Faculty Bibliography

It is estimated that 66% of patients with Paget's disease have involvement of the pelvis and 46% of the proximal femur. Therefore, it is not unexpected that hip pain is one of the major presenting complaints. Analysis of the radiographs of 25 hips with one or more articular sufaces involved by Paget's disease demonstrated narrowing in 24. Unlike the findings in primary degenerative joint disease, the majority of cases had a radiographic pattern characterized by uniform narrowing of the articular cartilage and minimal hypertrophic changes. Pathologic correlation was obtained from specimens of four patients who underwent total hip replacements. The pathogenesis of arthritic changes associated with osteitis deformans is not established. The evidence presented suggest that cartilagenous narrowing results from a disturbance in endochondral bone formation related to the hyperemia of Paget's disease. Secondary deformities of bone produce further derangement of joint mechanics. The secondary degenerative changes which ensue differ mechanically, and therefore radiographically, from primary degenerative joint disease.

The use of disodium ethane-1 hydroxy-1, 1-diphosphonate (EHDP) therapy for Paget's disease of bone was examined in 75 affected patients. Forty-eight patients received randomly assigned oral doses of either 0, 2.5, 5, 10, or 20 mg/kg/day in a controlled, double-blind protocol, and the remainder received either 10 or 20 mg/kg/day in a non-random protocol. The clinical status of the patients and appropriate laboratory tests were evaluated before treatment and at frequent intervals during a six-month period of initial therapy. There were no significant changes in either urinary hydroxyproline or serum alkaline phosphatase in those patients receiving placebos, while both these parameters decreased significantly at all dose levels of EHDP, with the greatest decline noted in the highest dose group. However, statistical analysis of the data related to changes in symptoms in the double-blind study revealed that patients receiving the higher dose of EHDP (10 or 20 mg/kg/day) had less favorable outcomes than those receiving the lower doses (2.5 or 5 mg/kg/day). The high does group had a relatively lower rate of symptom improvement and a relatively greater rate of deterioration than did the low dose group. Twenty-one of forty-nine patients followed for at least 18 months have shown a sustained suppression of their serum alkaline phosphatase and urinary hydroxyproline values for 12 months following cessation of EHDP, while therapy has been reinstituted for the other 28 patients because of increases in these measurements, with or without accompanying symptomatic deterioration. Eight patients sustained fractures through Pagetic bone during the period of study and all of these were treated with higher doses of EHDP. On the basis of the biochemical and clinical data in this study it appears that initial therapy of Paget's disease of bone with 5 mg EHDP/kg/day maximizes benefits while minimizing possible adverse effects.

The unique combination of male hypogonadism with hypoparathyroidism, hypoadrenalism, hypothyroidism, diabetes mellitus, and alopecia totalis has been documented in a male patient who has been followed over the past 28 years. In this patient, first seen at the age of six for hypoparathyroidism alone, repeated clinical and laboratory endocrine evaluation detected the sequential development of the additional endocrine deficiencies. The presence of abnormal serum antibodies is consistent with an atuoimmune pathogenesis of this syndrome.

A new radioimmunoassay for human procollagen showed that the sera of 46 of 50 untreated patients with Paget's disease of bone contained increased concentrations of procollagen protein as compared to normal adults. After therapy with disodium etidronate, all the elevated serum procollagen concentrations decreased significantly, falling to normal levels in 33 of 40 patients. The procollagen levels before and after treatment were coordinate with the values for urinary total hydroxyproline and serum alkaline phosphatase activity. The data show that the radioimmunoassay for procollagen is a dependable and useful adjunct to the study of Paget's disease of bone

In order to evaluate and quantitate the therapeutic efficacy of disodium etridonate (EHDP) in the treatment of Paget's disease, a prospective double-blind study was instituted. Subjects received either placebo, low-dose EHDP, or high-dose EHDP and were evaluated prior to therapy and 6 months later. Bone scans were performed with 99mTc or 18F and radioisotopic uptake studies were conducted. The results were correlated with clinical improvement, biochemical parameters, and radiographic skeletal surveys, and indicate that the radioisotopic uptake studies are both a sensitive and reproducible means of evaluating the degree of response to EHDP

The binding of both human chorionic gonadotropin (hCG) and human luteinizing hormone (hLH) to a homogeneous population of isolated intact granulosa cells from increasingly mature porcine ovaan follicles has been studied. The number of receptor sites per granulosa cell increases 35-fold as the follicle enlarges, although cell size remains constant. This may explain the increased biologic responsiveness to gonadotropin of mature cells from large follicles. The affinity for both hormones, as determined by equilibrium dissociation constants, is high, and does not appear to change significantly as the cells mature. Comparison of dissociation constants, numbers of binding sites, and competitive inhibition between hCH and hLH, indicates that these two hormones probably interact with the same receptor on the granulosa cells

Selective release of inflammatory materials from leukocyte lysosomes is reduced by compounds which increase cyclic 3',5'-adenosine monophosphate (cAMP) levels in suspensions of human leukocytes and is augmented by agents which increase cyclic 3',5'-guanosine monophosphate (cGMP) levels in these cell suspensions. Lysosomal enzymes are released in the absence of phagocytosis when cytochalasin B (5 mug/ml) converts polymorphonuclear leukocytes (PMN) to secretory cells: lysosomes merge directly with the plasma membrane upon encounter of PMN with zymosan, and cells selectively extrude substantial proportions of lysosomal, but not cytoplasmic enzymes. beta-Adrenergic stimulation of human leukocytes produced a dose-related reduction in beta-glucuronidase release (blocked by 10(-6) M propranolol) whereas alpha-adrenergic stimulation (phenylephrine plus propranolol) was ineffective. In contrast, the cholinergic agonist carbamylcholine chloride enhanced enzyme secretion, an effect blocked by 10(-6) M atropine. Incubation of cells with exogenous cAMP or with agents that increase endogenous cAMP levels (prostaglandin E1, histamine, isoproterenol, and cholera enterotoxin) reduced extrusion of lysosomal enzymes; in contrast, exogenous cGMP and carbamylcholine chloride (which increases endogenous cGMP levels), increased beta-glucuronidase release. Whereas colchicine (5 x 10(-4) M), a drug which impairs microtubule integrity, reduced selective enzyme release, deuterium oxide, which favors microtubule assembly, enhanced selective release of lyosomal enzymes. The data suggest that granule movement and acid hydrolase release from leukocyte lysosomes requires intact microtubules and may be modulated by adrenergic and cholinergic agents which appear to provoke changes in concentrations of cyclic nucleotides