Methylphenidate regulation of osteoclasts in a dose- and sex-dependent manner adversely affects skeletal mechanical integrity

Sardar M Z Uddin,Michael Hadjiargyrou,Evan Chernoff,Panayotis K Thanos,David E Komatsu,Lisa S Robison,Dennis Fricke

doi:10.1038/s41598-018-19894-x

Sardar M Z Uddin, Michael Hadjiargyrou + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-19894-x

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Abstract

Methylphenidate (MP) is the most prescribed psychostimulant for ADHD patients, with clinically demonstrated detrimental effects on bone quality, potentially leading to early onset osteoporosis and higher fracture risk. The underlying mechanism for the effects of MP on bone remains elusive. This study demonstrates that sex- and dose-dependent effects of MP on bone quality and quantity are mediated by osteoclast activity. Four-week-old male and female rats were treated with low and high dose MP for 13 weeks. Bone quality and quantity were analyzed using microCT, mechanical testing, histomorphometry, and TRAP staining. Male and female rat bone marrow-derived osteoclasts were treated in a dose-dependent manner (0–1000 ng/ml) and osteoclast activity was determined at days 5, 7, and 14 using TRAP staining, as well as a pit formation assay at day 18. Animal studies showed a dose- and a sex-dependent decrease in mechanical integrity in femora and increased TRAP staining in MP-treated rats. Primary cultures revealed that MP had direct dose- and sex-dependent effects on osteoclast activity, as seen by increased differentiation, activity, and resorption. This study demonstrates for the first time that osteoclasts are differentially regulated by MP in adolescent male and female rats, resulting in sex-dependent effects on the skeleton.

Highlights

Attention Deficit Hyperactivity Disorder (ADHD) is a psychiatric disorder associated with hyperactivity, impulsivity, and inattention
The effects of MP on skeletal growth and homeostasis have been studied for more than 40 years, this is the first study to mechanistically demonstrate that MP has sex- and dose-dependent effects on bone quality via changes in osteoclast activity
Weight gains were significantly lower in HD MP male and female rats independent of food intake, as pair-fed rats did not show any significant changes in weight gain over the 13-week study period

Summary

Introduction

Attention Deficit Hyperactivity Disorder (ADHD) is a psychiatric disorder associated with hyperactivity, impulsivity, and inattention. The skeletal effects of MP are limited to growth but have been shown to impair bone quality and quantity. Komatsu et al showed that adolescent male rats treated with MP demonstrated dose-dependent weight loss after 13 weeks, with a 5–9% decrease in femoral anterior-posterior (AP) diameter[9]. The study was the first to demonstrate adverse effects of MP on bone quality and quantity but was limited to male rats. While it is unequivocal that MP can impair skeletal growth and bone quality clinically and in animal models[6,9], the mechanism by which MP causes these adverse effects remains unclear. The objective of this study was to determine the effects of MP on skeletal development in male and female rats and identify the underlying mechanism(s)

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