Do methotrexate (MTX) or alendronate (bisphosphonate) interfere with levothyroxine (T4) therapy in patients with hypothyroidism?

Drug Interactions Between Methotrexate/Alendronate and Levothyroxine

Neither methotrexate nor alendronate clinically interfere with levothyroxine absorption or efficacy when used concurrently in patients with hypothyroidism.

Alendronate and Levothyroxine: No Clinically Significant Interaction

Alendronate does not materially affect levothyroxine absorption, and the two medications can be safely coadministered. 1

Evidence from Pharmacokinetic Studies

A randomized crossover study specifically evaluated the interaction between alendronate (using a new effervescent formulation) and levothyroxine in healthy adults 1:

• Geometric mean ratios for levothyroxine with concurrent alendronate versus levothyroxine alone were 1.049 (90% CI 0.983-1.119) for AUC and 1.075 (90% CI 1.006-1.148) for Cmax, demonstrating bioequivalence between treatments 1
• The 90% confidence intervals fell within the standard no-effect boundaries of 80-125%, confirming no clinically important pharmacokinetic interference 1
• Coadministration was well tolerated with no safety concerns 1

Practical Implications for Dosing

While both medications traditionally require fasting administration, the pharmacokinetic data support that concurrent administration does not compromise levothyroxine efficacy 1. This is particularly relevant for patients requiring both osteoporosis treatment and thyroid hormone replacement, as it simplifies the dosing regimen.

However, standard recommendations still suggest taking levothyroxine at least 30-60 minutes before food for optimal absorption 2, and alendronate should be taken on an empty stomach with water only.

Methotrexate and Levothyroxine: No Direct Interaction

Methotrexate is not listed among medications that interfere with levothyroxine absorption or metabolism. 3

Methotrexate Drug Interactions: What Actually Matters

The British Association of Dermatologists' guidelines on methotrexate prescribing comprehensively address drug interactions, focusing on medications that:

• Reduce renal elimination (NSAIDs, salicylates, penicillins) 3
• Cause hepatotoxicity (alcohol, azathioprine, retinoids) 3
• Reduce protein binding (phenytoin, penicillins, tetracyclines, sulfonamides) 3
• Cause folic acid deficiency (trimethoprim, sulfonamides) 3

Levothyroxine does not fall into any of these mechanistic categories and is not mentioned as an interacting medication 3.

Medications That Actually Interfere with Levothyroxine

The medications that genuinely reduce levothyroxine bioavailability include 4, 5:

• Proton pump inhibitors (reduce gastric acidity needed for dissolution) 4
• Calcium and iron supplements (form complexes with levothyroxine) 5
• Bile acid sequestrants (bind levothyroxine in the gut) 5
• Antacids (alter gastric pH and binding) 5

Neither methotrexate nor alendronate appear on this list of problematic medications 4, 5.

Common Pitfalls to Avoid

• Do not unnecessarily separate levothyroxine from methotrexate or alendronate based on unfounded interaction concerns 1
• Do not assume all medications require separation from levothyroxine—only those with documented absorption interference need specific timing 2, 4
• If TSH becomes elevated in a patient taking these combinations, investigate actual causes of poor levothyroxine control: non-adherence (28% of patients have MPR <80%), improper timing relative to food (61% take levothyroxine <30 minutes before eating), or concurrent use of genuinely interacting medications like PPIs or calcium 2
• Approximately 7% of patients concurrently use molecules that bind to levothyroxine without applying recommended dosing intervals—focus on these documented interactions rather than theoretical ones 2

Clinical Bottom Line

Patients with hypothyroidism who require methotrexate for autoimmune conditions or alendronate for osteoporosis can take these medications without concern for clinically meaningful interference with levothyroxine therapy. 1 Standard monitoring of TSH levels every 6-12 months remains appropriate 6, but dose adjustments should not be attributed to these specific drug combinations in the absence of other explanatory factors 2, 4.