Drugs that may harm bone: Mitigating the risk

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Managing the risk of glucocorticoid-induced osteoporosis

In 2010, the American College of Rheumatology published recommendations for preventing and treating glucocorticoid-induced osteoporosis, which were endorsed by the American Society for Bone and Mineral Research.20 To lessen the risk of osteoporosis, the recommendations are as follows:

Limit exposure. Patients receiving glucocorticoids should be given the smallest dosage for the shortest duration possible.

Advise lifestyle changes. Patients should be counseled to limit their alcohol intake to no more than two drinks per day, to quit smoking, to engage in weight-bearing exercise, and to ingest enough calcium (1,200–1,500 mg/day, through diet and supplements) and vitamin D.

Monitor bone mineral density. Patients starting glucocorticoids at any dosage for an expected duration of at least 3 months should have their bone mineral density measured at baseline. The frequency of subsequent measurements should be based on the presence of other risk factors for fracture, results of previous bone density testing, glucocorticoid dosage, whether therapy for bone health has been initiated, and the rate of change in bone mineral density. If warranted and if the results would lead to a change in management, patients can undergo dual-energy x-ray absorptiometry more often than usual, ie, more often than every 2 years. Prevalent and incident fragility fractures, height measurements, fall risk assessments, laboratory measurements of 25-hydroxyvitamin D, and consideration of vertebral fracture assessment or other imaging of the spine, as necessary, should be part of counseling and monitoring.

Osteoporosis treatment. For patients who will be taking glucocorticoids for at least 3 months, alendronate, risedronate, zoledronic acid, or teriparatide can be initiated to prevent or treat osteoporosis in the following groups:

  • Postmenopausal women and men over age 50 if the daily glucocorticoid dosage is at least 7.5 mg/day or if the World Health Organization Fracture Risk Assessment Tool (FRAX) score is more than 10% (the threshold for medium fracture risk)
  • Premenopausal women and men younger than 50 if they have a history of fragility fracture, the FRAX score is more than 20% (the threshold for high fracture risk), or the T score is less than –2.5.

Certain clinical factors can also put a patient into a higher-risk category. These include current tobacco use, low body mass index, parental history of hip fracture, consuming more than three alcoholic drinks daily, higher daily or cumulative glucocorticoid dosage, intravenous pulse glucocorticoid usage, or a decline in central bone mineral density that exceeds the least significant change according to the scanner used.20

The FRAX tool accounts for bone density only at the femoral neck, and while useful, it cannot replace clinical judgment in stratifying risk. Moreover, it does not apply to premenopausal women or men under age 40.

The implicated medications have important roles, so weigh their risks and benefits

The long-term risks of medications to treat glucocorticoid-induced osteoporosis are not well defined for premenopausal women (or their unborn children) or in men younger than 40, so treatment is recommended in those groups only for those with prevalent fragility fractures who are clearly at higher risk of additional fractures.20


Proton pump inhibitors are available by prescription and over the counter for gastric acid-related conditions. Concerns have been raised that these highly effective drugs are overused.21 Several of their adverse effects are self-limited and minor, but long-term use may entail serious risks, including propensity to bone fracture.22

Low acid leads to poor calcium absorption

Why fracture risk increases with proton pump inhibitors is controversial and may relate to their desired effect of suppressing gastric acid production: calcium salts, including carbonate and chloride, are poorly soluble and require an acidic environment to increase calcium ionization and thus absorption.23 For this reason, if patients taking a proton pump inhibitor take a calcium supplement, it should be calcium citrate, which unlike calcium carbonate does not require an acid environment for absorption.

Higher risk in older patients, with longer use, and with higher dosage

Since the first reports on proton pump inhibitors and fracture risk were published in 2006,24,25 a number of studies have reported this association, including several systematic reviews.

In 2011, the US Food and Drug Administration (FDA) updated a 2010 safety communication based on seven epidemiologic studies reporting an increased risk of fractures of the spine, hip, and wrist with proton pump inhibitors.24–31 Time of exposure to a proton pump inhibitor in these studies varied from 1 to 12 years. Fracture risk was higher in older patients,26 with higher doses,24,29 and with longer duration of drug use.24,27 On the other hand, one study that included only patients without other major fracture risk factors failed to find an association between the use of proton pump inhibitors and fractures.28

Is evidence sufficient for changing use?

The FDA report included a disclaimer that they had no access to study data or protocols and so could not verify the findings.26 Moreover, the studies used claims data from computerized databases to evaluate the risk of fractures in patients treated with proton pump inhibitors compared with those not using these drugs.24–31 Information was often incomplete regarding potentially important factors (eg, falls, family history of osteoporosis, calcium and vitamin D intake, smoking, alcohol use, reason for medication use), as well as the timing of drug use related to the onset or worsening of osteoporosis.26

Although 34 published studies evaluated the association of fracture risk and proton pump inhibitors, Leontiadis and Moayyedi32 argued that insufficient evidence exists to change our prescribing habits for these drugs based on fracture risk, as the studies varied considerably in their designs and results, a clear dose-response relationship is lacking, and the modest association is likely related to multiple confounders.

Bottom line: Use with caution

Although the increased fracture risk associated with proton pump inhibitors is likely multifactorial and is not fully delineated, it appears to be real. These drugs should be used only if there is a clear indication for them and if their benefits likely outweigh their risks. The lowest effective dose should be used, and the need for continuing use should be frequently reassessed.


Depression affects 1 in 10 people in the United States, is especially common in the elderly, and leads to significant morbidity and reduced quality of life.33 Selective serotonin reuptake inhibitors (SSRIs) are often prescribed and are generally considered first-line agents for treating depression.

Complex bone effects

Use proton pump inhibitors only if there is a clear indication for them and their benefits likely outweigh the risks

SSRIs antagonize the serotonin transporter, which normally assists serotonin uptake from the extracellular space. The serotonin transporter is found in all main types of bone cells, including osteoclasts, osteoblasts, and osteocytes.33 Serotonin is made by different genes in the brain than in the periphery, causing opposing effects on bone biology: when generated peripherally, it acts as a hormone to inhibit bone formation, while when generated in the brain, it acts as a neurotransmitter to create a major and positive effect on bone mass accrual by enhancing bone formation and limiting bone resorption.34,35

Potential confounders complicate the effect of SSRIs on bone health, as depression itself may be a risk factor for fracture. Patients with depression tend to have increased inflammation and cortisol, decreased gonadal steroids, more behavioral risk factors such as tobacco and increased alcohol use, and less physical activity, all of which can contribute to low bone density and risk of falls and fractures.33

Daily use of SSRIs increases fracture risk

A 2012 meta-analysis36 of 12 studies (seven case-control and five cohort), showed that SSRI users had a higher overall risk of fracture (adjusted odds ratio 1.69, 95% CI 1.51–1.90). By anatomic site, pooled odds ratios and 95% CIs were:

  • Vertebral fractures 1.34 (1.13–1.59)
  • Wrist or forearm fractures 1.51 (1.26–1.82)
  • Hip or femur fractures 2.06 (1.84–2.30).

A 2013 meta-analysis37 of 34 studies with more than 1 million patients found that the random-effects pooled relative risk of all fracture types in users of antidepressants (including but not limited to SSRIs) was 1.39 (95% CI 1.32–1.47) compared with nonusers. Relative risks and 95% CIs in antidepressant users were:

  • Vertebral fractures 1.38 (1.19–1.61)
  • Nonvertebral fractures 1.42 (1.34–1.51)
  • Hip fractures 1.47 (1.36–1.58).

A population-based, prospective cohort study38 of 5,008 community-dwelling adults age 50 and older, followed for 5 years, found that the daily use of SSRIs was associated with a twofold increased risk of clinical fragility fractures (defined as minimal trauma fractures that were clinically reported and radiographically confirmed) after adjusting for potential covariates. Daily SSRI use was also associated with an increased risk of falling (odds ratio 2.2, 95% CI 1.4–3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose-dependent and were similar for those who reported taking SSRIs at baseline and at 5 years.

Bottom line: Counsel bone health

Although no guidelines exist for preventing or treating SSRI-induced bone loss, providers should discuss with patients the potential effect of these medications on bone health, taking into account patient age, severity of depression, sex, duration of use, length of SSRI treatment, and other clinical risk factors for osteoporosis.34 Given the widespread use of these medications for treating depression, more study into this association is needed to further guide providers.

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