No vascular calcification on cardiac computed tomography spanning asfotase alfa treatment for an elderly woman with hypophosphatasia.

Abstract

Hypophosphatasia (HPP) is the inborn-error-of-metabolism characterized enzymatically by insufficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and caused by either mono- or bi-allelic loss-of-function mutation(s) of the gene ALPL that encodes this cell surface phosphomonoester phosphohydrolase. In HPP, the natural substrates of TNSALP accumulate extracellularly and include inorganic pyrophosphate (PPi), a potent inhibitor of biomineralization. This PPi excess leads to rickets or osteomalacia in all but the most mild "odonto" form of the disease. Adults with HPP understandably often also manifest calcium PPi dihydrate deposition, whereas enthesopathy and calcific periarthritis from hydroxyapatite (HA) crystal deposition can seem paradoxical in face of the defective skeletal mineralization. In 2015, asfotase alfa (AA), a HA-targeted TNSALP, was approved multinationally as an enzyme replacement therapy for HPP. AA hydrolyzes extracellular PPi (ePPi) and in HPP enables HA crystals to grow and mineralize skeletal matrix. In direct contrast to HPP, deficiency of ePPi characterizes the inborn-errors-of-metabolism generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE). In GACI and PXE, deficiency of ePPi leads to ectopic mineralization including vascular calcification (VC). Therefore, in HPP, ectopic mineralization including VC could hypothetically result from, or be exacerbated by, the persistently high circulating TNSALP activity that occurs during AA treatment. Herein, using a routine computed tomography (CT) method to quantitate coronary artery calcium, we found no ectopic mineralization in the heart of an elderly woman with HPP before or after 8 months of AA treatment. Subsequently, investigational high-resolution peripheral quantitative CT and dual-energy X-ray absorptiometry showed absence of peripheral artery and aortic calcium after further AA treatment. Investigation of additional adults with HPP could reveal if the superabundance of ePPi protects against VC, and whether long-term AA therapy causes or exacerbates any ectopic mineralization.