Inclusion Criteria:
* All races and ethnic groups will be eligible
* A minimum of 6 individuals aged \>= 40 years will be enrolled. These participants are considered high-risk.
* Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
* Participants must have pathologically confirmed diagnosis of osteosarcoma. Participants must be newly diagnosed and previously untreated, although initiation of doxorubicin/cisplatin prior to enrollment is permitted.
* Participants must have a recommended treatment plan for their osteosarcoma that includes planned MTX treatment at 8-12 g/m\^2.
* Absolute neutrophil count (ANC) \>= 1,000/mm\^3 (or \>= 1.0 x 10\^9/L).
* Platelet count 75,000/mm\^3 (or \>= 75 x 10\^9/L).
* Hemoglobin \>= 8 g/dL.
* Serum creatinine =\< 1.5 x the upper limit of normal (ULN), or glomerular filtration rate (GFR) \>= 60 ml/min/1.73 m\^2 as calculated by the Modification of Diet in Renal Disease (MDRD) formula.
* Total serum bilirubin =\< 2 x ULN.
* Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =\< 2.5 x ULN.
* Participants must be willing to use appropriate contraception for the duration of study treatment and four months after completing HDMTX therapy.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Malignant disease, other than those being treated in this study. Exceptions to this exclusion include the following:
* Malignancies that were treated curatively and have not recurred within 2 years after completion of treatment;
* Completely resected basal cell and squamous cell skin cancers;
* Any malignancy considered to be indolent and that has never required therapy;
* Completely resected carcinoma in situ of any type.
* Participants with rapidly progressive disease or organ dysfunction that would prevent them from receiving planned HDMTX treatment regimen.
* Previous MTX treatment at doses \>= 3 g/m\^2.
* Previous treatment with glucarpidase.
* Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis. Patients who have completed curative therapy for HCV are eligible. Patients with known history of human immunodeficiency virus (HIV) infection are eligible.
* Participants with a history of hypersensitivity reactions to study agent or its excipients.
* Participants with a history of hypersensitivity to Escherichia (E.)coli-derived proteins.
* Participants with large pleural or ascitic fluid collection.
* Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
* Uncontrolled intercurrent illness, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
* Unable or unwilling to discontinue use of agents that interact significantly with methotrexate metabolism or excretion.
