Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1)

Abstract

Context: Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects.

Objective: The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1.

Results: Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported following burosumab administration.

Conclusion: The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1.

Keywords: FGF23; burosumab; hypophosphatemic rickets; osteomalacia; pseudofractures.

Figure 1.

A, Computed tomography scan imaging of the cervical spine at presentation, showing fusion of the vertebral bodies by syndesmophytes (arrowheads) and ossification of the posterior longitudinal ligament (arrows) leading to central canal stenosis. B, Whole-body Tc-99m-MDP bone scan demonstrating bone tracer uptake at the ankles, knees, hips, wrists, and shoulders, consistent with arthropathy. C, Longitudinal view of serum levels for alkaline phosphatase (ALP) activity, bone Gla-protein (BGP), 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]₂D), parathyroid hormone (PTH), and phosphate (PO₄) before and following initiation of burosumab treatment (red arrow)/dashed line. Red circles indicate blood samples drawn 2 weeks following burosumab administration; red square indicates blood sample drawn just prior to the next burosumab dose. Normal ranges are indicated by the correspondingly colored rectangles. The treatment periods with ursodiol, cholecalciferol, and calcitriol are illustrated by black arrows.

Figure 2.

A, Radiograph demonstrating the marked bowing of the right femur (left panel). Intramedullary rod in the tibia. Sequela of a previous fracture that has healed (arrowhead), with distal tibia-fibula ankyloses at the level of the distal interosseous membrane (arrow) (right panel). B, Computed tomography scan imaging of the facial bones shows the ossification within the inferior aspect of the temporalis muscles bilaterally (arrows). C, Longitudinal view of serum levels for alkaline phosphatase (ALP) activity, bone Gla-protein (BGP), 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]₂D), parathyroid hormone (PTH), and phosphate (PO₄) before and following initiation of burosumab treatment (red arrow)/dashed line. Red circles indicate blood samples drawn 2 weeks following burosumab administration; red squares indicate blood samples drawn just prior to the next burosumab dose. Normal ranges are indicated by the correspondingly colored rectangles. The treatment periods with cinacalcet, cholecalciferol, and calcitriol are shown. D, Imaging of the right femur demonstrates a horizontal line with sclerotic edges at the level of the lesser trochanter, indicative of a pseudofracture (arrow, left panel). The same femur, 5 months into treatment with burosumab, with only a very subtle fracture line still visualized, consistent with ongoing healing (arrow, right panel). E, Following the second surgery, illustrating the maximal mouth opening achieved (2 fingerbreadths as compared to less than 1 fingerbreadth before surgery).