The goal of this short term prospective Phase II study is to compare the effects of two alternate daily doses of zinc (25 and 40 mg/day) in 34 randomly assigned homozygous Sickle Cell Disease (SCD-SS) patients aged 15-40 years old. The main question it aims to answer is: Which biomarkers are most responsive to zinc supplementation, and what is the maximum tolerated zinc dose that induces the desired changes in biomarkers of bone turnover? Participants will be recruited from 6 American Society Hematology Research Collaborative SCD Centers. Eligible SCD subjects will be invited to participate in the 16-week study, involving 2 baseline blood draws 4 weeks apart, followed by a 12-week zinc intervention. The findings from this study will be used to determine the dosage of zinc to be used in a larger, future study on the long term impact of zinc supplementation on bone health in SCD-SS.

The investigators propose a two-arm, double-blinded, Phase II study comparing the effects of two different daily doses of zinc (25 and 40 mg/day) in 34 patients with SCD-SS aged 15-40 years old, randomly assigned to either group. The aim of the study is to determine the maximum tolerated zinc dose that induces desired changes in rates of bone formation and resorption. The findings from this study will function as preliminary data for a future randomized clinical trial and provide a novel characterization of bone marker response to short term zinc supplementation in SCD that has not previously been described in the literature.

SCD is the most prevalent heritable disorder affecting red blood cells worldwide. It is an autosomal recessive genetic condition inherited at birth when a child receives two genes, one from each parent, coding for abnormal hemoglobin. The defective hemoglobin proteins characteristic of SCD give rise to sickle-shaped red blood cells causing serious health complications, including early onset bone morbidity. Over half of young adults with SCD have osteoporosis 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 frequently in patients with SCD and has been related to poor growth, increased vaso-occlusive crises 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. The investigators hypothesize that bone deficits in individuals with SCD are in part due to zinc deficiency caused by oxidative stress induced hemolysis and elevated bone turnover, and these bone defects can be ameliorated by zinc supplementation.

Studies indicate that zinc improves bone density in thalassemia, a related hemoglobinopathy (Fung, 2013). But thus far, there have not been any randomized prospective studies analyzing the impact of zinc on bone health in individuals with SCD. Although emerging studies have reported that zinc supplementation might improve growth and has the potential for reducing the number and severity of sickle-related painful events, these studies are single center, small and short term. Moreover, there are currently no therapies in SCD focused on bone morbidity, and there is much enthusiasm among individuals with SCD towards participation in a nutritional intervention. A large, multicenter, long term trial of zinc supplementation focused on disease outcomes in SCD is warranted.

In order to determine the optimal tolerated dose of zinc for implementation in a future randomized clinical trial, the investigators have proposed a short term interventional study comparing the effects of two different doses of zinc, 25 vs. 40 mg/day. Subjects will be included if they are between 15 and 40 years of age, have been diagnosed with SCD-SS and are in their steady state of health. The study is a 16-week program, involving 2 baseline blood draws 4 weeks apart, followed by a randomized 12-week zinc intervention. Over the course of the study, the change in measures of bone formation and resorption, will be compared between the usual care period (0 to 4 weeks) and the intervention period (4 to 16 weeks).

Inclusion Criteria:

• Age: ≥ 15.0 to ≤ 40.0 years
• Diagnosis: SCD-SS or SCD-S Beta zero Thalassemia, in steady state (defined as a minimum of 2 weeks days following pain crisis)
• Male or Female

Exclusion Criteria:

• Taking any supplement containing zinc and unable/willing to stop for 3 months prior to study start
• 25-Hydroxy Vitamin D < 20 ng/mL
• On chronic transfusion therapy (defined as >8 Transfusions/year) and iron overloaded (defined as liver iron concentration > 7 mg/g OR average serum ferritin >4000 ug/L)
• Unable swallow pills or take daily supplement as instructed
• Currently participating in another investigational drug trial
• Prior diagnosis of chronic kidney disease (eGFR < 30 mL/min/1.73m2)

Data sharing available upon request after the completion of the trial

upon completion of the trial the information will be available for 1 year

n/a the 2 zinc capsule dosages (25 and 40 mg) will be compounded to look identical