Etiopathogenesis of Hepatic Osteodystrophy in Wistar Rats with Cholestatic Liver Disease

The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct-ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 +/- A 336 vs. 30 days 1,062 +/- A 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine-paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.

Effects of Sevelamer Hydrochloride and Calcium Carbonate on Renal Osteodystrophy in Hemodialysis Patients

Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P = 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture.

Oral manifestations of Albright hereditary Osteodystrophy: a case report

Albright hereditary osteodystrophy is a hereditary metabolic disorder of dominant autosomal etiology that is commonly characterized by short stature, round face, small metacarpus and metatarsus, mental retardation, osteoporosis, subcutaneous calcification, variable hypocalcemia, and hyperphosphatemia. In this study, we report a clinical case of a 17-year-old woman with Albright hereditary osteodystrophy, and we discuss her clinical, radiographic, and laboratory test characteristics together with the oral manifestations, and we correlate them with the characteristics found in the literature. We also discuss the odontological management of treatment of related periodontal disease and planning for corrections of related malocclusions.

Nutritional fibrous osteodystrophy in goats

Seven out of 25 goats from a southern Brazilian flock developed nutritional fibrous osteodystrophy. Affected animals were younger than 1 year of age and were confined in stalls and fed a concentrate ration containing 1:6 calcium:phosphorus ratio. The remaining flock (35 goats) was managed at pasture and showed no disease. Clinical signs were characterized by mandibular and maxillary enlargements, varying degrees of mouth opening and protruding tongue, dyspnea, apart of abnormalities of prehension and mastication. Affected animals had increased seric levels of phosphorus and parathormone, as well as higher alkaline phosphatase activity. Postmortem examination on three succumbed goats revealed bilateral enlargement of the maxilla and mandibula, and loose teeth, apart of multiple incomplete rib fractures in one of them. Severe diffuse proliferation of loose connective tissue surrounded the osteoid trabeculae, many of which were partially or completely non-mineralized. Mineralized osteoid trabeculae showed osteoclasts in the Howship's lacunae.

Cytokine accumulation in osteitis fibrosa of renal osteodystrophy

Bone marrow fibrosis occurs in association with a number of pathological states. Despite the extensive fibrosis that sometimes characterizes renal osteodystrophy, little is known about the factors that contribute to marrow accumulation of fibrous tissue. Because circulating cytokines are elevated in uremia, possibly in response to elevated parathyroid hormone levels, we have examined bone biopsies from 21 patients with end-stage renal disease and secondary hyperparathyroidism. Bone sections were stained with antibodies to human interleukin-1alpha (IL-1alpha), IL-6, IL-11, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-ß (TGF-ß) using an undecalcified plastic embedding method. Intense staining for IL-1alpha, IL-6, TNF-alpha and TGF-ß was evident within the fibrotic tissue of the bone marrow while minimal IL-11 was detected. The extent of cytokine deposition corresponded to the severity of fibrosis, suggesting their possible involvement in the local regulation of the fibrotic response. Because immunoreactive TGF-ß and IL-6 were also detected in osteoblasts and osteocytes, we conclude that selective cytokine accumulation may have a role in modulating bone and marrow cell function in parathyroid-mediated uremic bone disease.

Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease

Bone mass loss is a major complication of chronic cholestatic liver disease (CCD). However, the long-term impact of CCD on bone mass acquisition is unknown. We longitudinally assessed bone mineral density (BMD) and factors involved in bone remodeling in 9 children and adolescents with CCD Child-Pugh A (5 boys/4 girls) and in 13 controls (6 boys/7 girls). The groups were evaluated twice, at baseline (T0) and after 3 years (T1), when osteocalcin, deoxypyridinoline, 25-hydroxyvitamin-D, parathyroid hormone, insulin-like growth factor-I (IGF-I), and BMD (L1-L4, proximal femur and total body) were determined. Serum levels of receptor activator for nuclear factor kB ligand (RANKL) and osteoprotegerin were measured only at T1. Lumbar spine BMD was reanalyzed twice: after adjustment for bone age and to compensate for the height factor. Volumetric density was also estimated mathematically in L2-L4. The BMD of L1-L4 was lower in the CCD group (Z-score at T0: control = -1.2 ± 0.8 vs CCD = -2.2 ± 1.4, P < 0.05; T1: control = -0.7 ± 0.8 vs CCD = -2.1 ± 1.1, P < 0.05). Osteocalcin and deoxypyridinoline were similar for the two groups. The CCD group presented lower IGF-I (Z-score at T1: control = 1.4 ± 2.8 vs CCD = -1.5 ± 1.0, P < 0.05) and RANKL (control = 0.465 ± 0.275 vs CCD = 0.195 ± 0.250 pM, P < 0.05) than control. Children with compensated CCD Child-Pugh A showed early impairment of bone acquisition, with the impact being more severe in an initial phase and then tapering in a slowly progressive way. Reduction in endocrine IGF-I has a crucial role in this process.

Fibrous Osteodystrophy in a Captive Common Eland Antelope (Taurotragus oryx).

Fibrous osteodystrophy (FO) is a common condition described mainly in domestic species, with only few cases described in wild ones kept in captivity. Herein we report a case of FO in a 2 yr-old female common eland antelope (Taurotragus oryx) maintained in captivity and fed with a horse pelleted ration plus hays. The animal showed a firm bilateral symmetrical enlargement of upper maxillary bones which was submitted to histological evaluation. Microscopic findings were those related to extensive bone resorption and fibroplasia.

Oral manifestations of Albright hereditary osteodystrophy: a case report.

Albright hereditary osteodystrophy is a hereditary metabolic disorder of dominant autosomal etiology that is commonly characterized by short stature, round face, small metacarpus and metatarsus, mental retardation, osteoporosis, subcutaneous calcification, variable hypocalcemia, and hyperphosphatemia. In this study, we report a clinical case of a 17-year-old woman with Albright hereditary osteodystrophy, and we discuss her clinical, radiographic, and laboratory test characteristics together with the oral manifestations, and we correlate them with the characteristics found in the literature. We also discuss the odontological management of treatment of related periodontal disease and planning for corrections of related malocclusions.

Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy

Chronic kidney diseasemineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild-type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-beta-catenin was observed both in mouse and human bones. Overall repression of Wnt/beta-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-?B ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/beta-catenin pathway is involved in the pathogenesis of renal osteodystrophy. (C) 2012 American Society for Bone and Mineral Research.

Facial lesions caused by renal osteodystrophy in a patient with chronic renal insufficiency: a case report

PURPOSE: Chronic renal insufficiency (CRI) is the last stage of a chronic renal condition in which the kidney loses its filtration and endocrine functions. Chronic endocrine hypofunction causes generalized damage to the body known as Uremic Syndrome, which affects the central nervous system as well as the cardiovascular, hematologic, dermatologic, ophthalmic, endocrine, respiratory, gastrointestinal and skeletal systems. The present study reports the case of a female patient with CRI who presented facial osteodystrophy of the osteitis fibrosa type, and highlights the main features of this condition. CASE DESCRIPTION: A 24-year old, female, Caucasian patient presented chronic glomerulonephritis recurrence and lost the transplanted kidney five years before, undergoing arteriovenous fistula hemodialysis three times a week. She presented swelling of the left masseter area with a hard consistency on palpation, covered by intact skin, swelling at the bottom of the left atrium, with a hard consistency on palpation, a mucosa-like color and absence of inflammation signs, suggesting expansive bone lesions on the face. These features were compatible with hyperparathyroidism brown tumor and/or osteodystrophy. The CT scan showed expansive bone lesions of heterogeneous appearance on the left jaw, maxilla/nasal floor, and right frontotemporal suture areas. The clinical and histopathological characteristics of the lesion, in association with PHT hormone high serum levels led to renal osteodystrophy diagnosis. The patient was referred to the nephrology services. CONCLUSION: Osteodystrophic bone alterations have a high prevalence in renal disease patients, and the dentist must take these alterations into consideration in bone lesion diagnosis for this specific group of patients.

Association of Changes in Bone Remodeling and Coronary Calcification in Hemodialysis Patients: A Prospective Study

Background: Vascular calcification is common and constitutes a prognostic marker of mortality in the hemodialysis population. Derangements of mineral metabolism may influence its development. The aim of this study is to prospectively evaluate the association between bone remodeling disorders and progression of coronary artery calcification (CAC) in hemodialysis patients. Study Design: Cohort study nested within a randomized controlled trial. Setting & Participants: 64 stable hemodialysis patients. Predictor: Bone-related laboratory parameters and bone histomorphometric characteristics at baseline and after 1 year of follow-up. Outcomes: Progression of CAC assessed by means of coronary multislice tomography at baseline and after 1 year of follow-up. Baseline calcification score of 30 Agatston units or greater was defined as calcification. Change in calcification score of 15% or greater was defined as progression. Results: Of 64 patients, 26 (40%) had CAC at baseline and 38 (60%) did not. Participants without CAC at baseline were younger (P < 0.001), mainly men (P = 0.03) and nonwhite (P = 0.003), and had lower serum osteoprotegerin levels (P = 0.003) and higher trabecular bone volume (P = 0.001). Age (P 0.003; beta coefficient = 1.107; 95% confidence interval [Cl], 1.036 to 1.183) and trabecular bone volume (P = 0.006; beta coefficient = 0.828; 95% Cl, 0.723 to 0.948) were predictors for CAC development. Of 38 participants who had calcification at baseline, 26 (68%) had CAC progression in 1 year. Progressors had lower bone-specific alkaline phosphatase (P = 0.03) and deoxypyridinoline levels (P = 0.02) on follow-up, and low turnover was mainly diagnosed at the 12-month bone biopsy (P = 0.04). Low-turnover bone status at the 12-month bone biopsy was the only independent predictor for CAC progression (P = 0.04; beta coefficient = 4.5; 95% Cl, 1.04 to 19.39). According to bone histological examination, nonprogressors with initially high turnover (n = 5) subsequently had decreased bone formation rate (P = 0.03), and those initially with low turnover (n = 7) subsequently had increased bone formation rate (P = 0.003) and osteoid volume (P = 0.001). Limitations: Relatively small population, absence of patients with severe hyperparathyroidism, short observational period. Conclusions: Lower trabecular bone volume was associated with CAC development, whereas improvement in bone turnover was associated with lower CAC progression in patients with high- and low-turnover bone disorders. Because CAC is implicated in cardiovascular mortality, bone derangements may constitute a modifiable mortality risk factor in hemodialysis patients.

K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients

The guidelines proposed by the Kidney Disease Outcomes Quality Initiative (K/DOQI) suggested that intact parathyroid hormone (iPTH) should be maintained in a target range between 150 and 300 pg ml(-1) for patients with stage 5 chronic kidney disease. Our study sought to verify the effectiveness of that range in preventing bone remodeling problems in hemodialysis patients. We measured serum ionized calcium and phosphorus while iPTH was measured by a second-generation assay. Transiliac bone biopsies were performed at the onset of the study and after completing 1 year follow-up. The PTH levels decreased within the target range in about one-fourth of the patients at baseline and at the end of the study. The bone biopsies of two-thirds of the patients were classified as showing low turnover and a one-fourth showed high turnover, the remainder having normal turnover. In the group achieving the target levels of iPTH 88% had low turnover. Intact PTH levels less than 150 pg ml(-1) for identifying low turnover and greater than 300 pg ml(-1) for high turnover presented a positive predictive value of 83 and 62%, respectively. Our study suggests that the iPTH target recommended by the K/DOQI guidelines was associated with a high incidence of low-turnover bone disease, suggesting that other biochemical markers may be required to accurately measure bone-remodeling status in hemodialysis patients.

Phosphate Binder Impact on Bone Remodeling and Coronary Calcification - Results from the BRiC Study

Background and Aims: Calcium-containing phosphate binders have been shown to increase the progression of vascular calcification in hemodialysis patients. This is a prospective study that compares the effects of calcium acetate and sevelamer on coronary calcification (CAC) and bone histology. Methods: 101 hemodialysis patients were randomized for each phosphate binder and submitted to multislice coronary tomographies and bone biopsies at entry and 12 months. Results: The 71 patients who concluded the study had similar baseline characteristics. On follow-up, the sevelamer group had higher levels of intact parathyroid hormone (498 +/- 352 vs. 326 +/- 236 pg/ml, p = 0.017), bone alkaline phosphatase (38 +/- 24 vs. 28 +/- 15 U/l, p = 0.03) and deoxypyridinoline (135 +/- 107 vs. 89 +/- 71 nmol/l, p = 0.03) and lower LDL cholesterol (74 +/- 21 vs. 91 +/- 28 mg/dl, p = 0.015). Phosphorus (5.8 +/- 1.0 vs. 6 +/- 1.0 mg/dl, p = 0.47) and calcium (1.27 +/- 0.07 vs. 1.23 +/- 0.08 mmol/l, p = 0.68) levels did not differ between groups. CAC progression (35 vs. 24%, p = 0.94) and bone histological diagnosis at baseline and 12 months were similar in both groups. Patients of the sevelamer group with a high turnover at baseline had an increase in bone resorption (eroded surface, ES/BS = 9.0 +/- 5.9 vs. 13.1 +/- 9.5%, p = 0.05), whereas patients of both groups with low turnover at baseline had an improvement in bone formation rate (BFR/BS = 0.015 +/- 0.016 vs. 0.062 +/- 0.078, p = 0.003 for calcium and 0.017 +/- 0.016 vs. 0.071 +/- 0.084 mu m(3)/mu m(2)/day, p = 0.010 for sevelamer). Conclusions: There was no difference in CAC progression or changes in bone remodeling between the calcium and the sevelamer groups. Copyright (C) 2008 S. Karger AG, Basel