Zinc Supplementation in SCD: A Precursor to the Think Zinc for Bones Trial

Abstract Patients with sickle cell disease (SCD) experience early onset bone morbidity; 60% of young adults with SCD live with low bone mass and are at increased risk for fracture. Zinc, an essential trace mineral, is crucial for red cell stability, growth, and bone metabolism. Zinc deficiency is reported in approximately 40% of young patients with SCD and has been related to poor growth, increased vaso-occlusive episodes, and decreased bone density. The etiology of zinc deficiency in SCD is multifactorial, including inadequate dietary intake, increased requirements due to escalations in red cell turnover, and elevated urinary losses from renal insufficiency. Our underlying hypothesis is that that zinc supplementation can ameliorate the steady deterioration of bone mass and structure in individuals with SCD. Though vitamin D has received much attention, zinc is perhaps more important for bone health, particularly for patients with SCD. In a previous interventional trial, we demonstrated that zinc supplementation increased bone density in patients with thalassemia, a hemoglobinopathy with similar bone deficits. Meta-analyses reported that zinc supplementation has the potential to improve growth and reduce the number and severity of sickle cell-related pain episodes. Yet, most of the reviewed studies are small, short-term, and single-center and none of the prior trials focused on bone outcomes. A Cochrane Review concluded that large, multi-center, long-term zinc supplementation trials focused on disease outcomes in sickle cell disease are needed. Although much attention has been paid recently to curative therapies for patients with SCD, very few patients will have access to these new therapeutics. Currently, no therapies in SCD focus on bone morbidity. The findings of this proposed research could lead to a new, low-cost adjunctive therapeutic paradigm that will improve the lives of individuals with SCD. Our investigative team demonstrates expertise to conduct a randomized multicenter nutritional study in SCD. The ASH Research Collaborative Clinical Trials Network is poised to facilitate such an interventional trial, and the patients with SCD and their families have expressed enthusiasm for participation in nutritional studies. This R34 phase is crucial for the follow-up UG3/UH3 funded study by obtaining data to: (1) clarify optimal skeletal sites to be studied by DXA imaging, (2) calculate more definitive sample size for the subsequent larger study, (3) establish an effective yet tolerable zinc dose, and (4) develop quality control imaging and blood collection protocols. The information gathered from this R34 study is indispensable for designing a robust, multi-center randomized clinical trial within the ASH Research Collaborative Clinical Trials Network. By determining these critical parameters, we will significantly enhance the likelihood of conducting a successful and scientifically rigorous larger ASH Research Collaborative Network UG3/UH3 funded study focused on bone response to zinc supplementation.