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Use of Bisphosphonates to Improve the Durability of Total Joint Replacements Abstract Total joint arthroplasty is very effective for improving the quality of life of patients with end-stage arthritis. Despite advances in materials, surgical technique, and rehabilitation regimens, joint replacements are still fraught with complications leading to their premature failure. Aseptic loosening and osteolysis are the primary causes of implant failure. Other reasons include early migration of components leading to instability, lack of ingrowth into implant porosities, and bone loss caused by stress shielding. Pharmaceutical agents used for preventing and managing postmenopausal osteoporosis (eg, bisphosphonates) may in the future play an important role in improving the long-term duration of joint arthroplasties. Early findings indicate that bisphosphonates upregulate bone morphogenetic protein-2 production and stimulate new bone formation. Because of their anabolic effect on osteoblasts, bisphosphonates have the potential to enhance bone ingrowth into implant porosities, prevent bone resorption under adverse conditions, and dramatically extend the long-term durability of joint arthroplasties. The long-term effects of bisphosphonate use on the mechanical properties of bone have not been adequately investigated. Along with improvements in implant design and material properties, bisphosphonates and other pharmaceutical agents may, in the near future, be part of the growing armamentarium that provides more durable joint arthroplasties. T otal joint replacements (TJRs) are effective surgical procedures for treating patients with end-stage arthritis. However, this procedure is associated with an incidence of failure that increases at the rate of ap- proximately 1% per year postoperatively. Failure is often due to aseptic loosening with bone loss surrounding the implant. Osteolysis is the localized manifestation of this bone loss. A primary cause of total hip arthroplasty (THA) failure, for exam- ple, is thought to be an inflammatory response to wear debris from the ultra-high–molecular-weight polyethylene (UHMWPE) acetabular liner. 1-4 The ensuing release of inflammatory mediators and cytokines, such as prostaglandin E 2 , interleukin-1, and tumor necrosis factor (TNF)–α, 5-9 plays an important role in recruiting and stimulating osteoclasts to resorb bone surrounding Arun S. Shanbhag, PhD, MBA Dr. Shanbhag is Assistant Professor, Harvard Medical School, Boston, MA. Dr. Shanbhag or the department with which he is affiliated has received research or institutional support from Merck. Dr. Shanbhag or the department with which he is affiliated has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research–related funding (such as paid travel) from Merck. Dr. Shanbhag or the department with which he is affiliated has stock or stock options held in Merck. Supported by the National Institutes of Health NIAMS Grant AR47465 A03. Reprint requests: Dr. Shanbhag, Massachusetts General Hospital, Biomaterials Lab, GRJ 1115, 55 Fruit Street, Boston, MA 02114. J Am Acad Orthop Surg 2006;14:215- 225 Copyright 2006 by the American Academy of Orthopaedic Surgeons. Orthopaedic Research Society Special Article Volume 14, Number 4, April 2006 215 the implants (Figure 1). Other reasons for periprosthetic bone loss include initial implant micromotion and migration, elevated fluid pres- sures at the bone bed, and the inflammatory response triggered by debris from other sources within the TJR. Regardless of etiology, failure necessitates revision surgery to re- place loose components. In the United States, approxi- mately 38,000 joint arthroplasties are revised each year because of osteolysis and aseptic loosening. 10 Re- vision surgeries have a higher rate of local and systemic complications, requiring longer hospital stays; con- sequently, they are more expensive than the initial surgery. Additional- ly, revision surgeries have less favor- able outcomes than do primary joint arthroplasties, which translates into more frequent surgeries in sequen- tially less optimal bone. Significant effort has been di- rected at preventing implant failure by developing improved bearing materials with higher wear resistance, such as cross-linked UHMWPE and alternative bearing materials. 11-13 Advances also have been made in understanding the biologic mechanisms of osteoclast-mediated bone loss. Targeting specific cytokines, such as TNF-α, by using their soluble receptors has proved to be inef- fective in controlling osteoclast- mediated bone resorption. 14 The effectiveness of broad-acting bisphosphonates in inhibiting osteoclasts and preventing bone resorption in metabolic bone diseases has led investigators to explore the potential of a similar utility in regard to TJRs. Bisphosphonates effectively inhibit bone resorption and are the pharmaceutical agents of choice in managing postmenopausal osteoporosis, hypercalcemia associated with malignancy, and Paget’s disease. 15 Bisphosphonates are also being evaluated for treatment of inflammatory bone diseases, such as rheumatoid arthritis, osteoarthritis, and fibrous dysplasia, as well as other disorders of the mus- culoskeletal system (eg, osteogenesis imper fecta, ankylosing spondylitis). 15-17 Inhibition of Bone Resorption by Bisphosphonates Bisphosphonates are synthetic ana- logs of pyrophosphate that contain a carbon atom [P–C–P] rather than an oxygen atom [P–O–P], as is found in situ. Bisphosphonates bind avidly to hydroxyapatite (HA) crystals and thus have a strong affinity for bone mineral. Bisphosphonates retard the dissolution of HA crystals in vitro and inhibit bone resorption in vivo. 18 When present in the surrounding fluid, bisphosphonates bind to HA wherever bone mineral is exposed. Bound bisphosphonates are easily released from the bone mineral on acidification of the medium. In newly formed bone, alendronate is deposited preferentially under the osteoclasts, where the bone is being Figure 1 The process of osteolysis. Wear debris generated at the articulating surfaces migrates to the bone-implant interface. Macrophages phagocytize the wear debris and are stimulated to release inflammatory mediators, such as tumor necrosis factor–α, interleukin-1, prostaglandin E 2 , and interleukin-6 (A). These cytokines and mediators initiate and perpetuate osteoclastic bone resorption (B). Periprosthetic bone resorption results in loss of fixation and a painfully loose implant (C). (Copyright© Arun S. Shanbhag, PhD, MBA.) Use of Bisphosphonates to Improve the Durability of Total Joint Replacements 216 Journal of the American Academy of Orthopaedic Surgeons actively resorbed. 19,20 Alendronate also is deposited on new bone formation surfaces lined by osteoid and osteoblasts. 21 Normal bone is formed on top of the bisphosphonate already incorporated within the HA, indicating that bisphosphonates do not im- pair osteoblastic bone formation. 19 In organ culture, bisphosphonates decrease the destruction of bone in embryonic long bones and in neona- tal calvaria. 20,22 When preincubated with bisphosphonates in vitro, mineralized substrata (eg, dentin, ivory, bone slices, bone particles) inhibit pit formation by isolated osteoclasts. The primary action of bisphosphonates is via an acidification process at the osteoclast-mineral interface. 19,23 Bisphosphonates appear to have a minimal effect on the formation, recruitment, and maturation of osteoclasts. In preparation for bone resorption, osteoclasts attach nor- mally to bisphosphonate-containing bone, forming the ruffled border and the underlying clear zone. The ensuing acidification process underneath the osteoclasts liberates the bisphosphonates within the clear zones (Fig- ure 2). The localized high concentra- tion of bisphosphonates increases membrane permeability to calcium and other ions and also causes an in- gress of bisphosphonates into the cy- toplasm. This disrupts actin attachment sites on bone surfaces, interfering with ruffled border func- tion and the required acidification, which in turn paralyzes the bone resorption process. 19 This sequence of events appears to be self-contained; as the clear zone returns to a neutral pH, readsorption of the bisphosphonates to the HA causes a drop in the free bisphosphonate at the interface. 24 Thus, the bisphosphonate re- mains conserved in the bone mineral and may be conceptualized as an enzyme catalyzing the inhibition of osteoclasts. Understanding of the biochemical and molecular mechanisms by which bisphosphonates inhibit osteoclasts is still evolving, and key steps have only recently been eluci- dated. 19,25 The mechanism of action of bisphosphonates largely varies depending on the presence of a nitrogen molecule in the chemical structure. 26 Bisphosphonates with no nitrogen functionality (eg, etidronate, clodronate, tiludronate) (Table 1) have relatively low antiresorptive potency and inhibit osteoclast func- tion via their intracellular metabo- lism to toxic adenosine triphosphate metabolites. 26 Nitrogen containing bisphosphonates (eg, alendronate, ibandronate, risedronate, zoledronate) are more potent inhibitors of osteoclastic bone resorption; they inhibit farnesyl pyrophosphate (FPP) synthase, a key enzyme in the biosynthetic pathway leading from mevalonate to synthesis of cholesterol 25,26 (Figure 3). Suppression of this enzyme in osteoclasts inhibits the synthesis of FPP and geranylgeranyl pyrophosphate (GGPP), which are the substrates for prenylation of guanosine triphosphate (GTP)–binding proteins, such as the cytoskeletal regulators Rho, Ras, Rab, Rac, and CdC42. 27,29 Transferring the isopre- nyls (FPP, GGPP) to a cysteine resi- due in the GTP-binding proteins is essential for localizing these proteins to cell membranes. Preventing this post-translational modification disrupts cytoskeletal reorganization and vesicular fusion, resulting in osteoclast apoptosis. Recent studies indicate that some nitrogen-containing bisphosphonates suppress bone resorption by mechanisms in addition to, or inde- pendent of, the inhibition of FPP activity. 26 Regardless of the presence of nitrogen, all groups of bisphosphonates ultimately inactivate osteoclasts, resulting in reduced bone resorption, lower bone turnover, and a positive bone balance. 19 Their effective potencies in clinical settings may be modified depending on vari- ations of their chemical str ucture and on their alternate pathways tak- en to inhibit osteoclasts. Preventing and Reversing Bone Loss Associated With Aseptic Loosening Managing aseptic loosening and osteolysis around a TJR with a pharmaceutical agent is not a straightfor- ward process. Bisphosphonates are Figure 2 The action of bisphosphonates on osteoclasts. The acidic environment below the osteoclasts releases bisphosphonate from the matrix. Osteoclasts take up the bisphosphonate. Bisphosphonate inhibits the mevalonate pathway. Osteoclasts lose the ruffled border and are inactivated as a result of apoptosis. (Copyright© Arun S. Shanbhag, PhD, MBA.) Arun S. Shanbhag, PhD, MBA Volume 14, Number 4, April 2006 217 efficacious for treating systemic diseases; however, bone loss around implants is generally localized to a region immediately surrounding the implant, and, with focal osteolytic lesions, is condensed even further. Thus, a systemic dosing regimen may not produce a therapeutic con- centration around the joint arthroplasty components. In a study of canine total hip arthroplasty (THA), oral alendronate at the postmenopausal osteoporosis dose (5 mg/d per dog, equivalent to the 10 mg/d adult human dose) prevented osteoclast-mediated bone loss and associated implant loosening. 30 Titanium-alloy components were used with a UHMWPE liner. To kindle the inflammatory cascade, clinically relevant wear debris was introduced intraoperatively around the femoral components. At 24 weeks postoperatively, endosteal scalloping and radiolucencies were observed surrounding the implants in untreated dogs, findings consistent with aseptic loosening. Oral Table 1 Bisphosphonates 20,27,28 Common Name Brand Name Chemical Name Non-nitrogen–containing Etidronate Didronel (Procter & Gamble, Cincinnati, OH) 1-hydroxyethylidene bisphosphonate Clodronate Bonefos (Schering AG, Berlin, Germany) Dichloromethylene bisphosphonate Tiludronate Skelid (sanoﬁ-aventis, Paris, France) Chloro-4-phenylthiomethylene bisphosphonate Nitrogen-containing Alendronate Fosamax (Merck, Rahway, NJ) 4-amino-1-hydroxybutylidene bisphosphonate Ibandronate Bondronate (Roche, Basel, Switzerland) 1-hydroxy-3-(methylpentylamino)-propylidene bisphosphonate Olpadronate Olpadronate* (Gador SA, Buenos Aires, Argentina) Dimethylamino-1-hydroxy propylidene bisphosphonate Pamidronate Aredia (Novartis Pharmaceuticals, East Hanover, NJ) 3-amino-hydroxypropylidene bisphosphonate Risedronate Actonel (Procter & Gamble) 2-(3-pyridinyl)-1-hydroxyethylidene bisphosphonate Zoledronate Zometa (Novartis) 1-hydroxy-2-imidazol-1-yl-phosphonomethyl bisphosphonate * Current clinical usage is not known Figure 3 Molecular action of nitrogen-containing bisphosphonates within the biosynthetic pathway leading from mevalonate to the synthesis of cholesterol. 19,25,26,29 GTP = guanosine triphosphate (Copyright© Arun S. Shanbhag, PhD, MBA.) Use of Bisphosphonates to Improve the Durability of Total Joint Replacements 218 Journal of the American Academy of Orthopaedic Surgeons alendronate treatment protected the dogs from osteoclast-mediated bone loss, in spite of the massive debris challenge. Although the bisphosphonates decreased bone resorption, the periprosthetic tissues har vested at sacrifice from alendronate-treated animals had notable macrophage and foreign body giant cell infiltra- tion, consistent with inflammation induced by wear debris. The periprosthetic tissues released elevated levels of PGE 2 and IL-1 in experimental groups with and without alendronate treatment, compared with non-debris controls. Thus, it appears that in treated animals, even though the macrophages were stimulated by the wear debris to initiate the inflammatory cascade, bisphosphonate treatment prevented the end effector cells—the osteoclasts— from excavating the surrounding bone. 30 This finding is consistent with literature indicating that bisphosphonates act as specific inhibitors of osteoclast-mediated bone resorption with no known anti-inflammatory effects. 19,31 But why the drug was effective locally, even though it was dosed systemically, remained a question. Likely the surgical procedures for preparing the femoral bone, including drilling and ream- ing, exposed large amounts of bone mineral, which adsorbed the bisphosphonate and created locally protected bone. Freshly exposed bone mineral acts as a large magnet for accumulating systemically de- livered bisphosphonates. These findings were confirmed in a rat model of osteolysis, in which a UHMWPE plug was placed in the proximal tibia and high-density polyethylene was injected intra- articularly. Millett et al 32 demonstrated with this model that infusing alendronate around the implant successfully prevented the peri-implant bone loss observed in control animals. The investigators also sought to test whether the bisphosphonate treatment could reverse bone loss after it had started. In separate rats, osteolysis was allowed to develop for 10 weeks postoperatively, and alendronate was infused for a subsequent 6 weeks. At the end of the treatment phase, bone volumes around the implants were preserved and even re- covered to near non-treated levels. 32 Thadani et al 33 reported similar findings. Reaping the benefits of zoledronate—the newer, more potent bisphosphonate—von Knoch et al 34 demonstrated in a mouse model that a single subcutaneous dose protects against particle-induced inflammation for 14 days. These animal models indicate that bisphosphonate treatment can inhibit osteoclast- mediated osteolysis around TJRs. These optimistic findings have not been reproduced in a clinical set- ting. Lyons et al 35 studied the effect of alendronate in patients with demonstrated aseptic loosening who were awaiting revision surgery in the United Kingdom. In this cohort, a 6-month oral treatment conferred no advantage to the patient and did not alter the need for revision surgery. 35 A placebo-controlled, double- blinded, prospective, randomized, multi-center trial was undertaken to evaluate the radiographic progres- sion of peri-implant osteolytic lesions after treating patients with two dosing regimens: an osteoporosis dose (10 mg/d) and a dose approved for Paget’s disease (35 mg/d). Patients with femoral osteolysis after THA (n = 123) were randomized to various treatment regimens; radiographs were digitized and osteolytic lesions measured. 36 Neither of the two alendronate doses had an effect on lesion size at the end of the 18-month study. The higher alendronate dosage may have decreased hip pain at 6 months, but this effect was not confirmed at 18 months. The lack of treatment effects may have been the result of the lack of sensitivity of the radiographs in de- tecting subtle changes in osteolytic lesions. 36 Preventing Bone Loss Associated With Stress Shielding and Immobilization Patients restricted to bed rest may lose as much as 2% of their bone density for every week of rest. The far-reaching consequences include an increased incidence of hip and vertebral fractures. In a rat model, Mosekilde et al 37 reported that either of the two approved bisphosphonate treatments—alendronate or risedronate for 28 days—effectively protected against immobilization-induced loss of bone mineral density (BMD), as measured using dual- energy x-ray absorptiometry. Bis- phosphonate treatment also preserved the mechanical strength of the tibial and femoral metaphyses. Several investigators have suggested that bisphosphonates may be effective in preventing the diffuse bone loss associated with stress shielding. 38 Particularly around THAs, insertion of a stiff metal implant alters the loading pattern of the surrounding bone. Body weight is transferred along the implant to the femoral diaphysis, thereby by- passing the proximal femur. During the first 3 months after implant insertion, BMD decreases 3% to 14% in all Gruen zones around the implant. 39 In the study by Venesmaa et al, 39 most of the decrease occurred within the first year, bottoming out at a nearly 23% loss from preopera- tive levels in the calcar region (Gruen zone 7). Further decreases do not generally occur in subsequent years; in fact, a slight restoration is seen. The “removal of load” results in artificially induced osteopenia; if allowed to progress, implant stability may be compromised. In an ovine femoral hemiarthro- plasty model, Goodship et al 38 demonstrated that local stress shielding in the region of the calcar and medi- al cortex resulted in marked bone loss, as assessed by radiography and bone mineral densitometry. In a par- Arun S. Shanbhag, PhD, MBA Volume 14, Number 4, April 2006 219 allel group of sheep, intravenous in- fusion of zoledronate initiated 1 month preoperatively and continued monthly, reduced calcar bone resorption and prevented the destructive effects of stress shielding for 4 months postoperatively. Venesmaa et al 40 reported similarly positive findings in a clinical trial in patients with cementless THA. A 6-month treatment of oral alendronate effectively prevented bone loss associated with stress shielding. In untreated patients, proximal femur BMD decreased by 17%; alendronate- treated patients experienced only a 0.9% decrease compared with preop- erative levels. Similarly, Lyons et al 35 reported slight increases in BMD in patients who received alendronate after primary THA compared with placebo. Soininvaara et al 41 demonstrated the protective effect of alendronate treatment (10 mg/d) in patients with total knee arthroplasty (TKA). Although distal femoral BMD remained at presurgical levels in treated patients, untreated patients experienced significant bone loss. These studies highlight the beneficial effects of bisphosphonate therapy in maintaining improved bone quality in patients after TJR. Preventing Bone Loss Associated With Instability and Pressure Around a TJR, gross instability of the implant may cause bone loss. Fluid pressure buildup, particularly around the cement mantle, also has been shown to cause bone resorption. Aspenberg and colleagues have systematically studied some of these conditions in simple rat models, and it is clear that bisphosphonates are not a panacea for all forms of bone resorption. 42-44 Astrand and Aspenberg 42 reported the ineffec- tiveness of bisphosphonates in inhibiting instability-induced bone resorption. In a rat model, daily rotation of an implanted plate mod- eled motion between the implant and the surrounding bone. The systemic administration of alendronate reduced osteoclastic activity, as observed by unremodeled cancellous bone and increasing ash weight, rep- resenting higher mineralization in the treated animals. Despite this systemic effect, movement-induced bone resorption at the test surface continued. 42 The findings from this model can be reconciled with known mechanisms of bisphosphonates. The likely explanation is that bone resorption during normal, continuous skeletal remodeling differs from the resorption process at the unstable bone-mineral interface. Further, the bone loss observed around the moving plate likely is a consequence of decreased osteoblastic bone formation with only a minor role, if any, for osteoclasts. Undeterred by these results—and to test a possible dose- related effect—the investigators re- peated the study using a range of doses, up to 50-fold higher of alendronate as well as clodronate. 43 The elevated doses successfully inhibited the osteoclasts and reduced the bone resorption around the moving plate. Considering that such high doses cannot be administered in patients with loose implants, creative local administration of high levels of bisphosphonates is required. To model bone exposed to pulsa- tile pressure, Astrand et al 44 implanted a titanium plate in a rat model. They used a piston attached to a dynamometer to create oscillating fluid pressure. Twice a day for 5 days, a cyclic pressure of 0.6 MPa was applied to the bone interface for 20 cycles. This oscillating pressure caused lytic lesions in the cortical bone under the plate. Compensatory new woven bone was also observed deeper to the lesion. Subcutaneous injections of alendronate prevented cortical bone lesions. However, nu- merous multinucleated osteoclasts were observed in Howship’s lacunae in the surrounding region, demon- strating a strong bone resorption stimulus with oscillating fluid pressure. The altered morphology of osteoclasts, along with the increased ash weight of the contralateral tibia, also attest to the effectiveness of bisphosphonate treatment, which was 50-fold higher than the comparable postmenopausal osteoporosis dose. 44 In this same study, etanercept, a soluble TNF-α receptor, was ineffec- tive in blocking the osteoclast- mediated bone resorption. Before placing the oscillating piston, a 1-min application of alendronate to the bone surface was effective in in- activating osteoclasts and inhibiting the deleterious effects of fluid pressure–associated bone resorption. 44 These in vivo studies highlight the potential application and benefits of using bisphosphonates to manage a variety of osteoclast-mediated pa- thologies around implants. Bisphosphonates and the Quality of Bone Ingrown Into Implants Long-term success of TJR, particularly with cementless components, is critically dependent on stable, initial biologic fixation of the components. To achieve stable fixation, close apposition of the bone to the implant (press-fit) is desirable, as is mechanical stability of the implants in the immediate postoperative period. Poor initial fixation is strongly associated with a high risk of subsequent implant loosening. After TKA, subtle migration of implant components can be determined by tracking the relative movement of implanted metal beads in sequential radiographs using roentgen stereophotogrammetric analysis. The majority of this migration occurs within 6 months after surgery and may continue for 1 year, at which time the components generally stabilize. 45 Components that never stabilize and continue to migrate lead to implant loosening. In a clinical trial of patients with TKA followed for >10 years, all instances of implant loos- Use of Bisphosphonates to Improve the Durability of Total Joint Replacements 220 Journal of the American Academy of Orthopaedic Surgeons ening were associated with continuous migration of tibial components. 45 Because bisphosphonates inhibit osteoclast-mediated bone resorption, there may be an expectation of a net positive bone mass, as osteoblasts remain unaffected. However, there is also a concern that bisphosphonates may retard bone mineralization and affect the durability of a TJR. In a canine model, Frenkel et al 46 tested the effect of subcutaneous alendronate treatment over 24 weeks postoperatively on new bone formation in test channels coated with implant material. Using histomorphometry, scanning electron microscopy and mechanical testing, the investigators demonstrated that alendronate did not adversely affect bone growth into test channels. The mechanical properties of the bone- implant interface also were not af- fected. In ovariectomized canines fed a calcium-deficient diet, alendronate increased bone penetration by 32% into titanium surfaces with plasma-sprayed HA coatings. 46 Earli- er studies on fracture healing in animal models confirmed that bisphosphonate treatment does not adversely affect bone formation and mineralization immediately after surgical placement of implant components. 47 Following up on these findings, Hilding et al 48 demonstrated in a double-blinded clinical trial that perioperative treatment of oral clodronate was effective in reducing tibial component migration in cemented TKA. Patients were dosed with oral clodronate beginning 3 months before surgery; treatment continued until 6 months after surgery. Component migration was assessed using roentgen stereophotogrammetric analysis at 6 months and 1 year postoperatively. Not only did the bisphosphonate treatment stabilize the implants (rotation and translation were notably reduced), but it also protected the components from migration at 1 year. The au- thors suggested that bisphosphonate treatment protects the necrotic bone layer under the tibial components, which would otherwise have been replaced by a fibrous tissue interface resulting in implant motion. 48 Astrand and Aspenberg 49 further explored this hypothesis in a rat model with necrosis in a bone chamber. They reported that a higher clinical dose of systemic alendronate effectively shut down osteoclastic resorption. They found that the necrotic bone provided a scaffold for new osteoid deposition. These au- thors have further suggested that because bisphosphonate prevents the detrimental effects of necrotic bone revascularization, this drug may be used to manage osteonecrosis. Re- sorption of the necrotic bone is reduced until sufficient new bone has formed, thus avoiding structural collapse of the femoral head. 49 Such protective effects indicate that bisphosphonates could be used to prevent resorption of structural bone autografts and allografts, simply by soaking the grafts for 10 minutes in a bisphosphonate solution and rins- ing in saline before implantation. 50 Shanbhag et al 30 reported that such perioperative use of bisphosphonate additionally could enhance bone ingrowth into implant porosities. In a canine model of the use of bisphosphonates to prevent wear debris–induced osteolysis, the femoral components were particularly well ingrown, and the fiber-metal mesh had to be torn apart to loosen the implant and harvest the peri-implant tissues. The clinically similar acetabular components in these same animals were analyzed using quanti- tative bone histomorphometry. The 23-week bisphosphonate treatment resulted in a greater than twofold higher amount of mineralized bone tissue into the titanium fiber metal porosities than in untreated control animals. 51 In another study of rabbits implanted with titanium fiber–metal covered cylinders, there was marked thickening of the adjacent tibial cortical bone after treatment with alendronate and zoledronate. 52 Using zoledronate was noteworthy because it must be administered in- travenously, and the effects are ap- parent for 1 year in clinical patients. Bone Formation in Clinical Trials for Osteoporosis With continued use over 7 years, bisphosphonate treatment for managing postmenopausal osteoporosis did not simply prevent additional bone loss; there was an 11.4% increase in BMD at the lumbar spine compared with baseline. 53 This further increased to 13.7% over a 10-year treatment period. 54 A careful analysis of the 7-year data reveals that after the initial 18-month treatment phase, subsequent bisphosphonate treatment resulted in a 0.8% increase in spine BMD per year, compared with an estimated drop of 0.5% to 1.0% in untreated patients. 53 Although the initial effect of bisphosphonates over 1 to 2 years was believed to be the result of the refill- ing of existing resorption sites, the continued increases are less well understood. Consequent to bisphosphonate treatment, it seems that the coupling between osteoclastic bone resorption and osteoblastic bone formation is severed. The amount of bone resorbed is clearly lower than the amount of bone subsequently formed. Investigators have suggested that by inhibiting excessive resorption, some bone trabeculae hitherto not involved in a structural capacity may respond to mechanical de- mands by thickening. 55 The reduced rate of bone turnover also increases the life span of bone structural units and permits a more complete mineralization of bone tissue, which in turn translates into the commonly measured metric of BMD. 19,56 Others have suggested that the presence of unresorbed trabeculae provides a Arun S. Shanbhag, PhD, MBA Volume 14, Number 4, April 2006 221 ready-made bone scaffold for quick- er deployment of osteoblasts and newer bone. 49,50 These effects, cou- pled with efficient inhibition of osteoclastic activity , result in a very fa- vorable bone balance. Experimental Evidence for the Anabolic Effects of Bisphosphonates Recent studies indicate that, in addition to inhibiting osteoclastic bone resorption, bisphosphonates have an anabolic effect on osteoblasts. 57-59 In- vestigators have reported that various bisphosphonates can stimulate proliferation of human osteoblast-like cells at doses three orders of magni- tude lower than the effective dose on osteoclasts. 60 Similar effects were observed in trabecular bone cells har- vested from the femoral heads of patients with osteoarthritis. 60 Bisphosphonates also stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures, and they promote early osteoblasto- genesis. 57 In recent reports, alendronate and zoledronate treatment increased differentiation of human bone marrow stromal cells to the osteoblastic lineage as indicated by the upregulation of the osteoblast mark- er Cbfa1 gene expression. 59 Further maturation of these newly differen- tiated osteoblasts was observed by the upregulation of type I collagen and osteocalcin gene expression. 59 Statins and Bone Formation Recent investigations demonstrate that statins, a class of drugs clinically used to suppress cholesterol synthesis, also have an innate ability to increase bone formation. 55 Statins are commonly prescribed to decrease hepatic cholesterol synthesis, thereby reducing serum cholesterol con- centrations and, thus, the risk of heart attack. 55 Statins inhibit the 3-hydroxy-3-methylglutaryl coen- zyme A reductase, which is up- stream from the mevalonate pathway. Similar to bisphosphonates, statins prevent prenylation of GTP- binding proteins and inhibit osteoclastic bone resorption. Because statins are selected for hepatic local- ization, they do not have a bone- binding capacity as do bisphosphonates; thus, statins are not clinically optimized for preventing bone loss. Mundy et al 55 demonstrated that statins, such as simvastatin and lovastatin, increased new bone formation two- to three-fold in mice, which is comparable to topical applications of bone morphogenetic protein-2 (BMP-2), a well-known in- ducer of new bone formation, and fibroblast growth factor-1. For more than a decade, statins have been used clinically to lower cholesterol. A retrospective analysis found that elderly women taking statins had elevated hip BMD and a lower risk of hip fractures. 61 Despite the plethora of evidence, the molecular pathways through which bisphosphonates and statins enhance osteoblastic activity are not clearly understood. Giuliani et al 62 reported that the anabolic effect of bisphosphonates was the result of their stimulation of basic-fibroblast growth factor. Several investigators have demonstrated that bisphosphonates and statins stimulate BMP-2 gene expression in vitro, thus enhancing osteoblast activity and new bone formation. 55,59,60 BMP-2 is well recognized for stimulating proliferation and differentiation of mesen- chymal progenitor cells, resulting in new bone formation. Bisphospho- nates also may prevent osteoblast apoptosis and indirectly contribute to the relative increase in cell number and activity. 63 It is not clear whether the observed enhancement in proliferation and differentiation also results in greater mineral con- tent and stronger bone structure. Such studies, along with further dis- section of the mechanism of action, are needed. Mechanical Properties of Bisphosphonate- treated Bone Clinical data clearly indicate that inhibiting osteoclastic bone resorption and reducing bone turnover leads to increased bone volume by filling in of remodeling spaces as well as by increased bone tissue mineralization. Investigators are concerned that increasing mineralization 55 at the expense of younger bone, which contains less crystalline apatite, can make the bone less ductile. Brittle bone has a decreased capacity to ab- sorb energy and is more prone to microcracks. 64 Suppressing bone remodeling also reduces repair of microcracks with undamaged bone and inadvertently reduces its ability to withstand long-term mechanical loading. In many patients with long-term bisphosphonate treatment, this is a significant concern. These concerns loom larger because bisphosphonates are being considered for use in relatively younger, more active indi- viduals with TJRs who have no underlying bone metabolic disease. In- vestigations of canine femurs in which bisphosphonate therapy prevented peri-implant osteolysis demonstrated that the 23-week bisphosphonate treatment did not reduce mechanical properties of bone, such as fracture toughness, elastic modu- lus, or tensile strength. 65 Bending and torsional properties were also unchanged. 66 Using more sophisti- cated techniques, such as backscat- ter electron microscopy, infrared microspectroscopy, and x-ray diffrac- tion, 12 months of bisphosphonate treatment too did not cause any deleterious changes in bone microarchi- tecture and properties. 64 A histomor- phometric study demonstrated no adverse effects on bone structure or mineralization after a 36-month oral bisphosphonate treatment. 67 Mechanical testing is currently limited to short-term studies, and clinical safety and efficacy data are Use of Bisphosphonates to Improve the Durability of Total Joint Replacements 222 Journal of the American Academy of Orthopaedic Surgeons restricted to 10-year follow-up of patients with severe postmenopausal osteoporosis (whose activity levels may be limited). Although the shor t- term data are encouraging, there is a need to study the long-term effects of bisphosphonates on the bone mineral, structure, damage accumula- tion, and load-bearing capacity. Future Directions Although these evolutionary uses are very encouraging, the revolution- ary applications of bisphosphonates hold far greater promise. In vitro and in vivo evidence indicates that bisphosphonates have an anabolic effect on bone formation. The implica- tions for enhancing bone ingrowth into implant porosities, stabilizing implants in compromised bone stock, protecting allografts, and preventing collapse of osteonecrotic femoral heads may have far-reaching consequences for patients. As has been found with statins, fundamental investigations must be performed of other drugs that may have selectively more positive bone effects. Basic science studies, possible with the introduction of gene expression profiling and proteomics tool kits, could catapult researchers to a greater understanding of the underlying principles of bone formation and drug interactions. The issues of bone fragility and interference with bone remodeling also require deliber- ation if bisphosphonates are to be considered for younger patients. De- termination of material and mechanical properties of bone tissue after long-term bisphosphonate treatment is currently lacking. Summary Bisphosphonates offer significant op- portunities for improving the long- term durability of TJRs. Early investigations indicate that systemic bisphosphonate use may prevent periprosthetic bone loss associated with osteolysis and aseptic loosening around TJRs. Considering that wear debris generation and associated inflammation continue in patients, it is not clear whether osteolysis will continue to remain suppressed after drug treatment is discontinued. Around TJRs, bisphosphonates also may prevent bone loss associated with stress shielding and initial component migration. It is not clear whether bisphosphonates are effective for reversing bone loss associated with osteolysis once it is detected ra- diographically. With the higher potency of newer bisphosphonates, creative therapeutic regimens may be explored to increase their local con- centrations. Bisphosphonates may one day join the growing armamentarium (materials development, implant designs, pharmaceutical agents) used to improve the quality of life for patients after TJR. References Evidence-based Medicine: Level I and II studies: references 14, 40, 41, and 48. Citation numbers printed in bold type indicate references published within the past 5 years. 1. Friedman RJ, Black J, Galante JO, Ja- cobs JJ, Skinner HB: Current concepts in orthopaedic biomaterials and implant fixation. Instr Course Lect 1994;43:233-255. 2. 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