The bone remodeling rate (BRR): the period of time needed for new bone to replace the existing bone and to allow for the adaptation of bone to its environment BRR is expressed as a percentage or volume of new bone within a specific time period.
Scheme of origin, interactions and local factors required for differentiation/function of the osteo-cells involved in bone remodeling.
Scheme of the interactions considered in the mathematical model describing forceinduced bone adaptation
3 days
4 weeks
Concurrently with osseointegration process, bone remodelling occurs, where the bone density is changed due to the implant induced mechanical loading [5]. Therefore, bone remodelling is in essence a process where the bone changes its own property to adapt to its changing mechanical loading environment [6]. As bone remodels positively, the quality of the bone will improve, therefore leading to the stabilization of the dental implant inside the dental bone. This will have the effect of reducing the rate of implant failure. Therefore, in order to optimize the dental implant design, it is crucial to understand the magnitude and the development of mechanical stress inside the bony tissues. Such predictions can help to minimize the possibility of implantation failure.
mechanotransduction
The conversion of biophysical force to cellular and biochemical response It comprises four phases 1-mechanocoupling 2-biochemical coupling 3-transmision of signal from sensor to effector cells 4-effector cell responses
Tissue Remodeling
add bone
Ddcell
Cellular Mechanoreception
Cells contain specialized structures to detect mechanical stimuli:
+ + + +
Mechanical loading requires signaling through the Lrp5 receptor to initiate bone formation. This signal is initiated by Wnt, which binds to the receptor complex made up of Lrp5 and Frizzled. Wnt signaling can be blocked by Dickkopf related protein (Dkk) when it binds Lrp5 and Kremen. Sclerostin (Sclr) inhibits Wnt signaling by binding Lrp5 and secreted Frizzled-related protein (sFrp) binds to Wnt and prevents signaling. Each of these inhibitors blocks mechanotransduction and reduces bone formation.
Lrp5 appears to be a potent regulator of bone mass, size, and strength. One of the main mechanisms of action for the receptor in bone is through mechanical signaling, Lrp5 is a late-acting mediator in the osteogenic response to mechanical loading, suggesting that skeletal fragility in individuals afflicted with OPPG might be related to inadequate processing of signals derived from mechanical stimulation.
intermittent PTH might be an effective treatment for improving bone mass in these patients.
Mechanotransduction in Cells
Pathways for mechanotransduction
forces applied through the ECM (A) or directly to the cell surface (B) travel to integrin-anchored focal adhesions through matrix attachments or cytoskeletal filaments, respectively. Internally-generated tension and forces transmitted through cell-cell contact similarly reach focal adhesions through the cytoskeleton. Forces concentrated within the focal adhesion (magnified at bottom of figure) can stimulate integrin clustering and induce recruitment of additional cytoskeletal linker proteins (Vin, vinculin; Pax, paxillin; Tal, talin) that connect directly to microfilaments and indirectly to microtubules. Forces applied to this specialized cytoskeletal adhesion complex also activate integrin-associated signal cascades. Focal adhesion kinase (FAK) may be involved in Shc recruitment as well as modulation of Rho activity which, in turn, can regulate the force response through mDia1. Caveolin-1 (cav-1) can also recruit Shc to integrins to activate the ERK cascade. CD47 associates with the integrin heterodimer to form a protein complex with seven transmembrane segments that mimics the action of G protein-coupled receptors. In the case shown, when integrins are mechanically stressed, the complex stimulates Gs-mediated up-regulation of the cAMP cascade through adenylate cyclase (AC), resulting in nuclear translocation of the catalytic subunit of protein kinase A, PKA-c
In non-human primate studies, it was observed that five out of eight implants lost osseointegration due to excessive occlusal overloading after 4.515.5 months of loading (Isidor 1996, 1997). Among the three remaining implants, one showed severe crestal bone loss and the other two showed the highest bone implant contact and density. The results suggested that implant loading might have significantly affected the responses of periimplant osseous structures. However, it should be noted that the loss of osseointegration observed might have been attributed to the unrealistically high-occlusal overload used in the study
Low-amplitude and low frequency specific strains (15-30 Hz) were demonstrated to have an osteogenic effect and act as a growth factor to encourage bone response to loading (19). Low-magnitude high frequency (30-50 Hz) mechanical signals produce, instead, anabolic effects on bone. If such loading regimens could be applied for dental implants, a favorable mechanical environment for osseointegration is promoted. Bone-implant interface maturation could be faster because bone deposition increases.
Local Regulation of Bone Healing Growth factors Cytokines Prostaglandins/Leukotrienes Hormones Growth factor antagonists
Preserving the Bone Level Marginal bone remodeling is obviously a multifactorial issue. The surgery-induced trauma can be highly detrimental for the release of a flap and induces some cell death, which provokes an inflammatory process and brings mediators of bone resorption. The more the bone is exposed and dried by suction, the more bone resorption occurs. This is the rationale for the use of conservative surgical approaches in these procedures.
the respect of the mucosal seal is essential to prevent bone remodeling and soft tissue aesthetic repercussions.
The transmucosal components design should be concave, inwardly narrowed in order to positively impact the soft tissues
The mobility of the peri-implant mucosa is highly deleterious because when tearing of connective tissue occurs with microbleeding, the protective role of the junctional epithelium induces the apicalization of the latter. By consequence, a layer of connective tissue of 1mm (in average) has to reform more apically often at the expense of the bone crest
Growth Factors Transforming growth factor Bone morphogenetic proteins Fibroblast growth factors Platelet-derived growth factors Insulin-like growth factors
BMP2-7,9 are osteoinductive BMP2,6, & 9 may be the most potent in osteoblastic differentiation Work through the intracellular Smad pathway Follow a dose/response ratio
BMP-7 equally effective as ICBG in nonunions Must be applied locally because of rapid systemic clearance ? Effectiveness in acute fractures ? Increased wound healing in open injuries Protein therapy vs. gene therapy
Fibroblast Growth Factors Both acidic (FGF-1) and basic (FGF-2) forms Increase proliferation of chondrocytes and osteoblasts Enhance callus formation FGF-2 stimulates angiogenesis
Stimulates bone cell growth Mitogen for cells of mesenchymal origin Increases type I collagen synthesis by increasing the number of osteoblasts PDGF-BB stimulates bone resorption by increasing the number of osteoclasts
Stimulates bone collagen and matrix synthesis Stimulates replication of osteoblasts Inhibits bone collagen degradation
Cytokines
Interleukin-1,-4,-6,-11, macrophage and granulocyte/macrophage (GM) colony-stimulating factors (CSFs) and Tumor Necrosis Factor Stimulate bone resorption
IL-1 is the most potent
Peak during 1st 24 hours then again during remodeling Regulate endochondral bone formation
Bone
+++ +++ +++ +++ ++ ++ 0 0 0
Prostaglandins / Leukotrienes
Effect on bone resorption is species dependent and their overall effects in humans unknown Prostaglandins of the E series
Stimulate osteoblastic bone formation Inhibit activity of isolated osteoclasts
Leukotrienes
Stimulate osteoblastic bone formation Enhance the capacity of isolated osteoclasts to form resorption pits
Angiogenic factors
Vascular-endothelial growth factors
Mediate neo-angiogenesis & endothelial-cell specific mitogens
Angiopoietin (1&2)
Regulate formation of larger vessels and branches
species
Table 1. Summary of four key attributes in terms of similarity between animal and human bone.
Canine
Macrostructure Microstructure Bone Composition Bone Remodelling ++ ++ +++ ++
Sheep/Goat Pig
+++ + ++ ++ ++ ++ +++ +++
Rabbit
+ + ++ +
Bone Remodeling
Bone structural integrity is continually maintained by remodeling
Osteoclasts and osteoblasts assemble into Basic Multicellular Units (BMUs) Bone is completely remodeled in approximately 3 years
Amount of old bone removed equals new bone formed
http://www.elixirindustry.com/resource/osteoporosis/jilka.htm
B. Resorption Urine
Hydroxyproline Free and total pyridinoline (Pyd) Free and total deoxypyridinoline (Dpd) N-telopeptide of collagen cross links (NTx) C-telopeptide of collagen cross links (CTx)
Serum
Cross-linked C-telopeptide of type I collagen (ICTP) Tartrate-resistant acid phosphatase (TRAP) NTx CTx
Osteocytes
Reversal
Endocrine
STH (somatotropic or growth hormone): increases cell division & all subsidiary processes (total protein synthesis, net protein synthesis, total turnover, tissue growth) ACH (adrenal-cortical hormone) : decreases cell division & subsidiary processes. T4 (thyroxine): affects all tissues. Estrogens: selectively decrease cell division & subsidiary processes; affect cartilage & lamellar bone. Vitamins A, C & D & calcitonin
Bone Remodeling
Bone of the skeleton are continually remodeled for 2 reasons
Bone remodeling helps maintain constant concentrations of Ca2+ and PO43- in bodily fluids Bones are remodeled in response to the mechanical stress it experiences
Osteons of compact bone and the trabeculae of spongy bone are constantly replaced by new osteons and trabeculae that are more precisely aligned with newly experienced compressive and tensile forces
Vitamins
Vitamin A stimulates activity of osteoblasts Vitamin C is needed for synthesis of collagen Vitamin D helps build bone by increasing the absorption of calcium from foods in the gastrointestinal tract into the blood Vitamins K and B12 are needed for synthesis of bone proteins
Copyright 2009, John Wiley & Sons, Inc. 61
medications
Simvastatin is a lipid lowering agent with osteoanabolic effects. Histomorphometric studies have shown increased bone ingrowth and mechanical examination, increased interface strength, superior stability and osseous adaptation at the bone/implant interface in the simvastatintreated group3
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Bisphosphonates inhibit osteoclast-mediated bone resorption and normalize the high rate of bone turnover that characterizes osteoporosis. Consequently, there is a rationale for using bisphosphonates to enhance early stability of implants in patients with low bone mass30,62,89-
indomethacin causes a transient decrease in attachment strength at early periods, but it does not seem to significantly affect longterm osseointegration of porous-coated implants98.
warfarin, Enoxaparin, dalteparin and unfractionated heparin led to a significant decrease of matrix collagen type II content and calcification in concentrations equal or higher than the therapeutic one.
fondaparinux, a synthetic anticoagulant substance similar to heparin, showed no inhibitory in vitro effects on human osteoblasts within the concentration range investigated (0.01-100 g/ml). Therefore, fondaparinux may be used to avoid the heparin-related negative influence on osteoblast-dependent fracture healing and endoprosthetic implant integration99,100.
Recently, cell-mediated regional gene therapy was introduced to deliver potent morphogens or growth factors in regenerative medicine. Direct application of the BMP-2 gene using a liposomal vector enhanced bone regeneration in a bony defect; gene delivery combined with bone grafting could induce rapid osseointegration of the bone-implant interface at an earlier stage121.
Brittleness
Results from a decreased rate of protein synthesis Collagen fibers give bone its tensile strength The loss of tensile strength causes the bones to become very brittle and susceptible to fracture
Copyright 2009, John Wiley & Sons, Inc.
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Meloxicam negatively influenced bone healing in the cortical and cancellous bone around titanium implants inserted in rats after continuous administration
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Bone Remodeling
Bone forming osteoblasts form from mesenchyme-like stem cells located in the periosteum, endosteum, and the connective tissue of nearby bone marrow Osteoclasts form in bone marrow from immature blood cells called hematopoietic stem cells Many of these stem cells fuse together to form each osteoclast, thus their multinucleate structure
Bone Remodeling
Osteoclasts release calcium ions (Ca2+) and phosphate ions (PO43-) that enters the tissue fluid and the bloodstream Lysosomal enzymes are also released by the osteoclasts and digest the organic part of the bone matrix Finally, osteoclasts take up collagen and dead osteocytes by phagocytosis
Bone Remodeling
The ruffled plasma membrane forms a tight seal against the bone and HCL dissolves the mineral portion of the matrix
Bone Remodeling
Osteoclasts are large cells with many nuclei Their plasma membrane is highly folded or ruffled
Bone Remodeling
Bone remodeling is coordinated by cohorts of adjacent osteoclasts called remodeling units Osteoclasts crawl along the bone surfaces digging pits as they break down bone surfaces
Bone Remodeling
Bone is dynamic and active tissue Long bone growth is accompanied by almost continuous remodeling in order to maintain proper proportions Large amounts of bone matrix and thousands of osteocytes are being continually removed and replaced The small scale architecture of bones changes constantly
Bone Remodeling
The spongy bone of the skeleton is replaced every 3 years The compact bone is replaced every 10 years The remodeling process is not uniform as some parts experiencing more stress are replaced at a faster rate (every 5-6 months) while other areas change more slowly
Frosts mechanostat
Disuse: Strain < circa 800Strain: Remodeling (bone adaptation and bone repair) Bone mass and bone strength is reduced. Adapted State: strain between ca. 800Strain and ca. 1500Strain: Remodeling (bone repair) Bone mass and bone strength stays constant Overload: Strain > circa 1500Strain: Modeling (bone growth) bone mass and bone strength his increased Fracture: Strain > circa 15000Strain: maximum elastically deformation excceded - bone fracture.
a stress diversion design, which promotes bone growth and maturation under normal loading conditions. Mechanical stimuli elicit the proliferation of bone cells
Primary cilia project from the apical surface of bone cells and bend during fluid flow. (Aand B) Primary cilia stained with anti-acetylated-tubulin (red) extend from centrosomes stained with anti-CEP135 (green) in MC3T3-E1 osteoblasts (A) and MLO-Y4 osteocytes (B).DNAis stained with DAPI (blue). (C) Maximum projection of a confocal z series shows a primary cilium marked by acetylated -tubulin (red) extending from the apical surface marked by CMFDA (green) of an MC3T3-E1 osteoblast. DNA is stained with DAPI (blue). (D) Side view of a primary cilium (arrowheads) extending from the apical surface of an MC3T3-E1 osteoblast before (Upper) and during (Lower) application fluidflowfrom left to right. Images are inverted frames from SI Movie 1. (Scale bars: 5 m.)
2. RNAi of polaris prevents primary cilium formation in cultured bone cells. (A) Western blot showing reduced levels of protein in MC3T3-E1 osteoblasts transfected with polaris siRNA (right lane) relative to cells transfected with control siRNA (left lane). Western blot for actin is a loading control. (B) Control MC3T3-E1 osteoblast showing polaris (green) at the primary cilium (arrowhead) marked by acetylated -tubulin (red). DNA is stained with DAPI (blue). (C) Polaris siRNA-treated MC3T3-E1 osteoblast showing reduced polaris staining (green) and the absence of a primary cilium extending from the centrioles (arrowhead). Stable cytoplasmic microtubules are marked by acetylated -tubulin (red) and DNA is stained with DAPI (blue). (Scale bars: 10 m.
Factors concerning implant design which affect the stress distribution to the periimplant bone of loaded dental implants.
1) The rough/smooth border on 1-piece nonsubmerged implants determines the initial bone-to-implant contact. (2) In 2-piece implants, the first bone-to-implant contact was located 1.5 to 2 mm apical to the microgap between the 2 pieces (Figure 1).7 (3) Osseous changes occur after the creation of a microgap at the implant-abutment interface.
The interproximal height of bone (IHB) has a distinct influence on interdental papillae mean papilla length for an implant-tooth relationship was found to be 6.5 mm; for an implant-implant relationship the mean papilla length was 4.5 mm. Adequate interdental soft tissue depends on the height of the interproximal bone and its relation to the contact point When the distance from the contact point to the interproximal height of bone is greater than 5 mm, avoiding the black triangle is difficult
Figure 5. Infringement of pr
If proximity guidelines were not obeyed when placing the implant next to an adjacent implant (3 mm) or tooth (1.5 mm), then interproximal bone will be insufficient to support papilla formation (and a black triangle may be evident.
Figure 7.
platform switching.
Use of nonsubmerged implants to eliminate bone loss is a proven way to accomplish this A scalloped implant platform has been developed to follow the osseous architecture and eliminate crestal bone loss by maintaining the microgap in a supracrestal position medializing the position of the microgap, ie, using a smaller abutment. platform switching.
minimal remodeling of the interproximal bone and the absence of bone loss relative to restorative platforms.
Radiograph at abutment connection, three days after implant placement. The implant restorative platforms of the abutments and implants are subcrestal.