The demand for total hip and total knee revisions in the US is projected to increase by 137% and 601%, respectively, between 2005 and 2030 (1). Periprosthetic osteolysis and aseptic loosening are 2 common indications for revision surgery. Wear and corrosion debris shed from the implants induces an inflammatory cytokine cascade that is widely considered to be the pathogenic mechanism for periprosthetic osteolysis. Specifically, these particles cause a local macrophage-mediated inflammatory reaction (2), which subsequently increases the activity of osteoclasts and may also decrease the activity of osteoblasts (3), leading to net bone loss and implant loosening.
Most investigators agree that particulate-induced osteolysis and implant loosening are mainly caused by increased bone resorption. Not surprisingly, anticatabolic agents, such as bisphosphonates (4, 5), and antagonists of cytokines that mediate the biologic process of bone resorption (6, 7) have been studied for the treatment or prevention of osteolysis and implant loosening. However, no clinical trial has demonstrated that bisphosphonates are effective in treating peri-implant osteolysis (8). Thus, there is a need for an alternative therapeutic strategy for the prevention and treatment of particulate-induced implant loosening. The potential of enhancing bone formation as a countermeasure to particle-induced implant loosening has not been investigated.
Modulation of the Wnt pathway is being examined as a novel means to manipulate bone remodeling. Inhibition of the canonical Wnt signaling pathway down-regulates bone formation (9). One of the Wnt signaling pathway inhibitors is sclerostin, which is the product of the SOST gene and is thought to be exclusively expressed by osteocytes in the adult skeleton (10). Sclerostin-null mice have a high bone mass phenotype (11), and this observation has motivated research on the use of neutralizing antibodies to sclerostin as an approach to enhance bone formation. Systemic administration of sclerostin antibody increased the mineralized surface, mineral apposition rate (MAR), bone formation rate (BFR), bone mass, and bone strength in a rat model of postmenopausal osteoporosis (12). Sclerostin antibody enhances fracture repair (13) and implant fixation in rats (14, 15). There is growing evidence that sclerostin antibody also suppresses bone resorption (16).
Therefore, treatment with sclerostin antibody is a potential therapeutic strategy for a variety of bone-related disorders, including particle-induced implant loosening in the setting of arthroplasty. In this study, we investigated the effect of sclerostin antibody for the prevention of particle-induced implant loosening, using an established rat model that was recently validated in our laboratory in terms of several important clinical criteria (17). We hypothesized that sclerostin antibody treatment would prevent implant loosening by accelerating bone formation and inhibiting bone resorption. Briefly, 3 groups of rats that had received bilateral femoral implants were used; each group comprised 12 rats. One group of rats received no particles and no antibody treatment (control), a second group received lipopolysaccharide (LPS)–doped polyethylene particles, and a third group received LPS-doped polyethylene particles plus sclerostin antibody treatment.
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To our knowledge, the current study is the first to demonstrate the effects of a bone-forming agent for preventing particle-induced implant loosening. In the control groups, LPS-doped polyethylene particles decreased implant fixation strength and peri-implant bone volume, which is consistent with the findings of an earlier independent study (17). Here, we show that the tissue-level mechanisms included suppressed bone formation and increased bone resorption. Systemic administration of sclerostin antibody completely blocked the local negative effects of the particles on implant fixation by enhancing bone formation and inhibiting bone resorption.
Most studies of the prevention of periprosthetic osteolysis or aseptic loosening have focused on anticatabolic agents, especially bisphosphonates (4, 5, 21–24). Other therapeutic agents that have been assessed in various in vivo models include RANKL antagonists (7, 25, 26), tumor necrosis factor (TNF) antagonists (27, 28), interleukin-1 (IL-1) receptor antagonist, IL-6 and IL-10 (29–32), erythromycin (33), osteogenic protein 1 (OP-1) (34), hydroxymethylglutaryl-coenzyme A reductase inhibitor (35), α-calcitonin (36), substance P (37), and pan-caspase (38). Of these previous studies, only the study with OP-1 included an anabolic agent. Those investigators observed that OP-1 appeared to increase the amount of trabecular bone present but did not significantly change bone formation (34).
The implant pull-out data obtained in the current study demonstrated that the group of rats that received particles only had significantly lower implant fixation strength than both the control group and the group that received particles and sclerostin antibody. This finding indicates that intraarticular injection of the polyethylene particles led to implant loosening, as previously observed in similar models (17, 39). The novel finding is that sclerostin antibody, when given contemporaneously with the polyethylene injections, completely abrogated the negative effects of the particles and prevented implant loosening.
Here, we report the effect of particles on peri-implant bone remodeling dynamics. Our findings provide insight into the tissue-level mechanisms underlying the negative effects of the particles on implant fixation and how sclerostin antibody treatment abrogated those negative effects. A previous study by our group showed that injection of LPS-doped polyethylene particles induced differences in static parameters (17), and we now report that bone mineral apposition and bone formation rates are depressed in the presence of particles, indicating that the particles inhibited the activity of osteoblasts in peri-implant trabecular bone. In addition, the finding of a decreased mineralized surface may indicate depressed osteoblastogenesis in the peri-implant bone microenvironment. These findings are consistent with current knowledge about the effects of particles from in vitro (40) and in vivo (41) work showing suppressed expression of type I collagen by osteoblasts. Interestingly, it was recently reported that particles increase the expression of sclerostin messenger RNA (42), which could also account for depressed bone formation.
Studies have also shown that wear particles stimulate the production of bone-resorptive cytokines (3) and increase the number of osteoclast-like cells (43); this is consistent with our findings of an increase in the eroded bone surface in rats receiving LPS-doped polyethylene particles. This increase in bone resorption was blocked by treatment with sclerostin antibody. Thus, treatment with sclerostin antibody reversed the biologic effects of particles on both sides of the bone remodeling equation (resorption and formation).
The interpretation that changes in bone remodeling dynamics in the peri-implant region account for the beneficial effects of sclerostin antibody treatment on implant fixation is further supported by the correlations of dynamic and static measurements of bone adjacent to the implant with the mechanical end points. Thus, the LPS-doped polyethylene particles induced lower mechanical fixation strength by stimulating bone resorption and inhibiting bone formation, resulting in derangements in the peri-implant bone architecture. The sclerostin antibody treatment strategy used in the current study completely blocked these negative effects of the polyethylene particles.
In the present study, we examined a prevention scenario, because antibody treatment was contemporaneous with administration of the particles. The study does not address the question of whether or not the antibody would have similar effects if the onset of its administration had been delayed. In addition, it is possible that the lack of loosening in the antibody-treated group was attributable to sclerostin antibody–enhanced bone formation around the implant, preventing ingress of particles along the interface and thus removing an important resorption stimulus. If that is the correct interpretation, the study findings are still important, because they would then provide further evidence that early enhancement of peri-implant bone formation is an effective strategy to guard against particle-induced osteolysis (44).
Clinically, periprosthetic osteolysis is a particle-induced inflammatory disease related to net bone loss that often leads to implant loosening. Some inflammatory cytokines, such as IL-1, IL-6, TNF, and RANKL, have been shown to play a key role in this inflammatory reaction (3, 45). Some of these cytokines are also known to participate in rheumatoid arthritis (another bone-related inflammatory disease) and have been targeted for therapy (46). Sclerostin antibody has shown the ability to down-regulate some inflammatory cytokines, such as TNFα (47) and RANKL (48), suggesting a potential effect on reversing inflammation. In addition, many patients with inflammatory bowel disease, such as colitis, have osteopenia (49). One study has shown that sclerostin antibody can prevent bone loss in an animal model of inflammatory bowel disease (50).
The results of this study indicate that sclerostin antibody is effective in preventing particle-induced implant loosening. It remains to be determined whether treatment with this antibody can slow or reverse the progression of established osteolysis.
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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Sumner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design.Liu, Virdi, Sena, Sumner.
Acquisition of data.Liu, Virdi, Sena, Sumner.
Analysis and interpretation of data.Liu, Virdi, Sena, Sumner.