Drugs that may harm bone: Mitigating the risk

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ABSTRACTGlucocorticoids, proton pump inhibitors, selective serotonin reuptake inhibitors (SSRIs), certain antiepileptic drugs, and aromatase inhibitors have significant adverse effects on bone. Healthcare providers should monitor the bone health of patients on these agents, supplement their intake of calcium and vitamin D, encourage weight-bearing exercise, and initiate osteoporosis-prevention treatment as indicated.


  • Professional society guidelines advise initiating treatment for bone loss in patients starting glucocorticoid therapy expected to last at least 3 months and for women taking an aromatase inhibitor.
  • If patients taking a proton pump inhibitor take a calcium supplement, they should take calcium citrate.
  • Daily SSRI use nearly doubles the risk of hip fracture in people over age 50.
  • Many drugs for epilepsy are associated with increased fracture risk, but so are seizures (which may confound the issue).



Drug-induced osteoporosis is common, and the list of drugs that can harm bone continues to grow. As part of routine health maintenance, practitioners should recognize the drugs that increase bone loss and take measures to mitigate these effects to help avoid osteopenia and osteoporosis.

Osteoporosis, a silent systemic disease defined by low bone mineral density and changes in skeletal microstructure, leads to a higher risk of fragility fractures. Some of the risk factors are well described, but less well known is the role of pharmacologic therapy. The implicated drugs (Table 1) have important therapeutic roles, so the benefits of using them must be weighed against their risks, including their potential effects on bone.

This review focuses on a few drugs known to increase fracture risk, their mechanisms of bone loss, and management considerations (Table 2).


Glucocorticoids are used to treat many medical conditions, including allergic, rheumatic, and other inflammatory diseases, and as immunosuppressive therapy after solid organ and bone marrow transplant. They are the most common cause of drug-induced bone loss and related secondary osteoporosis.

Multiple effects on bone

Glucocorticoids both increase bone resorption and decrease bone formation by a variety of mechanisms.1 They reduce intestinal calcium absorption, increase urinary excretion of calcium, and enhance osteocyte apoptosis, leading to deterioration of the bone microarchitecture and bone mineral density.2 They also affect sex hormones, decreasing testosterone production in men and estrogen in women, leading to increased bone resorption, altered bone architecture, and poorer bone quality.3,4 The bone loss is greater in trabecular bone (eg, the femoral neck and vertebral bodies) than in cortical bone (eg, the forearm).5

Glucocorticoids have other systemic effects that increase fracture risk. For example, they cause muscle weakness and atrophy, increasing the risk of falls.4 Additionally, many of the inflammatory conditions for which they are prescribed (eg, rheumatoid arthritis) also increase the risk of osteoporosis by means of proinflammatory cytokine production, which may contribute to systemic and local effects on bone.4,6

Bone mineral density declines quickly

Bone mineral density declines within the first 3 months after starting oral glucocorticoids, with the rate of bone loss peaking at 6 months. Up to 12% of bone mass is lost in the first year. In subsequent years of continued use, bone loss progresses at a slower, steadier rate, averaging 2% to 3% annually.5,7,8

Oral therapy increases fracture risk

Kanis et al9 performed a meta-analysis of seven prospective cohort studies in 40,000 patients and found that the current or previous use of an oral glucocorticoid increased the risk of fragility fractures, and that men and women were affected about equally.9

Van Staa et al10,11 reported that daily doses of glucocorticoids equivalent to more than 2.5 mg of prednisone were associated with an increased risk of vertebral and hip fractures; fracture risk was related mainly to daily dosage rather than cumulative dose.

Van Staa et al,12 in a retrospective cohort study, compared nearly 250,000 adult users of oral glucocorticoids from general medical practice settings with the same number of controls matched for sex, age, and medical practice. The relative risks for fractures and 95% confidence intervals (CIs) during oral glucocorticoid treatment were as follows:

  • Forearm fracture 1.09 (1.01–1.17)
  • Nonvertebral fracture 1.33 (1.29–1.38)
  • Hip fracture 1.61 (1.47–1.76)
  • Vertebral fracture 2.60 (2.31–2.92).

The risk was dose-dependent. For a low daily dose (< 2.5 mg/day of prednisolone), the relative risks were:

  • Hip fracture 0.99 (0.82–1.20)
  • Vertebral fracture 1.55 (1.20–2.01) .

For a medium daily dose (2.5–7.5 mg/day), the relative risks were:

  • Hip fracture 1.77 (1.55–2.02)
  • Vertebral fracture 2.59 (2.16–3.10) .

For a high daily dose (> 7.5 mg/day), the relative risks were:

  • Hip fracture 2.27 (1.94–2.66)
  • Vertebral fracture 5.18 (4.25–6.31).

Fracture risk rapidly declined toward baseline after the patients stopped taking oral glucocorticoids but did not return to baseline levels. The lessening of excess fracture risk occurred mainly within the first year after stopping therapy.

Other studies5,9,13 have suggested that the increased fracture risk is mostly independent of bone mineral density, and that other mechanisms are at play. One study14 found that oral glucocorticoid users with a prevalent vertebral fracture actually had higher bone mineral density than patients with a fracture not taking glucocorticoids, although this finding was not confirmed in a subsequent study.15

Inhaled glucocorticoids have less effect on bone

Inhaled glucocorticoids are commonly used to treat chronic obstructive pulmonary disease and asthma. They do not have the same systemic bioavailability as oral glucocorticoids, so the risk of adverse effects is lower.

Data are inconsistent among several studies that evaluated the relationship between inhaled glucocorticoids, bone mineral density, osteoporosis, and fragility fracture. The inconsistencies may be due to heterogeneity of the study populations, self-reporting of fractures, and different methods of assessing chronic obstructive pulmonary disease severity.16

A Cochrane review17 in 2002 evaluated seven randomized controlled trials that compared the use of inhaled glucocorticoids vs placebo in nearly 2,000 patients with mild asthma or chronic obstructive pulmonary disease and found no evidence for decreased bone mineral density, increased bone turnover, or increased vertebral fracture incidence in the glucocorticoid users at 2 to 3 years of follow-up (odds ratio for fracture 1.87, 95% CI 0.5–7.0).

The Evaluation of Obstructive Lung Disease and Osteoporosis study,16 a multicenter Italian observational epidemiologic study, reported that patients taking the highest daily doses of inhaled glucocorticoids (> 1,500 μg of beclomethasone or its equivalent) had a significantly higher risk of vertebral fracture (odds ratio 1.4, 95% CI 1.04–1.89).16

A meta-analysis18 of five case-control studies (43,783 cases and 259,936 controls) identified a possible dose-dependent relationship, with a relative risk for nonvertebral fracture of 1.12 (95% CI 1.0–1.26) for each 1,000-μg increase in beclomethasone-equivalent inhaled glucocorticoid per day.

In summary, the effects of inhaled glucocorticoids in adults are uncertain, although trends toward increased fracture risk and decreased bone mineral density are evident with chronic therapy at moderate to high dosages. The risks and benefits of treatment should be carefully considered in patients with osteoporosis and baseline elevated fracture risk.19

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