SSRIs have been around for a long time and generally are thought to have a fairly benign side effect profile. However, these are medications that are taken for many months or even years, and it is important to consider the potential long-term effects on your patients.
One highly-publicized possible sequela of long-term SSRI treatment is damage to bones. This could be a cause for concern particularly during adolescence, which is a time of rapid bone growth that likely has repercussions for skeletal health years down the road. The problem is compounded by the risk to bones inherent in adolescents with eating disorders and/or depression.
Do SSRIs and Depression Have an Impact on Bone Density?
Most studies of SSRIs and bone loss are in older adults. The majority of these have noted an association between SSRI use and lower bone density (see for example, Richards JB et al, Arch Intern Med 2007;167(2):188–194; Diem SJ et al, Arch Intern Med 2007;167(12):1240–1245). This has clinical impact as well: elderly women taking SSRIs had higher rates of fractures than those not taking them in a prospective cohort study of more than 8,000 women (Diem SJ, Calcif Tissue Int 2011;88(6):476–484).
However, the data in children is scarce. One study of boys taking risperidone (Risperdal) found that bone density was further decreased if they also were taking an SSRI (Calarge CA et al, J Clin Psychiatry 2010;71(3):338–47). In (presumably non-depressed) adolescent mice given SSRIs, the outcome was not only less bone mass overall, but also weaker bone architecture (Warden SJ et al, Endocrinology 2005;146(2):685–693). Could the impact of SSRIs on the long bones and spine during this period lead to shorter stature? One small study showed overall growth retardation in all of four adolescents that were followed longitudinally while taking SSRIs, with resumption of normal growth rate after stopping them. However, three of the patients had abnormally short stature to begin with, and some were taking other medications (Weintrob N et al, Arch Pediatr Adolesc Med 2002;156(7):696–701).
However, there is a classic chicken-and-egg conundrum here: depression, regardless of treatment, also is associated with osteopenia. Most studies that have looked at this (for example, Schweiger U et al, Am J Psychiatr 2000;157:118–120, and Michelson D et al, N Engl J Med 1996; 335:1176–1181) have found that depressed adults have about 5% to 15% less bone density than those who are not. Some studies adjusted for confounders frequently found in depression such as SSRI use and smoking, and others did not. In a prospective sample of adolescent girls, those who had either depression or anxiety were found to have decreased bone density compared to those who did not (Dorn LD et al, Arch Pediatr Adolesc Med 2008;162(12):1181–1188).
How Do SSRIs and Depression Affect Bones?
Although there is only limited knowledge about why there might be an impact on bones from SSRIs and/or depression, let’s take a look at the mechanisms postulated for each, largely based on animal studies. Back in the cobwebby recesses of the section of your mind devoted to “Things From Medical School Not Used on a Daily Basis,” you may recall that, like Lego towers in the hands of a maniacal toddler, bones are continuously modeled and remodeled. The osteoclasts are like Pac-Men that constantly chew up and remove bone, while the osteoblasts tirelessly and patiently lay down new bone in its place. This enables the skeleton to meet the changing demands of body weight, activity level, etc.
Whether bone becomes stronger or weaker at any given point primarily depends on which type of cell has more activity at that time. Both of these types of bone cells have serotonin receptors, and although it is difficult to measure directly, SSRIs are thought to preferentially suppress osteoblast activity, letting the osteoclasts get the upper hand. Interestingly, depression also works to suppress osteoblast activity, but by a different mechanism. Depression increases systemic norepinephrine and cortisol levels, which subsequently direct the osteoblasts to take a breather. Because anxiety disorders also increase systemic sympathetic tone and glucocorticoids, we can infer that they would have the same result—further complicating the study of bone loss with SSRIs used for that indication. In addition, common sense suggests that people with depression are likely to be more sedentary, which also is a risk factor for weaker bones.
So is the bone loss seen with SSRIs attributable more to SSRI use, or to an independent effect of the depression? While it’s hard to find a well-designed, placebo-controlled study to answer this question, a review of most of the literature suggests that SSRIs probably do have their own significant effect. This is not entirely cut and dried, though: if SSRIs really did independently cause bone damage, you would expect the bone loss associated with depression to worsen rather than improve during SSRI treatment. In fact, when premenopausal women with depression were studied both before and during SSRI treatment, their rates of bone formation actually increased, and rates of bone breakdown decreased (Aydin H, J Psychiatr Res 2001;45(10):1316–1320).
But what does this mean in the real world? Even if there is a decrease in bone density, will it have any clinical impact on our patients? It’s hard to tell. There have been a few case reports of adolescents on SSRIs with fractures, but it’s hard to know if they would have gotten those fractures anyway without an SSRI. The growth retardation study mentioned previously was very small. To date, we were unable to find any reliable studies on whether SSRI use in children translates into actual clinical bone impairment either during childhood or far down the line.
What About Kids With Eating Disorders?
Kids with eating disorders already are at risk for significant osteoporosis. The osteoporosis associated with anorexia nervosa tends not to reverse after refeeding. This may be because it is already too late: one of the biggest contributors to osteoporosis later in life is a lack of adequate bone density built up years earlier during adolescence. Thus, it is of paramount importance to address anorexia as early as possible during adolescence. Returning the patient to a normal weight and menstrual status are the most effective interventions to mitigate the risk. The good news is that anorexic eating patterns that occur for less than 12 months do not seem to have lasting effects on bones (Mehler PS, Int J Eat Disord 2003;33(2):113–126).
Where Do We Go from Here?
Some clinicians are starting to suggest that there should be guidelines for periodic bone density screening in older adults taking SSRIs. Bone density scans also are recommended for anorexic patients whether or not they are taking SSRIs. Perhaps, as more is known, this will be warranted in our non-anorexic pediatric patients as well. For now, though, patients and families should be informed that while bone weakness is a potential side effect of SSRI treatment, it is not known at this time to cause clinically important sequelae for children and adolescents, although there are many unanswered questions in this area.
In any case, it’s not necessary to restrict physical activity to avoid fractures. In fact, physical activity is important not only for alleviating depression, but for improving bone strength as well. Even in anorexic patients, moderate exercise—but no more than that—was shown to help increase bone mass.
What patients and their families can and should do is pay particular care to doing other things that will help their bone health: beyond staying active, they also should keep a healthy diet and weight and avoid smoking. Because increased dietary calcium and vitamin D yield improvements in the bone density of children and adolescents (Chan GM et al, J Pediatr 1995;126(4):551–556; and Bonjour JP et al, J Clin Invest 1997;99(6):1287–1294) a supplement might be a smart idea as well.