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woven bone [keywords]
- Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period. [JOURNAL ARTICLE]
- Bone 2014 Apr 13.
RANKL is a key regulator of bone resorption and osteoclastogenesis. Denosumab is a fully human IgG2 monoclonal antibody that inhibits bone resorption by binding and inhibiting the activity of RANKL. To determine the effects of denosumab on pre- and postnatal skeletal growth and development, subcutaneous injections of 0 (control) or 50mg/kg/month denosumab were given to pregnant cynomolgus monkeys from approximately gestation day (GD) 20 until parturition (up to 6 doses). For up to 6months postpartum (birth day [BD] 180/181), evaluation of the infants included skeletal radiographs, bone biomarkers, and oral examinations for assessment of tooth eruption. Infant bones were collected at necropsy for densitometry, biomechanical testing, and histopathologic evaluation from control and denosumab-exposed infants on BD1 (or within 2weeks of birth) and BD181, and from infants that died or were euthanized moribund from BD5 to BD69. In all denosumab-exposed infants, biomarkers of bone resorption and formation were markedly decreased at BD1 and BD14 and slightly greater at BD91 vs control, then similar to control values by BD181. Spontaneous long bone fractures were detected clinically or radiographically in 4 denosumab-exposed infants at BD28 and BD60, with evidence of radiographic healing at ≥BD60. In BD1 infants exposed to denosumab in utero, radiographic evaluations of the skeleton revealed decreased long bone length; a generalized increased radio-opacity of the axial and appendicular skeleton and bones at the base of the skull with decreased or absent marrow cavities, widened growth plates, flared/club-shaped metaphysis, altered jaw/skull shape, and reduced jaw length; and delayed development of secondary ossification centers. Densitometric evaluations in these infants demonstrated a marked increase in bone mineral density at trabecular sites, but cortical bone mineral density was decreased. Histologically, long bone cortices were attenuated and there was an absence of osteoclasts. Bones with active endochondral ossification consisted largely of a dense network of retained primary spongiosa with reduced marrow space consistent with an osteopetrotic phenotype. A minimal increase in growth plate thickness largely due to the expansion of the hypertrophic zone was present. Retained woven bone was observed in bones formed by intramembranous ossification consistent with absence of bone remodeling. These changes in bone tissue composition and geometry were reflected in reduced biomechanical strength and material properties of bones from denosumab-exposed infants. Material property changes were characterized by increased tissue brittleness reflected in reductions in calculated material toughness at the femur diaphysis and lack of correlation between energy and bone mass at the vertebra; these changes were likely the basis for the increased skeletal fragility (fractures). Although tooth eruption was not impaired in denosumab-exposed infants, the reduced growth and increased bone density of the mandible resulted in dental abnormalities consisting of tooth malalignment and dental dysplasia. Radiographic changes at BD1 persisted at BD28, with evidence of resumption of bone resorption and remodeling observed in most infants at BD60 and/or BD90. In 2 infants euthanized on BD60 and BD69, there was histologic and radiographic evidence of subphyseal/metaphyseal bone resorption accompanied by multiple foci of ossification in growth plates that were markedly increased in thickness. In infants necropsied at BD181, where systemic exposure to denosumab had been below limits of quantitation for approximately 3months, there was largely full recovery from all bone-related changes observed earlier postpartum, including tissue brittleness. Persistent changes included dental dysplasia, decreased bone length, reduced cortical thickness, and decreased peak load and ultimate strength at the femur diaphysis. In conclusion, the skeletal and secondary dental effects observed in infant monkeys exposed in utero to denosumab are consistent with the anticipated pharmacological activity of denosumab as a monoclonal antibody against RANKL and inhibitor of osteoclastogenesis. The resulting inhibition of resorption impaired both bone modeling and remodeling during skeletal development and growth. The skeletal phenotype of these infant monkeys resembles human infants with osteoclast-poor osteopetrosis due to inactivating mutations of RANK or RANKL.
- Three-Dimensional Anatomy of the Equine Sternum. [JOURNAL ARTICLE]
- Anat Histol Embryol 2014 Apr 9.
The sternum is a frequently used anatomical site to obtain bone marrow for diagnostic and therapeutic purposes in equine medicine and surgery. For a safe and reproducible aspiration of sternal bone marrow, a reliable anatomical description of the sternum is mandatory. However, the anatomical literature provides very heterogeneous information concerning the structure and number of sternebrae. Isolated sterna (horses of different ages) underwent clinical computed tomography, and single sternebrae were scanned by microcomputed tomography. Data sets were analysed in detail, the dimensions of each sternebra were determined, and correlations to the age and weight were generated. A uniform arrangement of seven sternebrae within the equine sternum was obtained, whereas the 6th and 7th sternebrae were fused in all sterna. The cranial sternebrae (sternebrae 1-3) had a lentiform shape with flattened lateral sides, while the caudal sternebrae (6 and 7) were flattened dorso-ventrally. In contrast, sternebrae 4 and 5 were spherical. The single sternebrae were well demarcated to the chondral sternum and showed two different zones. The periphery consisted of radiodense woven tissue, while in the centre the radiodense tissue was loosely arranged and contained large cavities with radiolucent tissue. A thin lamina (substantia corticalis) of <1 mm was arranged around the peripheral zone. There was no correlation between the body weight and the dimensions of the sternebrae, but there was a positive correlation to the age of the horses. The obtained data provide a sufficient basis to establish a standard nomenclature of the equine sternum.
- Trabecular microfractures in the femoral head with osteoporosis: Analysis of microcallus formations by synchrotron radiation micro CT. [JOURNAL ARTICLE]
- Bone 2014 Apr 2.
Trabecular bone microfracture pathogenesis and associated healing processes are not well understood. We analyzed the microcalluses that form subsequent to microfractures in patients with osteoporosis (OP) using synchrotron radiation micro CT (SRCT). Subchondral bone columns were extracted from the femoral heads of 11 female patients with a femoral neck fracture. SRCT scanning was performed with 5.9×5.9×5.9μm(3) voxel size and the microcallus number was measured in a 5-mm cubic subchondral bone region. The trabecular bone microstructure was measured and its relationship to the microcallus number was analyzed. In addition, the degree of mineralization of the microcallus region and that of the rest of the trabecular bone were measured and compared. Microcallus formations were detected in all cases, with a mean microcallus number of 4.9 (range, 2-11). The microcallus number had a significantly negative correlation with bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and degree of mineralization, and had a positive correlation with specific bone surface (BS/BV). The degree of mineralization of the microcallus region was lower than that of the rest of the trabecular bone and had a wider range of values. Microcallus formations were frequently detected in patients with OP, and more prevalent in the bone with thinner trabeculae, suggesting microfractures might occur due to activities of daily living as the OP progresses. The degree of mineralization of microcallus might represent the process of bone healing from immature woven bone to mature trabecular bone.
- Histologic, Histomorphometric, and Radiographic Monitoring of Bone Healing Around In-Office-Sterilized Orthodontic Mini-implants With or Without Immediate Load: Study in Rabbit Tibiae. [Journal Article]
- Int J Oral Maxillofac Implants 2014 Mar-Apr; 29(2):321-30.
Purpose:The objective of this study was to describe bone healing around self-drilling orthodontic mini-implants (MIs), sterilized in an office with an autoclave, with or without immediate orthodontic loading. Materials and
Methods:One hundred forty-four self-drilling MIs (TOMAS, Dentaurum) were inserted into the tibiae of 18 white rabbits, with full-thickness flaps elevated under general anesthesia. An immediate load (50 cN) was applied to 50% of the MIs. Two rabbits were sacrificed soon after the surgery and served as a control group. Four rabbits each were sacrificed at 15, 21, 30, or 60 days after the surgeries. Digital radiographs were obtained to measure the cortical bone thickness (CBT) around and between the implants. Sections were obtained and stained for histologic and histomorphometric analysis. Bone quantity (BQ), bone-to-implant contact (BIC), and CBT were evaluated statistically.
Results:At day 0, fractures were visible in the cortical area around the MIs. At days 15 and 21, intense proliferation of woven bone followed by formation of lamellar bone was seen. After 30 days, primary bone was visible, with less proliferation activity. At day 60, primary bone in the process of remodeling into secondary bone was apparent. BQ was better with loading after 15 days and increased throughout the healing period in the loaded and unloaded groups. Loading did not influence the BIC values, which increased with healing time for loaded and unloaded implants. CBT increased in all regions, and CBT was greater around the MIs than between them except for unloaded MIs in the 15-day group.
Conclusion:An immediate, light orthodontic load did not affect the bone healing process around orthodontic MIs. Osseointegration and CBT increased and were time-related.
- An Insight in to Paget's Disease of Bone. [REVIEW]
- Niger J Surg 2014 1; 20(1):9-15.
Paget's disease of bone (PDB) is a common disorder which may affect one or many bones. Although many patients are asymptomatic, a variety of symptoms and complications may occur. PDB is a focal disorder of bone turnover characterized by excessive bone resorption coupled with bone formation. PDB begins with a period of increased osteoclastic activity and bone resorption, followed by increased osteoblast production of woven bone that is poorly mineralized. In the final phase of the disease process, dense cortical and trabecular bone deposition predominates, but the bone is sclerotic and poorly organized and lacks the structural integrity and strength of normal bone. This article briefly reviews the etiopathogenesis, clinical radiographic and histological features of Paget's disease.
- Antagonizing the αv β3 Integrin Inhibits Angiogenesis and Impairs Woven but Not Lamellar Bone Formation Induced by Mechanical Loading. [JOURNAL ARTICLE]
- J Bone Miner Res 2014 Mar 18.
Angiogenesis and osteogenesis are critically linked, though the role of angiogenesis is not well understood in osteogenic mechanical loading. In this study, either damaging or non-damaging cyclic axial compression was used to generate woven bone formation (WBF) or lamellar bone formation (LBF), respectively, at the mid-diaphysis of the adult rat forelimb. αv β3 integrin targeted nanoparticles or vehicle was injected intravenously following mechanical loading. β3 integrin subunit expression on vasculature was maximal 7 days after damaging mechanical loading, but was still robustly expressed 14 days after loading. Accordingly, targeted nanoparticle delivery in WBF loaded limbs was increased compared to non-loaded limbs. Vascularity was dramatically increased after WBF loading (+700% on day 14) and modestly increased after LBF loading (+50% on day 14). This increase in vascularity was inhibited by nanoparticle treatment in both WBF and LBF loaded limbs at days 7 and 14 after loading. Decreased vascularity led to diminished woven, but not lamellar, bone formation. Decreased woven bone formation resulted in impaired structural properties of the skeletal repair, particularly in post-yield behavior. These results demonstrate that αv β3 integrin mediated angiogenesis is critical for recovering fracture resistance following bone injury, but is not required for bone modeling after modest mechanical strain. © 2014 American Society for Bone and Mineral Research.
- Three-dimensional structure of minipig fibrolamellar bone: Adaptation to axial loading. [JOURNAL ARTICLE]
- J Struct Biol 2014 Mar 14.
Fibrolamellar bone is transiently produced by large, fast growing mammals. The fibrolamellar bone unit is initially formed by elaboration of a network of blood vessels. This is followed by the deposition of a thin, porous and hypercalcified layer, then by the infilling of the vascular cavities by the sequential deposition of a relatively thick rapidly forming bone on both sides of the hypercalcified layer, and finally by lamellar bone. We investigated the 3D structure of the collagenous network of fibrolamellar bone from the femora of a young minipig using mainly the FIB-SEM dual beam microscope and the Serial Surface View method. This enabled us to identify the fibril orientation, the canalicular network organization and other structural motifs within each element of the fibrolamellar unit. The first formed primary hypercalcified layer (PHL) is composed of fibril arrays and multiple small pores, and appears to have an isotropic structure. The major bone component is deposited on both sides of the PHL, and is composed of collagen fibrils with a preferred orientation, mainly aligned parallel to the bone long axis. This bone component is therefore parallel-fibered bone and not woven bone. We also observed that the collagen fibers are organized into bundles. The lamellar bone has most of its collagen fibrils aligned with the bone long axis. This study therefore shows that the large majority of collagen fibrils in fibrolamellar bone are aligned with the bone long axis. This anisotropic structure therefore appears to be adapted to loading along the bone long axis.
- [Osteoconductive behaviour of beta-tricalcium phosphate ceramics in osteoporotic, metaphyseal bone defects of the distal radius]. [English Abstract, Journal Article]
- Handchir Mikrochir Plast Chir 2014 Feb; 46(1):12-7.
Surgical treatment of osteoporotic distal radius fractures with locking plates does not completely prevent loss of reduction. Additional bone deficit stabilisation with the use of bone substitute materials is receiving increased attention. Most knowledge on the in vivo behavior of bone substitutes originates from a small number of animal models after its implantation in young, good vascularized bone.This paper investigates the osteoconductivity, resorption and biocompatibility of beta-tricalcium phosphate as a temporary bone replacement in osteoporotic type distal radius fractures.15 bone samples taken from the augmented area of the distal radius of elderly people during metal removal were examined.The material was found to be osteoconductive, good degradable, and biocompatible. Degrading process and remodelling to woven bone seem to require more time than in available comparative bioassays.The material is suitable for temporary replacement of lost, distal radius bone from the histological point of view.
- Negotiating the severely resorbed extraction site: a clinical case report with histologic sample. [Journal Article]
- Quintessence Int 2014 Mar; 45(3):203-8.
The treatment of an infected socket with a severe facial dehiscence/ fenestration defect presents a therapeutic dilemma to the dental team. Both implant-supported restoration and fixed partial denture are viable options to restore function and occlusion, each with its benefits and disadvantages. In the present case report, a multi-stage regenerative approach was selected to enable implant-supported single crown. The first phase of the treatment after extraction of the maxillary central incisor was the stabilization of the blood clot with a collagen plug. Six weeks later, the surgical site was re-entered and the socket was grafted with biphasic calcium sulfate (BCS). Six months later, a dental implant was placed and a core biopsy taken. However, the central portion of the facial defect demonstrated only partial regeneration resulting in exposure of six implant threads. Freeze-dried bone allograft (FDBA) and a collagen membrane were utilized to augment the ridge and cover the exposed threads. The histology of the bone core showed a complete resorption of the grafted material with the presence of new woven bone throughout the specimen. Clinically, complete defect regeneration and augmentation of the alveolar ridge were attained after 4 months. Thus, the clinician should consider the pros and cons of this regenerative approach along with other more conservative treatment alternatives when dealing with similar cases.
- Continuous and intermittent exposure of neonatal rat calvarial cells to PTHrP (1-36) inhibits bone nodule mineralization in vitro by downregulating bone sialoprotein expression via the cAMP signaling pathway. [Journal Article]
- F1000Res 2013.:77.
The development and growth of the skeleton in the absence of parathyroid-hormone-related protein (PTHrP) is abnormal. The shortening of appendicular bones in PTHrP gene null mice is explained by an effect of PTHrP on endochondral bone growth. Whether or not PTHrP influences intramembranous ossification is less clear. The purpose of this study was to determine the effect of exogenous PTHrP on intramembranous ossification in vitro. Neonatal rat calvarial cells maintained in primary cell culture conditions that permit spontaneous formation of woven bone nodules by intramembranous ossification were studied. The expression of PTHrP, parathyroid hormone 1 receptor (PTH1R), and alkaline phosphatase (AP) by osteogenic cells in developing nodules and the effects of PTHrP (1-36) on nodule development was determined over 3-18 days. PTHrP and PTH1R were detected colonies of osteogenic cells on culture day three, and AP was detected on day six. PTHrP and its receptor were localized in pre-osteoblasts, osteoblasts, and osteocytes, and AP activity was detected in pre-osteoblasts and osteoblasts but not osteocytes. Continuous and intermittent exposure to PTHrP (1-36) decreased the number of mineralized bone nodules and bone sialoprotein (BSP) mRNA and protein, but had no effect on the number of AP-positive osteogenic cell colonies, cell proliferation, apoptosis, or osteopontin (OPN) mRNA. These results demonstrate that osteogenic cells that participate in the formation of woven bone nodules in vitro exhibit PTHrP and PTH1R before they demonstrate AP activity. Exogenous PTHrP (1-36) inhibits the mineralization of woven bone deposited during bone nodule formation in vitro, possibly by reducing the expression of BSP.