Additive enhancement of implant fixation following combined treatment with rhTGF-beta2 and rhBMP-2 in a canine model.

BACKGROUND: Gaps at the interface between implant and bone increase the risk of diminished implant fixation and eventual loosening. The purpose of the present study was to determine if combined use of recombinant human transforming growth factor-beta 2 (rhTGF-beta2) and bone morphogenetic protein 2 (rhBMP-2) led to greater implant fixation strength in the presence of interface gaps than the use of either growth factor alone. METHODS: Twenty-eight skeletally mature adult male dogs received one porous-coated titanium implant in the proximal part of each humerus, for a total of fifty-six implantation sites. Spacers were used to establish an initial 3-mm gap between the implant and the host bone at all fifty-six sites. Forty-two implants were coated with hydroxyapatite-tricalcium phosphate and were used in three growth-factor-treatment groups in which the implants placed in the left humerus were loaded with 12 microg of rhTGF-beta2 (Group 1, seven animals), 25 microg of rhBMP-2 (Group 2, seven animals), or 12 microg of rhTGF-beta2 combined with 25 microg of rhBMP-2 (Group 3, seven animals). In these animals, the twenty-one implants that were placed in the right humerus were loaded with buffer only to serve as contralateral controls. In Group 4 (seven animals), the implants were not coated with hydroxyapatite-tricalcium phosphate, the gap in the left humerus was lightly packed with autogenous bone graft, and the gap in the right humerus was left empty to serve as a contralateral control. All animals were killed at twenty-eight days. The primary end points included three mechanical variables: fixation strength, interface stiffness, and energy to failure. Secondary end points included bone ingrowth and bone volume and trabecular architecture in the gap and in a region located 2 mm medial to the implantation site. RESULTS: The hydroxyapatite-tricalcium phosphate coating had no effect on implant fixation, bone ingrowth, or bone formation in the 3-mm gap. Individual growth factor treatments led to 2.3 to 3.2-fold increases in fixation strength and stiffness as compared with the values for the contralateral controls (p < 0.05). The combined growth factor treatment led to 5.7-fold increases in fixation strength and stiffness compared with the values for the contralateral controls (p < 0.01). Autogenous bone graft treatment was associated with 4.5 to 6.4-fold increases in implant fixation strength and stiffness as compared with the values for the contralateral controls (p < 0.01). Compared with the relevant contralateral controls, energy to failure was increased 3.5-fold in association with TGF-beta2 alone (p < 0.05), 4.5-fold in association with TGF-beta2 combined with BMP-2 (p < 0.01), and 2.5-fold in association with autogenous bone-grafting. As much as 63% of the variance in the mechanical end points was associated with variance in bone volume and architecture in the 3-mm gap and in the region of interest located 2 mm medial to the implantation site (p < 0.01). CONCLUSIONS: In this animal model, the combined use of TGF-beta2 and BMP-2 led to more secure mechanical fixation of the implant than did the use of either growth factor alone and demonstrated results that were similar to those associated with the use of autogenous bone graft.

Unilateral hip replacement causes bilateral changes in tibial bone mineral content in a canine model.

The presence of asymmetry in tibial bone mineral content (BMC) of the operated and control limbs at the end of the experimental period following unilateral hip replacement surgery is used as a marker of limb function. The goal of the present study was to determine the contribution of ipsilateral and contralateral bone gain and loss to control-treated side differences in BMC of the tibia in dogs following unilateral hip replacement surgery. Seven animals were followed longitudinally with single beam photon absorptiometry for 6 months after unilateral hip hemiarthroplasty. Bone loss, compared with preoperative baseline values, was observed in both limbs, with recovery in bone mass beginning 1 month after surgery in the contralateral tibia and 3 months after surgery in the ipsilateral tibia. Thus, the asymmetry in tibial BMC frequently seen after unilateral experimental hip replacement in the canine appears to be caused by differential timing of recovery of bone mass following a transient loss in both limbs. The mechanism defined in this study is in contrast to an alternative mechanism involving bone loss in the treated limb coupled with bone gain in the control limb.

Aging does not lessen the effectiveness of TGFbeta2-enhanced bone regeneration.

Controversy exists over the potency of bone healing in the aged skeleton, and there is concern that enhancement of bone regeneration after use of bone-stimulating growth factors may not be effective in the aged. In this study, 30 skeletally mature beagles (1-2 or 10-12 years old) had titanium implants placed bilaterally in the proximal humerus for a period of 4 weeks in a model of intramembranous bone regeneration. A bony defect made at the time of surgery created a 3-mm gap between the implant surface and the host bone. Some of the implants were treated with recombinant human TGFbeta2 (rhTGFbeta2) at various does (0.32-35 microg per implant), and some served as paired controls. The dose response was similar in young and old animals. The most effective dose, 35 microg, led to a 3-fold increase in the volume fraction of new bone within the gap in both the young (p = 0.001) and old (p = 0.002) animals. At this dose, there was a 5-fold increase in osteoblast surface. While age did not significantly affect the quantity of new bone formed as assessed by backscatter scanning electron microscopy, the older animals had thinner regenerated trabeculae that tended to be spaced more closely than the younger animals. Coupled with the finding that the increase in osteoid was greater in the old animals compared with the young animals, these qualitative differences suggest that there may have been a slight delay in the rate or a defect of mineralization in the old animals.

Symmetry of the canine femur: implications for experimental sample size requirements.

The purpose of this study was to determine the degree of bilateral variability in cross-sectional geometric properties of the adult canine proximal femur and to use these data to determine minimum detectable treatment effects in paired and independent experimental designs. Thirteen pairs of canine femora were sectioned at nine locations and 16 cross-sectional geometric properties were determined for each section location. The canine femur was found to be bilaterally symmetrical. For a given sample size, the magnitude of the detectable treatment effect was (a) smaller for diameters than for areas and area moments of inertia and (b) smaller within the middiaphysis than proximally. The data from this study can be used to estimate sample size requirements for experiments in which the treatment effect is determined by using the contralateral femur as a control. It was found that an increase from 3 to 7 animals would have a much greater effect on improving the sensitivity of an experiment than would an increase from 7 to 11 animals.

The geometry of the adult canine proximal femur.

The canine is often used as a model to study functional bone adaptation after total hip replacement. To improve our understanding of the model, we defined the central tendencies and statistical variations in the cross-sectional geometry, angle of anteversion, and cervicodiaphyseal angle of the proximal femur in 15 adult male mongrel dogs and compared the results with published reports of the human femur. Numerous similarities in the cross-sectional geometry of the canine and the human femur were noted, supporting the use of the canine as a model. The two species differed in that the orientation of the principal axes in the proximal cross sections was not related to the angle of anteversion in the canine femur, whereas these angles are related in humans. In addition, the canine medullary canal is larger than the human medullary canal relative to the external dimensions of the femur, and hence the canine has relatively thinner cortical bone. This difference in femoral cross-sectional geometry may explain, in part, why the canine provides an accentuated model of bone loss in hip arthroplasty experiments.

Adaptive bone remodeling around bonded noncemented total hip arthroplasty: a comparison between animal experiments and computer simulation.

Severe loss of bone related to stress-shielding is one problem threatening the long-term integrity of noncemented total hip arthroplasty. It is widely accepted that this phenomenon is caused by adaptive bone remodeling according to Wolff's law. Recently, quantitative bone-remodeling theories have been proposed, suitable for use in computer-simulation models in combination with finite-element codes, which can be applied to simulate the long-term effect of the remodeling process. In the present paper, the results of such a computer simulation are compared with those in an animal experiment. A three-dimensional finite-element model was constructed from an animal experimental configuration concerning the implantation of a fully coated femoral hip prosthesis in dogs. The simulation results of the adaptive bone-remodeling process (geometric adaptations at the periosteal surface and density adaptations within the cancellous bone) were compared with cross-sectional measurements of the canine femurs after 2 years of follow-up. The detailed comparison showed that long-term changes in the morphology of bone around femoral components of total hip replacements can be fully explained with the present quantitative adaptive bone-remodeling theory.

Bone ingrowth into the tibial component of a canine total condylar knee replacement prosthesis.

The purpose of this study was to evaluate the occurrence of bone ingrowth in a porous coated tibial component of a canine total condylar design knee replacement model. The entire undersurface of the tibial prosthesis was covered by a titanium fiber metal porous composite pad. Projecting from this surface were three short, cylindrical, fiber metal coated pegs that along with a posterior screw provided initial stabilization of the device. Left total knee replacements were performed on six dogs using alignment and cutting jigs to prepare the bony surfaces. The dogs were killed 6 months following surgery. Extensive bone ingrowth was present in all pegs of every tibial component. Bone ingrowth was present in 12% of the pad area of one component, 22.7 to 41.6% in four components, and 81.1% in another. The void spaces in other areas were filled with fibrous tissue or in the periphery of the device with fibrocartilage. Bone ingrowth in the pad was consistent in the vicinity of the pegs and was variable in regions not adjacent to the pegs, suggesting that the pegs exerted a strong influence on the pattern of bone ingrowth into the pad.

Efficacy of autograft and freeze-dried allograft to enhance fixation of porous coated implants in the presence of interface gaps.

Autogenous cancellous bone and freeze-dried allogeneic cancellous bone were tested in a total of 41 adult male mongrel dogs. In each humerus, an implant with a commercially pure titanium fiber metal porous coating was placed in an overreamed cavity so that a uniform 3-mm gap was present between the implant and host cancellous bone. Graft material was placed in the gap of one humerus while the gap of the other humerus was left empty and served as a paired negative control. Histologically, both autograft and allograft appeared to aid repair of the defect, but quantitatively only autograft enhanced new bone formation within the defect. Treatment with autograft significantly increased the amount of bone ingrowth within the implants by nearly three-fold at 4 weeks and eight-fold at 8 weeks. The enhancing effect was recognizable as early as 2 weeks. The strength of fixation was increased by nearly seven-fold at 4 weeks and two-fold at 8 weeks in the autograft group, but this was only statistically significant at 4 weeks. Treatment with allograft did not enhance bone ingrowth at any time period, but had a small positive effect on strength of fixation at 4 weeks.

Changes in tibial bone mass after primary cementless and revision cementless total hip arthroplasty in canine models.

The purpose of this study was to examine right-left differences in tibial bone mass after unilateral (left) cementless total hip arthroplasty (THA). Of 39 dogs with THAs, 9 had primary cementless porous-coated femoral stems for 6 months and 15 had similar stems for 2 years. Five dogs had aseptically failed cemented hips, and 10 had aseptically failed cemented hips that were revised with cementless porous-coated femoral stems (5 without bone graft and 5 with autogenous bone graft). These animals were sacrificed 6 months after the revision surgery. The primary cementless dogs showed no right-left difference in tibial bone mineral content (BMC) or cortical bone cross-sectional geometry after 6 months, but after 2 years there was a distal right-left difference in BMC of 6% caused by expansion of the medullary canal in the tibia of the operated limb. Tibial BMC was more than 20% lower in the operated limb of the failed cemented dogs, approximately 15% lower in the nongrafted group, and 7% lower in the grafted group. The right-left tibial difference in BMC in the 2-year primary cementless group is most probably because of subclinical disuse of the operated limb. Among the dogs with failed cemented stems, the lower right-left difference in the two revised groups compared with the non-revised group suggests that improved limb function after cementless revision THA may cause gain of previously lost bone.

Locally delivered rhBMP-2 enhances bone ingrowth and gap healing in a canine model.

The purpose of the present study was to determine if recombinant human bone morphogenetic protein-2 (rhBMP-2) enhances bone ingrowth into porous-coated implants and gap healing around the implants. In the presence of a 3-mm gap between the implant and host bone, porous-coated implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs. In three treatment groups, the test implant was treated with HA/TCP and rhBMP-2 in buffer at a dose of 100 microg/implant (n=5), 400 microg/implant (n=6), or 800 microg/implant (n=5) and placed in the left humerus. In these same animals, an internal control implant was treated only with HA/TCP and buffer and placed in the right humerus. These groups were compared with a previously reported external control group of seven animals in which no growth factor was delivered [J. Orthop. Res. 19 (2001) 85]. The BMP treated implants in the two lower dose groups had significantly more bone ingrowth than the external controls with the greatest effect in the 100 g/implant group (a 3.5-fold increase over the external control, p=0.008). All three dose groups had significantly more bone formation in the 3-mm gap surrounding the BMP treated implants than the external controls with the greatest effect in the 800 microg group (2.9-fold increase, p<0.001). Thus, application of rhBMP-2 to a porous-coated implant stimulated local bone ingrowth and gap healing. The enhancement of bone formation within the implant (bone ingrowth) was inversely related to dose.

Locally delivered rhTGF-beta2 enhances bone ingrowth and bone regeneration at local and remote sites of skeletal injury.

The purposes of the present study were to determine if recombinant human transforming growth factor-beta-2 (rhTGF-beta2) enhances bone ingrowth into porous-coated implants and bone regeneration in gaps between the implant and surrounding host bone. The implants were placed bilaterally for four weeks in the proximal humeri of skeletally mature, adult male dogs in the presence of a 3-mm gap. In three treatment groups of animals, the test implant was treated with hydroxyapatite/tricalcium phosphate (HA/TCP) and rhTGF-beta2 in buffer at a dose per implant of 1.2 microg (n = 6), 12 microg (n = 7), or 120 microg (n = 7) and placed in the left humerus. In these same animals, an internal control implant treated only with HA/TCP and buffer was placed in the right humerus. In a non-TGF-beta treated external control group of animals (n = 7), one implant was treated with HA/TCP while the contralateral implant was not treated with the ceramic. In vitro analyses showed that approximately 15%, of the applied dose was released within 120 h with most of the release occurring in the first 24 h. The TGF-beta treated implants had significantly more bone ingrowth than the controls with the greatest effect in the 12 microg/implant group (a 2.2-fold increase over the paired internal control (P = 0.004) and a 4-fold increase over the external control (P < 0.001)). The TGF-beta treated implants had significantly more bone formation in the gap than the controls with the greatest effect in the 12 and 120 microg groups (1.8-fold increases over the paired internal controls (P = 0.003 and P = 0.012, respectively) and 2.8-fold increases over the external controls (P < 0.001 and P = 0.001, respectively)). Compared to the external controls, the internal control implants tended to have more bone ingrowth (1.9-fold increase, P = 0.066) and had significantly more bone formation in the gap (1.7-fold increase. P = 0.008). Thus, application of rhTGF-beta2 to a porous-coated implant-stimulated local bone ingrowth and gap healing in a weakly dose-dependent manner and stimulated bone regeneration in the 3-mm gap surrounding the contralateral control implant, a site remote from the local treatment with the growth factor.

Carcinoid tumor development in an intramedullary spinal cord mature teratoma.

The case of a 43-year-old woman with a several month history of severe back pain is reported. CT and MR imaging revealed an intramedullary cystic tumor, which was considered a dermoid cyst or teratoma. During surgery, the tumor was found within the base of the filum terminale and completely resected. Microscopic studies revealed a mature teratoma with an intramural carcinoid nodule. Thirteen-month follow-up after surgical resection showed no evidence of tumor recurrence or neoplasms elsewhere.

Revision, without cement, of aseptically loose, cemented total hip prostheses. Quantitative comparison of the effects of four types of medullary treatment on bone ingrowth in a canine model.

A model that replicated the radiographic and histological features of aseptic loosening of the femoral component of a total hip replacement that had been done with cement was created in thirty-seven dogs. A deep wound infection developed in one dog, and that dog was excluded from the study. Revision was performed without cement in twenty-nine dogs, which were then followed for six months. The remaining seven dogs were used for histological study only. The components that were used for revision were made from Ti-6-Al-4-V, and a titanium fiber-metal porous surface had been applied to the anterior, posterior, and medial surfaces of the proximal part of the stem. The femora were revised either with no graft material applied to the osseous defect; with hydroxyapatite/beta-tricalcium phosphate placed in the defect; with application of an autologous cancellous bone graft as part of a one-stage revision; or with application of an autologous cancellous bone graft as the first part of a two-stage revision, with implantation of the component four months later. The use of an autologous bone graft led to greater and more consistent ingrowth of bone. The greatest amount of bone ingrowth was found in the group in which the procedure had been done in two stages (18 +/- 4.1 per cent), followed by the group in which the prosthesis and the graft had been inserted in a single stage (15 +/- 5.0 per cent), the group that had been treated with hydroxyapatite/beta-tricalcium phosphate (10 +/- 9.1 per cent), and the control group, in which no graft had been used (7 +/- 7.0 per cent). Notably, all of the components in the animals in which an autologous graft had been used were well fixed by bone ingrowth, while the component in two of the animals in the group in which no graft had been used in one animal in the hydroxyapatite/beta-tricalcium phosphate group had only fibrous-tissue ingrowth. In contrast to the findings with respect to bone ingrowth, there was more medullary bone adjacent to the lateral aspect of the implant in the groups in which hydroxyapatite/beta-tricalcium phosphate or no graft had been inserted than in the groups that had had an autologous graft.(ABSTRACT TRUNCATED AT 400 WORDS)

A comparative study of porous coatings in a weight-bearing total hip-arthroplasty model.

The purposes of this study were to compare ingrowth of bone into three types of porous coating and to determine the effect of the type of porous coating and the degree of coverage of the stem on the remodeling of bone on the femoral side in cementless hip arthroplasty. A left total hip arthroplasty was performed in forty dogs. Thirty of the dogs had a titanium-alloy femoral prosthesis that had had one of three types of commercially pure titanium porous material applied along the length of the anterior and posterior surfaces of the stem: ten with sintered fiber-metal, ten with sintered beads, and ten with plasma flame-spray coating. The remaining ten dogs had a femoral component that was circumferentially coated with commercially pure titanium that was plasma flame-sprayed along the length of the stem. In each group, five animals were killed at one month and five were killed at six months. Ingrowth of bone into all three types of porous coating was observed, indicating secure fixation of all components. By six months, there was more ingrowth of bone and new medullary bone adjacent to the proximal and distal aspects of the stems compared with the middle level of the stems in all groups. No significant difference in ingrowth of bone was observed in the beaded surface (25.2 per cent) and the fiber-metal surface (16.6 per cent) at one month, but at six months there was significantly less ingrowth into the beaded surface (23.3 per cent) than into the fiber-metal surface (37.3 per cent). In all groups, a proximal-to-distal gradient of loss of cortical bone was observed by six months. The group of dogs that had the stem with the circumferential coating experienced more severe loss of bone than did the three groups that had a stem with a partial coating. The magnitude of loss of bone was dependent on the extent rather than the type of porous coating.

Remodeling and ingrowth of bone at two years in a canine cementless total hip-arthroplasty model.

Remodeling and ingrowth of bone in association with the use of uncemented femoral components were examined at two years in a canine total hip-arthroplasty model. Twenty-two dogs received a unilateral uncemented femoral stem that was made of Ti6A14V and was covered with one of three types of titanium porous coating: fiber-metal, beads, or plasma flame-spray. The amount and distribution of ingrowth of bone differed somewhat among the groups at two years, but the patterns of remodeling of bone in the medullary canal and cortex were similar. In general, about 15 to 18 per cent of the cortical bone was lost adjacent to the levels of the stem that were covered with the porous coating. Most of the loss of cortical bone was due to subperiosteal resorption proximally and endosteal resorption at the middle and distal levels of the stem. Increased cortical porosity accounted for only a small fraction of the loss of cortical bone. The amount of medullary bone increased proximally and distally, so that the loss of total bone mass was significantly only at the mid-part of the stem. The amount of loss of cortical bone was similar to that observed in a previous six-month study, suggesting that a steady state was achieved in the present model.

Maintenance of proximal cortical bone with use of a less stiff femoral component in hemiarthroplasty of the hip without cement. An investigation in a canine model at six months and two years.

A canine model of hemiarthroplasty of the hip was used to determine if the use of a less stiff femoral stem can reduce the amount of bone loss induced by stress-shielding. Two types of stem were used: the stiffer stems were made of a titanium alloy, and the less stiff stems were composed of a cobalt-chromium-alloy core with an outer polymer layer. The stems were identical in shape, and both types were circumferentially coated along their entire length (except for the distal five millimeters) with commercially pure titanium fiber metal. Ten dogs with each type of stem were followed for six months, and twelve dogs with each type of stem were followed for two years. Loss of cortical bone from the proximal part of the femur was associated with both types of stem, but typically 50 per cent less bone was lost with the less stiff implants. Most of the cortical loss occurred at the subperiosteal surface. The amount of medullary bone adjacent to the proximal and distal aspects of both types of stem increased; the less stiff stems were associated with a greater increase in the proximal region, and the stiffer stems were associated with a greater increase in the distal region. Similarly, there were peaks in the amount of bone growth into the proximal and distal portions of both types of stem, with a greater peak in proximal bone growth into the less stiff stems and a greater peak in distal bone growth into the stiffer stems.

Effects of radiation on fixation of non-cemented porous-coated implants in a canine model.

A non-weight-bearing porous-coated rod was implanted bilaterally in the proximal part of the humerus in thirty-five adult male mongrel dogs. In all of the animals, one limb was treated with radiation and the opposite limb served as the control. In twenty-one animals, the dose was 1000 centigrays (rads) and in fourteen, it was 500 centigrays. The strength of fixation and the volume fraction of ingrowth of bone were determined two, four, and eight weeks after the operation in the group that received 1000 centigrays and two and four weeks after the operation in the group that received 500 centigrays. Treatment with 500 centigrays had no significant effect on the strength of fixation or the amount of ingrowth of bone. In contrast, at two weeks, treatment with 1000 centigrays had reduced the strength of fixation to 50 per cent of the control value (p less than 0.01), although, at four and eight weeks, the strength of fixation was not significantly different than that in the control limb. The amount of ingrowth of bone in the irradiated limb was significantly reduced at two weeks (30 per cent of the control value) (p less than 0.01), four weeks (70 per cent of the control value) (p less than 0.05), and eight weeks (56 per cent of the control value) (p less than 0.05).

Enhancement of bone ingrowth by transforming growth factor-beta.

Enhancement of bone ingrowth with transforming growth factor-beta was evaluated in a canine model. Ten dogs had bilateral implantation of a titanium-fiber-metal-coated rod in the proximal part of the humerus. A three-millimeter gap between the outer surface of the porous coating and the surrounding cancellous bone was created to impair bone ingrowth. All of the implants were plasma-flame-sprayed with hydroxyapatite and tricalcium phosphate. In each animal, one implant was also treated with recombinant transforming growth factor-beta 1 while the other implant, which was not so treated, served as a paired control. Two doses of transforming growth factor-beta 1 were used: 335 micrograms in five animals and 120 micrograms in the other five. At four weeks, the amount of bone ingrowth in the implants that had been treated with 120 micrograms of transforming growth factor-beta 1 was threefold higher than that in the paired controls (p = 0.009), but with the numbers available there was no significant increase in bone ingrowth with the higher dose. The amount of new-bone formation in the three-millimeter gaps adjacent to the treated implants was twice that in the gaps of the paired controls, regardless of the dose. The differences between the treated and control implants with regard to the architecture of the new bone in the gap indicate that the mechanism of action of transforming growth factor-beta 1 may include both proliferation of osteoprogenitor cells and production of matrix by committed osteoblasts. Compared with the findings in a previous study in which this canine model was used, the data from the present investigation indicate that enhancement of bone ingrowth in implants that have been treated with a combination of a hydroxyapatite-tricalcium phosphate coating and transforming growth factor-beta 1 may exceed that obtainable with grafting of the gap with autogenous cancellous bone.

Distribution of Young's modulus in the cancellous bone of the proximal canine tibia.

Canine cancellous bone is used as a model for human bone in experimental orthopedic research, including models of total knee arthroplasty. Depth-force measurements produced by small-diameter indentation testing were used to derive the variation of Young's modulus over the transverse cross-sectional surface at three levels within the proximal canine tibia. At the most proximal section the presence of lateral and medial peaks of equal modulus (approximately 1100 MPa) was found. Modulus averages for the three resection levels revealed a trend of distally decreasing values, from 692 MPa proximally to 417 MPa distally. Average regional modulus values for the canine tibia were 50-75% higher than previously reported for the tibia of healthy young adult humans, although the local maxima were only 5-20% greater in canines.

ESB Research Award 1992. The mechanism of bone remodeling and resorption around press-fitted THA stems.

A major problem threatening the long-term integrity of total hip replacement is the loss of proximal bone often found around noncemented stems in the long term. It is generally accepted that 'stress shielding' is the cause for this problem: after implantation of the prosthesis the surrounding bone is partially 'shielding' from load carrying and starts to resorb. One of the proposed answers to this problem is the application of press-fitted stems. These smooth-surfaced implants are thought to provoke higher proximal bone loading, and, hence, less stress shielding than bonded implants, because they are wedged into the femur every time when loaded. However, in a two-year experiment in dogs, similar amounts of resorption of the proximal cortex were found around press-fitted and bonded implants. The question arises how similar resorption patterns can develop under completely different stress conditions, and whether this phenomenon can be explained by adaptive bone remodeling theories based on Wolff's law. In the present study an answer was sought for this question. An advanced iterative computer simulation model was used to analyze the remodeling process in the animal experiment. Three-dimensional finite element models were constructed from the animal experimental configuration, in which smooth, press-fitted stems were applied unilaterally in the canine. The FE model was integrated with iterative remodeling procedures, validated in earlier studies. In the model an appropriate non-linear representation of the loose bone-implant interface was realized, also capable of simulating the proximal interface gap that was found around the uncoated implants. The simulation models predicted similar amounts of proximal bone loss and distal bone densification as found in the animal model. Hence, the cortical bone loss could indeed be predicted by the strain-adaptive bone remodeling theory. By unraveling the simulation process, the question stated above could be answered. Densification of the distal bone bed during the initial remodeling process was found to cause reduced axial stem displacement (elastic subsidence), decreasing the wedging effect of the stem and, hence, decreasing the loading of the proximal bone, resulting in proximal bone loss. Hence, whereas in the case of bonded stems the proximal resorption process develops monotonously to a new equilibrium, the process around smooth, press-fitted stems develops nonmonotonously. This is due primarily to the unbonded interface conditions and the development of a proximal fibrous membrane. The remodeling process then gradually causes the stem to be jammed in the distal diaphyses (proximal 'stress bypass').