Bone Research in Biomechanies 33 G, Lower et al. (Eds.) 108 Press, 1997 Validation of Adaptive Bone-Remodeling Simulation Models Rik Huiskes Biomechanics Section, Institute of Orthopaedics, University of Nijmegen P.O.Box 9101, 6500 HB Nijmegen, The Netherlands Abstract. Using computer models based on Finite Element Analysis (FEA), Wolff's paradigm of mechanically-controlled adaptive bone remodeling can be simulated. These simulation models use empirical mathematical rales that describe the assumed relationships between local bone loads and bone mass. These models are particularly valuable for preclinical testing of orthopaedic implants, relative to their bone-maintaining capacities. In this Chapter the question of validity of these models for these purposes is considered. Furthermore, an overview is presented of validation studies that were performed by the research group of the author. 1. Introduction It has long been known that bones adapt to the functional mechanical requirements to which they are exposed, a principle which became known as ‘Wolff's Law’ [44]. Many orthopaedic surgical procedures are based upon its workings. A notorious example of where adaptive bone remodeling may work against us is after an arthroplasty. Suddenly, the load which is normally carried by the bone alone, is now shared with the implant. The bone is stress shielded and as an effect, bone resorbs. Although this will not produce a clinical failure immediately, it may eventually, and certainly reduces the prospects of a revision operation. ‘Assuming that the extent of bone loss is directly related to the extent of stress shielding implies it to depend on prosthetic and pre-operative bone properties, since stress shielding is governed by those as well. This begs the question whether the extent of long-term bone loss could not be predicted from the characteristics of an implant and those of the bone in Which itis to be fixed, We have studied this expectation in the last 14 years and now consider it true. The evidence for that consideration is discussed in this chapter. Wolff's paradigm of mechanically driven adaptive remodeling, had been discussed earlier in the writings of Roux [30]. Roux suggested the adaptive remodeling process to be governed by a cell-controlled, self-organizing regulatory process. Using our present under- standing of remodeling mechanisms, such a regulatory process can be characterized schemati- cally as in Fig. 1. If we are to predict its results in terms of bone structure quantitatively, we need to capture it in mathematical expressions. For that purpose we consider two parts of the scheme. One part regulates the transfor- mation of bone loads into tissue loads, given the bone structure at any particular time. This process can conveniently be quantified in finite-element analyses. The second part regulates the effects of tissue loads on bone structure, of which we know virtually nothing in quantita- tive terms. An approach typical for physics, designed to overcome this problem, is to start with intuitively sensible relationships, and check empirically whether they produce valid results [17]. Such a relationship is called a remodeling model, or rule.34 R, Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models External loads oo eo ‘Shape Figure 1: Schematic representation of Rowx's para- - Jaternal Structural Organization digm. Local mechanical signals, determined by ae external forces, bone shape and architecture, are appraised by sensors, which mediate bone-turnover Bone mass ; ne atta cells in their remodeling activities. This process y gives feed-back to the sensors, because adaptation (of shape and architecture influence the local signal values. ‘These rules generally take the form EE ~ faspylorssp) ~ caye0) @ where M(x,t) is the bone mass in location x, t is time, p(x,t) is density, f and c are weight factors, o is a mechanical signal (tensor or scalar), and o is a normal reference signal. The value of @ - ca can be construed as an error function in a local optimization process. The precise character of the mechanical signal is unknown, so empirical choices are to be made if the remodeling rule is to be applied. For its application FE-models are made and used in computer-simulation procedures in which the process is followed iteratively, starting from particular initial conditions - like the fixation of an implant, or alternative external loading characteristics - until no more changes in bone mass are predicted in the computations. An example of such a regulatory model is discussed in the next section. 2. A Regulatory Model for Trabecular Morphogenesis and Adaptation Roux [30] suggested that trabecular-bone architecture is formed, maintained and adapted by. mechanical loads, in a local self-organizational process, regulated by cells. In order to test the viability of such a paradigm in a regulatory model, we must specify the potential controlling variables and parameters, and relate them mathematically. We proposed a model based on the assumption that mechanical load is sensed by osteocytes [7], which then control the remodeling process through physical or chemical mediators. These are thought to stimulate the actor cells in their environments in the bone remodeling process. A scheme of such a regulatory process is depicted in Fig. 2.a [26]. The actor cells, of course, are the osteoblasts and osteoclasts, organized in Basic Multicellular Units (BMU’s [11]). Of all possible local expressions of load, we selected strain-energy density (SED) as the mechanical signal the osteocytes are supposed to sense. The stimulus distributed by an osteocyte, it is assumed, equals the difference between the signal sensed and a constant reference value. The amount of stimulus a BMU receives from a particular osteocyte depends on its distance away from it (Fig. 2.b). As a net effect of the total stimulus received by BMU’s we consider the development of the local degree of bone mineralization m(x,t) am _ 5 Fx,0, with 0 < m(x,t) < 1, Q) where 7 is a time constant and the local remodeling stimulus is Fea.) = EF@) (S00 - b. ®R. Huiskes/Vatidation of Aduptive Bone-Remodelirg Simulation Models 35 In this regulatory scheme S(t) (MPa) is the signal value in osteocyte i, N is the total number of osteocytes and k (Mpa) a reference energy value which the osteocytes are supposed to consider as normal. The function f@ - g(a?) O) weights the distances from the osteocytes (Fig. 2.b) and is characterized by the parameter D (um). Although it is expressed in a different form, the remodeling rule implied by equations (2), (3) and (4) can directly be transformed into the general format of equation (1). Hypothetical regulatory mechanism Osteocyte influence distance load fd) , \ t ee mechanical properties a ae D d A bone 4 a b Figure 2: (a) Assumed regulatory process for trabecular remodeling, with osteocytes as the sensors, and osteoclasts and osteoblasts (organized in BMU’s) as the actor cells. (b) The assumed weight function f(4), describing the fraction of osteocyte signal felt by a BMU at distance (adapted from Mullender and Huiskes 26). For the purpose of finite-element analysis, the variable tissue elastic modulus is calculated from the degree of mineralization using [8] 6) E(x,t) = Cm(x,0", where C (Mpa) and y are constants ‘The input to this regulatory model comprises the directions and magnitudes of the external loads applied to the volume of bone studied, and its output is architecture, represent- ed by a density pattern. Its physiological parameters are the reference energy k, the osteocyte density (derived from their total number N and the volume considered), the exponential osteocyte-influence function (characterized by the distance parameter D), and the constants 7, C and y. We applied this regulatory scheme to a 2-D FE model of a square plate, using realistic values for the parameters [26], with the exception of the osteocyte influence distance parameter D, about which virtually nothing is known. The result is the emergence of a trabecular architecture from a homogeneous field (Fig. 3). The morphology and dimensions of the trabeculae have a realistic appearance, with an orientation loosely in accordance with that of the (external) principal stresses. When we changed the orientation of the external stresses, the trabecular architecture adapted accordingly (Fig. 3).36 R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models a Morphogenesis a Adaptation ‘Figure 3: From a homogeneous density field the simulation model predicts a trabecular architecture, aligning with the external load (morphogenesis); from a trabecular lattice structure, aligning with the external faces, a similar trabecular architecture evolves (adaptation) (adapted from Mullender and Huiskes [26]). What we have accomplished here is to proof that the paradigm of self organization proposed by Roux [30] is feasible and can be realized with a relatively simple regulatory scheme, governed by a limited number of physiological parameters; no more, but no less than that, The establishment of such a fact is important, but it does not guarantee that the paradigm is true, nor that the regulatory model is a valid representation of the bone-remodel- ing process. In fact, the model can never be a valid representation in the true sense of the word, simply because many important factors are excluded, such as the effects of hormones, to name one. So the question is, what do we actually mean when we talk about validating these kinds of models? 3. Validation Objectives ‘A model is a reduction from a complex reality and can only be used to investigate those phenomena that are indeed captured by it. The model described above, for example, can not be used to predict how calcium deficiency would affect trabecular architecture. It is simply assumed that the amount of calcium required for the regulatory process to function normally is present. A model is invalid outside its scope. Inside its scope we can consider its numerical validity, its predictive validity and its mechanistic validity. Numerical validity implies that the algorithm used does not produce artifacts. Sources of such artifacts in this particular case may be inadequate refinement of mesh densities or iteration-time steps. A potential problem in the above example is that when the element-mesh size is taken too large relative to the osteocyte-influence distance (the parameter D), the algorithm produces checker-board density patterns and the solution becomes mesh dependent [38, 27]. These aspects of validity can be tested directly on the algorithm used. Mechanistic validity (or physiological validity) implies that the mathematical description of the model, and its variables and parameters, can be related directly to mechanisms and quantities in the real process. For bone-remodeling models the mechanistic validity is inherently poor as yet. For example, only the net amount of bone turnover is captured by the model discussed above, whereas in reality both resorption and formation occur. AlthoughR. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 37 some bone remodeling rules may include more physiological phenomena than others, they are still largely empirical, working with lumped rather than identifiable variables and parameters. This is also true for the empirical regulatory model discussed above; its mecha- nistic validity is not really an issue at the moment, simply because it's not adequately specified yet in its physiological details. ‘This leaves the predictive validity as the main issue: by what accuracy does the model predict the remodeling patterns occurring in reality? It is evident that the products of the regulatory model above fit reality in a generic sense. It produces trabecular architecture as in real bone, with alignment of trabeculae relative to external loads. When the magnitude of the load is changed, the trabecular thickness adapts, and when its orientation is changed, trabecular orientation adapts accordingly, as implied by Wolff's Law. The characteristic dimensions of the architecture - e.g. trabecular thickness and separation - are largely similar to those in reality, and seem to be governed by the osteocyte influence distance, Under particular loading conditions, plates are formed, rather than struts, just as we see in real bone. When loads are reduced, trabeculae reduce in thickness and plates are perforated, as we see in conditions such as in disuse osteoporosis. If trabeculae are disconnected, they disappear, as occurs in reality as well. All these aspects of the model we have investigated in 2-D and 3-D morphologies [26, 28, 37]. We have yet to find a general architectural feature in the model predictions which is contradicted by reality at large. However, all these considerations relate to bone in a generic sense; the model is yet to be tested relative to a well-controlled experimental reality. This regulatory model has not shown to be invalid in its predictive capacity for bone-remodeling behavior, but at what point can we actually call it valid? In general, validation of these kinds of models can be established at three levels: ( The qualitative validity of predictions relative to bone-remodeling phenomena at large. ‘The question addressed here is whether the simulation model produces patterns of bone- mass adaptations which are qualitatively similar to those seen in reality at large. Such a validation effort signifies whether the description implied by the model makes sense at all. If validation at this level is established, the model can be applied for research purposes [17]. (ii) The quantitative validity of predictions relative to a population of experimental realities. ‘Such a validation shows whether the predictions of the simulation model are adequately close to the average or typical results found in the population concerned. The issue to be addressed here is not purely one of numerical precision. If the model would produce the same conclusion about a particular issue as a series of experiments in which this issue is investigated, the model is valid for this purpose, even if the precision is not excellent. If validity at this level can be established, the simulation model can be applied in concert with experimental ones, for instance to specify later animal or clinical investigations. The quantitative validity of predictions relative to a single specimen of an experi- mental population. ‘Validation studies on this level require animal (or patient) specific models and precise evaluations of experimental bone patterns. After the model has shown to produce valid predictions repeatedly at this level, within an acceptable margin of quantitative preci- sion, it can be considered valid, and be used to replace other kinds of experimentation.38 R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Modets To date, virtually all validation efforts for bone remodeling models known were limited to the first level (i), in order to establish whether the models make sense at all [1,3,5,6,13,15,29]. Since a number of years we have been engaged in animal-experimental and clinical validation studies at the second level (ii), concerning our simulation models to predict long-term bone remodeling around implants. Recently we also started work on the third level (iii). These efforts and their results are summarized in the following pages. 4. Bone Remodeling around Hip Prostheses 4.1 Characteristics of the Simulation Model In the course of time, we have used several remodeling rules to predict periprosthetic bone behavior, These rules were largely similar and only. differed in details, however [19,20,21,35,36,39,40,41]. Other than in the trabecular regulatory model discussed above, detailed trabecular orientation is neglected in these models, and only apparent density is considered. Their main characteristics can be specified relative to the general format of equation (1). We use the strain-energy-density (SED) as the basis of the remodeling signal. ‘The SED-distribution in the periprosthetic bone U(x) is determined directly from the strain tensor e(x) and the stress tensor o(x), as U="4ea, by the finite-element code, based on the loads applied to the reconstruction by muscles and articular contact. We normalize this value to the apparent density p=p(x), thus obtaining the mechanical signal value for a loading case i as ,=U/p, which is in fact the local elastic (strain) energy stored per unit of bone mass for an external loading case i. Assuming that only the amplitudes of this strain-energy signal play a role, hence neglecting effects of frequency, we take s-1is5, © ™ int as the remodeling signal, whereby m is the number of relevant loading cases in a recent loading history [3]. The variable o in equation (1) is thus substituted by S from equation (6), as it is calculated from the FE-model representing the immediate post-operative configuration. The reference signal op is substituted by S,q, which represents the corresponding result of equation (© as it is calculated from the pre-operative, intact configuration, for the same loading history. The weight factor c in equation (1) is substituted by (Ls), in which s is a "dead zone’, a percentage of S,q, representing the "minimum effective strain’ concept of Frost [12]. This remodeling rule is illustrated in Fig. 4. Figure 4: Illustration of a computer-simulation model for strain-adaptive bone remodeling around implants. The relationship between ‘mechanical stimulus and remodeling - the re- ‘\\ modeling rule - is described by a nonlinear ‘function, featuring a threshold ‘dead zone’ = (inset). The stimulus is determined by the differ- ence between the actual strain energy (the sig- nal) in the periprosthetic bone and the reference values in the intact bone. To assess the signal- value distributions, two FE models are applied, subject to the same external loading conditions. Bone-mass tumover is effected per elapsed time increment in the THA model. The iterative simulation process continues until a new equi- librium signal distribution is obtained (repro- duced from Huiskes [18]). In od Reference ‘Sanat ‘Operated Femur Intact FemurR, Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 39 ‘The function f in equation (1) is substituted by 7A, where A=A(x) is the internal or external bone surface area locally available for the cells to resorb and form bone. Remodeling takes place concurrently both internally, around the bone pores, or externally, at the outside surface of the bone. In the former case, the apparent density p is adapted and A signifies the amount of pore-surface area available [24,25], in the latter case the outside boundary of the bone is adapted and A is the area of the periosteal surface. In the computer simulation program, the remodeling rule is integrated with a finite element model, whereby the resulting shape and internal apparent density distribution of a remodeling process are determined iteratively (Fig. 4). In every iteration, the signal value S is determined per element according to equation (6), for the loading cases considered, by the FE-code. From this value and the reference signal, the value of the stimulus is deter- mined. The adaptations of the outside surfaces and the apparent densities for each element are calculated. The former are implemented by a change of surface coordinates in the FE mesh, and the latter by a change of elastic moduli E, using the relationship E = cp’, mM where c and y are constants [4]. Then the next FE-iteration starts, and this procedure continues until in each element either _g > OF: B= Pain» ® Or: P = Poy » where Paix is the minimum allowable apparent density and p., is the maximal allowable density; that of cortical bone. Hence in the case of internal remodeling only, the process description reduces to dp _ - @ = saS - 5,4), 0 With: Prins P< Pop > where a is the pore-surface area per unit volume [24,25], which governs the rate of the remodeling process, assuming that this rate is proportional to the amount of trabecular surface area available to the bone turn-over cells. It is evident from this description that the bone is assumed as a continuous (albeit nonhomogeneous), isotropic, linear elastic material. The morphological variables p and a - the apparent density and the pore-surface area per unit volume - and the mechanical signal S, as derived from stresses and strains, are all considered as apparent variables, which are thought to be continuous over a finite volume. This implies that the local effects of disconti- nities - such as pores - are neglected, but that their combined effects are superimposed and averaged in the volume concerned. This is a reasonable approximation only if the dimensions of the discontinuities are small compared to those of the volume considered [14]. This approach also means that the morphological changes in bone structure are represented only by changes in local mass (or apparent density), hence directionality of bone trabeculae and its effects on anisotropy are not considered in this particular model. ‘Again this model is purely empirical. Assuming that S,=U,/o is the remodeling signal for an external bone load is hypothetical. It has no other defense than that it has interesting prospects. Equation (6) is not more than a very primitive representation of loading history, neglecting effects of loading frequencies. Equation (7) is a fair approximation of the stiffness of trabecular’structures, under the restrictions of continuity mentioned above. The parameters m, A, C, 7, Pniay Pas and a can be measured if necessary, but the "dead zone’ threshold level s and the time constant 7 can not be evaluated directly. These uncertainties, inaccuracies and simplifications notwithstanding, the results of this model are quite interesting, as we shall see in the next sections.i 40 R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 4.2 Animal-Experimental Confirmation Bone remodeling around hip stems was studied experimentally for many years in Chicago [33]. These authors developed a canine model for hig replacement, in which several kinds of stems were tested. Six months or two years post-operatively the animals were killed, the bones sectioned, and the periprosthetic bone mass compared to that of the contralateral, control side. For that purpose, two variables were quantified. One the cortical bone area (CBA), the other the medullary bone area fraction (MBAF), both determined per cross- sectional area as shown in Fig. 5. Change in Cortical Area (CA): (Cent * Aran! CBs Figure 5: In the experimental dog series 5 sec- : tions were studied. In the sections the changes ‘Medullary Bone Area Fraction (MBAF): in cortical bone areas (CA) and the medullary Medullary Bone Area / (Medullary Aro bone area fractions (MBAF) were measured, both expressed in percentages. ‘Section Location The prosthetic stems tested in this dog model in the course of time were divided in six series. In all series the stems were of the same overall shape. What differed were the material stiffness properties and the coating configurations. Because of the differences in stem coating and in material stiffness, differences in stress patterns were expected as well, hence also in remodeling patterns. The characteristics of the prosthetic stems used in the series are specified in Table I. Table I: Characteristics of the experimental dog series. Stems in the C and D series were coated at the anterior and posterior faces only, either over their full lengths, or over the proximal one-third. The results in D2 series were not, evaluated, because of stem loosening Series Material Coating Period ~N A Titanium = Full, = 24mo. ‘17 B Titaniun None 24mo. 6 ci Titanium AP full «24mo. 8 C2 Titanium AP prox. 24mo. 9 Di Composite AP full 6mo. 9 D2 Composite AP prox. 6mo. 7 The simulation studies of these experiments used two 3-D FE-models each, one for the reconstructed and one for the control bone (Fig. 4). Hip and muscle loading was identical in both cases, and based on in vivo telemetric studies of Bergmann et al. [2]. The geometry and density distribution of the control-bone model were derived from one experimental dog. For the direct-postoperative configurations the control model was simply provided with prostheses, of which the coating and material characteristics depended on those in the experimental series to be simulated. It was always assumed that ingrowth occurred where coating was present. That means that in the FE-models the contact between coating and bone was always fully bonded. Where coating was not present, a frictionless (sliding) contact wasR, Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 4 assumed, which was represented in the FE-model by so-called nonlinear gap elements. In the case of the uncoated stem an interface gap around the proximal part of the stem was assumed, reducing from 1 mm thickness at the resection plane to zero at 40 mm below [36]. This gap simulated the soft-tissue membrane seen in the dogs with the uncoated stems [32]. The results of the experimental series with fully coated stems were used to trigger the unknown parameters in the model, such as the width of the dead zone and the time constant, relating computer time steps in the iterative process to real time [40]. Using the parameter values thus determined, the results of the uncoated series were used to verify the model and optimize it relative to uncoated bone-implant contact [36]. Eventually, the simulation model was used to predict the 2-years outcome of the other experimental series, of which the results were unknown at the time [22]. ‘The animal results were characterized by trabecular hypertrophy around the stem and by periosteal cortical resorption, in all cases. These phenomena were also seen in the simulation of the coated-stem series (Fig. 6). After a simulated 6 months the proximal MBAF (section B) had already increased from 33 to 54 percent, Near the distal tip of the stem (section G) the increase was from 6 to 35 percent at this time. Further hypertrophy until 2 years post-operatively occurred particularly in this latter region, up to 44 percent. Cortical resorption developed slower than trabecular hypertrophy in the simulation. The cortical area CBA reduced by about 5 percent in six months, up to about 20 percent in 2 years, with a maximum in section F. Comparing the 2 years prediction with the canine measurements (Fig. 6) yields a satisfactory similarity; the predictions are within the 95 percent confidence intervals of the experimental results - or close in two sections. The simulation model predicted that after 2 years remodeling would still continue, but no dogs were kept longer than that. Fully coated TI6AI4V stems Change in Cortical Area Medullary Bone Area Fraction 20% - aa 20% iE 7 os cos gure 6: Comparison of experimental results and predictions for dog series A, at 2 years. ‘The animal results are shown with error bars of the 95% confidence intervals. The MBAF ‘values (right) are compared to the initial, preoperative values as used in the simulation, based on measurements in one dog [40] It is quite interesting to regard the distribution of remodeling patterns in the individual cross-sections, which are really very similar in experiment and simulation. In both cases, trabecular hypertrophy was associated predominantly with the edges of the stem and in regions of narrow trabecular width, which act as stress risers. Cortical resorption occurred mostly medial-anteriorly [40] ‘The animal results of the uncoated stems gave rise to controversy. After 6 months,a2 R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models cortical resorption was significantly less in comparison with the fully coated stems [34]. This was expected, in view of the bone stress-increasing wedging efféct of the unbonded stem. However, after three years, the amount of cortical resorption appeared even higher in the second series, which seemed to defy Wolff’s Law [32]. The simulation study provided the explanation [36], which was related to gradual changes in load-transfer, as discussed below. ‘Again the 6-month and 2-years predictions of CBA and MBAF were satisfactorily close to the experimental ones, but only after the FE-model was adapted to account for interface ‘membrane formation (Fig. 7). Cortical resorption was similar but trabecular hypertrophy was higher distally, when compared to the fully bonded stem series after two years. Uncoated TI6AI4V stems with fibrous interface Change in Cortical Area Medullary Bone Area Fraction a {jatar — oo in 2y ow ox | Umit 20% 40% Figure 7: Comparison of experimental results and predictions for dog series B, at 2 years. ‘The animal results are shown with error bars of the 95% confidence intervals. The MBAF values (right) are compared to the initial, preoperative values as used in the simulation, based on measurements in one dog [36] The simulation revealed that initially, cortical stress shielding is reduced around the unbonded stem relative to the bonded one, and proximal trabecular interface compression is increased, just as expected. Remodeling then develops accordingly in the initial stage. However, in the course of time, the stem sinks in the medullary canal, thus increasing distal interface compression and trabecular hypertrophy. As a result, a stress bypass develops, which emphasizes increasing distal versus proximal load transfer, distal hypertrophy and proximal atrophy in a self-perpetuating cycle. This phenomenon is amplified by the gradual development of a fibrous membrane at the proximal interface, probably as an effect of relative motion, which reduces proximal load transfer even more. After this membrane was accounted for in the model, the similarity between 2 years predicted and experimental values improved, indicating its mechanical significance [36]. The results of the comparison between 2-years animal-experimental results and predictions from the simulation model for all the series are summarized in Table Il. For the last series (D2), the proximally AP-coated composite stems, only 6-month data was available, and dependable data could only be collected for the cortex, due to prosthetic loosening in many dogs; so this one was left out of the summary in Table II. The results were considered per cross section, as average CBA and MBAF values per series, as presented for two series (A and B) in Figs. 6 and 7. A prediction was considered valid if it deviated less than two standard deviations from the average experimental value, and almost valid if the deviation was between two and three times the standard deviation. Predictions with higher deviations were considered invalid.R, Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 4B Table I: Summary of predictions relative to experimental results in 5 of the dog series (compare Table 1) for cortical area (CA) fraction, left, and trabecular area fraction (MBAF), ‘measured in 5 sections (see Fig. 5); * = prediction deviates less than 2 SD’s from experimental average; + = deviation more than 2 but less than 3 SD’s. Cortical Area Fraction ‘Trabecular Area Fraction Cc D F H J Cc DF H J wr oF yor Ss A ae a eee: er B ae Bee eee eee) + oe oe c1 ar S80 0 C2 ao 5 se eee D1 ae no dependable data D2 no dependable data ‘As can be seen in Table I, no invalid predictions according to the above definition were found. Valid cortical predictions occurred for 22 out of 25 sections, and trabecular predic- tions in 20 out of 25 ones. The remaining predictions were almost valid, again according to the definition above. It must be noted that the results of the experiments and the simulations were evaluated only to the detail of bone area per section and that the cross sectional measurements were susceptible to sectioning location. It must also be stressed that the geometry and the initial density of the bone were the same in all simulation models, whereas in each series of dogs there tends to be variation. Given these restrictions and the definitions applied, it can be concluded that the results of the simulation model were largely valid. Furthermore, if the different prosthetic features tested in the experiments would have been assessed with the simulation model only, the same conclusions would have been drawn about their periprosthetic bone-preserving capacities. Hence, the simulation model has shown to be valid at the level (ii), discussed above. This implies that this model can be useful for the pre- selection of animal experiments, thus saving time, money and animal suffering. It can also be used as an analytical basis to explain experimental bone remodeling patterns and extrapo- late those to human cases. Present work relative to the dog experiments is now directed towards animal-specific models and validation at level (iii) [42]. 4.3 Human Retrieval Studies Validation of the simulation models relative to human cases is more complicated. Radiograph- ic measurements of bone density is notoriously imprecise [43] and post-mortem evaluation is not common. Recently, Engh and associates [9] published a study of femoral specimens, retrieved post mortem from patients who had received AML hip replacements. Five bilateral pairs of specimens were studied, of which each non-treated contralateral served as the control for the treated one, to estimate pre-operative bone density. It is, of course, not entirely certain that the density distribution of the non-operated femur represents that of the one which was to be operated upon so many years earlier, but the authors provided enough arguments and test results to make this a reasonable assumption. The subject ages at the time of the operation ranged from 61 to 87 years. The AML has a porous coated stem, made out of CoCrMo alloy. The prostheses had been in situ for 17, 84, 77, 72 and 76 months in speci- mens 1 through 5, respectively, and the stem diameters were 12.0, 13.5, 13.5, 15.0, and 13.5 mm, respectively. Subject weights varied between 53.5 and 86 kg. Dual-energy X-ray absorptiometry (DEXA) scans were made along the lengths of the treated and control femurs, antero-posteriorly and medio-laterally, on both sides of the stem. The results were reported44 R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models as grams of bone mineral content (BMC) per section, level, and whole bone, representing sums of values measured by the DEXA system. Comparing left to right, estimated percentag- es of bone loss were also reported. The authors found vastly different bone mass in the intact controls, between about 25 and 50 grams overall BMC. They also saw that these ’preoperative’ values correlated nicely with those of overall postoperative bone loss, in the sense that denser (hence stiffer) bones had lost less bone mass than the less dense ones. When comparing the results of these measurements with earlier predictions of our simulation models, the generic similarity was obvious, both in the amounts of bone resorbed and the periprosthetic resorption patterns. Even the correlation between amounts of bone eventually lost and pre-operative density was apparent in the simulation predictions as well [18]. This suggested validity of the simulation model at level (ii), although without rigorous proof. Earlier it was already established, comparing bone remodeling patterns predicted with clinical reports in the literature about long-term periprosthetic bone loss, that the predictions were valid at level (i); they made sense relative to what was found clinically [21]. We then attempted to establish validity at level (iii), relative to the above retrieval study. In collabora- tion with the authors we developed patient-specific FE-models of the retrieved specimens and applied our remodeling model to predict long-term bone loss. The preliminary results are discussed below [23]. Four patient-specific 3-D FE-models of the treated and untreated contralateral femurs were developed - not enough dependable radiographic material was available for the fifth one - using contact radiographs and DEXA measurements of the specimens to reconstruct pre- operative geometry and bone density. The stems were assumed to be fully bonded in porous- coated regions, and in frictionless (nonlinear) contact elsewhere. Bone-density development in the course of post-operative time was calculated iteratively, using a remodeling rule as in Huiskes et al. (21]. This is similar to the one discussed above, but without adaptations in (external) bone geometry. Three hip and muscle loading cases were used, scaled to body weights. Bone reactivity corresponding to a dead-zone of 75% was applied [21]. The simulation predicted bone loss mainly along the proximal part of the stem, with bone retention lateral/proximally, where muscle forces attach, and increases of bone density near the distal tip. The qualitative correspondence in the patterns of bone loss and gain between simulation and retrievals was good, as illustrated in Fig. 8. In the simulations, the remodeling tate and the amount of bone loss were determined (Fig. 9) and found to be inversely correlated to initial bone mineral content. The inverse linear correlation between pre-operative bone mineral density and the eventual amount of bone lost found in the retrieval study was also apparent in those of the simulation. However, when considering the predictions for the converged state, the slope of the linear relationship measured was higher than predicted, indicating very good similarity in cases of relatively low pre-operative bone-mineral density, but overestimated predictions when it is relatively high (Fig. 10). If the state after 60 time units was considered, rather than the converged state, the correspondence between prediction and reality was excellent (Fig. 10). Hence, the results of the simulations, using the patient-specific models, produced valid results in comparison with clinical reality, in terms of overall proximal bone loss and in the details of resorption patterns, after a particular post-operative time period. It must be noted here that the values of the unknown parameters for the dog-model simulation studies - the *dead-zone’ threshold level s and the. time constant 7 - were also triggered to the 2-years results of the first animal series A, as discussed above. The results of in the other series where then compared at a period of 3 years, in all cases, although the remodeling process in the simulation still continued [40]. Whether it would have continued in the dogs, we don’t know, since none were kept longer.R. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 45 2y. (adapted from Engh et al. (10)). [g] Total BMC Remodeling time [%] Change in BMC 60 Simulation 0 (converged) ao} SNe | ~ + ~\ simulation 90 F retrievals time 60) 20 10 ees 4060 -80~—«100 Initial BMC [% of densest bone] 30 100 150 Sy. Figure 8.a: Radiographs of an AML hip reconstruction at zero (left) and two and five years postoperatively; periprosthetic bone-resorption patterns can be seen ine. 0 ine. 4 ine. 6 ine. 8 Figure 8.b: Bone-remodeling patterns as predicted by the computer simulation, at zero (left) and 4 time incre- ments [23]. Figure 9: Predicted time development of periprosthetic bone loss in the 4 specimens analyzed. The less bone is present initially, the higher the resorption rate, and the more bone is lost. The moment of 60 computer-time units is indicated [23] Figure 10: Correlation between initial BMC in the 4 speci- mens analyzed and the percentage total periprosthetic bone lost [23]. The triangular dots represent the predicted results after full convergenge in all 4 models, the open, square ones the results after 60 computer-time units (see Fig. 9); the intercept- ed line represents the correlation reported by Engh et al. [9]. J conclude that the simulation study confirms the periprosthetic remodeling process as an effect of mechanical stimuli (stress shielding), and that its consequences, dependent on prosthetic and bone parameters, can be estimated with adaptive bone-remodeling theory. We hypothesize, however, that the adaptive process is limited to a particular post-operative time period, after which the bone no longer “remembers” its pre-operative loads.i i 46 R, Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models 5. Discussion ‘As suggested by Schipper et al. [31], when discussing a new framework for cancer research, involving the application of systems control theory, "The mathematical model is not the solution, but offers an important handle for efficient exploration of fundamental concepts." This is certainly true, and relevant for our simulation models as well; they should be seen in this light. The essential question relative to analytical models of this kind are not just whether they are valid, but rather if they are suitable for their purposes. In other words, whether they are useful. The matter of validity is an involved one, as argued above. Although Newton’s laws are used daily in mechanical engineering, to design all kinds of useful structures and machines, they were in fact invalidated by Einstein. We can’t even be sure that Einstein’s theories will not be invalidated in the future. Of course, we know precisely under which conditions Newton’s laws produce results which are valid by a precision adequate for our purposes, and that is the whole point. I cannot say the same about our bone-remodeling simulation models at this time, but we are certainly trying to get it to that point, as shown above. Others have formulated alternative empirical models to describe bone-remodeling processes and for all I know, these could even be more realistic. But none of them has been subject to validation studies as described here. The questions we still have relative to our models imply that we cannot predict the future of a bone in which a prosthesis is placed with certainty. However, we can make a good ‘guess, apparently. Where does that leave us with respect to applicability? That really depends on the purpose. First of all, the models serve as an analytical basis for clinical and experimental findings. Above, I described how the simulation results could explain the bone remodeling patterns around the uncoated stems in the dogs. On an equal basis, the models give explanations for clinical results reported in the literature, and can put them in perspective relative to each other. Similarly, the effects of prosthetic design features, such as stem flexibility, stem fit, coating extent and placement, cemented versus noncemented on bone-resorption behavior could be explained [19,21,39,41]. Secondly, extrapolating the clinical data and their associated analytical explanations, the effects of prosthetic design adaptations can be estimated. For example, we now know that pre-operative density of the femur largely determines the amounts of bone eventually lost, as discussed above. The simulation model can be used to evaluate this relationship relative to the design characteristics of the prosthesis, or even to select a prosthesis based on pre- operative DEXA scans. ~ Thirdly, the models can be applied to extrapolate animal-experimental results to human conditions. Where their predictive capacities for human joint replacement are concerned, animal experiments suffer from similar problems as simulation models, in that their results do not provide absolute certainty, partly as an effect of the different anatomy. Simulation models can improve their applicability in that respect. Fourthly, the models can conveniently be used to pre-select protocols for exploratory animal experimentation with new prosthetic devices. Looking back over our canine validation studies performed with the research group in Chicago, it is clear now that much time, money and many animals could have been saved if the simulation model would have been available earlier. Then, finally, the purpose of pre-clinically testing innovative prosthetic designs. I have argued that the last decade of prosthetic innovation in Total Hip Arthroplasty has basically failed as a result of the ‘trial-and-error’ culture in Orthopaedics [16]. This could improve by the application of step-wise introduction of new devices in the market, the first step of which would be pre-clinical testing, in order to avoid unsafe or ineffective prostheses to be tried in patients at all. The simulation models discussed here could be versatile tools for thatR. Huiskes/Validation of Adaptive Bone-Remodeling Simulation Models a7 purpose. Relative to this purpose the questions of validity and precision are important in particular. Errors in predictions relative to the expected behavior of ‘prosthetic devices could Fave direct consequences, in the sense of false positive or false negative results, hurting either the innovators or the patients. Suppose that a test is done for a design already developed, would the manufacturer drop it if the results are negative? Probably not, but he would certainly monitor the first clinical trials very closely. That would already be a step forward jn the innovation and testing procedures. Time will tell when the results of the models can be trusted in a more absolute sense. Acknowledgements: The work described in this Chapter was funded by Grants from the Netherlands Organization for Research (NWO, section Medical Sciences) and several private sources, over a period of 14 years. 'm particularly grateful for the contributions of my former and present graduate students Michel Dalstra, PhD, Jan Herman Kuiper, PhD, Harry van Lenthe, MS, Margriet Mullender, MS, Bert van Rietbergen, PhD, and Harrie Weinans, PhD, and research fellow Jan Kerner, MS. References [1] G.S. Beaupré, T.E. Orr, D.R. Carter, An approach for time-dependent bone modeling and remodeling - theoretical development. 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