Can lithium reduce risk of osteoporosis in bipolar patients?

Bipolar disorder is associated with an increased risk of osteoporosis. This risk is reduced by lithium therapy, but not by any other antipsychotics, a retrospective cohort study conducted by the Psychosis Research Unit, Aarhus University Hospital, Denmark, has shown.

The nationwide study recruited 22,912 patients with bipolar disorder (median age, 50.4 years; female, 56.6 percent) from the Danish Psychiatric Central Research Register from January 1996 to January 2019. For each patient, five age- and sex-matched reference individuals (n=114,560; median age, 50.4 years; female, 56.6 percent) were randomly selected from the Danish Civil Registration System. The primary outcome, osteoporosis, was detected by hospital diagnosis and prescribed medications. [JAMA Psychiatry 2022;79:454-463]

Results showed that patients with bipolar disorder had a significant risk of osteoporosis vs reference individuals (incidence rate, 8.70 vs 7.90 per 1,000 patient-years; hazard rate ratio [HRR], 1.14; 95 percent confidence interval [CI], 1.08 to 1.20) over a median follow-up of 7.68 years. This finding aligns with recent evidence suggesting that bipolar disorder may be a risk factor for osteoporosis. [J Affect Disord 2019;249:262-269; Front Psychiatry 2020;11:530] “Furthermore, the association was substantially more pronounced among men than among women [HRR, 1.42 vs 1.07],” wrote the researchers.

Among patients with bipolar disorder, 8,750 (38.2 percent) received lithium, 16,864 (73.6 percent) received an antipsychotic, 3,853 (16.8 percent) received valproate, and 7,588 (33.1 percent) received lamotrigine (not mutually exclusive).

“A wide range of medications may affect the risk of osteoporosis. Lithium, a cornerstone in the pharmacological treatment of bipolar disorder, is of interest in this regard,” noted the researchers. Treatment with lithium was associated with a reduced risk of osteoporosis vs no treatment with lithium (HRR, 0.62; 95 percent CI, 0.53 to 0.72) in a fully adjusted model, whereas antipsychotics (HRR, 1.01; 95 percent CI, 0.88 to 1.16), valproate (HRR, 1.17; 95 percent CI, 0.97 to 1.40), and lamotrigine (HRR, 0.99; 95 percent CI, 0.85 to 1.16) were not associated with such benefit.

“This resonates well with prior studies that suggested a potential bone-protective effect of lithium, likely mediated by its activation of β-catenin via inhibition of glycogen synthase kinase-3β,” explained the researchers.

However, the duration of treatment and dosage seemed to play a major role in this bone-protecting benefit. Only a lithium treatment duration of over 2 years was related to a decreased risk of osteoporosis, and higher cumulative doses were associated with a greater decrease in osteoporosis risk (log-rank test p<0.001).

“The finding of an elevated risk of osteoporosis in bipolar disorder adds to a growing body of evidence suggesting that bone health should be a priority in the clinical management of bipolar disorder,” concluded the researchers. “The potential bone-protective effect of lithium should be subjected to further study, both in the [setting] of bipolar disorder and in osteoporosis.”