Risks for adverse effects upon bone density from ICS use low

March 2006

This month’s Pharmacology Consult column concludes a series of three columns discussing adverse effects of corticosteroid therapy for asthma. The previous columns reviewed adverse effects of orally administered burst corticosteroid therapy (January) and the potential for growth and HPA suppression from orally inhaled corticosteroids, ICS (February).

Systemically administered corticosteroids may adversely affect bone metabolism through several mechanisms, including increased bone resorption, decreased osteoblast activity and calcium absorption, decreased vitamin D–mediated intestinal calcium absorption and decreased renal calcium reabsorption. Up to 30% to 50% of patients receiving chronic oral corticosteroids may experience fractures. In one published study, 11% of patients with asthma receiving oral corticosteroids for one year had fractures. Although systemic absorption is certainly much less when corticosteroids are administered by oral inhalation compared with oral administration, the potential for adverse bone effects exists with inhalation therapy. Although several studies have shown that ICS decrease serum osteocalcin concentrations, investigators have yet to demonstrate that this predicts the development of osteoporosis.

Published studies

Several published studies have investigated ICS use and bone density or fractures in adults. Several case-control and cohort studies have found that ICS, in a dose-dependent manner, decrease bone mineral density (BMD; ie, lumbar spine, femoral neck and trochanter). However, one large study of postmenopausal women, with a mean duration of ICS exposure of 8.2 years, did not find a relationship between ICS use and BMD. Although these data are informative, they may not translate to ICS effects upon pediatric bone formation, strength and function.

Pediatric studies evaluating ICS use upon bone density have been published. In a 2003 joint statement from three professional medical societies on complications of ICS use, investigators concluded, at the highest graded level of evidence, that ICS use is not associated with a reduction in bone density in children with asthma (Leone). Data from eight published studies were reviewed for this statement. Although two of these studies did report a reduction in BMD or rate bone mass accretion, they have been criticized for flawed methodology. Of the remaining studies, three controlled trials did not find a negative effect of ICS use upon bone density. The other studies, although uncontrolled with potentially flawed methodology, also did not report negative effects of ICS use on bone density.

In addition to the studies alluded to above, several other important trials evaluating ICS use and bone density in the pediatric population have been published. A long-term study evaluated 157 children with asthma who received inhaled budesonide at a mean dose of 504 µg (range of 189 to 1322 µg; mean dose is classified as medium dose by the 2002 National Asthma Education and Prevention Program guidelines) for a mean duration of 4.5 years (3 to 6 years) compared with 111 matched children with asthma who did not receive exogenous corticosteroids for longer than 14 days (Agertoft). The mean age of children evaluated was approximately 10 years. DEXA (dual-energy x-ray absorptiometry) scans were used to assess several measures of bone structure: total body mineral density, total body mineral capacity and total bone calcium. There were no statistically significant differences in any of these markers of bone density or structure between the two groups. Although this study was not prospectively controlled, it does provide useful evidence and reassurance that medium doses of ICS (budesonide) do not negatively alter bone density in asthmatic children.

Kelly and colleagues re-evaluated children enrolled in the CAMP (Childhood Asthma Management Program) study. The CAMP study, published in 2000, compared budesonide (low-medium dosing) with nedocromil (Tilade, King Pharmaceuticals) and placebo for four to six years in 1,041 children (aged 5 to 12 years) with mild-moderate asthma. In the extended cross-sectional study, the investigators sought to determine if mild-moderate asthma or its treatment produced adverse effects upon growth and BMD of the lumbar spine. BMD was assessed by DEXA scan. In their analysis, it was demonstrated that the independent past use of ICS did not negatively correlate with BMD (or growth). Overall, the investigators concluded that mild-moderate asthma of as long as four to seven years’ duration does not produce an adverse effect BMD or linear growth.

Another controlled study compared fluticasone (low-medium dose) to nedocromil in a randomized, blinded fashion in 174 children (age 6 to 14 years) with asthma for a duration of two years (Roux). BMD was assessed at the lumbar spine and femoral neck by DEXA scan. After 24 months of treatment, lumbar spine BMD increased by 11.6% in children receiving fluticasone as compared with a 10.4% increase in children receiving nedocromil, a difference that was not significant. Neither were there differences in femoral neck BMD or growth between the two treatment groups.

Adverse effects of ICS are reviewed in the “National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma — Update on Selected Topics 2002.”

These guidelines conclude that studies of six years of observation indicated that low-medium doses of ICS have no adverse effects on BMD in children. The studies described above have evaluated low-medium ICS dosing. The potential for adverse effects upon bone density may be greater when high doses of ICS are used. Although no trials investigating the potential for adverse effects upon BMD from long-term, high-dose ICS use in children have been published, several studies have investigated the effects of high-dose ICS upon markers of bone formation and bone degradation. These studies indicate some evidence that high-dose ICS (eg, 800 µg) may adversely affect bone formation. The clinical significance of these effects is not clear.

Conclusion

The studies reviewed here indicate that the risks of clinically significant adverse effects upon bone density from low-medium dose ICS use are very low. As ICS are the most effective means of pharmacotherapy for long-term control of persistent asthma, these data should provide reassuring evidence that ICS are safe. If high doses of ICS are needed to control asthma in some children, the risks of high-dose ICS use upon bone density are not as clear. It may be helpful to periodically assess bone density in these children, especially if additional risk factors are present (eg, frequent use of oral corticosteroid courses or use of additional corticosteroids with other routes of administration, such as intranasal application).

For more information:

• Allen DB. Inhaled steroids for children: effects on growth, bone, and adrenal function. Endocrinol Metab Clin North Am. 2005;34:555-564.
• Kelly HW, Strunk RC, Donithan M, et al. Growth and bone density in children with mild-moderate asthma: a cross-sectional study in children entering the Childhood Asthma Management Program (CAMP). J Pediatr. 2003;142:286-291.
• Leone FT, Fish JE, Szefler SJ, West SL. Systematic review of the evidence regarding potential complications of inhaled corticosteroid use in asthma: collaboration of American College of Chest Physicians, American Academy of Allergy, Asthma, and Immunology, and American College of Allergy, Asthma, and Immunology. Chest 2003;124:2329-2340.
• Roux C, Kolta S, Desfourgeres JL, et al. Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma. Pediatrics. 2003;111:e706-e713.
• National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics 2002. J Allergy Clin Immunol. 2002;110:S142-219.
• Agertoft L, Petersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med. 1998;157:178-183.