Harvard Mental Health Letter

Heavy heart, thin bones?

The evidence suggests that selective serotonin reuptake inhibitors may erode bone.

People suffering through the pain of depression may feel as though their hearts are heavy. Evidence is growing that those taking selective serotonin reuptake inhibitors (SSRIs) may also be at risk for thin bones.

In the late 1990s, researchers began reporting an association between depression and bone loss. Many of the studies, but not all, concluded that compared with other people, patients with depression had lower bone mineral density (a measure of bone strength) and a greater risk for fractures.

But a 2008 review noted that the research consisted mainly of case reports, small samples, or larger population-based studies that didn't control for confounding factors, such as medication use. Tricyclic antidepressants, for example, may cause dizziness — which increases the risk of falling and could explain an increase in bone fractures.

In the past few years, however, better-designed studies have not only strengthened the case for a biological link between bone and brain, but also suggested something previously unsuspected — that SSRIs may be particularly harmful to bone.

Key points

  • Researchers began investigating the link between depression and bone loss in the late 1990s.

  • Although multiple factors may contribute to bone loss, growing evidence implicates SSRI use.

  • Clinicians prescribing SSRIs (and patients taking these drugs) may want to address bone health during office visits.

The brain-bone connection

Although typically depicted as something solid, bone is actually a dynamic, living tissue undergoing constant remodeling (see illustration). During a stage called resorption, cells known as osteoclasts break bone down into calcium and other constituent components that are returned to the bloodstream for use elsewhere in the body. During bone formation, other cells known as osteoblasts assemble calcium and other biological materials to rebuild the harvested area.

Nutrient intake, exercise, and cigarette smoking all affect this remodeling process, and likely contribute to findings of low bone mineral density in patients with depression. For example, a severely depressed patient who stays indoors for extended periods may not get enough sunlight exposure to produce vitamin D, which helps the body convert calcium into bone. Patients with depression are also less likely to exercise, and more likely to smoke, compared with healthy people.

But researchers have identified several possible biological mechanisms linking brain and bone. For example, studies have reported that depression elevates levels of both the stress hormone cortisol and various immune system cells that promote inflammation — changes that can harm bone.

How bone is lost

illustration of bone damage due to resorption

Bone is constantly being demolished and rebuilt. During resorption, osteoclasts gnaw at bone, releasing calcium and other minerals into the bloodstream and leaving troughs behind.

illustration of weakened bone growth

If bone-building cells known as osteoblasts cannot keep pace, these tunnels are not completely refilled, and bone becomes weaker and may fracture.

More recently, scientists have discovered that bone cells have receptors for various neurotransmitters and are responsive to changes in the brain. A traumatic brain injury, for example, activates cannabinoid type 1 receptors in osteoblasts, which respond by building new bone at a rapid rate. (In the brain, activation of these receptors by smoking marijuana causes euphoria.)

Other researchers have found that osteoblasts also have receptors for neurotransmitters that are involved in regulation of appetite, such as neuropeptide Y and leptin. An emerging theory is that the hypothalamus, which helps control hunger, thirst, and behaviors related to circadian rhythm, may regulate the bone remodeling system in response to signals about food intake and energy stores that it receives from the gastrointestinal system.

The serotonin pathway

Most recently, researchers have focused on the impact of serotonin (5-hydroxytryptamine, or 5-HT) on bone health. Depressed mood results in part from abnormal levels of this neurotransmitter. SSRIs enhance serotonin activity by inhibiting a brain target known as the 5-HT transporter, 5-HTT. Although other antidepressants act in part by affecting 5-HTT, SSRIs most powerfully inhibit this target. When investigators discovered that bone also has receptors for 5-HTT, they wondered if SSRIs might influence bone health.

It's an intriguing theory, but so far the basic research has produced mixed results. One team found that inhibiting 5-HTT in mice slowed bone formation while accelerating bone resorption. But another animal study found just the opposite: that 5-HTT inhibition increased bone mass. Other preliminary research suggests that serotonin affects bone remodeling through targets other than 5-HTT.

Despite these conflicting laboratory findings, results from four of five epidemiological studies included in the 2008 review cited earlier support the theory that SSRI use weakens bone and increases the chance of fracture — even after adjusting for depression or other confounding factors.

For example, the Canadian Multicentre Osteoporosis Study Research Group, which followed 5,008 men and women 50 and older for five years, found that the 137 participants who were taking SSRIs every day had bone mineral density measurements that were 4% lower in the hip, compared with participants not taking SSRIs. Participants who took SSRIs daily were also twice as likely as nonusers to suffer a bone fracture.

Three other large studies found lower bone mineral density among SSRI users. And a smaller study of 89 premenopausal women with a history of depression found that participants had 2% lower bone mineral density than healthy controls. This deficit of bone mineral density was similar to that reported by studies of the impact of known risk factors for osteoporosis, such as smoking or low calcium intake.

The large, prospective Women's Health Initiative Observational Study of postmenopausal women ages 50 to 79, however, found no relationship between use of antidepressants (SSRIs or others) and reductions in bone mineral density over a three-year period in a subset of more than 4,000 women. The study did find that antidepressant treatment was associated with an increased risk of a bone fracture.

Federal recommendations for calcium and vitamin D

The U.S. Institute of Medicine (IOM) established the following daily recommendations in 1997, but is currently reviewing them and expects to issue new advice in 2010.



Vitamin D*

1 to 3

500 mg/day

200 IU

4 to 8

800 mg/day

9 to 18

1,300 mg/day

19 to 50

1,000 mg/day

51 to 70

1,200 mg/day

400 IU

71 and older

1,200 mg/day

600 IU

*Most Americans are deficient in vitamin D; based on studies published since the IOM issued these guidelines, some experts recommend getting at least 1,000 IU of this vitamin per day.

Source: IOM, "Dietary Reference Intakes," accessed at www.iom.edu.

How to protect bones

Many questions remain about the link between brain and bone. Notably, none of the research has involved children or adolescents. And current treatment guidelines for osteoporosis do not list SSRI treatment as a risk factor, although the National Osteoporosis Foundation now warns that these drugs may cause bone loss.

But because a growing body of evidence suggests that SSRIs cause bone loss, it may make sense for clinicians and patients to discuss bone health along with mental health. Patients with depression can follow the same bone-building advice provided to other people at risk of osteoporosis.

Calcium. This mineral is the principal component of bone. When diet doesn't supply the necessary amount, osteoclasts raid the bone "bank" to release calcium into the bloodstream. Federal recommendations for calcium intake vary by age (see table).

Vitamin D. This vitamin enables calcium to travel out of the intestines and into the bloodstream, where it can be used for a variety of purposes — including the building of bone. As with calcium, federal recommendations vary by age.

Beverages. Both caffeine and alcohol, consumed to excess, may harm bone. To be on the safe side, consume moderate amounts of both — such as less than four cups of coffee a day, and no more than one daily alcoholic drink for women or two for men.

Exercise. Weight-bearing exercise, such as walking, weight lifting, or climbing stairs, helps to keep bones strong and may help build bone. Aim for 30 minutes a day.

Supplements. The best way to obtain calcium and vitamin D is through food, but vitamin or mineral supplements provide a backup. Just don't overdo it with super supplements that far exceed the daily recommended amounts.

Medications. Bisphosphonates help slow bone resorption. Options include alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva). Bisphosphonates may be difficult to digest, so patients need to follow the instructions carefully. However, these medications can be taken with antidepressants and other medications.

Haney EM, et al. "Skeletal Effects of Serotonin (5-Hydroxytryptamine) Transporter Inhibition: Evidence from Clinical Studies," Journal of Musculoskeletal and Neuronal Interactions (April–June 2008): Vol. 8, No. 2, pp. 133–45.

Rosen CJ. "Serotonin Rising — The Bone, Brain, Bowel Connection," New England Journal of Medicine (March 5, 2009): Vol. 360, No. 10, pp. 957–59.

For more references, please see www.health.harvard.edu/mentalextra.