Low Bone Density Associates with Severe Outcomes in Young Adults with Sickle Cell Disease

Introduction

Skeletal complications are prevalent in sickle cell disease (SCD) and cause severe pain, disability, missed school and employment opportunities. Our previous study in a pediatric SCD cohort, showed that bone mineral density (BMD) declines with age, and low BMD independently associates with hip avascular necrosis (AVN) and chronic pain. The natural history of low BMD in adults with SCD is less well understood. Prior studies had limited ability to identify risk factors that prospectively predicted low BMD. Using data from the longitudinal Sickle Cell Clinical Research and Intervention Program (SCCRIP), we investigated the prevalence of and clinical risk factors for low BMD in children, adolescents and young adults.

Methods

We analyzed areal BMD (aBMD) data in SCCRIP participants (ages 6-25 years), with atleast one dual energy X-ray absorptiometry (DXA) scan of the posterior anterior spine and whole body (WB) obtained between Apr 2014 to Dec 2021. Participants were grouped as: school-age (6 to <12 years), adolescents (12 to <18 years) and young adults (18-25 years). We collected clinical variables from birth up to the DXA date: frequency of vaso-occlusive episodes (VOEs), hydroxyurea (HU), chronic red blood cell transfusions (CTX), and concurrent hip AVN; and laboratory data obtained at steady state on or within 30 days of the DXA scan (complete blood count, quantitative fetal hemoglobin (Hb F), creatinine, calcium, lactate dehydrogenase, liver enzymes, high-sensitivity C-reactive protein, and 25-hydroxyvitamin D (vitamin D) levels).

Spine and WB aBMD were expressed as age-, sex-, and ancestry-specific aBMD Z-scores of the spine and WB for all study participants. To account for growth stunting or delayed puberty, aBMD Z-scores from participants <18 years were height-adjusted using published equations. Participants with aBMD Z-scores ≤ −2 were grouped as low BMD, while those with aBMD Z-scores >−2 were grouped as normal BMD. We compared clinical and laboratory values for the low and normal aBMD groups using Fisher’s exact test or χ² test for categorical variables, and a 2-sample Student t test or Wilcoxon rank sum test for continuous variables. Unadjusted variables with a p<0.1 were included in the multivariate generalized linear mixed model (GLMM) with binomial link function to determine the odds ratio (OR) and 95% confidence interval (CI) for low aBMD.

Results

Of the 572 DXA scans obtained from 441 participants (49% females, mean age 12.56 years) with SCD (HbSS/Sβ⁰ genotype), 180 (31%) came from children, 317 (55%) adolescents, and 75 (13%) young adults. Low WB aBMD prevalence was 34% in children, 51% in adolescents, and 58% in young adults (p<0.0001), low spine a BMD prevalence was 2% in children, 12% in adolescents and 28% in young adults (p=0.009).

Univariate analyses showed that low WB aBMD associated with older age (OR 1.08 95%CI: 1.03-1.14), low hemoglobin (OR 0.83; 95%CI: 0.69-0.99), and low Hb F (OR 0.95; 95%CI: 0.92-0.97), all p<0.05. In reduced multivariable GLMM analysis, age (OR 1.06; 95%CI: 1.01-1.11,) and Hb F (OR 0.96, 95% CI: 0.93-0.98) significantly associated with low WB aBMD.

Using a threshold of p<0.1 for the univariate analyses, we found that low PA spine aBMD associated with age(OR 1.57, 95% CI: 1.11-1.71), VOEs (OR 1.02, 95%CI: 0.99-1.04), hip AVN (OR 8.08, 95%CI: 2.01-32.5), HU or CTX use (OR 21.7, 95%CI: 8.4-56), alkaline phosphatase (OR 0.994, 95%CI 0.99-0.999), calcium (OR 0.08, 95%CI 0.04-0.20), serum creatnine (OR >99, 95%CI: >99->99), Vitamin D (OR 0.96, 95%CI 0.93-0.99), and WBC count (OR 1.07, 95%CI 0.99-1.16). In multivariable GLMM analysis, age (OR 1.48; 95%CI: 1.35-1.61), WBC (OR 1.16; 95%CI: 1.05-1.27), and HU use (OR=18, 95%CI: 6-58) significantly associated with low PA spine aBMD, all p<0.005.

Conclusion

We found that aBMD declined with age, and low aBMD was more prevalent in the WB than the spine. In addition to age, lower Hb F associated with low WB aBMD, while higher WBC and HU use associated with low spine aBMD. These findings suggest that underlying inflammation and more severe SCD complications contribute to low aBMD, while Hb F is protective. Ongoing analysis of this longitudinal cohort will clarify SCD-related factors that predict low aBMD. Our study underscores the need to investigate the age-related increase in prevalence of low aBMD and develop strategies to improve skeletal health in people with SCD.