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Atypical Antipsychotic Effect on Bone Mineral Density
Introduction
According to the National Research Council and the Institute of Medicine, about 14% to 20% of children and adolescents have a psychiatric illness. Up to 80% of these children and adolescents are on multiple psychotropics simultaneously, including atypical antipsychotics. The US-FDA has approved the use of antipsychotics in specific psychiatric disorders, including Tourette and other tic 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 the standard of practice today to manage children and adolescents' emotional and behavioral symptoms.[1]
A meta-analysis reported a median prevalence of antipsychotic use in autism spectrum children and adolescents of about 17%. Risperidone is the most commonly prescribed antipsychotic (55%), followed by aripiprazole (35%).[2] While the antipsychotics trending pattern in adult psychiatric inpatients shows olanzapine is 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 with 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] The use of antipsychotics causes an increased risk of hip fracture up to 1.6 times.[9] The US-FDA warns about this adverse effect in the prescribing information.[2]
Etiology
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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 via prolactin receptors on osteoblasts, independent of gonadotrophic hormonal levels.[6]
High prolactin levels can reduce calcium absorption and activate parathyroid hormone-related peptides, which increase bone resorption. Antipsychotics can also delay bone maturation by modulating serotonergic and adrenergic receptors on osteoblasts and osteoclasts.[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 SSRIs 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 1 fracture every 3 seconds.[13] Primary osteoporosis is an aging process. However, secondary osteoporosis is widespread among the young. Chronic exposure to neuroleptics/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 bone 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% of men and 21% women without schizophrenia. Elderly patients with schizophrenia have a double risk of osteoporosis compared to 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 gonadotropin levels. 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] A nonspecific clinical presentation may delay 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, tibia, and rib bones are signs of osteomalacia. The neck of the femur and wedged vertebral fractures are classic osteoporosis.[15]
Evaluation
Currently available modalities for assessing BMD include metacarpal morphometry, quantitative bone ultrasound (QUS), quantitative computed tomography (QCT), dual-energy X-ray absorptiometry (DXA), and magnetic resonance imaging (MRI). A plain skeletal radiograph detects BMD when the bone loss exceeds 40% and is, 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 a lower cost than QCT. However, it does not directly measure actual volume or assess BMD, and a 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 antipsychotics 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, 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, a fall prevention program, monitoring prolactin level, vitamin D supplement, avoiding smoking, and alcohol exposure.[16]
Mechanical stimulation of bone through whole-body vibration therapy may provide positive results.[17] Medications such as bisphosphonates, raloxifene, denosumab, and glucagon-like peptide-1 (GLP-1) are currently used 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](A1)
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, and thyrotoxicosis.[23]
- Autoimmune and chronic diseases, including rheumatic disorders, chronic renal, pulmonary, and gastrointestinal diseases, transplantation, and granulomatous diseases.
- Bone marrow and malignant disorders, multiple myeloma, lymphomas and leukemias, metastatic bone disease, chronic anemia.[23]
- Medications like glucocorticoid excess, anticonvulsants, antituberculosis agents, long-term heparin, cyclosporin A, or methotrexate.
- Nutritional deficiencies, such as vitamin K, D, and C, and malnutrition.
- Genetic disorders like osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome, and Marfan syndrome.
- Other factors include smoking, alcoholism, immobilization, and weight loss.[23]
Pertinent Studies and Ongoing Trials
Yvette Roke et al (2012) reported lower lumbar spine bone density in antipsychotic-treated boys (n = 56) with hyperprolactinemia compared to non-antipsychotic-treated controls (n = 47), with a mean antipsychotic exposure duration of 52 months.[24] While Bonnot et al (2011), in a retrospective observational study of 136 institutionalized adolescents, found significant vitamin-D deficiency unrelated to the specific antipsychotics.[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 3-year cross-sectional retrospective observational study (n = 108 boys, mean age = 11.7 years) was conducted with DSM-IV clinical diagnoses.[11]
In a retrospective observational study, Al-Omran et al (2016) found that over 80% of adult psychiatric patients on chronic antipsychotics have low bone mineral density, and 44% of patients were osteoporotic, and 45% were osteopenic.[13]
Prognosis
The prognosis of the antipsychotic-induced impaired bone mineral density is good if it is detected early and managed properly.[13] However, chronic pain, osteomalacia, osteoporosis, and bone fractures 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 sequelae, 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 antipsychotic side effects that the clinician has not thoroughly studied and has missed. Antipsychotic 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]
Many studies have reported this correlation (see pertinent studies section). Given the large patient population that is taking these medications.[1] Understanding the level of risk, properly recognizing drug-induced bone changes, and considering early prevention or treatment are essential for clinicians and patient populations.
Deterrence and Patient Education
The patient's family should be more oriented to bone mineral density complications.[4][15] Consultation with a psychiatrist or a pharmacist can assist with antipsychotic 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.[5][27] A team approach should be applied with the involvement of mental health providers, with open communication between the inter-professional team members 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, and MRI bone density to screen and assess the BMD in children and adults.[8][11] 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 levels, bone turnover markers such as alkaline phosphatase, and physical activity.[4][15]
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.[11][15][24][15]
References
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