Fibrodysplasia ossificans progressiva. A survey of forty-two cases.

Fibrodysplasia ossificans progressiva in children can often be recognized at birth because of the presence of shortening of the great toe, characteristic hallux valgus, and short thumbs. The majority of patients have the onset of symptoms by the age of four years, but there is often a delay of many months before the diagnosis is made. Early recognition will allow protection of the child from injuries in which the damaged tissue will serve as a focus of calcification. Most patients with this condition are physically disabled. The site of onset and of greatest involvement is axial. Biopsy and surgery are best avoided. Use of EHDP (disodium ethane 1-hydroxy, 1-diphosphonate, or disodium etidronate) is not as yet of proved value in most patients. Data from this study support the concept that most cases of this lesion arise as dominant mutations.

Use and complications of high-dose disodium etidronate therapy in fibrodysplasia ossificans progressiva.

A boy with fibrodysplasia ossificans progressiva received nearly twice the usual therapeutic dose of disodium etidronate for 13 months in an attempt to prevent reossification following a second operation to correct severe torticollis. The operation was successful, but during therapy he developed weakness and distinctive bone lesions characterized by general osteopenia, widened physes, and unique radiolucent bands in the metaphyses. The osseous abnormalities were distinct from those of rickets and healed after withdrawal of the drug.

Metabolic effects of diphosphonate in primary hyperparathyroidism.

Six patients with primary hyperparathyroidism (PHPT) and one with squamous cell carcinoma of the esophagus with parathyroid hormone excess received disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) at a daily dose of 20 mg/kg orally. During treatment, the decrease in urinary calcium, total urinary hydroxyproline, and fasting urinary calcium suggested an inhibition of bone resorption. Serum calcium intestinal absorption of calcium and urinary cyclic adenosine monophosphate (cAMP) did not change significantly. This preliminary study indicates a possible role of diphosphonates in the management of inoperable cases of primary hyperparathyroidism or pseudohyperparathyroidism.

Effect of dichloromethane diphosphonate on calcium homeostatic mechanisms in pregnant cows.

The administration of 4 mg/kg/day of dichloromethane diphosphonate (Cl2MDP) subcutaneously to pregnant cows fed a low-calcium diet significantly reduced bone resorption as indicated by microradiographic evaluation of endosteal surfaces of cross sections of ribs. Plasma parathyroid hormone levels were similar between Cl2MDP-treated and control cows prepartum, during EDTA infusions, and near parturition. Ultrastructurally, chief cells of the parathyroid glands of both groups of cows were in the active stage of the secretory cycle. The chronically stimulated chief cell from cows administered Cl2MDP had a large cytoplasmic area containing many lipofuscin granules and lysosomal bodies and a few secretory granules near the large Golgi apparatus or aligned along the plasma membrane. Uptake of calcium 45 by the duodenal mucosa incubated in vitro was greater in Cl2MDP-treated cows compared to control cows. The administration of Cl2MDP significantly reduced rapidly mobilization calcium reserves. Following an intravenous EDTA infusion and the spontaneous calcium drain associated with parturition and the beginning of lactation, Cl2MDP-treated cows developed severe hypocalcemia. The rapid mobilization of calcium reserves in cows administered Cl2MDP prepartum was impaired mainly because of diminished resorption of bone despite adequate parathyroid hormone secretion in response to severe postpartal or EDTA-induced hypocalcemia.

Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the ultrastructure of parathyroid glands and plasma immunoreactive parathyroid hormone in pregnant cows fed a low calcium diet.

The long term (70 days) effects of administering ethane-1-hydroxy-1,1-diphosphonate (EHDP) (4 mg. per kg. per day) on parathyroid function was investigated in pregnant cows fed a low calcium diet. Serum calcium and phosphorus were significantly lower at parturition and postpartum in EHDP-treated cows compared to pregnant control cows fed the low calcium diet. Plasma immunoreactive parathyroid hormone levels were similar prepartum, at parturition, and postpartum in cows administered EHDP and control cows. Immediately available calcium reserves were greater preparation in control cows than in cows receiving EHDP as indicated by a more rapid rate of return of serum calcium toward normal levels following ethylenediaminetetraacetic acid (EDTA)-induced hypocalcemia approximately 10 days prepartum. EHDP-treated cows responded to the hypocalcemic challenge with similar changes in plasma immunoreactive parathyroid hormone levels as in control cows; however, urinary hydroxyproline excretion increased at certain intervals only in control cows. Ultrastructurally, chief cells in parathyroid glands of both groups of cows were in an active stage of the secretory cycle with well developed organelles concerned with hormonela synthesis. Chief cells in cows administered EHDP were degranulated and contained fewer secretory granules in response to the hypocalcemia than those in control cows. Chief cells in EHDP-treated cows often had prominent perinuclear accumulations of microfilaments, scattered vacuolated mitochondria, and lysosomal bodies in the cytoplasm. Thyroid C-cells were densely granulated and thyroid calcitonin content was similar in both groups of cows. The principal defect in calcium homeostasis of EHDP-treated cows appeared to be an impairment both in bone calcium mobilization and bone matrix catabolism in response to the secretion of parathyroid hormone. In vitro uptake of 45Ca by duodenal mucosa and urinary excretion of cyclic adenosine monophosphate were similar in both groups of cows. The ability of the parathyroid glands to synthesize and secrete parathyroid hormone in response to hypocalcemia induced either by EDTA or associated with parturition was not impaired by the administration of EHDP.

Experimental parturient hypocalcemia in cows following prepartal chemical inhibition of bone resportion.

Cows fed a balanced diet with the required amounts of calcium and phosphorus developed acute hypocalcemia and hypophosphatemia shortly after parturition, even in the presence of the a responsive parathyroid gland, when bone resorption was selectively inhibited by the prepartal administration of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP). When serum total and ionized calcium levels declined below 6.0 and 1.0 mg/100 ml, respectively, cows developed clinical signs similar to naturally occurring parturient paresis. The plasma immunoreactive parathroid hormone levels were similar prepartum, at parturition, and 1 day postpartum in cows administered EHDP as in control cows. Parathyroid chief cells were predominately in the actively synthesizing phase of the secretory cycle with a prominent Golgi apparatus and lamellar arrays of rough endoplasmic reticulum. Many chief cells were degranulated of mature secretory gransules. Calcitonin activity in thyroid extracts, determined by bioassay, and the numbers of secretory granules in thyroid C-cells were similar in both groups of cows. EDTA infusion after 60 days of the experiment demonstrated that the immediately available calcium reserves were reduced in EHDP-treated cows. The serum calcium remained significantly lower and did not return to preinfusion levels by 24 hours. Serum calcium in control cows returned to within the normal range by 6 hours after EDTA infusion. The urinary excretion of hydroxyproline was consistently reduced prepartum and following EDTA infusion in cows receiving EHDP. The experimental induction of parturient of parturient hypocalcemia by the prepartal administration of EHDP provides a valuable model for studies to investigate the mechanisms in bone responsible for the development of severe hypocalcemia that occurs in response to the increased calcium demand imposed by parturition and the initiation of lactation.