In order to establish whether the favorable effect of estrogen therapy on postmenopausal bone loss was dose related, we measured sequential changes in the cortical diameters of the metacarpals by radiographic morphometry in 120 normal postmenopausal women who were being treated with ethinyl estradiol in doses ranging from 5 to 50 micrograms daily. There was a net loss of bone at doses below 15 micrograms per day and a net gain at doses of 25 micrograms per day and above. At doses between 15 and 25 micrograms daily, bone was neither gained nor lost. The loss of bone with the low doses was due to expansion of the medullary cavity that was unaccompanied by any change in total bone width. There was no change in bone volume with the intermediate doses because endosteal resorption of bone was offset by periosteal apposition. The net gain of bone with the higher doses occurred because endosteal resorption was totally inhibited but periosteal bone apposition continued. Thus, in postmenopausal women the reduction in the rate of cortical bone loss in response to estrogen therapy depends on the dose administered.

1. Plasma alkaline phosphatase activity and urine hydroxyproline excretion were measured in age-matched premenopausal and postmenopausal women. 2. Both measurements were found to be significantly higher in postmenopausal women. 3. It is proposed that the rise in the plasma alkaline phosphatase, like that in the hydroxyproline excretion, may reflect the onset of bone loss that occurs after the menopause.

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Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new dimercaptosuccinic acid (DMSA) analog with enhanced lipophilic properties, was evaluated for potential developmental toxicity. Intraperitoneal injections of Mi-ADMS were given to female Swiss mice (0, 47.5, 95, and 190 mg/kg) on gestational d 6-15. The maternal clinical status was monitored daily during treatment. At termination (gestational d 18), dams were evaluated for clinical status and gestational outcome. Each live fetus was weighed and examined for external, visceral, and skeletal abnormalities. Although no maternal mortality was observed, treatment with 95 and 190 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain during treatment and increased relative liver weight. Embryo/fetal toxicity, consisting of a significant increase in the number of late resorptions as well as in the percentage of postimplantation loss, reduced (nonsignificant) fetal body weight, and an increase in the incidence of skeletal defects, was also observed at 190 mg/kg/d. However, no treatment-related external or soft-tissue malformations or developmental variations were found in any group. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 47.5 mg/kg/d, whereas the NOAEL for developmental toxicity was 95 mg/kg/d. These results indicate that Mi-ADMS did not produce developmental toxicity in mice in the absence of maternal toxicity.

Among patients with cystic fibrosis (CF), those in the subset who develop hypergammaglobulinemia and circulating immune complexes often have relatively severe disease and a decreased likelihood of survival. Because Fc receptors have an important role in the removal of immune complexes and because defective Fc receptor function has been associated with inheritance of the histocompatibility antigens HLA DR2 and HLA DR3, we postulated that HLA DR2 and/or HLA DR3 might be genetic markers for this subset of patients with CF. However, in a group of 20 carefully documented patients with CF, we found no association of HLA DR2 or HLA DR3 with serum immunoglobulin, immune complex levels, or evidence of rapidly progressive disease.