Juvenile Doxorubicin Exposure Causes Lasting Trabecular Bone Loss in Mice: A Preclinical Model of Long-Term Skeletal
Veli Kaan Aydın1, Aliye Uysal2, Gülçin Abban Mete2
1Department of Biophysics, Faculty of Medicine, Pamukkale University, 20160 Denizli, Türkiye.
Background/Objectives:
Anthracyclines such as doxorubicin (DOX) are integral to pediatric cancer protocols, yet little is known about how juvenile DOX exposure shapes the long-term trajectory of bone growth, microarchitectural connectivity, and the functional balance of bone turnover after treatment cessation. This study aimed to define how juvenile DOX exposure remodels trabecular architecture and bone homeostasis both acutely and after recovery.
Methods:
Four-week-old female BALB/c mice were treated with 6 mg/kg DOX or saline once weekly for four weeks. Bone parameters were analyzed immediately after treatment and after a 4-week drug-free recovery period. Assessments included high-resolution µCT for bone structure and connectivity, H&E and TRAP staining for histological evaluation, and ELISA for bone turnover markers (PINP, OC/BGP, TRACP-5b) in both serum and bone marrow.
Results:
DOX exposure significantly compromised trabecular bone mass and network connectivity, with persistent bone loss extending into the recovery period. Histologically, DOX caused marked degeneration in the epiphyseal growth plate and calcified zones, alongside a marked increase in osteoclast numbers. Functionally, an acute increase in circulating bone formation markers was observed post-treatment. However, during the recovery phase, this transitioned to a significant suppression of these systemic markers, coupled with significantly increased localized bone resorption.
Conclusions:
Juvenile DOX exposure produces sustained trabecular network impairment and growth plate degeneration. This durable structural deterioration is functionally associated with the establishment of a localized, pathologically uncoupled remodeling environment.
Insights
Juvenile doxorubicin (DOX) exposure impairs bone growth and structure, leading to lasting damage and an imbalanced bone remodeling environment. This study reveals persistent trabecular network deterioration and growth plate degeneration even after treatment cessation.
Area of Science:
- Pediatric oncology
- Bone biology
- Pharmacology
Background:
- Anthracyclines like doxorubicin (DOX) are crucial in pediatric cancer treatment.
- Long-term effects of juvenile DOX exposure on bone growth and homeostasis are not well understood.
Purpose of the Study:
- To investigate how juvenile DOX exposure impacts bone microarchitecture, connectivity, and turnover.
- To define the acute and recovery-phase effects of DOX on bone remodeling.
Main Methods:
- Four-week-old mice received weekly DOX or saline for four weeks.
- Bone structure analyzed via micro-CT; histology (H&E, TRAP) and serum/bone marrow markers (PINP, OC/BGP, TRACP-5b) assessed.
- Analyses performed immediately post-treatment and after a 4-week recovery period.
Main Results:
- DOX exposure led to significant bone loss and impaired trabecular connectivity, persisting into recovery.
- Histology showed growth plate degeneration and increased osteoclasts.
- Bone turnover markers initially increased then suppressed, with increased localized resorption during recovery.
Conclusions:
- Juvenile DOX exposure causes sustained impairment of trabecular networks and growth plate degeneration.
- This structural damage is linked to a localized, imbalanced bone remodeling environment.
- DOX-induced bone deficits persist long after treatment cessation.
