Calcitriol in Friedreich Ataxia

We read with interest the recent open label trial (n = 20) of 0.25 mcg/24 h of oral calcitriol in individuals 16 to 65 years old with genetically confirmed Friedreich Ataxia (FRDA).¹

The authors performed this trial to follow up on previous in vitro studies in which supplementation with calcitriol (eg, 20 nmol/L) in dorsal root ganglion neurons produced biochemical changes, including restoration of mitochondrial membrane potential, decrease in markers of apoptosis and degeneration, and cell survival.² Of note, the highest upper limit of the physiologic reference range for peripheral blood 1,25-dihydroxyvitamin D (eg, Mayo Clinic, females <16 years) is 86 pg/mL or 215 pmol/L or 0.2 nmol/L, two orders of magnitude below the values achieved in vitro with calcitriol supplementation. Therefore, dose selection becomes a highly relevant consideration for this translational study. Moreover, vitamin D metabolism is cell- and tissue-specific. Thus, it challenging to extrapolate from 1,25-dihydroxyvitamin D measurements made in vitro or even in vivo in peripheral blood to predict the effects of calcitriol supplementation in cardiac, musculoskeletal, or central nervous system in humans.³

The dose of 0.25 mcg of calcitriol is cited as “low” by the group, but this designation is misleading, because calcitriol is most often prescribed to address hypocalcemia or secondary hyperparathyroidism in individuals with kidney disease or hypocalcemia in individuals with hypoparathyroidism. Individuals with FRDA do not have these disorders, nor is there clear evidence of overt deficiency in 1,25-OH-vitamin D in FRDA. Therefore, whereas this calcitriol dose might be considered “low” for individuals who meet typical indications, the dose is supra-physiologic for most others, including those with FRDA.

The most concerning claim of this study is that this regimen is safe. Of the 20 participants initially studied, five were withdrawn for what were indeed conservative stopping criteria for hypercalcemia; still, one quarter represents a sizeable proportion. Moreover, the study did not include additional safety assessments to support the safety claim, for example, measurement of urinary calcium excretion (a more sensitive measurement of excess 1,25-OH-vitamin D exposure depleting calcium stores from bone) or dual energy x-ray absorptiometry (to assess areal bone mineral density), which is relevant given many individuals with FRDA already have impaired bone health.^{4, 5} Perhaps most relevant, participants were required to stop taking any supplemental calcium and/or vitamin D3 in the 30 days before enrollment. If these individuals were not consuming the typical recommended daily intake of calcium and vitamin D3, and given the established risk of vitamin D insufficiency in this population from previous studies, then such a decision is contrary to care guidelines that advocate ensuring adequate calcium and vitamin D intake in all individuals, especially those at risk for fragile bones.⁶

Moreover, the modest change in frataxin in this uncontrolled study was not accompanied by any changes in clinically relevant outcomes. Studies of even higher doses of calcitriol are proposed by the authors, which do not seem warranted until and unless the above issues are considered and addressed. Especially given the ready availability of calcitriol, the FRDA community deserves clarity on the safety and efficacy of its supplementation.

SEM, DRW, DRL: writing and editing of the final version of the manuscript.