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Bone Remodeling (bone + remodeling)
Selected AbstractsIf bone is the answer, then what is the question?JOURNAL OF ANATOMY, Issue 2 2000R. HUISKES In the 19th century, several scientists attempted to relate bone trabecular morphology to its mechanical, load-bearing function. It was suggested that bone architecture was an answer to requirements of optimal stress transfer, pairing maximal strength to minimal weight, according to particular mathematical design rules. Using contemporary methods of analysis, stress transfer in bones was studied and compared with anatomical specimens, from which it was hypothesised that trabecular architecture is associated with stress trajectories. Others focused on the biological processes by which trabecular architectures are formed and on the question of how bone could maintain the relationship between external load and architecture in a variable functional environment. Wilhelm Roux introduced the principle of functional adaptation as a self-organising process based in the tissues. Julius Wolff, anatomist and orthopaedic surgeon, entwined these 3 issues in his book The Law of Bone Remodeling (translation), which set the stage for biomechanical research goals in our day. ,Wolff's Law' is a question rather than a law, asking for the requirements of structural optimisation. In this article, based on finite element analysis (FEA) results of stress transfer in bones, it is argued that it was the wrong question, putting us on the wrong foot. The maximal strength/minimal weight principle does not provide a rationale for architectural formation or adaptation; the similarity between trabecular orientation and stress trajectories is circumstantial, not causal. Based on computer simulations of bone remodelling as a regulatory process, governed by mechanical usage and orchestrated by osteocyte mechanosensitivity, it is shown that Roux's paradigm, conversely, is a realistic proposition. Put in a quantitative regulatory context, it can predict both trabecular formation and adaptation. Hence, trabecular architecture is not an answer to Wolff's question, in the sense of this article's title. There are no mathematical optimisation rules for bone architecture; there is just a biological regulatory process, producing a structure adapted to mechanical demands by the nature of its characteristics, adequate for evolutionary endurance. It is predicted that computer simulation of this process can help us to unravel its secrets. [source] Targeting Bone Remodeling for the Treatment of Osteoporosis: Summary of the Proceedings of an ASBMR Workshop,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2009John P Bilezikian First page of article [source] Editorial: Positive Effects of Intravenous Zoledronic Acid on Bone Remodeling and Structure: Are Different Effects on Osteoblast Activity to Other Oral Bisphosphonates Responsible?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2008Peter R Ebeling MD No Abstracts. [source] Bone Remodeling: Biochemical Markers or Bone Biopsy?JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2006Pascale M Chavassieux No abstract is available for this article. [source] Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Monique Arlot MD Abstract An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 ,g with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment. Introduction: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. Materials and Methods: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 ,g and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests. Results: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. Conclusions: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide. [source] Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005B Lawrence Riggs MD Abstract There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification. The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature. [source] Cancellous Bone Remodeling Occurs in Specialized Compartments Lined by Cells Expressing Osteoblastic MarkersJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2001Ellen M. Hauge Abstract We describe a sinus, referred to as a bone remodeling compartment (BRC), which is intimately associated with cancellous bone remodeling. The compartment is lined on its marrow side by flattened cells and on its osseous side by the remodeling bone surface, resembling a roof of flattened cells covering the bone surface. The flat marrow lining cells are in continuity with the bone lining cells at the margins of the BRC. We examined a large number of diagnostic bone biopsy specimens received during recent years in the department. Furthermore, 10 patients (8 women and 2 men, median age 56 [40,69] years) with the high turnover disease of primary hyperparathyroidism who were treated with parathyroidectomy and followed for 3 years were included in the histomorphometric study. Bone samples for the immuno-enzyme staining were obtained from an amputated extremity of child. The total cancellous bone surface covered by BRC decreases by 50% (p < 0.05) following normalization of turnover and is paralleled by a similar 50% decrease in remodeling surface (p < 0.05). The entire eroded surface and two-thirds of the osteoid surface are covered by a BRC. BRC-covered uncompleted walls are 30% (p < 0.05) thinner than those without a BRC. This indicates that the BRC is invariably associated with the early phases of bone remodeling, that is, bone resorption, whereas it closes during the late part of bone formation. Immuno-enzyme staining shows that the flat marrow lining cells are positive for alkaline phosphatase, osteocalcin, and osteonectin, suggesting that they are bone cells. The first step in cancellous bone remodeling is thought to be the lining cells digesting the unmineralized matrix membrane followed by their disappearance and the arrival of the bone multicellular unit (BMU). We suggest that the lining cell barrier persists during bone remodeling; that the old lining cells become the marrow lining cells, allowing bone resorption and bone formation to proceed under a common roof of lining cells; that, at the end of bone formation, new bone lining cells derived from the flattened osteoblasts replace the marrow lining cells thereby closing the BRC; and that the two layers of lining cells eventually becomes a single layer. The integrity of the osteocyte-lining cell system is reestablished by the new generation of lining cells. The BRC most likely serves multiple purposes, including efficient exchange of matrix constituents and minerals, routing, monitoring, or modulating bone cell recruitment, and possibly the anatomical basis for the coupling of bone remodeling. [source] High-Turnover Periprosthetic Bone Remodeling and Immature Bone Formation Around Loose Cemented Total Hip JointsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2001Michiaki Takagi Abstract Aseptic loosening and periprosthetic osteolysis are the major problems awaiting solution in total hip surgery. The clinical investigation focused on the analysis of periprosthetic bone remodeling to clarify one important key event in the cascade of periprosthetic connective tissue weakening and osteolysis around loose artificial hip joints. Twelve acetabular bone samples adjacent to granulomatous synovial-like membrane of loose hip prosthesis were retrieved at revision surgery and processed for Villanueva bone staining for morphological observation and bone histomorphometric analysis. Eight well-fixed bony samples were used as control. Although osteoclastic surface and eroded surface by osteoclasts were evident in the periprosthetic bone from loose hip joints (p = 0.003 and p = 0.027), increased osteoid/low-mineralized bone matrix (p < 0.001) and osteoid width (p < 0.001) also were significant findings in structural analysis. In addition, not only elevated mineral apposition rate (MAR; p = 0.044) but also increased mineralizing surface (p = 0.044) and bone formation rate (BFR; p = 0.002) in loose periprosthetic bones were shown in dynamic data analysis. These results were confirmed by precise morphological observation by confocal laser scanning microscopy. Active coupling of bone formation and resorption and increased osteocytes with abundant bone canalicular projections were found in combined with the presence of immature bone matrices (osteoid and low-mineralized bone areas) in periprosthetic bones from loose hip joints. These results indicated that active osteoclastic bone resorption and/or defective bone formation are coupled with monocyte/macrophage-mediated foreign body-type granuloma in the synovial-like interface membrane of loose hip joints. Thus, this unique high-turnover periprosthetic bone remodeling with bad bone quality probably is caused by the result of cellular host response combined with inappropriate cyclic mechanical loading. The fragile periprosthetic bone may contribute to hip prosthesis loosening. [source] Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Olivier Verborgt Abstract As a result of fatigue, bone sustains microdamage, which is then repaired by bone-remodeling processes. How osteoclastic activity is targeted at the removal of microdamaged regions of bone matrix is unknown. In the current studies, we tested the hypothesis that changes in osteocyte integrity, through the initiation of regulated cell death (apoptosis), are associated with fatigue-related microdamage and bone resorption. Ulnae of adult rats were fatigue-loaded to produce a known degree of matrix damage. Osteocyte integrity was then assessed histomorphometrically from terminal deoxynucleotidyl transferase,mediated deoxyuridine triphosphate,nick end labeling (TUNEL),stained sections to detect cells undergoing DNA fragmentation associated with apoptosis; toluidine blue,stained sections were used for secondary morphological confirmation. Ten days after loading, large numbers of TUNEL-positive osteocytes were found in bone surrounding microcracks and in bone surrounding intracortical resorption spaces (,300% increases over controls, p < 0.005). TUNEL labeling in loaded ulnae at sites distant from microcracks or resorption foci did not differ from that in control bone. Osteocytes in toluidine blue,stained sections showed equivalent trends to TUNEL-stained sections, with significant increases in pyknotic nuclei and empty lacunae associated with microcracks and intracortical resorption spaces. TUNEL-positive osteocytes were observed around bone microdamage by 1 day after loading (p < 0.01 relative to baseline), and their number remained elevated throughout the entire experimental period. Increases in empty lacunae and decreases in normal osteocyte numbers were observed over time as well. These studies show that (1) osteocyte apoptosis is induced by bone fatigue, (2) this apoptosis is localized to regions of bone that contain microcracks, and (3) osteoclastic resorption after fatigue also coincides with regions of osteocyte apoptosis. The strong associations between microdamage, osteocyte apoptosis, and subsequent bone remodeling support the hypothesis that osteocyte apoptosis provides a key part of the activation or signaling mechanisms by which osteoclasts target bone for removal after fatigue-induced matrix injury. [source] Osteoprotegerin in the Inner Ear May Inhibit Bone Remodeling in the Otic Capsule,THE LARYNGOSCOPE, Issue 1 2005Andreas F. Zehnder MD Abstract Objectives: To elucidate factors that may be responsible for the inhibition of remodeling of bone within the otic capsule. Methods: Expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and RANK ligand (RANKL) were assayed in samples of bone obtained from the otic capsule, calvarium, and femur, and from the soft tissue within the cochlea using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) in mice. Immunostaining was used for histologic localization of the gene products. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the amount of OPG within perilymph, serum, and cerebrospinal fluid. The micro-anatomy of the interface between the otic capsule and the fluid spaces of the cochlea was investigated by brightfield and phase-contrast microscopy and by three-dimensional reconstruction in the mouse and human. Results: OPG, a powerful inhibitor of bone remodeling, was expressed at extremely high levels within the soft tissue of the cochlea and was present in the perilymph at very high concentrations. The OPG produced within the inner ear may diffuse into the surrounding otic capsule, where it may be responsible for inhibition of bone turnover. Our anatomic studies revealed an extensive system of interconnected canaliculi within the otic capsule that had direct openings into the fluid spaces of the inner ear, thus providing a possible anatomic route for the diffusion of OPG from the inner ear into the surrounding bone. Conclusion: OPG, a potent inhibitor of osteoclast formation and function, is expressed at high levels within the inner ear and is secreted into the perilymph and the surrounding bone and may serve to inhibit active bone remodeling within the otic capsule, especially immediately adjacent to the cochlea. By this means, the cochlear soft tissue may control the nature of the surrounding petrous bone. [source] Expanding field of purinergic signalingDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Geoffrey Burnstock Abstract This article attempts to paint a broad picture of the extraordinary explosive recent developments in the purinergic signaling field. After a brief historical review and update of purinoceptor subtypes, the focus is on the physiological roles of purines and pyrimidines. These are considered both in terms of short-term signaling in neurotransmission, secretion, and vasodilatation and in long-term (trophic) signaling in development, regeneration, proliferation, and cell death. Examples of trophic signaling include cartilage development in limb buds, glial cell proliferation, development of skeletal muscle, changes in receptor expression in smooth-muscle phenotypes, maturation of testicular spermatids, and bone remodeling. Plasticity of purinoceptor expression in pathological conditions is described, including the increase in the purinergic component of parasympathetic nervous control of the human bladder in interstitial cystitis and outflow obstruction and in sympathetic cotransmitter control of blood vessels in hypertensive rats, the appearance of P2X7 receptors in the glomeruli of the kidney from diabetic and transgenic hypertensive animal models, and up-regulation of P2X1 and P2Y2 receptor mRNA in hearts of rats with congestive heart failure. The role of P2X3 receptors in nociception is considered, and a new hypothesis about purinergic mechanosensory transduction in the gut is explored. A personal view of some of the areas ripe for future development concludes this article, including a discussion of different strategies that could lead to the development of purinergic therapeutic agents. Drug Dev. Res. 52:1,10, 2001. © 2001 Wiley-Liss, Inc. [source] Osteopontin as a new player in mast cell biologyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2008Silvia Bulfone-Paus Abstract The secreted glycoprotein osteopontin (OPN) sets into motion an astounding variety of activities that range from bone remodeling via immunomodulation to the inhibition of apoptosis. In the current issue of the European Journal of Immunology, OPN now also enters mast cell biology and the regulation of IgE-dependent immune responses since it is reported that connective tissue-type mast cells from fetal murine skin constitutively secrete biologically active OPN. Moreover, it is shown that, in vitro, OPN augments IgE-mediated mast cell degranulation and migration via ligand binding to cognate OPN receptors on the mast cell surface (CD44, ,v integrin) and that the magnitude of an IgE-mediated passive cutaneous anaphylaxis reaction is augmented by OPN in vivo. Here, we discuss why this newly discovered property of OPN fits well into the emerging concept that OPN may serve as a multi-purpose environmental damage-response protein. See accompanying article: http://dx.doi.org/10.1002/eji200737057 [source] Polymer Matrix Nanocomposites from Biodegradable Thermoplastic Elastomers,ADVANCED ENGINEERING MATERIALS, Issue 5 2009Miroslawa El Fray Soft and elastomeric poly(ester,ether,ester) multiblock terpolymers were synthesized in presence of 0.5 wt % hydroxyapatite (HAp) nanoparticles to form nanocomposites. The addition of sintered HAp particles enhanced cell proliferation and diminished the number of dead and apoptotic cells. Implantation tests indicated that the observed hard tissue changes led to intense bone remodeling (see picture) [source] Numerical simulation of canine bodily movementINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING, Issue 2 2010Yingli Qian Abstract The aim of this study was to develop finite element (FE) models to simulate bodily movement of an orthodontic treatment of mandibular canine with decayed loads during a therapy period (4 weeks). The normal strain of periodontal ligament was assumed as the key mechanical stimulus for the surface bone remodeling. During the simulation processes, changes in tooth position and in the geometry of the tooth supporting structures and the decayed loads were taken into account. In this numerical simulation, the tooth movement displacements were 1.00,mm in the end of the therapy. The results of the simulation were similar to the observed in clinical studies. It was acceptable to simulate clinical tooth movements by FE method based on these mechanical assumptions. Such a numerical simulation would allow the understanding of tooth movements and help in better planning of individual strategies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Wintertime Vitamin D Supplementation Inhibits Seasonal Variation of Calcitropic Hormones and Maintains Bone Turnover in Healthy Men,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2009Heli T Viljakainen Abstract Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21,49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 ± 5.1 (SD) ,g/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 ,g (800 IU), 10 ,g (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5,20 ,g (700,800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men. [source] Gene Expression Profiling in Paget's Disease of Bone: Upregulation of Interferon Signaling Pathways in Pagetic Monocytes and Lymphocytes,,§JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2008Zsolt B Nagy Abstract We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf-,. Our result suggest that IFN-mediated signaling may play important roles in aberrant osteoclastogenesis of PD. Introduction: Paget's disease of bone (PD) is characterized by focal regions of highly exaggerated bone remodeling and aberrant osteoclastogenesis. Under physiological conditions, circulating monocytes may serve as early progenitors of osteoclasts and along with peripheral blood lymphocytes produce a wide variety of factors important in bone metabolism. Nevertheless, little is known about the roles of circulating monocytes and lymphocytes in relation to the pathological bone turnover in PD. Materials and Methods: In this study, we aimed at investigating the gene expression pattern of PD using quantitative real-time PCR in monocytes and lymphocytes isolated from peripheral blood mononuclear cells (PBMCs). Fifteen genes known to be involved in osteoclastogenesis were studied in cells from 23 patients with PD and in cells from 23 healthy controls. Eight human genes including ifn-, (3.48-fold, p < 0.001), ifn-, (2.68-fold, p < 0.001), ifn-, (1.98-fold, p = 0.002), p38 ,2 mapk (2.47-fold, p = 0.002), ifn-,r1 (2.03-fold, p = 0.01), ifn-,r2 (1.81-fold, p = 0.02), stat1 (1.57-fold, p = 0.037), and tnf-, (,2.34, p < 0.001) were found to be significantly altered in pagetic monocytes compared with monocytes of healthy controls. Results: In pagetic lymphocytes, significant changes in the expression of ifn-, (2.17-fold, p < 0.001), ifn-, (2.13-fold, p = 0.005), ifn-, (1.89-fold, p < 0.001), ifn-,r1 (1.02-fold, p = 0.04), ifn-,r2 (1.01-fold, p = 0.031), stat2 (1.79-fold, p < 0.001), and tnf-, (,1.49, p < 0.001) were found compared with lymphocytes of healthy controls. Furthermore, IFN-, protein was significantly elevated in the sera of PD patients (18.7 ± 6.69 pg/ml) compared with healthy controls (3.87 ± 6.48 pg/ml, p = 0.042). Conclusions: In conclusion, our data suggest that novel pathways mainly related to the IFN-mediated signaling may play important roles in the aberrant osteoclastogenesis of PD. [source] Perspective: Quantifying Osteoblast and Osteocyte Apoptosis: Challenges and Rewards,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2007Robert L Jilka Abstract Since the initial demonstration of the phenomenon in murine and human bone sections ,10 yr ago, appreciation of the biologic significance of osteoblast apoptosis has contributed greatly not only to understanding the regulation of osteoblast number during physiologic bone remodeling, but also the pathogenesis of metabolic bone diseases and the pharmacology of some of the drugs used for their treatment. It is now appreciated that all major regulators of bone metabolism including bone morphogenetic proteins (BMPs), Wnts, other growth factors and cytokines, integrins, estrogens, androgens, glucocorticoids, PTH and PTH-related protein (PTHrP), immobilization, and the oxidative stress associated with aging contribute to the regulation of osteoblast and osteocyte life span by modulating apoptosis. Moreover, osteocyte apoptosis has emerged as an important regulator of remodeling on the bone surface and a critical determinant of bone strength, independently of bone mass. The detection of apoptotic osteoblasts in bone sections remains challenging because apoptosis represents only a tiny fraction of the life span of osteoblasts, not unlike a 6-mo -long terminal illness in the life of a 75-yr -old human. Importantly, the phenomenon is 50 times less common in human bone biopsies because human osteoblasts live longer and are fewer in number. Be that as it may, well-controlled assays of apoptosis can yield accurate and reproducible estimates of the prevalence of the event, particularly in rodents where there is an abundance of osteoblasts for inspection. In this perspective, we focus on the biological significance of the phenomenon for understanding basic bone biology and the pathogenesis and treatment of metabolic bone diseases and discuss limitations of existing techniques for quantifying osteoblast apoptosis in human biopsies and their methodologic pitfalls. [source] Cyclin D1 as a Target for the Proliferative Effects of PTH and PTHrP in Early Osteoblastic CellsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2007Nabanita S Datta MS Abstract PTHrP induced a proliferative cyclin D1 activation in low-density osteoblastic cells. The process was PKA and MAPK dependent and involved both AP-1 and CRE sites. In ectopic ossicles generated from implanted bone marrow stromal cells, PTH upregulated cyclin D1 after acute or intermittent anabolic treatment. These data suggest a positive role of PTH and PTHrP in the cell cycle of early osteoblasts. Introduction: The mechanisms underlying the actions of PTH and its related protein (PTHrP) in osteoblast proliferation, differentiation, and bone remodeling remain unclear. The action of PTH or PTHrP on the cell cycle during osteoblast proliferation was studied. Materials and Methods: Mouse calvarial MC3T3-E1 clone 4 cells were synchronized by serum starvation and induced with 100 nM PTHrP for 2,24 h under defined low serum conditions. Western blot, real-time PCR, EMSAs, and promoter/luciferase assays were performed to evaluate cyclin D1 expression. Pharmacological inhibitors were used to determine the relevant signaling pathways. Ectopic ossicles generated from implanted bone marrow stromal cells were treated with acute (a single 8- or 12-h injection) or intermittent anabolic PTH treatment for 7 days, and RNA and histologic analysis were performed. Results: PTHrP upregulated cyclin D1 and CDK1 and decreased p27 expression. Cyclin D1 promoter/luciferase assays showed that the PTHrP regulation involved both activator protein-1 (AP-1) and cyclic AMP response element binding protein (CRE) sites. AP-1 and CRE double mutants completely abolished the PTHrP effect of cyclin D1 transcription. Upregulation of cyclin D1 was found to be protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) dependent in proliferating MC3T3-E1 cells. In vivo expression of cyclin D1 in ectopic ossicles was upregulated after a single 12-h PTH injection or intermittent anabolic PTH treatment for 7 days in early developing ossicles. Conclusions: These data indicate that PTH and PTHrP induce cyclin D1 expression in early osteoblastic cells and their action is developmental stage specific. [source] Thyroid-Stimulating Hormone Restores Bone Volume, Microarchitecture, and Strength in Aged Ovariectomized Rats*,,§JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2007T Kuber Sampath PhD Abstract We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo. Introduction: Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro. Materials and Methods: Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n = 80) or 7 mo later (restoration mode; n = 152). Hind limbs and lumbar spine BMD was measured at 2- or 4-wk intervals in vivo and ex vivo on termination at 8,16 wk. Long bones were subjected to ,CT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test. Results: In the prevention mode, low doses (0.1 and 0.3 ,g) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 ,g TSH had increased BMD (10,11%), trabecular bone volume (100,130%), trabecular number (25,40%), trabecular thickness (45,60%), cortical thickness (5,16%), mineral apposition and bone formation rate (200,300%), and enhanced mechanical strength of the femur (51,60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate. Conclusions: These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling. [source] Treatment of Skeletally Mature Ovariectomized Rhesus Monkeys With PTH(1-84) for 16 Months Increases Bone Formation and Density and Improves Trabecular Architecture and Biomechanical Properties at the Lumbar Spine,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2007John Fox PhD Abstract Histomorphometric studies of treatments for osteoporosis in humans are restricted to iliac crest biopsies. We studied the effects of PTH(1-84) treatment at the lumbar spine of skeletally mature ovariectomized rhesus monkeys. PTH increased bone turnover, rapidly normalized BMD, and increased vertebral compressive strength. PTH increased trabecular bone volume primarily by increasing trabecular number by markedly increasing intratrabecular tunneling. Introduction: Histomorphometric studies of the anabolic properties of PTH(1-84) (PTH) and related peptides in human bone are restricted to iliac crest biopsies. The ovariectomized (OVX) monkey is an accepted model of human postmenopausal bone loss and was used to study the effects of PTH treatment at clinically relevant skeletal sites. Materials and Methods: Skeletally mature rhesus monkeys were OVX or sham-operated and, after a bone depletion period of 9 months, treated daily for 16 months with PTH (5, 10, or 25 ,g/kg). Markers of bone formation (serum osteocalcin) and resorption (urine N-telopeptide [NTX]) and lumbar spine BMD were measured throughout the study. Trabecular architecture and vertebral biomechanical properties were quantified at 16 months. Results: PTH treatment induced dose-dependent increases in bone turnover but did not increase serum calcium. Osteocalcin was significantly increased above OVX controls by 1 month. NTX was significantly elevated at 1 month with the highest dose, but not until 12 months with the 5 and 10 ,g/kg doses. Lumbar spine BMD was 5% lower in OVX than in sham animals when treatment was started. All PTH doses increased BMD rapidly, with sham levels restored by 3,7 months with 10 and 25 ,g/kg and by 16 months with 5 ,g/kg. PTH treatment increased trabecular bone volume (BV/TV), primarily by increasing trabecular number, and dose-dependently increased bone formation rate (BFR) solely by increasing mineralizing surface. The largest effects on BV/TV and yield load occurred with the 10 ,g/kg dose. The highest dose reduced trabecular thickness by markedly increasing intratrabecular tunneling. Conclusions: PTH treatment of OVX rhesus monkeys increased bone turnover and increased BV/TV, BMD, and strength at the lumbar spine. All PTH doses were safe, but the 10 ,g/kg dose was generally optimal, possibly because the highest dose resulted in too marked a stimulation of bone remodeling. [source] Remodeling and Vascular Spaces in BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2007Erik Fink Eriksen Abstract In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed. [source] Update on the Epidemiology of Paget's Disease of BoneJOURNAL OF BONE AND MINERAL RESEARCH, Issue S2 2006Cyrus Cooper Abstract Paget's disease of bone (PDB) is characterized by rapid bone remodeling and the formation of bone that is structurally abnormal. Recent studies have confirmed that both genetic and environmental factors are important in its etiology. Epidemiological studies in Europe and North America have revealed that PDB shows an increasing frequency of occurrence with age and is more prevalent among men than women. There is marked geographic variation in the prevalence of PDB throughout western nations, with the highest rates reported during the 1970s in Britain. Recent studies of the secular trends in PDB suggest declining rates in both prevalence and severity at diagnosis. Thus, the overall age/sex standardized prevalence rate in Britain during the period 1993,1995 was found to be 2.5% among men and 1.6% among women ,55 years of age. Prevalence rates had fallen by ,50% in several of the centers studied, suggesting an environmental contribution to the etiology of this disorder. Similar findings have been reported from other European countries and New Zealand. Recent study of the incidence and clinical manifestations of PDB have emerged from large cohort studies in primary care record linkage resources, such as the General Practice Research Database. Over the period 1988,1999, the incidence rate of clinically diagnosed PDB was found to be 5 per 10,000 person-years among men and 3 per 10,000 person-years among women 75 years of age. The disorder was associated with an increased risk of back pain (RR, 2.1; 95% CI, 1.9,2.3); osteoarthritis (RR, 1.7; 95% CI, 1.5,1.9); and fracture (RR, 1.2; 95% CI, 1.0,1.5). Using life table methodology, the estimated proportion of patients dying within 5 years of follow-up was 32.7% among the cohort with PDB compared with 28.0% among control patients (p < 0.05). [source] Accentuated Ovariectomy-Induced Bone Loss and Altered Osteogenesis in Heterozygous N-Cadherin Null Mice,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2006Chung Fang Lai Abstract Ovariectomy-induced bone loss is accentuated in mice with germline Cdh2 haploinsufficiency, the result of a decreased osteoblastogenesis in the face of normal osteoclast number. Reduced N-cadherin abundance in these mice decreases cell,cell adhesion and alters signaling pathways important for osteoblast commitment and differentiation, thus providing in vivo evidence that N-cadherin,mediated cell,cell interactions are involved in homeostatic responses to increased bone remodeling. Introduction: We have shown that targeted expression of a dominant negative truncated form of N-cadherin (Cdh2) delays acquisition of peak bone mass in mice and retards osteoblast differentiation. We tested the role of this molecule in the skeletal homeostatic response to ovariectomy in mice with germline Cdh2 haploinsufficiency. Materials and Methods: Heterozygous Cdh2 null (Cdh2+/,) and wildtype mice were ovariectomized and followed up to 13 weeks by in vivo radiodensitometric and ex vivo histologic assessment of bone mass and turnover. Cells isolated from wildtype and Cdh2+/, mice were used to determine the alterations in bone cell function produced by partial loss of N-cadherin. Results: Bone mass was not significantly different between Cdh2+/, and wildtype littermates, but on ovariectomy, bone loss in Cdh2+/, mice was initially slower, but with time it became significantly greater than in wildtype mice. This accentuated bone loss was associated with lower osteoblast number and serum osteocalcin levels, with no differences in bone resorption. Although development of calcified nodules was faster in calvaria cells isolated from Cdh2+/, mice relative to Cdh2+/+ cells, bone marrow osteogenic precursors were lower in the former than in the latter genotypes. Cdh2 expression was downregulated with differentiation in wildtype calvaria cells, whereas cadherin-11 abundance remained unchanged. Furthermore, cell,cell adhesion (postconfluence) was decreased among heterozygous calvaria cells, as was cell proliferation (preconfluence), relative to wildtype cells. Finally, the abundance and cellular distribution of ,-catenin was minimally decreased in Cdh2+/, cells, whereas mitogen-activated protein kinase (MAPK) signaling was more active in Cdh2 insufficient cells. Conclusions:Cdh2 is involved in the homeostatic bone formation response to ovariectomy, presumably by regulating osteoprogenitors number and differentiation through stabilization of cell,cell adhesion and/or signaling modulation. [source] In Silico Modeling and Simulation of Bone Biology: A ProposalJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Nadine A Defranoux Abstract Contemporary, computer-based mathematical modeling techniques make it possible to represent complex biological mechanisms in a manner that permits hypothesis testing in silico. This perspective shows how such approaches might be applied to bone remodeling and therapeutic research. Currently, the dominant conceptual model applied in bone research involves the dynamic balance between the continual build-up and breakdown of bone matrix by two cell types, the osteoblasts and osteoclasts, acting together as a coordinated, remodeling unit. This conceptualization has served extraordinarily well as a focal point for understanding how mutations, chemical mediators, and mechanical force, as well as external influences (e.g., drugs, diet) affect bone structure and function. However, the need remains to better understand and predict the consequences of manipulating any single factor, or combination of factors, within the context of this complex system's multiple interacting pathways. Mathematical models are a natural extension of conceptual models, providing dynamic, quantitative descriptions of the relationships among interacting components. This formalization creates the ability to simulate the natural behavior of a system, as well as its modulation by therapeutic or dietetic interventions. A number of mathematical models have been developed to study complex bone functions, but most include only a limited set of biological components needed to address a few specific questions. However, it is possible to develop larger, multiscale models that capture the dynamic interactions of many biological components and relate them to important physiological or pathological outcomes that allow broader study. Examples of such models include Entelos' PhysioLab platforms. These models simulate the dynamic, quantitative interactions among a biological system's biochemicals, cells, tissues, and organs and how they give rise to key physiologic and pathophysiologic outcomes. We propose that a similar predictive, dynamical, multiscale mathematical model of bone remodeling and metabolism would provide a better understanding of the mechanisms governing these phenomena as well as serve as an in silico platform for testing pharmaceutical and clinical interventions on metabolic bone disease. [source] Differential Effects of Teriparatide and Alendronate on Bone Remodeling in Postmenopausal Women Assessed by Histomorphometric Parameters,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Monique Arlot MD Abstract An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 ,g with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment. Introduction: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. Materials and Methods: Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 ,g and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n = 23) or 18 months (n = 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n = 8; alendronate, n = 9) and 15 patients at 18 months (teriparatide, n = 8; alendronate, n = 7). Data were analyzed by two-sample tests. Results: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. Conclusions: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide. [source] Inactivation of the Na-Cl Co-Transporter (NCC) Gene Is Associated With High BMD Through Both Renal and Bone Mechanisms: Analysis of Patients With Gitelman Syndrome and Ncc Null Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2005Laurence Nicolet-Barousse Abstract Chronic thiazide treatment is associated with high BMD. We report that patients and mice with null mutations in the thiazide-sensitive NaCl cotransporter (NCC) have higher renal tubular Ca reabsorption, higher BMD, and lower bone remodeling than controls, as well as abnormalities in Ca metabolism, mainly caused by Mg depletion. Introduction: Chronic thiazide treatment decreases urinary Ca excretion (UVCa) and increases BMD. To understand the underlying mechanisms, Ca and bone metabolism were studied in two models of genetic inactivation of the thiazide-sensitive NaCl cotransporter (NCC): patients with Gitelman syndrome (GS) and Ncc knockout (Ncc,/,) mice. Materials and Methods: Ca metabolism was analyzed in GS patients and Ncc,/, mice under conditions of low dietary Ca. BMD was measured by DXA in patients and mice, and bone histomorphometry was analyzed in mice. Results: GS patients had low plasma Mg. They exhibited reduced UVCa, but similar serum Ca and GFR as control subjects, suggesting increased renal Ca reabsorption. Blood PTH was lower despite lower serum ionized Ca, and Mg repletion almost corrected both relative hypoparathyroidism and low UVCa. BMD was significantly increased in GS patients at both lumbar (+7%) and femoral (+16%) sites, and osteocalcin was reduced. In Ncc,/, mice, serum Ca and GFR were unchanged, but UVCa was reduced and PTH was elevated; Mg repletion largely corrected both abnormalities. Trabecular and cortical BMD were higher than in Ncc+/+ mice (+4% and +5%, respectively), and despite elevated PTH, were associated with higher cortical thickness and lower endosteal osteoclastic surface. Conclusions: Higher BMD is observed in GS patients and Ncc,/, mice. Relative hypoparathyroidism (human) and bone resistance to PTH (mice), mainly caused by Mg depletion, can explain the low bone remodeling and normal/low serum Ca despite increased renal Ca reabsorption. [source] Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2005B Lawrence Riggs MD Abstract There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification. The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature. [source] Focal Adhesion Kinase pp125FAK Interacts With the Large Conductance Calcium-Activated hSlo Potassium Channel in Human Osteoblasts: Potential Role in Mechanotransduction,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2003Roger Rezzonico Abstract Molecular events of mechanotransduction in osteoblasts are poorly defined. We show that the mechanosensitive BK channels open and recruit the focal adhesion kinase FAK in osteoblasts on hypotonic shock. This could convert mechanical signals in biochemical events, leading to osteoblast activation. Introduction: Mechanical strains applied to the skeleton influence bone remodeling and architecture mainly through the osteoblast lineage. The molecular mechanisms involved in osteoblastic mechanotransduction include opening of mechanosensitive cation channels and the activation of protein tyrosine kinases, notably FAK, but their interplay remains poorly characterized. The large conductance K+ channel (BK) seems likely as a bone mechanoreceptor candidate because of its high expression in osteoblasts and its ability to open in response to membrane stretch or hypotonic shock. Propagation of the signals issued from the mechanosensitivity of BK channels inside the cell likely implies complex interactions with molecular partners involved in mechanotransduction, notably FAK. Methods: Interaction of FAK with the C terminus of the hSlo ,-subunit of BK was investigated using the yeast two-hybrid system as well as immunofluorescence microscopy and coimmunoprecipitation experiments with a rabbit anti-hslo antibody on MG63 and CAL72 human osteosarcoma cell lines and on normal human osteoblasts. Mapping of the FAK region interacting with hSlo was approached by testing the ability of hSlo to recruit mutated ot truncated FAK proteins. Results: To the best of our knowledge, we provide the first evidence of the physical association of FAK with the intracellular part of hslo. We show that FAK/hSlo interaction likely takes place through the Pro-1-rich domain situated in the C-terminal region of the kinase. FAK/hSlo association occurs constitutively at a low, but appreciable, level in human osteosarcoma cells and normal human osteoblasts that express endogenous FAK and hSlo. In addition, we found that application of an hypo-osmotic shock to these cells induced a sustained activation of BK channels associated to a marked increase in the recruitment of FAK on hSlo. Conclusions: Based on these data, we propose that BK channels might play a triggering role in the signaling cascade induced by mechanical strains in osteoblasts. [source] Irreversible Perforations in Vertebral Trabeculae?,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2003X Banse In human cancellous bone, osteoclastic perforations resulting from normal remodeling were generally considered irreversible. In human vertebral samples, examined by backscatter electron microscopy, there was clear evidence of bridging of perforation defects by new bone formation. Hence trabecular perforations may not be irreversible. Introduction: Preservation of the trabecular bone microarchitecture is essential to maintain its load-bearing capacity and prevent fractures. However, during bone remodeling, the osteoclasts may perforate the platelike trabeculae and disconnect the structure. Large perforations (>100 ,m) are generally considered irreversible because there is no surface on which new bone can be laid down. In this work, we investigated the outcome of these perforations on human vertebral cancellous bone. Materials and Methods: Using backscatter electron microscopy, we analyzed 264 vertebral bone samples from the thoracic and lumbar spine of nine subjects (44,88 years old). Nine fields (2 × 1.5 mm) were observed on each block. Several bone structural units (BSUs) were visible on a single trabecula, illustrating a dynamic, historical aspect of bone remodeling. A bridge was defined as a single and recent BSU connecting two segments of trabeculae previously separated by osteoclastic resorption. They were counted and measured (length and breadth, ,m). Results and Conclusion: We observed 396 bridges over 2376 images. By comparison, we found only 15 microcalluses on the same material. The median length of the bridge was 165 ,m (range, 29,869 ,m); 86% being longer than 100 ,m and 35% longer than 200 ,m. Their breadth was 56 ,m (range, 6,255 ,m), but the thinnest were still in construction. Bridges were found in all nine subjects included in the study, suggesting that it is a common feature of normal vertebral bone remodeling. These observations support the hypothesis that perforation could be repaired by new bone formation. and hence, might not be systematically irreversible. [source] Alendronate Interacts With the Inhibitory Effect of 1,25(OH)2D3 on Parathyroid Hormone-Related Protein Expression In Human Osteoblastic Cells,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2003L Gómez-García Abstract The bisphosphonate alendronate is a potent inhibitor of bone resorption by its direct action on osteoclasts. In addition, there is some data suggesting that alendronate could also inhibit bone resorption indirectly by interacting with osteoblasts. Parathyroid hormone-related protein (PTHrP) produced by osteoblasts and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are regulators of bone remodeling, which have interrelated actions in these cells. In this study, we assessed whether alendronate can affect PTHrP expression in the presence or absence of 1,25(OH)2D3 in human primary osteoblastic (hOB) cells from trabecular bone. Cell total RNA was isolated, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out using human PTHrP-specific primers. PTHrP in the hOB cell-conditioned medium was analyzed by a specific immunoradiometric assay. We found that PTHrP mRNA and secreted PTHrP were maximally inhibited by 10,8 -10,6 M of 1,25(OH)2D3 treatment within 8,72 h in hOB cells. Alendronate (10,14 -10,8 M) modified neither PTHrP mRNA nor PTHrP secretion, although it consistently abrogated the decrease in PTHrP production induced by 1,25(OH)2D3 in these cells. On the other hand, alendronate within the same dose range did not affect either the vitamin D receptor (VDR) mRNA or osteocalcin secretion, with or without 1,25(OH)2D3, in hOB cells. The inhibitory effect of alendronate on the 1,25(OH)2D3 -induced decrease in PTHrP in these cells was mimicked by the calcium ionophore A23187 (5 × 10,6 M), while it was eliminated by 5 × 10,5 M of nifedipine. Furthermore, although alendronate alone failed to affect [Ca2+]i in these cells, it stimulated [Ca2+]i after pretreatment of hOB cells with 10,8 M of 1,25(OH)2D3, an effect that was abolished by 5 × 10,5 M of nifedipine. These results show that alendronate disrupts the modulatory effect of 1,25(OH)2D3 on PTHrP production in hOB cells. Our findings indicate that an increase in calcium influx appears to be involved in the mechanism mediating this effect of alendronate. [source] | ||||||||||||||||||||||||||||