Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Abstract

Inactivating mutations in human ecto‐nucleotide pyrophosphatase/phosphodiesterase‐1 (ENPP1) may result in early‐onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1‐deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1‐Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono‐ and biallelic ENPP1 mutations, 5‐week‐old Enpp1asj/asj mice on the high‐phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1‐Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Musculoskeletal Comorbidities and Quality of Life in ENPP1-Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models

“…ENPP1 deficiency can be associated with elevation of PTH in both humans (28,37) and mice. (22,27) This is also true of other models of elevated FGF23, such as in Hyp mice (38) and humans affected with XLH. (39) Our murine model is consistent with these observations.…”

“…The aforementioned protocols were approved by the National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB). For consistency, naming convention was retained with prior papers characterizing other aspects of the disease (P8 and P11 previously reported in Ferreira et al (2) in 2020; P16, P17, and P18 previously reported in Ferreira et al (22) in 2021).…”

“…The expression, purification, and characterization of the biologic for in vivo use was performed as described. (22,26) Measurement of plasma analytes…”

“…(19) It is unknown whether burosumab can prevent the development of enthesis calcification in patients, but an anti-FGF23 blocking antibody has been shown to attenuate the enthesopathy in a mouse model of XLH. (14) Although ENPP1 enzyme replacement therapy has been previously shown to improve survival, (20) cardiovascular function, (21) and complications from rickets (22) in mouse models of ENPP1 deficiency, no prior work has evaluated the effect of treatment on musculoskeletal comorbidities.…”

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice

“…It has been shown that phosphate and vitamin D supplementation improved rickets and limb deformity in some patients with XLH ( 38–40 ) and ARHR2. ( 41 ) Interestingly, ARHR2 patients treated with phosphate supplementation continue to exhibit low bone mineral density, ( 41 ) and heterozygous ENPP1 deficiency in humans is associated with early onset osteoporosis. ( 21 ) In our study, the asj mice on acceleration diet demonstrated osteopenia/osteoporosis, which was corrected with INZ‐701 treatment.…”