 levels, or delayed with poor growth, bone deformities, fractures, and vascular calcifications, leading to increased morbidity and mortality. The global management of CKD-MBD has been detailed in international guidelines for adults and children, however, with difficulties to obtain an agreement on the ideal PTH targets. The clinical management of hyperphosphatemia is a daily challenge for nephrologists and pediatric nephrologists, notably because of the phosphate overload in occidental diets that is mainly due to the phosphate "hidden" in food additives. The management begins with a dietary restriction of phosphate intake, and is followed by the use of calcium-based and non-calcium-based phosphate binders, and/or the intensification of dialysis. The objective of this review is to provide an overview of the pathophysiology of hyperphosphatemia in CKD, with a focus on its deleterious effects and a description of the clinical management of hyperphosphatemia in a more global setting of CKD-MBD.

Background and objectives Over the past decade, the management of CKD–mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis. Design, settings, participants, & measurements Sixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performed baseline bone biopsies while the patients were on dialysis and repeated the procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantation was not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently. Results A total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from 8% to 38%. Abnormal bone mineralization increased in transplant recipients from 33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings. Conclusions Bone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

Aim: Renal failure is a growing public health problem, and is mainly treated by hemodialysis. This study aims to estimate the societal costs of hemodialysis in Lebanon. Methods: This was a quantitative, cross-sectional cost-of-illness study conducted alongside the Nutrition Education for Management of Osteodystrophy trial. Costs were assessed with a prevalence-based, bottom-up approach, for the period of June-December 2011. The data of 114 patients recruited from six hospital-based units were collected through a questionnaire measuring healthcare costs, costs to patients and family, and costs in other sectors. Recall data were used for the base-case analysis. Sensitivity analyses employing various sources of resources use and costs were performed. Costs were uprated to 2015US$. Multiple linear regression was conducted to explore the predictors of societal costs. Results: The mean 6-month societal costs were estimated at $9,258.39. The larger part was attributable to healthcare costs (91.7%), while costs to patient and family and costs in other sectors poorly contributed to the total costs (4.2% and 4.1%, respectively). In general, results were robust to sensitivity analyses. Using the maximum value for hospitalization resulted in the biggest difference (+15.5% of the base-case result). Female gender, being widowed/divorced, having hypertension comorbidity, and higher weekly time on dialysis were significantly associated with greater societal costs. Limitations: Information regarding resource consumption and cost were not readily available. Rather, they were obtained from a variety of sources, with each having its own strengths and limitations. Conclusion: Hemodialysis represents a high societal burden in Lebanon. Using extrapolation, its total annual cost for the Lebanese society is estimated at $61,105,374 and the mean total annual cost ($18,516.7) is 43.70% higher than the gross domestic product per capita forecast for 2015. Measures to reduce the economic burden of hemodialysis should be taken, by promoting chronic kidney disease's prevention and encouraging transplantation.

Osteodystrophy is a frequent complication in primary sclerosing cholangitis (PSC). The aim was to test the feasibility of vertebral bone diffusion-weighted imaging (DWI) in routine liver MRI for detection of osteoporosis using dual-energy X-ray absorptiometry (DXA) as gold standard. Forty PSC patients (50 ± 12.6 years) and ten controls (49.5 ± 13.0 years) were scanned using a DWI spin echo echo-planar sequence (b-factors 0–800 s/mm2) on a 3-T MRI system and DXA (76 kVp). The apparent diffusion coefficient (ADC) and T-score were correlated to laboratory and clinical details using Pearson correlation. In DXA-diagnosed osteoporosis (n = 3) and osteopenia (n = 12), the mean ADC was decreased (0.26 ± 0.03 and 0.30 ± 0.07 × 10−3 mm2/s) compared to patients with normal DXA scan results (n = 25; 0.32 ± 0.06 × 10−3 mm2/s). No significant correlation of the ADC and T-score (r = 0.24; p = 0.13) was found, but the T-score correlated significantly to disease duration (r = −0.33; p = 0.04). In patients with prednisolone therapy (n = 7), the DXA T-score was significantly lower (−1.46 ± 0.49 vs. −0.16 ± 0.23; p = 0.03). Diffusion-weighted MRI of the vertebral spine is a feasible technic to detect diffusion alterations caused by osteoporosis but lacks diagnostic capacities for diagnosing minor reductions of the bone mineral density detected by DXA.

Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. This review on hereditary deafness focuses on three examples considered at first glance to be uncomplicated, however, upon inspection, are enigmatic and ripe for future research efforts. The three examples of clinical and genetic complexities are drawn from studies of (i) Pendred syndrome/DFNB4 (PDS, OMIM 274600), (ii) Perrault syndrome (deafness and infertility) due to mutations of CLPP (PRTLS3, OMIM 614129), and (iii) the unexplained extensive clinical variability associated with TBC1D24 mutations. At present, it is unknown how different mutations of TBC1D24 cause non-syndromic deafness (DFNB86, OMIM 614617), epilepsy (OMIM 605021), epilepsy with deafness, or DOORS syndrome (OMIM 220500) that is characterized by deafness, onychodystrophy (alteration of toenail or fingernail morphology), osteodystrophy (defective development of bone), mental retardation, and seizures. A comprehensive understanding of the multifaceted roles of each gene associated with human deafness is expected to provide future opportunities for restoration as well as preservation of normal hearing.

Diabetes and osteoporosis are rapidly growing diseases. The link between the high fracture incidence in diabetes as compared with the non-diabetic state has recently been recognized. While this review cannot cover every aspect of diabetic osteodystrophy, it attempts to incorporate current information from the First International Symposium on Diabetes and Bone presentations in Rome in 2014. Diabetes and osteoporosis are fast-growing diseases in the western world and are becoming a major problem in the emerging economic nations. Aging of populations worldwide will be responsible for an increased risk in the incidence of osteoporosis and diabetes. Furthermore, the economic burden due to complications of these diseases is enormous and will continue to increase unless public awareness of these diseases, the curbing of obesity, and cost-effective measures are instituted. The link between diabetes and fractures being more common in diabetics than non-diabetics has been widely recognized. At the same time, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures. Although it cannot cover every aspect of diabetic osteodystrophy, this review will attempt to incorporate current information particularly from the First International Symposium on Diabetes and Bone presentations in Rome in November 2014.

DOOR syndrome is an extremely rare genetic disorder. "DOOR″ is an acronym to describe the combination of: deafness, onychodystrophy, osteodystrophy and mental retardation. We present a patient, with all of the above-mentioned main symptoms, that was rehabilitated with convencional hearing aids. The presented case suggested that every case of deafness and abnormal nails and phalanges in the hands and feet should have a clinical diagnosis of possible DOOR syndrome. Based on embryological process, congenital abnormal nails or phalanges highlights the importance for detailed hearing screening.

Introduction: Otospongiosis is temporal bone osteodystrophy, characterized by disordered bone resorption and neoformation in genetically predisposed individuals. Clinically, otospongiosis is characterized by progressive conductive and/or mixed hearing loss and by tinnitus. Objective: A review of the last two decades of publications that report the degree of tinnitus improvement with stapes surgery. Methods: 125 articles published in the last 20 years mentioning the relationship between otosclerosis and tinnitus. Literature has always shown that the hearing improvement after stapes surgery was the main result sought and found. However, recent articles has reinforced the need for surgery for the tinnitus improvement. The ideal time to assess tinnitus through different scales is in the sixth month post-operative. The estimated average hearing improvement is 93% and tinnitus is 85.52%. Results: Summaries of 12 articles were reviewed which fulfilled the search criteria of the survey, and 8 studies were included in the study according the selection criteria. This studies investigating the degree of tinnitus improvement with stapes surgery, using different scales as: tinnitus functional index, visual analog scale, tinnitus functional index and visual analog scale, visual analog scale and “questionnaire asking about tinnitus”, Newman's method and Tinnitus Score Advocated by the Japan Audiological Society. The total of the samples of the evaluated articles was of 254 participants. Conclusion: We conclude that stapes surgery is effective for the treatment of tinnitus (average improvement is 85.52%), and hearing loss (average improvement is 93%). When deciding about the surgical indication in patients with otosclerosis, the presence and level tinnitus should be considered as well as the level of hearing. Resumo: Introdução: A otosclerose é uma osteodistrofia do osso temporal, caracterizada pela reabsorção e neoformação óssea desordenadas em indivíduos geneticamente predispostos. Clinicamente, a otosclerose é caracterizada por perda auditiva progressiva condutiva e/ou mista e por zumbido. Objetivo: Uma revisão das últimas duas décadas de publicações que relatam o grau de melhora do zumbido com a estapedectomia Método: Foram analisados 125 artigos publicados nos últimos 20 anos que mencionavam a relação entre otosclerose e zumbido. A literatura sempre mostrou a melhoria auditiva como principal objetivo e resultado da estapedectomia. No entanto, artigos recentes reforçaram a necessidade de cirurgia para a melhoria do zumbido. O momento ideal para avaliar o zumbido através de diferentes escalas é no sexto mês pós-operatório. A melhoria auditiva média estimada é de 93% e a do zumbido, de 85,52%. Resultados: Foram revisados resumos de 12 artigos que preencheram os critérios de pesquisa, sendo incluídos no estudo 8 artigos de acordo com os critérios de seleção. Este estudo investiga o grau de melhora do zumbido com a estapedectomia, utilizando diferentes escalas: tinnitus functional index, escala visual analógica, tinnitus functional index e escala visual analógica, escala visual analógica e “questionário sobre o zumbido”, método de Newman e o Tinnitus Score Advocated, da Sociedade Audiológica do Japão (Japan Audiological Society). O total das amostras dos artigos avaliados foi de 254 participantes. Conclusão: Concluímos que a estapedectomia é bastante eficaz no tratamento do zumbido (melhora média de 85,52%) e perda auditiva (melhora média de 93%). Ao decidir sobre a indicação cirúrgica em pacientes com otosclerose, a presença e o nível de zumbido devem ser considerados, assim como o nível de audição. Keywords: Otosclerosis, Tinnitus, Stapes surgery, Palavras-chave: Otosclerose, Zumbido, Estapedectomia

Progressive chronic kidney diseases (CKDs) are on the rise worldwide. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Here we report the generation of a CKD mouse model through the inducible podocyte-specific ablation of an essential endogenous molecule, the chromatin structure regulator CCCTC-binding factor (CTCF), which leads to rapid podocyte loss (iCTCFpod–/–). As a consequence, iCTCFpod–/– mice develop severe progressive albuminuria, hyperlipidemia, hypoalbuminemia, and impairment of renal function, and die within 8–10 weeks. CKD progression in iCTCFpod–/– mice leads to high serum phosphate and elevations in fibroblast growth factor 23 (FGF23) and parathyroid hormone that rapidly cause bone mineralization defects, increased bone resorption, and bone loss. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces an animal model with significant advantages for the study of CKD progression, and it highlights the need for podocyte-protective strategies for future kidney therapeutics.

25-hydroxyvitamin D [25(OH)D] may not optimally indicate vitamin D receptor activity. Higher concentrations of its catabolic product 24,25-dihydroxyvitmin D [24,25(OH)2D] and a higher ratio of 24,25(OH)2D to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide additional information on receptor activity. We compared the strength of associations of these markers with serum PTH concentrations, hip bone mineral density (BMD), and risk of incident hip fracture in community-living older participants in the Cardiovascular Health Study. Among 890 participants, the mean age was 78 years, 60% were women, and the mean 25(OH)D was 28 ± 11 ng/ml. In cross-sectional analysis, the strength of association of each vitamin D measure with PTH was similar; a 1% higher 25(OH)D, 24,25(OH)2D, and VMR were associated with 0.32%, 0.25%, and 0.26% lower PTH, respectively (p< 0.05 for all). Among 358 participants with available BMD data, we found no associations of 25(OH)D or VMR with BMD, whereas higher 24,25(OH)2D was modestly associated with greater hip BMD (1% higher 24,25(OH)2D associated with 0.04% [95% CI 0.01−0.08%] higher BMD). Risk of incident hip fracture risk was evaluated using a case-cohort design. There were 289 hip fractures during a mean follow up time of 8.4 years. Both higher 24,25(OH)2D and VMR were associated with lower risk of hip fracture (HR per SD higher, 0.73 [0.61, 0.87] and 0.74 [0.61, 0.88], respectively) whereas 25(OH)D was not associated with hip fracture (HR 0.93 [0.79, 1.10]). We conclude that evaluating vitamin D status by incorporating assessment of 24,25(OH)D and the VMR provides information on bone health above and beyond 25(OH)D alone.

Objective Assess the effect of intensive nutrition education by trained dedicated dietitians on osteodystrophy management among hemodialysis patients. Methods Randomized controlled trial in 12 hospital-based hemodialysis units equally distributed over clusters 1 and 2. Cluster 1 patients were either assigned to usual care ( n = 96) or to individualized intensive staged-based nutrition education by a dedicated renal dietitian ( n = 88). Cluster 2 patients ( n = 210) received nutrition education from general hospital dietitians, educating their patients at their spare time from hospital duties. Main outcomes were: (1) dietary knowledge(%), (2) behavioral change, (3) serum phosphorus (mmol/L), each measured at T0 (baseline), T1 (post 6 month intervention) and T2 (post 6 month follow up). Results Significant improvement was found only among patients receiving intensive education from a dedicated dietitian at T1; the change regressed at T2 without statistical significance: knowledge (T0: 40.3; T1: 64; T2: 63) and serum phosphorus (T0: 1.79; T1: 1.65; T2: 1.70); behavioral stages changed significantly throughout the study (T0: Preparation, T1: Action, T2: Preparation). Conclusion The intensive protocol showed to be the most effective. Practice implications Integrating dedicated dietitians and stage-based education in hemodialysis units may improve the nutritional management of patients in Lebanon and countries with similar health care systems.

Osteocytes respond to kidney damage by increasing production of secreted factors important to bone and mineral metabolism. These circulating proteins include the antianabolic factor, sclerostin, and the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Elevated sclerostin levels correlate with increased FGF23, localized reduction in Wnt/β-catenin signaling in the skeleton and reduced osteoblast differentiation/activity. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders but additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent preclinical studies support this hypothesis, as treatment with antisclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation suggesting additional roles outside the skeleton in normal and disease states. In patients with chronic kidney disease (CKD), serum levels are elevated several fold relative to healthy individuals. Emerging data suggest that these changes are associated with increased fracture rates but the relationship between sclerostin and cardiovascular disease is unclear. Additional epidemiologic studies that examine stage specific and patient sub-populations are needed to assess whether sclerostin elevations influence comorbidities associated with CKD.

A long-term dialysis patient with end-stage renal disease (ESRD) also referred to as chronic kidney disease (CKD) due to IgA nephropathy complicated by severe secondary hyperparathyroidism and renal osteodystrophy was successfully treated with dental implant-supported fixed prostheses. Phosphate binders, vitamin D, calcium cinacalcet calcimimetic therapy, and dialysis 3 times weekly had been instituted with standard divalent ion serum assessments. Successful control of the patient's secondary hyperparathyroidism was achieved. Long and wide diameter implants were used with an anterior guidance occlusion scheme to reduce the per-square-millimeter off-axial implant force delivered to the bone. Patients with ESRD and renal osteodystrophy may be successfully surgically and prosthetically treated with long wide dental implants supporting fixed full arch splinted dental prostheses with an appropriate occlusal scheme.

Interstitial deletions of the long arm of chromosome 20 are rarely reported in the literature. We report a 2-year-old child with a 2.6 Mb deletion of 20q13.32-q13.33, detected by microarray-based comparative genomic hybridization, who presented with poor growth, feeding difficulties, abnormal subcutaneous fat distribution with the lack of adipose tissue on clinical examination, facial dysmorphism and low bone mass. This report adds to rare publications describing constitutional aberrations of chromosome 20q, and adds further evidence to the fact that deletion of the GNAS complex may not always be associated with an Albright's hereditary osteodystrophy phenotype as described previously.

BackgroundThe Nutrition Education for Management of Osteodystrophy trial showed that stage-based nutrition education by dedicated dietitians surpasses existing practices in Lebanon with respect to lowering serum phosphorus among general haemodialysis patients. The present study explores the effect of nutrition education specifically on hyperphosphataemic patients from this trial.MethodsHyperphosphataemic haemodialysis patients were allocated to a dedicated dietitian (DD), a trained hospital dietitian (THD) and existing practice (EP) protocols. From time-point (t)-0 until t-1 (6 months), the DD group (n = 47) received 15 min of biweekly nutrition education by dedicated dietitians trained on renal nutrition; the THD group (n = 89) received the usual care from trained hospital dietitians; and the EP group (n = 42) received the usual care from untrained hospital dietitians. Patients were followed-up from t-1 until t-2 (6 months). Analyses used two-way repeated measures analysis of variance and Cohen's effect sizes (d).ResultsAt t-1, phosphataemia significantly decreased in all groups (DD:-0.27 mmol L-1; EP:-0.15 mmol L-1; THD:-0.12 mmol L-1; P ConclusionsThe results of the present study suggest that the DD protocol decreases serum phosphorus compared to EP and THD, at the same time as maintaining the nutritional status of hyperphosphataemic haemodialysis patients. Assessing the cost-effectiveness of the DD protocol is recommended.

BACKGROUND AND OBJECTIVES: In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT). RESULTS: SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS

Indoxyl sulfate is a uremic toxin, and cannot be removed efficiently by hemodialysis due to its protein-binding. Indoxyl sulfate induces cellular dysfunction by producing reactive oxygen species (ROS) such as superoxide by activating nicotinamide adenine dinucleotide phosphate oxidase, and by activating aryl hydrocarbon receptor through its uptake via organic anion transporters (OAT1 and OAT3). Indoxyl sulfate shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts, osteoclasts, and myocytes. Indoxyl sulfate stimulates the progression of chronic kidney disease (CKD), cardiovascular disease (CVD), osteodystrophy, and sarcopenia. The carbon adsorbent AST-120 might be useful to delay the progression of not only CKD but also CVD, osteodystrophy, and sarcopenia by adsorbing its precursor, indole, in the intestines, and consequently reducing the serum levels of indoxyl sulfate. In this review, the author provides an overview on the current status of knowledge on the effects of AST-120 on uremic toxins, CKD animals, CKD patients, and CKD patients with CVD, and safety of AST-120. A large clinical study (EPPIC-1 and EPPIC-2) has failed to demonstrate the efficacy of AST-120 on the progression of CKD. However, the post-hoc subgroup analysis suggested that AST-120 might delay the progression of CKD patients. Further clinical studies are required to demonstrate the clinical efficacy of AST-120 on the progression of CKD by administering AST-120 only to those patients with progressive CKD and good compliance.

CASE: The authors describe the case of an 8-year-old boy with pansynostosis in the context of Albright's hereditary osteodystrophy (AHO). This condition had lead to raised intracranial pressure (ICP). The elevated ICP was a consequence of the rigid skull impeding brain growth. Therefore, a decompressive cranioplasty was performed successfully, leaving further space for the growing brain. Affection of the central nervous system has been documented in AHO. However, affection of the skull bones has rarely been described in literature.CONCLUSION: We suggest that craniosynostosis may develop in patients with AHO and other types of pseudohypoparathyroidism (PHP). Furthermore, we suggest regular head circumference-for-age and ophthalmic examination for children with AHO or other types of PHP.

In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD–mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-α, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder.

Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.

Hepatic encephalopathy (HE) is a reversible neuropsychiatric disorder in cirrhotic patients. The cognitive dysfunction and increased accidental falls in HE and osteodystrophy in cirrhotic patients may contribute to orthopedic fractures. This study investigated the fracture incidence and risk factors in cirrhotic patients with HE.In total, 3764 cirrhotic patients with HE were identified from the Taiwan National Health Insurance database between 2000 and 2009. The fracture incidence of the HE patients was compared with that of 3764 age-, sex-, and comorbidity-matched cirrhotic patients without HE and non-cirrhotic controls. Cox proportional hazard models were used to estimate the risk of fracture in the HE patients.Cirrhotic patients with and without HE had comparable increased risks of fracture (p0.05) and cumulative incidences of fracture than controls (log-rank p0.001). The estimated fracture rates were 7.09% for the HE group, 7.72% for the cirrhosis without HE group, and 4.05% for the controls, during the 18-month follow-up. The HE group had a higher incidence rate of skull fractures (IRR=2.61, 95% CI 1.04-6.57), but a lower rate of upper limb fractures (IRR=0.45, 95% CI 0.29-0.70) than the cirrhosis without HE group. Alcoholism, heart failure, and cerebrovascular disease were associated with increased risk of fracture in HE patients.Cirrhotic patients, with or without HE, are at an increased risk of orthopedic fractures. Skull fractures, rather than fractures in weight-bearing bones, are more frequently observed in HE patients, particularly those with comorbidities.

Background: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-α type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. Methods: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. Results: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. Conclusion: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes, especially by both the mother's bisphosphonate drug therapy and the amniocentesis performed during her pregnancy to drain polyhydramnios. In our analysis, those environmental factors could have interacted with an already altered genetic substratum, contributing to develop this rare combination of congenital disorders.

Results are presented of measurements of skeletal blood flow made in 80 patients with painful benign or malignant diseases of the skeleton, excluding patients with Paget's disease. In crush fracture osteoporosis, total bone blood flow was slightly lower than normal although skeletal perfusion was normal. High values of bone blood flow were seen in 14 20 patients with osteomalacia and 3 12 patients with primary hyperparathyroidism. Very high values, comparable to those seen in the most severely affected patients with Paget's disease, were seen in polyostotic fibrous dysplasia, 2 out of 4 cases of Engelmann's disease and 1 out of 3 cases of renal osteodystrophy. Results were less elevated in myositis ossificans, secondary skeletal involvement with breast and prostatic carcinomata, myelomatosis and sympathetic osteodystrophy.

Context: The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects. Objective: The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects. Design: With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain. Results: Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A/B:TSS-DMR. Multihormone resistance with no Albright’s hereditary osteodystrophy (AHO) signs (61/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18/407, 4%) and progressive osseous heteroplasia (7/407, 2%) were exclusively caused by point mutations. Conclusion: With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.

Background In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. Methods All children, SCOPUS: ar.j, info:eu-repo/semantics/published

Osteoporosis and osteomalacia are, to date, among the most common metabolic diseases in the world. Lately, an association between metabolic bone diseases and chronic liver disease has been increasingly reported, inducing many authors to create a new nosographic entity known as 'hepatic osteodystrophy.' The importance of such a condition is further increased by the morbidity of these two diseases, which greatly reduce the quality of life because of frequent fractures, especially vertebral and femoral neck ones. For this reason, early identification of high-risk patients should be routinely performed by measuring bone mass density. The explanation for the association between bone diseases and chronic liver disease is still uncertain, and involves many factors: from hypogonadism to use of corticosteroid drugs, from genetic factors to interferon therapy. To date, few studies have been conducted, and all with a small number of patients to establish definitive conclusions about the possible treatment, but some evidence is beginning to emerge about the safety and efficacy of bisphosphonates.