Non-nutritional rickets: Approach, precision medicine, and outcomes

Table 1 Therapies available for X-linked hypophosphatemic rickets and their outcomes

Treatment modalities	Dose	Improvement	No improvement	Caution
Oral phosphorus	Children: 20-60 mg/kg/day in 3-5 divided doses. Adolescents: 3 divided doses. Adults: 800-1600 mg/day in 2 divided doses	Children: (1) Height velocity; and (2) Lower limb deformities. Adults: (1) Osteomalacia related pain[68]; and (2) Periodontitis, dental function[69]. Clinical improvement has been seen in 1-2 years[72]. Corrective surgery for deformities is required in about half the adolescents. Over half may have short stature as adults	Children: Hearing loss. Adults: (1) Osteo-arthritis related pain; and (2) Enthesiopathies	(1) Acidic taste; (2) Gastric discomfort and diarrhoea (doses > 80 mg/kg/day); and (3) SHPT and sub-optimal radiological response, if given without activated forms of vitamin D
Calcitriol	Children: 20-30 ng/kg/day (0.5-1.5 μg/day) in 2-3 divided doses. Adults: 0.50-0.75 μg/day in 2-3 divided doses			(1) To be given only along with oral phosphorus in children; (2) Hypercalciuria; and (3) Nephrocalcinosis[69]
Alphacalcidiol	Children: 40-60 ng/kg/day (1-3 μg/day) in a single daily dose. Adults: 0.75-1.5 μg/day in a single daily dose
Burosumab[62,70]	Children: [Above 6months (as per United States-FDA) or 1 year (as per EMA)] start at 0.8 mg/kg body weight sub-cutaneously every 14 days. In children with weight < 10 kg, start at 1 mg/kg. Maximum dose 2 mg/kg or 90 mg every 14 days. Adults: Initiate at 1 mg/kg sub-cutaneously every 14 days. Increase to maximum dose of 1.8 mg/kg or 90 mg sub-cutaneously every 14 days	Children: (1) Height velocity (normalizes by 2 years); (2) Decreased periodontal abscess; (3) Physical function; and (4) Pain (12 months). Clinically deformities improve in 2-3 years[62]. Biochemically: TmP-GFR increases within 1 week, ALP normalises by 1 year[70]. Adults: (1) Musculoskeletal pain (6-12 months); (2) Decreased renal PO4 wasting and rise in serum PO4 levels (6 months); (3) Stiffness (12 months); (4) ALP (12 months); (5) Radiological signs (12 months); and (6) Fewer endo-dontic infections	Children: Catch-up growth may be slow. Adults: Physical function stiffness	(1) Stop oral phosphorus 1 week prior to initiation of burosumab; (2) Ensure adequate oral calcium intake; (3) Stop in adolescent and adult females who are sexually active unless using contraception; and (4) Contraindicated in pregnancy but not in lactation
Recombinant growth hormone	Children: 0.6-1 U/kg/week	Children: (1) Height velocity; and (2) PO4 retention	Children: No difference in final height compared to none	Adjunct to conventional therapy or burosumab. Pre-requisite: Adequately controlled bony deformities, ALP and PTH

FDA: Food and Drug Administration; EMA: European Medicines Agency; TmP: Tubular maximum reabsorption of phosphate; GFR: Glomerular filtration rate; ALP: Alkaline phosphatase; PO₄: Phosphorus; SHPT: Secondary hyperparathyroidism; PTH: Parathyroid hormone.