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

JAMA Psychiatry. 2022 May 1;79(5):454-463. doi: 10.1001/jamapsychiatry.2022.0337.


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 participants: This 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 from 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 measures: The 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, 50.4 [41.2-61.0] years; 12 967 [56.6%] women) and 114 560 reference individuals (median [IQR] age, 50.4 [41.2-61.0] years; 64 835 [56.6%] women) were followed up for 1 213 695 person-years (median [IQR], 7.68 [3.72-13.24] 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 relevance: In this study, bipolar disorder was associated with an increase in risk of osteoporosis, and lithium treatment was associated with a decrease in risk of osteoporosis. These findings suggest that bone health should be a priority in the clinical management of bipolar disorder and that the potential bone-protective properties of lithium should be subjected to further study, both in the context of bipolar disorder and in osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antimanic Agents / adverse effects
  • Antipsychotic Agents* / adverse effects
  • Bipolar Disorder* / drug therapy
  • Bipolar Disorder* / epidemiology
  • Bipolar Disorder* / psychology
  • Female
  • Humans
  • Lamotrigine / adverse effects
  • Lithium / adverse effects
  • Lithium Compounds / adverse effects
  • Male
  • Middle Aged
  • Osteoporosis* / chemically induced
  • Osteoporosis* / drug therapy
  • Osteoporosis* / epidemiology
  • Retrospective Studies
  • Valproic Acid / therapeutic use


  • Antimanic Agents
  • Antipsychotic Agents
  • Lithium Compounds
  • Valproic Acid
  • Lithium
  • Lamotrigine