Manifestations Of Bone Disease Research Articles

Mastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation

Osteoporosis and other manifestations of bone disease are frequent in patients with systemic mastocytosis (SM) in association with the presence of mast cell infiltrates in bone marrow, although the mechanisms behind bone disease remain poorly understood. We find that extracellular vesicles (EVs) released by neoplastic mast cells and present in the serum of patients with SM (SM-EVs) block osteoblast differentiation and mineralization in culture, and when injected into mice diminish the expression of osteoblast markers, and trabecular bone volume and microarchitecture. We demonstrate that miRNA-30a and miRNA-23a, increased in SM-EVs and neoplastic mast cell-derived EVs, attenuate osteoblast maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. Thus, SM-EVs carry and deliver miRNAs that epigenetically interfere with bone formation and can contribute to bone mass reduction in SM. These findings also suggest possibilities for novel approaches to the management of bone disease in mast cell proliferative disorders.

Serum osteocalcin level in end-stage renal disease patients on maintenance hemodialysis after parathyroidectomy in relation to parathyroid hormone level

BackgroundParathyroidectomy (PTX) is an effective treatment for refractory hyperparathyroidism in end-stage renal disease (ESRD) patients on maintenance hemodialysis (MHD). However, adynamic bone disease, a possible complication, is associated with persistent bone pain and increased fracture risk. Osteocalcin (OC) is a bone formation marker, produced by osteoblasts, stimulated by parathyroid hormone and active vitamin D, associated with overall survival. Late changes in its level after PTX need to be evaluated.AimThe aim of this study was to determine serum OC and its relation to intact parathyroid hormone (iPTH) in patients on MHD with and without a history of PTX.Patients and methodsThis case–control study was conducted on 50 patients with ESRD on MHD, subdivided into two groups (group I and group II), according to the history of PTX. Patients having diabetic mellitus or autoimmune disease were excluded. Patients were inquired about manifestations of bone disease. Serum concentrations of ionized total calcium, magnesium, phosphorus, alkaline phosphatase (ALP), iPTH, and OC (by ELISA) were determined. Serum OC concentration was also measured in the samples of 20 healthy participants (group III) to evaluate its reference value.ResultsBone fracture was present in nine patients with or without PTX, with no significant difference from the other patients, as regards the studied parameters. Patients with ESRD on MHD had a significantly higher serum OC level than controls (P<0.001). Serum OC in patients who underwent PTX, and with adynamic bone disease (iPTH<150 pg/ml) (group IA), was significantly lower than that in the corresponding subgroup without PTX (group 2A) (P=0.001); similarly, the two subgroups were different, as regards serum ALP (P<0.001) and serum iPTH (P<0.001). There were significant positive correlations between serum OC and total ALP and iPTH in the total patient sample (P<0.001 and <0.001, respectively).ConclusionAdynamic bone disease after PTX in patients on MHD in comparison with those who have not undergone PTX is associated with a lower level of bone formation marker OC.

The role of the oncologist

Several oncological and hematological malignancies may present with bone disease. Clinical manifestations of bone disease are mainly osteolytic and /or osteoblastic skeletal lesions. Preclinical models both in vivo and in vitro have been developed to study tumor cell biology within bone microenvironment and have allowed investigators to better understand pathogenesis of neoplastic bone disease. These studies represented the basis to design targeted drugs that were able to restore normal bone microenvironment and turnover. Among these drugs, bisphosphonates (BPs) are the current mainstay of bone disease treatment. Indeed, BPs have been shown to be very efficient drugs, and are able to revert neoplastic bone turnover. However, BPs may have important toxicity and among the main side effects, we recognize osteonecrosis of the jaw. Because of these sequelae, international oncology societies and networks have suggested clinical guidelines to allow clinical oncologists to use these drugs in order to obtain the best results with least toxicities. Furthermore, prevention and treatment strategies of BP side effects can be best achieved through close interaction with other related clinical practitioners such as the dentist and maxillofacial surgeon.

Antiepileptic Drugs and Bone Disease

Numerous studies have provided evidence of an association between antiepileptic drugs (AEDs) and adverse effects. Manifestations of bone disease in persons treated with AEDs include rickets, osteomalacia, osteoporosis, and fracture. There exists pathological and radiographic evidence of bone disease in persons with epilepsy treated with AEDs. As well, numerous biochemical abnormalities have been described including hypocalcemia, hypophosphatemia, reduced levels of biologically active vitamin D metabolites, hyperparathyroidism, and accelerated bone turnover, as measured by markers of bone formation and bone resorption. The AEDs most commonly reported as affecting bone include inducers of the cytochrome P450 enzyme system (phenytoin, phenobarbital, primidone, carbamazepine). In addition, there is growing evidence to suggest that valproate, an enzyme inhibitor, also affects bone. Limited data exists regarding the newer AEDs. Several mechanisms for AED-associated bone disease have been proposed, but no single mechanisms adequately addresses all the reported findings. Reported mechanisms include hepatic induction of the cytochrome P450 enzyme system leading to increased catabolism of vitamin, impaired absorption of calcium, inhibition of response to parathyroid hormone, hyperparathyroidism, impaired bone resorption and formation, vitamin K deficiency, and calcitonin deficiency. Few studies have evaluated the effect of treatment in bone disease associated with AEDs.

The spectrum of bone disease in 200 chronic hemodialysis patients: a correlation between clinical, biochemical and histological findings.

Renal osteodystrophy includes the complete range of mineral metabolism disorders that affect the skeleton in patients with chronic renal failure. 200 patients with end-stage renal disease and on dialysis were investigated regarding the clinical, biochemical and histological findings of bone disease. The spectrum of renal osteodystrophy consisted mainly of high turnover bone lesions (74.5%), including osteitis fibrosa in 57.5%. Patients with mild bone disease were on dialysis for shorter periods of time and were mostly asymptomatic. Patients with aluminum-related bone disease (16.5%) had the greatest aluminum exposure, either orally or parenterally, and together with patients with high turnover mixed disease, were the most symptomatic. Although on a non-regular basis, the vast majority of the patients (82.5%) had been receiving vitamin D. The incidence of adynamic bone disease was high (n = 8) among parathyroidectomized patients (n = 12). Significantly higher serum levels of alkaline phosphatase were observed in osteitis fibrosa. The use of calcitriol and phosphate-binding agents on a non-regular basis seems to be the reason for the apparent reduced response to the treatment of secondary hyperparathyroidism. Alkaline phosphatase has been shown to be a fair marker for bone turnover in patients with osteitis fibrosa. The severity of the clinical manifestations of bone disease correlates with the histological features of bone lesion and to the time spent on dialysis.

Nutritional management of bone mineralization and metabolic bone disease

Metabolic bone disease in the neonatal period is with a few rare exceptions seen principally in premature infants. The paper summarizes the typical manifestations of bone disease in preterm infants, its short-term management and longer-term outcomes. The effects of early diet, both during the period of hospitalization and after discharge home, on skeletal growth and development are addressed.