The investigations of Shipley, Park, Simmonds and McCollum have shown that when the diet is satisfactory in every respect except for a deficiency of calcium, the phosphate content and content of fat-soluble A being near the optimal, changes take place in the skeleton which bear a fundamental resemblance to rickets as it occurs in the human being. There is a tendency to increased persistence of the proliferative cartilage of the epiphysis. The cartilage becomes invaded by blood-vessels from the marrow of the shaft. There is failure to deposit calcium salts in the intercellular substance of the cartilage, which forms the initial feature of the process of normal calcification. A rachitic metaphysis is formed. There is likewise over-production of osteoid tissue. The gross deformities in young rats maintained on such defective diets (deficient only in calcium) cannot be differentiated from those seen in rickets.

There are, however, decided differences in the histological picture seen in bone sections derived from animals selectively fasted for calcium alone, as compared with those ordinarily seen in rickets. It has been pointed out that normally the band of proliferative cartilage consists of cells which are arranged in columns. In true rickets this orderly arrangement is lost, and the cartilage cells become irregularly disposed. In the animals deprived of calcium, but supplied with all other dietary essentials in normal amounts, the orderly arrangement of the cartilage cells is not disturbed, notwithstanding the formation of abnormal amounts of osteoid, and the development of the metaphysis. There is also evidence that resorption of bone and osteoid in the shaft is rapid under these dietary conditions.

When calcium carbonate, in appropriate amount, is added to such diets as produce the picture described above, none of the abnormalities described occur. When, on the other hand cod liver oil is included in the diets which are deficient in calcium, but in no other respect, and the deficiency is sufficiently marked to cause the rickets-like condition to develop, the bones remain essentially normal and no metaphysis forms. When the cod liver oil is administered after the pathological changes due to deprivation of calcium have developed, healing of the lesion results. The calcium necessary for deposition in the zone of primary calcification under these circumstances appears to be borrowed from the shaft, for this becomes osteoporotic, or fragile owing to resorption of its mineral salts.

The administration of butter fat instead of cod liver oil to animals which are deprived of a sufficient amount of calcium, does not protect them in the way that cod liver oil does. Even large doses (20 per cent of the food mixture) exerts but a feeble protective action. It must be concluded, tentatively, therefore, that cod liver oil is rich in some substance which is intimately concerned with bone growth, which is not abundant in butter fat, and that the evidence available at present, points to the possible existence of a separate dietary factor analogous to the recognized vitamins, which can be recognized by its effects on the changes in the bones of animals which have been prepared for a period by restricting them to diets which lead to the development of rickets.

When young rats are restricted to diets which contain the normal amounts of calcium and of phosphate, a deficiency in fat-soluble A causes changes in the bone of a pathological nature. This factor alone cannot, however, be responsible for the development of rickets. This statement also applies to a relative shortage of the hypothetical anti-rachitic factor which we tentatively suggest is distinct from fat-soluble A, and abundant in cod liver oil. A specific starvation for this substance cannot of itself produce rickets.

When in the nutrition of young rats, a diet is employed which is deficient in utilizable phosphorus compounds and also in the organic factor which exerts an anti-rachitic effect, there is produced a pathological condition of the skeleton which bears fundamental resemblances to rickets, but differs from rickets in certain respects. The chief difference consists in the presence of scattered or irregular deposits of calcium salts in the metaphy-sis and cartilage. The appearance of histological sections of the bones of these animals closely resembles those of animals which have suffered from rickets but in which healing of the lesion is in progress. The addition of a suitable amount of the phosphate ion to such a diet, the deficiency of the organic factor still existing, results in the prevention of the development of the changes of a rickets-like nature, though the bone is not normal.

The remarkable effect of the administration of cod liver oil to animals which are deprived of sufficient calcium, in protecting them from the detrimental effects of such deficiency - a protection which is not afforded by four or five times the amount of butter fat necessary to entirely meet the needs of the growing rat for fat-soluble A, when its diet is satisfactorily constituted with respect to calcium and phosphate, makes it imperative that we accept the view that there is an organic factor which exerts an anti-rachitic effect, and is concerned in the normal nutrition of the bones.