A. Caniggia

Pathophysiology of the adverse effects of glucoactive corticosteroids on calcium metabolism in man.

Abstract Long-term treatments with corticosteroids are frequently responsible for a particular kind of osteoporosis which develops more rapidly than other varieties of the disease. This condition is mainly due to an increase in the rate of bone resorption that exceeds that of bone formation. Clinical features include bone pain and fractures. Adverse effects of corticosteroids on calcium and phosphate metabolism are also noticeable after short-term treatments. This allowed a better understanding of the pathophysiology of corticosteroid osteoporosis. Corticosteroid treatment determines a rapid impairment of calcium transport in the intestine, leading to: —a decrease in the availability of calcium that is the main responsible for the negative calcium balance; —a decrease in the renal reabsorption of calcium (and phosphate) which results in an increase in the urinary losses of these minerals, so contributing to the negative calcium balance; —a direct action on the skeleton leading to an increase in bone resorption. These actions are all capable of promoting a negative calcium balance which requires a proportional release of calcium from the skeleton. The three different pathophysiological mechanisms are discussed in detail. Their coexistence can explain the rapid development of corticosteroid osteoporosis.

Long-term treatment with calcitriol in postmenopausal osteoporosis

In order to assess the long-term effects of calcitriol treatment in postmenopausal osteoporotic patients, 1.0 micrograms/d of calcitriol was administered in two divided doses for 1 to 8 years to 270 women with symptomatic, histologically proven postmenopausal osteoporosis. No calcium supplementation was given. Clinically, the treatment resulted in substantial relief from pain, with improvement of ambulancy. Intestinal calcium absorption, which was lower than normal at baseline, increased significantly and remained higher than the baseline value as long as calcitriol was administered. Urinary calcium absorption also increased, but hypercalcemia occurred, exceptionally and transiently, in only a few patients. Urinary hydroxyproline excretion did not increase, indicating that hypercalciuria was not of resorptive origin. Total-body density, determined by dual-photon total-body absorptiometry in 56 patients, showed an increase after 18 to 24 months of therapy in most cases. The occurrence of nontraumatic, clinically relevant fractures decreased noticeably as compared with the period preceding calcitriol treatment. No change occurred in renal function, and no renal stones developed. Calcitriol was an effective and safe treatment of postmenopausal osteoporosis.

Effect of a long-term treatment with 1,25-dihydroxyvitamin D3 on osteocalcin in postmenopausal osteoporosis

SummarySerum bone Gla-protein (BGP or osteocalcin) was measured in 25 women with histologically confirmed postmenopausal osteoporosis before and during long-term treatment with 1 μg/day of 1,25-dihydroxyvitamin D3(1,25(OH)2D3).Basal serum BGP was significantly lower in osteoporotic women (3.8±1.4 ng/ml) than in agematched controls (6.8±2.0 ng/ml). During 1,25(OH)2D3 therapy serum BGP increased so that the mean of the values observed on treatment (4.8±1.5) was significantly higher than the mean basal value.It is known that BGP synthesis is stimulated by 1,25 (OH)2D3 and that serum BGP is a specific marker of bone formation; therefore, it is possible that the low basal levels of osteocalcin we observed were related to the low serum 1,25(OH)2D concentrations reported in osteoporotic women and that the increase in BGP levels observed under 1,25(OH)2D3 treatment was a consequence of osteoblast stimulation.

Kinetics of99mTechnetium-Tin-methylene-diphosphonate in normal subjects and pathological conditions: A simple index of bone metabolism

SummaryThe blood clearance and the urinary excretion of the bone scanning complex technetium-tin-methylene-diphosphonate (99mTc-Sn-MDP) administered intravenously have been measured in 27 normal subjects and 104 patients with post-menopausal osteoporosis, osteomalacia, primary hyperparathyroidism, Pagets disease, pagetoid metastases of prostatic cancer, osteolyses, chronic renal failure, and liver cirrhosis to quantitate the skeletal uptake of the radiopharmaceutical.Kinetic analysis of the data was performed in terms of a four-compartment model; correspondent rate constants and fitted values were estimated.In normal subjects the whole-body retention (WBR) up to 24 h was 33.3%±7.4 SD, whereas significantly more elevated values were observed in several pathological conditions, the highest values being ascertained in patients with pagetoid metastases, primary hyperparathyroidism, and chronic renal failure and whenever large osteoid seams were present.Differences were found between osteoporosis and osteomalacia, monostotic and polyostotic Pagets, pagetoid and osteolytic metastases of bone.In Pagets disease significant correlations have been observed between WBR and the exchangeable calcium pool, WBR and the serum alkaline phosphatase, and WBR and the urinary excretion of hydroxyproline.Kinetic analysis demonstrated that WBR provided overestimate of the skeletal retention by an average of 16%, the retention in the “extravascular space” being greater in patients with chronic renal failure.This simple method shows significant promise for a quantitative approach to the skeletal turnover in metabolic bone disease.

The hormonal form of vitamin D in the pathophysiology and therapy of postmenopausal osteoporosis

Sixty-two women with symptomatic postmenopausal osteoporosis underwent longterm treatment with 1,25-dihydroxyvitamin D3. The following results were obtained: i) a dramatic improvement of the intestinal transport of radioactive calcium, which was impaired prior to the treatment; ii) non significant increases in fasting serum calcium; iii) significant increases in the24 h urinary excretion of calcium and phosphate, resulting from the improvement of intestinal calcium absorption, and a decrease in the urinary cAMP/Cr ratio; iv) non significant changes in serum phosphate, serum alkaline phosphatase, urinary hydroxyproline; v) non significant increases in bone mineral content; vi) relief from pain and improvement of motility in all the patients; vii) no side effect was noticed. In conclusion the treatment with 1,25-dihydroxyvitamin D3 was shown to be useful in postmenopausal osteoporosis.

Serum levels of 25-hydroxyvitamin D in postmenopausal osteoporosis

SummarySerum concentrations of 25-hydroxyvitamin D were measured in a group of women with symptomatic postmenopausal osteoporosis, assessed by bone biopsy. A competitive protein binding assay was used, which included a chromatographic step. Accurate surveys of dietary or therapeutic vitamin D intake and light environment were obtained in each patient.Women with severe postmenopausal osteoporosis were found to have significantly (P<0.001) higher serum levels of 25-hydroxyvitamin D than age-matched normal women, the mean values being 27.5 ng/ml (±13.6 SD) and 8.2 ng/ml (±5.7), respectively.The authors hypothesize that the reduction in 1,25-dihydroxyvitamin D, recently reported in postmenopausal osteoporotic women, might be responsible for the increased serum levels of 25-hydroxyvitamin D through an inadequate product inhibition of liver vitamin D 25-hydroxylase.

Effect of the administration of 1,25-dihydroxyvitamin D3 on serum levels of 25-hydroxyvitamin D in postmenopausal osteoporosis

SummarySerum concentrations of 25-hydroxyvitamin D were measured in a group of women with symptomatic postmenopausal osteoporosis, before and after long-term treatment with physiological doses of 1,25-dihydroxyvitamin D3. A competitive protein binding assay was used, which included a chromatographic step. The treatment resulted in a significant decrease in serum 25-hydroxyvitamin D levels that were higher than normal in basal conditions, the mean values before and after therapy being 27.7 ng/ml (±17.1 SD) and 19.7 ng/ml (±12.7), respectively. These findings seem to confirm the hypothesis that an inadequate product-inhibition of liver 25-hydroxylase is responsible for the increased basal levels of 25-hydroxyvitamin D found in postmenopausal osteoporosis.

Effects of parathroid hormone and calcitonin on plasma and nephrogenous cclic adenosine‐3.,5 ‐monophosphate in normal subjects and in pathological conditions

Abstract. To evaluate the response of bone cells and kidne to parathroid hormone (PTH) and calcitonin (CT), the acute effects of these hormones given intravenousl on plasma cclic adenosine 3′,5′‐monophos‐phate (cAMP), nephrogenous cAMP and clearance ratio (cAMPxreatinine), have been studied in normal subjects and in patients with Pagets disease, hpoparathroidism and osteopetrosis.

Intestinal absorption of radio phosphate in osteomalacia before and after vitamin D treatment

evidence of improvement of pseudofractures on long-term oral phosphate treatment has been given recently [4, 8]. The intestinal absorption of radiophosphate has been studied in animals [5, 6, 7, 10], and recently in human subjects [2, 3]. The test for evaluating the intestinal absorption of radiophosphate is based on the oral administration of 50 microcuries of Na2Ha2P04 and measuring the plasma radioactivity levels, expressed as the percentage of dose per litre of plasma, in the 4 h after the administration of the dose. We have tested by this method 2 cases of nutritional osteomalacia and a case of hypophosphataemic rickets; basal conditions showed low levels of plasma radioactivity in 2 cases (T. M. and G. C.) and normal levels in the third case (B. R.). After one month of treatment with large doses of Vitamin D 2 (15 mg daily i.m.) the intestinal absorption of

Early effects of synthetic bovine parathyroid hormone and synthetic salmon calcitonin on urinary excretion of cyclic AMP, phosphate and calcium in man.

Bovine synthetic parathyroid hormone infused intravenously in man increased both the urinary excretion of cyclic AMP and the urinary excretion of phosphate whereas a Salmon synthetic calcitonin infusion increased the urinary excretion of phosphate without change in urinary excretion of cyclic AMP. These data are consistent with the hypothesis that different renal mechanisms are involved in the response to each hormone.