03. Can Lithium Protect Against Osteoporosis?

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Lithium’s Positive Effect on Bone Mineral Density in Bipolar Disorder Patients

Regular listeners to Quick Takes may remember an episode on the association between antidepressants and increased risk of vertebral and hip fractures. The increased risk is concerning, but the magnitude of the absolute risk is unclear.

The quandary is due to a possible confound by indication. A substantial portion of the increased risk could be due to the indication – major depression – as well as the antidepressant medication.

But in this episode of Quick Takes, we have a whole different situation to consider:

• A different medication – lithium
• An improved study design that only includes subjects with bipolar disorder to assess changes in bone mineral density

Study Design: Comparing Bone Mineral Density in Bipolar Patients With and Without Lithium

The authors recruited 117 women aged 20 years or older with a diagnosis of bipolar disorder 1, 2 or not otherwise specified. Areal bone mineral density was measured at the posterior-anterior spine, total hip and total body. 35 of those 117 women were currently taking lithium with a median duration of use of 64 months.

One improvement in this study is that all subjects had a diagnosis of bipolar disorder. The only difference in the groups was the current use of lithium.

Lithium Users Show Greater Bone Mineral Density After Adjusting for Confounding Factors

Using an unadjusted model, the women taking lithium had a significantly greater bone mineral density in the spine and a trend towards greater density in the hip and total body.

After adjusting for age and weight, bone mineral density was significantly greater in both the hip and the spine. Other factors like smoking status, physical activity, alcohol and calcium intake, socioeconomic status, past lithium use and other psychotropic medication use were not significant or did not improve the model.

Adding bone active medications improved the model. This included both medications that improved bone health (antiresorptives, hormone therapy, calcium and vitamin D supplements) and those with a negative effect (oral glucocorticoids and thyroid hormones).

Controlling for the prescription of bone active medications along with weight and age, lithium users had a statistically significant:

• 5.1% increase in bone mineral density at the spine
• 4.2% increase at the total hip
• 2.2% greater total body mineral density (not statistically significant)

Lithium Users Less Likely to Have Low Bone Mass

Low bone mass was defined as a bone mineral density T-score of less than -1.0 at the spine or hip. Lithium users were significantly less likely to have low bone mass:

• 43.9% of non-users had low bone mass
• Only 22.9% of lithium users had low bone mass

The groups did not differ significantly in any characteristic including age, weight, height, alcohol or calcium intake, smoking status or activity measures. The only exceptions were bone mineral density and socioeconomic status, with lithium users overrepresented in the middle two quartiles but underrepresented in the lowest and highest quartile.

Evidence Supports Lithium’s Positive Effect on Bone Health Compared to Other Bipolar Treatments and Healthy Controls

This study supports a positive effect of lithium on bone mineral density compared to other treatment options for patients with bipolar disorder.

But what about the net effect compared to healthy controls? The authors cite another study showing that bipolar patients on lithium have a lower incidence of osteoporosis than those without bipolar disorder.

Potential Mechanisms for Lithium’s Positive Effect on Bone Density

The authors discussed potential mechanisms for lithium’s positive effect on bone mineral density:

• Increased activation of osteoblasts through activation of Wnt/beta-catenin via inhibition of GSK3

In contrast, an in vitro study suggested SSRIs may negatively affect bone density. Serotonin at low concentrations inhibited osteoblast proliferation, differentiation and mineralization.

All medications in the meta-analysis on antidepressants and bone health had serotonergic activity, including SSRIs, TCAs and SNRIs, with the notable exception of bupropion. A rat study showed bupropion’s osteoprotective action through:

• Suppressing osteoclastogenesis inducing factors and inflammation
• Stabilizing osteoclasts
• Decreasing bone matrix degradation and resorption

Future Research Directions

The quandary on the effect of antidepressants on bone health could potentially be resolved by following the methodology of this lithium study. Researchers could compare bone mineral density of patients with major depression taking only SSRIs to patients with major depression taking only bupropion.

Conclusion: Weighing Lithium’s Benefits Against Risks for Each Patient

This study provides evidence for lithium’s positive effect on bone mineral density in patients with bipolar disorder. This effect could be added to lithium’s relatively unique positive effect on incidence of suicide.

Both effects can be considered as the benefits of lithium. They should be balanced against the risks to renal and thyroid function for each individual patient.

Abstract

Lithium use and bone health in women with bipolar disorder: A cross-sectional study

Lana J. Williams, M.D., Bruno Agustini, M.D., Amanda L. Stuart, M.D., Julie A. Pasco, M.D., Jason M. Hodge, M.D., Rasika M. Samarasinghe, M.D., Ottar Bjerkeset, M.D., Shae E. Quirk, M.D., Heli Koivumaa-Honkanen, M.D., Risto Honkanen, M.D., Jeremi Heikkinen, M.D. & Michael Berk. M.D.

Introduction

Several psychiatric disorders and medications used to treat them appear to be independently associated with skeletal deficits. As there is increasing evidence that lithium possesses skeletal protective properties, we aimed to investigate the association between lithium use and bone health in a group of women with bipolar disorder.

Method

Women with bipolar disorder (n = 117, 20+ years) were recruited from south-eastern Australia. Bipolar disorder was confirmed using a clinical interview (SCID-I/NP). Bone mineral density (BMD; g/cm²) was measured at the spine, hip and total body using dual-energy x-ray absorptiometry and low bone mass determined by BMD T-score of <−1.0. Weight and height were measured, socioeconomic status (SES) determined and information on medication use and lifestyle factors self-reported. Linear and logistic regression were used to test associations between lithium and (i) BMD and (ii) low bone mass, respectively.

Results

Thirty-five (29.9%) women reported current lithium use. Lithium users and non-users differed in regard to SES and BMD; otherwise, groups were similar. After adjustments, mean BMD among lithium users was 5.1% greater at the spine (1.275 [95% CI 1.229–1.321] vs. 1.214 [1.183–1.244] g/cm², p = 0.03), 4.2% greater at the total hip (0.979 [0.942–1.016] vs. 0.938 [0.910–0.966] g/cm², p = 0.03) and 2.2% greater at the total body (1.176 [1.148–1.205] vs. 1.150 [1.129–1.171] g/cm², p = 0.08) compared to participants not receiving lithium. Lithium users were also less likely to have low bone mass (22.9% vs. 43.9%, p = 0.031). Associations persisted after adjustment for confounders.

Conclusion

These data suggest lithium is associated with greater BMD and reduced risk of low bone mass in women with bipolar disorder. Research into the underlying mechanisms is warranted.

Reference

Williams, L. M.D., Agustini, B. M.D., Stuart, A. M.D., Pasco, J. M.D., Hodge, J. M.D., Samarasinghe, R. M.D., Bjerkeset, O. M.D., Quirk, E. M.D., Koivumaa-Honkanen, H. M.D.,Honkanen, R. M.D.,Heikkinen, J. M.D. & Berk. M. M.D. (2024). Lithium use and bone health in women with bipolar disorder: A cross-sectional study. Acta Psychiatrica Scandinavica. Volume149, Issue4. Pages 332-339