What is the role of pharmacologic therapy in the treatment of hypophosphatemic rickets?

Updated: May 18, 2020
  • Author: James CM Chan, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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In April 2018, the FDA approved burosumab, the first drug for X-linked hypophosphatemia (XLH). Burosumab is a monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23). This action normalizes phosphorus levels, improves bone mineralization, improves rickets in children, and helps to heal fractures in adults. [8, 9, 10]

Approval for children followed a 64-week, randomized, open-label study in 52 patients aged 5 to 12 years, in which burosumab therapy was associated with an improvement in rickets, a rise in serum phosphorus levels, a reduction in serum alkaline phosphatase activity, and an increase in growth. Forty-week data from an open-label study in 13 patients aged 1 to 4 years also back up the indication, with burosomab showing similar benefits to the 64-week study. [8, 9, 10]

Approval in adults with XLH (n=134) was supported by a randomized, double-blind, placebo-controlled study. Compared with patients on placebo, a higher proportion of burosumab-treated adults attained serum phosphorus levels above the lower limit of normal. In addition, the rate of complete healing for active fractures and pseudofractures for burosumab treatment outpaced that of placebo therapy. A 48-week, open-label, single-arm bone biopsy study in 14 adults also bolstered the adult indication, with osteomalacia healing revealed by decreases in osteoid volume/bone volume, osteoid thickness, and mineralization lag time. [31, 32, 8, 9, 10]

The usual vitamin D preparations are not useful for treatment in this disorder because they lack significant 1-alpha-hydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000-50,000 U/d (at the lower limit of toxic dosage), which placed the patient in jeopardy of frequent hypercalcemic episodes. Calcitriol is now more widely available and substantially diminishes, but does not eliminate, this risk. Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis. [11]

Healing of the rachitic changes typically occurs within 6-8 weeks of instituting treatment. During this time, maintain the calcitriol within the recommended dosage to maintain serum calcium and phosphate levels within reference ranges. Monitor these levels weekly over the first 2-3 months of treatment. Urinary calcium and phosphate excretion monitoring also are important.

The patient's requirements for calcium deposition and vitamin D to expedite the healing process diminish as healing progresses; thus, the patient with hypophosphatemic rickets becomes highly susceptible to hypercalcemia during this phase. Consider reducing the calcitriol dosage at this time, guided by the weekly calcium and phosphorus measurements, until a reduced and stable dosage is reached.

Attempts have been made in clinical trials to address patient stature by adding growth hormone (GH) to the usual treatment protocol to stimulate growth plates in the long bones. At least one study reported a mild degree of disproportionate truncal growth, which requires further evaluation. (See Medication.) [33, 34] Although GH therapy has been effective in promoting short-term growth, its high cost discourages widespread use.

A randomized, controlled, open-label study by Meyerhoff et al suggested that growth hormone (GH) therapy in short prepubertal children with X-linked hypophosphatemic rickets does not effectively increase adult height. In terms of exceeding baseline values, standard deviation scores (SDSs) for adult height, leg length, and arm length were not significant in patients who underwent 3 years of GH treatment (although the SDS for sitting height was). Body disproportion was not found to be exaggerated by GH. [35]

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