M. Peacock

The Cause of Idiopathic Calcium Stone Disease: Hypercalciuria or Hyperoxaluria?

Hypercalciuria is common in patients who form calcium oxalate urinary stones and is considered by many to be the cause of the disorder. This review shows that there is little relationship between either the rate of stone-formation or calcium oxalate crystalluria and the urinary excretion of calcium. There is, however, a strong relationship between these parameters and the urinary excretion of oxalate which is slightly, but significantly, elevated in stone-formers compared with normals. It is concluded that this mind degree of hyperoxaluria may be much more important than hypercalciuria in the genesis of calcium oxalate stones.

Osteoporosis in hypogonadal men: Role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation

To investigate the pathogenesis of osteoporosis in male hypogonadism we have investigated a heterogeneous group of 13 men with hypogonadism: 7 men (median age 60, range 31-79) with two or more vertebral crush fractures and 6 men (median age 61.5, range 28-76) without vertebral fractures. The group with crush fractures had trabecular and cortical osteoporosis as assessed by Singh grade, iliac crest trabecular bone volume, and metacarpal cortical area/total area. This was accompanied by an altered trabecular architecture with a reduction in number of trabeculae but no change in trabecular width, which contrasts with age-related bone loss in men where there is no reduction in trabecular number but thinning of trabeculae. The fracture group had significantly lower plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations than the nonfracture group, and this was associated with malabsorption of calcium. Irrespective of the presence or absence of osteoporosis, treatment with testosterone led to a significant increase in total and free plasma 1,25(OH)2D and an improvement in calcium absorption measured with radiocalcium and by balance techniques. In addition, urine biochemistry, metabolic balance studies, and bone biopsy suggest that skeletal retention of calcium and bone formation are increased by testosterone treatment. We conclude that male hypogonadism causes both cortical and trabecular osteoporosis and altered trabecular architecture. A major risk factor for the development of osteoporosis is reduction in plasma 1,25(OH)2D, leading to malabsorption of calcium and reduced bone formation.

Saturation-inhibition index as a measure of the risk of calcium oxalate stone formation in the urinary tract.

Studies were carried out on multiple urine samples from eight patients with recurrent idiopathic calcium oxalate stone formation and eight normal persons to define an index of the risk of forming calcium oxalate stones. Under the same conditions of dietary and fluid intake the urine samples of the patients with stone formation were more supersaturated with calcium oxalate (P less than 0.001) and had lower concentrations of protective inhibitors of crystallization (P less than 0.001) than those of the controls. However, the best separation between the groups was defined by a discriminant line relating inhibitory activity and urine saturation. A measure of the risk of forming large crystals, the saturation-inhibition index, was defined as the distance of each urine from the discriminant line. The patients with stone formation had a significantly higher mean saturation-inhibition index than the controls (P less than 0.001). Both the percentage of large calcium oxalate crystals excreted (P less than 0.001) and the stone episode rate (P less than 0.005) were significantly correlated with the saturation-inhibition index.

CALCIUM CRYSTALLURIA IN RECURRENT RENAL-STONE FORMERS

Abstract The volume of crystals excreted by controls and stone-forming patients was measured in fresh urine at body temperature. Six male patients with idiopathic recurrent renal-stone disease had a sustained crystalluria on a normal but constant dietary intake of calcium, phosphorus, oxalate, and fluid. Below pH 6.2 the crystals consisted only of calcium oxalate and above pH 6.2 mainly of calcium phosphate. Six healthy male controls investigated under the same conditions of diet and fluid intake excreted significantly less crystalline calcium oxalate than did the stone-formers. Separate oral doses of calcium citrate and sodium oxalate further enhanced the crystalluria of the stone-formers but had little effect in the controls. The difference between the two groups was due mainly to a difference in crystal size rather than crystal numbers. The calcium-oxalate crystalluria in the recurrent stone-formers was mainly of octahedral crystals of calcium oxalate dihydrate, often in aggregates up to 200 μ in diameter, whereas in the controls the calcium oxalate was in the form of very small particles with little or no aggregation. The increased crystalluria of the stone-formers was assor ciated with increased concentrations of calcium and oxalate in the urine.

Ethinyl Estradiol and Norethindrone in the Treatment of Primary Hyperparathyroidism in Postmenopausal Women

Treatment with ethinyl estradiol or norethindrone reduces the bone-turnover rate and plasma calcium levels in normal postmenopausal women, without affecting the secretion of calcium-regulating hormones. To assess the effect of these sex steroids in patients with primary hyperparathyroidism, we treated postmenopausal women who had hyperparathyroidism with either ethinyl estradiol (n = 6) or norethindrone (n = 11). After three weeks of treatment, the bone-turnover rate declined and plasma calcium fell from a mean (+/- 1 SE) of 2.77 +/- 0.07 mmol per liter (11.1 +/- 0.3 mg per deciliter) to 2.58 +/- 0.05 mmol per liter (10.3 +/- 0.2 mg per deciliter; P less than 0.01) in the group treated with ethinyl estradiol, and from 2.93 +/- 0.08 mmol per liter (11.7 +/- 0.3 mg per deciliter) to 2.84 +/- 0.08 mmol per liter (11.4 +/- 0.3 per deciliter; P less than 0.05) in the patients who received norethindrone. No significant changes in the plasma levels of parathyroid hormone, calcitonin, or calcitriol were observed after the estrogen-induced increases in vitamin D-binding protein had been taken into account. Since the decline in plasma calcium levels did not stimulate secretion of parathyroid hormone, we conclude that treatment with either sex steroid resets the threshold for secretion of parathyroid hormone. Thus, although the reductions in plasma calcium levels were moderate, sex-hormone therapy may be useful in the treatment of mild hyperparathyroidism in postmenopausal women.

Calcium malabsorption in the elderly: the effect of treatment with oral 25-hydroxyvitamin D3.

Abstract. Calcium malabsorption is common in the elderly and may contribute to the development of age‐related bone loss. To investigate its cause, we have measured radio‐calcium absorption, plasma 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D and parathyroid hormone in forty‐eight elderly women with a normal plasma creatinine. Calcium malabsorption was associated with low 25‐hydroxyvitamin D concentrations and was corrected by increasing these into the normal range by treatment with oral 25‐hydroxyvitamin D3. Treatment also increased 1,25‐dihydroxyvitamin D, and decreased parathyroid hormone concentrations.

ROLE OF KIDNEY IN REGULATION OF PLASMA-CALCIUM

Abstract It is suggested that it is the action of parathyroid hormone on renal tubular reabsorption of calcium which is mainly responsible for plasma-calcium homœostasis in man.

Contrasting microanatomy of idiopathic and corticosteroid-induced osteoporosis.

Previous studies of microanatomic changes in normal bone with age have suggested that underlying differences in bone remodeling between male subjects and female subjects give rise to different patterns of bone loss. The relationship between microanatomic and histologic levels of organization are herein examined in two groups of osteoporotic subjects, one with idiopathic and the other with corticosteroid-induced osteoporosis. Using tissue from the iliac crest, total trabecular surface and trabecular width and number were measured, together with bone volume and static and dynamic indices of formation (osteoid surface, seam width, mean wall thickness, lamellar thickness, calcification fronts, and mineralization rate) and resorption (total resorption cavities and osteoclast incidence). The results suggest that while a similar loss of trabecular bone volume is common to both groups, there is a marked distinction in the distribution of the remaining bony tissue and indices of remodeling. A decline in trabecular number accompanied by a relative increase in resorption characterized both sexes with primary osteoporosis, whereas a decline in trabecular width associated with depressed formation was the predominant feature in the secondary disease. Thus trabecular attenuation is principally the manifestation of depressed formation, while trabecular discontinuity is primarily the manifestation of bone resorption.

ACTION OF 1α-HYDROXY VITAMIN D3 ON CALCIUM ABSORPTION AND BONE RESORPTION IN MAN

Abstract Synthetic 1α-hydroxy-vitamin D 3 (1α-hydroxycholecalciferol, 1α-H.C.C.) was given orally in a dose of 25 μg. per day to groups of patients in whom calcium malabsorption is a recognised feature. Patients responded with an increase in plasma calcium and phosphate and in calcium absorption irrespective of their pre-treatment values. Net calcium resorption from bone was increased in all patients with normal renal function. In patients with renal failure, however, net bone resorption tended to decrease. The onset of action was rapid and could be seen within 24 hours. On stopping the vitamin the effects were not maintained and their disappearance depended on the duration of treatment. 1α-H.C.C. is very potent in man and will be useful in treatment of patients with calcium malabsorption. The malabsorption of calcium of elderly people is not due to failure of the absorptive mechanism in the small bowel since it responds to 1α-H.C.C. but the dose will need to be less than 25 μg. per day to avoid excessive bone resorption and hypercalcaemia.

Renal Effects of Calcitonin

Porcine calcitonin in a slow-release gelatin vehicle was given by intramuscular injection to 10 patients—four with primary hyperparathyroidism, four with Pagets disease, and two with carcinoma of the breast and hypercalcaemia. All cases showed a fall in serum calcium with an immediate rise in urine calcium. All except three patients with primary hyperparathyroidism showed a fall in serum phosphorus, but an immediate rise in urine phosphorus occurred in all cases. Urine hydroxyproline output fell in three patients with severe Pagets disease. Urine sodium rose in all cases, but the effects on potassium, magnesium, water, and pH were not appreciably different from results obtained in four control subjects who were given the gelatin vehicle alone. The data suggest that calcitonin caused a decrease in the tubular resorption of calcium and phosphorus. The hypocalcaemic effect appeared to be due to a decrease in bone resorption in the patients with Pagets disease but in the remaining cases could be accounted for in part or entirely by the rise in urine calcium.