EffectsofResveratrolSupplementationon MethotrexateChemotherapy-InducedBoneLoss.

Alice Lee,Cory Xian,Peter Howe,Yu‐Wen Su,Tetyana Shandala,Pei Soo,Ke‐Ming Chen,Tristan King

doi:10.3390/nu9030255

Abstract

Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five-day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX-treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects.

Highlights

Chemotherapy is often the first line modality commonly used in the treatment of various types of cancer-including solid tumours and leukaemia [1,2]
We have shown a significant reduction in the thickness of the growth plate and shorter primary spongiosa height after MTX chemotherapy compared to normal control, a damage which was prevented in RES-supplemented MTX-treated rats
Our analyses have shown that MTX chemotherapy caused an increased osteoclast formation in the bone marrow, resulting in an elevated osteoclast density on the bone surface, and that RES supplementation could partially prevent these adverse effects

Summary

Introduction

Chemotherapy is often the first line modality commonly used in the treatment of various types of cancer-including solid tumours and leukaemia [1,2]. One of the most challenging aspects of chemotherapy is the associated side effects in many organs, including severe long-term skeletal defects, which can negatively impact the quality of life of cancer patients and survivors. Experimental studies in rats have demonstrated that methotrexate (MTX) chemotherapy (which is commonly used in childhood oncology) significantly reduces growth plate thickness [4,5]. Dysfunction of the growth plate induced by MTX chemotherapy is suggested to cause bone growth arrest. Previous studies in rats revealed a significant reduction in the volume of metaphysis trabecular bone

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Discussion

Conclusion