Association of Lithium Treatment With the Risk of Osteoporosis in Patients With Bipolar Disorder

Abstract

IMPORTANCE Osteoporosis, a systemic skeletal disorder associated with substantial morbidity and mortality, may be particularly common among individuals with bipolar disorder. Lithium, a first-line mood-stabilizing treatment for bipolar disorder, may have bone-protecting properties.OBJECTIVE To evaluate if treatment with lithium is associated with a decrease in risk of osteoporosis among patients with bipolar disorder. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included 22 912 adults from the Danish Psychiatric Central Research Register who received an initial diagnosis of bipolar disorder in the period from January 1, 1996, to January 1, 2019. For each patient with bipolar disorder, 5 age-and sex-matched individuals were randomly selected from the general population as reference individuals. Individuals with bipolar disorder prior to January 1, 1996, those with a diagnosis of schizophrenia or schizoaffective disorder prior to being diagnosed with bipolar disorder, and those with osteoporosis prior to the index date were excluded. Of the 114 560 reference individuals included, 300 were diagnosed with bipolar disorder during follow-up and were censored from the reference group fromn the date of diagnosis forward. For patients with bipolar disorder, treatment periods with lithium, antipsychotics, valproate, and lamotrigine were identified. Analyses were performed between January 2021 and January 2022.EXPOSURES Bipolar disorder and treatment with lithium, antipsychotics, valproate, and lamotrigine. MAIN OUTCOMES AND MEASURESThe primary outcome was osteoporosis, identified via hospital diagnoses and prescribed medications. First, incidence of osteoporosis was compared between patients with bipolar disorder and reference individuals (earliest start of follow-up at age 40 years) using Cox regression. Subsequently, incidence of osteoporosis for patients receiving treatment with lithium, antipsychotics, valproate, and lamotrigine, respectively, was compared with that of patients who were not treated with these medications.RESULTS A total of 22 912 patients with bipolar disorder (median [IQR] age, years; 12 967 [56.6%] women) and 114 560 reference individuals (median [IQR] age,] years; 64 835 [56.6%] women) were followed up for 1 213 695 person-years (median [IQR],.24] years). The incidence of osteoporosis per 1000 person-years was 8.70 (95% CI, 8.28-9.14) among patients and 7.90 (95% CI, 7.73-8.07) among reference individuals, resulting in a hazard rate ratio (HRR) of 1.14 (95% CI, 1.08-1.20). Among patients with bipolar disorder, 8750 (38.2%) received lithium, 16 864 (73.6%) received an antipsychotic, 3853 (16.8%) received valproate, and 7588 (33.1%) received lamotrigine (not mutually exclusive). Patients with bipolar disorder treated with lithium had a decrease in risk of osteoporosis (HRR, 0.62; 95% CI, 0.53-0.72) compared with patients not receiving lithium. Treatment with antipsychotics, valproate, and lamotrigine was not associated with reduced risk of osteoporosis. CONCLUSIONS AND RELEVANCEIn ...

Physiological Mineralization during In Vitro Osteogenesis in a Biomimetic Spheroid Culture Model

“…Recently, a large cohort study demonstrated that lithium can significantly reduce the risk of osteoporosis [ 90 ], which confirms earlier results from animal studies, demonstrating a positive effect on (osteoporotic) bone regeneration in humans [ 91 , 92 ]. Ultimately, we thus used lithium chloride as a well-established inhibitor of cWnt signaling, which has been reported to stimulate or inhibit osteoblast differentiation and mineralization in vitro [ 86 ], to study its potentially different pharmacological effects on MC3T3-E1 in 2D and 3D.…”

Bipolar Disorder and Bone Mineral Density Z-Scores in Relation to Clinical Characteristics and Lithium Medication

“…Lithium has been associated with increased BMD, osteoporosis, and lower fracture risk [ 7 , 23 , 24 ]. Interestingly, patients with a high Z-score used lithium more frequently and more often had used lithium > 1 year.…”

“…Lithium has been associated with higher BMD and a decreased risk of fractures [ 23 , 24 , 25 , 26 ], and animal studies have also shown that lithium enhances bone formation in mice [ 27 ]. A recent large Danish register study also supported that lithium medication in bipolar disorder was associated with decreased risk of osteoporosis [ 7 ]. A positive effect of lithium on BMD might have masked osteoporosis in some earlier studies of osteoporosis in BD.…”

“…BD has also been linked to a range of both psychological and medical comorbidities, including attention deficit hyperactivity disorder, substance-related disorders, anxiety disorder, obsessive-compulsive disorder, migraine, diabetes, and cardiovascular disease [ 2 , 3 ]. BD has also been associated with an increased risk of bone fractures [ 4 , 5 , 6 ] and osteoporosis [ 7 ].…”

“…Unipolar depression and schizophrenia have both been associated with osteoporosis and reduced BMD [ 9 , 10 ]. The association between BD and osteoporosis have been less clear [ 11 ], but recent studies conclude that patients with BD compared to the general population have a higher risk of fractures and osteoporosis [ 4 , 5 , 6 , 7 , 12 ]. However, the risk of low BMD seems to be lower in bipolar depression than in unipolar depression and schizophrenia [ 13 ].…”