Endocrine Abstracts

JOINT933

Background: Biallelic loss-of-function (LOF) ENPP1 variants cause generalized arterial calcification of infancy type 1 (GACI1) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 encodes an enzyme that generates inorganic pyrophosphate (PPi), a mineralization inhibitor. Loss of ENPP1 function leads directly to PPi deficiency and indirectly to fibroblast growth factor 23 (FGF-23) excess. Animal data support a role for ENPP1 as a regulator of bone mass; case reports suggest that humans with monoallelic ENPP1 variants may develop osteoporosis. The objective of this study was to characterize bone density, strength, and mineral metabolism in adults with monoallelic ENPP1 variants.

Methods: Symptomatic (atraumatic vertebral or long bone fractures, pain interference, early onset cardiovascular disease) and asymptomatic individuals with monoallelic ENPP1 variants were eligible. Outcome measures included whole body, hip, lumbar spine, and forearm areal bone mineral density (aBMD) by dual energy X-ray absorptiometry (DXA, Hologic), cortical and trabecular volumetric BMD (vBMD) and strength (stiffness, failure load) of the radius and tibia by high resolution peripheral quantitative computed tomography (HR-pQCT, Scanco) expressed as Z-scores for age and sex. Mineral metabolism markers were determined by standard clinical assays, PPi by an ATP sulfurylase/luminescence-based enzymatic method (Inozyme).

Results: Twenty individuals (11 female, 10 symptomatic), median age 38 years (range 20-54) completed the study. Thirteen participants (65%) reported a total of 27 lifetime fractures. Within the symptomatic cohort, pain interfering with daily activities was the most prevalent symptom (80%); demographics did not differ by symptomatic status. Mean (±SD) aBMD-Z ranged from -0. 4±0. 8 (forearm) to 0. 3±0. 6 (whole body); no subjects had low aBMD at any site. HR-pQCT analysis revelaed relative deficits in trabecular vBMD vs cortical vBMD at distal radius (-0. 9±1. 1 vs 0. 3±0. 7, P < 0. 01) with a similar trend at distal tibia (-0. 9±1. 1 vs -0. 3±1. 2, P = 0. 18). Failure load and stiffness Z-scores were both -0. 4±0. 6 at the radius and -0. 8±0. 9 at the tibia. Blood phosphate and alkaline phosphatase were normal in all participants; FGF-23 was elevated in one male. PPi did not differ by symptomatic status and was not correlated with bone outcomes.

Conclusion: Fractures and musculoskeletal pain were common in this cohort of adults with monoallelic ENPP1 variants. In contrast to prior reports, aBMD was normal in all participants. Mild deficits in trabecular vBMD and bone strength were found by HR-pQCT; however, these were not related to symptomatic status, serum PPi, or markers of mineral metabolism. Further genotype/phenotype studies may clarify the contribution of ENPP1 to bone health.