Drugs that may harm bone: Mitigating the risk

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Antiepileptic drugs are used to treat not only seizure disorders but also migraine headaches, neuropathy, and psychiatric and pain disorders. Many studies have linked their use to an increased risk of fractures.

The mechanism of this effect remains controversial. Early studies reported that inducers of cytochrome P450 enzymes (eg, phenobarbital, phenytoin) lead to increased vitamin D degradation, causing osteomalacia.39 Another study suggested that changes in calcium metabolism and reduced bone mineral density occur without vitamin D deficiency and that drugs such as valproate that do not induce cytochrome P450 enzymes may also affect bone health.40 Other bone effects may include direct inhibition of intestinal calcium absorption (seen in animal studies) and the induction of a high remodeling state leading to osteomalacia.41,42

Epilepsy itself increases risk of fractures

Patients with seizure disorders may also have an increased risk of fractures because of falls, trauma, impaired balance, use of glucocorticoids and benzodiazepines, and comorbid conditions (eg, mental retardation, cerebral palsy, and brain neoplasm).43

A 2005 meta-analysis43 of 11 studies of epilepsy and fracture risk and 12 studies of epilepsy and bone mineral density found that the risks of fractures were increased. The following relative risks and 95% CIs were noted:

The benefit of preventing seizures outweighs the risks of fractures

  • Any fracture 2.2 (1.9–2.5), in five studies
  • Forearm 1.7 (1.2–2.3), in six studies
  • Hip 5.3 (3.2–8.8), six studies
  • Spine 6.2 (2.5–15.5), in three studies.

A large proportion of fractures (35%) seemed related to seizures.

Certain drugs increase risk

A large 2004 population-based, case-control, study44 (124,655 fracture cases and 373,962 controls) found an association between the use of antiepileptic drugs and increased fracture risk. After adjusting for current or prior use of glucocorticoids, prior fracture, social variables, comorbid conditions, and epilepsy diagnosis, excess fracture risk was found to be associated with the following drugs (odds ratios and 95% CIs):

  • Oxcarbazepine 1.14 (1.03–1.26)
  • Valproate 1.15 (1.05–1.26)
  • Carbamazepine 1.18 (1.10-1.26)
  • Phenobarbital 1.79 (1.64–1.95).

The risk was higher with higher doses. Fracture risk was higher with cytochrome P450 enzyme-inducing drugs (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and primidone; odds ratio 1.38, 95% CI 1.31–1.45) than for noninducing drugs (clonazepam, ethosuximide, lamotrigine, tiagabine, topiramate, valproate, and vigabatrin; odds ratio 1.19, 95% CI 1.11–1.27). No significant increased risk of fracture was found with use of phenytoin, tiagabine, topiramate, ethosuximide, lamotrigine, vigabatrin, or primidone after adjusting for confounders.

Bottom line: Monitor bone health

With antiepileptic drugs, the benefit of preventing seizures outweighs the risks of fractures. Patients on long-term antiepileptic drug therapy should be monitored for bone mineral density and vitamin D levels and receive counseling on lifestyle measures including tobacco cessation, alcohol moderation, and fall prevention.45 As there are no evidence-based guidelines for bone health in patients on antiepileptic drugs, management should be based on current guidelines for treating osteoporosis.


Depression itself may be a risk factor for fracture

Breast cancer is the most common cancer in women and is the second-leading cause of cancer-associated deaths in women after lung cancer. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, are the standard of care in adjuvant treatment for hormone-receptor-positive breast cancer, leading to longer disease-free survival.

However, aromatase inhibitors increase bone loss and fracture risk, and only partial recovery of bone mineral density occurs after treatment is stopped. The drugs deter the aromatization of androgens and their conversion to estrogens in peripheral tissue, leading to reduced estrogen levels and resulting bone loss.46 Anastrozole and letrozole have been found to reduce bone mineral density, increase bone turnover, and increase the relative risk for nonvertebral and vertebral fractures in postmenopausal women by 40% compared with tamoxifen.47,48

Base osteoporosis treatment on risk

Several groups have issued guidelines for preventing and treating bone loss in postmenopausal women being treated with an aromatase inhibitor. When initiating treatment, women should be counseled about modifiable risk factors, exercise, and calcium and vitamin D supplementation.

Baseline bone mineral testing should also be obtained when starting treatment. Hadji et al,49 in a review article, recommend starting bone-directed therapy if the patient’s T score is less than –2.0 (using the lowest score from three sites) or if she has any of at least two of the following fracture risk factors:

  • T score less than –1.5
  • Age over 65
  • Family history of hip fracture
  • Personal history of fragility fracture after age 50
  • Low body mass index (< 20 kg/m2)
  • Current or prior history of tobacco use
  • Oral glucocorticoid use for longer than 6 months.

Patients with a T score at or above –2.0 and no risk factors should have bone mineral density reassessed after 1 to 2 years. Antiresorptive therapy with intravenous zoledronic acid and evaluation for other secondary causes of bone loss should be initiated for either:

  • An annual decrease of at least 10% or
  • An annual decrease of at least 4% in patients with osteopenia at baseline.49

In 2003, the American Society of Clinical Oncology updated its recommendations on the role of bisphosphonates and bone health in women with breast cancer.50 They recommend the following:

  • If the T score is –2.5 or less, prescribe a bisphosphonate (alendronate, risedronate, or zoledronic acid)
  • If the T score is –1.0 to –2.5, tailor treatment individually and monitor bone mineral density annually
  • If the T score is greater than –1.0, monitor bone mineral density annually.

All patients should receive lifestyle counseling, calcium and vitamin D supplementation, and monitoring of additional risk factors for osteoporosis as appropriate.50

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