Parathyroid hormone (PTH) administered intermittently is a bone-building peptide. In joint replacements, implants are unavoidably surrounded by gaps despite meticulous surgical technique and osseointegration is challenging. We examined the effect of human PTH(1–34) on implant fixation in an experimental gap model. We inserted cylindrical (10 × 6 mm) porous coated titanium alloy implants in a concentric 1-mm gap in normal cancellous bone of proximal tibia in 20 canines. Animals were randomized to treatment with PTH(1–34) 5 μg/kg daily. After 4 weeks, fixation was evaluated by histomorphometry and push-out test. Bone volume was increased significantly in the gap. In the outer gap (500 μm), the bone volume fraction median (interquartile range) was 27% (20–37%) for PTH and 10% (6–14%) for control. In the inner gap, the bone volume fraction was 33% (26–36%) for PTH and 13% (11–18%) for control. At the implant interface, the bone fraction improved with 16% (11–20%) for PTH and 10% (7–12%) (P = 0.07) for control. Mechanical implant fixation was improved for implants exposed to PTH. For PTH, median (interquartile range) shear stiffness was significantly higher (PTH 17.4 [12.7–39.7] MPa/mm and control 8.8 [3.3–12.4] MPa/mm) (P < 0.05). Energy absorption was significantly enhanced for PTH (PTH 781 [595–1,198.5] J/m2 and control 470 [189–596] J/m2). Increased shear strength was observed but was not significant (PTH 3.0 [2.6–4.9] and control 2.0 [0.9–3.0] MPa) (P = 0.08). Results show that PTH has a positive effect on implant fixation in regions where gaps exist in the surrounding bone. With further studies, PTH may potentially be used clinically to enhance tissue integration in these challenging environments.
Parathyroid hormone; Prostheses and implants; Canine; Biomechanics; Histomorphometry
Impaction allograft is an established method of securing initial stability of an implant in arthroplasty. Subsequent bone integration can be prolonged, and the volume of allograft may not be maintained. Intermittent administration of parathyroid hormone has an anabolic effect on bone and may therefore improve integration of an implant.
Using a canine implant model we tested the hypothesis that administration of parathyroid hormone may improve osseo-integration of implants surrounded by bone graft. In 20 dogs a cylindrical porous-coated titanium alloy implant was inserted into normal cancellous bone in the proximal humerus and surrounded by a circumferential gap of 2.5 mm. Morsellised allograft was impacted around the implant. Half of the animals were given daily injections of human parathyroid hormone (1-34) 5 μg/kg for four weeks and half received control injections. The two groups were compared by mechanical testing and histomorphometry. We observed a significant increase in new bone formation within the bone graft in the parathyroid hormone group. There were no significant differences in the volume of allograft, bone-implant contact or in the mechanical parameters.
These findings suggest that parathyroid hormone improves new bone formation in impacted morsellised allograft around an implant and retains the graft volume without significant resorption. Fixation of the implant was neither improved nor compromised at the final follow-up of four weeks.
Uncemented fixation of components in joint arthroplasty is achieved primarily through de novo bone formation at the bone-implant interface and establishment of a biological and mechanical interlock. In order to enhance bone-implant integration osteoconductive coatings and the methods of application thereof are continuously being developed and applied to highly porous and roughened implant substrates. In this study the effects of an electrochemically-deposited dicalcium phosphate dihydrate (DCPD) coating of a porous substrate on implant osseointegration was assessed using a standard uncemented implant fixation model in sheep.
Plasma sprayed titanium implants with and without a DCPD coating were inserted into defects drilled into the cancellous and cortical sites of the femur and tibia. Cancellous implants were inserted in a press-fit scenario whilst cortical implants were inserted in a line-to-line fit. Specimens were retrieved at 1, 2, 4, 8 and 12 weeks postoperatively. Interfacial shear-strength of the cortical sites was assessed using a push-out test, whilst bone ingrowth, ongrowth and remodelling were investigated using histologic and histomorphometric endpoints.
DCPD coating significantly improved cancellous bone ingrowth at 4 weeks but had no significant effect on mechanical stability in cortical bone up to 12 weeks postoperatively. Whilst a significant reduction in cancellous bone ongrowth was observed from 4 to 12 weeks for the DCPD coating, no other statistically significant differences in ongrowth or ingrowth in either the cancellous or cortical sites were observed between TiPS and DCPD groups.
The application of a DCPD coating to porous titanium substrates may improve the extent of cancellous bone ingrowth in the early postoperative phase following uncemented arthroplasty.
Bone ingrowth; Interfacial shear strength; Calcium phosphate; Osteoconduction; Bone remodeling
Background and purpose Parathyroid hormone (PTH) has attracted considerable interest as a bone anabolic agent. Recently, it has been suggested that PTH can also enhance bone repair after fracture and distraction osteogenesis. We analyzed bone density and strength of the newly regenerated mineralized tissue after intermittent treatment with PTH in rabbits, which undergo Haversian bone remodeling similar to that in humans.
Methods 72 New Zealand White rabbits underwent tibial mid-diaphyseal osteotomy and the callus was distracted 1 mm/day for 10 days. The rabbits were divided into 3 groups, which received injections of PTH 25 µg/kg/day for 30 days, saline for 10 days and PTH 25 µg/kg/day for 20 days, or saline for 30 days. At the end of the study, the rabbits were killed and the bone density was evaluated with DEXA. The mechanical bone strength was determined by use of a 3-point bending test.
Results In the 2 PTH-treated groups the regenerate callus ultimate load was 33% and 30% higher, absorbed energy was 100% and 65% higher, BMC was 61% and 60% higher, and callus tissue volume was 179% and 197% higher than for the control group.
Interpretation We found that treatment with PTH during distraction osteogenesis resulted in substantially higher mineralized tissue volume, mineral content, and bending strength. This suggests that treatment with PTH may benefit new bone formation during distraction osteogenesis and could form a basis for clinical application of this therapy in humans.
Early bone ongrowth secures long-term fixation of primary implants inserted without cement. Implant surfaces roughened with a texture on the micrometer scale are known to be osseoconductive. The aim of this study was to evaluate the bone formation at the surface of acid etched implants modified on the micro-scale. We compared implants with a nonparticulate texture made by chemical milling (hydrofluoric acid, nitric acid) (control) with implants that had a dual acid etched (hydrofluoric acid, hydrochloric acid) microtexture surface superimposed on the primary chemically milled texture. We used an experimental joint replacement model with cylindrical titanium implants (Ti-6Al-4V) inserted paired and press-fit in cancellous tibia metaphyseal bone of eight canines for 4 weeks and evaluated by histomorphometric quantification. A significant twofold median increase was seen for bone ongrowth on the acid etched surface [median, 36.1% (interquartile range, 24.3–44.6%)] compared to the control [18.4% (15.6–20.4%)]. The percentage of fibrous tissue at the implant surface and adjacent bone was significantly less for dual acid textured implants compared with control implants. These results show that secondary roughening of titanium alloy implant surface by dual acid etching increases bone formation at the implant bone interface.
osseointegration; surface texture; acid etching; implants; histology
Interaction between implant surface and surrounding bone influences implant fixation. We attempted to improve the bone-implant interaction by 1) adding surface micro scale topography by acid etching, and 2) removing surface-adherent pro-inflammatory agents by plasma cleaning. Implant fixation was evaluated by implant osseointegration and biomechanical fixation.
The study consisted of two paired animal sub-studies where 10 skeletally mature Labrador dogs were used. Grit blasted titanium alloy implants were inserted press fit in each proximal tibia. In the first study grit blasted implants were compared with acid etched grit blasted implants. In the second study grit blasted implants were compared with acid etched grit blasted implants that were further treated with plasma sterilization. Implant performance was evaluated by histomorphometrical investigation (tissue-to-implant contact, peri-implant tissue density) and mechanical push-out testing after four weeks observation time.
Neither acid etching nor plasma sterilization of the grit blasted implants enhanced osseointegration or mechanical fixation in this press-fit canine implant model in a statistically significant manner.
Acid etching; biocompatibility; endotoxin; implant surgery; grit blasting; plasma sterilization; titanium.
Intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of cancellous and periosteal bone by increasing the number of osteoblasts. Previous studies of ours in mice demonstrated that intermittent PTH increases cancellous osteoblast number at least in part by attenuating osteoblast apoptosis, but the mechanism responsible for the anabolic effect of the hormone on periosteal bone is unknown. We report that daily injections of 100 ng/g of PTH(1–34) to 4–6 month old mice increased the number of osteoblasts on the periosteum of lumbar vertebrae by 2–3 fold as early as after 2 days. However, the prevalence of apoptotic periosteal osteoblasts was only 0.2% in vehicle treated animals, which is ~20-fold lower than is the case for cancellous osteoblasts. Moreover, PTH did not have a discernable effect on periosteal osteoblast apoptosis. Administration of BrdU for 4 days failed to label periosteal osteoblasts under either basal conditions or following administration of PTH. Cancellous osteoblasts, on the other hand, were labeled under basal conditions, but PTH did not increase the percentage of BrdU-positive cells. Thus, intermittent PTH does not increase cancellous or periosteal osteoblast number by stimulating the proliferation of osteoblast progenitors. Consistent with high turnover of cancellous osteoblasts as compared to that of periosteal osteoblasts, ganciclovir-induced ablation of replicating osteoblast progenitors in mice expressing thymidine kinase under the control of the 3.6kb rat Col1A1 promoter resulted in disappearance of osteoblasts from cancellous bone over a 7–14 day period, whereas periosteal osteoblasts were unaffected. However, 14 days of pre-treatment with ganciclovir prevented PTH anabolism on periosteal bone. We conclude that in cancellous bone, attenuation of osteoblast apoptosis by PTH increases osteoblast number because their rate of apoptosis is high, making this effect of the hormone profound. However, in periosteal bone where the rate of osteoblast apoptosis is low, PTH must exert pro-differentiating and/or pro-survival effects on post-mitotic pre-osteoblasts. Targeting the latter cells is an effective mechanism for increasing osteoblast number in periosteal bone where the production of osteoblasts from replicating progenitors is slow.
bone formation; PTH; osteoblasts; apoptosis; periosteal bone; cancellous bone
Based on its proven anabolic effects on bone in osteoporosis patients, recombinant parathyroid hormone (PTH1-34) has been evaluated as a potential therapy for skeletal repair. Research in animals has investigated the effect of PTH1-34 in various skeletal repair models such as fractures, allografting, spinal arthrodesis, and distraction osteogenesis. These studies demonstrated that intermittent PTH1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms, which includes effects on mesenchymal stem cells (MSC), angiogenesis, chondrogenesis, bone formation and resorption. Furthermore, PTH1-34 was demonstrated to enhance bone repair in challenging animal models of aging, inflammatory arthritis and glucocorticoid-induced bone loss. This pre-clinical success has led to off-label clinical use, and a number of case reports documenting PTH1-34 treatment of delayed-unions and non-unions have been publish. Moreover, a phase 2 clinical trial of PTH1-34 treatment of patient with a radius fracture has now been completed. Although this trial failed to achieve its primary outcome, largely due to effective healing in the placebo group, several secondary outcomes were statistically significant, highlighted several important issues about the appropriate patient population for PTH1-34 therapy for skeletal repair. Here we review our current knowledge of the effects of PTH1-34 therapy for bone healing, enumerate several critical unresolved issues (e.g. appropriate dosing regimen and indications), and discuss this drug’s long term potential as an adjuvant for endogenous tissue engineering.
Parathyroid Hormone (PTH); skeletal repair; fracture insufficiency; allograft
Insertions of orthopedic implants are traumatic procedures that trigger an inflammatory response. Macrophages have been shown to liberate gold ions from metallic gold. Gold ions are known to act in an antiinflammatory manner by inhibiting cellular NF-κB–DNA binding and suppressing I-κ B-kinase activation. The present study investigated whether gilding implant surfaces augmented early implant osseointegration and implant fixation by its modulatory effect on the local inflammatory response. Ion release was traced by autometallographic silver enhancement. Gold-coated cylindrical porous coated Ti6Al4V implants were inserted press-fit in the proximal part of tibiae in nine canines and control implants without gold inserted contralateral. Observation time was 4 weeks. Biomechanical push-out tests showed that implants with gold coating had ~50% decrease in mechanical strength and stiffness. Histomorphometrical analyses showed gold-coated implants had a decrease in overall total bone-to-implant contact of 35%. Autometallographic analysis revealed few cells loaded with gold close to the gilded implant surface. The findings demonstrate that gilding of implants negatively affects mechanical strength and osseointegration because of a significant effect of the released gold ions on the local inflammatory process around the implant. The possibility that a partial metallic gold coating could prolong the period of satisfactory mechanical strength, however, cannot be excluded.
gold; in vivo; mechanical test; metal ion release; osseointegration
Skeletal bone consists of hydroxyapatite (HA) [Ca10(PO4)6(OH)2] and collagen type I, both of which are osseoconductive. The goal of osseointegration of orthopedic and dental implants is the rapid achievement of a mechanically stable long-lasting fixation between bone and an implant surface. In this study, we evaluated the mechanical fixation and tissue distribution surrounding implants coated with three surfaces: plasma-sprayed HA coating, thinner coating of electrochemical-assisted deposition of HA, and an identical thin coating with a top layer of mineralized collagen. Uncoated plasma-sprayed titanium (Ti-6Al-4V) served as negative control. The electrochemical-assisted deposition was performed near physiological conditions. We used a canine experimental joint replacement model with four cylindrical implants (one of each treatment group) inserted in the humeri cancellous metaphyseal bone in a 1 mm gap. Observation time was 4 weeks. The mechanical fixation was quantified by push-out test to failure, and the peri-implant tissue formation by histomorphometric evaluation. HA coatings deposited by plasma spray technique or electrochemically, increased the mechanical fixation and bone ongrowth, but there was no statistical difference between the individual HA applications. Addition of collagen to the mineralized phase of the coating to create a more bone natural surface did not improve the osseoconductive effect of HA.
hydroxyapatite; electrochemistry; implants; osseointegration; materials testing
Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic leading to osteoporosis, yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated five hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected 2-3 times daily for 18 months, with doses individualized to maintain serum calcium at 1.9-2.25 mmol/L. Biochemical markers and bone density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged, however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z-scores were unchanged at the spine and femoral neck. Total hip Z-scores increased, however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone.
How parathyroid hormone (PTH) increases bone mass is unclear but understanding this phenomenon is significant to the improvement of osteoporosis therapy. Nmp4/CIZ is a nucleocytoplasmic shuttling transcriptional repressor that suppresses PTH-induced osteoblast gene expression and hormone-stimulated gains in murine femoral trabecular bone. To further characterize Nmp4/CIZ suppression of hormone-mediated bone growth we treated 10 wk-old Nmp4-knockout (KO) and wild-type (WT) mice with intermittent human PTH (1-34) at 30μg/kg/day or vehicle, 7 days/wk, for 2, 3, or 7 wks. Null mice treated with hormone (7 wks) gained more vertebral and tibial cancellous bone than WT animals paralleling the exaggerated response in the femur. Interestingly, Nmp4/CIZ suppression of this hormone-stimulated bone formation was not apparent during the first 2 wks of treatment. Consistent with the null mice enhanced PTH-stimulated addition of trabecular bone these animals exhibited an augmented hormone-induced increase in serum osteocalcin 3 wks into treatment. Unexpectedly the Nmp4-KO mice displayed an osteoclast phenotype. Serum C-terminal telopeptides, a marker for bone resorption, was elevated in the null mice, irrespective of treatment. Nmp4-KO bone marrow cultures produced more osteoclasts, which exhibited an elevated resorbing activity, compared to WT cultures. The expression of several genes critical to the development of both osteoblasts and osteoclasts were elevated in Nmp4-KO mice at 2 wks but not 3 wks of hormone exposure. We propose that Nmp4/CIZ dampens PTH-induced improvement of trabecular bone throughout the skeleton by transiently suppressing hormone-stimulated increases in the expression of proteins key to the required enhanced activity/number of both osteoblasts and osteoclasts.
c-fos; Fra-2; ephrins; osteoclastogenesis; osteocalcin; osteoporosis
Parathyroid hormone (PTH) is used clinically in osteoporotic patients to increase bone mass by enhancing bone formation. PTH therapy is not uniformly effective at all skeletal sites and “lifestyle” factors may further modulate the skeletal response to PTH. Alcohol may represent one of those factors. Chronic alcohol abuse is associated with osteoporosis and impaired fracture healing. Therefore, the present study investigated the effects of alcohol on the bone anabolic response to a dose of PTH similar to a human therapeutic dose 1) during normal cancellous and cortical bone growth and turnover, and 2) in a model of demineralized allogeneic bone matrix (DABM)-induced osteoinduction. Three-month-old male Sprague Dawley rats were fed the Lieber-DeCarli liquid diet with 35% of the calories derived from ethanol. The controls were pair-fed an alcohol-free isocaloric diet containing maltose-dextran. Following adaptation to the liquid diets, the rats were implanted subcutaneously with DABM cylinders prepared from cortical bone of rats fed normal chow. The rats were subsequently treated daily with PTH (1 μg/kg/d sc, 5d/wk) or vehicle and measurements on bone and DABM implants performed 6 w later. Total bone mass was evaluated on the day of necropsy using DXA. Tibiae were processed for histomorphometry. Bone mass and architecture in tibial diaphysis and DABM implants was evaluated by μCT. PTH treatment increased whole body bone mineral content (BMC) and bone mineral density (BMD). The hormone also increased bone formation and bone area/tissue area in the proximal tibial metaphysis. In contrast, PTH treatment had no effect on periosteal bone formation and minimal effects on DABM-induced osteoinduction. Alcohol consumption decreased whole body BMC. Alcohol also decreased cancellous as well as cortical bone formation and bone mass in tibia and impaired DABM-mediated osteoinduction. There was no interaction between PTH treatment and alcohol consumption for any of the endpoints evaluated. Our results indicate that the bone anabolic response to a therapeutic dose of PTH in the rat is largely confined to cancellous bone. In contrast, alcohol consumption inhibits bone formation at all sites. Furthermore, alcohol inhibits osteoinduction and reduces periosteal and cancellous bone formation, irrespective of therapeutic PTH administration. Based on the animal model, our findings suggest that alcohol consumption could impair the beneficial effects of PTH therapy in osteoporosis.
Osteoporosis and age-related bone loss is associated with changes in bone remodeling characterized by decreased bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Stimulating the function of bone-forming osteoblasts, is the preferred pharmacological intervention for osteoporosis. Recombinant parathyroid hormone (PTH), PTH(1-34), is an anabolic agent with proven benefits to bone strength and has been characterized as a potential therapy for skeletal repair. In spite of PTH’s clinical use, safety is a major consideration for long-term treatment. Studies have demonstrated that intermittent PTH treatment enhances and accelerates the skeletal repair process via a number of mechanisms. Recent research into the molecular mechanism of PTH action on bone tissue has led to the development of PTH analogs to control osteoporotic fractures. This review summarizes a number of advances made in the field of PTH and bone fracture to combat these injuries in humans and in animal models. The ultimate goal of providing an alternative to PTH, currently the sole anabolic therapy in clinical use, to promote bone formation and improve bone strength in the aging population is yet to be achieved.
Osteoporosis; Fracture repair; Parathyroid hormone; Parathyroid hormone-1 receptor; Emerging therapies
Intermittent application of parathyroid hormone (PTH) has well established anabolic effects on bone mass in rodents and humans. Although transcriptional mechanisms responsible for these effects are not fully understood, it is recognized that transcriptional factor cAMP response element binding protein (CREB) mediates PTH signaling in osteoblasts, and that there is a communication between the PTH-CREB pathway and the BMP2 signaling pathway, which is important for osteoblast differentiation and bone formations. These findings, in conjunction with putative cAMP response elements (CREs) in the BMP2 promoter, led us to hypothesize that the PTH-CREB pathway could be a positive regulator of BMP2 transcription in osteoblasts. To test this hypothesis, we first demonstrated that PTH signaling activated CREB by phosphorylation in osteoblasts, and that both PTH and CREB were capable of promoting osteoblastic differentiation of primary mouse osteoblast cells and multiple rodent osteoblast cell lines. Importantly, we found that the PTH-CREB signaling pathway functioned as an effective activator of BMP2 expression, as pharmacologic and genetic modulation of PTH-CREB activity significantly affected BMP2 expression levels in these cells. Lastly, through multiple promoter assays, including promoter reporter deletion, mutation, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA), we identified a specific CRE in the BMP2 promoter which is responsible for CREB transactivation of the BMP2 gene in osteoblasts. Together, these results demonstrate that the anabolic function of PTH signaling in bone is mediated, at least in part, by CREB transactivation of BMP2 expression in osteoblasts.
Intermittent (pulsatile) administration of parathyroid hormone (PTH) is known to improve bone micro-architecture, mineral density and strength. Therefore, daily injection of PTH has been clinically used for the treatment of osteoporosis. However, this regimen of administration is not convenient and is not a favorable choice of patients. In this study, an implantable delivery system has been developed to achieve pulsatile release of PTH. A well-defined cylindrical device was first fabricated with a biodegradable polymer, poly(lactic acid) (PLLA), using a reverse solid free form fabrication technique. Three-component polyanhydrides composed of sebacic acid, 1,3-bis(p-carboxyphenoxy) propane and poly(ethylene glycol) were synthesized and used as isolation layers. The polyanhydride isolation layers and PTH-loaded alginate layers were then stacked alternately within the delivery device. The gap between the stacked PTH-releasing core and the device frame was filled with PLLA to seal. Multi-pulse PTH release was achieved using the implantable device. The lag time between two adjacent pulses were modulated by the composition and the film thickness of the polyanhydride. The released PTH was demonstrated to be biologically active using an in vitro assay. Timed sequential release of multiple drugs has also been demonstrated. The implantable device holds promise for both systemic and local therapies.
The mechanical environment at a fracture site can influence the course of healing. Intermittent parathyroid hormone (PTH) has been shown to accelerate fracture healing. Intact bone models show that mechanical loading and PTH have a synergistic beneficial effect on osteogenesis. We hypothesized that PTH and mechanical loading would have a similar synergistic effect on fracture healing. Eighty mice underwent surgical osteotomy and intramedullary nailing of the tibia. The mice were divided into four groups: one underwent daily loading, one received daily subcutaneous PTH injections (30 µg/kg/day), one received both loading and PTH, and a control group received sham loading and vehicle injection. Daily loading was applied to the ends of the tibia with an external loading device for 2 weeks. Fracture healing was assessed by microcomputed tomography, histology, and biomechanical testing. The group with both loading and PTH had increased osteoblast and osteoclast activity and was the only group with a significantly larger callus mineral density and bone volume fraction. The PTH only group had significantly more osteoid in the callus compared to the control group, indicating enhanced early osteoblast activity. This group also had a significantly higher bone mineral content and total bone volume compared to controls. The group that received loading as the only intervention had significantly greater osteoclast activity versus controls. The contribution of loading and PTH administration to the fracture healing cascade indicates a synergistic effect. This finding may be of potential clinical utility when weight bearing is utilized to stimulate lower extremity fracture healing.
parathyroid hormone; fracture healing; mouse tibia; in vivo mechanical loading; microcomputed tomography; mechanosensitivity
A fundamental pre-requisite for the clinical success in dental implant surgery is the fast and stable implant osseointegration. The press-fit phenomenon occurring at implant insertion induces biomechanical effects in the bone tissues, which ensure implant primary stability. In the field of dental surgery, the understanding of the key factors governing the osseointegration process still remains of utmost importance. A thorough analysis of the biomechanics of dental implantology requires a detailed knowledge of bone mechanical properties as well as an accurate definition of the jaw bone geometry.
In this work, a CT image-based approach, combined with the Finite Element Method (FEM), has been used to investigate the effect of the drill size on the biomechanics of the dental implant technique. A very accurate model of the human mandible bone segment has been created by processing high resolution micro-CT image data. The press-fit phenomenon has been simulated by FE analyses for different common drill diameters (DA = 2.8 mm, DB = 3.3 mm, and DC = 3.8 mm) with depth L = 12 mm. A virtual implant model has been assumed with a cylindrical geometry having height L = 11 mm and diameter D = 4 mm.
The maximum stresses calculated for drill diameters DA, DB and DC have been 12.31 GPa, 7.74 GPa and 4.52 GPa, respectively. High strain values have been measured in the cortical area for the models of diameters DA and DB, while a uniform distribution has been observed for the model of diameter DC . The maximum logarithmic strains, calculated in nonlinear analyses, have been ϵ = 2.46, 0.51 and 0.49 for the three models, respectively.
This study introduces a very powerful, accurate and non-destructive methodology for investigating the effect of the drill size on the biomechanics of the dental implant technique.
Further studies could aim at understanding how different drill shapes can determine the optimal press-fit condition with an equally distributed preload on both the cortical and trabecular structure around the implant.
Background and purpose Hydroxyapatite (HA) coating stimulates the osseointegration of cementless orthopedic implants. Recently, locally released osteogenic growth factors have also been shown experimentally to stimulate osseointegration so that bone fills gaps around orthopedic implants. Here, we have compared the effect of local release of TGF-β 1 and IGF-1 with that of hydroxyapatite coating on implant fixation.
Method Weight-bearing implants with a 0.75-mm surrounding gap were inserted bilaterally in the knees of 10 dogs. Growth factors were incorporated in a biodegradable poly(D,L-lactide) coating on porous coated titanium implants. Plasma-sprayed HA implants served as controls. The dogs were killed at 4 weeks and the implants were evaluated by mechanical push-out test and by histomorphometry.
Results There was no difference in any of the mechanical parameters. Bone ongrowth was 3-fold higher for HA-coated implants (p < 0.001). For growth factor-coated implants, bone volume was 26% higher in the inner half of the gap and 28% higher in the outer half compared to HA (p < 0.03).
Interpretation- The mechanical fixation of porous-coated titanium implants with local growth factor release is comparable to that of HA coating. While HA mainly stimulated bone ongrowth, local release of TGFβ 1 and IGF-1 stimulated gap healing.
Intermittent treatment with parathyroid hormone (PTH) increases bone mass in experimental animals and humans. In vitro studies have suggested that the anabolic effect of PTH may be mediated by local growth factors. However, the relevance of these findings to in vivo situations remains unclear. In this study, we examined a time course of daily s.c. injections of hPTH (1-34) on the skeletal concentration of insulin-like growth factor (IGF)-I, IGF-II, and transforming growth factor beta (TGF-beta) in the proximal tail vertebrae of male rats. PTH caused a time and dose-dependent increase in the bone mineral density of the lumbar spine. This anabolic effect on bone mass was accompanied by progressive increases in bone matrix-associated IGF-I and TGF-beta 1. Increases in IGF-I and TGF-beta 1 became apparent after four and eight weeks of PTH treatment respectively and persisted through week 12. PTH had no effect on circulating IGF-I, suggesting that the increase of bone matrix IGF-I was due to the local effect of PTH on bone tissue directly rather than to an increase of circulating IGF-I. These data are consistent with the hypothesis that IGF-I and TGF-beta 1 may play a role as local mediators of the anabolic effects of PTH on bone metabolism.
Critically sized large bone defects commonly result from trauma, radical tumor resections or infections. Currently, massive allografting remain as the clinical standard to treat these critical defects. Unfortunately, allograft healing is limited by the lack of osteogenesis and bio-integration of the graft to the host bone. Based on its widely studied anabolic effects on the bone, we have proposed that teriparatide [recombinant parathyroid hormone (PTH1–34)] could be an effective adjuvant for massive allograft healing. In support of this theory, here we review studies that have demonstrated that intermittent PTH1–34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms including: effects on mesenchymal stem cells (MSC), angiogenesis, chondrogenesis, bone formation and remodeling. We also review the current literature on the effects of PTH1–34 therapy on bone healing, and discuss this drug’s long term potential as an adjuvant for endogenous tissue engineering.
Parathyroid Hormone (PTH); teriparatide; osseointegration; bio-integration; fracture healing; non-union; allograft repair; biomaterials
Parathyroid hormone (PTH) is a potent pharmacologic inducer of new bone formation, but no physiologic anabolic effect of PTH on adult bone has been described. We investigated the role of PTH in fetal skeletal development by comparing newborn mice lacking either PTH, PTH-related peptide (PTHrP), or both peptides. PTH-deficient mice were dysmorphic but viable, whereas mice lacking PTHrP died at birth with dyschondroplasia. PTH-deficient mice uniquely demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1, and reduced metaphyseal osteoblasts and trabecular bone. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants. These results indicate that coordinated action of both PTH and PTHrP are required to achieve normal fetal skeletal morphogenesis, and they demonstrate an essential function for PTH at the cartilage-bone interface. The effect of PTH on fetal osteoblasts may be relevant to its postnatal anabolic effects on trabecular bone.
Parathyroid hormone (PTH) is currently the only approved anabolic agent for osteoporosis pharmacotherapy in the USA. However, the molecular and cellular mechanisms underlying which intermittent PTH stimulates bone formation are not fully established.
Activating transcription factor 4 (ATF4) was recently identified to be a downstream target of PTH signaling in osteoblasts and FGF2 is able to rapidly increase ATF4 mRNA and protein expression in osteoblasts. Furthermore, ATF4 expression is markedly reduced in Fgf2−/− osteoblasts. In addition, FGF2 is required for the anabolic action of PTH on bone formation. Therefore, we hypothesize that the impaired anabolic effect of PTH in Fgf2−/− mice is partially due to reduced ATF4 expression. To test this hypothesis, we examined the ability of PTH to increase ATF4 expression in vitro and in vivo. In vitro data showed that PTH induced a significant increase in ATF4 mRNA expression as early as 15 min in Fgf2+/+ primary bone marrow stromal cells (BMSCs) but not in Fgf2−/− BMSCs. In vivo data showed that treatment with PTH (1–34) (40 μg/kg/d) treatment for 2 weeks in 21–23 months female mice increased lumbar vertebrae bone mineral density in Fgf2+/+ (13.8% increase). In contrast there was a 2.1% decrease in Fgf2−/− mice. Interestingly, basal ATF4 mRNA expression in tibiae was significantly lower in Fgf2−/− mice (46% decrease) compared to Fgf2+/+ mice. PTH treatment increased ATF4 mRNA by 97% (p< 0.05) in Fgf2+/+ compared to 8% (p = 0.57) in Fgf2−/− mice. Immunohistochemistry of vertebrae showed less ATF4 staining in Fgf2−/− tissue, and treatment with PTH increased ATF4 staining in Fgf2+/+ but the increase was attenuated in Fgf2−/− tissue.
In summary, reduced ATF4 expression may result in decreased osteoblast differentiation, and possibly contribute to the impaired stimulation of PTH on bone formation in Fgf2−/− mice.
FGF2; PTH; ATF4; Osteoblasts; Osteoporosis
The use of bone grafting is a well-established way to enhance initial implant fixation in situations with reduced bone stock. Ceramic bone substitutes are inferior alternatives to autogenous or allogeneic bone graft. Improvement of bone graft substitutes is needed. We investigated whether biomechanical implant fixation and osseointegration of experimental implant grafted with β-TCP granules (Conduit) could be improved by soaking the β-TCP granules in bisphosphonate (zoledronate).
In 10 dogs, a pair of titanium coated implants surrounded by a 2.5 mm gap was inserted into the proximal part of each tibia. The gap was grafted with β-TCP granules either soaked with zoledronate or saline. At 12 weeks, the implants were evaluated with biomechanical push-out test and histomorphometrical analysis.
We found that bisphosphonate increased one of the three biomechanical parameters, but found no difference in the amount of new bone or β-TCP granules between the two treatment groups.
This study indicates that local treatment of β-TCP granules with zoledronate not only has the potential to increase implant fixation but also calls for further experimental research in order to optimize the dose of zoledronate.
Implant fixation; bisphosphonate; biomechanical fixation; histomorphometry; bone graft substitute.
Intermittent parathyroid hormone (PTH) treatment is a potent bone anabolic principle that suppresses expression of the bone formation inhibitor Sost. We addressed the relevance of Sost suppression for PTH-induced bone anabolism in vivo using mice with altered Sost gene dosage. Six-month-old Sost overexpressing and 2-month-old Sost deficient male mice and their wild-type littermates were subjected to daily injections of 100 µg/kg PTH(1–34) or vehicle for a 2-month period. A follow-up study was performed in Sost deficient mice using 40 and 80 µg/kg PTH(1–34). Animals were sacrificed 4 hours after the final PTH administration and Sost expression in long bone diaphyses was determined by qPCR. Bone changes were analyzed in vivo in the distal femur metaphysis by pQCT and ex vivo in the tibia and lumbar spine by DXA. Detailed ex vivo analyses of the femur were performed by pQCT, µCT, and histomorphometry. Overexpression of Sost resulted in osteopenia and Sost deletion in high bone mass. As shown before, PTH suppressed Sost in wild-type mice. PTH treatment induced substantial increases in bone mineral density, content, and cortical thickness and in aging wild-type mice also led to cancellous bone gain owing to amplified bone formation rates. PTH-induced bone gain was blunted at all doses and skeletal sites in Sost overexpressing and deficient mice owing to attenuated bone formation rates, whereas bone resorption was not different from that in PTH-treated wild-type controls. These data suggest that suppression of the bone formation inhibitor Sost by intermittent PTH treatment contributes to PTH bone anabolism. © 2010 American Society for Bone and Mineral Research
PTH; Sost; osteocytes; genetic mouse models; osteoporosis