1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression

Abstract

X-linked hypophosphatemia (XLH) is characterized by impaired renal tubular reabsorption of phosphate due to increased circulating FGF23 levels, resulting in rickets in growing children and impaired bone mineralization. Increased FGF23 decreases renal brush border membrane sodium-dependent phosphate transporter IIa (Npt2a) causing renal phosphate wasting, impairs 1-α hydroxylation of 25-hydroxyvitamin D and induces the vitamin D 24-hydroxylase leading to inappropriately low circulating levels of 1,25-dihydroxyvitamin D (1,25D). The goal of therapy is prevention of rickets and improvement of growth in children by phosphate and 1,25D supplementation. However, this therapy is often complicated by hypercalcemia and nephrocalcinosis, and does not always prevent hyperparathyroidism. To determine if 1,25D or blocking FGF23 action can improve the skeletal phenotype without phosphate supplementation, mice with XLH (Hyp) were treated with daily 1,25D repletion, FGF23 antibodies (FGF23Ab), or biweekly high dose 1,25D from d2 to d75 without supplemental phosphate. All treatments maintained normocalcemia, increased serum phosphate and normalized parathyroid hormone levels. They also prevented the loss of Npt2a, α-Klotho and pERK1/2 immunoreactivity observed in the kidneys of untreated Hyp mice. Daily treatment with 1,25D decreased urine phosphate losses despite a marked increase in bone FGF23 mRNA and in circulating FGF23 levels. Daily 1,25D was more effective than other treatments in normalizing the growth plate and metaphyseal organization. In addition to being the only therapy that normalized lumbar vertebral height and body weight, daily 1,25D therapy normalized bone geometry and was more effective than FGF23Ab in improving trabecular bone structure. Daily 1,25D and FGF23Ab improved cortical microarchitecture and whole-bone biomechanical properties more so than biweekly 1,25D. Thus, monotherapy with 1,25D improves growth, skeletal microarchitecture and bone strength in the absence of phosphate supplementation despite enhancing FGF23 expression, demonstrating that 1,25D has direct beneficial effects on the skeleton in XLH, independent of its role in phosphate homeostasis.

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

“…It is not clear whether or not a calcitriol-alone therapy will prove beneficial for other forms of FGF23-mediated hypophosphatemia such as TIO, ADHR, ARHR, and CSHS, which do not appear to have a primary phosphate-sensing defect. Furthermore, although 1,25-D can stimulate gastrointestinal phosphate absorption, which appeared to be the case in the study by Liu and colleagues, (19) the extent to which it can stimulate gastrointestinal phosphate absorption may be limited (48) and not sufficient in cases of more profound hypophosphatemia.In addition to the previously mentioned novel therapy of FGF23Abs, is the recently reported efficacy of FGFR signaling inhibition by the specific pan FGFR inhibitor, BGJ398, in both preclinical (49) and clinical settings.(50) FGF23Ab (KRN23) and BGJ398 are currently under investigation and, if eventually available, will add to the armamentarium of drugs to treat FGF23-mediated phosphate-wasting disorders. The latest approach to be considered for treating FGF23 excess is the very recently reported inhibition of renal 24-hydroxylation of 25-hydroxyvitamin D with the 24-hydroxylase inhibitor, CTA102.…”

“…(47) Therefore, revisiting this issue in the modern era, as proposed by Liu and colleagues, (19) is important. It is not clear whether or not a calcitriol-alone therapy will prove beneficial for other forms of FGF23-mediated hypophosphatemia such as TIO, ADHR, ARHR, and CSHS, which do not appear to have a primary phosphate-sensing defect.…”

“…(35) In spite of these issues, the data presented by Liu and colleagues (19) are convincing and may have important clinical implications. If these findings prove promising in further preclinical studies with appropriate controls, and confirmed in well-controlled studies in subjects with XLH, it could bring about a major change in the way disorders of FGF23 excess are treated.It is of interest and import to note though that over 35 years ago, in the pre-FGF23-discovery era, the calcitriol-alone approach suggested by Liu and colleagues (19) had been assessed and judged to be an effective treatment in both hyp mice (31,36) and XLH. (35) Interpretation of these studies is difficult though due to both design flaws in the early clinical studies (lack of systematic treatment and control groups) and lack of modern reagents and assays.…”

“…Hypercalciuria can ensue, especially if calcium is increased enough to suppress PTH below the point necessary to promote adequate renal calcium reabsorption. In this context, Liu and colleagues (19) explored the therapeutic effects of calcitriol without phosphate supplementation on several biochemical and skeletal parameters in hyp mice.Hyp mice were treated for 75 days with calcitriol, either daily or twice weekly at a dose to maintain eucalcemia, and compared to mice treated with an anti-FGF23 antibody (FGF23Ab), and untreated hyp and wild-type (WT) mice. All treatment modalities resulted in a significant increase in serum phosphate with decreases in urinary phosphate excretion and serum PTH without inducing hypercalcemia or affecting renal function; urinary calcium excretion was not assessed.…”

“…(17,18) In this issue of the Journal of Bone and Mineral Research, Liu and colleagues (19) undertake a straightforward, interesting, and potentially clinically relevant approach to the study and treatment of the hyp mouse, the animal model for XLH. The hyp mouse was the first genetic animal model employed to study disorders of FGF23.…”