The Effects of Chronic Psychostimulant Administration on Bone Health: A Review
Abstract
:1. Introduction
2. Literature Criteria for Inclusion
3. Mechanism of Action
3.1. AMP
3.2. MP
4. Behavioral Effects of Psychostimulants in Rodent Models
5. Reported Effects of Psychostimulants on Bone Properties
5.1. Dopaminergic Regulation of Osteogenic Cells
5.2. Pathways
5.3. Gene Expression
5.4. Bone Structure
5.5. Reported Effects in Humans
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Criteria | Decision |
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Articles published in English | Inclusion |
Published as a scientific peer-reviewed journal article | Inclusion |
Keywords defined previously found in titles and/or abstracts | Inclusion |
Primary research, meta-analysis and review papers | Inclusion |
Papers published before 1985 | Exclusion |
Case studies and editorials | Exclusion |
Reference | Subject | Study Design | Findings |
---|---|---|---|
Fernandez et al. [61] | Human and rat bone mesenchymal stem cells (BMSCs) | BMSC were subject to varying concentrations of DA during proliferation and differentiation and were then analyzed for ALP, q-PCR, Western blot, and chromatin immunoprecipitation | Osteogenesis of osteoblasts are reliant on D1R; hBMSC, subjected to an increased concentration of DA, resulted in an inhibitory effect of osteogenesis, similar to blocking the cAMP-PKA pathway |
Wang et al. [62] | RAW 264.7 osteoclast cell line; C57BL/6J mice and bone marrow cells | RT-qPCR, Western blot, CREB luciferase reporter assay and cAMP immunoassay detection were carried out on cells after differentiation following exposure to DA and the D1R/D2R agonist/antagonist | DA suppressed osteoclast differentiation in vitro via D2R while the activation of the cAMP/PKA/CREB pathway reversed osteoclast inhibition |
Lee et al. [64] | MC3T3-E1 pre-osteoblasts | Pre-osteoblasts were subjected to RT-PCR and Western blot analysis following DA exposure | Osteoblasts are under the control of the D1R receptor through in vitro investigation. DA is a positive modulator of OB gene expression; however, increased concentrations of DA causes toxicity |
Hanami et al. [65] | Human CD14+/osteoclast | CD14+ cells were subject to osteoclast differentiation and testing, such as immunofluorescence staining, TRAP staining, pit formation assay, cAMP and osteoclast gene expression | D2R signaling inhibits osteoclast differentiation, cAMP formation, and c-fos expression |
Schwendich et al. [69] | Peripheral blood mononuclear cells (PBMC), human osteoblast, and bone matrix | Cells were cultured with the D1R or D2R agonist and treated with DA followed by testing including TRAP staining, bone resorption assay | Bone matrix treatment with D2R agonist increased mineralization; PBMC cells treated with D1R agonist inhibited osteoclastogeneis, whereas the D2R agonist increased. DA receptor stimulation had no effect on OC activity |
Moytl et al. [70] | MC3T3-E1 pre-osteoblast; bone marrow stromal cells | MC3T3-E1 cells were cultured and treated with DA and/or risperidone (RIS) followed by qRT-PCR and staining; bone marrow stromal cells were treated with RANKL and M-CFS and subjected to DA and or RIS | DA suppressed Mc3T3-E1 mineralization and gene expression; DA suppressed OC differentiation |
Sun et al. [71] | PDLSC | Cells were treated with DA and subjected to alizarin red-staining, qRT-PCR, and Western blot | Osteogenic protein expression is most effective at optimally determined concentrations; the ERK1/2 pathway was promoted by DA |
Reference | Genes | Study Design | Summary Findings |
---|---|---|---|
Wang et al. [61] | DRD1 DRD2 OCN BSP RUNx2 ALP OSX | Human BMSD incubated with DA and subjected to RT-PCR, Western blot, CHiP analysis, and the D1R agonist SKF-38393 | 50 μM of DA promoted cell proliferation and the expression of BSP, ALP, Runx2, and OCN whereas 500 μM of DA significantly inhibited cell proliferation and associated genes; osteogenic markers were upregulated by SKF-38393; cAMP-PKA signaling suppression inhibited osteogenic differentiation; and SKF-38393 increased the activation of ERK1/2 and expression of Runx2, BSP, ALP, OCN, but not OSX |
Wang, et al. [62] | CRB C-FOS STAT3 NFATC1 TRAP CTSK | RAW cells treated with DA were observed for OC differentiation, and genes followed via treatment with the D2R agonist or quinpirole | DA treatment inhibited the differentiation and expression of osteoclastic genes in a dose-dependent manner; similar effects were observed for quinpirole with reduced CREB phosphorylation; the blocking of D2R abolished the inhibitory effect; the decreased expression of cAMP, PKA and p-CREB due to dopamine was reversed with the activation of cAMP |
Comim, et al. [63] | ERK1/2 | Male Wistar rats were treated with MP for 28 days or 1 day and subjected to striatum dissection | Chronic treatment of MP increased the phosphorylation of ERK1, whereas acute exposure had no effect on the phosphorylation of ERK1/2 |
Konradi, et al. [79] | CaRE ATF | Male Sprague-Dawley rats were treated with AMP and subjected to further testing | fos protein expression increased after AMP exposure, but CREB did not; CREB expression only increased when bound to regulatory elements of c-fos; CREB expression is dependent on D1R/D5R |
Brandon, et al. [72] | C-FOS ZIF268 DYNORPHIN | Male Sprague-Dawley rats were treated with MP and subjected to in situ hybridization histochemistry | MP exposure produced a dose-dependent increase in expression of c-fos and zif268, and chronic, repeated exposure resulted in D1R damage due to enhanced dynorphin expression |
Hanami, et al. [65] | cAMP C-FOS NFATc1 CTSK | Human CD14+ were differentiated into OC precursor cells and treated with DA, and the D2R-like agonists, pramipexole and quinpirole | DA, pramipexole, and quinpirole produced the same effects of decreased osteoclast differentiation and expression of the osteoclast-related proteins CTSK, NAFTc1, cAMP, and C-FOS. |
Reference | Subject | Study Design | Findings |
---|---|---|---|
Komatsu, et al. [57] | Rat | SD rats were treated dose-dependently with MP and assessed for bone size, BMD, BMC, biomechanics, and serum biomarkers | The diameter of femoral bone decreased in a dose-dependent manner, along with BMD, BMC, biomechanical properties, and serum alkaline phosphatase levels that were abolished under the recovery protocol. |
Comim, et al. [63] | Rat | Young male Wistar rats were subjected to MP and then decapitated | Chronic treatment of MP significantly increased ERK1/2 phosphorylation |
Zhu, et al. [66] | Mice and osteoblast | BMSC and MC3T3-E1 cells were subjected to the D1R agonist and/or Dex then tested via staining and Western blot; C57BL/6J mice were divided into a control, vehicle, Dex + D1R agonist, Dex + D1R agonist + D1R inhibitor or Dex + D1R inhibitor group, and then tested through micro-CT and analyses | The overexpression of D1R reserves the inhibition of osteoblasts induced by Dex in which ERK ½ pathways have a protective effect, and D1R promotes bone formation that was previously lost due to Dex |
Brandon, et al. [72] | Mice | SD rats were injected with a vehicle or MP and tissue was prepared for histochemistry and autoradiogram | The acute and chronic use of MP resulted in the attenuation of osteoclast genes, c-fos, and zif268 |
Konradi, et al. [79] | Rat | SD rats were subjected to AMP, and brain samples were collected to be tested via immunohistochemistry and electrophoretic mobility-shift assays | AMP induced CREB phosphorylation in the striatum that was blocked via D1R/D5R antagonist |
Uddin, et al. [81] | Rat | SD rats were divided into control, low-dose MP, high-dose MP, and pair-fed groups to be tested through an open-field test, caliper measurements, biomechanics, micro-CT, histomorphometry, ex vivo and in vitro TRAP staining, and pit assay | Reduction in weight gain and increases in locomotive activity were noted with MP use, along with negative effects on biomechanics and a male sensitivity of MP on osteoclast differentiation and activity compared to female rats |
Chirokikh, et al. [82] | Rat | SD rats were subjected to MP and/or fluoxetine (FLX) and screened for bone morphology and biomechanical properties | MP + FLX rats had shorter and narrower femora and tibia along with a reduction in biomechanical properties and BMC and BMD |
Gökçe Nur Say, et al. [52] | Rat | Male Wister–Albino rats were divided into control, low-dose MP, and high-dose MP groups for 13 weeks and then evaluated for weight and biomechanical properties | Dose-dependent effects were noted in weight gain reduction, femur length/size, BMC, and BMD |
Reference | Subject | Study Design | Findings |
---|---|---|---|
Feuer, et al. [58] | Human | Cross-sectional analysis of data collected from children ages 8–20 with DXA; demographic and prescription medication data available (n = 6498) | Patients with reported stimulant use had reduced BMC and BMD of the lumbar spine and femur |
Swanson, et al. [59] | Human | Using the Preschool ADHD Treatment Study (PATS), height and weight were recorded 29 times (n = 140) over about 1.3 years | Children who continued the use of medication had a decrease in growth rate compared to children not using medication |
National Institute [60] | Human | Patients were evaluated longitudinally using a 14- to 24-month assessment of symptoms and growth | The continued use of medication will result in continued maintenance of symptoms and growth suppression |
Ortiz, et al. [84] | Human | The optical density technique was used to assess traumatic fractures of the distal radius within a pediatric population at the time of fracture and when the fracture healed (n = 188) | Patients using psychostimulant medication for 3–5 years had a negative effect on healing, whereas more than five years of use had no effect on healing |
Calarge, et al. [85] | Human | Observational and longitudinal studies of male adolescents taking risperidone (n = 194) | There was no significant difference found between boys chronically using MP and those who never used it; however, those using MP had reduced height |
Lawson, et al. [86] | Human | Retrospective study of adults using medications for ADHD with DXA scans (n = 7961) | BMD was found to be decreased in the skull and thoracic spine of adults using ADHD medication |
Diez-Suarez, et al. [88] | Human | An observational longitudinal study of pediatric patients (ages 6–18) diagnosed with ADHD and with MP (n = 342) | Decreased weight was noted over 2.2 years of use, whereas height was noted to decrease if MP was started before age 12 |
Ben-Ami, et al. [87] | Human | Retrospective study of combat soldiers diagnosed with at least one stress fracture diagnosed by a bone scan and with reported exposure to MP (n = 100,000) | The majority of soldiers diagnosed with a stress fracture reported the use of MP |
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Nowak, J.; Aronin, J.; Beg, F.; O’Malley, N.; Ferrick, M.; Quattrin, T.; Pavlesen, S.; Hadjiargyrou, M.; Komatsu, D.E.; Thanos, P.K. The Effects of Chronic Psychostimulant Administration on Bone Health: A Review. Biomedicines 2024, 12, 1914. https://doi.org/10.3390/biomedicines12081914
Nowak J, Aronin J, Beg F, O’Malley N, Ferrick M, Quattrin T, Pavlesen S, Hadjiargyrou M, Komatsu DE, Thanos PK. The Effects of Chronic Psychostimulant Administration on Bone Health: A Review. Biomedicines. 2024; 12(8):1914. https://doi.org/10.3390/biomedicines12081914
Chicago/Turabian StyleNowak, Jessica, Jacob Aronin, Faraaz Beg, Natasha O’Malley, Michael Ferrick, Teresa Quattrin, Sonja Pavlesen, Michael Hadjiargyrou, David E. Komatsu, and Panayotis K. Thanos. 2024. "The Effects of Chronic Psychostimulant Administration on Bone Health: A Review" Biomedicines 12, no. 8: 1914. https://doi.org/10.3390/biomedicines12081914