Bone Matrix Mineralization and Response to Burosumab in Adult Patients With X-Linked Hypophosphatemia: Results From the Phase 3, Single-Arm International Trial

Abstract

X-linked hypophosphatemia (XLH) is characterized by excess fibroblast growth factor 23 (FGF23) secretion, renal phosphate wasting, and low 1,25(OH) 2 D 3 . Adult patients present with osteomalacia, hypomineralized periosteocytic lesions, bone fragility, and pain. Burosumab is a fully human monoclonal FGF23 antibody approved for XLH treatment. UX023-CL304 was an open-label, phase 3 study investigating the effects of burosumab on osteomalacia in adults with XLH, who remained untreated at least 2 years prior enrollment. Here, we present the effect of burosumab on bone material properties. We analyzed transiliac bone biopsy samples from 11 individuals before and after 48 weeks of subcutaneous burosumab treatment (1.0 mg/kg administered every 4 weeks). We used quantitative backscattered electron imaging (qBEI) and Fourier transform infrared imaging (FTIRI) to assess bone mineralization density distribution (BMDD), mineralized bone volume, properties of the organic matrix, and size of periosteocytic lesions. The outcomes were compared with reference values from healthy adults and with four XLH patients either untreated or treated by conventional therapy. Prior to burosumab, the average mineralization in cancellous bone was lower than in healthy reference. CaLow, the fraction of lowly mineralized matrix, and CaHigh, the fraction of highly mineralized matrix, were both elevated resulting in a broad heterogeneity in mineralization (CaWidth). Burosumab resulted in a decrease of CaHigh toward normal range, whereas CaLow and CaWidth remained elevated. The mineralized bone volume was notably increased (+35.9%). The size of the periosteocytic lesions was variable but lower than in untreated XLH patients. FTIRI indicated decreased enzymatic collagen crosslink ratio heterogeneity. In summary, matrix mineralization in XLH is very heterogeneous. Highly mineralized regions represent old bone packets, probably protected from osteoclastic resorption by osteoid seams. The concomitant decrease of highly mineralized matrix, persistence of lowly mineralized matrix, and increase in mineralized bone volume after burosumab suggest a boost in mineralization of preexisting unmineralized or very lowly mineralized matrix, providing a potential explanation for previously observed improved osteomalacia.

Approaching virtual osteoid volume estimation and in-depth tissue characterization in patients with tumor-induced osteomalacia

“…Consistent with these findings, the qBEI analysis revealed larger areas of low mineral content (Ca low ) in TIO, supporting previous observations in TIO 35 and other phosphate wasting disorders such as X-linked hypophosphatemia. 36 However, mean mineralization was not changed significantly between TIO and OPO, yet TIO samples exhibited an intermediate state of mineralization when considering control and OPO, pinpointing the HR-pQCT results with only light differences in mineralization. When analyzing Ca low in OPO patients, elevated values became evident in comparison to control subjects.…”

Real‐world data of Brazilian adults with X‐linked hypophosphatemia (XLH) treated with burosumab and comparison with other worldwide cohorts

“…Surprisingly, as mentioned in the results, patients experienced a significant increase in stature during treatment with burosumab, despite being adults and having already completed the growth period. This finding could be attributed to the improvement of deformities in the lower limbs with a better bone mineralization in different compartments (Fratzl‐Zelman et al., 2022).…”

Interactions between FGF23 and vitamin D

“…Burosumab, a human MAB, binds and blocks the action of FGF23. A double-blind, placebo-controlled, phase 3 trial with burosumab on symptomatic adults with XLH showed improvements in the mineralization process of preexisting unmineralized bone matrix ( 52 ). The safety profile of FDA-approved burosumab is claimed to be similar to placebo ( 53 ).…”