Written by Marcia J. Egles, MD. Resveratrol at 1mg/kg (but not 10 mg/kg) prevented reduction in bone volume and growth plate thickness when administered to healthy 6-week old methotrexate-treated male rats.

blueberriesMethotrexate is an important chemotherapy drug used to treat cancer and other diseases such as rheumatoid arthritis. One undesirable side-effect of methotrexate, particularly in children, can be severe long-term skeletal defects 1,2. Currently, there is a lack of treatment for this damage. In a recent study performed in young rats, resveratrol supplementation was shown to lessen bone damage caused by methotrexate 3.

Resveratrol is a naturally occurring polyphenol produced by certain plants including red grapes, peanuts and blueberries. In addition to antioxidant and anti-inflammatory properties, resveratrol has been identified to have actions that may be important to bone health. Resveratrol may have a role in promoting osteoblast formation 4. Osteoblasts are the cells that make bone. Resveratrol may also have a role in inhibiting osteoclasts (the cells that break down bone) and bone fat cells 5.

The study looked at the effects of resveratrol supplementation on bone development in healthy six-week old male rats given methotrexate. Two separate trials were conducted to evaluate both a higher dose and a lower dose of resveratrol. In both trials, the rats were divided into four groups of six rats each. The first, the control group, received saline injections instead of methotrexate. The second, the MTX group, received five daily methotrexate (MTX) injections under the skin at 0.75mg/kg/day. The third group received resveratrol (RES) alone, and the fourth group received resveratrol plus MTX. The resveratrol was given by gastric lavage both daily for seven days prior to the first MTX injection, and then daily during the five-day MTX treatment. In the first trial, the dose of resveratrol was 10 mg/kg. In the lower dose trial, the dose was ten times less at 1 mg/kg. (1mg/kg is the equivalent of 68.18mg /150 lb adult or 50 mg /110 lb adult).

Both the control groups and the two RES groups of rats had normal healthy bone development. As expected, the MTX group had multiple boney abnormalities including decreased bone plate thickness, decreased bone volume, and increased numbers of bone fat cells. Multiple other abnormalities in cell biology tests were also reported. The rats in the higher dose resveratrol group had normal development, but in the MTX plus resveratrol group at the higher dose, all the rats had even worsened MTX bone toxicity as evidenced by multiple parameters. However, at the lower dose of 1 mg/kg, there were multiple beneficial results in the MTX group.

MTX bone toxicity appeared much lessened in the low dose resveratrol group as compared to the rats which received MTX alone. Resveratrol at 1mg/kg was found to prevent reduction in bone volume after MTX treatment. Most impressively, the reduction in growth plate thickness commonly encountered with MTX use was better maintained in the resveratrol (1mg/kg) supplemented rats. Gene-expression analysis showed that resveratrol may be active in regulating cell signals to osteoblasts, osteoclasts, and the fat cells. (P values were less than 0.05 in all reported comparisons.)

This study highlights the importance of dosage. The higher dose of resveratrol showed detrimental effects while the lower dose showed benefits. This study done in healthy rats may with further studies help to alleviate the bone disorders that can accompany methotrexate treatments. Next steps would include determining whether resveratrol would interfere with the effectiveness of methotrexate in diseased animals. If resveratrol might counteract methotrexate’s side-effects, it might diminish its intended effects as well.  

Source: Lee, Alice, Tetyana Shandala, Pei Pei Soo, Yu‐Wen Su, Tristan J. King, Ke‐Ming Chen, Peter R. Howe, and Cory J. Xian. “Effects of Resveratrol Supplementation on Methotrexate Chemotherapy‐Induced Bone Loss.” Nutrients 9, no. 3 (2017): 255.

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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 Posted October 2, 2017.

Marcia Egles, MD, graduated from Vanderbilt University School of Medicine in 1986.  She completed her residency in Internal Medicine at St. Louis University Hospital.  Dr. Egles is certified in Internal Medicine and is a member of the American College of Physicians.  She resides in Avon, IN with her husband and two sons.

References:

  1. Xian CJ, Cool JC, Scherer MA, et al. Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects. Bone. 2007;41(5):842-850.
  2. Fan C, Cool JC, Scherer MA, et al. Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment. Bone. 2009;44(1):61-70.
  3. Lee A, Shandala T, Soo PP, et al. Effects of Resveratrol Supplementation on Methotrexate Chemotherapy‐Induced Bone Loss. Nutrients. 2017;9(3):255.
  4. Zhou H, Shang L, Li X, et al. Resveratrol augments the canonical Wnt signaling pathway in promoting osteoblastic differentiation of multipotent mesenchymal cells. Experimental cell research. 2009;315(17):2953-2962.
  5. Fischer-Posovszky P, Kukulus V, Tews D, et al. Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. The American journal of clinical nutrition. 2010;92(1):5-15.