Osteosarcoma is the most common malignant bone tumor. It predominantly affects adolescents between 10 and 30 years of age, with 10%–15% of these individuals being diagnosed with metastasis. Survival rates drop from 60% for localized cases to 20% for metastatic or recurrent cases (Meltzer and Helman, 2021; Su et al., 2024). Current treatment combines neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. This combination yields a 5-year survival rate of 60%–70% (Papakonstantinou et al., 2020; Smrke et al., 2021; Panez-Toro et al., 2023). First-line agents such as adriamycin, cisplatin, high-dose methotrexate, and ifosfamide often induce bone marrow suppression, leading to anemia in 70.69% of patients (Bajpai et al., 2017; Sanguanboonyaphong et al., 2022). Postoperative anemia is further exacerbated by surgical blood loss (Abu-Zaid et al., 2021; Zhou et al., 2023), necessitating hemoglobin (Hb) levels ≥8 g/dL to reduce the risk of mortality (Musallam et al., 2011; Cata, 2015; Moncur et al., 2021; Shander et al., 2023; Aoyama et al., 2024).

Anemia management involves allogeneic transfusion and pharmacotherapy. Risks associated with transfusion include infections, hemolytic reactions, and supply shortages (Kramer et al., 2017; Zhang et al., 2024). However, pharmacological approaches focus on erythropoiesis-stimulating agents (Roy et al., 2024), such as rhEPO, which stimulate red blood cell production. Studies have indicated that rhEPO effectively maintains Hb levels during chemotherapy, reduces transfusion needs, and improves perioperative anemia (Cao et al., 2020; Guan et al., 2020; Kaufner et al., 2020). In orthopedic surgeries (for instance, spinal fusion and hip/knee arthroplasty), preoperative rhEPO with iron supplementation optimizes Hb levels, lowers transfusion rates, and enhances recovery without increasing thrombosis risk (Cao et al., 2020; 2023).

However, evidence for the use of rhEPO in osteosarcoma surgery remains limited. Key uncertainties include its efficacy in minimizing postoperative Hb decline, optimal dosing timing. To address this, we retrospectively analyzed children and young patients with osteosarcoma treated at our institution, evaluated the ability of rhEPO to improve postoperative anemia and identified Hb-influencing factors. Our findings aim to guide clinical strategies for improving outcomes in this high-risk population.

Patients with osteosarcoma often experience severe anemia in the postoperative period due to the dual effects of chemotherapy and surgery; this test is much more difficult than the average postoperative orthopedic procedure is and has a direct effect on the survival of patients with tumors (Cata, 2015; Makar et al., 2024). However, owing to the relative rarity of patients with osteosarcoma, relatively few clinical studies exist on this topic, and relatively few reports exist in the available literature on perioperative blood management protocols that specifically address this issue. Current perioperative blood management strategies generally focus on minimizing blood transfusions and optimizing patient outcomes through comprehensive management of anemia, blood loss, and coagulopathy. These strategies include (1) optimizing preoperative hemoglobin through a multidisciplinary approach; (2) minimizing perioperative blood loss; and (3) adhering to evidence-based transfusion guidelines (Holt et al., 2016).

Erythropoietin is an effective drug for the treatment of anemia. The mechanism of action of rhEPO involves stimulating hematopoietic stem cells in the bone marrow, thereby increasing the amounts of raw materials available for hemoglobin synthesis to promote the maturation and release of red blood cells into the bloodstream. In addition, rhEPO can activate the division of primitive red blood cells to promote the proliferation and release of reticulocytes, which ultimately leads to increased levels of hemoglobin, erythrocytes, and reticulocytes in the patient’s body to reduce the number of blood transfusions. Van Iperen C reported that rhEPO levels in the blood were significantly elevated after smajor surgery and peaked on the 5th postoperative day (Van Iperen et al., 1998). Moreover, in a mouse model of cancer, the hemoglobin concentration in the rhEPO-treated group was significantly greater than that in the control group. Currently, researchers can genetically intervene with erythropoietin at the molecular level and better express the gene locus for anemia treatment, suggesting that rhEPO is effective for both surgery and cancer-related anemia (Nguyen et al., 2013; Cao et al., 2020). Although rhEPO has been associated with venous thromboembolism, elevated blood pressure, and adverse cardiovascular events, previous studies have shown that rhEPO does not increase the risk of thrombosis following orthopedic surgery (Ruan et al., 2020). This study confirms that finding, with no significant increase in hypertension or cardiovascular event risk.

We chose a target population within the age of 20 years because the first peak incidence of osteosarcoma is within the age of 20 years, and the treatment strategy for this population is essentially the same (Ahlawat et al., 2024). In this study, rhEPO treatment effectively improved anemia. Specifically, the use of rhEPO significantly shortened hospital stays, with an average reduction of up to 3.459 days. These findings indicate that rhEPO can effectively prolong patients’ hospitalization and recovery periods while also lowering medical costs, possibly because patients need time to recover from chemotherapy after experiencing myelosuppression. The use of erythropoietin significantly reduces the waiting time before surgery or hospitalization after surgery because patients who were not treated previously needed to wait for hemoglobin recovery after chemotherapy, prolonging their hospitalization. Conversely, patients who had mild anemia before surgery and severe postoperative anemia due to blood loss during surgery needed to improve their anemia, thereby prolonging hospitalization.

The main cause of perioperative anemia in osteosarcoma patients is the insufficient erythropoietic function in the bone marrow, likely due to tumor consumption, surgical blood loss, and chemotherapy-induced suppression. rhEPO can improve anemia through several mechanisms. It binds to its receptor and activates the EPO-EPOR-JAK2-STAT5 signaling pathway, which promotes the proliferation and differentiation of erythroid progenitor cells and inhibits apoptosis, thus restoring erythrocyte production in suppressed bone marrow (Bunn, 2013). EPO also regulates iron metabolism by reducing ferritin levels and enhancing iron absorption and utilization, providing sufficient materials for erythropoiesis (Rishi and Subramaniam, 2017). Additionally, it has anti-inflammatory effects by suppressing cytokine production and alleviating inflammatory responses (Tsavlis et al., 2024). During chemotherapy, EPO can reduce chemotherapy drug toxicity (Miltenburg and Boogerd, 2014; Liu et al., 2024). These mechanisms collectively enhance erythropoiesis, alleviate anemia symptoms, and improve patients’ quality of life.

In previous studies, iron supplements combined with rhEPO were expected to improve postoperative recovery by addressing anemia. Iron provided essential materials for red blood cell production, while rhEPO stimulated this process (Correnti et al., 2022; Maltaneri et al., 2024), significantly enhancing erythropoietic efficiency. Enteral nutrition powder supported recovery by offering comprehensive nutrition and enhance hemoglobin levels, decrease the incidence of infections, and accelerate the recovery process (Liu et al., 2013; Martínez-Ortega et al., 2022). However, our study showed that while rhEPO significantly shortened hospital stays, the contributions of iron supplements and enteral nutrition powder were not statistically significant. Chemotherapy for osteosarcoma caused bone marrow suppression and chronic inflammation, leading to hepcidin-mediated iron sequestration (Rishi and Subramaniam, 2017). This reduced the effectiveness of iron supplements in supporting erythropoiesis. Additionally, chemotherapy damaged erythroid progenitor cells and decreased EPO receptor numbers, further suppressing rhEPO’s effects (Doshi et al., 2013). Consequently, iron supplementation did not significantly improve postoperative recovery or shorten hospital stays. Enteral nutrition powder was most beneficial for perioperative patients with moderate-to-severe malnutrition and impaired digestion/absorption, criteria that osteosarcoma patients may not meet, thus limiting the impact of nutritional support on length of stay.

In this study, no significant difference was observed between the rhEPO group and the untreated group in postoperative transfusion requirements. First, the small sample size limited the statistical power of the analysis, which may have masked rhEPO’s potential efficacy. Second, in the rhEPO group, some patients only started treatment postoperatively—with delayed administration and possibly insufficient dosing. This may have prevented the full erythropoietic effect from being realized, thereby limiting any reduction in transfusion requirements. Finally, postoperative transfusion requirements in osteosarcoma patients are affected by multiple factors, rhEPO was not a decisive factor (Dupuis et al., 2015).

Preoperative administration of rhEPO significantly elevates hemoglobin levels postoperative day 3, with this effect being particularly pronounced when comparing the preoperative administration group to the non-preoperative administration group. This can be attributed to two main factors. First, patients who have completed chemotherapy often experience myelosuppression, and the use of erythropoietin can help mitigate this condition. Second, erythropoietin mobilization requires 4–5 days; therefore, preoperative medication can promote the immediate mobilization of blood. This helps control the decrease in hemoglobin during the postoperative hemoglobin trough period, enabling patients to successfully navigate through this critical phase (Van Iperen et al., 1998). Previous studies (Cao et al., 2020) have indicated that a 3-day course of preoperative rhEPO combined with iron supplementation significantly reduces intraoperative bleeding and improves postoperative Hb levels without significantly increasing the risk of complications. Furthermore, preoperative rhEPO treatment may be a more effective blood conservation regimen for total knee arthroplasty (TKA) surgery. The results of this study align with those of previous studies, suggesting that the timing of the administration of preoperative medication is crucial since erythropoietin mobilization requires time.

We found a slight negative correlation between the total perioperative dose of rhEPO and postoperative hemoglobin values on postoperative day 3 in a correlation analysis, but this correlation was not significant in binary logistic regression modeling (Table 5). This may be due to the relationship between treatment duration and initial Hb levels. Lower Hb on day 3 may indicate a need for longer erythropoietin therapy to achieve the desired therapeutic goal, though the impact on outcomes remains uncertain. With a fixed daily dose of rhEPO, a higher total dose indicates a longer administration period. Patients with lower initial Hb levels require more time to reach the target Hb range of 10–13 g/dL. As indicated in the literature (Doshi et al., 2013), CKD patients on dialysis with a baseline Hb of 8 g/dL may need 10–15 weeks of treatment, while those with a baseline Hb near 10 g/dL may need only 6–8 weeks. This extended treatment period results in a higher total dose, creating the observed negative correlation. This correlation reflects the adjustment of treatment duration based on disease severity rather than a direct causation of Hb reduction by the rhEPO dose itself. The goal of treatment is to elevate Hb to the target range, and the initial Hb level determines the required treatment duration. Therefore, the negative correlation is a result of the treatment strategy rather than the effect of the drug dose on Hb levels.

Beyond the role in erythropoiesis, rhEPO have been reported to promote tumor cell growth or survival. A leading hypothesis proposed to explain these safety findings was that functional erythropoietin receptors (EPORs) are expressed in tumor cells and/or endothelial cells, allowing ESAs to directly stimulate tumor growth and/or counteract tumor-ablative therapies. A recent review evaluating evidence supporting the EPO–EPOR tumor-stimulation hypothesis highlighted critical limitations in much of the existing research (Elliott et al., 2006). Specifically, putative positive results were frequently confounded by two key issues: the lack of controls to rule out false-positive effects, and the use of nonspecific reagents. Additionally, EPOR expression levels outside the erythroid compartment—including on tumor cells—are extremely low. Current data fail to convincingly demonstrate that such low-level EPORs can bind sufficient amounts of ESAs to elicit a functional biological response (Sinclair et al., 2010; Swift et al., 2010). Collectively, the available evidence indicates that ESAs do not directly stimulate tumor cells. Furthermore, the cytoprotective and other nonhematopoietic effects of ESAs reported in previous studies do not appear to result from direct ESA-EPOR signaling in nonerythroid cells (Steve and Angus, 2012).

Our study has several limitations. First, it is single-center with a modest sample size, the generalizability of the findings remains limited. These limitations stem from the low incidence of this rare pediatric disease, as well as the practical challenges associated with collecting cases from other institutions. Nevertheless, our study offers valuable insights into osteosarcoma, the most common primary malignant bone tumor in this pediatric population. Second, the retrospective design of this study introduces potential confounding factors and selection bias. In addition to the use of rhEPO combined with iron supplements, perioperative nutritional support also positively impacts the improvement of postoperative anemia. However, these factors are intertwined, making it difficult to completely exclude them, which may introduce some interference into the study results. Therefore, a prospective, randomized, controlled trial is recommended to reduce bias and confounding factors. Third, hospitalization durations varied, preventing standard 1-week postoperative hemoglobin comparisons, Follow-up was limited to the third postoperative day. This was due to the varying patient recovery times, short hospital stays, and data gaps in our system. Obtaining informed consent for follow-up from all patients also took time. Previous studies have suggested that rhEPO has adverse effects on long-term cancer survival, including potential tumor progression. In our study, we did not conduct long-term follow-up of these patients to assess these risks (Pradeep et al., 2015). In future studies, rigorous protocols should be developed to precisely manage the timing of administration, dosage, dosage frequency, and total amount of medication. Such improvements may help identify the most effective timing and total dosage for treatment. These findings may also clarify the influence of rhEPO on long-term patient survival.

Our findings demonstrate that rhEPO significantly shortens the duration of hospital stays, with no significant increase in adverse events observed. Notably, preoperative administration of rhEPO emerges as a potential critical factor contributing to this favorable outcome. However, we also acknowledge the inherent limitations of the present study, and thus stress the need for further well-designed research to validate, refine, and extend these preliminary findings.