With this new insight into the pathophysiology of the PHOSPHO1 deficiency, we surmised that treating Phospho1−/− mice with mineral‐targeted TNAP, which targets the ECM directly, might lead to a therapeutic benefit, not unlike that experienced by the Alpl−/−and AlplPrx1/Prx1 models of HPP. Here, PHOSPHO1 is linked to hypophosphatasia.