Curr Osteoporos Rep DOI 10.1007/s11914-013-0182-z
REGENERATIVE BIOLOGY AND MEDICINE IN OSTEOPOROSIS (EM SCHWARTZ AND RE GULDBERG, SECTION EDITORS)
Pharmacologic Augmentation of Implant Fixation in Osteopenic Bone R. D. Ross & J. L. Hamilton & B. M. Wilson & D. R. Sumner & A. S. Virdi
# Springer Science+Business Media New York 2013
Abstract Osteoporosis presents a challenge for successful implant fixation due to an impaired healing response. Preclinical studies have consistently reported reduced osseointegration capability in trabecular bone. Although clinical studies of implant success in dentistry have not found a negative effect due to osteoporosis, low bone mass is a significant risk factor for implant migration in orthopedics. Pharmacologic treatment options that limit bone resorption or upregulate formation have been studied preclinically. While, both treatment options improve implant fixation, direct comparisons to-date have found anti-catabolic more effective than anabolic treatments for establishing implant fixation, but combination approaches are better than either treatment alone. Clinically, anti-catabolic treatments, particularly bisphosphonates have been shown to increase the longevity of implants, while limited clinical evidence on the effects of anabolic treatment exists. Preclinical experiments are needed to determine the effects of osteoporosis and subsequent treatment on the long-term maintenance of fixation and recovery after bone loss.
Keywords Implant fixation . Bone-implant contact . Osseointegration . Augmentation . Enhancement . Osteoporosis . Osteopenia . Anti-catabolic . Anabolic
R. D. Ross : J. L. Hamilton : B. M. Wilson : D. R. Sumner : A. S. Virdi (*) Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Street, Suite # AcFc 507, Chicago, IL 60612, USA e-mail:
[email protected] D. R. Sumner : A. S. Virdi Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA
Introduction Osteoporosis is a frequent co-indication of osteoarthritic patients undergoing total joint arthroplasty (TJA) [1, 2•, 3]. Both the number of people undergoing orthopedic implant surgery [4] and the number of individuals with low bone mass [5] are projected to grow considerably by the year 2030. Clinically, the presence of compromised bone is already a factor in the decisions made by orthopedic surgeons [6•]. In dentistry, there is some clinical controversy about the importance of osteopenia and dental implant failure [7]. However, women with low initial bone mass lose more teeth than healthy women [8, 9] and subsequently require implant surgeries. Therefore, there is a need to understand the challenges presented by osteopenia and what treatment options are available to improve implant longevity in these patients. Biologically, osteoporosis and osteopenia are characterized by an imbalance in the bone formation and resorption processes, leading to a loss of bone mass [10]. Structurally, this imbalance leads to a thinning of the cortical and trabecular bone, an increase in the cortical porosity, and a loss of trabecular connectivity [11]. The clinical concern with osteoporosis in the context of implant surgeries is two-fold, the first is lower initial bone mass, which may make surgical procedures more challenging and the second is diminished healing capacity of the osteopenic bone.
Implant Fixation Osseointegration is defined histologically as the direct contact between living bone and the implant surface, without intervening fibrous tissue [12]. The rigid fixation of implant materials into the host bone is thought to be important for the long-term survivability of orthopedic implants. Indeed, radiostereometric analysis (RSA) studies have demonstrated
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the importance of early fixation on implant success, as early implant migration is a good predictor of later clinical failure [13, 14, 15•, 16]. Substantial micromotion, or the relative motion between implant and the host bone, early in the healing process, has been shown to inhibit the initial osteogenic response to implant placement and instead favors the formation of a fibrous membrane around the implant, which prevents successful osseointegration and implant stability [17]. The immediate response to implant placement surgery is similar to that seen following fracture, and the reduced fracture healing in osteopenic animals [18, 19] suggests potential for compromised bone-implant integration in osteopenic patients. The in vivo biological response following implant surgery is summarized below, concentrating specifically on steps in the healing response that are likely compromised by osteoporosis. For a more thorough review of the host biological response to implant placement the reader is directed to the literature [20, 21, 22•, 23]. Immediately following implant surgery, the implant material comes into contact with blood and blood cells, which release various biological signals necessary to trigger the subsequent osteogenic response. The formation of a clot proceeds and serves as a scaffold for osteogenic cells. A provisional matrix is then formed near or directly on the implant surface, which develops into woven bone similar to that seen in the early phase of fracture healing. The woven bone is then remodeled into lamellar bone, a process that involves coordination between bone resorption and formation processes. Failure of peri-implant osteogenesis can be caused by a number of factors, including an imbalance between formation and resorption, decreased number or activity of osteogenic cells, elevated osteoclastic activity, abnormal proliferation of bone cells, reduced responsiveness to mechanical stimuli, and impaired vascularization [21, 22•]. Many of these factors are directly affected by osteoporosis. An imbalance between formation and resorption is considered a defining hallmark of the disease, while a reduction in estrogen concentration has been shown to increase osteoclast differentiation and activity and reduce the lifespan of osteoblasts and osteocytes, thereby reducing the activity of osteogenic cells and reducing the osteocyte-derived response to mechanical stimuli, respectively [24]. Similarly, angiogenesis has been shown to be negatively impacted by age [25] and is therefore likely to contribute to delayed osseointegration. Clinically, RSA provides a noninvasive method to determine the 3-dimensional migration of implants, giving a precise measurement of fixation. However, it is more common that less precise single plane radiographic measurements are made or surrogate measurements are used such as quantification of the amount of peri-implant bone. Peri-implant bone can be assessed radiographically and is often quantified using dual energy x-ray absorptiometry to measure the bone mineral density (BMD). Finally, the in vivo lifespan of implanted
materials provides a true clinical assessment, but the reason for failure may not always include loss of fixation. In preclinical models, mechanical fixation of the implant within the host bone can be measured more directly by pull-out and push-out tests, which measure the amount of force required to dislodge the implant from the host bone. Osseointegration of the implant material is commonly assessed by measuring boneimplant contact (BIC), sometimes referred to as the affinity index, through histology or backscatter scanning electron microscopy. Similar to the clinical endpoints mentioned above, peri-implant BMD is also commonly reported, as is 3-dimensional peri-implant bone volume per total volume (BV/TV), trabecular architecture and cortical bone geometry using micro-computed tomography (microCT).
Osteoporosis and Implants Preclinical Studies Animal models provide an opportunity to rapidly evaluate the response of normal and osteopenic bone to implant placement and are important in the development and testing of treatments. Numerous preclinical animal models of osteoporosis have been described [26, 27], with ovariectomy (ovx) being the most commonly reported. Similar to postmenopausal osteoporosis, ovx surgery triggers an elevated bone remodeling response with an overall loss of bone mass, thinning of the cortex, and deterioration of the trabecular microarchitecture. The most commonly reported species used to study implant placement in osteopenic bone are the rat, rabbit, and sheep with ovx as the most frequently used method to induce osteopenia [28–36], although osteopenia in rabbits has also been induced through calcium restricted diets [37] and glucocorticoid injections [38]. Implants are commonly placed either transcortically, through the cortex and into the trabecular bed of the tibial metaphysis, or within the medullary cavity of the femur or tibia using a surgical approach through the knee joint. These models have their advantages, which are discussed below, but are limited to studying the initial implant fixation period, as neither model creates a weight-bearing implant. Weight-bearing is crucial to understanding the maintenance of implant stability, as bone will eventually remodel to better handle the new stresses associated with implant placement [39]. The transcortical model has the advantage of allowing for assessment of both cortical and trabecular bone responses and provides a good small animal model of dental implant placement. Despite the varied materials and implant surface treatments tested in the transcortical models, the general findings are in agreement, that BIC is negatively impacted in the trabecular compartment in the ovx animals, but relatively unchanged from control animals in the cortical bone [28–30,
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37, 38]. Although, Lugero et al. [31] did not directly measure BIC, their results from titanium screw insertion into the tibia metaphysis of ovx rabbits did find reduced trabecular bone volume fraction, implying a loss of bone surrounding the implant. In a similar study, however, Mori et al. reported no significant differences between the BIC measured in sham and ovx animals, although the authors did note a delay in the formation of new peri-implant bone in the ovx group [32]. Transcortical approaches have also been employed using sheep as a large animal model [34, 35]. Fini et al. [34] reported reduced BIC in ovx sheep when compared with sham controls, while Borsari et al. [35] noted no difference in the BIC or mechanical push-out strength between ovx and sham animals. The expense and time associated with the sheep model tends to limit the number of studies and the sample size, thereby making it difficult to draw firm conclusions. Animal models of intramedullary implant placement are less commonly reported as a means to assess the effects of osteopenia on the process of osseointegration, but are more common in the study of pharmacologic treatments (see below, Table 1 and Table 2). These surgeries are more involved than transcortical approaches, but more accurately approximate clinical joint replacement. Trabecular bone is found within the intramedullary space of long bones in the metaphysis and epiphysis and therefore, it is not surprising that ovx rats had significantly reduced BIC when compared with sham animals [33]. The majority of the preclinical studies have investigated the effect of osteopenia on the initiation of osseointegration, with the implant being placed after the establishment of osteopenia. However, the rat ovx model has also been used to demonstrate that performing ovx surgery after implantation led to a considerable loss in BIC [36]. The development of local osteopenia is a clinical concern due to patient unloading of the affected limb [40] and further an increasing number of young patients are receiving orthopedic implants [41]. It is likely that some of these young patients will develop osteoporosis and therefore maintenance of BIC is another important clinical consideration of implant success. It is unknown; however, what length of follow-up is sufficient in preclinical studies to model long-term success in the clinic. Most animal studies present results within 3–4 months of implant placement and it is unknown whether the continued effects of the negative bone remodeling balance will eventually lead to long-term loosening in these models. Another confounding factor in animal models, as well as clinically, is the use of calcium phosphate coatings such as hydroxyapatite (HA). In several models, the comparisons between implant materials of various compositions have found improved osseointegration for HA coated implants, even in osteopenic animals [34, 35, 42–44]. Further, in studies in which the BIC was not different between sham and ovx animals, it is common to find that HA coatings were used [37,
42, 45]. Indeed, a recent meta-analysis has summarized the positive influence of calcium phosphate coatings, including hydroxyapatite, on bone-implant healing in preclinical animal models of osteoporosis [46]. Clinical Reports Clinical investigation into the effects of osteopenia on implant fixation has led to variable conclusions depending on the implantation site. Numerous retrospective analyses of the success rate of dental implants in osteopenic patients have been unable to find an association between failure and low bone mass [7]. Simulation studies have demonstrated the importance of cortical bone on the pull-out stiffness of transcortical implants [47] and therefore, the lack of a significant reduction in BIC in the cortical compartment in the preclinical models likely explains the success of dental implants in osteopenic patients. An alternative explanation is that osteopenia may not affect the site of dental implantation [48], but at least 2 analyses indicate BMD measurements at sites commonly used to assess osteoporosis (hip and spine) are correlated with jaw BMD [49, 50]. Osteoporosis has been shown as an important risk factor for failure of orthopedic implants, particularly in total hip arthroplasty (THA). RSA studies have found that low systemic BMD is associated with increased implant migration and delayed osseointegration clinically [51•]. Low preoperative BMD has also been found to correlate with peri-implant BMD loss [52]. Increased stem instability is attributed primarily to endocortical and intracortical bone remodeling changes [51•] and not due to loss of proximal femoral trabecular bone [53]. These same geometry changes in the femoral cortical bone have been described by Dorr et al. [54] in which a transition occurs from healthy (type A) to compromised (type C) bone, characterized by a widening of the anteroposterior and lateral endocortical diameters and thinning of the cortex. The transition from type A to type C bone correlates with the loss of BMD [55] and therefore the development of osteoporosis. This classification may impact the type of implant design that an orthopedic surgeon chooses [6•], although both cemented [56] and uncemented THA implant designs [57, 58] have been associated with loosening in patients with compromised femurs. The current gold standard for the treatment of osteoporosis is bisphosphonate treatment (see anti-catabolic section), and there is some concern about the consequences of implant placement surgery in patients on long-term bisphosphonate treatment. The American Association of Oral and Maxillofacial Surgeons has urged caution for surgeons placing implants in patients on long-term bisphosphonate treatment as oral surgery is one risk factor for the development of osteonecrosis of the jaw [59, 60]. Review of the literature does not support a negative relationship between dental implant success and
Curr Osteoporos Rep Table 1 The effects of anti-catabolic treatments on preclinical animal models investigating implant fixation in osteopenic bone Anti-catabolic treatments Experimental design
Experimental endpoints
Reference information
Drug used
Model Implant used
Peri-implant bone volume
Bone-implant Implant fixation contact strength
Chen, et al. 2011 [74] Kurth, et al. 2005 [71] Kurth, et al. 2005 [71] Peter, et al. 2006 [80]
Systemic CT Systemic IBN Systemic IBN Local ZOL
Rat Rat Rat Rat
Not studied Not studied Not studied ↑
↑ ↔ ↑ ↑
Not studied Not studied Not studied ↑
Viera-Negrón, et al. 2008 [75] Stadelmann, et al. 2008 [81] Skripitz, et al. 2009 [73] Gao, et al. 2009 [122] a Gao, et al. 2009 [79•]
Systemic ALN
Rat
↑
↑
Not studied
Local ZOL
Sheep
↑
↑
Not studied
Systemic ALN Local ZOL Local IBN, PAM or ZOL Systemic ZOL
Rat Rat Rat
Yildiz, et al. 2010 [78] Li, et al. 2010 [123]a Chen, et al. 2011 [74] Qi, et al. 2012 [76] Tsetsenekou, et al. 2012 [77] Chen, et al. 2013 [72] Chen, et al. 2013 [72] Li, et al. 2013 [124]a
Local ZOL Systemic ALN Systemic and Local ZOL Systemic ALN Systemic ALN Systemic ZOL Local ZOL
Intra-medullary HA Intra-medullary Ti Intra-medullary Ti-HA Transcortical Ti-HA inserted into distal femur TranscorticalTi microscrew in maxillary arch Transcortical Ti-HA inserted into distal femur Intra-medullary PMMA Intra-medullary HA-Ti rods Intra-medullarly tibial HA-Ti
↔ ↑ ↑ ↑ ↑ PAM < IBN < ZOL. ↑
Not studied ↑ ↑ PAM < IBN < ZOL.
Rabbit Transcortical resorbable dental implants Rat Transcortical Ti screws Rat Intra-medullary HA Rabbit Transcortical HA-Ti screws
↑
↑
↔
↑ Not studied ↑
Not studied ↑ ↑
↑ Not studied ↑
Rabbit Transcortical CaP-Ti screws in tibila condyle Rat Intra-medullary HA-Ti Rat Intra-medullary HA-Ti Rat Intra-medullary HA-Ti rods
↔
↔
Not studied
↑ ↑ ↑
↑ ↑ ↑
↑ ↑ ↑
ALN alendronate, CaP calcium phosphate, CT calcitonin, HA hydroxyapatite, IBN ibandronate, Ti titanium, ZOL zolendronic acid a
Indicates a reference that compared anti-catabolic to anabolic. Results from the comparison of the two regimes are mentioned in the text.
All models are ovx, unless noted in the table. Unless otherwise noted, intramedullary implants are placed into the distal femur and transcortical implants are placed into the metaphysis of the proximal tibia.
bisphosphonates [61, 62], but this may be due to decreased use of intravenous bisphosphonate treatments, which are known to pose more of a risk for osteonecrosis compared with the oral route of drug delivery [63]. In orthopedics, there have been similar concerns about the use of bisphosphonates, due to case reports about atypical femoral fractures in bisphosphonate treated patients [64, 65], and case reports have found these same fractures within the peri-implant region of patients taking bisphosphonates [66, 67]. A population-based study of patients that had undergone total hip arthroplasty has found that although there was an increased risk of deep infection for bisphosphonate treated patients, long-term treatment was found to reduce the risk of revision surgery [68•].
remodeling process. Numerous preclinical animal models have been used to study various pharmacologic treatments to augment implant fixation in osteopenic bone. These treatments include those that antagonize the bone resorption process, anti-catabolic treatments (Table 1), and those that attempt to accelerate/enhance the bone formation process, or anabolic treatments (Table 2). There is considerable overlap between the treatments used to improve implant fixation and treatments that have been proposed, or are currently in use, to treat osteoporosis. In both cases the goal is to prevent continued bone loss or to increase bone mass, by either systemic or local treatment. Anti-catabolic Treatments
Pharmacologic Augmentation of Implant Fixation In the current review we define pharmacologic augmentation to biological or small molecule treatments that target the bone
Anti-catabolic treatments target osteoclastic bone resorption in an attempt to prevent bone loss. Bisphosphonates are a class of anti-catabolic agents that are currently used to treat Paget’s disease, bone metastasis, and osteoporosis [69, 70]. There are
Curr Osteoporos Rep Table 2 The effects of anabolic treatments on preclinical animal models investigating implant fixation in osteopenic bone osteopenic bone Anabolic treatments Experimental design
Experimental endpoints
Reference information
Drug used
Model used Implant
Gabet, et al. 2006 [110] Ohkawa, et al. 2008 [111] Du, et al. 2009 [117] Gao, et al. 2009 [125] Gao, et al. 2009 [122]a Skripitz, et al. 2009 [73] Li, et al. 2010 [114] Maïmoun, et al. 2010 [126] Hayashi, et al. 2010 [115] Hayashi, et al. 2010 [115] Li, et al. 2010 [123]a Okamoto, et al. 2011 [127]
Systemic iPTH Systemic iPTH Systemic SIM Local bFGF Local bFGF Systemic iPTH Systemic SR Systemic SR Systemic EP4 Systemic EP4 Systemic estrogen Local BMSCs
Rat, ORX Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat
Li, et al. 2012 [113] Zhou, et al. 2012 [116] Chen, et al. 2013 [72] Li, et al. 2013 [124]a
Systemic SR Systemic vit D Systemic SR Systemic iPTH
Rat Rat Rat Rat
Peri-implant bone volume
↑ Not studied Not studied ↑ ↑ ↑ ↑ ↑ Not studied Not studied ↑ ↑ (↔ in cortical compartment at 56 days) Intra-medullary Ti ↑ Transcortical Ti screws ↑ Intra-medullary HA-Ti ↑ Intra-medullary HA-Ti rods ↑
Transcortical Ti screws Intra-medullary HA-Ti Transcortical Ti screws Intra-medullarly tibial Ti Intra-medullary HA-Ti rods Intra-medullary PMMA Transcortical Ti screws Transcortical Ti rods Intra-medullary Ti Intra-medullary HA-Ti Transcortical Ti screws Transcortical Ti inserted in the femoral metaphysis
Bone-implant contact
Implant fixation strength
↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ Not studied ↑ (Only in the trabecular compartment) ↑ ↑ ↑ ↑
↑ ↑ Not studied ↑ ↑ Not studied ↑ ↑ ↑ ↑ ↑ Not studied ↑ ↑ ↑ ↑
bFGF basic fibroblast growth factor, BMSCs bone marrow stromal cells, CaP calcium phosphate, EP4 EP4 receptor antagonist, HA hydroxyapatite, iPTH intermittent parathyroid hormone, ORX orchiectomy, SIM simvastatin, SR strontium ralenate, Ti titanium, vit D 1,25 dihydroxy vitamin D(3). All models are ovx, unless noted in the table. Unless otherwise noted, intramedullary implants are placed into the distal femur and transcortical implants are placed into the metaphysis of the proximal tibia. a
Indicates a reference that compared anti-catabolic to anabolic. Results from the comparison of the two regimes are mentioned in the text.
several bisphosphonate molecules that have demonstrated clinical efficacy through a high binding affinity to the mineral component of bone and an ability to trigger osteoclastic apoptosis, thereby limiting bone resorption [69]. Systemic delivery of bisphosphonates has been studied in rat [71–75] and rabbit [76–78] ovx implant models. In each case the experimental endpoints most closely associated with increased implant stability (bone-implant contact, peri-implant bone volume, and implant fixation strength), were positively impacted by bisphosphonate treatment. Bisphosphonates have also been delivered locally by binding the treatments to HA coatings on the surface of implant materials in rat [79•, 80] and sheep [81] ovx models. These models have also demonstrated improved implant stability parameters and may limit the concerns about long bisphosphonate half-lives and detrimental side effects, although local delivery has been demonstrated to be less effective than systemic delivery in a direct comparison using the rabbit ovx model [76]. Direct comparisons between various bisphosphonate molecules have found that amine terminal bisphosphonates, such as zoledronic acid, are associated with the greatest peri-
implant bone density and volume, as well as, increased mechanical fixation [79•]. These results are consistent with the greater potency of these amine terminal bisphosphonates in treating osteoporosis [82]. Chen et al. [74] compared alendronate with another anti-catabolic treatment, calcitonin for improving osseointegration of intramedullary femoral implants. Although both treatments increased the BIC when compared with untreated ovx controls, the animals receiving alendronate treatment showed significantly greater BIC than those treated with calcitonin [74]. Preclinical results are consistent in finding that bisphosphonate treatment can improve the fixation of implants in osteopenic bone (Table 1). These studies have primarily investigated the initial response to implant placement to determine whether the anti-catabolic effects of bisphosphonates limit the healing response to the implant surgery, thereby preventing osseointegration of implants. Clinical studies have investigated whether bisphosphonate treatment can improve implant longevity by preventing peri-implant BMD loss [83–94]. In all but 1 study [92], systemic bisphosphonate treatment significantly preserved peri-implant BMD.
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Bisphosphonate treatment has also been shown to reduce acetabular cup migration [95] and to improve the longevity of implants [65, 68•]. The differentiation of osteoclasts is triggered by the interaction of receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) [96]. Osteoprotegerin (OPG) is the decoy receptor to RANKL that prevents osteoclast differentiation. Modulating the ratio of RANKL to OPG has emerged as a promising anti-catabolic strategy to limit bone resorption. Indeed clinical trials have demonstrated the efficacy of a RANKL inhibitor (Denosumab) in the preservation of bone mass in osteoporotic women [97, 98]. Although, there have been no reports using RANKL inhibition as a means to augment implant fixation, preclinical animal models of periimplant osteolysis have demonstrated that targeting the RANKL to OPG ratio can be an effective method for preventing wear-particle-induced osteolysis [99–106] and may even be more effective than bisphosphonates [107]. Anabolic Treatments Anabolic treatments are an emerging class of osteoporosis treatments [108, 109] that work to increase bone mass by upregulating osteoblastic bone formation. Clinically, parathyroid hormone (PTH) is the only FDA approved anabolic agent for the treatment of osteoporosis, but several other molecules have been investigated in preclinical models of implant fixation in osteopenic bone. Systemic PTH treatment has increased BIC and mechanical endpoints in the ovx rat model with titanium screws [110], intramedullary PMMA [73], and HA-coated titanium implants [111]. Strontium ranelate (SR) is another anabolic agent that has been shown to increase BMD and prevent osteoporotic fractures in clinical trials [112]. Similar to PTH, preclinical experiments with SR have shown increased BIC in animal models of osteopenia [72, 113, 114]. Additional systemic treatments, such as EP4 receptor antagonist [115], vitamin D [116], and simvastatin [117] have demonstrated positive effects of increased bone formation on implant stability. Clinically, no prospective or retrospective studies have been performed that investigate the effects of anabolic treatments on implant stability. However, recently a case report has suggested PTH treatment can improve the osseointegration of orthopedic implants [118]. Several additional anabolic agents are currently in various states of clinical trials to treat osteoporosis. For instance, sclerostin antibody [119] and Dickkopf1 (Dkk1) antibody [120] have been shown to increase periimplant bone volume and implant fixation strength in intact rats. Further, sclerostin antibody has also been shown to improve BIC in the added challenge of peri-implant osteolysis [121•]. Currently, no preclinical reports have shown increased implant fixation in osteopenic animals following treatment with sclerostin or Dkk1 antibodies, although the authors have data from a rat ovx study showing that sclerostin antibody
enhances implant fixation strength (manuscript under review). Emerging research will determine the effects of these treatments on implant fixation in preclinical models and as more patients are prescribed anabolic agents it is likely that new case studies will emerge. Combination and Comparison of Anti-catabolic and Anabolic Treatments Combining anti-catabolic and anabolic treatments has also been proposed as a means to positively affect the bone remodeling balance. Gao et al. [122] studied a combination approach with local zoledronic acid (ZOL) and local basic fibroblast growth factor, with combined treatment increasing each experimental endpoint more than either treatment alone. The anti-catabolic (ZOL) treatment significantly increased the mechanical endpoint when compared with the anabolic treatment (basic fibroblast growth factor). Two additional studies compared systemic anabolic treatments to local anti-catabolic treatments and in combination and confirmed that local anticatabolic treatment (ZOL in both cases) increased the periimplant bone volume and implant fixation strength when compared with systemic anabolics (either estrogen [123] or PTH [124]) and in both cases the combined approach was significantly greater than either individually [123, 124]. Each of the preclinical studies comparing combinatory approaches began treatment coincident with the implant placement and therefore the effects on the initial healing phase were the primary interest. It is unknown which of the treatments preserves implant stability with the continued loss of bone mass. Despite the finding of improved implant stability following anti-catabolic treatment, anabolic treatments remain the only option to recover lost bone mass and may have promise in the reversal and improvement in stability following the development of loosening.
Conclusions The prevalence of osteoporosis will continue to grow along with the number of patients receiving implants and therefore it is critical to recognize the challenges osteoporosis presents to implant fixation and what potential treatments are available. Pharmacologic augmentation through targeting the bone remodeling process presents an attractive method to improve implant fixation. Both anti-catabolic and anabolic treatments have demonstrated success in improving fixation strength in preclinical studies. Many of the pharmacologic agents demonstrated to improve implant fixation in animal models are currently in use clinically or undergoing clinical trials as treatments for osteoporosis and time will tell what effects these agents will have on the longevity of implant stability. Suggested topics for continued research include long-term
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maintenance of implant fixation strength and recovery of depressed implant fixation in situations where bone loss occurs after initial implant placement. Compliance with Ethics Guidelines Conflict of Interest R. D. Ross declares that he has no conflicts of interest. J. L. Hamilton declares that he has no conflicts of interest. B. M. Wilson declares that she has no conflicts of interest. D. R. Sumner has received research support from the Musculoskeletal Transplant Foundation, Department of Army, Amgen, NIH, and Grainger Foundation. He has received travel reimbursement and honoraria from the University of Pennsylvania for a seminar and travel reimbursement from the American Association of Anatomist for Board of Directors meetings. A. S. Virdi has received honoraria from NIH and Oklahoma State and travel reimbursement from Oklahoma State. Human and Animal Rights and Informed Consent This article does not contain any previously unreported studies with human or animal subjects performed by any of the authors.
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