香京julia种子在线播放

Arthroplasty has been widely utilized to improve the life quality of patients with end-stage osteoarthritis. However, the occurrence of complications still impacts some patients. Among those complications, implant failure is the most severe one, which might result in revision surgeries eventually. The survival rate of implants is reported to be only 71% at 20 years (1). Aseptic loosening, the major reason for arthroplasty failure, is caused by an inflammatory response to the debris generated from the prosthesis, leading to a promotion of periprosthetic bone loss and pseudomembrane formation, as well as a reduction of prosthesis stability (2, 3). So far, the only treatment for arthroplasty failure is revision surgery, which requires higher technical demand and higher costs but results in a higher complication rate and lower satisfaction rate (4, 5). In the meantime, there is also an essential concern that those patients with revision surgery are likely to be older and frailer, which might result in a higher surgical risk. Therefore, an effective tactic with minimal invasion to prevent prosthetic loosening is of great value.

As reported previously, over 50% of patients undergoing total hip arthroplasty (THA) are combined with osteoporosis (6). Nevertheless, osteoporosis has been proven to negatively regulate implant osseointegration and further increase prosthetic migration (7, 8). Moreover, poor bone quality also increases the prevalence of periprosthetic osteolysis. A study has shown that aseptic loosening is associated with low lumbar bone mineral density (BMD) (9). Additionally, more significant bone loss has been observed in the femoral component in female patients associated with low systemic BMD (10). Excessive osteoclast activities are confirmed to be responsible for both periprosthetic osteolysis and osteoporosis, which are characterized by increasing bone remodeling, especially increasing bone loss (11, 12). Due to the vital role of and similar mechanism with osteoporosis, the utilization of agents with a capacity of regulating bone remodeling has the potential to be an effective approach for implant-loosening prevention.

Many systemic antiosteoporotic agents have been tested to prevent implant loosening by inhibiting periprosthetic osteolysis or improving periprosthetic osseointegration (13). Bisphosphonates, generally regarded as the first-line treatment for osteoporosis, have been verified to demonstrate a beneficial effect on suppressing periprosthetic osteolysis in animal models (14, 15). A clinical study also confirmed that a single infusion of zoledronic acid (ZOL) could reduce the early implant migration in hip arthroplasty (16). Additionally, intermittent parathyroid hormone (PTH) 1-34 is another classical mediation for the treatment of osteoporosis, with the capacity of anabolic effects. Our and other research groups have revealed that intermittent PTH treatment could prevent particle-induced osteolysis in vivo (17–19). Recently, several cases reported that PTH has a protective effect on prosthetic loosening clinically (20–22). Therefore, both PTH and ZOL are promising to be therapeutic options for implant loosening. In addition, the combined use of PTH and ZOL has been found to have an additive-promoting effect in several animal models of skeletal diseases, such as posterior lumbar vertebral fusion in ovariectomized (OVX) rats and fracture healing (23, 24). However, to date, PTH and ZOL still have not been licensed to treat implant loosening. Also, bisphosphonate use was found to increase the incidence rate of periprosthetic fractures after THA in patients with normal bone quality (25). As the crucial role of osteoporosis mentioned above in implant loosening, it is reasonable and meaningful to detect the effects of approved antiosteoporotic agents, PTH and ZOL, on early-stage periprosthetic osteolysis in patients with poor bone quality. In this study, we established a particle-induced periprosthetic osteolysis model in OVX rats and further investigated and compared the effects of combined PTH and ZOL with monotherapy on preventing implant loosening.

In the present study, the combined treatment and monotherapy of PTH and ZOL enhanced periprosthetic bone volume and bone-implant contact and intramedullary implant stability in a debris wear-induced periprosthetic osteolysis under a condition of osteoporosis. Moreover, combined PTH and ZOL therapy revealed an additive effect on preventing periprosthetic osteolysis and improving prosthetic anchorage, exhibiting a greater improvement than monotherapy, even similar or higher than the NC group. Thus, our findings indicated that combination or monotherapy with PTH and/or ZOL might be a promising strategy for preventing early-stage implant loosening in patients with severe osteoporosis.

Various strategies have been attempted to attenuate periprosthetic osteolysis and subsequently implant loosening, including prosthesis modification and systemic agent administration (13). Particularly, agents targeting at regulating bone metabolism have been found effective on implant loosening prevention in animal models, such as sclerostin antibody, alendronate (14, 29). Our group has previously proved the protective effect of intermittent PTH administration or weekly ZOL injection on periprosthetic osteolysis, indicating that these were potential ways to prevent implant loosening (17, 19, 32). Additionally, clinical case reports and trials also provided evidence that agents (such as denosumab and PTH) inhibited periprosthetic bone loss and improved early-stage implant loosening after arthroplasty (20, 21, 33). However, considerable concern should be taken into account, as all these agents are only approved for osteoporosis treatment rather than the treatment of implant loosening. Osteoporosis has been found to increase the morbidity of implant loosening and accelerate the disease progression due to the poor periprosthetic bone quality (8, 9). In this study, we performed the OVX surgery 12 weeks before establishing the debris wear-induced periprosthetic osteolytic model. Female SD rats weighing 200–250 g are regarded as sexually mature preoperatively, in which bone remodeling prevails to bone modeling and is suitable for OVX surgery (34). Simultaneously, constant bone mass was reported to be observed in rats 12 weeks after OVX previously, with a significant bone loss, indicating that the animal model was approaching to aged- or postmenopausalrelated osteoporosis clinically (35). Reduced bone mass, atrophic uterus, and elevated weight observed 12 weeks after OVX surgery in our study certified the successful establishment of the animal model of osteoporosis, meeting the indications of anti-osteoporotic drugs. The subsequent surgery for implant loosening was performed based on the osteoporotic model afterward. A clinical study has shown that osteoporosis is found to be a comorbidity with aseptic loosening (9). Consistent with this clinical study, our research demonstrated that significantly decreased maximal pull-out force and peri-implant bone mass were observed in the OVX group, further confirming that osteoporosis might increase the chance of aseptic loosening. Moreover, a murine study proved that osteoporosis aggravated Ti particle-induced calvarial osteolysis in vivo (18). In our research, increased pseudomembrane and decreased BIC were observed between the OVX group and the O+T group, while no significant differences but downregulated trends were found in biomechanical strength and periprosthetic bone mass. The dense pseudomembrane formation and reduced bone contact confirmed that the periprosthetic osteolytic model has also been built successfully. By contrast, biomechanical strength and periprosthetic bone mass results exhibited no differences but reduced trends, which might be caused by 12-week OVX-induced severe bone loss. Although debris wears accelerated bone loss, it might attenuate the variation between the OVX groups with and without Ti particles.

ZOL, a representative bisphosphonate, serves as the first-line antiosteoporotic agent clinically worldwide. Several nationwide clinical studies clarified that bisphosphonate in patients with THA exhibited a lower risk for revision surgery, indicating that bisphosphonate use is encouraged in patients suffering from osteoporosis and candidates for THA (25, 36). Animal studies also proved that both local and system administrations of bisphosphonate displayed a capacity to prevent particle-induced osteolysis by diminishing bone loss and fiber formation (18, 19, 32). In this study, the systemic administration of ZOL has not improved implant anchorage compared with the O+T group. However, micro-CT and histological results demonstrated that periprosthetic bone loss induced by the synergistic effect of osteoporosis and particles was reversed markedly under ZOL treatment via manifesting the increased BMD, BV/TV, Tb.N, Tb.Th, and Conn.D, as well as reduced BS/BV and Tb.Sp. Inflammation and osteoclastic resorption play crucial roles in osteoporosis and particle-induced osteolysis, resulting in excessive bone destruction. ZOL has confirmed the suppressive effects on bone loss in several animal models, aiming to inhibit osteoclast differentiation and osteoclastic function and induce apoptosis by modulating the mevalonate pathway and diminishing adherence to osteoclast onto the bone surface (37, 38). According to those studies above, in our research, the obviously elevated number and size of osteoclasts were confirmed under the synergistic action of osteoporosis and periprosthetic osteolysis while they were impaired after ZOL treatment. Mechanically, RANKL initiates the activation of signaling cascades and drives osteoclast differentiation and function (39). Ramage et al. indicated that RANKL was highly expressed in fibroblast cells located at the periprosthetic membrane, regulating focalized bone resorption (40). Our IHC results showed the abundant expression of RANKL in the pseudomembrane, whereas ZOL administration attenuated RANKL expression in fibrous tissues. In addition, reduced fibrous pseudomembrane formation was observed under ZOL administration. Since bisphosphonates have not exhibited inhibitory effects on wear debris-induced inflammation in a dog model and human specimens, the explanation was that ZOL decreased osteoclastic resorptive regions, which was presumably filled with fibrous tissues formed by ongoing inflammation-facilitated cell necrosis and fibrosis (41, 42). The inhibition of bone formation by ZOL has been reported previously that ZOL downregulates the proliferation, differentiation, maturation, and function of osteoblasts (23, 43). Our findings further demonstrated a similar result that ZOL reduced the bone formation rate and OCN expression in this animal model. Simultaneously, the serum level of GLA-OCN and CTX-1 further confirmed the suppressive effects of ZOL on both bone formation and bone resorption. Thus, our result demonstrated that ZOL could inhibit peri-implant bone loss but played a limited role in preventing implant loosening.

A considerable enhancement on implant fixation was exhibited under daily PTH treatment, compared with that in the O+T group, with improved stiffness and maximal pull-out force. Several studies from our group and other groups have exhibited beneficial effects on improving prosthetic fixation (17, 32, 44). Recently, some case reports also indicated the clinical efficacy of PTH on the improvement of early-stage implant loosening, with the disappearance of the radiographic line, which is consistent with our findings (20–22). Moreover, PTH showed a more substantial beneficial effect on the biomechanical test than ZOL in this study, which has been proven in other studies before (45). On the contrary, the local administration of ZOL contributed a better potential than PTH on the maximal push-out force in a rat model of initial stability, suggesting that different methods of administration might produce different efficiencies (44). Increased periprosthetic bone mass and decreased pseudomembrane formation are considered to contribute to the enhancement of implant stability (26). PTH is a commonly used anabolic agent on bone remodeling regulation, demonstrating accelerative effects on osteoblastic bone formation and osteoclastic resorption (46). Furthermore, intermittent administration of PTH has shown a greater promotive effect on bone formation than bone resorption, resulting in an elevation of bone mass (47). In this study, elevated trabecular bone and reduced periprosthetic fibrous membrane formed around the implants after PTH treatment, with a significantly raised bone formation rate. The presence of wear debris stimulates the process of chronic inflammation, which disrupts bone formation by impairing osteoblastic proliferation, differentiation, and maturation, as well as inducing apoptosis (48). PTH has been reported to enhance cell activity, prolong the lifespan, reduce the apoptosis of osteoblasts, and promote osteogenic differentiation of MSCs, which greatly supports our findings (49, 50). A higher expression of OCN in peri-implant bone and serum with PTH treatment further confirmed the anabolic effects on bone formation. In addition, less fibrous tissue was observed in the BIC region under PTH treatment, providing better contact between bone and the implant. This finding was consistent with the results reported in a previous study, in which the authors found that PTH exerted a suppressive effect on fibrosis (51).

The exact effects of combined administration with PTH and ZOL remain controversial. No additive effect of PTH and alendronate was exerted in the treatment of osteoporosis in men or postmenopausal women (52, 53); However, Cosman et al. found that the combination therapy of PTH (20 μg daily) and ZOL (5 mg per year) showed an additive effect and a substantial increments in the BMS of spine and hip (54). In addition, some animal studies also confirmed the beneficial effects of combination therapy on promoting implant fixation, preventing disuse-induced osteopenia, and improving posterior lumbar vertebral fusion, compared with PTH or ZOL monotherapy (23, 24, 44). Thus, we hypothesized that conjunctive use of PTH and ZOL exhibited a better preventive effect than PTH or ZOL alone on particle-induced implant loosening in a rat model with osteoporosis. In the present study, the combined PTH with ZOL was found to be effective in maintaining peri-implant bone mass and facilitating the stability of the implant, which is in accordance with the previous studies. Outstanding improvement of maximal pull-out force and stiffness was observed in the combination therapy group, with a similar efficiency with PTH alone but higher than in the ZOL and NC groups. The additive effect on bone mass raise was also exhibited in micro-CT and histomorphological results, along with significantly decreased pseudomembrane thickness. Nevertheless, the major concern is whether the anabolic effect of PTH would be blunted when combined with bisphosphonates (55). Our study demonstrated a similar anabolic effect with the PTH group, which is not impaired obviously by ZOL administration. On the other hand, ZOL-induced inhibition of osteoclasts was slightly counteracted by the utilization of PTH, which is confirmed by the serum results and TRAP staining, resulting in good bone homeostasis. Unexpectedly, the inhibited serum CTX-1 level by PTH or ZOL was reversed with the combination therapy at the level of the NC group. There is no plausible explanation for the interesting phenomenon. Taken together, the combination therapy of PTH and ZOL exerted a superior effect than monotherapy, with better fixation strength and peri-implant bone mass and restoring the bone turnover to the normal level.

Various cells are involved in the process of periprosthetic osteolysis, such as osteoclasts, osteoblasts, fibroblasts, and osteocytes. Osteoblasts and osteoclasts play crucial roles in regulating bone metabolism, and reactions were observed in osteoblasts and osteoclasts after particle wear stimulation during the process of prosthetic osteolysis. Chemokines and proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-11, and macrophage colony-stimulating factor (M-CSF), were secreted in the presence of debris wears, which is in response to an innate host immune stimulation, resulting in excessive osteoclast formation and activity (56, 57). RANKL-RANK-osteoprotegerin (OPG) axis plays an essential role in osteoclastogenesis, while TNF-α and IL-1β support the survival, differentiation, and activation of osteoclasts (58, 59). When RANKL binds to RANK, a series of downstream signaling cascades are initiated, including the ERK, p38, JNK, and NF-κB pathways, subsequently promoting the auto-amplification of the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1, the key molecule of osteoclastogenesis), resulting in osteoclastogenesis (26). ZOL has been widely used to treat osteoporosis with preventive effects on osteoclastogenesis. Inhibiting farnesyl diphosphate (FPP) synthase, a key enzyme of the mevalonate pathway, is generally considered the main molecular mechanism of ZOL on suppressing osteoclast formation antiresorptive potency (60). With a similar mechanism of osteoclastogenesis in periprosthetic osteolysis and osteoporosis, the suppression of the mevalonate pathway might also be the mechanism of ZOL on preventing periprosthetic osteolysis. In the meantime, osteoblast functions are impaired under particle wear stimulation, exhibiting supranuclear vacuolization, cell cycle arrest, and elevated DNA damage (61). Moreover, the adverse effects of viability, proliferation, adhesion, migration, osteogenic differentiation, and mineralization on osteoblasts were also observed in the presence of particle wear (48). In the mechanism, wnt/β-catenin and BMP/Smad signaling pathways were impaired by particles during osteogenic differentiation (62). In addition, OPG, secreted by osteoblasts, is found to be suppressed in periprosthetic osteolysis, resulting in the imbalance of OPG/RANK/RANKL axis (63). Teriparatide (PTH 1-34) has exhibited its capacity to improve bone formation via PKA (protein kinase A) and Wnt/b-catenin pathways and also stimulate OPG secretion (64). Here, we think that the Wnt/β-catenin pathways and OPG/RANK/RANKL axis might be involved in the mechanism of PTH-treated periprosthetic osteolysis by improving osteogenic differentiation, viability, proliferation, adhesion, and migration, as well as attenuating DNA damage.

Some limitations are worth being concerned to our study. Although polyethylene wear particles are considered the leading cause for implant loosening rather than metal particles, metal particles still play a role. They are confirmed to be effective during the initiation and process of peri-implant osteolysis in vivo and in vitro (65). Thus, we used Ti particles here to establish the animal model. In addition, the 6-week duration of particle-induced osteolysis could not represent the entire process of pathological changes. A study with a long period is needed further. Moreover, as the maximum treatment duration with PTH is approved to 24 months in lifespan and the withdrawal of PTH has been proven to lead to the deterioration of implant fixation in a particle-induced osteolytic model, it would be valuable to explore whether the usage of ZOL should be continued when withdrawing PTH, after a period of combined PTH with ZOL (32, 66).

In conclusion, Ti particles deteriorated implant fixation strength, along with periprosthetic bone loss and increased pseudomembrane formation in an OVX rat model. PTH monotherapy or combined PTH with ZOL exerted a protective effect on maintaining implant stability by elevating periprosthetic bone mass and inhibiting pseudomembrane formation via regulating bone metabolism. Moreover, an additive effect was observed when combining PTH with ZOL, resulting in better fixation strength, higher periprosthetic bone mass, and less pseudomembrane than PTH monotherapy. Taken together, our results suggested that combination therapy of PTH and ZOL might be a promising approach for the intervention of early-stage implant loosening in patients with osteoporosis.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.

CZ, SY, HW, and MS: designed the experiment. CZ, YW, JM, FB and HZ: performed the experiment. MY and HX: performed the measurement and analysis. CZ, GY, and CW: drafted the manuscript. CZ and MS: revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was supported by research grants from Zhejiang Natural Science Foundation (No.LQ21H060006), the National Natural Science Foundation of China (No.82001461, No.81902279, No.82102628), and the fellowship of China Postdoctoral Science Foundation (No.2020M671758, No. 2021M692795).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.