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

Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency leads to cardiovascular calcification in infancy, fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets in childhood, and osteomalacia in adulthood. Excessive enthesis mineralization and cervical spine fusion have been previously reported in patients with biallelic ENPP1 deficiency, but their effect on quality of life is unknown. We describe additional musculoskeletal complications in patients with ENPP1 deficiency, namely osteoarthritis and interosseous membrane ossification, and for the first time evaluate health-related quality of life (HRQoL) in patients with this disease, both subjectively via narrative report, and objectively via the Brief Pain Inventory-Short Form, and a Patient Reported Outcome Measurement Information System Physical Function (PROMIS PF) short form. Residual pain, similar in magnitude to that identified in adult patients with X-linked hypophosphatemia, was experienced by the majority of patients despite use of analgesic medications. Impairment in physical function varied from mild to severe. To assess murine ENPP1 deficiency for the presence of enthesopathy, and for the potential response to enzyme replacement therapy, we maintained Enpp1^asj/asj mice on regular chow for 23 weeks and treated cohorts with either vehicle or a long-acting form of recombinant ENPP1. Enpp1^asj/asj mice treated with vehicle exhibited robust calcification throughout their Achilles tendons, whereas two-thirds of those treated with ENPP1 enzyme replacement exhibited complete or partial suppression of the Achilles tendon calcification. Our combined results document that musculoskeletal complications are a significant source of morbidity in biallelic ENPP1 deficiency, a phenotype which is closely recapitulated in Enpp1^asj/asj mice. Finally, we show that a long-acting form of recombinant ENPP1 prevents the development of enthesis calcification at the relatively modest dose of 0.3 mg/kg per week, suggesting that suppression of enthesopathy may be attainable upon dose escalation. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Keywords: ENPP1 DEFICIENCY; ENTHESOPATHY; ENZYME REPLACEMENT THERAPY; HEALTH-RELATED QUALITY OF LIFE.

Fig. 1.

(A) Calcification of the common extensor tendon enthesis (arrow) (P8, 25 years 6 months). (B) Fusion of the C2-C3 and C4-C5 posterior vertebral bodies, articular processes, and laminae (arrows) (P8, 25 years 6 months). (C) Mild calcification of the interosseous membrane of the leg (arrow) (P11, 25 years 3 months). (D) Calcification of the Achilles tendon enthesis (arrow) and enthesophyte in the plantar fascia (arrowhead) (P11, 25 years 3 months).

Fig. 2.

(A) Histopathology of representative Achilles entheses in 23-week-old WT (top) and Enpp1^asj/asj mice (bottom) treated with vehicle. Calcific deposits are highlighted by Alizarin Red deposits embedded in the Achilles tendon, which appears green. (B) Histopathology of representative Achilles entheses in 23-week-old Enpp1^asj/asj mice treated with weekly subcutaneous injections of 0.3 mg/kg BL-1118. Top panels illustrate representative histologic response in complete responders, middle panels illustrate the histologic response in partial responders, and bottom panels illustrate the histologic response in nonresponders. Scale bar = 10 μm.

Fig. 3.

(A) Quantification of calcified tissue in Alizarin Red–stained sections in WT and Enpp1^asj/asj mice treated with vehicle, and Enpp1^asj/asj mice treated with BL-1118. Although there was not significant difference in the WT and treated Enpp1^asj/asj mice, the data spread suggested that the response could be grouped into complete, partial, and nonresponders (circled data points). (B) Calcified tissue in Alizarin Red–stained sections where treated Enpp1^asj/asj mice are analyzed according to treatment response (CR, 6 animals; PR, 7 animals; NR, 6 animals). Black type denotes statistical significance between WT and treatment groups. Orange type denotes statistical significance between treatment groups. Statistical significance is explicitly stated between 0.05 > p > 0.001; ***p < 0.0001, ****p < 0.0001 (ANOVA comparison of means). CR, complete response; NR, nonresponse; PR, partial response.