Paul Rødbro

Cigarette Smoking, Serum Estrogens, and Bone Loss during Hormone-Replacement Therapy Early after Menopause

To elucidate the effect of smoking on estrogen metabolism, we examined 136 postmenopausal women treated for one year with one of three different doses of combined estrogen-progestogen or placebo. The women were grouped according to smoking status, and serum levels of estrone and estradiol were measured before and after treatment. The results showed reduced levels of both estrogens in smokers as compared with nonsmokers in all three dosage groups. This reduction was most pronounced in the high-dose group (4 mg of estradiol), in which the serum levels of estrone and estradiol in smokers were only 50 per cent of those in nonsmokers (P less than 0.001 and less than 0.05, respectively). In contrast, no significant changes could be demonstrated in the corresponding placebo groups. Moreover, it was possible to demonstrate significant inverse correlations between the number of cigarettes smoked daily and the changes in the levels of serum estrone and estradiol, respectively, (P less than 0.001). This study suggests that an increased hepatic metabolism of estrogens results in lower estrogen levels among postmenopausal smokers. This may contribute to the reported risk of osteoporosis among smokers.

Incidence of Anticonvulsant Osteomalacia and Effect of Vitamin D: Controlled Therapeutic Trial

The bone mineral content (B.M.C.) in both forearms (related to total body calcium) was measured by photon absorptiometry for a controlled therapeutic trial in a representative sample of epileptic outpatients, comprising 226 patients treated with one or two major anticonvulsant drugs (phenytoin, phenobarbitone, primidone). Initially the mean B.M.C. value for all epileptic patients was 87% of normal. During treatment with 2,000 international units of vitamin D2 daily for three months an average B.M.C. increase of 4% was found, whereas the B.M.C. values remained unchanged in the placebo group and in the control groups. The incidence of hypocalcaemia and raised serum alkaline phosphatase was 12% and 43% respectively. The biochemical indices of osteomalacia were related to B.M.C. These results indicate that epileptic patients should be closely supervised for the occurrence of anticonvulsant osteomalacia, and, possibly, receive prophylactic treatment with vitamin D.

The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis

SummaryIt has been debated whether postmenopausal osteoporosis is characterized by high or low bone turnover and whether circulating levels of sex steroids contribute to the occurrence of osteoporotic fractures. We examined 154 70-year-old women with or without osteoporotic fractures, and 178 early postmenopausal women with a “rapid” or a “slow” bone loss. In all participants, we determined markers of bone formation (serum alkaline phosphatase (AP) and serum bone Gla protein (BGP)), markers of bone resorption (fasting urinary calcium/creatinine (FU Ca/Cr) and hydroxyproline/creatinine (FU Hpr/Cr)), and serum estrone (E1), estradiol (E2), androstenedione (A), and fat mass. The 70-year-old womenwith osteoporotic fractures had significantly elevated AP (P<0.001), BGP (P<0.001), and FU Hpr/Cr (P<0.001) compared with the groupwithout fractures. In the group of early postmenopausal women, the “rapid” bone losers had significantly increased FU Hpr/Cr (P<0.001) and FU Ca/Cr (P<0.001). E1, E2, A, and the fat mass did not differ in the groups with and without osteoporotic fractures, whereas the “rapid” bone losers had significantly lower E1 (P<0.05), E2 (P<0.05), and fat mass (P<0.01) than the ‘slow” bone losers. It is concluded that patients with manifest osteoporosis and early postmenopausal women with a rapid bone loss have increased biochemical markers of bone turnover. Moreover, the present study demonstrates that early postmenopausal women with an “excessive” bone loss have significantly decreased serum estrogens, whereas it is not possible to detect low estrogens in women with osteoporotic fractures.

Long-term bone loss in insulin-dependent diabetic patients with microvascular complications

Insulin-dependent diabetic patients have an approximately 10% decreased bone mineral content (BMC) when they are studied a few years after clinical onset of diabetes. After that time, patients without diabetic microvascular complications have no, or only very little, further bone loss. The aim of the present study was to investigate if any substantial long-term bone loss occurs in diabetic patients with microvascular complications. We studied 19 insulin-dependent diabetic patients with neither physiologic nor pathologic conditions known to interfere with bone metabolism, other than diabetes. BMC was determined twice, with an interval of 11 years. At initial examination, no patient had diabetic microangiopathy, but at final examination 7 patients had developed diabetic microvascular complications while 12 patients had not. As compared with gender- and age-matched controls, both subgroups had significantly decreased BMC at the initial examination. During the study period, the patients with complications showed further bone loss, whereas the subgroup without complications had unchanged decreased BMC. At final examination, BMC was significantly lower in patients with microvascular complications than in patients without them. The biochemistry of bone metabolism showed a significantly increased fasting urinary excretion of calcium and hydroxyproline in patients with complications, but not in the group without complications, and there was a negative correlation between plasma BGP (osteocalcin) and hemoglobin A1C for all patients. These findings indicate that, in addition to a decreased BMC (before or shortly after clinical onset of diabetes), patients who develop microvascular complications also develop ongoing bone loss. This loss may be caused by an increased bone resorption, but decreased bone formation during periods of poor diabetic control may be involved as well.

Anticonvulsant action of vitamin D in epileptic patients? A controlled pilot study.

The frequency of epileptic seizures was observed in a controlled therapeutic trial on 23 epileptic inpatients before and after treatment with vitamin D2 or placebo in addition to anticonvulsant drugs. The number of seizures was reduced during treatment with vitamin D2 but not with placebo. The effect was unrelated to changes in serum calcium or magnesium. The results may support the concept that epileptics should be treated prophylactically with vitamin D.

Effect of vitamin D on bone mineral mass in normal subjects and in epileptic patients on anticonvulsants: a controlled therapeutic trial.

The bone mineral mass was estimated by photon absorptiometry in 23 epileptic patients on long-term treatment with phenytoin and in 20 normal subjects before and during treatment with vitamin D or placebo. Initially, subnormal values of bone mineral mass were found in the epileptic patients. The group of epileptic patients treated with vitamin D showed a significant increase in bone mineral mass. The group of epileptic patients treated with placebo and the normal subjects treated with vitamin D or placebo showed no change in bone mineral mass.

Development of anticonvulsant osteomalacia in epileptic patients on phenytoin treatment.

In 151 epileptic patients, who had been treated with phenytoin for from 3 months to 31 years, the three indices of anticonvulsant osteomalacia: Serum calcium, serum alkaline phosphatase, and bone mineral content were studied to find the relation between the pathological changes and the duration of phenytoin treatment. The results indicate that anticonvulsant osteomalacia sets in quite early after institution of phenytoin treatment, and is kept at a constant level thereafter. If epileptics should have prophylactic vitamin D treatment, the extra supply of vitamin D probably should he given from the beginning of the anticonvulsant therapy.

INITIAL AND MAINTENANCE DOSES OF VITAMIN D2 IN THE TREATMENT OF ANTICONVULSANT OSTEOMALACIA

Bone mineral content (BMC), serum calcium and serum alkaline phosphatase levels were measured in 40 epileptics on long‐term phenytoin treatment, before and during treatment with vitamin D2 Initially the patients were divided into 3 groups, who received 2000, 4000, and 8000 international units daily for 105 days. Hereafter the 27 patients on the two higher doses were subdivided into two groups, who for a further 150 days received either 1000 I.U. or 200 I.U. daily. During the whole study the biochemical parameters were unaffected by the vitamin D treatment. With all 3 doses an initial increase in BMC (corresponding to a positive calcium balance) was observed, which was highest with 4000 I.U. daily. With this dose the mean BMC value was normalized. In the following maintenance dose period an estimated calcium balance close to zero was seen with 1000 I.U. daily, whereas the patients on 200 I.U. daily showed a negative calcium balance, as their BMC values returned to the initial figures. It is a cost‐benefit problem whether it is advisable to give prophylactic vita‐min D treatment to epileptic patients. To elucidate this problem a controlled therapeutic trial on a large scale would be needed, so planned as to clarify the clinical benefit of such treatment.

Quantitative estimation of parietal cell secretory function in man.

With measurement of volume, acid, and intrinsic factor after maximal histamine stimulation the gastric secretory patterns in healthy persons and patients with duodenal ulcer, atrophic gastritis, and pernicious anaemia are described. In duodenal ulcer patients a higher than normal secretion of acid and intrinsic factor was found, but the secretory patterns in duodenal ulcer patients and healthy persons were identical, the essential difference being a higher secretory volume in duodenal ulcer patients corresponding to a greater but normally functioning parietal cell mass. In atrophic gastritis the gastric secretion of acid and intrinsic factor was decreased compared to that of healthy persons. The acid secretion was more reduced than the secretion of intrinsic factor, and the findings may indicate a dissociation between these parietal cell secretory components in hyposecretory states. In patients with pernicious anaemia an abolished parietal cell function was found.

Biochemical status in epileptic patients during treatment with vitamin D. A controlled therapeutic trial.

In a controlled therapeutic trial, serum calcium and serum alkaline phophatase levels were measured during treatment with different doses of vitamin D2 in 45 epileptic inpatients. The results demonstrate that, in spite of the curative effect of vitamin D2 with regard to total body calcium, this vitamin has no effect on serum calcium or serum alkaline phosphatase in anticonvulsant osteomalacia.