Lithium for bone health? Researchers performed a retrospective cohort study to evaluate the effects of lithium on risk of osteoporosis in bipolar disorder.
“Ms Coat” is a 46-year-old Caucasian female with a 10-year history of bipolar disorder with psychotic features, who was clinically stable on a regimen that included clozapine 450 mg daily and lithium 300 mg TID. In 2020, she had a fall and fractured 2 metatarsals in her right foot. Ms Coat was evaluated by neurology for recurrent falls and jerking movements. She was diagnosed with negative myoclonus (asterixis), and both clozapine and lithium were noted as potential offending agents. She was adamant against reducing clozapine, but agreeable to tapering down on lithium to 300 mg BID. Subsequent improvement in falls and asterixis were noted, but she declined further reduction in lithium. Then in late 2021, she had another fall and fractured her right ankle, which required surgical repair. Thereafter, lithium was discontinued, but her absolute neutrophil counts (ANCs) dropped to 900-1400 for over a month. This required up to 3 times weekly blood draws for clozapine monitoring, and she reported a decrease in her mood. After a detailed discussion of risks and benefits, lithium was restarted at 300 mg daily. Her mood improved, ANCs returned to the normal range, and she has not had any subsequent falls.
Bipolar disorder may be a risk factor for osteoporosis.1 Depression is a risk factor for poor bone health and osteoporosis, potentially mediated by diet and physical activity.2 A recent meta-analysis found that patients with bipolar disorder have an increased risk of fractures,1 but findings on the effects of lithium on this association are mixed. There is evidence in animal studies that lithium stimulates bone formation and therefore offers theoretical protection against osteoporosis.3 However, this association has not been investigated in longitudinal human studies.
The Current Study
Köhler-Forsberg et al4 performed a nationwide longitudinal register-based study to investigate (1) osteoporosis risk in patients with bipolar disorder compared to the general population, and (2) effects of lithium on osteoporosis risk in patients with bipolar disorder. They used the Danish Psychiatric Central Research Register to identify all individuals in Demark first diagnosed with bipolar disorder between 1996 and 2019. Individuals with a diagnosis of bipolar disorder or primary psychotic disorder prior to 1996 were excluded. Then, using the Danish National Patient Register and Prescription Registry, patients with prior diagnosis of or treatment for osteoporosis were excluded. All prescriptions for lithium valproate, lamotrigine, or any antipsychotic after the index date were identified.
For each individual with bipolar disorder, 5 random age- and sex-matched individuals from the entire Danish population were selected from the Danish Civil Registration System. Osteoporosis was defined as a new diagnosis of or treatment for osteoporosis (with or without fracture). Incidence rates of osteoporosis per 1000 person-years of follow-up were calculated and compared between individuals with bipolar disorder and controls using Cox proportional hazard regression. For individuals with bipolar disorder, incidence rates of osteoporosis were calculated between individuals that did and did not redeem a prescription for lithium using Cox proportional hazard regression. In order to control for other factors that may contribute to osteoporosis risk, the investigators controlled for systemic corticosteroid and sedative prescriptions, the Charlson Comorbidity Index, and a diagnosis of an eating disorder. They also investigated whether lithium affects osteoporosis risk in a dose-dependent fashion by calculating the cumulative lithium dose during the study period.
The investigators identified 22,912 individuals with incident bipolar disorder. The mean subject age was 50.4, and 57% were female. Median follow-up duration was 7.7 years. There was a significant increased risk of osteoporosis in patients with bipolar disorder (Hazard rate ratio [HRR]=1.14 95% Confidence Interval [CI] 1.08-1.20), with a stronger association in males versus females (HRR=1.42 vs 1.07). More than 1 in 3 (38.2%) individuals with bipolar disorder received lithium. Treatment with lithium—but not valproate, lamotrigine, or antipsychotics—was associated with a significant decreased risk of osteoporosis in patients with bipolar disorder (HRR=0.62 95% CI 0.53-0.72). In the cumulative dose-response analyses, only lithium treatment more than 2 years was associated with decreased osteoporosis risk, and higher cumulative lithium doses were associated with greater decreases in osteoporosis risk.
The authors concluded that bipolar disorder was associated with an increased risk of osteoporosis compared to the general population, but in patients with bipolar disorder, treatment with lithium was associated with a decreased risk of osteoporosis. Study strengths included a large nationwide sample with register-based data. Study limitations included the absence of quantitative measures of bone health, the absence of data on lifestyle factors (ie, diet, exercise, alcohol, and tobacco), and the potential for a healthy user bias associated with lithium treatment.
The Bottom Line
Bone health is important in the clinical management of patients with bipolar disorder. Bone protective effects of lithium warrant further investigation in the context of both bipolar disorder and osteoporosis.
Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times™. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Chandrasekaran V, Brennan-Olsen SL, Stuart AL, et al. Bipolar disorder and bone health: a systematic review. J Affect Disord. 2019;249:262-269.
2. Cizza G, Primma S, Coyle M, et al. Depression and osteoporosis: a research synthesis with meta-analysis. Horm Metab Res. 2010;42(7):467-482.
3. Wong SK, Chin KY, Ima-Nirwana S. The skeletal-protecting action and mechanisms of action for mood-stabilizing drug lithium chloride: current evidence and future potential research areas. Front Pharmacol. 2020;11:430.
4. Köhler-Forsberg O, Rohde C, Nierenberg AA, Østergaard SD. Association of lithium treatment with the risk of osteoporosis in patients with bipolar disorder. JAMA Psychiatry. 2022. Online ahead of print.