Bone Abstracts

Biallelic ENPP1 deficiency in humans induces hypophosphatemic rickets in children characterized by increased circulating FGF23 levels and renal phosphate wasting (‘Autosomal Recessive Hypophosphatemic Rickets Type 2’, or ARHR2), but osteopenia or osteoporosis has not been described in adults. Here, we describe three adult male patients (ages 43, 59, and 62) suffering from early-onset osteoporosis who presented to the Institute of Osteology and Biomechanics at the University Hospital Hamburg, Germany. Two patients suffered from fractures in their thoracic spine and one a radial fracture. All patients exhibited elevated FGF23 levels and hypophosphatemia. DXA scans of hip demonstrated T-scores below −2.5 and HRpQCT demonstrated significantly reduced trabecular and cortical thickness of the tibia and radius. Next generation sequencing revealed that all 3 patients had heterozygous missense mutations in ENPP1: Y471C (1412A>G) (2 patients) and H777R (2330A>G) (1 patient). Enpp1asj/asj mice, a model of Enpp1 deficiency, were studied to understand the bone pathophysiology underlying this condition. Similar to what was observed in patients, 10 week-old male Enpp1asj/asj mice exhibited elevations in plasma FGF23 (350% of WT), hypophosphatemia (77% of WT), and osteopenia with reduced trabecular bone (trabecular BV/TV was 62% WT) and reduced cortical thickness (78% of WT). Other mineralization parameters in 10 week Enpp1asj/asj mice were as observed in ARHR2 – osteoid width was increased 130% of WT and mineralization lag time (MLT) was 214% of WT. Osteopenia progressed in 23 week-old male Enpp1asj/asj mice – BV/TV was 40% of WT, bone formation rate/bone surface area was 33% of WT, and mineral apposition rate (MAR) was 41% of WT. In conclusion, murine models of Enpp1 deficiency recapitulate the osteomalacia present in ARHR2 children and the osteoporosis present in adults with heterozygous ENPP1 mutations, and can therefore be used to model human bone mineralization disorders associated with ENPP1 deficiency. Our findings further suggest that parents of ARHR2 children may be at risk for early onset osteoporosis.

Disclosure: D.T.B. is an inventor of patents owned by Yale University, which describe therapeutics to treat ENPP1 deficiency. D.T.B is an equity holder and receives research and consulting support from Inozyme Pharma, Inc.