The osteomalacias.

Osteomalacia is characterized by large osteoid seams and a preserved volume of bone trabeculae. The mineralization of newly formed bone requires adequate concentrations of calcium and phosphate: the Ca.P product has been regarded as a useful, empirical diagnostic test of osteomalacia. It decreases in patients with osteomalacia mainly because they have very low plasma phosphate levels. At present total body bone mineral and total body bone density can be directly measured by whole body absorptiometry, which indicates the lowest total mineral content of the skeleton which can increase quickly after adequate treatment. The main symptoms of osteomalacia are: bone pain; muscular weakness (commonly as pelvic girdle myopathy); Looser-Milkman pseudofractures or more often a pattern of generalized demineralization at X-ray. The main biochemical parameters in osteomalacia include: defective calcium absorption with hypocalcemia and hypocalciuria; defective intestinal phosphate absorption with hypophosphatemia; there is often increased renal phosphate clearance due to hypocalcemia and secondary hyperparathyroidism; elevated alkaline phosphatase and osteocalcin levels; high bone turnover confirmed by kinetic studies carried out with radiocalcium or 99mTc-MDP. An etiological classification of the osteomalacias includes: 1) nutritional osteomalacia: a) inadequate exposure to sunlight and/or insufficient vitamin D intake; b) defective intestinal absorption of vitamin D because of malabsorption syndromes (e.g. jejuno-ileal bypass for obesity).(ABSTRACT TRUNCATED AT 250 WORDS)

[The diagnosis of postmenopausal osteoporosis]. / La diagnosi di osteoporosi post-menopausale.

Post-menopausal osteoporosis is a metabolic bone disease which is histologically characterised by a reduction of bone mass with normal mineral content of the remaining bone tissue. In clinical term, the symptoms of disease include pain in the bones, pathological fractures (of the vertebra, femur, wrist) and consequent deformations of the skeletons. X-ray is still the most efficient diagnostic tool, although it is only capable of revealing osteopenia when bone has lost more than 40% of its mineral content. Bone densitometry is an important stage in the diagnosis and study of osteoporosis. It is first performed at the distal extremity of the forearm, then at the lumbar vertebra and head of the femur. Bone mineralometry is also currently used to study the skeleton as a whole (total body absorptiometry). This method, which has a high level of precision and no positioning problems, is able to provide extremely reliable measurements of bone mineral content, in particular during monitoring. It is worth underlining, however, that other bone metabolic diseases, namely osteomalacia, are also characterised by reduced bone density: the level of bone density should therefore not be considered as an expression of bone mass. In biochemical terms, post-menopausal osteoporosis leads to minimum modifications of the phospho-calcium metabolism: only during stages of accelerated bone turnover is it possible to observe a small increase in calciuria, hydroxyprolinuria and serum osteocalcin levels. A prime factor for the diagnosis of post-menopausal osteoporosis is the intestinal calcium absorption test: post-menopausal osteoporosis is characterized by insufficient intestinal calcium transport.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Main endocrine modulators of vitamin D hydroxylases in human pathophysiology.

Vitamin D is considered to be devoid of direct biological activity. It must be first hydroxylated in the liver by a 25-hydroxylase (25OHase), then in the kidney by a 1 alpha-hydroxylase (1 alpha OHase) which is responsible for the synthesis of the active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The activity of 1 alpha OHase is known to be under the control of a series of endocrine modulators, particularly parathyroid hormone (PTH) and estrogens. We report here our studies in humans concerning the behaviour of vitamin D hydroxylases in some pathological conditions. In chronic liver disease no severe impairment of vitamin D-25-hydroxylation has been observed, except in the latest stages: this is probably due to the great functional reserve of the liver, so that normal levels of serum 25OHD can be maintained on condition that the vitamin D supply is adequate. 1 alpha OHase is impaired in chronic renal failure due to the decrease in the number of functioning nephrons. It has been demonstrated that kidney transplantation restores normal 1,25(OH)2D levels. A decrease in 1,25(OH)2D production due to reduced PTH stimulation has been observed in hypoparathyroidism: in these patients a subcutaneous substitution therapy with synthetic human parathyroid hormone resulted in restoration of normal 1,25(OH)2D levels. A reduced activity of 1 alpha OHase due to reduced estrogen stimulation plays a key role in postmenopausal osteoporosis. In these patients estrogens increase 1,25(OH)2D levels, as it has been demonstrated directly and indirectly. In the aforementioned pathological conditions an impairment of calcium absorption has been observed; it was directly related to the reduced production of 1,25(OH)2D. Treatment with 1,25(OH)2D3 was effective in restoring normal calcium absorption. In postmenopausal osteoporosis the reduced levels of 1,25(OH)2D were accompanied by serum levels of 25-hydroxyvitamin D (25OHD) higher than in age-matched control women. In these cases long-term treatment with physiological doses of 1,25(OH)2D3 resulted in a progressive decrease in 25OHD serum levels which approached to the normal range. These findings are likely to be related one to another: the low 1,25(OH)2D levels are responsible for reduced product-inhibition of 25OHase, so that the synthesis of 25OHD increases. A similar mechanism occurs in renal failure and in hypoparathyroidism.

Myxoma of the left ventricle.

We report a case of left ventricular myxoma in a 19-year-old man which presented as intermittent aortic valve obstruction. Echocardiography provided a comprehensive diagnosis, and excision through a left ventriculotomy was safely accomplished.

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

Serum bone Gla-protein (BGP or osteocalcin) was measured in 25 women with histologically confirmed postmenopausal osteoporosis before and during long-term treatment with 1 microgram/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 age-matched 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.

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

Sixty-two women with symptomatic postmenopausal osteoporosis underwent long-term 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 the 24 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.

Clinical, biochemical and histological results of a double-blind trial with 1,25-dihydroxyvitamin D3, estradiol and placebo in post-menopausal osteoporosis.

Twenty-eight women with postmenopausal osteoporosis were studied in a double-blind trial aimed to compare the effects of a one-year treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), estradiol valerate (E2) and placebo. Patients were divided into 4 groups: group 1 was given 1,25(OH)2D3 alone, group 2 was given E2 alone, group 3 was given 1,25(OH)2D3 + E2, group 4 received a placebo. The evaluation of the effects of the treatments included clinical examination of patients, the measurement of a number of biochemical parameters, such as plasma and urinary calcium and phosphate, urinary hydroxyproline, serum alkaline phosphatase, the measurement of intestinal calcium absorption and bone mineral content (BMC) and a histomorphometric study of bone biopsies from the iliac crest. The best clinical results were obtained in the patients who were given 1,25(OH)2D3 alone; appreciable results were also noticed in the patients who were given E2 alone or in combination with 1,25(OH)2D3, while patients in the placebo group worsened. BMC decreased in the placebo group and increased, although non significantly, in the patients treated with 1,25(OH)2D3 or E2 or both. The histomorphometric study showed a significant increase in the mean trabecular diameter in patients treated with 1,25(OH)2D3 alone or in combination with E2. Changes in the volume density of trabecular bone paralleled those in BMC. The results of the trial indicate that 1,25(OH)2D3 is an effective therapeutic agent in postmenopausal osteoporosis.

[Asu(1,7)E-CT, an analog of eel calcitonin. A comparative study in man with reference to other synthetic calcitonins]. / La (Asu) E-CT, un analogo della calcitonina di anguilla. Studio comparativo nell'uomo rispetto ad altre calcitonine sintetiche.

(Asu) E-CT is a deaminodicarba-analog of the synthetic eel-calcitonin (E-CT) that shows specific activity and the potency reasonably high in comparison with that of the most potent natural hormone. The structure of its molecule indicates that the disulphide bond in calcitonins is not essential for the biological activity but only for the maintenance of the specific conformation by forming an intramolecular bridge. The instability of calcitonins should mainly be attributed to the presence of the disulfide bond and (Asu)E-CT proved to be more stable "in vitro" than native calcitonins. The more prolonged hypocalcemic effect of E-CT and its aminosuberic analog (Asu)E-CT has been accounted for to a greater stability of and persistence at the receptor site. (Asu) E-CT has been largely studied in Japan on experimental animals and successfully used in the treatment of hypercalcemia in man. On the contrary investigations on human administration of this analog are very scarce. The present paper reports studies carried out in normal subjects and Paget's disease patients to investigate the effects of (Asu)E-CT in man in comparison with the effects of synthetic human calcitonin (H-CT) and synthetic salmon calcitonin (S-CT). Two different experimental procedures have been used: 1) rapid intravenous injection of (Asu)E-CT (80 MRC. U.) or respectively of H-CT and S-CT (100 MRC. U.) in 15 subjects (7 normals and 8 with Paget's disease); 2) slow 7 days continuous subcutaneous infusion of similar daily amounts of (Asu)E-CT, H-CT and S-CT administered by a microjet pump device in 21 subjects (7 normals and 14 with Paget's disease). The intravenous administration of (Asu)E-CT induced a rapid and persistent decrease in total plasma calcium, ionized calcium and plasma phosphate that was more evident in Paget's disease patients than in normal subjects. No clearly cut differences have been observed with the hypocalcemic and hypophosphatemic effect of H-CT and S-CT administered intravenously; nevertheless the hypocalcemic effect proved to be more persistent in Paget's disease patients treated with (Asu)E-CT. After intravenous infusion of (Asu)E-CT the plasma level of cAMP rose more evidently in pagetic than in normal subjects but the rise was lower than in H-CT and S-CT treated subjects.(ABSTRACT TRUNCATED AT 400 WORDS)