Continuing Education Activity

Atypical antipsychotic use in psychiatric patients, particularly children and adolescents (C/A), has increased recently. Autism spectrum, bipolar, psychosis, and other psychiatric or emotional disorders are psychiatric conditions that need Antipsychotics today. There is limited data on the long-term safety of Antipsychotics on growth and development, specifically on bone metabolism. This activity outlines the clinical presentation, evaluation, and management by an interprofessional team of atypical antipsychotics induced bone changes in children and adults.

Objectives:

• Provide the summary of the indications for antipsychotics agents.
• Describe the mechanism of atypical antipsychotics-induced bone changes.
• Review the clinical presentation and differential diagnosis of impaired bone mineral density.
• Emphasize the importance of early recognition and treatment options used by the interprofessional team for the atypical antipsychotics-induced bone changes.

Introduction

According to the National Research Council and Institute of Medicine, about 14% to 20% of  C/A have a psychiatric illness. Up to 80% of these C/A are on multiple psychotropics simultaneously, including atypical antipsychotics. The US - FDA has approved the use of antipsychotics in specific psychiatric disorders include Tourette's and other tics disorders, behavioral and emotional symptoms associated with developmental delay, autistic spectrum disorder, bipolar disorder, and schizophrenia. Also, significant off-label antipsychotic uses (without FDA approval) are of the standard of practice today to manage C/A emotional and behavioral symptoms.[1]

A metanalysis reported a median prevalence of antipsychotics use in autism spectrum C/A of about 17%. Risperidone is the most commonly prescribed antipsychotic (55%), followed by aripiprazole (35%).[2] While the antipsychotics trending pattern in adult psychiatric inpatient show olanzapine prescribed chiefly (51%) followed by risperidone (23%).[3] Antipsychotics cause various endocrine and metabolic side effects, including overweight, hyperlipidemia, uncontrolled diabetes, and hyperprolactinemia.[4] Hyperprolactinemia and movement disorder side effects are common with first-generation antipsychotics due to potent dopamine receptor blocking effects.[5] 

Studies indicate that up to two-thirds of patients treated with atypical antipsychotics experience impaired bone marrow density, leading to osteoporosis.[6] The risk of bone disease and bone fracture positively correlates to this category of medication. Antipsychotics can directly alter bone mineral density or indirectly cause obesity due to limited physical activity or excessive somnolence.[7][8] Evidence shows early onset osteoporosis in patients with mental illness like schizophrenia related to chronic exposure to antipsychotics.[9] Antipsychotics use causes an increased risk of hip fracture up to 1.6 times.[9] The US-FDA cautions in the prescribing package insert of this adverse effect.[2]

Etiology

Antipsychotics cause detrimental effects on bone growth. Antipsychotics negatively affect bone metabolism by blocking dopamine receptors, causing hyperprolactinemia and hypogonadotropic hypogonadism. Hyperprolactinemia directly affects bone growth through prolactin receptors on the osteoblast, regardless of the gonadotrophic hormonal level.[6] 

The high prolactin levels can lower calcium absorption and activate parathyroid hormone-related peptides, which increase bone resorption. Antipsychotics can also delay bone maturation by modulating serotoninergic and adrenergic receptors on the osteoblast and osteoclast cells.[6] 

High cortisol levels are frequently seen in psychiatric patients on antipsychotics, adding another risk factor for impaired bone mineralization.[6] Patients on multiple psychotropic medications like antipsychotics and SSRI are at higher risk for deformed bones.[10] Finally, adolescents with severe chronic mental health conditions are at increased risk for low vitamin D levels due to poor diet, limited physical activities, low sun exposure, and high substance use, which increase vulnerability to exaggerated detrimental effects of antipsychotics on bone mineralization.[11][12]

Epidemiology

Osteoporosis affects about 200 million people globally. Osteoporosis causes one fracture every 3 seconds.[13] Primary osteoporosis is an aging process. However, secondary osteoporosis is widespread among the young. Chronic exposure to neuroleptic/antipsychotics can cause secondary osteoporosis.[13] About 85% of critical bone growth occurs before the age of 18, and a loss of 5 to 10 % of the peak bond density can significantly increase the chance of fractures or bone disease later in life.[10] 

One study found that 44% of the male and 48.9% of the female schizophrenia patients have osteopenia compared to 9.2% male and 21% female without schizophrenia. Elderly patients with schizophrenia have a double risk of osteoporosis than a matched control.[6] Up to 65% of patients on antipsychotics endure osteopenia (bone loss), with a subsequent higher risk of future osteoporosis. Antipsychotics raise prolactin levels and consequent osteoporosis affects males and females equally.[14] Although osteoporosis is miscalled as "women's disease."[14] 

No significant sex difference in terms of antipsychotic-induced bone mineralization defect was observed since hyperprolactinemia has inhibitory effects on gonadotrophins level. However, hyperprolactinemia prevalence is higher in postmenopausal females. Risperidone causes the early-onset and prolonged duration of hyperprolactinemia.[6]

History and Physical

Osteopenia is called a 'silent disease' as it is often asymptomatic until a fracture develops.[14] Nonspecific clinical presentation may be the reason for a delayed diagnosis. Typical clinical presentation of impaired bone mineral density includes diffuse bone pain, tenderness, muscle weakness, and fragility fractures. The fracture patterns in osteomalacia (bone mineral density or BMD over 1 but less than 2.5 SD) are typically different from osteoporosis (standard deviations 2.5 times below the healthy population T-score). Fragility fractures of the pelvic bone, foot, tibial, and ribs bone are signs of osteomalacia. The neck of the femur and wedged vertebral fractures are classic osteoporosis.[15]

Evaluation

Currently available modalities used to assess BMD include metacarpal morphometry, quantitative bone ultrasound (QUS), quantitative computed tomography (QCT), and dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI) bone density. A plain skeletal radiograph detects BMD when the bone loss exceeds 40% and hence insensitive for routine clinical use. QCT measures the bone volume and accurately assesses volumetric BMD, and it can differentiate between cortical and trabecular bone.

Peripheral (PQCT) is an alternative technique with less radiation risk and is more convenient for children. DXA is the primary tool for assessing bone density. It has low radiation exposure, precise results, and lower cost than QCT. However, it does not directly measure actual volume or assessing BMD, and rarely bone biopsy may be needed to confirm the diagnosis.[8]

Treatment / Management

Practice guidelines are lacking for testing for prolactin level or bone assessment during APs exposure. Besides, there is no clear correlation between antipsychotics, prolactin level concentration, and skeletal complications in children or adults.[6] There is no clear correlation between the patient's age, duration of treatment, and sex or race with BMD in the psychiatric population compared to the general population.[7] 

Proactive preventive measures to improve BMD in psychiatric patients chronically treated with antipsychotics, including lifestyle modification, fall prevention program, monitoring prolactin level, vitamin D supplement, avoid smoking, and alcohol exposure.[16] 

Mechanical stimulation of bone through whole-body vibration therapy may provide positive results. [17] Medications like bisphosphonate, raloxifene, denosumab, and glucagon-like peptide-1 (GLP-1) are currently utilized in clinical practice.[16][18][19][20] Moreover, teriparatide, anabolic, and hormonal replacement therapy are other options to improve bone mineral density.[17][21][22]

Differential Diagnosis

Low bone mineral density like osteoporosis or osteomalacia could be a primary condition or appear secondary due to the following factors or conditions:

• Endocrine disorders like hypogonadism, pituitary disorders, diabetes mellitus, thyrotoxicosis.[23]
• Autoimmune and chronic diseases like rheumatic disorders, chronic renal, pulmonary, gastrointestinal diseases, transplantation, granulomatous diseases.
• Bone marrow and malignant disorders, multiple myeloma, lymphomas and leukemias, metastatic bone disease, chronic anemia.[23]
• Medications like glucocorticoid excess, anticonvulsants, antituberculosis agent, long-term heparin, cyclosporin A, or methotrexate.
• Nutritional and deficiency like vitamin K, D, C, and malnutrition.
• Genetic disorders like osteogenesis imperfect, homocystinuria, Ehlers-Danlos syndrome, and Marfan syndrome.
• Other factors like smoking, alcoholism, immobilization, and weight loss.[23]

Pertinent Studies and Ongoing Trials

Yvette Roke et al. (2012), in a retrospective observational study, reported lower lumbar spine bone density in antipsychotic-treated boys (n = 56) with hyperprolactinemia compared to the non-antipsychotics treated control (n = 47), with a mean duration of 52 months antipsychotics exposure.[24] [Level 4] While Bonnot et al. (2011), in a retrospective observational study of 136 institutionalized adolescents, found significant vitamin-D deficiency unrelated to the specific antipsychotics (level IV).[15] 

Calarge et al. (2010) have reported a significant reduction in BMD in adolescents with risperidone and SSRI combination induced hyperprolactinemia compared to controls with risperidone exposure only. A three-year cross-sectional retrospective observational study (n = 108 boys, mean age = 11.7 years) was enrolled with DSM-IV clinical diagnoses.[11] [Level 4]

In a retrospective observational study, Al-Omran et al. (2016) found that over 80% of adult psychiatric patients on chronic antipsychotic have low bone mineral density, and 44% of patients were osteoporotic, and 45% were osteopenic.[13] [Level 4]

Prognosis

The prognosis of the antipsychotics-induced impaired bone mineral density is good if it is detected early and managed properly.[13] However, chronic pain, osteomalacia, osteoporosis, and bone fracture are common sequels if the condition is left untreated.[6] High morbidity and mortality are associated with a bone fracture in psychiatric patients.[25][26] The risk of complications can be minimized with lifestyle changes, exercise, and a well-balanced diet.[16] And or add-on medications.[24]

Complications

Antipsychotics can cause various metabolic and hormonal side effects, including obesity, dyslipidemia, uncontrolled diabetes mellitus, metabolic syndrome, QTc abnormality, and the extrapyramidal sequel, myocarditis, bone marrow suppression, cataracts, hyperprolactinemia with or without hypogonadism, and sexual adverse effects.[8][11] 

Impaired bone mineral density with or without bone fracture is one of the potential APs side effects that the clinician has not thoroughly studied and missed. Antipsychotics medications diffuse to both the bone marrow and the central nervous system. Consequently, antipsychotics related bone disease or fracture could be a consequence of direct and indirect adverse effects on bone turnover.[2] 

Frequent studies refereed to this correlation [see pertinent studies section]. Given the large patient population that is taking these medications.[1] Understanding the level of risk, proper recognition, and possible early preventing or treatment of drug-induced bone changes is essential for clinicians and patient populations.

Deterrence and Patient Education

The patient family should be more oriented to bone mineral density complications.[15][4] Consultation with a psychiatrist or a pharmacist can assist with antipsychotics selection, guide the ideal dosing, and explore safer alternatives. Providers should be aware of the need for early assessment of possible adverse effects from the antipsychotics, employ early screening, and prevent iatrogenic complications.[27][5] A team approach should be applied with the involvement of mental health providers with open communication between the inter-professional team member and the patient's family.[28]

Enhancing Healthcare Team Outcomes

Clinicians should be aware of the potential adverse effects of antipsychotics on bone mineral density, especially in children and elderly patients who are physically and emotionally more prone to the medication's side effects due to their body size, different metabolism rate, and evolving physiology.[24] Antipsychotic-exposed patients should have frequent screening, especially with concomitant hyperprolactinemia.[15] 

Providers need to utilize a more sensitive diagnostic tool like QUS, PQCT, MRI Bone density to screen and assess the BMD in children and adults.[11][8] Volumetric BMD is a more sensitive indicator of mineral density for growing children considering their height and pubertal stage. The physicians should educate the patient's family about the potential long-term side effects of antipsychotics and evaluate calcium and phosphorus intake, sun exposure, vitamin D level, bone turnover markers like alkaline phosphatase, and physical activity.[15][4] 

The antipsychotic dose should be adjusted if clinically safe and suitable. Prolactin levels should be checked at baseline and then regularly annually and should be normalized promptly. A switch to antipsychotics without prolactin-elevating qualities may be a useful alternative and or add-on antiresorptive medications.[24][15][11]