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Feuer AJ, Thai A, Demmer RT, Vogiatzi M. Association of Stimulant Medication Use With Bone Mass in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. JAMA Pediatr. 2016;170(12):e162804. doi:10.1001/jamapediatrics.2016.2804
Are the stimulant medications used to treat attention-deficit/hyperactivity disorder associated with low bone mass in growing children?
In this cross-sectional study using population data from the National Health and Nutrition Examination Survey, children and adolescents reporting stimulant use had significantly lower bone mass of the lumbar spine and femoral neck compared with nonusers.
Stimulant use may lead to suboptimal bone accrual and failure to achieve sufficient peak bone mass.
Murine studies reveal that sympathetic nervous system activation leads to decreased bone mass. Stimulant medications used to treat attention-deficit/hyperactivity disorder (ADHD) increase sympathetic tone and may affect bone remodeling. Because bone mass accrual is completed by young adulthood, assessing stimulant effects on bone density in growing children is of critical importance.
To investigate associations between stimulant use and bone mass in children and adolescents.
Design, Setting, and Participants
This cross-sectional analysis used data collected from January 1, 2005, to December 31, 2010, from the National Health and Nutrition Examination Survey (NHANES) database. NHANES is a series of cross-sectional, nationally representative health and nutrition surveys of the US population. All children, adolescents, and young adults aged 8 to 20 years with dual-energy x-ray absorptiometry (DXA), anthropometric, demographic, and prescription medication use data were eligible for participation. Of the 6489 respondents included in the multivariable linear regression analysis, 159 were stimulant users and 6330 were nonusers. Data were analyzed from October 8, 2015, to December 31, 2016.
Stimulant use, determined by questionnaires administered via interview.
Main Outcomes and Measures
The association between stimulant use and total femur, femoral neck, and lumbar spine bone mineral content (BMC) and bone mineral density (BMD) was assessed using DXA.
Study participants included 6489 NHANES participants with a mean (SD) age of 13.6 (3.6) years. Stimulant use was associated with lower bone mass after adjustment for covariates. Mean lumbar spine BMC was significantly lower in stimulant users vs nonusers (12.76 g; 95% CI, 12.28-13.27 g vs 13.38 g; 95% CI, 13.26-13.51 g; P = .02), as was mean lumbar spine BMD (0.90 g/cm2; 95% CI, 0.87-0.94 g/cm2 vs 0.94 g/cm2; 95% CI, 0.94-0.94 g/cm2; P = .03) and mean femoral neck BMC (4.34 g; 95% CI, 4.13-4.57 g vs 4.59 g; 95% CI, 4.56-4.62 g; P = .03). Mean BMD of the femoral neck (0.88 g/cm2; 95% CI, 0.84-0.91 g/cm2 vs 0.91 g/cm2; 95% CI, 0.90-0.91 g/cm2; P = .08) and total femur (0.94 g/cm2; 95% CI, 0.90-0.99 g/cm2 vs 0.99 g/cm2; 95% CI, 0.98-0.99 g/cm2; P = .05) were also lower in stimulant users vs nonusers. Participants treated with stimulants for 3 months or longer had significantly lower lumbar spine BMD (0.89 g/cm2; 95% CI, 0.85-0.93 g/cm2 vs 0.94 g/cm2; 95% CI, 0.94-0.94 g/cm2; P = .02) and BMC (12.71 g; 95% CI, 12.14-13.32 g vs 13.38 g; 95% CI, 13.25-13.51 g; P = .03) and femoral neck BMD (0.87 g/cm2; 95% CI, 0.74-0.83 g/cm2 vs 0.91 g/cm2; 95% CI, 0.83-0.84 g/cm2; P = .048) than nonusers.
Conclusions and Relevance
Children and adolescents reporting stimulant use had lower DXA measurements of the lumbar spine and femur compared with nonusers. These findings support the need for future prospective studies to examine the effects of stimulant use on bone mass in children.
Mounting evidence indicates that the sympathetic nervous system plays a critical role in bone remodeling.1-9 In humans and murine models, bone is innervated by sympathetic and sensory nerve fibers. β-Adrenergic receptor knockout mice display a high bone mass phenotype, as do mice deficient in dopamine β-hydroxylase, an enzyme necessary for the synthesis of norepinephrine.2,5 In addition, pharmacologic blockade of β-adrenergic receptors increases bone density in mice, whereas administration of β-adrenergic agonists decreases bone mass.7 These studies support the hypothesis that increased sympathetic tone via β-adrenergic signaling leads to decreased bone mass. Similarly, adults using β-adrenergic blocking medications have higher bone mineral density (BMD) and a reduced risk for fracture compared with age-matched control individuals.10 These findings suggest that β-adrenergic signaling may also affect bone remodeling and bone mass in humans.
Amphetamines increase the concentration of postsynaptic norepinephrine and are therefore classified as indirect sympathomimetic agents that activate peripheral β-adrenergic receptors.11,12 During normal bone remodeling, norepinephrine suppresses bone formation and stimulates bone resorption, an effect that is mediated by the β2-adrenergic receptors expressed by osteoblasts.13 In recent years, synthesized amphetamine analogues, or stimulant medications, have been prescribed for conditions including attention-deficit/hyperactivity disorder (ADHD). Attention-deficit/hyperactivity disorder is an increasingly prevalent neurodevelopmental disorder with an estimated 6.4 million children affected in the United States and a worldwide prevalence of 7.2%. Stimulants, such as methylphenidate hydrochloride, are the first-line pharmacotherapies for pediatric ADHD.14,15
Stimulants have been shown to decrease growth velocity in pediatric patients, but their effect on bone mass is not clear.16,17 Because amphetamines increase β-adrenergic signaling, they may exert detrimental effects on the growing skeleton. At present, the effects of stimulants on bone have not been well studied in adults, and there is a dearth of data in children. The 3 published pediatric studies18-20 reveal conflicting results. The single longitudinal study by Poulton et al18 revealed significant reductions in bone mass during a 3-year period. Another study by Lahat et al19 found no significant differences in BMD in pediatric stimulant users vs healthy controls. The final study, a cross-sectional analysis by Howard et al,20 showed that stimulant use was associated with lower bone mass compared with that of controls. This lack of data is of particular concern given how frequently stimulants are prescribed to children. Childhood and adolescence are the times for rapid bone accrual, and diminished bone acquisition during this period is thought to put the individual at increased risk for osteoporosis.21-23 Therefore, assessing the possible effects of stimulant medications on bone density in the pediatric population is of critical importance. This cross-sectional study was designed to elucidate whether an association exists between stimulant use and bone mass in children and adolescents.
The National Health and Nutrition Examination Survey (NHANES) consists of a series of cross-sectional, nationally representative health and nutrition examination surveys of the US civilian population. NHANES data include in-person interviews and results of standardized health examinations and laboratory tests. We analyzed NHANES data collected from January 1, 2005, to December 31, 2010. All children 8 years or older were asked to complete a dual-energy x-ray absorptiometry (DXA) scan. Because our goal was to determine the effect of stimulants on bone mass in children and adolescents, we included all participants aged 8 to 20 years with DXA, anthropometric, demographic, and prescription medication use data. The Centers for Disease Control and Prevention and National Center for Health Statistics Ethics Review Board approved the original NHANES data collection, and participants provided written informed consent. Because all NHANES data are deidentified and publicly available on the Centers for Disease Control and Prevention website, institutional review board approval was not sought for this analysis.
Medication use data were obtained via questionnaires administered by an interviewer. Medications were self-reported for participants older than 16 years and reported by proxies for younger participants. Duration of stimulant use was reported within data sets. Secondary analyses split stimulant use into 3 groups (none, <3 months, and ≥3 months). We used the Lexicon Plus database (Cerner Multum, Inc) to match reported medications. Stimulant users were defined as participants who reported use of amphetamine, methylphenidate, lisdexamfetamine dimesylate, dextroamphetamine sulfate, or levoamphetamine. Nonusers were defined as participants who did not report use of those medications. Both groups included participants who reported use of medications other than stimulants. Sensitivity analyses were conducted comparing participants who only reported stimulant use with those who reported stimulant and other medication use. Sensitivity analyses were also conducted to compare participants who reported no medication use with those who reported stimulant use.
Bone mineral content (BMC) and BMD were measured using DXA scans of the left hip and lumbar spine administered by certified technologists using a fan-beam densitometer (QDR-4500A; Hologic). Calibration was maintained with daily spine phantom and weekly femur phantom scans. The manufacturer’s Discovery software (version 12.4; Hologic) was used from 2005 to 2008, and APEX software (version 3.0; Hologic) was used from 2009 to 2010. Standardized radiologic protocols developed by the University of California, San Francisco, for NHANES were applied. The DXA data used included BMC and BMD measurements of the lumbar spine, femoral neck, and total femur. For the spine, mean values of lumbar vertebrae (L1-L4) were used.
Several variables were related to BMD and BMC measurements. Demographic variables included age, sex, and race or ethnicity. We calculated z scores for height, weight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) using the macro from the Centers for Disease Control and Prevention (http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm). Adjustment was performed for physical activity and socioeconomic status using the poverty income ratio, an index calculated by dividing family income by a poverty threshold specific to family size. Serum levels of 25-hydroxyvitamin D (25[OH]D) were measured using a commercially available assay (DiaSorin). Tobacco exposure was adjusted for using serum cotinine levels.
Data were analyzed from October 8, 2015, to December 31, 2016. All analyses were performed using survey procedures in SAS software (version 9.3; SAS Institute Inc). NHANES sample weights were used to account for unequal probability of selection, nonresponse, and planned oversampling of non-Hispanic black and Mexican American participants. Design variables accounting for the stratified, clustered NHANES design were also incorporated into the analysis to appropriately estimate the variance of BMD and BMC outcomes. Subpopulation analyses (via a domain statement in SAS survey procedures) were conducted because we excluded individuals with missing data for stimulant use and imported covariates. Multivariable linear regression analysis investigated BMD and BMC values at all anatomical sites by comparing participants who reported stimulant use with those who did not, with mean adjusted values (95% CIs) for the BMC and BMD outcomes. In analyses of lumbar spine BMD and BMC outcomes, natural log-transformed values were modeled owing to lack of normality, and we present adjusted geometric means. Models included the variables age, sex, race or ethnicity, height z score, weight z score, physical activity, poverty income ratio, and serum cotinine level, which met a 10% change in the regression coefficient, suggestive of confounding. Age was treated as a continuous variable. Sensitivity analyses were also conducted comparing participants who reported no medication use with those who reported stimulant use. Further subgroup analysis assessed duration of treatment by analyzing participants who used stimulants for at least 3 months or less than 3 months. Serum 25(OH)D concentrations were only available among a subset of participants, which precluded adjustment for 25(OH)D values in the full sample. Owing to the known correlation between height and weight z scores, we tested for collinearity by calculating a variance inflation factor. If the variance inflation factor was greater than 10, the variable was removed. We found no evidence of meaningful collinearity in these data.
Of the 6489 eligible participants (mean [SD] age, 13.6 [3.6] years), 159 individuals reported stimulant use. The demographic distribution of stimulant users vs nonusers differed. Stimulant users were predominately male and non-Hispanic white (Table 1).
Baseline characteristics of study participants are compared by sex and by stimulant use vs nonuse in Table 1. Male stimulant users had significantly lower BMIs, BMI z scores, weight, and weight z scores than nonusers of stimulants, whereas female stimulant users had significantly lower weight and BMI. However, the mean BMI and weight z scores were clinically within the reference range in both groups. Male and female stimulant users had significantly shorter heights than nonusers, but we found no significant difference in height z scores. All statistical models were adjusted to control for these differences. The poverty income ratio and physical activity level were similar in both groups. Serum 25(OH)D concentrations, available among a small subset of participants (2359 stimulant nonusers and 42 stimulant users), were significantly higher among stimulant users vs nonusers (Table 1).
Table 2 provides the summary of DXA measurements of stimulant users vs nonusers after adjustment for covariates. Stimulant use was associated with lower bone mass at all anatomical sites (lumbar spine, total femur, and femoral neck). Stimulant use remained associated with lower bone mass after adjusting for age, sex, race or ethnicity, height and weight z scores, poverty income ratio, physical activity level, and cotinine level (model 3 in Table 2). Specifically, mean lumbar spine BMC was significantly lower in stimulant users vs nonusers (12.76 g; 95% CI, 12.28-13.27 g vs 13.38 g; 95% CI, 13.26-13.51 g; P = .02), as was mean lumbar spine BMD (0.90 g/cm2; 95% CI, 0.87-0.94 g/cm2 vs 0.94 g/cm2; 95% CI, 0.94-0.94 g/cm2; P = .03) and femoral neck BMC (4.34 g; 95% CI, 4.13-4.57 g vs 4.59 g; 95% CI, 4.56-4.62 g; P = .03). Stimulant users had lower mean BMD of the femoral neck (0.88 g/cm2; 95% CI, 0.84-0.91 g/cm2 vs 0.91 g/cm2; 95% CI, 0.90-0.91 g/cm2; P = .08) and total femur (0.94 g/cm2; 95% CI, 0.90-0.99 g/cm2 vs 0.99 g/cm2; 95% CI, 0.98-0.99 g/cm2; P = .052) compared with nonusers; however, these differences did not reach statistical significance (Table 2). Sensitivity analyses comparing the 5084 NHANES participants who reported no medication use with those who reported stimulant use revealed similar results with significantly lower mean BMD of the total femur and significantly lower BMD and BMC of the lumbar spine and femoral neck. We found no significant differences between mean BMC and BMD at all anatomical sites in participants reporting stimulant use alone vs stimulant use concomitant with other medications.
Participants reported receiving stimulant therapy for a mean (SD) of 1120 (916) days. Because the range was broad, further subgroup analysis was performed to assess whether duration of treatment was associated with bone mass. Three months of therapy was chosen as the minimal duration of treatment at which an effect on bone physiologic features would likely be observed.18 Participants were stratified as receiving less than or at least 3 months of stimulant therapy. Twenty-four participants received stimulant therapy for less than 3 months, whereas 135 received therapy for at least 3 months. Stimulant users receiving more than 3 months of therapy had significantly lower BMD (0.89 g/cm2; 95% CI, 0.85-0.93 g/cm2 vs 0.94 g/cm2; 95% CI, 0.94-0.94 g/cm2; P = .02) and BMC (12.71 g; 95% CI, 12.14-13.32 g vs 13.38 g; 95% CI, 13.25-13.51 g; P = .03) of the lumbar spine and BMD (0.87 g/cm2; 95% CI, 0.74-0.83 g/cm2 vs 0.91 g/cm2; 95% CI, 0.82-0.84 g/cm2; P = .048) and BMC (4.33 g; 95% CI, 4.06-4.60 g vs 4.59 g; 95% CI, 4.55-4.62 g; P = .050) of the femoral neck compared with nonusers, whereas the association was lost in the group with less than 3 months of use (Table 3). The same analysis was performed using an exposure cutoff of 6 months and yielded similar results.
Our results show that use of stimulants in children and adolescents is associated with lower bone mass compared with nonusers. We observed significantly lower mean lumbar spine BMD and BMC and lower femoral neck BMC and total femur BMD in stimulant users compared with nonusers. This lower bone mass in stimulant users is likely to be of clinical importance. Reduction in bone mass during the critical period of bone accrual in adolescence and early adulthood can lead to chronic reductions in bone density. Longitudinal tracking of DXA measurements indicates that skeletal status during childhood is a strong predictor of peak bone mass in young adulthood. Furthermore, a 5% to 10% reduction in peak BMD (equivalent to a reduction of BMD from 0.5 to 1 SD) can substantially increase the incidence of future fractures.21-23
Attention-deficit/hyperactivity disorder is increasingly prevalent, and the rates of ADHD diagnoses continue to rise approximately 5% annually.14 Stimulants such as methylphenidate and amphetamine are the first-line pharmacotherapies for pediatric ADHD. In 2010 alone, half of the 46 million prescriptions for stimulants were dispensed for children.15 Data examining the effects of stimulant medications on bone mass in this population are scarce. Most studies on the skeletal effects of stimulants examine linear growth, and most reveal a decrement in growth velocity in treated children. Poor growth can be also attributed to slow weight gain; however, the Multimodal Treatment Study of Children with ADHD failed to reveal catch-up growth 14 months after treatment cessation, despite normalization of weight gain.17 Because linear growth is coupled to bone remodeling, Lahat et al19 used DXA and measurement of bone turnover markers to assess the effects of stimulants on bone mass. They revealed no significant differences in BMD of the lumbar spine and femoral neck or bone turnover markers between treated and untreated children. This study was limited by a sample size of only 10 male participants. A longitudinal study by Poulton et al18 assessed body composition, bone density, and markers of bone turnover in 34 children (29 boys) using stimulants. During the 3-year study, significant reductions in sex- and height-corrected z scores were found for lean mass, BMC, BMD, and the ratio of central fat to total fat. Bone turnover markers were significantly reduced at 3 months but recovered after 3 years.18 A recent study by Howard et al20 also used NHANES data to determine associations between stimulant use and bone density in children; however, their study has significant differences from ours. The study by Howard et al20 did not adjust DXA data for height z score, which is of critical importance when interpreting pediatric densitometry.24 Failure to adjust pediatric DXA data for height z score can lead to erroneously low bone density measurements, particularly in children with poor linear growth or short stature.24 In addition, no adjustment was performed for physical activity or exposure to tobacco, which are known to influence bone density. Our results are in concordance with those of their study, albeit our data reveal smaller but significant differences in BMD and BMC between controls and stimulant users, which is likely due to our DXA data being appropriately adjusted for height z score and other covariates.
In terms of stimulant use and fracture risk, a recent retrospective study by Perry et al25 assessed fracture incidence in young patients with ADHD who were treated with stimulant and nonstimulant medications vs no treatment. Results reveal that treated individuals had a significantly increased hazard of fracture compared with untreated individuals. No statistically increased hazard of fracture was found between the 2 treatment groups (stimulant vs nonstimulant medications). The authors assert that these results indicate that untreated patients with ADHD are at greater risk for fractures and that concerns regarding bone health and bone loss owing to ADHD medication should not preclude therapy. The study by Perry et al25 does not discuss the effects ADHD medications may have on bone mass or the concern that stimulant medication may be associated with decreased bone accrual, low peak bone mass, and the risk for future osteoporosis and fragility fractures. Therefore, the authors postulate that the observed increased incidence of fracture in nontreated individuals may be owing to higher rates of trauma associated with hyperactivity, greater distractibility, and increased risk-taking behaviors rather than diminished bone health.25
Our study is significant because it provides clear evidence of a negative association between use of stimulants and height-adjusted bone mass in growing children. However, because of the cross-sectional design, we cannot prove causality or determine whether our findings relate to direct effects of stimulants on the skeleton.
The mechanism of action of stimulants involves the inhibition of presynaptic catecholamine reuptake, which leads to increased neurotransmission of norepinephrine.12 The potential effects of stimulants on bone are likely to be mediated through norepinephrine-stimulated sympathetic activation, which decreases bone mass in murine studies.1-9 Relevant to these findings, osteoblasts reside next to sympathetic neurons within the bone marrow and express β2-adrenergic receptors.8,9 Togari9 has postulated that increased sympathetic tone stimulates these receptors in osteoblasts and decreases their activity. In rats, β-adrenergic blockade with propranolol administration leads to increased osteoblast activity and mineral apposition rate. The reverse is observed with the use of adrenergic agonists.7,26 In addition, use of adrenergic agonists in mice has been shown to increase osteoclastogenesis and bone resorption through the RANKL (receptor activator of NFκB ligand)-osteoprotegrin group of cytokines.1
In human adults, treatment with β-blockers is associated with higher bone mass and a reduced risk for hip fracture.7,10 The adverse effects on dentition that occur with methamphetamine abuse have been extensively described. Because dental standing may be indicative of trabecular bone status, the dental effects of methamphetamine may mirror effects occurring in the skeleton.27 Kim et al28 assessed BMD in methamphetamine abusers and found that the mean BMD was significantly lower in users compared with controls. Katsuragawa29 found that methamphetamine abuse reduced bone strength of the calcaneus, and a recent study by Mosti et al30 revealed whole body and total hip BMD was lower in adult amphetamine users.
Interpretation of pediatric bone mass as measured by DXA is challenging; bone accrual is affected by multiple factors, including age, sex, ethnicity, height, physical activity, socioeconomic status, and tobacco exposure.24,31,32 After these factors in our analysis were adjusted, treatment with stimulants remained significantly associated with lower bone mass. In addition, stimulant users whose duration of therapy was longer than 3 months showed lower BMC and BMD of the lumbar spine and femoral neck compared with nonusers, whereas total femur BMD approached significance. The association was lost in participants receiving treatment for less than 3 months. These findings are especially concerning for children and adolescents who require long-term therapy with stimulants because they may not obtain optimal peak bone mass. Our results also suggest that stimulants affect trabecular bone more than cortical bone. The DXA measurements of the spine are considered to more accurately reflect bone mass in children than measurements in the femur, and one should account for this when interpreting the results.24
Our study has several limitations. Because it is a cross-sectional study, it establishes associations but cannot prove causality. Hence, we cannot determine whether our findings relate to a direct effect of increased sympathetic tone on the skeleton. NHANES does not provide pubertal stage or bone age, and therefore we cannot adjust for these factors in our analysis. Finally, inaccurate reporting of medication use may have occurred, because NHANES surveys are based on individual or parents’ interviews and questionnaires.
Overall, our data suggest that stimulant use is associated with lower BMD and BMC in pediatric patients. These findings can have potential clinical significance as the prevalence of ADHD continues to rise. Because adolescence and young adulthood are critical times for bone mass accrual, further investigation of the effects of stimulants on bone remodeling and bone density is necessary. Further longitudinal studies are needed to confirm our findings and to determine future risk for fracture. Because stimulants are commonly prescribed in pediatrics, the need to clarify their skeletal effects is vital.
Corresponding Author: Alexis J. Feuer, MD, Weill Cornell Medicine, New York Presbyterian Hospital, 525 E 68th St, PO Box 103, New York, NY 10021 (firstname.lastname@example.org).
Accepted for Publication: July 31, 2016.
Published Online: October 3, 2016. doi:10.1001/jamapediatrics.2016.2804
Author Contributions: Dr Feuer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Feuer, Vogiatzi.
Acquisition, analysis, or interpretation of data: Thai, Demmer.
Drafting of the manuscript: Feuer, Vogiatzi.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Thai, Demmer.
Administrative, technical, or material support: Feuer, Demmer, Vogiatzi.
Study supervision: Feuer, Demmer, Vogiatzi.
Conflict of Interest Disclosures: None reported.