Lithium Treatment for Bipolar Disorder May Protect Bones from Osteoporosis

Bipolar disorder, also called manic-depressive illness, is characterized by severe, unusual, cycling changes in mood, energy, activity and the ability to carry out day-to-day tasks.[1] For decades, oral lithium (LITHOBID) has been the cornerstone of bipolar disorder treatment, especially to lessen the frequency and intensity of manic episodes of that illness — the drug’s only Food and Drug Administration-approved use.[2]

Osteoporosis is a disease characterized by decreases in bone density and mass that increases the risk of fractures.[3] Prevention of osteoporosis is an important goal of good health care, especially for persons with episodes of depression (including those that occur in bipolar disorder), which plausibly may adversely affect lifestyle factors (such as diet and exercise) that are critical for maintaining bone health.[4]

A recent Danish population-based study provided evidence that lithium treatment in persons with bipolar disorder may decrease the risk of osteoporosis.[5]

Lithium’s possible effects on bone health

It presently is unclear whether and how lithium influences bone integrity in humans, but two animal studies from the mid-2000s are suggestive of a biochemical mechanism, and these two studies are important motivators towards more studies in humans, which to date have been limited.[6]

The first, published in a November 2005 issue of Proceedings of the National Academy of Sciences, tested oral lithium in normal mice and two strains of mice genetically engineered to experience reduced bone mass or inadequate bone building.[7] Feeding lithium to these mice improved bone mass across all three mice strains. Related lab assays also showed that lithium acted to build bone and increase bone mass through a biochemical mechanism involving substances known as WNT ligands.

A separate study published in a July 2007 issue of PLOS Medicine reported on a lithium trial in mice subjected to intentional, surgically made hind-leg fractures.[8] It found that bone healing was enhanced if the mice were fed lithium after the fracture was made, and it also confirmed the involvement of WNT ligands in this bone-healing process. However, oral lithium instead interfered with bone healing if it was given before the fracture was made.

The recent Danish study[9]

The aforementioned population study was published in the May 2022 issue of the Journal of the American Medical Association (JAMA) Psychiatry. The study evaluated whether lithium treatment for bipolar disorder was associated with decreased osteoporosis risk. It looked back at records from the medical registries maintained by the Danish government that included 22,912 adults (mean age 50 years) who received the diagnosis of bipolar disorder between the years of 1996 and 2019, as well as approximately 114,000 control patients without bipolar disorder or other major psychiatric disorders. Pharmacy records for the bipolar disorder patients were used to identify those patients treated with lithium and other medications for bipolar disorder.

Among the patients with bipolar disorder, 8,750 (38%) initiated lithium treatment, and 1,585 (9 per 1,000 patient-years) were diagnosed with osteoporosis at some point during the follow-up years. Compared with the control patients with no major psychiatric disorders, bipolar disorder patients had a 14% greater risk of developing osteoporosis.

Notably, bipolar disorder patients on lithium had a 38% lower risk of developing osteoporosis than those not treated with lithium, after adjustments for the following factors related to bone health: the duration of lithium treatment, age, sex, corticosteroid use, sedative use, other illnesses and eating disorders. Moreover, further analyses revealed that longer duration of lithium treatment was associated with even greater declines in osteoporosis risk.

Similar osteoporosis risk reductions were not seen in bipolar disorder patients treated with any of the following alternative medications: antipsychotics (for example: olanzapine [ZYPREXA, ZYPREXA ZYDIS], risperidone [RISPERDAL]), valproate (generic only) or lamotrigine (LAMICTAL).

Although these results suggest lithium may be protective against osteoporosis, the study authors noted limitations to their study. For example, bone mineral density measurements for the patients were not available to the researchers. In addition, the Danish registry analyses did not assess any of the following factors that are known to impact bone health: diet, exercise, alcohol consumption and smoking.

Importantly, there was no evidence in this study that lithium treatment would more broadly be appropriate for bone protection in individuals without bipolar disorder. In fact, lithium treatment in anyone without bipolar disorder would be off-label and dangerous because the drug’s use at recommended doses also increases the risk of the following adverse effects: tremors, lack of coordination, weakness, clonus (uncontrollable muscle contractions and extensions), confusion, seizures, coma and death.[10] Using lithium in combination with other drugs for cardiovascular disease, psychosis or depression exacerbates many of these concerns and others.[11]

Finally, prior to the relatively large study from JAMA Psychiatry highlighted in this article, several small observational studies yielded conflicting results regarding the potential bone-protective effects of lithium.[12]

What You Can Do

If you are currently taking lithium or any other prescription medication for bipolar disorder, do not discontinue or alter your medication regimen without first talking to your doctor. If you are concerned about your risk of developing osteoporosis, consult with your doctor about ways to decrease your risk of this bone disorder (good nutrition, exercise, and avoidance of drinking and smoking will likely be important components of that conversation).[13] If you are diagnosed with bipolar disorder, work with a psychiatrist to select the best treatment for you, including the possible use of lithium. In selecting a treatment for bipolar disorder, consider with your doctor how to simultaneously optimize your bone health. Finally, note that lithium use does carry significant risks, so its use should be limited to treatment of confirmed bipolar disorder.

For example, lithium causes severe toxicity at higher-than-prescribed doses, so it requires regular monitoring for its levels in the blood. Lithium also can cause heart problems in newborns of mothers who took the drug during pregnancy, as well as kidney damage. It also can affect the body’s ability to adjust to heat, causing heat stress (inability of the body to adjust to increased heat).
 

References

[1] National Institute of Mental Health. Bipolar disorder. September 2022. https://www.nimh.nih.gov/health/topics/bipolar-disorder. Accessed January 11, 2023.

[2] ANI Pharmaceuiticals, Inc. Label: lithium (LITHOBID). October 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/018027s069lbl.pdf. Accessed January 11, 2023.

[3] National Institutes of Health, Osteoporosis and Related Bone Diseases National Resource Center. Osteoporosis overview. October 2019. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed January 11, 2023.

[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;79(5):454-463.

[5] Ibid.

[6] Ibid.

[7] Clément-Lacroix P, Ai M, Morvan F, et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc Natl Acad Sci. 2005;102(48):17406-17411.

[8] Chen Y, Whetstone HC, Lin AC, et al. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med. 2007;4(7):e249.

[9] 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;79(5):454-463.

[10] ANI Pharmaceuticals, Inc. Label: lithium (LITHOBID). October 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/018027s069lbl.pdf. Accessed January 11, 2023.

[11] Worst Pills, Best Pills. Drug profile: lithium (LITHOBID). July 21, 2022. https://www.worstpills.org/monographs/view/75. Accessed January 11, 2023.

[12] 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;79(5):454-463.

[13] National Institutes of Health, Osteoporosis and Related Bone Diseases National Resource Center. Osteoporosis overview. October 2019. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed January 11, 2023.