New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia

Abstract

Phosphorus is one of the most abundant minerals in the human body; it is required to maintain bone integrity and mineralization, in addition to other biological processes. Phosphorus is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], and fibroblast growth factor 23 (FGF-23) in a complex set of processes that occur in the gut, skeleton, and kidneys. Different molecular mechanisms -overproduction of FGF-23 by tumors responsible for oncogenic osteomalacia, generation of an FGF-23 mutant that is resistant to cleavage by enzymes, and impaired FGF-23 degradation due to a reduction in or loss of the PHEX gene -can lead to FGF-23-stimulating activity and the consequent waste of urinary phosphate and low levels of 1,25(OH) 2 D 3 . Conventional treatment consists of multiple daily doses of oral phosphate salts and vitamin D analogs, which may improve radiographic rickets but do not normalize growth. Complications of the conventional longterm treatment consist of hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired renal function, and potentially chronic kidney disease. Recently, burosumab, an antibody against FGF-23, was approved as a novel therapy for children and adults with X-linked hypophosphatemia and patients with tumor-induced osteomalacia. Burosumab showed good performance in different trials in children and adults. It increased and sustained the serum phosphorus levels, decreased the rickets severity and pain scores, and improved mineralization. It offers a new perspective on the treatment of chronic and disabling diseases.

A Case of Tumor-Induced Osteomalacia Detected by Venous Sampling

“…When surgery is difficult due to inability to localize the tumor or for other reasons, treatment with phosphorus and vitamin D supplementation is the second choice, although it is associated with the risk of nephrocalcinosis, nephrolithiasis, hypoadrenocorticism, and hypercalciuria. 3 , 12 Since 2018, burosumab has become clinically available in Europe and other countries for the treatment of X-linked hypophosphatemia in children. 13 Furthermore, burosumab resulted in increased serum phosphorus levels and improved fracture healing, bone pain, functional mobility, and health-related quality of life in patients with TIO in Phase 2 studies.…”

The Intricacies of Renal Phosphate Reabsorption—An Overview

“…Already, knowledge of the cellular mechanisms has indicated potentially useful ways to treat conditions with disordered phosphate metabolism. Treatment with Burosomab, an FGF23 antibody is now an approved therapy for X-linked hypophosphatemic rickets and inoperable TIO, to tackle persistent hypophosphatemia due to a primary increase in FGF23 production [32]. In cystic fibrosis due to F508del CFTR, the CFTR corrector VX-809 increases the binding affinity between NHERF1 PDZ1 and the mutant protein and its membrane stability [361,362].…”

“…Another approach under investigation is to increase FGF23 clearance by inhibiting 0-glycosylation by GALNT3, which normally protects FGF23 from proteolysis. Use of FGF23 C-terminal fragments to block interaction of FGF23 with FGFR1c-klotho and of other agents to inhibit FGFR signalling are also being considered [32]. The demonstration that PTH signalling continues after PTH/PTH1R internalisation [23] is driving research to develop a PTHrP derivative with extended activity will enhance the benefits of intermittent treatment with abaloparatide, a human parathyroid hormone-related peptide analogue, on bone mineral density in osteoporosis [9,23,112].…”

“…With the very powerful analytical tools now available, the complexity, speed 2 and amazing co-ordination of the processes involved have become increasingly apparent [11,12,23,24]. Already, findings have shown new avenues for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders [12,19,23,[25][26][27][28][29][30][31][32][33].…”

The Intricacies of Renal Phosphate Reabsorption—An Overview

“…With the very powerful analytical tools now available, the complexity, speed, and amazing co-ordination of the processes involved have become increasingly apparent [11,12,23,24]. Already, findings have shown new avenues for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders [12,19,23,[25][26][27][28][29][30][31][32][33][34].…”