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A Holstein fetus was delivered by Caesarean section at a gestational age of 441 days. The pituitary pars distalis was aplastic and the adrenal and thyroid glands were severely hypoplastic. Arrested or retarded cartilage cell maturation resulted in absence or minimal development of epiphyseal ossification centers, delayed ossification of carpal bones, and arrest of longitudinal growth of bones. The pathophysiology of prolonged gestation and of skeletal pathology is discussed.

Five expressions of dental fluorosis are described in cattle exposed to industrial fluoride pollution: 1. Hypercementosis with tooth ankylosis, cementum necrosis and cyst formation; 2. Delayed eruption of permanent incisor teeth; 3 Necrosis of alveolar bone with recession of bone and gingiva; 4. Oblique eruption of permanent teeth, hypoplasia of teeth with diastemata; and 5. Rapid progression of dental lesions. The five entities are not recognized in the "standard for the classification of dental fluorosis" by the National Academy of Sciences. Since this classification it too limited and superficial, adherence to this standard has left severe cases of fluoride intoxication in cattle undetected in field surveys.

The left thoracic limb was immobilized in a plaster cast in 6 grade weanling ponies for 6 weeks. Two ponies were injected intramuscularly each day with 2.4 micrograms of 25-hydroxycholecalciferol [25(OH)D3] per kg bodyweight, two with 1.2 micrograms and two received no injections. Immobilization of 25(OH)D3 treatment had no significant effect on mineral metabolism. Immobilization resulted in significantly decreased weight and specific gravity of metacarpus III (MCIII). Histologic examination and triple fluorochrome incorporation showed that the osteopenia was caused by atrophy of osteoblasts with failure of bone apposition. Immobilization caused retardation or cessation of proliferation of cartilage in the epiphyseal plate with thinning or premature closure. Treatment with 25(OH)D3 further reduced apposition and enhanced significantly the osteopenia as shown by quantitative morphometry of microradiographs of the MCIII metaphyses. There was parathyroid gland atrophy and fibrosis in proportion to the level of 25(OH)D3 treatment, which, in absence of hypercalcemia in all ponies, was interpreted to be a direct result of vitamin D treatment. It was concluded that immobilization osteopenia under the present design and duration is caused by failure of bone apposition and that treatment with 25(OH)D3 at dose levels applied is contraindicated.

Calcium absorption was measured by 47Ca disappearance from ligated duodenal loops and 47Ca uptake by tibiae in chicks fed diets containing one of four levels of Mg for two weeks. The diets, otherwise identical, contained 88 (group 1), 150 (group 2), 200 (group 3) and 1000 (group 4) ppm Mg. There were no statistically significant differences in 47Ca absorption. Mucosal CaBP and intestinal alkaline phosphatase were slightly, but not significantly, elevated in the Mg depleted chicks in groups 1 and 2 compared to groups 3 and 4. Microscopic examination of the tibiae showed marked alterations in morphology in chicks fed the 88 ppm Mg diet. The thickness of the epiphyseal plate was reduced, and the morphologic signs of osteolysis and chondrolysis, normally observed in the metaphysis, appeared to be absent. The mid-diaphysis was thickened and showed marked reduction in both osteoblast and osteocytie activity. Blood calcium levels were significantly reduced in the Mg deficient chicks. It was concluded that Mg depletion in chicks altered Ca homeostasis primarily by changing bone structure and function.

A chronic debilitating disease is described in Florida horses. There is progress weight loss and lameness of increasing severity. Plasma calcium is elevated to moderate or severe degree. Anatomical changes include dystrophic calcinosis of elastic tissues, viz. major arteries, tendons and ligaments. A generalized osteopetrosis is present and may be related to hypoparathyroidsim and hypercalcitoninism. The presence of Cestrum diurnum (day-blooming jessamine, day cestrum, wild jasmin) in areas accessible to affected animals, the observation that leaves of the plant were stripped in these areas, and the finding of a potent, active vitamin D-like substance in this plant constitute strong evidence that Cestrum diurnum is the agent causing the abnormalities of mineral metabolism.

A commercial feed concentrate and a mineral mix with excessive amounts of fluoride were introduced into a Holstein dairy herd with an average milk production well above national standards. Milk production decreased drastically, and during the following 6 years the deficit in milk production in the herd ranging from 52 to 120 milking cows was 1.5 million Kg (3 1/4 million lbs.). The tolerance levels set by the National Academy of Sciences for fluoride ingestion by lactating cow were found to be inadequate.

Inhibition of osteocytic osteolysis in bats given calcitonin injections during late hibernation supported previous morphologic evidence that the bone loss during hibernation is associated with decreased calcitonin and increased parathormone activity.

Plasma ascorbic acid (PAA) in normal Labrador Retriever dogs less than one year of age averaged 1.22 +/- 0.05 mg/dl (x +/- sem) and was significantly higher than the value of 0.89 +/- 0.03, for Labrador Retrievers two years of age and older. No significant diurnal variation in PAA was observed. Oral or intravenous administration of 0.5 or 1.0 g of ascorbic acid (AA) elevated PAA for less than 8 hours. Injection of ACTH caused a significant decline in PAA for the initial 2 days, with variable results thereafter. Labrador Retriever puppies fed a ration high in protein, energy and calcium developed the typical skeletal diseases of overnutrition, including hypertrophic osteodystrophy (HOD). The addition or oral AA (0.5 g twice daily) had no ameliorating effect on the skeletal lesions. Instead AA supplementation resulted in relatively higher serum calcium values which, presumably by enhanced hypercalcitoninism, decreased bone resorption. Thus, AA treatment of dogs with HOD is contraindicated, as it can only aggravate the osseous lesions of HOD. The decreased PAA reported in dogs with HOD is interpreted to be the result of stress from pain.

Pseudohyperparathyroidism was diagnosed in a mature stallion presented for anorexia, weight loss, pollakiuria and constipation. Laboratory findings included hypercalcemia, hypophosphatemia, anemia and isosthenuria. Thoracocentesis indicated an exfoliating squamous cell carcinoma. At necropsy, a squamous cell carcinoma of the stomach with metastases to the abdominal and thoracic cavities was diagnosed. No osseous metastases were found. No gross or microscopic renal lesions were noted. Bone tissue showed arrested resorption, and the parathyroid gland was atrophic.

In examination of ground sections of human third maxillary molar teeth, the granular layer of Tomes was shown to consist of expansion of dentinal tubules. The microradiographic density was decreased well inside the layer. It was postulated that the findings were expressions of dentin resorption. The theory was tested experimentally in rats fed a cariogenic diet with low calcium and phosphorus. The morphology of mandibular molar teeth was studied by electron probe microanalysis and by microradiography. It was concluded that the primary event in cariogenesis was an expansion of peripheral dentinal tubules with formation of confluent microcavities and, thus, an unmasking of the granular layer of Tomes, which normally is only potential. A subsequent loss of mineral density in the outer enamel eventually caused breakdown of the outer enamel with caries visible from the surface. The loss of density within the enamel was postulated to result from interruption of the normal flux of nutrients, metabolites and ions between the dentin and enamel. Whereas an increase in dietary calcium and phosphorus delayed and reduced significantly, but did not prevent cariogenesis, it supported the theory that experimental caries in rats is a metabolic disease with the peripheral dentin the primary target.

Hypothyroidism was diagnosed in a 5-month-old Thorough-bred colt by clinical and clinico-pathology examinations, thyroid stimulating hormone response test and by microscopic evaluation of the thyroid gland. Skeletal lesions included delayed appearance of ossification centers and delayed development of bone in cartilage models, delayed closure of epiphyseal plates, transverse trabeculation in metaphyses, osteochondrosis dissecans and subchondral cysts.

Chronic fluoride intoxication in dairy cattle, caused by feeding fluoride contaminated commercial feed, was previously described in a dairy herd. Dental fluorosis and a catastrophic decrease in milk yield were the foremost findings. In calves born to the fluoride intoxicated cows, congenital fluorosis was manifested by brown discoloration of enamel, enamel hypoplasia, brown mottling of bone, severe retardation of cartilage cell differentiation, atrophy of osteoblasts, osteopenia, atrophy of bone marrow cells, serous atrophy of bone marrow fat and severely stunted growth.

Five groups of 4 weanling pigs were fed a diet with 1.2% calcium and 1.0% phosphorus for 8 weeks with vitamin D3 at 1, 5, 25, 125 and 625 times the recommended levels, respectively. Hypercalcemia and hypophosphatasemia developed rapidly and persisted in Group 5 and developed more slowly but steadily in Group 4. Increasing levels of vitamin D3 influenced progressively and negatively the activity of resorbing osteocytes with osteopetrosis in Groups 2 and 3 and with osteonecrosis in Group 5. Atrophy of osteoblasts further contributed to the osteopenia in Group 5. Cartilage growth activity was arrested in Group 5. The negative effect on the resorbing osteocytes, which finally lead to death of the cells, was ascribed directly to vitamin D3 toxicosis since hypoparathyroidism and hypercalcitonism, both resulting from hypercalcemia, are not known to induce osteonecrosis. Since hypercalemia was finally as severe in Group 4 as in Group 5 and since there was soft tissue calcinosis only in Group 5, the calcinosis was always considered dystrophic, an interpretation supported by the observation that degenerative histologic changes preceded soft tissue calcinosis.

Fluoride emissions from an aluminum plant in New York State just west to the bridge to Cornwall, Ontario, Canada, are in compliance with New York State and U.S. Federal standards. Ambient air fluoride virtually never exceeds New York State standards. In a New York State dairy farm, downwind from the aluminum plant about 40% of the time and with the fields within 1300 to 2800 m from the plant, fluoride contamination of forage ranged from 13 to 25 ppm, well below the 40 ppm which is the "tolerance" level by National Academy of Sciences. Sixty-three of 82 dairy cattle on that farm were slaughtered in 1979 because of chronic fluoride poisoning. In the 19 cattle left on the farm in June, 1979, there was no dental fluorosis in calves less than 4 months of age, mild to moderate dental fluorosis in older calves and heifers and severe dental fluorosis in the 4 young adult cattle. Ash fluoride in a stillborn calf was 280 ppm and in the oldest cattle 2800; the increase was significantly correlated to age. It is concluded that New York State and U.S. Federal standards for fluoride emissions, New York State standards for ambient air fluoride and National Academy of Sciences "tolerance" levels for ingestion of fluoride do not protect cattle health.

Reduction of ingested fluoride in a skulk of silver foxes resulted in the reduction of fluoride burden, decreased neonatal mortality and increased kit production during a two breeding and whelping season period.

Adult mallard ducks were administered steel pellets to determine the rate of excretion from the gastrointestinal tract. In separate studies the ducks were administered 5 number 6 lead pellets. Birds were examined for clinical signs and sacrificed at given intervals over a 20 day period to assess changes in tissue structure and concentrations of lead with time. The above studies were conducted in 2 groups of ducks, fed a low or a high fiber diet. The rate of steel pellet excretion on birds on the low fiber diet decreased with an increase in pellet size. Pellet excretion was greatly reduced in birds fed the high fiber diet. Administration of lead shot resulted in the development of green diarrhea, anorexia and weakness. It also produced high concentrations of lead in the blood, kidney, liver and bone with lower concentrations in skeletal muscle. The major lesions were destruction of the mitotically active proventricular epithelium and medullary osteocytes, destruction of pectoral muscle cells and the presence of intranuclear inclusion bodies in the proximal tubular epithelium of the kidneys. Birds on the high fiber diet demonstrated more severe clinical signs and higher concentrations of lead in the tissues.

Three mature Thoroughbred geldings were given 13.63 mg phenylbutazone/Kg bodyweight intravenously for 3 days and repeated in one horse 4 days later. After 4, 7 and 10 days (double treatment), degeneration of the wall of small veins occurred in all horses. The veins were dilated and/or showed hyalin degeneration. The phlebopathy was interpreted to be paramount in phenylbutazone intoxication. All other manifestations, including erythro- and leukodiapedesis, submucosal edema and ulceration of the gastrointestinal mucosa, phlebothrombosis and significant changes in the hemogram and serum chemistry, were considered secondary to the vein lesions.

Two groups of weanling pigs, injected with 45Ca, were fed diets containing optimal calcium and phosphorus, and vitamin D3 at 1320 IU/kg feed in the control group, and 825,000 IU/kg feed in the test group. The groups were further subdivided with 2 pigs in each subgroup, with survival times of 1, 2, 3, 4, 7, and 14 days. Pigs fed the high level of vitamin D3 lost weight and anorexia, weakness, rough hair coat and labored breathing were observed. Hypercalcemia began at 12 hours and progressed rapidly after 2 days. Radioisotope sutdies interpreted in the light of histopathologic findings indicated that bone was the primary source of increased plasma calcium. Calcium was released at a rapid rate into blood from prelabeled bone which was undergoing necrosis; it was also removed from blood and deposited into bone at a slower rate due to decreased apposition. Histopathologic examination of bones from test pigs showed regressive changes in the osteocytes, chondrocytes and osteoblasts which bean within 1 day of treatment and resulted in evidence osteopenia within 7 days. Arrested osteocytic osteolysis led to the appearance of cementing lines and to chondroid core retention. Further regressive changes in the osteocytes resulted in osteocytic death and osteonecrosis with subsequent osteoclasia and osteopenia. Retardation and arrest of cartilage maturation as well as osteoblastic deficiency contributed to the osteopenia. The osteopenia was further evidenced by decreased specific gravity and ash content per unit volume of humerus. The initial negative effect on the osteocytes, chondrocytes and osteoblasts is attributed to a direct toxic effect of excessive dietary vitamin D3 since hypoparathyroidism and hypercalcitoninism, which occur secondarily to hypercalcemia, could not account for the rapid appearance of this effect, nor are they known to induce osteocytic death. The release of bone calcium and the resulting hypercalcemia in vitamin D3 toxicosis is therefore due to a direct toxic effect of the vitamin, or its metabolites, on the osteocyte resulting in osteonecrosis. It is not due to increased resorption as has been reported previously from both in vivo and in vitro investigations. Degeneration, with subsequent inflammation, but without calcification, was observed in the kidneys and in the lungs. Epithelial cells, basement membranes, and smooth muscle were affected. This conclusively demonstrates that degeneration is the primary soft tissue lesion in vitamin D3 toxicosis, and that the subsequent calcification is therefore dystrophic. Degenerative changes occurred in the parathyroid glands within 1 day of treatment resulting in necrosis, inflammation and atrophy within 4 days. Relative fibrosis was seen as the parenchyma receded. The parathyroid gland changes were considered a direct effect of vitamin D3 toxicity since they occurred with only mild hypercalcemia and since necrosis of parathyroid cells has not been demonstrated with hypercalcemia either in vivo or in vitro.

Young rabbits on high (0.57%) or low (0.24%) calcium were given an aqueous extract of Solanum malacoxylon (S.m.) leaves (20 g dried leaves/200 ml distilled water) intragastrically at 0, 12 and 36 hours. On bothe diets S.m. induced progressive hypophosphatasemia but serum calcium and phosphorus underwent only minor changes. In rabbits necropsied at 0, 12, 36, 60, 84 and 108 hours, S.m. was shown to have a negative effect on the resorbing osteocytes. With retarded osteocytic osteolysis, osteopetrosis resulted. Further regressive changes in the osteocytes resulted in osteonecrosis which was observed within 12 hours after administration of S.m. extract. The osteonecrosis, combined with retarded apposition, later resulted in osteopenia. It was concluded that the recommended dietary calcium for growing rabbits--about 0.6%--is too high. Whereas the histologic appearance of bone in rabbits fed low calcium was normal, bones from rabbits on high calcium showed retarded resorption and the rabbits had a relative hypophosphatasemia.

Chronic ingestion of excessive amounts of fluoride from commercial fox food is associated with agalactia in vixens resulting in the starvation deaths of large numbers of kits in three fox herds. Evidence of infectious disease or poor management could not be found and a causal relationship between fluoride and high kit mortality is suggested.

Epiphyseal and articular cartilages were examined in pony foals treated with intramuscular injections of either 0.5 mg dexamethasone per 100 kg bodyweight daily for 3, 8 or 11 months, or 5.0 mg per 100 kg for 11 months, and in horse foals treated with 5.0 mg per 100 kg for 20 weeks. The proximal femoral growth plates exhibited increased spatial separation between chondrocyte columns, narrowed zones of disorganized columnar and hypertrophic cartilage, abnormal penetration of hypertrophic cartilage by metaphyseal capillaries, retained cartilage in the spongiosa, distal terminal plate formation, transverse trabeculation, chondronecrosis and metaphyseal osteochondrosis dissecans. Destructive articular lesions were observed after 3 months of treatment with 0.5 mg per 100 kg bodyweight. Joint damage originated either at the joint surface or deep within the cartilage. Signs of surface deterioration included edema, fibrillation, enlargement of lacunae, pitting, shredding and erosions of cartilage. Inactivity of articular cartilage growth centers was common, with failure of epiphyseal capillaries to penetrate the lacunae in the calcified cartilage. Chondronecrosis adjacent to the calcification front was accompanied by cartilage ulceration and fracture. Intracartilaginous cysts and subchondral chondroid cysts were also observed. Healing responses included reparative chondrogenesis (focal cartilage hyperplasia), formation of fibrous or fibrocartilaginous "scars," subchondral osteopetrosis and epiphyseal marrow petrosis. Lactate dehydrogenase specific activities per chondrocyte, 35S uptake per cell and glycosaminoglycan contents of articular cartilages were all reduced 55% by 3 months of treatment. This inhibition of articular chondrocyte metabolism initiated cartilage degeneration. Surface destruction and osteochondrosis dissecans followed continued mechanical stress of compromised cartilage.

The incidences of fractures and soft tissue injuries during 68397 starts of thoroughbred horses at New York Racing Association tracks were analyzed concerning track condition, dirt and turf tracks, environmental conditions, length of races, location of fractures on the track, and age of horses. It was concluded that the conditions evaluated are of no importance in the occurrence of racing injuries to thoroughbred horses.

Cestrum diurnum poisoning was described in a Florida bull. Clinical signs included chronic wasting and progressive lameness. Plasma calcium was elevated for long periods of time but decreased toward low normal values. There was pronounced C-cell hyperplasia. Osteopetrosis was very severe and reflected retarded osteocytic osteolysis and chondrolysis. Further negative effects on the osteocytes eventually lead to osteonecrosis. Soft tissue calcinosis involved tendons and ligaments, major arteries and veins but kidneys and lungs were spared. Whereas the osteopetrosis could be explained by hypercalcitoninism, the osteonecrosis was believed to result from direct action by the Cestrum diurnum factor, previously shown to have an action similar to that of 1,25-dihydroxy-cholecalciferol, which is the biologically active metabolite of vitamin D3.

The effect of ingestion of dried leaves of Cestrum diurnum, a plant shown to contain a 1,25-dihydroxycholecalciferol-like principle, was tested in normal pigs fed 1.2% calcium and 1.0% phosphorus for 10 weeks from weaning and in hyperparathyroid pigs fed 0.8% calcium and 1.6% phosphorus for the same periods of time. Addition of 3% Cestrum diurnum leaf meal rapidly resulted in decreased feed consumption and weight gain, hypercalcemia and hypophosphatasemia. In normal pigs, plasma calcium rose to 16 mg/100 ml within one week and remained high for the 4 week experimental period. In hyperparathyroid pigs with hypocalcemia, plasma calcium rose to 12.75 mg/100 ml within one week and later approached 15 mg/100 ml. Ingestion of Cestrum diurnum retarded cell differentiation of growth cartilages. Arrested osteocytic osteolysis was observed within one week with osteopetrosis of epiphyses and metaphyses. The negative effect on the resorbing osteocytes then caused osteonecrosis which, in combination with lack of bone formation because of atrophy of osteoblasts, resulted in osteopenia within 4 weeks. Dystrophic calcinosis occurred within 2 weeks and was widespread after 4 weeks in lungs, kidneys, heart and vessels. Atrophy of parathyroid cells was severe after one week. Hyperparathyroid pigs responded with skeletal lesions, dystrophic calcinosis and parathyroid atrophy more rapidly and severely than normal pigs. The biochemical and anatomical changes in Cestrum diurnum ingestion are closely similar to those in vitamin D3 intoxication in pigs. Whereas pigs can tolerate large amounts of vitamin D3 because of feed-back control of 1 alpha-hydroxylation in the kidney, this control point is by-passed in Cestrum diurnum ingestion and intoxication occurs promptly.

An aluminum plant on the south bank of the St. Lawrence river, southwest of Cornwall Island, Ontario, Canada, has emitted 0.816 metric tons of fluoride daily since 1973; considerably higher amounts were emitted from 1959 to 1973. The plant has been designated as the "major source of fluoride emissions impacting on Cornwall Island." Chronic fluoride poisoning in Cornwall island cattle was manifested clinically by stunted growth and dental fluorosis to a degree of severe interference with drinking and mastication. Cows died at or were slaughtered after the third pregnancy. The deterioration of cows did not allow further pregnancies. Fluoride concentrations in ash of biopsied coccygeal vertebrae increased significantly with age and were dependent on distance from and direction to the aluminum plant. Fluoride in bone ash of a 7-month old-fetus exceeded 500 ppm; fluoride thus was passed transplacentally. Analyses of fluoride in ash of bones obtained at necropsy of cattle from 4 months of age to 4 to 5 years of age showed increased amounts with age. Cancellous bone retained far higher amounts than cortical bone, a reflection of the normally higher metabolic rate of cancellous bone. Concentrations exceeding 10,000 ppm fluoride were recorded in cancellous bone of a 4-to 5-year-old cow. The target cells for fluoride in chronic fluorosis were shown to be the ameloblasts, the dental pulp cells and the odontoblasts and, in bone, primarily the resorbing osteocytes and also the osteoblasts. Atrophy and necrosis of the ameloblasts were responsible for enamel defects. The existing enamel showed brown discoloration from fluoride deposits. The pulp cells underwent fibrous and osseous metaplasia and necrosis of the ectopic bone occurred. The odontoblasts were atrophic and the dentin showed brown discoloration. The resorbing osteocytes were inactive and osteosclerosis resulted. This was especially pronounced in areas of normally great apposition, i.e. in the metaphyses. The epiphyseal plate became squeezed between petrotic bone and growth was stunted. Resorption of alveolar bone surrounding the deciduous teeth was severely retarded or arrested. A delay in eruption of permanent teeth occurred; it was up to 3.5 years in incisor teeth. Interference with the resorbing osteocytes in fluorotic bone was also demonstrated by loss of collagen birefringency in such bone. Failure of bone resorption also caused retention of trabecular bone in the cortices; this was observed even in a 4-t0-5-year-old cow. In areas where modeling into osteonic bone had begun, fluoride deposits were extremely heavy but this bone showed numerous soft osteons in microradiographs. The toxic effect of fluoride on osteocytes also resulted in the death of the cells. Such osteonecrosis occurred mainly in gnathic bone. There was atrophy of the osteoblasts. Osteopenia thus resulted from osteonecrosis and osteoporosis. Subperiosteal exostoses were not observed in long bones. The degree of fluorosis in Cornwall Island cattle was severe...

Yearling heifers overfed protein, calcium and phosphorus with a feed recommended for high producing dairy cows developed osteopetrosis and skeletal malformations as a result of retarded bone resorption. Histologic and electron microscopic examinations showed that C cell hyperplasia was also present. The presence of C cell hyperplasia and osteopetrosis supported the diagnosis of hypercalcitoninism. Clinically unaffected heifers were studied by serum chemistry after 1 to 1.5 months on the same diet at age 6 months and after 3 months on an optimal diet to learn whether they showed evidence of hypercalcitoninism as expressed by retarded bone resorption and/or hypercalcitoninemia. The data indicated that bone resorption was retarded and that serum gastrin was elevated in the heifers without skeletal malformations while on the high calcium feed. The heifers were isocalcitoninemic. The data suggested that overfeeding calcium was sufficient to produce hypercalcitoninism but the rate of calcitonin secretion had not exceeded the rate of removal of calcitonin from blood by binding to tissue receptors and by metabolic degradation. Since calcitonin is rapidly removed from blood, hypercalcitoninism may occur without concomitant hypercalcitoninemia.

Changes in the developing femoral epiphysis, especially those concerning the osteocytes, were examined in pony foals systemically treated with daily intramuscular injections of either 0.5 or 5.0 mg of dexamethasone per 100 kg bodyweight for either 3, 8 or 11 months. Midsagittal sections of proximal femur from animals treated for 3 months contained significantly more bone tissue subchondrally and epiphyseally than did sections from untreated ponies. Large portions of the bone tissue appeared necrotic, although osteoblasts and patent capillaries were abundant. After 8 months the bone sections revealed marked osteoporosis. Abnormally dense bone was again observed after 11 months. There were significant increases in the severity of these changes in bone from the animals treated with the higher dosage. Calcium kinetics studies revealed an inhibition of calcium deposition (bone formation) in the treated animals after 2 and 7 months. However, calcium removal (bone resorption) was inhibited to a greater extent. Osteopetrosis (radiographic sclerosis) resulted from the initial resorption/formation imbalance, and was accompanied by osteonecrosis and osteocyte death. Continued treatment resulted in osteopenia, caused by the removal of necrotic bone debris and the inhibition of new bone formation. The primary event in the development of glucocorticoid-induced bone disease was shown to be suppression of osteolysis with the development of osteonecrosis.