Genes may compound effects of depression on bone loss

May 14, 2015

In the last few years, psychiatric research has increasingly focused on a functional polymorphism of the serotonin transporter promoter gene (5-HTTLPR). The polymorphism produces two main alleles, short (s) and long (l). Patients with one or two s alleles (s/s or s/l) have a decreased response to therapy with selective serotonin reuptake inhibitor (SSRI) antidepressants, and some evidence suggests they are at higher risk of depression, especially in the presence of past childhood abuse or stressful events. Some studies also suggest that s/s and s/l genotypes may be associated with an increased risk of bone loss.


Many studies report an association between depression and reduced bone mineral density (BMD). A population-based retrospective cohort study in the January 2015 issue of Mayo Clinic Proceedings found that adults with depression were 1.3 times more likely to develop osteoporosis than those who weren't depressed. The risk was higher for people with severe depression and for middle-aged men and women.

Maria I. Lapid, M.D., a geriatric psychiatrist and palliative care specialist at Mayo Clinic's campus in Minnesota, says several potential factors may lead to reduced BMD in depressed patients, including ongoing inflammation, inactivity, low vitamin D levels, hypercortisolism and poor nutrition.

"People who are depressed are also more likely to smoke and drink, which can also affect bone mineral density," she explains, adding that the link between depression and bone loss is serious because "depression is common in older adults, who are already more prone to fractures and who experience more morbidity and mortality from falls."

Dr. Lapid says current thinking is that antidepressants, too, may directly or indirectly affect bone formation and resorption, independent of depression. She points to a 2014 study published in The World Journal of Biological Psychiatry that reported reduced bone formation in older adults taking venlafaxine who had high-expressing 5-HTTLPR and low-expressing serotonin receptor (HTR1B) genotypes.

To further explore the relationship between serotonin transporter genotype (l/l, s/l, s/s) and bone loss, Dr. Lapid, Simon Kung, M.D., and colleagues conducted a retrospective analysis of 289 patients with diagnosed depression or anxiety. The patients, mainly women, had undergone bone mineral studies and genotype testing. They were then stratified according to age, sex and genotype. BMD T-scores were used for patients 50 and older and Z-scores for those younger than 50.

The researchers found that the s allele was associated with lower bone density at the hip and spine in younger adults, especially women, and that bone loss increased with an additive s allele. Surprisingly, Dr. Kung says, there was no statistically significant association between genotype and BMD in patients over 50.

He notes limitations of the study, including selection bias; patients already had depression or anxiety and possibly bone mineral problems since all had already undergone DXA testing. Nonetheless, the research draws attention to the potential effects depression, serotonin transporter genotype and antidepressant use may have on bone health.

"We normally focus on mental health and don't pay much attention to bone health, but our findings have helped us become more aware of potential bone issues when we see a younger female patient with depression who has the s genotype and needs antidepressant therapy," Dr. Kung says. "We may want to make sure she is taking vitamin D and calcium and assess for other risk factors for osteoporosis."

For more information

Lee CW-S, et al. Increased risk of osteoporosis in patients with depression: A population-based retrospective cohort study. Mayo Clinic Proceedings. 2015;90:63.

Garfield LD, et al. Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults. The World Journal of Biological Psychiatry. 2014;15:404.