Age-related osteogenesis on lateral force application to rat incisor – Part III: Periodontal and periosteal bone remodeling

Objectives: This study was aimed to compare the histological pattern of bone modeling on either periodontal or periosteal side induced by lateral orthodontic tooth movement in different age groups. Material and Methods: A total of 50 male Sprague-Dawley rats (25 rats in the adult group – 52 weeks and 25 rats in the young group – 10 weeks) were utilized in this study. Each age group was classified into the control, 3 days, 7 days, 14 days, and 21 days groups (five rats in each) by the duration of experimental device application. A double-helical spring was produced using 0.014” stainless steel wire to provide 40 g lateral force to the left and right incisors. Hematoxylin-eosin staining, proliferating cell nuclear antigen (PCNA) immunohistochemical staining, fibroblast growth factor receptor 2 (FGFR2) immunohistochemical staining, and Masson trichrome staining were performed; and the slides were subject to histological examination. Results: In 7 days, active bone modeling represented by the scalloped surface was observed on the periosteal side of the crestal and middle alveolus at the pressure side in the young group, while similar changes were observed only on the crestal area in the adult group. In the young group, the number of PCNA-positive cells increased significantly on the crestal area and middle alveolus on the 3, 7, and 14 day groups, with subsequent decrease at 21 days. In the adult group, PCNA-positive cells were localized on the crestal area throughout the period. In the young group, FGFR2-positive cells were observed mainly on the crestal and middle alveolus at 3, 7, and 14 days than the control group. In the adult group, these cells appeared on the crestal and middle alveolus in the 3 days group, but mainly on the crestal area at 14 days. In the young group, FGFR2-positive cells were observed on the crestal and middle alveolus on the 3, 7, and 14 days groups more than on the control group. In the adult group, these cells appeared on the crestal and middle alveolus in the 3 days group, but mainly on the crestal area in the 14 days group. In Masson trichrome stain, an increased number of type I collagen fibers were observed after helical spring activation in both age groups. Large resorption lacunae indicating undermining bone resorption were progressively present in both young and adult groups. Conclusion: According to these results, orthodontic tooth movement may stimulate cell proliferation and differentiation primarily on the periosteal side according to progressive undermining bone resorption on the periodontal side. This response may lead to prominent bone modeling during tooth movement in the young group, compared to the relatively delayed response in the adult group.

Reactive Oxygen Species (ROS)-Responsive Biomaterials for the Treatment of Bone-Related Diseases

Reactive oxygen species (ROS) are the key signaling molecules in many physiological signs of progress and are associated with almost all diseases, such as atherosclerosis, aging, and cancer. Bone is a specific connective tissue consisting of cells, fibers, and mineralized extracellular components, and its quality changes with aging and disease. Growing evidence indicated that overproduced ROS accumulation may disrupt cellular homeostasis in the progress of bone modeling and remodeling, leading to bone metabolic disease. Thus, ROS-responsive biomaterials have attracted great interest from many researchers as promising strategies to realize drug release or targeted therapy for bone-related diseases. Herein, we endeavor to introduce the role of ROS in the bone microenvironment, summarize the mechanism and development of ROS-responsive biomaterials, and their completion and potential for future therapy of bone-related diseases.

Effect of Physical Therapy on Bone Remodelling in Preterm Infants. A Multicenter Randomized Controlled Clinical Trial

Background: Preterm infants have a low level of bone mineralization compared to those born at term, since 80% of calcium incorporation occurs at the end of pregnancy. The purpose of the present study was to investigate the effect of reflex locomotion therapy on bone modeling and growth in preterm infants and to compare its effect with those of other Physiotherapy modalities.Methods: A multicentre randomized controlled clinical trial was conducted (02/2016 – 07/2020). 106 preterm infants born at the Virgen de la Arrixaca University Clinical Hospital, the General University Hospital of Elche and the Torrecárdenas Hospital in Almería, between 29 and 34 weeks with hemodynamic stability, complete enteral nutrition and without any metabolic, congenital, genetic, neurological or respiratory disorders were evaluated for inclusion. Infants were randomly assigned to three groups: one group received reflex locomotion therapy (EGrlt); another group received passive mobilizations with gentle joint compression (EGpmc); and the control group received massage (CG). All treatments were carried out in the neonatal units lasting one month. The main outcome measure was bone formation and resorption measured with bone biomarkers. A mixed ANOVA was used to compare the results of bone biomarkers, and anthropometric measurements. Results: Infants were randomized to EGrlt (n = 38), EGpmc (n = 32), and CG (n = 36). All groups were similar in terms of gender (p = 0.891 female 47.2%), gestational age (M = 30.753, SD = 1.878, p = 0.39) and birth weight (M = 1413.45, SD = 347.36, p = 0.157). At the end of the study, significant differences were found between the groups in their interaction in bone formation, measured with osteocalcin [F (2,35) = 4.92, p = 0.013, ηp2 = 0.043], in benefit of the EGrlt. Conclusions: Reflex locomotion therapy has been effective in improving bone formation, more so than other Physiotherapy modalities. Therefore, reflex locomotion therapy could be considered one of the most effective physiotherapeutic modalities for the prevention and treatment of osteopenia of prematurity Trial registrstion: Trial retrospectively registered at ClinicalTrials.gov. First posted on 22/04/2020. Registration number: NCT04356807. URL: https://clinicaltrials.gov/ct2/show/NCT04356807?cond=Physical+Therapy+to+Prevent+Osteopenia+in+Preterm+Infants&draw=2&rank=1

Peculiarities of calcium-phosphorus homeostasis of the oral fluid in young patients with primary hypothyroidism, having generalized periodontitis

The problem of hormonal imbalance in periodontal diseases, as well as the importance of endocrine diseases in its development, plays a significant role. In the professional literature there are data that thyroid disease is a risk factor for the occurrence and further progression of periodontal diseases. The processes of bone modeling and remodeling and its mineralization are closely related to calcium metabolism. The biochemical manifestation of osteoporotic processes in the alveolar bone in generalized periodontitis is a violation of calcium-phosphorus homeostasis against the background of altered markers of bone metabolism. The aim of our investigation was to study the calcium-phosphorus homeostasis of the oral fluid in patients with primary hypothyroidism and persons without endocrine pathology, with generalized periodontitis. Since in the structure of periodontal diseases in the study groups generalized periodontitis of the initial-I and II degree had the largest percentage, biochemical studies were performed in this sample of patients. The first group included 50 people with generalized periodontitis against the background of primary hypothyroidism: 25 patients – with generalized periodontitis of the initial-I degree and 25 patients with generalized periodontitis of the II degree of development. The second group included 50 patients with generalized periodontitis without endocrinological pathology (25 patients with GP of the initial-I degree and 25 patients with GP of the II degree of development). In young people with generalized periodontitis, against the background of hypothyroidism, there were observed negative changes in calcium-phosphorus homeostasis of the oral fluid: there was a tendency to the decrease of calcium content in the oral fluid with the development of inflammatory-dystrophic process in the periodontium, on the contrary, phosphorus level has increased. Negative dynamics of calcium-phosphorus molar coefficient was found in patients with hypofunction of the thyroid gland. Thus, the analysis of research results shows that in young people with periodontal diseases and hypothyroidism there is a pathological change in metabolic processes, increased excretion of mineral components, especially calcium. Periodontal pathology against the background of hypothyroidism is characterized by the development of a chronic inflammatory process together with a pronounced decrease in calcium-phosphorus homeostasis of the oral fluid.

Role of K+ and Ca2+-Permeable Channels in Osteoblast Functions

Bone-forming cells or osteoblasts play an important role in bone modeling and remodeling processes. Osteoblast differentiation or osteoblastogenesis is orchestrated by multiple intracellular signaling pathways (e.g., bone morphogenetic proteins (BMP) and Wnt signaling pathways) and is modulated by the extracellular environment (e.g., parathyroid hormone (PTH), vitamin D, transforming growth factor β (TGF-β), and integrins). The regulation of bone homeostasis depends on the proper differentiation and function of osteoblast lineage cells from osteogenic precursors to osteocytes. Intracellular Ca2+ signaling relies on the control of numerous processes in osteoblast lineage cells, including cell growth, differentiation, migration, and gene expression. In addition, hyperpolarization via the activation of K+ channels indirectly promotes Ca2+ signaling in osteoblast lineage cells. An improved understanding of the fundamental physiological and pathophysiological processes in bone homeostasis requires detailed investigations of osteoblast lineage cells. This review summarizes the current knowledge on the functional impacts of K+ channels and Ca2+-permeable channels, which critically regulate Ca2+ signaling in osteoblast lineage cells to maintain bone homeostasis.

Congenital Metabolic Bone Disorders as a Cause of Bone Fragility

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.

Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

Mineral and Bone Consequences of High Dose Denosumab Therapy to Treat an Aneurysmal Bone Cyst, a Child Case Report

Aneurysmal bone cysts (ABCs) are rare benign pseudotumoral bone lesions with potential aggressive behavior due to the extensive destruction of surrounding bone. Traditionally, these tumors were treated with open surgery, but there is more and more a shift to less invasive procedures. In particular, treatment for spinal ABCs is generally unsatisfactory due to the risk of morbidity, neurological impairment and recurrence, and there is a need for innovative therapies. Denosumab has been reported as a useful treatment in giant cell tumors of bone (GCTB), so its efficacy has been tested also in other fibro-osseus lesions affecting children and adolescents, such as spinal aneurysmal bone cysts. The pediatric literature is limited to case reports and small series, all of which highlight the efficacy of this treatment on lesions growth and associated bone pain. Some of these reports have already reported well known side effects associated with denosumab, such as hypocalcemia at the beginning of the treatment, and rebound hypercalcemia at the discontinuation. The latter seems to be more frequent in children and adolescents than in adults, probably due to the higher baseline bone turnover in children. In addition, the use of denosumab in young patients could affect both bone modeling and remodeling, even if the consequences on the growing skeleton have not been reported in detail. Here we describe the case of a spinal ABC diagnosed in an 8-year old young boy which was not accessible to surgery but responded favorably to denosumab. Our aim is to describe the rapid changes in mineral and bone homeostasis in this patient, that required advice from the experts of the European Reference Network (ERN) for rare bone and endocrine diseases.