Alkaline phosphatase (ALP) was discovered by Robert Robison, PhD in London in 1923. In New York in 1932, he added to his hypothesis that ALP functioned in skeletal calcification by liberating inorganic phosphate (Pi) for hydroxyapatite crystal formation, perhaps from a hexosephosphoric ester, some unknown factor also conditioning this process. In 1948 in Toronto, Canada, hypophosphatasia (HPP) was coined by John C. Rathbun, MD to describe a unique rickets without reductions in circulating calcium or Pi levels and seemingly paradoxically low serum ALP activity. HPP would become the dento-osseous disease that features tooth loss and rickets in childhood and osteomalacia in adult life due to deficiency of the tissue nonspecific (bone/liver/kidney) isoenzyme of ALP (TNSALP). In the 1960s, Graham Russell, PhD in Leeds and Herbert Fleisch, PhD in Davos, Switzerland found inorganic pyrophosphate (PPi) levels were elevated in the blood and urine of patients with HPP. Robisons unknown would prove to be this ALP natural substrate and inhibitor of biomineralization. In 1985, we discovered elevated plasma levels of pyridoxal 5′-phosphate in HPP revealing that TNSALP is a cell-surface enzyme. In 1988, HPP became the inborn-error-of-metabolism featuring TNSALP deficiency upon discovery in Philadelphia, USA that a boy in Halifax, Canada with lethal HPP harbored a homozygous loss-of-function missense mutation within the candidate ALPL gene that encodes TNSALP. HPP as an experiment-of-nature awakened interest in the bisphosphonates, synthesized by European chemists decades earlier, for their potential to improve some skeletal diseases as their P-C-P core rather than the P-O-P core of PPi resisted hydrolysis by TNSALP. In 2015, multinational approval of asfotase alfa, pioneered in Montreal, Canada as a TNSALP-replacement therapy for HPP, would decrease endogenous PPi levels and restore hard tissue mineralization. The first clinical trial began with an infant flown from Belfast, Northern Ireland to Winnipeg, Canada. How ALP is essential for bone has been a transatlantic story.