Effect of Long-term Corticosteroid Use on Bone Mineral Density in Children: A Prospective Longitudinal Assessment in the Childhood Asthma Management Program (CAMP) Study

Patient Population

The demographics of the patients who were initially enrolled in CAMP have been extensively described previously.^27–29 All patients who were randomly assigned to the CAMP treatment phase were eligible for the follow-up study. The follow-up study was approved by each of the local institutional review boards, and appropriate signed consent and assent forms were obtained from patients and their parents/guardians. Of the initial 1041 patients enrolled in CAMP, 941 elected to continue in the follow-up study. Unable to standardize the initial DEXA values obtained in CAMP at 1 center, we excluded those patients. All other patients who had a baseline BMD determination and at least 1 follow-up BMD (n = 877) were included. The children ranged in age from 5 to 12 years on entry into CAMP. Tanner staging for sexual maturity was assessed annually until full maturity. Height by stadiometry and weight were measured every 6 months, and BMI was estimated by standard equations. Because accrual of bone mass differs by age in boys and girls as a result of different ages for pubertal maturation, boys and girls are presented separately.^30–32

Corticosteroid Dosages

During the CAMP trial phase, patients received prednisone bursts per protocol with a standard regimen of 2 mg/kg per day up to 60 mg of prednisone for 2 days followed by 1 mg/kg per day up to 30 mg for 2 days, with an option to continue dosing if there was insufficient improvement in peak flows. Duration and dosage during the trial phase were recorded on daily diaries as well as reports of bursts by interview (date started, duration, and daily dosage) at 3 per year of follow-up visits (in-person) and during interim telephone contacts. During the follow-up study, patients received OCS bursts of variable duration and dosage as determined by their asthma care providers, with the number of bursts since the last contact obtained by interview at semiannual follow-up visits and interim telephone contacts. Bursts during the follow-up study were assumed to conform to the CAMP trial regimen and were assumed to be equally spaced through the interval since the last contact. For analysis purposes, the total dosage (mg) received during the 2 phases was divided by 180 to reexpress the total dosage received by each patient as the number of equivalent 4-day bursts (60/60/30/30 mg/day over 4 days) for a patient who weighed at least 30 kg. Cumulative number of bursts was divided into 3 categories (0, 1–4, and ≥5). The ≥5 category represented a median of 8.9 (quartiles: 6.5, 12.3) bursts during the study period.

The ICSs included the blinded budesonide and unblinded ICSs during the CAMP treatment phase and then any ICS that the patients' primary care physicians prescribed during the follow-up study. Dosage form, dosage, and frequency were recorded at each visit, and total dosage for the duration was calculated. The ICS dosage was divided into 3 categories (0, 1–437, and ≥438 mg). The cut point of 438 mg was somewhat arbitrary and represents 3 years of full dosage (400 μg/day) of budesonide. The median cumulative dosage in the 1- to 437-mg category was 153 mg, whereas patients in the ≥438 category had a median dosage of 690 mg. Thus, the ≥438 category represents patients who received almost continuous ICSs through the trial and follow-up study phases, whereas the 1- to 437-mg category represents a periodic or intermittent use.

BMD and Fracture Measurements

The BMD measurements were made at baseline, yearly during the treatment phase, and then twice during the follow-up study, at 7 and 9 years after randomization. Lumbar spine (L1–L4) BMD was measured by DEXA using either the Hologic (Waltham, MA) QDR-1500 (6 centers) or the Lunar (Madison, WI) DPX at 2 centers initially; however, the DEXA machines were not purchased by the study, so upgrades and changes were made at a number of the clinical centers (ie, changing from Lunar to Hologic and vice versa, and changing within Hologic from pencil beam to fan beam). Density measures on an anthropomorphic spine Phantom (Hologic model DPA/QDR-1, S/N: 1550) were obtained annually at each clinical center; these density measures were used to derive equations for converting density measurements to a Hologic fan-beam equivalent. Lunar measures were converted to Hologic by the following: Hologic BMD = 0.885 × Lunar BMD.³³ As patients became larger, the pencil-beam and fan-beam values deviate, requiring additional correction.³³ This occurred at the height of 1.40 m in our patients (Fig 1), so all values were standardized to Hologic fan beam by the following: fan-beam BMD = pencil-beam BMD + 0.0549 if height ≥1.40 m. The final corrected BMD measures are reported as total BMD (g/cm²). The BMD z scores were calculated using CAMP internal references, mean, and SD of patients in the lowest to medium category for cumulative oral and inhaled corticosteroid dosages (n = 398 [45% of the population]). Because children with asthma might not be considered as references, we also analyzed our patients on the basis of references provided by both Boot et al³⁴ and vanderSluis et al.³⁵ Fractures were prospectively collected on the data history forms.

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FIGURE 1

BMD versus height according to beam type of densitometer.

Data Analysis

The primary outcome was yearly bone mineral accretion (g/cm² per year) over the duration of both phases of CAMP, defined as last visit BMD − baseline BMD/years since baseline. The independent variables of interest included cumulative bursts of OCSs, cumulative ICS dosage in milligrams, BMI, and active and passive smoking. Both simple and stepwise multiple linear regressions were used to assess the total and direct effects bone mineral accretion.³⁶ Analyses were stratified by gender, and predictors were tested for effect modification by gender. Multiple linear regressions were adjusted for race and BMD at baseline, OCS and ICS use, active and passive smoking, race, age, Tanner stage, machine type, beam type, BMI for age percentile, and height evaluated at the last visit. The interaction between OCSs and ICSs was assessed by χ² analysis. Assessment of risk factors for causing fracture used the Cox model with time to first fracture as the outcome. P values are nominal and 2-sided. All analyses were performed by using SAS/STAT 8 software (SAS Institute, Inc, Cary, NC).

Patient Demographics

We obtained baseline BMD and at least 1 follow-up BMD at a median duration of 7 years from 877 (93%) of the children from the eligible 7 centers involved in the treatment and observational phases, providing a total of 1709 female and 2708 male BMD measurements. The majority of patients (85% of boys and 75% of girls) were at Tanner stage 1 at the beginning of CAMP, and the vast majority of patients progressed through the peak period of bone mineral accretion (Tanner stages 2 and 4) during the follow-up study (Table 1).

Factors That Affect BMD

Initial regression analyses showed that age, gender (Fig 2), Tanner stage, and race had significant effects on BMD, with black children having significantly greater (P = .04) BMD (0.81 g/cm²) than Hispanic (0.80 g/cm²) and white children (0.79 g/cm²); therefore, all multiple regression models for bone mineral accretion were controlled for these variables, as well as BMD at baseline, DEXA machine and beam type, BMI-for-age percentile, height, and smoking history.

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FIGURE 2

Age-specific BMD according to gender.

Factors That Affect Bone Mineral Accretion

There was no effect of initial CAMP treatment randomization using intent-to-treat analysis on bone mineral accretion (budesonide versus placebo, P = .31 for girls and P = .84 for boys; nedocromil versus placebo, P = .15 for girls and P = .82 for boys) or any effect of either passive or active smoking on bone mineral accretion, but only 6% of patients smoked actively by the last visit (Table 2). Bone mineral accretion was lowest in both boys and girls in the lowest BMI quartile (P < .0001, Table 3).

Effects of Corticosteroids on Bone Mineral Accretion

The effect of both OCSs and ICSs on bone mineral accretion was gender specific. A cumulative OCS use of ≥5 bursts resulted in a decreased bone mineral accretion in boys (P = .0009) but not in girls (P = .29; Table 2). Test for trend indicated that the effect in boys was dosage dependent (P = .0002). Boys who received ICSs had a significantly decreased bone mineral accretion that did not seem to be dosage dependent. There was no effect of ICSs on bone mineral accretion in girls. No significant interaction between OCS and ICS on bone mineral accretion was found (P = .97 for girls and P = .23 for boys).

Using the World Health Organization's definition of osteopenia (BMD between 1 and 2.5 SDs below age- and gender-adjusted means), 80 (15%) boys and 77 (22%) girls were classified as having osteopenia at their last BMD determination.³⁷ Only 4 patients (2 boys and 2 girls) were classified as having osteoporosis (z score less than −2.5) and so were included with the children with osteopenia for analysis. Similar to the effects on bone mineral accretion, only cumulative dosage of OCSs in boys demonstrated a dosage-dependent risk for developing osteopenia (10.2%, 13.8%, and 20.6%) for 0, 1 to 4, and ≥5 courses, respectively (P = .02 for trend; Table 4). χ² analysis showed that a significantly greater proportion of children who were classified with osteopenia were in the lowest quartile of bone mineral accretion (72% for boys, P < .0001; 58% for girls, P < .0001). Using the other published reference values,^34,35 the percentage of patients who were classified as having osteopenia varied at most by 4%, and the OCS dosage-dependent increase in percentage of male patients who were classified as having osteopenia was not significantly changed (Table 4).

Fractures

There were only 27 fractures in the girls and 40 fractures in the boys of 6339 person-years of follow-up. The overall fracture rate for boys and girls was 11 and 12 per 1000 person-years, respectively. Neither OCS nor ICS use was related to time of first fracture in boys or girls (adjusted values for trend all P > .5).

Clinical Centers of the CAMP Research Group

ASTHMA, Inc, Seattle, WA: Gail G. Shapiro, MD (director); Thomas R. DuHamel, PhD (co-director); Mary V. Lasley, MD (co-director); Tamara Chinn, MSN, ARNP (coordinator); Michele Hinatsu, MSN, ARNP; Clifton T. Furukawa, MD; Leonard C. Altman, MD; Frank S. Virant, MD; Paul V. Williams, MD; Michael S. Kennedy, MD; Jonathan W. Becker, MD; Grace White; C. Warren Bierman, MD (1992–1997); Dan Crawford, RN (1996–2002); Heather Eliassen, BA (1996–1999); Babi Hammond (1996–1999); Dominick A. Minotti, MD (1992–2003); Chris Reagan (1992–2003); Marian Sharpe, RN (1992–1994); and Timothy G. Wighton, PhD (1994–1998).

Brigham & Women's Hospital, Boston, MA: Scott Weiss, MD, (director); Anne Fuhlbrigge, MD (principal investigator); Anne Plunkett, NP, MS (coordinator); Nancy Madden, RN, BSN; Peter Barrant, MD; Christine Darcy; Kelly Thompson, MD; Walter Torda, MD (co-investigator director, 1993–2003); Martha Tata, RN (1993–2002); Sally Babigian, RN (1997–1999); Linda Benson (1998–2004); Jose Caicedo (1998–1999); Tatum Calder (1998–2001); Anthony DeFilippo (1994–2000); Cindy Dorsainvil (1998–2001); Julie Erickson (1998–1999); Phoebe Fulton (1997); Mary Grace, RN (1994–1996); Jennifer Gilbert (1997–1998); Dirk Greineder, MD (1993–2000); Stephanie Haynes (1993–1998); Margaret Higham, MD (1996–1998); Deborah Jakubowski (1999); Susan Kelleher (1993–1997); Jay Koslof, PhD (1993–1995); Dana Mandel (1996–1998); Patricia Martin (2001–2003); Agnes Martinez (1994–1997); Jean McAuliffe (1994–1995); Erika Nakamoto (2002–2004); Paola Pacella (1993–1998); Paula Parks (1993–1995); Johanna Sagarin (1998–1999); Kay Seligsohn, PhD (1995–2004); Susan Swords (2003–2005); Meghan Syring (1998–2001); June Traylor, MSN, RN (1996–1998); Melissa VanHorn, PhD (1996–1999); Carolyn Wells, RN (1993–1995); and Ann Whitman, RN (1994–1996).

Hospital for Sick Children, Toronto, Ontario, Canada: Ian MacLusky, MD, (director); Joe Reisman, MD, MBA (director, 1996–1999); Henry Levison, MD, (director, 1992–1996); Anita Hall, RN (coordinator); Jennifer Chay; Melody Miki, RN, BScN; Renée Sananes, PhD; Yola Benedet (1994–1999); Susan Carpenter, RN (1998–2001); Michelle Collinson, RN (1994–1998); Jane Finlayson-Kulchin, RN (1994–1998); Kenneth Gore, MA (1993–1999); Noreen Holmes, RRT (1998–1999); Sharon Klassen, MA (1999–2000); Joseé Quenneville, MSc (1993–1995); and Christine Wasson, PhD (1999).

Johns Hopkins Asthma and Allergy Center, Baltimore, MD: N. Franklin Adkinson, Jr, MD (director); Peyton Eggleston, MD (co-director); Elizabeth H. Aylward, PhD; Karen Huss, DNSc (co-investigator); Leslie Plotnick, MD (co-investigator); Margaret Pulsifer, PhD (co-investigator); Cynthia Rand, PhD (co-investigator); Nancy Bollers, RN (coordinator); Deborah Bull, LPN; Robert Hamilton, PhD; Kimberly Hyatt; Susan Limb, MD; Mildred Pessaro; Stephanie Philips, RN; and Barbara Wheeler, RN, BSN.

National Jewish Medical and Research Center, Denver, CO: Stanley Szefler, MD (director); Harold S. Nelson, MD (co-director); Bruce Bender, PhD (co-investigator); Ronina Covar, MD (co-investigator); Andrew Liu, MD (co-investigator); Joseph Spahn, MD (co-investigator); D Sundström (coordinator); Melanie Phillips; Michael P. White; Kristin Brelsford (1997–1999); Jessyca Bridges (1995–1997); Jody Ciacco (1993–1996); Michael Eltz (1994–1995); Jeryl Feeley, MA (coordinator, 1992–1995); Michael Flynn (1995–1996); Melanie Gleason, PA-C (1992–1999); Tara Junk-Blanchard (1997–2000); Joseph Hassell (1992–1998); Marcia Hefner (1992–1994); Caroline Hendrickson, RN (1995–1998; coordinator, 1995–1997); Daniel Hettleman, MA (1995–1996); Charles G. Irvin, PhD (1992–1998); Jeffrey Jacobs, MD (1996–1997); Alan Kamada, PharmD (1994–1997); Sai Nimmagadda, MD (1993–1996); Kendra Sandoval (1995–1997); Jessica Sheridan (1994–1995); Trella Washington (1993–1997); and Eric Willcutt, MA (1996–1997). We also thank the pediatric allergy and immunology fellows for participation (Kirstin Carel, MD; Neal Jain, MD; Harvey Leo, MD; Beth Macomber, MD; Chris Mjaanes, MD; Lora Stewart, MD; and Ben Song, MD).

University of California, San Diego and Kaiser Permanente Southern California Region, San Diego, CA: Robert S. Zeiger, MD, PhD (director); Noah Friedman, MD (co-investigator); Michael H. Mellon, MD (co-investigator); Michael Schatz, MD (co-investigator); Kathleen Harden, RN (coordinator); Elaine M. Jenson; Serena Panzlau; Eva Rodriguez, RRT; James G. Easton, MD (co-director, 1993–1994); M. Feinberg (1997–1998); Linda L. Galbreath (1991–2002); Jennifer Gulczynski (1998–1999); Ellen Hansen (1995–1997); Al Jalowayski, PhD (co-investigator, 1991–2005); Alan Lincoln, PhD (co-investigator, 1991–2003); Jennie Kaufman (1994); Shirley King, MSW (1992–1999); Brian Lopez (1997–1998); Michaela Magiari-Ene, MA (1994–1998); Kathleen Mostafa, RN (1994–1995); Avraham Moscona (1994–1996); Catherine A. Nelle, RN (1991–2005); Jennifer Powers (2001–2003); Karen Sandoval (1995–1996); and Nevin W. Wilson, MD (co-director, 1991–1993).

University of New Mexico, Albuquerque, NM: H. William Kelly, PharmD (director); Aaron Jacobs (co-investigator); Mary Spicher, RN (coordinator); Hengameh H. Raissy; Robert Annett, PhD (co-investigator, 1993–2004); Teresa Archibeque (1994–1999); Naim Bashir, MD (co-investigator, 1998–2005); H. Selda Bereket (1995–1998); Marisa Braun (1996–1999); Shannon Bush (2002–2006); Michael Clayton, MD (co-investigator, 1999–2001); Angel Colon-Semidey, MD (co-investigator, 1997–2000); Sara Devault (1993–1997); Roni Grad, MD (co-investigator, 1993–1995); David Hunt, RRT (1995–2004); Jeanne Larsson, RN (1995–1996); Sandra McClelland, RN (coordinator, 1993–1995); Bennie McWilliams, MD (co-investigator, director, 1992–1998); Elisha Montoya (1997–2000); Margaret Moreshead (1996–1999); Shirley Murphy, MD (co-investigator, 1992–1994); Barbara Ortega, RRT (1993–1999); David Weers (1997–1998); and Jose Zayas (1995–1996).

Washington University, St Louis, MO: Robert C. Strunk, MD (director); Leonard Bacharier, MD (co-investigator); Gordon R. Bloomberg, MD (co-investigator); James M. Corry, MD (co-investigator); Denise Rodgers, RFPT (coordinator); Lila Kertz, MSN, RN, CPNP; Valerie Morgan, RRT; Tina Oliver-Welker, CRTT; and Deborah K. White, RPFT, RRT.

Resource Centers of the CAMP Research Group

Chair's Office, National Jewish Medical and Research Center, Denver, CO: Reuben Cherniack, MD (study chair).

Coordinating Center, Johns Hopkins University, Baltimore, MD: James Tonascia, PhD (director); Curtis Meinert, PhD (co-director); Patricia Belt; Karen Collins; Betty Collison; Ryan Colvin, MPH; John Dodge; Michele Donithan, MHS; Judith Harle; Rosetta Jackson; Hope Livingston; Jill Meinert; Kapreena Owens; Michael Smith; Alice Sternberg, ScM; Mark VanNatta, MHS; Margaret Wild; Laura Wilson, ScM; Robert Wise, MD; and Katherine Yates, ScM.

Project office, National Heart, Lung, and Blood Institute, Bethesda, MD: Virginia Taggart, MPH (project officer); Lois Eggers; James Kiley, PhD; Gang Zheng, PhDl Paul Albert, PhD (1991–1999); Suzanne Hurd, PhD (1991–1999); Sydney Parker, PhD (1991–1994); Pamela Randall (1992–2003); and Margaret Wu, PhD (1991–2001).

Committees of the CAMP Research Group

Data and Safety Monitoring Board: Howard Eigen, MD (chair); Michelle Cloutier, MD; John Connett, PhD; Leona Cuttler, MD; David Evans, PhD; Meyer Kattan, MD; Rogelio Menendez, MD; F. Estelle R. Simons, MD; Clarence E. Davis, PhD (1993–2003); and Sanford Leikin, MD (1993–1999).

Executive Committee: Reuben Cherniack, MD (chair);Robert Strunk, MD; Stanley Szefler, MD; Virginia Taggart, MPH; James Tonascia, PhD; and Curtis Meinert, PhD (1992–2003).

Steering Committee: Reuben Cherniack, MD (chair); Robert Strunk, MD (vice chair); N. Franklin Adkinson, MD; Robert Annett, PhD (1992–1995, 1997–1999); Bruce Bender, PhD (1992–1994, 1997–1999); Mary Caesar, MHS (1994–1996); Thomas R. DuHamel, PhD (1992–1994, 1996–1999); H. William Kelly, PharmD; Henry Levison, MD (1992–1996); Alan Lincoln, PhD (1994–1995); Ian MacLusky, MD; Bennie McWilliams, MD (1992–1998); Curtis L. Meinert, PhD; Sydney Parker, PhD (1991–1994); Joe Reisman, MD, MBA (1991–1999); Denise Rodgers (2003–2005); Kay Seligsohn, PhD (1996–1997); Gail G. Shapiro, MD; Marian Sharpe (1993–1994); D Sundström (1998–1999); Stanley Szefler, MD; Virginia Taggart, MPH; Martha Tata, RN (1996–1998); James Tonascia, PhD; Scott Weiss, MD; Barbara Wheeler, RN, BSN (1993–1994); Robert Wise, MD; and Robert Zeiger, MD, PhD.