THE INFLUENCE OF AGE AND OF DURATION OF TREATMENT ON THE PRODUCTION AND REPAIR OF BONE LESIONS IN EXPERIMENTAL HYPERPARATHYROIDISM.
These studies have shown that the bones of guinea pigs given daily injections of parathormone from the age of 2 to 7 days to the age of 110 to 120 days, show relatively very little effect after receiving 20 units daily during the last 65 to 87 days of treatment. But it is probable that their bones underwent decalcification early in the treatment and that subsequently the parathormone, continued at the same dosage, did not maintain the effects on the bones. Healing finally occurred despite it. The bones of guinea pigs treated with intermittent injections of large doses of parathormone from the time they were 1 week old to the age of 95 to 145 days also showed relatively few changes at the end of the treatment. The injections were given at intervals of 7 to 11 days, and were stepped up from 60 units to 140 units. From our previous experience (1) we infer that the earlier injections of parathormone produced very extensive bone changes which healed in the intervals between the injections. As the guinea pigs became older the injections of parathormone did not produce as severe effects. We have found in our studies of experimental hyperparathyroidism that the bone changes after a single large dose of parathormone in young guinea pigs are soon healed. The study of a series of animals shows that healing begins at about the 48th hour after injection, and proceeds rapidly. Between the 8th and 14 days, callus may be observed at the costochondral junctions, where fractures had occurred. Now the endosteum may be lined by osteoblasts and the vessel canals by new formed bone. In adult guinea pigs extremely large single doses had little effect on the bones in 48 hours, even though the dose killed the animal. It was only when three doses pyramided over a period of 48 hours and totaling 2580 units of parathormone were given, that moderately severe bone resorption could be demonstrated in the adult. The elevation of serum calcium may be considered as one of the indices of calcium mobilization in experimental hyperparathyroidism. When the rate of calcium excretion exceeds the rate of its mobilization, or when the animal is on a low calcium diet, hypercalcemia may be absent. It is possible to raise the serum calcium of adult guinea pigs by large single doses of parathormone, but the resulting rise is not as great as in the young (2). This is confirmatory evidence of the fact that calcium is mobilized much less rapidly from the bones of old animals than from those of young ones. Collip pointed out that young normal dogs are more susceptible to parathormone (6). This observation was corroborated by Morgan and Garrison (7). We found that the same difference held also in experimental hyperparathyroidism produced in dogs by repeated doses of parathormone (8). In man, clinical experience likewise indicates the necessity of using relatively large doses of parathormone to raise the serum calcium of adults. The serum calcium of middle-aged or old adults does not rise significantly unless as much as 100 units or more of parathormone are given daily for a number of days. Charts VI and VII, in a recent paper by Merritt and Bauer (9), support our findings of the relative difficulty of obtaining a significant elevation of serum calcium in adults. If adult guinea pigs are given daily injections of parathormone which are rapidly stepped up, the animals may be killed by the ensuing acute hyperparathyroidism, only slight bone changes being produced. However, a careful avoidance of the induction of acute hyperparathyroidism by gradual stepping up of the parathormone dose permits the employment of doses continued over a long period of time that could not possibly have been tolerated otherwise. Furthermore, healing of the lesions thus produced may occur, in spite of the continuance of parathormone at this level. It seems likely that the difference in response of young and old guinea pigs to single doses of parathormone, as indicated by the bone changes, as well as by the serum calcium and phosphorus, is related to the more rapid rate of mineral metabolism in the young, actively growing animals. The calcium mobilizing effect of parathormone is most prominent in actively growing young animals, the calcium being withdrawn from the most readily available stores-the regions of most active new bone formation and most active bone reconstruction (10). In the adult animal the calcium reserves (in the formed bone) are less susceptible to the calcium mobilizing effect of parathormone. The adult guinea pig will show relatively slight bone changes even as a result of extremely large, fatal doses of parathormone. Repeated doses, as is well known, will produce, by pyramiding, greater effects than the entire amount administered at one time. In this type of experiment the young again show greater susceptibility of the bone than the adult. In time, however, some compensation takes place, and the effects of the same doses are decreased until finally healing may occur in spite of the continued treatment. Increase of the dose, however, again elicits the parathormone effects upon the bone, as well as upon the serum calcium and phosphorus, without toxic changes (1, 8). It would seem that some compensation sets in which may be overcome by increasing the dose. This compensation is especially evident in the experiments in which the parathormone doses were stepped up gradually from small amounts. In addition to the compensation observed in young and adult animals as a result of repeated injections of parathormone, we must also consider the possibility that there is a compensating mechanism in adult animals more effective than in the young. That compensation occurs is unquestionable but its nature is not clear. Apparently it is less effective during pregnancy, doses of parathormone which produce only slight bone changes in ordinary adults causing very severe lesions in advanced pregnancy (11). Parathormone has been shown to produce only one primary effect on bone, and that is decalcification. This may come about as the result of a change in the circulating tissue fluids, the salts being dissolved out of the organic matrix, and the latter disappearing secondarily. The process is most rapid in the vicinity of most active bone formation. The osteoblasts disappear from the surfaces of bone where dissolution is occurring, and at the same time the marrow connective tissue proliferates. Fusion of cells produces osteoclasts (12), which then proceed to remove the decalcified organic matrix, with the production of the deep lacunae of Howship. Frequently leucocytes are also observed actively phagocyting the decalcified organic matrix, and often leucocytes are observed within the osteoclasts (12). Healing is associated with the complete reversal of the process. The osteoclasts disappear, the connective tissue diminishes, osteoblasts reappear, and bone formation is resumed. As we have previously stated (13), parathormone produces a more continuous effect than experimental acidosis and greater changes than are seen in experimental osteoporosis. A pronounced decalcification results from it which, with its sequelae, simulates von Recklinghausen's disease. The emphasis which the older pathologists laid on osteoclasts as a special feature of ostitis fibrosa cystica is justified, for in the experimental condition the appearance of great numbers of osteoclasts is a constant feature, whenever decalcification occurs (13). There seems to be no doubt that the giant cell tumors found in ostitis fibrosa cystica are expressions of the same pathological response. The other features of the bone changes of hyperparathyroidism-marrow hemorrhage, cysts, fractures, and osteoid proliferation-are secondary to the primary decalcification. Progress of the pathological changes leads to circulatory stasis and cyst formation. Stresses and strains exerted on the progressively weakening bone may result in microscopical or gross fractures. Osteoid tissue is, as we have previously pointed out (13), merely reparative in nature, being laid down as support to the weakened or fractured bone, or as a part of healing. Osteoid borders appear on bone surfaces 48 hours after one large dose of parathormone. The mosaic picture which we have observed in the bones of some of our animals is produced by short and irregularly disposed cement lines resulting from rapid bone transformation. Schmorl (14) recently emphasized the mosaic-like appearance of the newly formed lamellar bone in Paget's disease (ostitis fibrosa deformans). The mosaic-like appearance of bone has also been described in local bone conditions, as e.g. syphilitic periostitis, and in bone in the vicinity of cysts and giant cell tumors in von Recklinghausen's disease (ostitis fibrosa cystica). However, Schmorl claims that in no disease is the mosaic appearance so constant and the arrangement of the cement lines so irregular as in Paget's disease. In chronic experimental hyperparathyroidism (von Recklinghausen's disease), the mosaic structure is not a prominent feature because of the progressive decalcification. But the bones of our young guinea pigs which received intermittent injections showed a mosaic-like appearance indicative of the periodic decalcifications and restorations which they had undergone.
Laboratory Division of the Hospital for Joint Diseases, New York.
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Jaffe
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Bodansky
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Blair