This article originally appeared in the June 2007 Harvard Women’s Health Watch and is provided courtesy of Harvard Health Publications.

Exploring the depression-bone connection

A new study finds that antidepressant use doubles fracture risk. Other research points to links between depression and bone loss.

Most of us can tick off the major risk factors for osteoporosis: age, gender, race, family history, smoking, inactivity, low body weight, and inadequate calcium and vitamin D. Depression isn’t on the list, but some evidence suggests that it should be. In particular, a study in the Jan. 22, 2007, Archives of Internal Medicine found that people ages 50 and over who regularly took the widely prescribed antidepressants known as selective serotonin reuptake inhibitors (SSRIs) had double the rate of fractures as people not using such medications. Other research points to depression itself as a source of endocrine changes that can damage bone.

Whether the danger comes from depression, the drugs used to treat it, or something else, this is a problem that researchers and clinicians are paying more attention to. The implications for women, particularly older women, are enormous: As many as one woman in 10 suffers from depression, and more than 30 million women ages 50 and over have osteoporosis or are at risk for it. Identifying depression as a risk factor could improve the diagnosis and treatment of this potentially devastating condition.

Making the connection
The idea that osteoporosis and depression might be linked goes back at least to the 1980s, when observational studies concluded that depression was an emotional response to living with the pain and disability of osteoporosis. But during the 1990s, depression began to emerge as a possible cause of bone loss, rather than a result. Scientists studied women who didn’t have osteoporosis symptoms or even know they had the condition. Using new technologies, they found lower bone mineral density (BMD) — a risk factor for osteoporosis and fractures — in those who were depressed. Moreover, the link was found in both younger women (where such bone loss is uncommon) and women past menopause.

A controlled study in the Oct. 17, 1996, New England Journal of Medicine involving mostly premenopausal women found that those with a history of major depression had bone densities that were 10% to 15% lower at the hip and 6.5% lower at the spine than those without depression, regardless of physical activity levels. The depressed women also had higher levels of cortisol, a stress hormone known to cause bone loss.

Since then, many studies have found a similar relationship, so investigators have been looking at hormones and brain chemicals that could be involved in both depression and bone loss. For example, Israeli researchers working with an animal model of depression found that depression activates the sympathetic nervous system and triggers the release of noradrenaline, which interferes with bone-building cells. (The sympathetic nervous system connects the brain to the internal organs and skeleton.) Moreover, they found that imipramine, one of an older class of drugs called tricyclic antidepressants, reversed both depression and depression-induced bone loss. These findings were published in the November 2006 Proceedings of the National Academy of Sciences.

A National Institute of Mental Health (NIMH) study of bone loss in premenopausal women with and without major depression showed that those who were depressed had unfavorable levels of cytokines that specifically affect bone mass. (Cytokines are chemical messengers that interact with the immune, nervous, and endocrine systems.) Studies have also found brain-bone connections involving other substances, including the hormone leptin. Dr. Giovanni Cizza, who directed the NIMH study and has been investigating depression and bone loss for several years, says these discoveries herald a new discipline, which he calls “the neuropsychoendocrinology of bone regulation."

Depression may be a risk factor for osteoporosis in other ways: “If you’re very depressed, you may not be taking care of yourself — not eating right, for example — and you’re more likely to have bone loss,” says Dr. Jessica Gören, a clinical psychiatric pharmacist at Harvard Medical School–affiliated Cambridge Health Alliance. She believes that depressed patients need more aggressive counseling about osteoporosis, “because regardless of whether depression is an independent factor, lifestyle is.”

What about antidepressants?
The findings on depression and bone loss raise another question: Are all depressed people at risk for osteoporosis and fractures, or only those taking antidepressants? If so, which antidepressants? And if certain antidepressants are the problem, or part of the problem, is it because they can increase the risk of falling, particularly in older people — or because they have biological effects that weaken bone? The available studies show inconsistent results and don’t always take into account all potentially relevant factors.

For example, the 2007 Archives of Internal Medicine study mentioned above, while generally well designed, has some significant flaws. As part of a long-term study of osteoporosis in community-dwelling adults, the authors followed 5,008 randomly selected women and men age 50 and over to see who experienced fragility fractures (ones that occur with minimal or no trauma) over a five-year period. They found that people taking SSRIs — including citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) — had twice the risk of such fractures, increased odds of falling, and somewhat lower BMD at the hip, compared with individuals not taking antidepressants. But only 137 of the 5,000-plus subjects took SSRIs regularly, and the SSRI users were more likely to also be taking corticosteroids and anticonvulsants — drugs that have also been associated with lower BMD. Moreover, the women taking SSRIs had a higher rate of lifetime estrogen use, and it’s not known if or when they discontinued estrogen before entering the study. That’s a concern because bone loss accelerates in the year after stopping estrogen.

Despite these shortcomings, the findings bear further investigation, especially since SSRIs are so widely prescribed: “Certainly if there were an association with fracture, it would change the risk-benefit ratio,” says endocrinologist Dr. Karen K. Miller.

What now?
It may be a long time before the depression-osteoporosis connection is fully explored and elucidated. In the meantime, here are some things to keep in mind if you’ve been diagnosed with depression and are concerned about your bone health:

 If you’re taking an antidepressant, don’t stop out of concern over a possible link to osteoporosis. Depression is a serious illness that can have profound emotional and physical consequences, including suicide and heart disease, if it is left untreated. You and your clinician need to consider your individual risk before making any changes in treatment. 

Talk to your clinician about getting a bone density test, suggests Dr. Miller. If the results are normal, that can be reassuring. If your bone density is low, you and your clinician should discuss ways to reduce your risk for bone loss.  

 Certainly if you’re suffering from major depression (see “Indications of major depression”), antidepressants are a vital part of treatment. They can help you feel better and allow you to participate more fully in psychotherapy and other activities. But feeling sad because of a personal loss or painful life event — the death of someone close to you, a divorce, job loss, or other major upset — may not always call for antidepressant therapy. Talking to a counselor or therapist might be enough to help you through these difficult times. Regular exercise — 30 minutes a day, most days of the week — also improves mood, and the weight-bearing kind (such as walking, weight lifting, and aerobics) can help protect your bones as well. 

  Make sure you get adequate calcium (1,000–1,200 mg/day) and vitamin D (800–1,000 IU/day). Vitamin D is essential to bone health, and many women, particularly in northern climes, don’t get enough of it. If you’re at risk for osteoporosis, and lifestyle changes aren’t enough, you may be a candidate for drug treatment. All drugs have side effects, so you and your clinician will need to weigh the options in light of your personal risk profile.