1. Stable strontium in large amount in the diet of rats initially inhibits calcification and induces rickets.

2. Changes later become atypical and a complex series of epiphysial plate defects develops: formation of localised osteoid wedges in the metaphysis; invagination of the epiphysial plate and sequestration of multiple cartilage nodules into the marrow cavity; and, in severely affected animals, localised loss of part or parts of the epiphysial plate with formation of large cartilage nodules in the metaphysis and epiphysis.

3. The appearance of cartilage nodules in the metaphysis in man has been shown to be associated with changes in the epiphysial plate, but much of the information is radiological and therefore incomplete, and detailed cellular changes are seldom available.

4. Some of the conditions mentioned, which have presented difficulty in interpretation, partly because of their rarity but also because of lack of knowledge of the fundamental processes concerned, are multiple exostoses and endochondromatoses, metaphysial dysostosis and osteochondritis.

5. Comparison of basic mechanisms revealed in this study with those supposed to occur in human cartilage dystrophies demonstrates that strontium rickets mimics some changes occurring in chronic renal rickets; that invagination of the epiphysial plate and cartilage nodule sequestration could account for the development of multiple exostoses and some endochondromatoses; and that localised endochondral defects in calcification can induce epiphysial changes resembling osteochondritis juvenilis, demonstrating that avascular necrosis is not necessarily the mechanism initiating epiphysial deformity.

Continuous strontium administration first induces typical "rickets" in young rats receiving adequate calcium phosphorus and vitamin D but later the widened cartilage spontaneously calcifies intermittently leaving transverse bands consisting largely of osteoid tissue in the metaphysis; in addition to intermittent calcification bone changes indicate that skeletal growth is not uniformly progressive.

Subsequently areas of the epiphysial cartilage fail to calcify and localised defects develop; among these are wedge-shaped metaphysial osteoid tissue masses, "invagination" of the epiphysial plate to form multiple nodules of cartilage with proliferating cells in the middle and hypertrophic ones at the periphery, perforation and fragmentation of the epiphysial plate with formation of large cartilage nodules. Multiple cartilage nodules of different sizes appear in the epiphysis, metaphysis and bone shaft.

Most bone margins are lined by osteoid seams which only slowly calcify and concomitantly resorption is decreased so that the rate of remodelling of the skeleton is diminished. This type of process may help to explain the results of treatment of osteoporosis by strontium administration.

When large daily doses of vitamin D were administered to rats endochondral growth was inhibited and bone resorption occurred; later in the process uncalcified matrix (osteoid) like that seen in rickets formed on trabecular margins. When vitamin D was given only for a short period and then discontinued, little resorption of bone was seen during the withdrawal period and wide seams of osteoid material appeared which eventually calcified in an irregular manner. When normal endochondral growth was resumed a wide transverse band of dense bone with enclosed cartilaginous cores was left in the marrow cavity. If, after a few days, a second large dose of the vitamin was given resorption again occurred and calcification of osteoid material was accelerated, the first microscopic sign being a dense, wide, granular, deeply staining line at the junction of the bone and new osteoid. After a second withdrawal period a second layer of osteoid formed; eventually another transverse band appeared in the metaphysis. If this hypervitaminosis D cycle (+4 -12) was continued rats continued to form new bone with relatively little remodelling, so that after three such cycles bones became dense and hard.

Histological study showed that little marrow cavity remained in either skull, vertebrae or epiphyses and a dense mass of bone enclosing cartilage cores filled the metaphysial part of the long bones. In addition, ankylosis ofteeth, calcification of spinal ligaments and widespread metastatic calcification were present.

When hypervitaminosis D cycles (+1 -12, +1 -21) were adjusted to produce minimal resorptive changes a wide range of bone change was observed. This varied from uniform dense metaphysial bone containing abnormal cartilage matrix arranged in longitudinal striations, dense transverse bands parallel to the epiphysial cartilage, to remnants of dense trabeculae extending into the marrow cavity.

Bone changes in osteopetrosis structurally closely resembled the induced bone changes in the rat. It is concluded that an important mechanism in the production of osteopetrosis is an accentuated rhythm of bone change like that shown experimentally to be produced in these animals. It is emphasised that these changes are but part of a range of bone disorders associated with abnormalities of cycles of resorption and deposition of bone, the type of change differing with the nature of the cycles.

1. When cortisone is administered to rabbits there is early rapid resorption of bone and a partial inhibition of new bone formation. After a few days the effect becomes less obvious, so that, if observations are made at later stages, the results may be ascribed then to simple inhibition of bone growth.

2. The effect of mechanical stress has been studied in the jaw. When tooth movement is induced mechanically there is, in ordinary circumstances, a resorption of bone on the side to which the tooth is moving (the "pressure" side) and bone formation on the opposite side (the "tension" side). After administration of cortisone there is increased resorption on the "pressure" side and there is greater resorption of connective tissues here. On the "tension" side there is resorption and inhibition of bone formation.

3. In the areas of stress, when cortisone is administered, collagen fibres are no longer in apposition, being separated by spaces presumably filled with altered ground substance; this kind of change may be responsible for many of the observed phenomena.

4. A.C.T.H. does not produce a demonstrable resorptive effect on bone or connective tissue until it has been administered for periods longer than is required for cortisone (three weeks); even then the change is not pronounced.

5. In the guinea pig there is slight delay in bone formation with large doses of both cortisone and A.C.T.H., but no significant bone resorption occurs.

The intermittent administration of cortisone in both the young and the mature rabbit is associated with appositional bone growth on the periosteal surfaces of the cranium, premaxilla and middle of the shaft of the femur; each new layer of bone is separated from the next by a darkly haematoxylin-staining "reversal" line. The internal architecture of the bone also changes in consequence of the repeated waves of resorption and deposition of bone round vascular spaces.

Cartilaginous growth at the epiphysis in the young rabbit is also affected. The long columns of metaphysial cartilage are replaced by a layer of new bone which partly seals the epiphysial cartilage from the marrow spaces.