Effects of chronic cobalt and chromium exposure after metal‐on‐metal hip resurfacing: An epigenome‐wide association pilot study

Metal‐on‐metal (MOM) hip resurfacing has recently been a popular prosthesis choice for the treatment of symptomatic arthritis, but results in the release of cobalt and chromium ions into the circulation that can be associated with adverse clinical effects. The mechanism underlying these effects remains unclear. While chromosomal aneuploidy and translocations are associated with this exposure, the presence of subtle structural epigenetic modifications in patients with MOM joint replacements remains unexplored. Consequently, we analyzed whole blood DNA methylation in 34 OA patients with MOM hip resurfacing (MOM HR) compared to 34 OA patients with non‐MOM total hip replacements (non‐MOM THR), using the genome‐wide Illumina HumanMethylation 450k BeadChip. No probes showed differential methylation significant at 5% false‐discovery rate (FDR). We also tested association of probe methylation levels with blood chromium and cobalt levels directly; there were no significant associations at 5% FDR. Finally, we used the “epigenetic clock” to compare estimated to actual age at sample for all individuals. We found no significant difference between MOM HR and non‐MOM THR, and no correlation of age acceleration with blood metal levels. Our results suggest the absence of large methylation differences systemically following metal exposure, however, larger sample sizes will be required to identify potential small effects. Any DNA methylation changes that may occur in the local periprosthetic tissues remain to be elucidated. © 2017 The Authors. Orthopaedic Research Society. Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2323–2328, 2017.

     

The roles of TNFR1 in lipopolysaccharide‐induced bone loss: Dual effects of TNFR1 on bone metabolism via osteoclastogenesis and osteoblast survival

LPS (lipopolysaccharide), a major constituent of Gram‐negative bacteria, regulates proliferation and differentiation of osteoclasts directly or indirectly. This study sought to investigate the functions of the RANK/RANKL pathway in LPS‐induced bone loss in vivo. Wild‐type mice or TNFR1?/? mice were injected LPS with or without osteoprotegerin (OPG) and analyzed histologically. Bone volume was reduced by LPS injection in all groups, and OPG administration prevented the LPS‐induced bone loss regardless of genotypes. LPS‐induced enhancement of osteoclastogenesis in wild‐type mice was blocked by OPG administration. LPS or OPG did not affect osteoclastogenesis in TNFR1?/? mice. Interestingly, osteoblast surface was remarkably reduced in LPS‐treated TNFR1?/? mice as a result of enhanced osteoblast apoptosis. TRAIL, induced by TNF‐α in BMC, triggered apoptosis of primary osteoblast only when TNFR1 signal was ablated in vitro. In conclusion, RANK signaling plays a prominent role in osteoclastogenesis downstream of LPS. Furthermore, TNFR1 regulates bone metabolism through not only the regulation of osteoclast differentiation but also osteoblast survival. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:657–663, 2010     

脂肪因子Chemerin对骨代谢影响的研究进展

现代社会肥胖人群逐年增多,肥胖相关代谢性骨病的患者也日益增多,严重危害人群健康。Chemerin作为一种脂肪因子,主要由脂肪细胞和肝细胞分泌,在循环中水平高于经典脂肪因子如Leptin和Adiponectin,对全身代谢和免疫发挥重要作用。近年研究发现,肥胖状态下伴随着外周脂肪组织的增多,骨髓内脂肪组织也急剧增加。骨髓内脂肪细胞分泌Chemerin,通过旁分泌或自分泌方式抑制成骨细胞分化和促进破骨细胞分化以及影响骨髓腔微环境。本文将系统回顾国内外有关Chemerin与骨代谢相关研究的文献,并探讨Chemerin对骨代谢的影响及其机制。     

Blockade of JNK and NFAT pathways attenuates orthopedic particle‐stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis

Particles released from orthopedic implants attract immune host defense cells to the bone‐implant interface and contribute to development of inflammation. The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt/PI3K pathway, NF‐κB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose‐dependently block PMMA‐induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK/JNK inhibitor SP600125 and calcineurin/NFAT inhibitor cyclosporine‐A effectively blocked PMMA‐induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK/NFATc1‐based regulation of PMMA‐induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine‐A abolished particle‐induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle‐induced osteolysis in humans. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:67–72, 2012     

Effects of cobalt and chromium ions at clinically equivalent concentrations after metal-on-metal hip replacement on human osteoblasts and osteoclasts: implications for skeletal health

Metal-on-metal hip replacement (MOMHR) using large diameter bearings has become a popular alternative to conventional total hip arthroplasty, but is associated with elevated local tissue and circulating levels of chromium (Cr) and cobalt (Co) ions that may affect bone health. We examined the effects of acute and chronic exposure to these metals on human osteoblast and osteoclast formation and function over a clinically relevant concentration range previously reported in serum and within hip synovial fluid in patients after MOMHR. SaOS-2 cells were cultured with Co²⁺, Cr³⁺ and Cr⁶⁺ for 3 days after which an MTS assay was used to assess cell viability, for 13 days after which alkaline phosphatase and cell viability were assessed and for 21 days after which nodule formation was assessed. Monocytes were isolated from human peripheral blood and settled onto dentine disks then cultured with M-CSF and RANKL plus either Co²⁺, Cr³⁺ or Cr⁶⁺ ions for 21 days from day 0 or between days 14 and 21. Cells were fixed and stained for TRAP and osteoclast number and amount of resorption per dentine disk determined. Co²⁺ and Cr³⁺ did not affect osteoblast survival or function over the clinically equivalent concentration range, whilst Cr⁶⁺ reduced osteoblast survival and function at concentrations within the clinically equivalent serum range after MOMHR (IC₅₀ = 2.2 μM). In contrast, osteoclasts were more sensitive to metal ions exposure. At serum levels a mild stimulatory effect on resorption in forming osteoclasts was found for Co²⁺ and Cr³⁺, whilst at higher serum and synovial equivalent concentrations, and with Cr⁶⁺, a reduction in cell number and resorption was observed. Co²⁺ and Cr⁶⁺ within the clinical range reduced cell number and resorption in mature osteoclasts. Our data suggest that metal ions at equivalent concentrations to those found in MOMHR affect bone cell health and may contribute to the observed bone-related complications of these prostheses.     

Bio‐corrosion of stainless steel by osteoclasts—in vitro evidence

Most metals in contact with biological systems undergo corrosion by an electrochemical process. This study investigated whether human osteoclasts (OC) are able to grow on stainless steel (SS) and directly corrode the metal alloy leading to the formation of corresponding metal ions, which may cause inflammatory reactions and activate the immune system. Scanning electron microscopy analysis demonstrated long‐term viable OC cultures and evident resorption features on the surface of SS discs on which OC were cultured for 21 days. The findings were confirmed by atomic emission spectrometry investigations showing significantly increased levels of chromium, nickel, and manganese in the supernatant of OC cultures. Furthermore, significant levels of pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α, which are considered to be major mediators of osteolysis, were revealed in the same cultures by cytometric bead array analysis. Within the present study, it was shown that human osteoclast precursors are able to grow and differentiate towards mature OC on SS. The mature cells are able to directly corrode the metal surface and release corresponding metal ions, which induce the secretion of pro‐inflammatory cytokines that are known to enhance osteoclast differentiation, activation, and survival. Enhanced corrosion and the subsequently released metal ions may therefore result in enhanced osteolytic lesions in the peri‐prosthetic bone, contributing to the aseptic loosening of the implant. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 841–846, 2009     

Elevated serum concentrations of cobalt, chromium, nickel, and manganese after metal-on-metal alloarthroplasty of the hip: a prospective randomized study

In this prospective randomized study, we investigate metal ion concentrations and clinical outcome 2 years after metal-on-metal (28 patients) or metal-on-polyethylene (26 patients) hip arthroplasty with 28-mm modular heads. Metal ion concentrations in patient serum were analyzed by high-resolution plasma mass spectrometry. The clinical outcome was almost identical in both groups with respect to the Harris hip score and the Medical Outcome Study Short Form–36; and on plain radiography, no signs of loosening occurred in any group. In the metal-on-metal group, concentrations of all investigated ions increased significantly when compared with preoperative values: cobalt, 15.3-fold (95% confidence interval [CI], 9.4-21.2); chromium, 5.2-fold (CI, 3.5-7.0); nickel, 2.1-fold (CI, 1.2-3.0); and manganese, 1.6-fold (CI, 1.3-2.0). In the metal-on-polyethylene group, a smaller but significant increase in the concentrations of cobalt and nickel occurred, whereas concentrations of the other ions did not change significantly.     

Hypoxia‐like effect of Cobalt Chromium alloy micro particles on fibroblasts in vitro

Periprosthetic osteolysis leading to asceptic loosening remains the primary cause of failure of joint replacement. Although many inflammatory cell types have been implicated, the exact pathomechanisms of asceptic loosening have not been delineated. In the present study we have adopted a proteomic approach to elucidate the initial signals that are expressed to particulate material, using an in vitro cell culture system. Human lung fibroblasts MRC‐5 were cultured with Cobalt Chromium (CoCr ASTM F‐75, 1–7 µm) particles. Cells were harvested after 72 h incubation and total cellular proteins extracted for downstream analysis via 2D Gel Electrophoresis and tandem mass spectrometry using MALDI‐TOF‐TOF‐MS. Thirteen protein spots showed greater than twofold increase, following 72 h incubation of fibroblast with CoCr particles. Four of these proteins were identified by tandem mass spectrometry. These were Annexin II, Pyruvate kinase, Triose phosphate isomerase, and N‐myc downstream regulated gene 1 protein. Cobalt is a hypoxia mimicking agent and N‐myc downstream regulated gene 1 protein, Triose phosphate isomerase, Pyruvate kinase, and Annexin II are important hypoxia regulated gene products that are found to be over expressed in cellular oxidative stress response. Our data indicates that exposure of fibroblast to CoCr alloy induces the transition of these cells into a hypoxia like state and oxidative stress even in normoxic culture conditions. The study reflects the possibility of the presence of a hypoxic environment in the periprosthetic tissue surrounding metallic implants. Published by Wiley Periodicals, Inc. J Orthop Res 28:1360–1367, 2010     

Differential distribution of cobalt,chromium, and nickel between whole blood,plasma and urine in patients after metal‐on‐metal (MoM) hip arthroplasty

Evidence shows that raised cobalt (Co), chromium (Cr), and nickel (Ni) whole blood concentrations correlate with poor device outcome in patients following metal‐on‐metal (MoM) hip arthroplasty. To understand the local and systemic pathological effects of these raised metal concentrations it is important to define their distribution between whole blood, plasma, and urine. The metals were measured by Inductively Coupled Plasma Mass Spectrometry (ICPMS). Two hundred and five plasma, 199 whole blood, and 24 sets of urine samples were analyzed from 202 patients with Co–Cr alloy MoM hip prostheses implanted between 8 months to 12 years (mean 6.0 years) prior to analysis. Plasma Co (median 39.1 nmol/L) showed significantly positive 1:1 correlation with whole blood Co (median 45.9 nmol/L; R² = 0.98, p < 0.001, slope = 1.0). Plasma Cr (median 53.8 nmol/L) and whole blood Cr (median 40.3 nmol/L) were also correlated; however, concentrations were significantly higher in plasma indicating relatively little blood cell uptake (R² = 0.96, p < 0.001, slope = 1.6). Urinary Co was up to threefold higher than Cr (median 334.0 vs. 97.3 nmol/L respectively). Nickel concentrations in whole blood, plasma, and urine were low relative to Co and Cr. The analysis shows fundamental differences in the physiological handling of these metals: Co is distributed approximately equally between blood cells and plasma, whereas Cr is mainly in plasma, despite which, Cr had far less renal excretion than Co. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1640–1646, 2012     

Distribution of chromium and cobalt ions in various blood fractions after resurfacing hip arthroplasty

The most appropriate blood fraction for the measurement of metal ions in patients with metal-on-metal implants is controversial. We compared chromium (Cr) and cobalt (Co) ion levels in 29 patients after unilateral hip resurfacing with a size 54-mm femoral Birmingham Hip Resurfacing Prosthesis (Smith and Nephew, London, UK). All had well-functioning arthroplasties between 5 and 59 months after implantation. Ion levels were measured in serum, plasma, red cells, and whole blood in each patient. Our results indicate that only very minor amounts of Cr and Co are associated with red blood cells, with most being associated with serum/plasma. Previous studies using corrosion to produce the ion load have showed a predominance of Cr in the red blood cells. They have also shown that the cellular uptake of Cr is an indicator of its valence. This difference in distribution with our results is indirect evidence that the Cr released from wear of this implant is probably in the more benign trivalent form. It also suggests that most of the metal loss from a normally wearing bearing may be from wear rather than corrosion. If blood is to be used to assess rates of wear and systemic ion levels, then serum gives a better reflection of the true levels than red blood cells.     

Effects of cobalt and chromium ions on glycolytic flux and the stabilization of hypoxia‐inducible factor‐1α in macrophages in vitro

Implant wear and corrosion have been associated with adverse tissue reactions that can lead to implant failure. Wear and corrosion products are therefore of great clinical concern. For example, Co²⁺ and Cr³⁺ originating from CoCrMo‐based implants have been shown to induce a proinflammatory response in macrophages in vitro. Previous studies have also shown that the polarization of macrophages by some proinflammatory stimuli is associated with a hypoxia‐inducible factor‐1α (HIF‐1α)‐dependent metabolic shift from oxidative phosphorylation (OXPHOS) towards glycolysis. However, the potential of Co²⁺ and Cr³⁺ to induce this metabolic shift, which plays a determining role in the proinflammatory response of macrophages, remains largely unexplored. We recently demonstrated that Co²⁺, but not Cr³⁺, increased oxidative stress and decreased OXPHOS in RAW 264.7 murine macrophages. In the present study, we analyzed the effects of Co²⁺ and Cr³⁺ on glycolytic flux and HIF‐1α stabilization in the same experimental model. Cells were exposed to 6 to 24 ppm Co²⁺ or 50 to 250 ppm Cr³⁺. Glycolytic flux was determined by analyzing extracellular flux and lactate production, while HIF‐1α stabilization was analyzed by immunoblotting. Results showed that Co²⁺, and to a lesser extent Cr³⁺, increased glycolytic flux; however, only Co²⁺ acted through HIF‐1α stabilization. Overall, these results, together with our previous results showing that Co²⁺ increases oxidative stress and decreases OXPHOS, suggest that Co²⁺ (but not Cr³⁺) can induce a HIF‐1α‐dependent metabolic shift from OXPHOS towards glycolysis in macrophages. This metabolic shift may play an early and pivotal role in the inflammatory response induced by Co²⁺ in the periprosthetic environment.     

Role of myeloid early endothelial progenitor cells in bone formation and osteoclast differentiation in tissue construct based on hydroxyapatite poly(ester‐urethane) scaffolds

Engineering of a vascularized bone construct is a highly challenging task which needs to take into account the impact of different components on the bone regeneration process. Bone repair influencing factors in such constructs range from the material properties and scaffold design, to the interaction of different cell types contributing to bone formation and remodeling or neovascularization, respectively. In this context, early endothelial progenitor cells (EPC), mononuclear cells isolated from the peripheral blood, express the endothelial marker CD31 but also a series of myeloid markers and have been shown to support the formation of vessel‐like structures. These cells are also characterized by a highly adaptable phenotype influenced by other cells creating an instructive niche. The present study was designed to investigate the impact of EPC on bone formation or remodeling using a co‐culture system of outgrowth endothelial cells, mature endothelial cells isolated from the peripheral blood cell cultures, and mesenchymal stem cells grown on hydroxyapatite poly(ester‐urethane) scaffolds. The formation of vessel‐like structures in these constructs was shown by CLSM and immunohistochemistry and further evaluated by real time RT‐PCR. Osteogenic differentiation in these constructs was investigated by von Kossa, Alizarin Red, and real time PCR. Data indicated that osteogenic differentiation occurred within the constructs after 14 days of culture but without a direct influence by EPC in this process. Finally, although we observed a series of osteoclast related makers in the constructs when EPC were included, no indications for an increased osteoclast‐like activity, which might lead to increased bone resorption, were observed. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1922–1932, 2016.     

Adverse local tissue reaction (ALTR) associated with corrosion products in metal‐on‐metal and dual modular neck total hip replacements is associated with upregulation of interferon gamma‐mediated chemokine signaling

Adverse local tissue reactions (ALTR) associated with tribocorrosion following total hip arthroplasty (THA) have become a significant clinical concern in recent years. In particular, implants featuring metal‐on‐metal bearing surfaces and modular femoral stems have been reported to result in elevated rates of ALTR. These tribocorrosion‐related tissue reactions are characterized by marked necrosis and lymphocytic infiltration, which contrasts sharply with the macrophagic and foreign body giant cell inflammation associated with polyethylene wear particle induced peri‐implant osteolysis. In this study, we characterize tribocorrosion‐associated ALTR at a molecular level. Gene expression profiling of peri‐implant tissue around failing implants identifies upregulation of numerous inflammatory mediators in ALTR, including several interferon gamma inducible factors, most notably the chemokines MIG/CXCL9 and IP‐10/CXCL10. This expression profile is distinct from that associated with polyethylene wear induced osteolysis, which is characterized by induction of markers of alternative macrophage activation, such as chitotriosidase (CHIT‐1). Importantly, MIG/CXCL9 and IP‐10/CXCL10 are also elevated at the protein level in the synovial fluid and, albeit more moderately, the serum, of ALTR patients, raising the possibility that these factors may serve as circulating biomarkers for the early detection of ALTR in at‐risk patients. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1487–1497, 2015.     

Substrain‐specific differences in bone parameters,alpha‐2‐macroglobulin circulating levels,and osteonecrosis incidence in a rat model

Osteonecrosis of the femoral head (ONFH) is a potentially devastating complication that occurs in up to 40% of young adults receiving chronic glucocorticoid (GC) therapy. Through a validated GC therapy rat model, we have previously shown that Wistar Kyoto ( WK) rats exhibit a genetic susceptibility to GC‐induced ONFH compared to Sasco Fischer (F344) rats. We have undertaken this study in order to investigate differences between these two strains for their bone parameters, alpha‐2‐macroglobulin (A2M) circulating levels and incidence of GC‐induced osteonecrosis of the femoral head. WK and F344 rats were treated either with 1.5 mg/kg/day of prednisone or placebo for 6 months. Blood was taken every month. The femoral heads were harvested for histological examination to detect ONFH and analyzed with micro‐computed tomography. After 3 months of GC‐therapy, plasma A2M was elevated in treated rats only. GC‐treated WK rats exhibited histological evidence of early ONFH through higher rates of cellular apoptosis and empty osteocyte lacunae in the subchondral bone compared to placebos and to F344 rats. Furthermore, micro‐CT analysis exhibited femoral head collapse only in GC‐treated WK rats. Interestingly, GC‐treated F344 rats exhibited significant micro‐CT changes, but such changes were less concentrated in the articular region and were accompanied histologically with increased marrow fat. These µCT and histological findings suggest that elevated A2M serum level is not predictive and suitable as an indicative biomarker for early GC‐induced ONFH in rodents. Elevated A2M levels observed during GC treatment suggests that it plays role in the host reparative response to GC‐associated effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1183–1194, 2017.

     

Intraosseous growth of human prostate cancer in implanted adult human bone: relationship of prostate cancer cells to osteoclasts in osteoblastic metastatic lesions

BACKGROUND: More than 80% of patients with advanced prostate cancer have skeletal involvement, but the biology of bone metastasis is poorly understood. This study investigated the in vivo formation and progression of bone metastases under conditions that resembled the human bone environment as closely as possible. METHODS: Adult human bone fragments were implanted subcutaneously into 120 male NOD/SCID mice. Four weeks later, 1 x 10(7) LNCaP prostate cancer cells or phosphate-buffered saline were injected intravenously into 80 or 40 mice, respectively. The implanted bone fragments were removed from 20 to 10 mice in each group at 2, 4, 6, and 8 weeks after injection. RESULTS: LNCaP colonized the bone marrow blood vessels within 2 weeks, and then gradually expanded into the entire medullary cavity. An osteoblastic response often occurred at the edges of metastatic foci (intertrabecular bone metaplasia). In addition, new bone formation was observed adjacent to mature lamellar bone (appositional bone formation). These two processes appeared to occur through different mechanisms, but might similarly cause osteosclerosis. Osteoclasts showed a marked increase in numbers at sites of early tumor invasion, whereas few osteoclasts were observed at sites where tumor invasion was complete. CONCLUSIONS: The predominance of osteoblastic change with resorption may lead to bone remodeling in metastatic lesions, and osteoclasts may play an important role in bone metastasis from prostate cancer.     

Functionally deficient mesenchymal stem cells reside in the bone marrow niche with M2‐macrophages and amyloid‐β protein adjacent to loose total joint implants

We sought to demonstrate whether there is a difference in the local mesenchymal stem cells (MSC) niche obtained from patients undergoing their first total joint replacement surgery versus those patients undergoing a revision surgery for an failing total joint implant. Bone marrow aspirates collected from patients undergoing revision total joint arthroplasty were observed to be less clonal and the expression of PDGFRα, CD51, ALCAM, endoglin, CXCL12, nestin, and nucleostemin were decreased. Revision MSC were also less able to commit to an osteoblast‐lineage or an adipocyte‐lineage. Further, in revision MSC, OPG, and IL6 expression were increased. Monocytes, derived from revision whole marrow aspirates, were less capable of differentiating into osteoclasts, the cells implicated in the pathologic degradation of bone. Osteoclasts were also not observed in tissue samples collected adjacent to the implants of revision patients; however, the alternatatively activated M2‐macrophage phenotype was observed in parallel with pathologic accumulations of amyloid‐β, τ‐protien and 3‐nitrotyrosine. Despite the limited numbers of patients examined, our data suggest that nucleostemin may be a useful functional marker for MSC while the observation of M2‐macrophage infiltration around the implant lays the foundation for future investigation into a novel mechanism that we propose is associated with loose total joint implants. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:615–624, 2014.     

The effects of local and systemic alendronate delivery on wear debris‐induced osteolysis in vivo

We investigated the effects of locally and systemically administered alendronate on wear debris‐induced osteolysis in vivo. Endotoxin‐free titanium particles were injected into rabbit femurs, prior to insertion of a nonweight‐bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee 2, 4, and 6 weeks after the implantation. Alendronate was incorporated at three different concentrations (0.1, 0.5, and 1.0 wt %) into bone cement for local delivery. For systemic delivery, alendronate was subcutaneously injected (1.0 mg/kg/week) 1 week after the implantation and then once a week until sacrifice. Eight weeks postoperatively, there was significant evidence of osteolysis surrounding the plug in the control group compared with markedly blocked osteolysis in the 0.5 wt % and the 1.0 wt % groups, and the systemic group. There was a concentration‐dependent effect of alendronate‐loaded bone cement on the improvement of peri‐prosthetic bone stock. Notably, no significant differences were found between the 0.5 wt % and the systemic group in peri‐prosthetic bone stock and implant fixation. Collectively, although the biological efficacy after the systemic delivery of alendronate was slightly higher than that in the local treatment groups, alendronate‐loaded bone cement may be therapeutically effective in inhibiting titanium particle‐induced osteolysis in vivo. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:893–899, 2010