DESCRIPTION (provided by applicant): The overall goal of this research project is to determine if and how chronic methylphenidate (MP) treatment is detrimental to skeletal development, as well as evaluate the ability of altered dosing regimens to mitigate any adverse skeletal effects. MP is the most widely prescribed drug for treating attention deficit hyperactivit disorder (ADHD), with ~5% of US adolescents currently taking it. While generally well-tolerated and effective for alleviating the symptoms of ADHD, MP administration is associated with growth suppression of ~1cm/year. Consistent with these clinical observations, studies in our laboratory demonstrated that treatment of adolescent rats with MP resulted in decreased bone size, bone mineral density, bone mineral content, and biomechanical integrity in appendicular, but not axial skeletal sites. Although these adverse effects were ameliorated within 5 weeks of treatment cessation, these data suggest that during the course of MP treatment, patients may be at an increased risk for bone fractures. Given the large and growing number of US adolescents taking MP, a thorough evaluation of the potential adverse effects of this drug on skeletal development is warranted. As well, alternative dosing regimens that may be able to mitigate these effects, while still providing symptomatic relief, need to be tested. As such, this proposal seeks to furthe elucidate the effects of MP on skeletal development by testing the hypothesis that MP administration results in acute impairment of appendicular skeletal development in adolescent rats. We will test this hypothesis by the following specific aims: 1) Assess skeletal development in male and female rats treated with MP at 2 clinically relevant dosages, as well as in vehicle treated and pair-fed controls; 2) Determine if alternative dosing protocols (i.e., 5 days on/2 days off and 3 weeks on/1 week off) can mitigate the adverse effects of MP on skeletal development; and 3) Evaluate the direct and indirect effects of MP on primary rat osteoblast viability, proliferation, differentiation, and activity. These studies will provide a comprehensive understanding of the precise effects of MP on skeletal development, evaluate the ability of alternative dosing protocols to mitigate the adverse of MP on skeletal development, and begin to elucidate the mechanism underlying these effects. In turn, these data will aid clinicians in the design of future clinical trials, as well as make more informed prescribing decisions to protect the skeletal health of patients with ADHD.

PUBLIC HEALTH RELEVANCE: The overall goal of this research is to determine if methylphenidate (MP), sold as Ritalin, is harmful to skeletal development and if so, how to reduce its adverse effects. MP is used as a treatment for attention deficit hyperactivity disorder (ADHD), one of the most commonly diagnosed psychological disorders in adolescents. This medication is currently prescribed to ~5% of American adolescents, a rate that has doubled in the last decade (Dopheide et al., 2009). Although MP works well to control the symptoms of ADHD, clinical studies have shown that growth in adolescents taking MP is reduced by ~1cm/year (MTA cooperative, 2004; Swanson et al., 2006). As it has been shown that these patients achieve normal height in adulthood, some researchers have concluded that MP-induced growth suppression is not a clinically important issue (Pliszka et al., 2006). However, preliminary studies conducted in our laboratory have shown that MP treatment not only reduces bone growth, but also reduces bone mineralization and, more importantly, bone strength. These data suggest that adolescents taking MP may be at an increased risk for bone fractures, a finding that we believe is quite clinically relevant. Therefore, the proposed studies are designed to: A) More precisely measure the adverse effects of MP on skeletal development in both males and females; B) Test whether or not different dosing regimens (other than daily) can reduce or eliminate the adverse effects of MP on skeletal development; and C) Begin to determine how MP treatment leads to impaired skeletal development. The successful completion of these studies has the potential to help improve the skeletal health of the millions of American adolescents that are currently, or will soon be, taking this medication.