Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens

Background Body phosphorus metabolism exhibits a circadian rhythm over the 24-h daily cycle.The egg laying behavior makes laying hens a very special model for investigating phosphorus circadian rhythms.There is lack of information about the impact of adjusting phosphate feeding regimen according to daily rhythm on the phosphorus homeostasis and bone remodeling of laying hens.Methods and results Two experiments were conducted.In Exp.1,Hy-Line Brown laying hens(n=45)were sampled according the oviposition cycle(at 0,6,12,and 18 h post-oviposition,and at the next oviposition,respectively;n=9 at each time point).Diurnal rhythms of body calcium/phosphorus ingestions and excretions,serum calcium/phosphorus levels,oviduct uterus calcium transporter expressions,and medullary bone(MB)remodeling were illustrated.In Exp.2,two diets with different phosphorus levels(0.32%and 0.14%non-phytate phosphorus(NPP),respectively)were alternately presented to the laying hens.Briefly,four phosphorus feeding regimens in total(each included 6 replicates of 5 hens):(1)fed 0.32%NPP at both 09:00 and 17:00;(2)fed 0.32%NPP at 09:00 and 0.14%NPP at 17:00;(3)fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00;(4)fed 0.14%NPP at both 09:00 and 17:00.As a result,the regimen fed 0.14%NPP at 09:00 and 0.32%NPP at 17:00,which was designed to strengthen intrinsic phosphate circadian rhythms according to the findings in Exp.1,enhanced(P<0.05)MB remodeling(indicated by histological images,serum markers and bone mineralization gene expressions),elevated(P<0.05)oviduct uterus calcium transportation(indicated by transient receptor potential vanilloid 6 protein expression),and subsequently increased(P<0.05)eggshell thickness,eggshell strength,egg specific gravity and eggshell index in laying hens.Conclusions These results underscore the importance of manipulating the sequence of daily phosphorus ingestion,instead of simply controlling dietary phosphate concentrations,in modifying the bone remodeling process.Body phosphorus rhythms will need to be maintained during the daily eggshell calcification cycle.

Fractional Order Nonlinear Bone Remodeling Dynamics Using the Supervised Neural Network

This study aims to solve the nonlinear fractional-order mathematical model(FOMM)by using the normal and dysregulated bone remodeling of themyeloma bone disease(MBD).For themore precise performance of the model,fractional-order derivatives have been used to solve the disease model numerically.The FOMM is preliminarily designed to focus on the critical interactions between bone resorption or osteoclasts(OC)and bone formation or osteoblasts(OB).The connections of OC and OB are represented by a nonlinear differential system based on the cellular components,which depict stable fluctuation in the usual bone case and unstable fluctuation through the MBD.Untreated myeloma causes by increasing the OC and reducing the osteoblasts,resulting in net bone waste the tumor growth.The solutions of the FOMM will be provided by using the stochastic framework based on the Levenberg-Marquardt backpropagation(LVMBP)neural networks(NN),i.e.,LVMBPNN.The mathematical performances of three variations of the fractional-order derivative based on the nonlinear disease model using the LVMPNN.The static structural performances are 82%for investigation and 9%for both learning and certification.The performances of the LVMBPNN are authenticated by using the results of the Adams-Bashforth-Moulton mechanism.To accomplish the capability,steadiness,accuracy,and ability of the LVMBPNN,the performances of the error histograms(EHs),mean square error(MSE),recurrence,and state transitions(STs)will be provided.

Effects of acupotomy on the activity of osteoclasts and osteoblasts in the subchondral bone of rabbits with early and mid-stage knee osteoarthritis models

Objective:To investigate whether acupotomy could inhibit subchondral bone remodeling in knee osteoarthritis(KOA)rabbits by regulating the activity of osteoblasts and osteoclasts.Methods:KOA rabbits were prepared by immobilization for 6 and 9 weeks by Videman method.Nine groups of rabbits(control,6 weeks and 9 weeks model,6 weeks and 9 weeks acupotomy,6 weeks and 9 weeks electroacupuncture,and 6 weeks and 9 weeks drug groups)received acupotomy,electroacupuncture and risedronate sodium intervention,respectively,for 3 weeks.Results:Acupotomy can inhibit the activity of osteoclasts and osteoblasts in subchondral bone by reducing the proteins expression of cathepsin K(CK)and tartrate-resistant acid phosphatase(TRAP)and decreasing the proteins expression of osteocalcin(OCN)and alkaline phosphatase(ALP),to intercept the abnormal bone resorption and bone formation of subchondral bone in 6-week and 9-week immobilization-induced KOA rabbits.Conclusion:These findings indicated that acupotomy may be more advantageous than risedronate sodium intervention in modulating subchondral bone remodeling in KOA rabbits,especially in 9-week immobilization-induced KOA rabbits.

The role of exosomes in bone remodeling and osseointegration of implants

Dental implant is an effective method in the treatment of missing teeth.The process of osseointegration of implant teeth involves the coordinated operation of immune system and bone system.The interaction between cells is closely related to bone formation and repair.Exosomes are important intercellular communication molecules.They were originally found in the supernatant of sheep erythrocytes cultured in vitro.They are micro vesicles with a diameter of 40~150 nm.They exist in a variety of cells and body fluids.They enter the target cells by endocytosis and transport,affecting the expression of cell genes and changing the fate of cells.It has an important regulatory function in the microenvironment of implant bone binding.It plays a role in bone remodeling through small molecular RNA,specific proteins and other growth factors secreted by different cells.This article reviews the role of bone derived cellderived exosomes in bone remodeling and their function in implant osseointegration.

A model of bone adaptation as a topology optimization process with contact

Topology optimization is presently used in most diverse scientific, technologic and industrial areas, including biomechanics. Bone remodelling models and structural optimization has mutually provided inspiration for new developments in biomechanics and biomedicine. Considering that bone has the ability to adapt its internal structure to mechanical loading (Wolff’s law and Roux’s paradigm), it is possible to model the behaviour of the bone structure by the use of a topology optimization methodology whose optimization variables can be the relative densities and the orthotropic directions. In this work, the internal bone adaptation of a proximal femur is considered. The bone-remodelling scheme is numerically described by a time-dependent evolutionary procedure with anisotropic material parameters. The remodelling rate equation is obtained from the structural optimization task of maximizing the stiffness subject to a biological cost associated with metabolic maintenance of bone tissue in time. The situation of multiple load conditions is considered for a three-dimensional finite element model of the proximal femur. The bone density distribution of a real femur is used as the initial design for the onset of the remodelling mechanism. Examples of bone adaptation resulting from load changes are presented. The three-dimensional finite element model of the proximal femur with initial bone density distribution was adapted to implant a cementless stem. A remeshing technique is used to assign the bone relative density distribution to the new geometry and mesh. The time adaptation of the bone is assessed considering contact with friction at the bone-stem interface. Results of bone density evolution and osteointegration distribution are obtained.

The role of microRNAs in bone remodeling

Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that micro RNAs（mi RNAs）, known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression,and growing numbers of novel mi RNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis,and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of mi RNAs in regulating bone remodeling as well as novel applications for mi RNAs in biomaterials for therapeutic purposes.

Mechanisms of altered bone remodeling in children with type 1 diabetes

Bone loss associated with type 1 diabetes mellitus(T1DM)begins at the onset of the disease,already in childhood,determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life.The mechanisms underlying diabetic bone fragility are not yet completely understood.Hyperglycemia and insulin deficiency can affect the bone cells functions,as well as the bone marrow fat,thus impairing the bone strength,geometry,and microarchitecture.Several factors,like insulin and growth hormone/insulin-like growth factor 1,can control bone marrow mesenchymal stem cell commitment,and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover.Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects.The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.

Autophagy in fate determination of mesenchymal stem cells and bone remodeling

Mesenchymal stem cells(MSCs)have been widely exploited as promising candidates in clinical settings for bone repair and regeneration in view of their self-renewal capacity and multipotentiality.However,little is known about the mechanisms underlying their fate determination,which would illustrate their effectiveness in regenerative medicine.Recent evidence has shed light on a fundamental biological role of autophagy in the maintenance of the regenerative capability of MSCs and bone homeostasis.Autophagy has been implicated in provoking an immediately available cytoprotective mechanism in MSCs against stress,while dysfunction of autophagy impairs the function of MSCs,leading to imbalances of bone remodeling and a wide range of aging and degenerative bone diseases.This review aims to summarize the up-to-date knowledge about the effects of autophagy on MSC fate determination and its role as a stress adaptation response.Meanwhile,we highlight autophagy as a dynamic process and a double-edged sword to account for some discrepancies in the current research.We also discuss the contribution of autophagy to the regulation of bone cells and bone remodeling and emphasize its potential involvement in bone disease.

Abnormal subchondral bone remodeling and its association with articular cartilage degradation in knees of type 2 diabetes patients

Type 2 diabetes （T2D） is associated with systemic abnormal bone remodeling and bone loss. Meanwhile, abnormal subchondral bone remodeling induces cartilage degradation, resulting in osteoarthritis （OA）. Accordingly, we investigated alterations in subchondral bone remodeling, microstructure and strength in knees from T2D patients and their association with cartilage degradation. Tibial plateaus were collected from knee OA patients undergoing total knee arthroplasty and divided into non-diabetic （n---70） and diabetes （n = 51） groups. Tibial plateaus were also collected from cadaver donors （n = 20） and used as controls. Subchondral bone microstructure was assessed using micro-computed tomography. Bone strength was evaluated by micro-finite-element analysis. Cartilage degradation was estimated using histology. The expression of tartrate-resistant acidic phosphatase （TRAP）, osterix, and osteocalcin were calculated using immunohistochemistry. Osteoarthritis Research Society International （OARSI） scores of lateral tibial plateau did not differ between non-diabetic and diabetes groups, while higher OARSI scores on medial side were detected in diabetes group. Lower bone volume fraction and trabecular number and higher structure model index were found on both sides in diabetes group. These microstructural alterations translated into lower elastic modulus in diabetes group. Moreover, diabetes group had a larger number of TRAP~ osteoclasts and lower number of Osterix~ osteoprogenitors and Osteocalcin~ osteoblasts. T2D knees are characterized by abnormal subchondral bone remodeling and microstructural and mechanical impairments, which were associated with exacerbated cartilage degradation. In regions with intact cartilage the underlying bone still had abnormal remodeling in diabetes group, suggesting that abnormal bone remodeling may contribute to the early pathogenesis of T2D-associated knee OA.

LRP6 in mesenchymal stem cells is required for bone formation during bone growth and bone remodeling

Lipoprotein receptor-related protein 6 （LRP6） plays a critical role in skeletal development and homeostasis in adults. However, the role of LRP6 in mesenchymal stem cells （MSCs）, skeletal stem cells that give rise to osteoblastic lineage, is unknown. In this study, we generated mice lacking LRP6 expression specifically in nestin＋ MSCs by crossing nestin-Cre mice with LRP6 flox mice and investigated the functional changes of bone marrow MSCs and skeletal alterations. Mice with LRP6 deletion in nestin＋ cells demonstrated reductions in body weight and body length at I and 3 months of age. Bone architecture measured by microCT （uCT） showed a significant reduction in bone mass in both trabecular and cortical bone of homozygous and heterozygous LRP6 mutant mice. A dramatic reduction in the numbers of osteoblasts but much less significant reduction in the numbers of osteoclasts was observed in the mutant mice. Osterix＋ osteoprogenitors and osteocalcin＋ osteoblasts significantly reduced at the secondary spongiosa area, but only moderately decreased at the primary spongiosa area in mutant mice. Bone marrow MSCs from the mutant mice showed decreased colony forming, cell viability and cell proliferation. Thus, LRP6 in bone marrow MSCs is essential for their survival and proliferation, and therefore, is a key positive regulator for bone formation during skeletal growth and remodeling.

A mathematical model of cortical bone remodeling at cellular level under mechanical stimulus

A bone cell population dynamics model for cor- tical bone remodeling under mechanical stimulus is devel- oped in this paper. The external experiments extracted from the literature which have not been used in the creation of the model are used to test the validity of the model. Not only can the model compare reasonably well with these ex- perimental results such as the increase percentage of final values of bone mineral content （BMC） and bone fracture en- ergy （BFE） among different loading schemes （which proves the validity of the model）, but also predict the realtime devel- opment pattern of BMC and BFE, as well as the dynamics of osteoblasts （OBA）, osteoclasts （OCA）, nitric oxide （NO） and prostaglandin E2 （PGE2） for each loading scheme, which can hardly be monitored through experiment. In conclusion, the model is the first of its kind that is able to provide an in- sight into the quantitative mechanism of bone remodeling at cellular level by which bone cells are activated by mechan- ical stimulus in order to start resorption/formation of bone mass. More importantly, this model has laid a solid foun- dation based on which future work such as systemic control theory analysis of bone remodeling under mechanical stimu- lus can be investigated. The to-be identified control mecha- nism will help to develop effective drugs and combined non- pharmacological therapies to combat bone loss pathologies. Also this deeper understanding of how mechanical forces quantitatively interact with skeletal tissue is essential for the generation of bone tissue for tissue replacement purposes in tissue engineering.

Anterior bone loss after cervical disc replacement: A systematic review

BACKGROUND Anterior bone loss(ABL)is a relatively easily neglected condition after cervical disc replacement(CDR).Whether this phenomenon is a radiological anomaly or a complication remains controversial.Several studies have reported the clinical characteristics of ABL and speculated on the pathogenic mechanism based on a certain type of artificial disc,while the overall understanding of ABL is lacking.AIM To describe the prevalence,impacts,and risk factors of ABL after CDR.METHODS We searched the PubMed,Cochrane Library,and Excerpta Medica databases using the terms“bone loss”or“bone remodeling”or“bone absorption”or“osteolysis”or“implant loosening”or“implant migration”or“hypersensitivity”or“hyperreactivity”,“cervical disc replacement”or“cervical disc arthroplasty”or“total disc replacement”.Eligible manuscripts on the prevalence and impacts of ABL were reviewed by the authors.Data extraction was performed using an established extraction form.The results of the included studies were described narratively.RESULTS Six studies met the inclusion and exclusion criteria.One was a prospective study and the others were retrospective studies.A total of 440 patients with 536 segments were included.The artificial cervical discs included Bryan,Baguera-C,Discocerv,and Mobi-C.The prevalence of ABL ranged from 3.13%to 91.89%,with a combined overall prevalence of 41.84%.ABL occurred within 6 mo and stopped 12 mo after surgery.Several cases were noted to have a self-healing process.Severe ABL resulted in segmental kyphosis,implant subsidence,and persistent neck pain.ABL may be related to heterotopic ossification.Multilevel surgery may be one of the risk factors for ABL.CONCLUSION ABL is a common condition after CDR.The underlying mechanisms of ABL may include stress concentration and injury to nutrient vessels.ABL should be considered a complication after CDR as it was associated with neck pain,implant subsidence,and heterotopic ossification.

Bone remodeling in sigmoid sinus diverticulum after stenting for transverse sinus stenosis in pulsatile tinnitus: A case report

BACKGROUND Pulsatile tinnitus(PT)is a potentially disabling symptom that has received increasing attention.Multiple causes of PT have been confirmed by targeted treatment.However,dynamic changes of related structures in PT patients with multiple causes after stenting for ipsilateral transverse sinus stenosis(TSS)have not been previously reported.We report such a case and present postoperative computed tomography venography(CTV)follow-up findings to demonstrate the decreased sigmoid sinus diverticulum and bone remodeling.CASE SUMMARY A 45-year-old man suffered from left-sided PT for 15 years that was occasionally accompanied by headache and dizziness.Pre-operative CTV revealed left-sided sigmoid sinus wall anomalies(SSWAs),TSS,outflow dominance,large posterior condylar emissary vein,and an empty sella turcica.A cerebrospinal fluid pressure of 270 mmH2O was further detected.The sound disappeared immediately after stenting for ipsilateral TSS,with no recurrence during 2 years of follow-up.After the procedure,the patient underwent four consecutive CTV examinations.The diverticulum decreased 6 mo after the procedure with new bone remodeling.The density of the remodeled bone was further increased 1 year later,and a hardened edge was formed 2 years later.CONCLUSION PT associated with SSWAs,TSS,and idiopathic intracranial hypertension can be cured by stenting for TSS alone.And bone remodeling around SSWAs is a more significant finding.

Type 2 diabetes and bone fragility in children and adults

Type 2 diabetes(T2D)is a global epidemic disease.The prevalence of T2D in adolescents and young adults is increasing alarmingly.The mechanisms leading to T2D in young people are similar to those in older patients.However,the severity of onset,reduced insulin sensitivity and defective insulin secretion can be different in subjects who develop the disease at a younger age.T2D is associated with different complications,including bone fragility with consequent susceptibility to fractures.The purpose of this systematic review was to describe T2D bone fragility together with all the possible involved pathways.Numerous studies have reported that patients with T2D show preserved,or even increased,bone mineral density compared with controls.This apparent paradox can be explained by the altered bone quality with increased cortical bone porosity and compromised mechanical properties.Furthermore,reduced bone turnover has been described in T2D with reduced markers of bone formation and resorption.These findings prompted different researchers to highlight the mechanisms leading to bone fragility,and numerous critical altered pathways have been identified and studied.In detail,we focused our attention on the role of microvascular disease,advanced glycation end products,the senescence pathway,the Wnt/β-catenin pathway,the osteoprotegerin/receptor-activator of nuclear factor kappa B ligand,osteonectin and fibroblast growth factor 23.The understanding of type 2 myeloid bone fragility is an important issue as it could suggest possible interventions for the prevention of poor bone quality in T2D and/or how to target these pathways when bone disease is clearly evident.

Parametric study of control mechanism of cortical bone remodeling under mechanical stimulus

The control mechanism of mechanical bone remodeling at cellular level was investigated by means of an extensive parametric study on a theoretical model described in this paper. From a perspective of control mechanism, it was found that there are several control mechanisms working simultaneously in bone remodeling which is a complex process. Typically, an extensive parametric study was carried out for investigating model parameter space related to cell differentiation and apoptosis which can describe the fundamental cell lineage behaviors. After analyzing all the combinations of 728 permutations in six model parameters, we have identified a small number of parameter combinations that can lead to physiologically realistic responses which are similar to theoretically idealized physiological responses. The results presented in the work enhanced our understanding on mechanical bone remodeling and the identified control mechanisms can help researchers to develop combined pharmacological-mechanical therapies to treat bone loss diseases such as osteoporosis.

Bone Remodeling, Biomaterials And Technological Applications: Revisiting Basic Concepts

Presently, several different graft materials are employed in regenerative or corrective bone surgery. However current misconceptions about these biomaterials, their use and risks may compromise their correct application and development. To unveil these misconceptions, this work briefly reviewed concepts about bone remodeling, grafts classification and manufacturing processes, with a special focus on calcium phosphate materials as an example of a current employed biomaterial. Thus a search on the last decade was performed in Medline, LILACS, Scielo and other scientific electronic libraries using as keywords biomaterials, bone remodeling, regeneration, biocompatible materials, hydroxyapatite and therapeutic risks. Our search showed not only an accelerated biotechnological development that brought significant advances to biomaterials use on bone remodeling treatments but also several therapeutic risks that should not be ignored. The biomaterials specificity and limitations to clinical application point to the current need for developing safer products with better interactions with the biological microenvironments.

25-hydroxycholecalciferol reverses heat induced alterations in bone quality in finisher broilers associated with effects on intestinal integrity and inflammation

Background:Alterations in ambient temperature have been associated with multiple detrimental effects on broilers such as intestinal barrier disruption and dysbiosis resulting in systemic inflammation.Inflammation and 25-hydroxycholecalciferol(25-OH-D_(3))have shown to play a negative and positive role,respectively,in the regulation of bone mass.Hence the potential of 25-OH-D_(3)in alleviating heat induced bone alterations and its mechanisms was studied.Results:Heat stress(HS)directly induced a decrease in tibia material properties and bone mass,as demonstrated by lower mineral content,and HS caused a notable increase in intestinal permeability.Treatment with dietary 25-OH-D_(3)reversed the HS-induced bone loss and barrier leak.Broilers suffering from HS exhibited dysbiosis and increased expression of inflammatory cytokines in the ileum and bone marrow,as well as increased osteoclast number and activity.The changes were prevented by dietary 25-OH-D_(3)administration.Specifically,dietary 25-OH-D_(3)addition decreased abundance of B-and T-cells in blood,and the expression of inflammatory cytokines,especially TNF-α,in both the ileum and bone marrow,but did not alter the diversity and population or composition of major bacterial phyla.With regard to bone remodeling,dietary 25-OH-D_(3)supplementation was linked to a decrease in serum C-terminal cross-linked telopeptide of type I collagen reflecting bone resorption and a concomitant decrement in osteoclast-specific marker genes expression(e.g.cathepsin K),whereas it did not apparently change serum bone formation markers during HS.Conclusions:These data underscore the damage of HS to intestinal integrity and bone health,as well as that dietary 25-OH-D_(3)supplementation was identified as a potential therapy for preventing these adverse effects.

Numerical Simulation of Bone Remodeling Coupling the Damage Repair Process in Human Proximal Femur

Microdamage is produced in bone tissue under the long-termeffects of physiological loading,as well as age,disease and other factors.Bone remodeling can repair microdamage,otherwise this damage will undermine bone quality and even lead to fractures.In this paper,the damage variable was introduced into the remodeling algorithm.The new remodeling algorithm contains a quadratic term that can simulate reduction in bone density after large numbers of loading cycles.The model was applied in conjunction with the 3Dfinite elementmethod(FEM)to the remodeling of the proximal femur.The results showed that the initial accumulation of fatigue damage led to an increase in density but when the damage reached a certain level,the bone density decreased rapidly until the femur failed.With the accumulation of damage,bone remodeling was coupled with fatigue damage to maintain the function of bone.When the accumulation of damage reached a certain level,bone remodeling failed to repair the accumulated fatigue damage in time,and continued cyclic loading significantly weakened the loadbearing capacity of the bone.The new mathematical model not only predicts fatigue life,but also helps to further understand the compromise between damage repair and damage accumulation,which is of great significance for the prevention and treatment of clinical bone diseases.

Effects of time delays in a mathematical bone model

In this paper we propose a mathematical model of bone remodeling with time delays of both osteoclast-derived paracrine signaling of tumor and tumor-derived paracrine signaling of osteoclast. The effects of time delays on the growth of tumor cells and bone system are studied in multiple myeloma-induced bone disease. In the case of small osteoclast-derived paracrine signaling, it is found that the growth of tumor cells slows down, the oscillation period of the ratio of osteoclasts to osteoblasts is extended with increasing time delay, and there is a competition between the delay and osteoclast-derived paracrine signaling. In the ease of large tumor-derived paraerine signaling, the tumor-derived paracrine signaling can induce a more significant decline in tumor growth for long time delay, and thus slowing down the progression of bone disease. There is an optimal coupling between the tumor-derived paracrine signaling of osteoclasts and time delay during the progressions of bone diseases, which suppresses the tumor growth and the regression of bone disease.

Evaluation of bone remodeling in regard to the age of scaphoid non-unions

AIM: To analyse bone remodeling in regard to the age of scaphoid non-unions(SNU) with immunohistochemistry.METHODS: Thirty-six patients with symptomatic SNU underwent surgery with resection of the pseudarthrosis. The resected material was evaluated histologically after staining with hematoxylin-eosin(HE), tartrate resistant acid phosphatase(TRAP), CD 68, osteocalcin(OC) and osteopontin(OP). Histological examination was performed in a blinded fashion.RESULTS: The number of multinuclear osteoclasts in the TRAP-staining correlated with the age of the SNU and was significantly higher in younger SNU(P = 0.034; r = 0.75). A higher number of OP-immunoreactive osteoblasts significantly correlated with a higher number of OC-immunoreactive osteoblasts(P = 0.001; r = 0.55). Furthermore, a greater number of OP-immunoreactive osteoblasts correlated significantly with a higher number of OP-immunoreactive multinuclear osteoclasts(P = 0.008; r = 0.43). SNU older than 6 mo showed a signifi-cant decrease of the number of fibroblasts(P = 0.04). Smoking and the age of the patients had no influence on bone remodeling in SNU.CONCLUSION: Multinuclear osteoclasts showed a significant decrease in relation to the age of SNU. However, most of the immunhistochemical findings of bone remodeling do not correlate with the age of the SNU. This indicates a permanent imbalance of bone formation and resorption as indicated by a concurrent increase in both osteoblast and osteoclast numbers. A clear histological differentiation into phases of bone remodeling in SNU is not possible.