This topic found its way into an unlikely place—a Luann comic strip (April 1, 2009). Luann, the teenage main character, asks her high school friend, Gunther, why he is blaming himself for his mother's fracture. He replies, “Well, I read that depression may weaken bones….” He blames his mother's depression on the hardships in raising him as a single mother.
Depression and Osteoporosis: A Cause or an Effect?
Depression itself has been shown to be associated with hip fracture in older women, a finding not entirely explained by falls. Is depression a cause of osteoporosis? Or does depression only develop after osteoporosis and fractures? Certainly, depression is a common complication after one suffers a life-altering hip fracture. However, the answers are complex and seem to lead to more questions. Another relevant question is, does the treatment of depression cause fractures?
Multiple studies have reported that women and men diagnosed with major depression or even depressed mood had lower bone mass. However, not all studies have agreed on this finding. The association between depression and bone density and fractures has been inconsistent. Many reasons may explain the conflicting results, including differences in the study populations, differences in the tools used to assess depressive symptoms and to make the diagnosis of depression, and the effects of different medicines.
Study results indicate that the association between depression and bone density was similar in the spine, hip, and forearm. The effect was stronger in women than in men and it was stronger in postmenopausal women, who are at highest risk of bone loss and fracture, than in premenopausal women.
Low bone density among those with depression is not site dependent. This suggests a general process effect rather than one related to falls or inactivity. Researchers have suggested several plausible mechanisms for the link between depression and bone health. For example, depression is associated with higher levels of the “stress” hormone called cortisol.
Elevated levels of cortisol rev up bone metabolism so that bone breaks down faster. Over a long period of time, this would add up to more bone loss than expected. Indeed, studies measuring bone turnover show higher levels of bone breakdown in depressed patients. What is not known is whether the increased cortisol levels in depressed patients are high enough to cause this. Proteins that cause inflammation, called cytokines, have also been implicated. The evidence for these theories is inconclusive.
Behaviors associated with depression and depressed mood may indirectly influence bone health. For example, smoking, alcohol use, and decreased physical activity could contribute to bone loss and lower bone density. Higher risk of falls and weight loss may also be factors.
Is it the disease itself or does this observed risk apply only to those who take antidepressant medicines? The older antidepressants in the tricyclic class (named for their chemical structure) may increase fracture due to falls. Side effects of the tricyclic antidepressants, such as difficulty with balance, increased heart rate, and decreased blood pressure, particularly on standing, increase the risk of falls.
These side effects are usually not associated with the class of medicines called selective serotonin reuptake inhibitors, referred to as SSRIs. Recent major research studies have connected the use of SSRIs with a direct effect on the bone, which causes an increased risk of bone loss and fractures. While studies evaluating the association between depression and bone density are mixed, studies on SSRIs are more consistent.
SSRIs
SSRIs are the most commonly prescribed antidepressants. Although they are classified for treatment of depression, they are prescribed for many other problems. Because they are used so extensively, you might think “SSRIs are good for everything.” A frequent reason for postmenopausal women to receive prescriptions for SSRIs is to relieve hot flashes and night sweats.
Selective Serotonin Reuptake Inhibitors: SSRIs
Depression is linked to an imbalance of the brain's chemicals that allow brain nerve cells to communicate. These chemicals are called neurotransmitters. They send messages back and forth between nerve cells. After the neurotransmitter sends its message, it is absorbed back into the brain nerve cell. This process is called “reuptake.” One of the neurotransmitters is a chemical known as serotonin. The serotonin transporter regulates its uptake.
Selective serotonin reuptake inhibitors (SSRIs) work by blocking the reuptake process in brain nerve cells. SSRIs inhibit the serotonin transporter so that the serotonin is not taken up in the nerve cells. By increasing the amount of serotonin in between the nerve cells, the proper chemical balance is restored, and this may resolve the depression.
| Brand Name | Generic Name |
| Celexa® | citalopram |
| Lexapro® | escitalopram |
| Luvox® | fluvoxamine |
| Paxil® Pexeva® |
paroxetine |
| Prozac® Rapiflux® Sarafem® Selfemra® |
fluoxetine |
| Zoloft® | sertraline |
Starting in the late 1980s with Prozac, SSRI agents for the treatment of depression entered the marketplace. Over the years, their use has expanded to many other ailments. SSRIs remain a popular choice for treatment of depression. Antidepressants that include SSRIs and other products, called SNRIs, including Savella®, Cymbalta®, and Effexor®, rank second among the top therapeutic classes of medicines by number of prescriptions written in 2010. This equated to US sales of $11.6 billion, just behind the $11.9 billion spent for proton pump inhibitors. Of the SSRIs, Lexapro has the largest share of the market.
Most, but not all, studies in large populations of individuals taking SSRIs have shown harmful bone effects. However, the large number of men and women examined had an association that was consistent among studies. Those on SSRIs had lower bone density at all sites, and over time had an increased rate of bone loss. SSRIs were associated with increased risk of hip, spine, nonspine, and forearm fractures. Daily SSRI use in adults aged fifty years and older was associated with an increase in fracture risk of 50 to 100 percent. In addition, higher doses and longer duration of use increased the negative effect on bone density and risk of fracture.
Researchers from the Osteoporotic Fractures in Men Study (MrOS) found that the use of SSRIs in older men over the age of sixty-five was associated with lower bone density. No bone density differences were observed for other types of antidepressants. The MrOS researchers reported that the observed difference in bone density for SSRIs was similar to that of steroid use, such as prednisone. After examining fractures in other populations, investigators have also concluded that the magnitude of fracture risk is similar to steroid use.
However, the link between long-term use of SSRIs and greater likelihood of osteoporosis-related fractures is based on observational studies. Observational studies describe the association, but unlike clinical trials, they do not prove cause and effect.
Like SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) work in part by blocking reuptake of serotonin. Antidepressants in this class share some common characteristics with SSRIs. However, these newer medicines, like Cymbalta, Savella, and Effexor, have not been systematically studied in terms of bone effects.
The Serotonin Connection: Brain, Bone, and Gut
SSRIs may increase the risk of bone loss and fracture through a mechanism that has recently been discovered—the serotonin connection of the brain, bone, and gut. This new research in bone biology may potentially explain the bone effects observed in patients using SSRIs. As it turns out, all the bone cells—osteoclasts, osteoblasts, and osteocytes—have serotonin receptors. Bone cells take up serotonin like nerve cells through a serotonin transporter. SSRIs inhibit the serotonin transporter in the bone cells in a process similar to one in the nerve cells of the brain. An amazing discovery, but what does it mean?
The serotonin produced in the brain does not cross into the circulation of the body due to a barrier membrane, called the blood-brain barrier. So where does the serotonin come from that is used by the bone cells? The source of this serotonin was a total mystery until 2008, when a team of researchers led by Dr. Gerard Karsenty, professor and chair of genetics and development at Columbia University Medical Center, cracked the code. They found that serotonin produced in the gut circulates to the bone cells to activate the serotonin receptors.
Serotonin made by the gut can directly control bone formation. The researchers found that as more serotonin reached the bone, more bone was lost. On the other hand, lower levels of serotonin resulted in denser, stronger bones. They were able to prevent bone loss in mice by slowing the production of serotonin in the gut.
However, the negative bone effects produced by circulating serotonin do not fully explain the bone effects of SSRIs. Instead, the serotonin transporters in bone cells may have a role in determining bone mass and structure. It is still too early to understand all of the ramifications of this exciting discovery in bone biology, since not all of the mechanisms operating in the bone-brain-gut connection have been defined.
Observations thus far suggest that this connection may be very important. It could even lead to development of new medicines for treating osteoporosis. In addition, perhaps a “new SSRI” will be developed that targets the brain's serotonin transporters without affecting the serotonin transporters in the rest of the body.
Balancing Benefits of SSRIs and Risk of Fracture
I am certainly not going to tell you to stop taking your SSRIs. They are effective medicines for depression and other problems. Discuss your bone health in light of this information with your doctor. I believe that the evidence and possible biologic reasons for the action of SSRIs on bone are strong enough to consider these medicines a significant risk factor for osteoporosis and fractures. Your risk of fracture should be assessed in conjunction with the “whole picture” of all other risk factors.
Pay special attention to the general measures for bone health, including adequate calcium intake and vitamin D supplementation, exercise, and fall prevention. Clinical trials have not been done to address any special considerations beyond the usual options for prescription medicine therapy for osteoporosis.
Use of SSRIs in children and teenagers is largely unexplored. What effect SSRIs may have on bone during the growth phase is not known at this time. Because of the potential for harmful bone effects, it would be prudent to minimize use of this class of medicines in this age group.
Whether the disease, depression, itself also “weakens bones,” as the comic strip character, Gunther, told Luann, is not clear. New insights from bone biology discoveries will hopefully provide answers in the near future.
|
The Bare Bones
|