Breaking It Down: A Systematic Review Unravelling the Impact of Attention Deficit Hyperactivity Disorder and Methylphenidate on Childhood Fractures

Limb fractures are a common cause of pediatric hospital admissions and surgeries, with a significant prevalence in the United Kingdom across all injury categories. Among psychiatric conditions in children, attention deficit hyperactivity disorder (ADHD) stands out as frequently associated with fractures, particularly those involving extremities. ADHD, with diagnoses prevalent among a significant proportion of school-age children and adolescents, has witnessed a growing global incidence. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist for our systematic literature search, using various databases and specific search terms related to ADHD and fractures. We considered articles from 2018 to 2023, focusing on English language papers with free full-text access. Our selection process used the PRISMA flowchart. We began with 1,890 articles and, after deduplication, title screening, abstract assessment, and quality evaluation included nine research papers in our review. Our primary focus was on examining fracture-related outcomes in individuals with ADHD compared to those without, considering medication status. These studies encompassed various designs, with a focus on the ADHD-fracture relationship and methylphenidate’s (MPH) impact. Our study confirms that ADHD increases fracture risk and suggests that MPH may help mitigate this risk. Early ADHD detection is vital for nonpharmacological interventions. Orthopedic surgeons should proactively identify ADHD, while healthcare professionals should offer injury prevention guidance, particularly for at-risk groups.


Introduction And Background
Limb fractures are one of the most common causes of pediatric hospital admissions and surgeries [1].Fractures are one of the most frequent types of injury in the United Kingdom, even when all other categories are taken into account [2].If we consider all psychiatric conditions in children, then the most common condition associated with fractures is attention deficit hyperactivity disorder (ADHD) [3,4].More specifically, it is also the most commonly studied psychiatric condition associated with extremity fractures in children [5,6].
ADHD is a neurodevelopmental disorder diagnosed in around 3-5% of school-age children and adolescents [7].Additionally, children and adolescents with ADHD have also been reported to experience certain coexisting emotional conditions like anxiety and depression [8].The worldwide occurrence of ADHD has displayed a consistent rise over the last few decades [9].A meta-analysis released in 2015 determined an overall prevalence rate of 7.2% [10].More current statistics indicate that 9.4% of children and adolescents in the United States have received an ADHD diagnosis at some point [11,12].ADHD is categorized into three primary subtypes: hyperactivity-impulsivity ADHD, inattention ADHD, and combined inattentive/hyperactive-impulsive ADHD, often referred to as combined ADHD [13][14][15][16].
The diagnosis of ADHD primarily relies on gathering information from the child's parents, school, and, if consulted, healthcare professionals.This process is complemented by interviews and examinations [16][17][18].Numerous scales and questionnaires are accessible for evaluating ADHD characteristics in an individual or for aiding in the diagnostic process.Being diagnosed with ADHD has been demonstrated to elevate the likelihood of experiencing a traumatic fracture.This correlation is likely attributable to the behavioral traits linked to the disorder, which encompass recklessness, clumsiness, an elevated inclination to disregard rules in games or sports, and a diminished focus on safety precautions [19,20].Most studies suggest that all fracture outcomes are more common in children diagnosed with ADHD when compared to non-ADHD cohorts [12,16,21,22].
There are various treatment options available for children diagnosed with ADHD, including behavioral therapy and pharmacological treatment.Among pharmacological treatments, different classes of medications are available, broadly classified as stimulants and nonstimulants.Among stimulants, the phenidate group with the drug methylphenidate (MPH) is one of the most common medications used for ADHD.These medications are called stimulants because they stimulate specific parts of the brain, especially those that play a role in controlling attention and behavior [23].
The majority of research in the literature has focused on investigating the association between ADHD and fractures.Nevertheless, there remains a scarcity of comprehensive data regarding the intricacies of this connection.For instance, there is a need for a deeper understanding of how ADHD contributes to an elevated risk of fractures and the various factors that play a role in this relationship.Similarly, there is a need to delve into the relationship between MPH, including its mechanism of action and its overall impact on this association.
In this systematic review, our objective is to thoroughly investigate the connection between ADHD and fractures.We aim to examine various facets of ADHD, the contributing factors, and their impact on the occurrence and frequency of fractures in children and young individuals.Additionally, we will analyze the influence of MPH on the trajectory of fractures in cohorts diagnosed with ADHD.This comprehensive study aims to enhance our comprehension of this relationship, ultimately leading to improved strategies for preventing fractures in children.This, in turn, can alleviate the strain on countless families and the healthcare system.

Materials and methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist to search for the relevant literature [24].

Search Sources and Strategy
We searched PubMed, PubMed Central (PMC), Medline, Google Scholar, and MDPI to search for the relevant literature.We used various combinations of ADHD, drug therapy, MPH, and fractures to search all the databases.However, in PubMed, adjacent to these keywords, the following strategy was formed and used to search relevant literature in PubMed's MeSH (Medical Subject Headings) database: ("Attention Deficit Disorder with Hyperactivity/complications''[Mesh] OR "Attention Deficit Disorder with Hyperactivity/drug therapy"[Mesh] OR "Attention Deficit Disorder with Hyperactivity/therapy"[Mesh] ) AND "Methylphenidate/therapeutic use"[Majr] AND ("Fractures, Bone/epidemiology"[Mesh] OR "Fractures, Bone/prevention and control"[Mesh] ).
Table 1 below mentions all the sources, strategies used, and the number of papers identified in each of them.Articles with free full text online were selected.A few of the articles, which passed the screening process but whose full text was not freely available, were requested at the library at King's Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust, Sutton-in-Ashfield, United Kingdom.Hence, access was provided by the library.
Exclusion criteria: Other articles for whom the full text could not be retrieved were excluded.Articles focusing on stress fractures and the relationship between ADHD and traumatic brain injuries, specifically those involving patients with rare comorbid conditions, were not included.Articles that included gross injuries without clearly mentioning whether fractures were included or not were also excluded.Gray literature and proposal papers were also rejected.

Selection Process
All the identified articles from all the databases were transferred to EndNote.Then, initially, duplicates were removed.Each article was screened by going through titles and abstracts and independently assessed by two authors.If there were any conflicts, those were discussed among the other co-authors, and hence the final decision was made by mutual consensus.Articles shortlisted after that were evaluated by going through the full text, and relevant ones were selected.All articles went through the inclusion and exclusion criteria and were shortlisted.

Quality Assessment of the Studies
All the shortlisted articles passed through the quality assessment tools.All co-authors did many quality checks.Observational studies were assessed on the JBI Critical Appraisal Checklist, while the Assessment of Multiple Systematic Review (AMSTAR) tool was used for systematic reviews.Only the studies that had satisfactory quality appraisals were included.

Data Collection Process
After the quality assessment, a final number of articles that were included in the systematic review were obtained.Then, the authors went through these articles multiple times to extract the data to be used for the study.Data was extracted both manually and via a data questionnaire method.

Study Identification and Selection
We initially located 1,890 articles across all the databases.After eliminating 276 duplicate articles, we subjected 1,608 remaining articles to title screening, of which only 71 met the criteria.Further assessment of the abstracts narrowed it down to 37 articles.Subsequently, we retrieved the full-text versions of these articles and conducted a thorough quality assessment.Ultimately, we included nine articles in our review.The detailed study selection process is visually represented in Figure 1 within the PRISMA flowchart.The articles were assessed for eligibility using the relevant quality appraisal tools [25].Table 2, Table 3, and Table 4 show the results of the quality appraisal.The main focus of our analysis involved extracting primary outcomes from the selected research papers.These outcomes included examining fracture-related results in individuals with ADHD compared to those without ADHD in cohort studies.Additionally, we assessed individuals with ADHD who were on medication and compared them to those without ADHD who were not on medication, providing valuable insights.In certain studies, we further delved into the comparison between individuals with ADHD on medication and those with ADHD not on medication, which offered a more nuanced understanding of the relationship.Furthermore, we closely examined the characteristics of the fractures in these studies.

Study Characteristics
We conducted a comprehensive review of nine research papers, involving approximately 357,995 participants assigned to various study groups.Among these finalized studies, four adopted a cohort design, three followed a case-control approach, one combined elements of both cohort and case-control methodologies [22], and one was a descriptive cross-sectional study [16].All of these studies focused on examining the connection between ADHD and fractures, with one of them specifically investigating the dose-response relationship between MPH and fractures.Some of the studies also considered the impact of MPH on the risk of fractures.The detailed characteristics of the included studies can be found in

Discussion
The most important findings of the study are discussed below in three categories as follows.

ADHD: Factors and Fracture Characteristics
Every study included in the review demonstrates a higher occurrence of fractures in the ADHD group when compared to the non-ADHD group [4,6,12,16,[20][21][22]26,27].There is a notably stronger association between ADHD and more serious injuries, such as skull, neck, and trunk fractures, intracranial injuries without a skull fracture, and injuries to the nerves and spinal cord, compared to less severe injuries [20,28].Hence, there is an increased incidence of hospitalizations due to severe injuries in the ADHD group [6].
In the ADHD and non-ADHD cohorts, the upper limb was the most frequent site of fractures (67.0% vs. 60.1%),followed by the lower limb (18.8% vs. 17.5%), the face or skull (4.3% vs. 4.0%), and the trunk (3.7% in both groups).To be more specific, fractures of the radius and ulna were more prevalent than fractures of any other bones in both groups.The most commonly fractured bone in the lower limb was found to be the tibia [6,12].

Mechanisms and Clinical Implications
There are different scales developed both for screening and determining the severity of symptoms associated with ADHD.A few of them, which were used in recent studies, are mentioned here.These scales offer a systematic approach to identifying, diagnosing, and quantifying the severity of ADHD symptoms.They help clinicians make informed treatment decisions and enable researchers to collect standardized data for a deeper understanding of the disorder.4) CPRS-conduct disorder (CPRS-OD).They found significantly higher scores for hyperactivity for patients who were getting admitted to orthopedics with complaints of trauma.Similarly, a diagnosis of ADHD has been demonstrated to elevate the likelihood of experiencing a traumatic fracture, likely due to the behavioral traits linked to the condition.These traits encompass inattention, hyperactivity, impulsive actions, lack of coordination, aggression, challenges in motor coordination, an elevated inclination to disregard rules in recreational activities, and a diminished focus on safety measures or engaging in risky behaviors [19,20,26,[29][30][31][32].
Another study used scales including the Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Parents Form (T-DSM-IV-S), the Screen for Child Anxiety-Related Emotional Disorders (SCARED), and the Children's Depression Inventory (CDI).These forms were filled out by the parents of patients two days after the injury, so as to prevent any impact of an acute emotional response on answers.Their discovery indicated that incidents like slips or trips, pedestrian mishaps, high falls, and bicycle-related fractures occurred more frequently than injuries from playground activities, sports, or altercations.This observation underscores the recurring connection between ADHD-related attributes, such as clumsiness, inattentiveness, disregard for risk, and impulsivity, contributing to accidents [6].
Conversely, injuries occurring in playgrounds, sports, or fights might be attributed to impolite and aggressive conduct, often associated with behavioral disorders, rather than hyperactivity [6].
Additional factors that showed a significant connection with patients who had both ADHD and fractures included being male, having a reported tendency toward injuries according to parents, and having a previous history of trauma [4,6].
Gender disparity is a natural occurrence because neurodevelopmental disorders like ADHD tend to be more prevalent among males [4].Although fractures were more common in males compared to females, the hazard ratio for fractures was found to be higher in females.The rates might be lower in girls than boys; however, they are higher in the ADHD cohort as compared to the non-ADHD matched cohort [12,33].
Some studies in the past have presented findings showing a relationship between injuries in patients with low socioeconomic status (SES) with and without ADHD.Shem-Tov et al. revealed a 94% higher incidence of injuries in children with low SES with ADHD than low SES without ADHD [22].The findings in this study indicated that there may be a relationship between SES and the risk of injury (increases with age and is higher among individuals with low SES).Nonetheless, a 2018 study explored the connection between the SES of children and psychiatric factors, yet it did not establish a noteworthy correlation between the two [6].
As we discussed, a previous history of trauma was significantly associated with ADHD patients; hence, in agreement with the same, it was seen that re-fractures are also common in these groups.Duramaz et al. observed a re-fracture rate of approximately 38.4% within their study cohort.These re-fractures were most frequent in the vicinity of the wrist, particularly involving the distal radius and forearm shaft.The primary contributors to these re-fractures were activities marked by recklessness and danger, along with depressive moods and unmanageable behaviors [6].Other studies also supported the evidence; they found a significantly higher risk of having multiple fractures in children who are diagnosed with ADHD when compared with non-ADHD matched cohorts.The ratios were as follows for two fractures (HR 1.32, 95% CI 1.26-1.38,p < 0.001) or three fractures (HR 1.35, 95% CI 1.24-1.46,p < 0.001) [12].
Karayagmurlu et al. also found higher subscale scores on CPRS-IA and CPRS-HA in patients with recurrent trauma.It might be explained as ADHD is a chronic neurobehavioral condition; hence, it is present in the majority of an individual's life, thus increasing the probability of presenting with recurrent traumas [27,34].

MPH and Fracture Risk
The median age for starting treatment was around 8.24 years, and this was consistent for both boys and girls [12].
Studies have been conducted to gain insights into the risks associated with MPH.In all studies investigating the impact of MPH, it is consistently observed that the overall fracture risk diminishes with the utilization of these medications.However, we might see a slight change in responses when different characteristics of cohorts are compared [12,20,21].
MPH decreases the risk of various types of fractures (overall, central, and upper limb).However, it might not have any significant difference in reducing the risk of lower limb fractures [21].
Studies have been done that involve comparing a cohort of ADHD patients on medication with two other cohorts: those with ADHD but not on medication and patients without ADHD (who are carefully matched for all other relevant variables).It depicts that treatment in the ADHD cohort reduces the risk of experiencing a fracture, although it might remain slightly elevated when compared to the group without ADHD.However, the use of medication significantly reduces the risk of fracture among children with ADHD (p < 0.001) when compared among themselves [12].To understand and compare the responses in these three different cohorts, it will be useful to dive further into them.Various aspects of MPH therapy exhibit distinct impacts on its effectiveness, including factors such as the type of medication (short-acting, intermediate-acting, and long-acting), dosage intensity (low, medium, and high), and duration of treatment.Medium-and longacting are associated with significantly decreased risk.On the other hand, short-acting was not able to reduce the risk significantly.In regards to the proportion of days covered (PDC), there was a decreased trend in all the PDC groups, with significantly reduced risk in the low PDC group (low PDC <0.32, with 270 days being complete coverage of yearly weekdays) [22].
In regards to dose, there are variable results available, especially when we consider higher dosages [20,22].Research conducted in Israel reveals an inverse dose-response relationship, particularly among males, indicating a negative effect of MPH usage on the risk of fractures.Even in females, despite the absence of a dose-response effect, it was evident that using MPH led to a reduced risk of fractures [20].It has been seen that the negative dose-response effect in males was persistent, meaning the highest exposure group depicted the lowest risk [20].
Then there is a claim that MPH has a negative effect on bone mineral density (BMD) [35,36].Hence, there have been many discussions on the use of MPH for reducing fractures.Stimulant medications like MPH increase the levels of catecholamines (dopamine and norepinephrine) at synapse levels by inhibiting their reuptake.Physiologically, during bone remodeling, sympathetic neurons in bones release catecholamines like norepinephrine, which, in turn, inhibits bone formation [37,38] and increases the resorption of bones [39,40].This sympathetic innervation and bone remodeling are mediated by beta-2 adrenergic receptors expressed on the surface of osteoblasts [41,42].
Another mechanism is by altering the levels of leptins.Leptin promotes the activity of osteoblasts [43] and downgrades the differentiation and proliferation of osteoclasts [44].However, stimulants lead to decreased levels of leptins.Hence, long-term use of these medications decreases bone health.
It has been shown through recent studies that males with ADHD who were prescribed these stimulant medications, especially for more than three months, have reduced bone mineral content and BMD for the total body, especially at the lumbar spine and pelvis (femur), when compared with patients who were not prescribed these drugs [35,45,46].
In spite of all the above side effects, several studies have consistently proven that MPH treatment in patients with ADHD is associated with a reduced risk of fracture.This effect of MPH is linked to the behavioral modification effect of the stimulant class of drugs [12,20,22].
Considering the elevated prevalence of ADHD in children, we recommend employing various ADHD symptom checklists.Additionally, it is advisable to inquire with parents about their child's hyperactive or impulsive behaviors, any prior incidents of injury, and their child's tendency toward accidents.Seeking a neurodevelopmental and behavioral evaluation when there are suspicions of ADHD may enable early diagnosis and intervention.This proactive approach can help prevent additional injuries and potential comorbid conditions, ultimately reducing overall treatment costs.
Hence, there is an immediate need to formulate additional strategies or guidelines for preventing fractures in children with ADHD.While the causal relationship has been elucidated, its real value lies in the development and implementation of practical strategies in the daily lives of children with ADHD, encompassing settings such as schools, homes, and playgrounds.

Limitations
Our paper is not exempt from limitations.It lacks randomized clinical trials, which are considered a robust form of evidence.The review relies solely on qualitative evidence, and no quantitative analysis has been conducted.A meta-analysis would offer deeper insights into the association between ADHD, MPH, and fractures, allowing for a more precise assessment of their significance.Furthermore, the impact of other potential variables, such as mental health conditions, has not been investigated.Additionally, this review does not encompass emerging medications that are gaining prominence in the market.

FIGURE 1 :
FIGURE 1: PRISMA flowchart depicting article selection PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Figure 2 ,
Figure 3, and Figure 4 also depict the results of quality appraisal in chart format.

TABLE 3 : JBI Critical Appraisal Tool for case-control studies 2024
Garg et al.Cureus 16(3): e56833.DOI 10.7759/cureus.568336 of 17 JBI Prevalence Studies Alqarni et al. [16] Appropriate sample frame to address the target population Yes Appropriate way of sampling study participants Yes

Table 5 ,
Table 6, and Table 7 of the review.

TABLE 5 : Detailed geographic characteristics of the included studies
* Cases included children with a first injury occurring during the study period and those who had a weight measurement within a six-month period before and after the injury ** Controls were children who did not experience traumatic injuries during the study period, matched by exact year of period, matched by exact year of birth, and sex at a ratio of 1:1 ADHD, attention deficit hyperactivity disorder 2024 Garg et al.Cureus 16(3): e56833.DOI 10.7759/cureus.56833

TABLE 7 : Details of the outcome characteristics of the included studies
KSADS-PL, Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime; MPH, methylphenidate; NOS, not otherwise specified; SCARED, Screen for Child Anxiety Related Disorders; T-DSM-IV-S, Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Parents Form 2024 Garg et al.Cureus 16(3): e56833.DOI 10.7759/cureus.56833 ADHD significantly increases fracture risk, while MPH plays a role in mitigating this risk by addressing ADHD-related mechanisms and affecting bone cells.On the basis of the relationship evident in our review, early ADHD detection can lead to timely interventions, including nonpharmacological methods like parent education and behavioral interventions tailored to developmental stages.Orthopedic surgeons should prioritize ADHD recognition through screening tools and direct inquiries, reducing injury risk through proactive measures and facilitating early identification and treatment of ADHD.Healthcare staff should educate children, adolescents, and caregivers on injury prevention during various stages of diagnosis and follow-up.Targeted screening efforts are required for the groups at high risk of ADHD, such as boys, children with a history of fractures, or those who are deemed accident prone.