Selected indicators of calcium-phosphate metabolism in patients with diabetes mellitus

The changes in blood serum concentrations of calcium, magnesium, inorganic phosphate, total activity of alkaline phosphatase and the activity of its bone fraction, as well as urinary excretion of calcium, phosphate, hydroxyproline and oxalate have been measured in 31 patients with insulin-dependent (type I) diabetes, in 31 patients with non-insulin-dependent (type II) diabetes and in 29 healthy subjects in the condition of low-calcium diet. The elevated urinary excretion of calcium, phosphate, hydroxyproline and oxalate, lowered blood serum level of magnesium, and increased total and bone fraction activities of alkaline phosphatase were found in diabetic patients. The urinary excretion of calcium and hydroxyproline, and the activity of bone fraction alkaline phosphatase were significantly higher in patients with type II diabetes than in those with type I diabetes. It was concluded that there is a significant relation between the state of metabolic normalization of diabetes and the degree of biochemical aberrations concerning calcium-phosphate metabolism.     

Treatment of Paget's Disease of Bone with Mithramycin

We report data from three patients with severe Paget''s disease of bone who were treated with mithramycin.Mithramycin infusion resulted in a fall in plasma calcium, phosphate, alkaline phosphatase, and urinary hydroxyproline excretion. There was an improvement in calcium and phosphorus balance in two of the three subjects studied. A pronounced or complete relief of bone pain occurred in all three.We suggest that mithramycin exerts its beneficial effect in Paget''s disease of bone by stimulating parathyroid hormone release. The parathyroid hormone released has a predominantly anabolic action on bone since its catabolic action is blocked by mithramycin, which inhibits bone resorption.     

Human parathyroid hormone (1-34) increases urinary excretion of lysosomal enzymes in rats

The kidney is the major target of parathyroid hormone (PTH), and PTH influences the urinary excretion of calcium, phosphate and hydrogen ions. It was previously reported that the urinary, excretion of N-acetyl-beta-D-glucosaminidase (NAG), a lysosomal enzyme, transiently increases after human PTH (hPTH) (1-34) infusion in normal subjects and idiopathic hypoparathyroidism patients, but not in pseudohypoparathyroidism type I patients. Here we report that intravenous infusion of hPTH(1-34) to rats transiently increased the urinary excretion of various lysosomal enzymes, such as beta-glucuronidase and acid phosphatase as well as NAG. However, it did not affect the urinary excretion of tubular brush border membrane enzymes, i.e. alkaline phosphatase, leucine aminopeptidase and gamma-glutamyl transpeptidase. Human PTH(1-34) dose-dependently increased the urinary excretion of NAG in rats with a peak at 30 min, which returned to a baseline within 60 min. The increase in the urinary NAG excretion caused by hPTH(1-34) positively correlated with the increase in the urinary cAMP excretion (r = 0.844, p < 0.01), and infusion of dibutyryl cAMP at a dose of 20 mg/kg similarly increased the urinary excretion of NAG. These results suggested that the increase in the urinary excretion of lysosomal enzymes caused by hPTH(1-34) may be a functional response to hPTH(1-34) occurring in the renal tubules via PTH signaling pathway.     

Familial hypocalciuric hypercalcaemia and acute pancreatitis.

Four families with familial hypocalciuric hypercalcaemia were studied. The probands presented with abdominal pain, which in three was due to acute pancreatitis; in two the condition was life threatening. Serum concentrations of calcium, magnesium, phosphate, and immunoassayable parathyroid hormone, urinary calcium excretion, and the rate of renal tubular reabsorption of phosphate were measured; the findings were compared with results in 10 patients with primary hyperparathyroidism matched for serum calcium concentration to establish differences between the diseases. Familial hypocalciuric hypercalcaemia should be suspected in patients with hypercalcaemia in whom daily urinary calcium excretion is below 5 mmol (200 mg) provided renal insufficiency, vitamin D deficiency, and ingestion of drugs that reduce calcium excretion have been excluded. Most cases appear to run a benign course, but some may suffer considerable morbidity. Surgical treatment should be reserved for patients with severe complications, when all parathyroid tissue should be removed.     

Secondary Hyperparathyroidism in Osteomalacia

Twenty-one patients with histologically proved osteomalacia from various causes were investigated for biochemical and radiological evidence of osteomalacia and secondary hyperparathyroidism. Among the 15 who maintained a normal serum calcium, seven had a raised phosphate excretion index, seven had a raised serum alkaline phosphatase, and six had phalangeal erosions. On the other hand, six patients had a subnormal serum calcium; of these, none showed a raised phosphate excretion index, one had a raised serum alkaline phosphatase, and one had erosions. The phosphate excretion index and the alkaline phosphatase were strongly correlated (r = +0·84). It is concluded that this absence of manifest secondary hyperparathyroidism in some patients with osteomalacia is due to failure of an increase in the release of parathyroid hormone. Measurement of phosphaturia does not appear to be a useful means of detecting osteomalacia. Subsequently, the 24-hour (stable) strontium space measurement was found to be the most sensitive single biochemical screening test for osteomalacia.     

Calcium oxalate crystal formation in patients with hyperparathyroidism and hyperthyroidism and related metabolic disturbances

The crystallization of calcium oxalate in the urine of patients with hyperparathyroidism and hyperthyroidism was studied using a mixed suspension mixed product removal (MSMPR) system. In addition, calcium metabolism in hyperthyroidism and its relationship to urolithiasis was investigated. The urines from all the three groups (normal subjects, hyperparathyroid and hyperthyroid patients) showed reduced nucleation rates and increased growth rates in comparison with the control synthetic urine. The nucleation rate was not significantly different between the three human urine groups, while the growth rate was significantly higher in the hyperparathyroid group compared to the normal and hyperthyroid groups. Crystal volume (suspension density) in the hypetparathyroid group was approximately twice that in the other two groups. Serum and ionized calcium levels in hyperparathyroid patients were higher than in normal subjects, while hyperthyroid patients had levels only slightly higher than those in normal subjects. The hyperparathyroid and hyperthyroid groups differed significantly from the normal group in urinary calcium excretion. These two groups also showed significantly higher levels of serum alkaline phosphatase and urinary hydroxyproline than did the normal group. Although hyperthyroid patients have a calcium metabolism similar to hyperparathyroid patients, the incidence of urolithiasis is no different between hyperthyroid and normal subjects. The results of both crystallization and calcium metabolism in hyperparathyroid patients were not significantly different between those with and without urolithiasis. The result of crystallization was also not significantly different between hyperparathyroid patients with and without hypercalciuria. This study suggests that hypercalciuria alone does not produce urinary stones and that urine from hyperparathyroid patients may contain promotors of calcium oxalate crystallization and calcium stone formation.     

Day-care surgery in British Columbia: a 7-year experience (1968-74).

Twenty-eight patients with symptomatic Paget''s disease of bone were treated with synthetic salmon calcitonin for periods of 9 to 42 months (average, 23 months). Serum alkaline phosphatase concentration and urinary hydroxyproline excretion, which had been elevated before treatment, were decreased by calcitonin treatment in all patients, and some decrease was sustained in 23 in association with variable decreases in pain, heat and stiffness of major joints. Improvement was sustained further in approximately half of these patients; the other half had partial return of symptoms. Calcium absorption was increased in 9 of 10 patients studied; the increase did not correlate with plasma concentrations of parathyroid hormone. The mean endogenous fecal calcium excretion was decreased significantly but there was no significant change in mean urinary calcium excretion. Mean accretion rate of calcium to bone, studied in 10 patients, was decreased by 35% after 6 months of treatment and by a further 23% 1 year later. There was no consistent effect of calcitonin treatment on bone mineral mass. No serious adverse effects of treatment such as allergic reactions were observed. Calcitonin appears to be effective initially in most patients with Paget''s disease of bone, but with long-term treatment resistance may be acquired.     

Indices of calcium metabolism in women with hip fractures

We have assessed indices of calcium metabolism in 41 women with hip fractures and compared them with two elderly control groups. The women with hip fractures had lower serum concentrations of albumin, 25-hydroxyvitamin D and osteocalcin than the controls. Serum concentrations of calcium, alkaline phosphatase and parathyroid hormone, as well as urinary hydroxyproline/creatinine ratios were similar in the three groups of women. The small reduction in serum osteocalcin concentration in fracture patients is consistent with the hypothesis that reduced osteoblast function may contribute to the osteoporosis which results in hip fracture.     

Calcium homeostasis during oral glucose load in healthy women.

It has been demonstrated that in healthy subjects during oral glucose tolerance test, serum calcium declines, while urinary calcium excretion increases, even if there is not a general agreement in this regard. The study was carried out in order to evaluate the effects of glucose oral load on calcium homeostasis in eight healthy adult women, also considering ionized calcium, plasma insulin and parathyroid hormone changes. The results showed a decline of total and ionized serum calcium (p < 0.05 and p < 0.01, respectively; maximum of the decrease at time 120'), in parallel with the increase of urinary calcium/ creatinine ratio (p < 0.05). Serum glucose and insulin increase (p < 0.0001 and p < 0.0005 respectively; maximum value at time 60'), while the parathyroid hormone level decreases (maximum decline at time 120', p < 0.01). No changes were observed in fasting control subjects for all parameters considered. The changes of these parameters with time suggest that the effects of glucose oral load on calcium metabolism in healthy adult women may be the consequence of parathyroid hormone suppression induced by acute hyperglycemia/hyperinsulinemia. The results confirm in vivo the PTH behaviour in vitro, on cultured bovine parathyroid cells, with high glucose concentration.     

Effect of calcium administration on renal responsiveness to parathyroid hormone in pseudohypoparathyroidism type I and II -- in comparison with normals, idiopathic and surgical hypoparathyroidism.

A 31-year-old man and a 12-year-old girl were diagnosed as pseudohypoparathyroidism (PHP) Type I because of a failure to respond to the administration of parathyroid hormone (PTH) with increased urinary excretion of phosphate and cyclic adenosine-3', 5'-monophosphate (cAMP). A 22-year-old woman was diagnosed as PHP Type II because there was no increase in the urinary excretion of phosphate despite of a marked increase in urinary cAMP excretion. With the combined calcium-PTH infusion or PTH infusion after vitamin D therapy, renal response was improved in these patients. Also dibutyryl adenosine-3'-5'-cyclic monophosphate (dbcAMP) infusion evoked an increased urinary phosphate excretion in all of the patients. The metabolic defect of our patients with PHP Type I may be caused not by a lack or defective form of PTH-sensitive receptor adenylate cyclase complex but rather by an abnormal conformation in the plasma membrane-associated receptor adenylate cyclase enzyme complex in kidney. In the patient with PHP Type II, as cAMP generation is intact, the metabolic defect might be related to a defect of calcium mobilization in renal tubular cells in response to PTH.     

Effect Modifying Role of Serum Calcium on Mortality-Predictability of PTH and Alkaline Phosphatase in Hemodialysis Patients: An Investigation Using Data from the Taiwan Renal Registry Data System from 2005 to 2012

Predicting mortality in dialysis patients based on low intact parathyroid hormone levels is difficult, because aluminum intoxication, malnutrition, older age, race, diabetes, or peritoneal dialysis may influence these levels. We investigated the clinical implications of low parathyroid hormone levels in relation to the mortality of dialysis patients using sensitive, stratified, and adjusted models and a nationwide dialysis database. We analyzed data from 2005 to 2012 that were held on the Taiwan Renal Registry Data System, and 94,983 hemodialysis patients with valid data regarding their intact parathyroid levels were included in this study. The patient cohort was subdivided based on the intact parathyroid hormone and alkaline phosphatase levels. The mean hemodialysis duration within this cohort was 3.5 years. The mean (standard deviation) age was 62 (14) years. After adjusting for age, sex, diabetes, the hemodialysis duration, serum albumin levels, hematocrit levels, calcium levels, phosphate levels, and the hemodialysis treatment adequacy score, the single-pool Kt/V, the crude and adjusted all-cause mortality rates increased when alkaline phosphatase levels were higher or intact parathyroid hormone levels were lower. In general, at any given level of serum calcium or phosphate, patients with low intact parathyroid hormone levels had higher mortality rates than those with normal or high iPTH levels. At a given alkaline phosphatase level, the hazard ratio for all-cause mortality was 1.33 (p < 0.01, 95% confidence interval 1.27–1.39) in the group with intact parathyroid hormone levels < 150 pg/mL and serum calcium levels > 9.5 mg/dL, but in the group with intact parathyroid hormone levels > 300 pg/mL and serum calcium levels > 9.5 mg/dL, the hazard ratio was 0.92 (95% confidence interval 0.85–1.01). Hence, maintaining albumin-corrected high serum calcium levels at > 9.5 mg/dL may correlate with poor prognoses for patients with low intact parathyroid hormone levels.     

Urinary Pyrophosphate in Normal Subjects and in Stone Formers

The urinary excretion of inorganic pyrophosphate was determined in nine normal subjects and also in eight patients with recurrent calcium-containing renal stones during varied levels of phosphate intake. The excretion of pyrophosphate and orthophosphate is virtually the same in the two groups at all levels of phosphate intake. It appears unlikely that a consistently reduced urinary excretion of pyrophosphate is a factor in the formation of urinary calculi. Pyrophosphate excretion rose and calcium excretion fell with increasing phosphate intake; this might be expected to have a beneficial effect in patients with recurrent calcium stones.     

The mechanism of action of citrinin on rabbit kidney alkaline phosphatase activity in vivo.

The effect of citrinin poisoning on rabbit kidney alkaline phosphatase was investigated. After seven days administration of citrinin (2 mg/kg body weight daily) the animals were sacrificed and the level of enzymes estimated in serum and kidney. Serum enzymes showed no variation in activity in the citrinin-treated animals, but in kidney, alkaline phosphatase activity decreased significantly. The decreased activity was mainly associated with the cytoplasmic fraction and in fractions Ib and II. The enzyme II obtained from citrinin-treated animal showed no kinetic difference in substrate specificity, inhibition by phenylalanine, phosphate, sodium-EDTA and Zn2+ ions, activation by Mg2+ ions, thermal inactivation and electrophoretic mobility to that of control Enzyme II. Immunological studies showed that the decrease in enzyme activity was due to existence of inactive enzyme protein. Hormones like cyclic AMP, prostaglandin E1 and parathyroid hormone reversed the decreased enzyme activity due to citrinin poisoning in mouse and rabbit. This study favours the possible existence of active and inactive forms of alkaline phosphatase in the system.     

Suppression of secondary hyperparathyroidism in children with chronic renal failure by high dose phosphate binders: calcium carbonate versus aluminium hydroxide.

Secondary hyperparathyroidism was suppressed over a period of one year in 12 children with chronic renal failure by using a regimen of mild dietary phosphate restriction and high dose phosphate binders. The patients were randomised to receive either aluminium hydroxide or calcium carbonate by mouth for six months and then crossed over to the other medication. Vitamin D (dihydrotachysterol) dosage was unchanged. Serum parathyroid hormone concentrations were reduced to within the normal range, urinary cyclic adenosine monophosphate values fell, plasma phosphate concentrations decreased, and the theoretical renal phosphate threshold increased significantly. Transiliac bone biopsy findings improved in four patients with adequate suppression of parathyroid hormone concentrations, deteriorated in two patients who were not compliant, and did not change in five patients in whom initial bone disease was mild. Growth velocity improved significantly. There was no difference in the clinical response, biochemical changes, or incidence of complications during treatment with the two agents. In view of the risk of aluminium toxicity the use of high dose calcium carbonate with dietary phosphate restriction and vitamin D supplementation is recommended in the control of secondary hyperparathyroidism in children with chronic renal failure.     

Effect of 1alphaOH-vitamin D3 in a case of pseudohypoparathyroidism.

A 37-year-old woman with typical features of pseudohypoparathyroidism (chronic tetany, paresthesia, persistent hypocalcemia, round face, short stature, short metacarpals and metatarsals, cucutaneous calcification and lack of response to exogenous and endogenous parathyroid hormone as regards urinary phosphate and cyclic AMP excretion) was treated with oral administration of 2 microgram/day of 1alphaOH-vitamin D3. Serum calcium started to rise within 3 days returning to the normal level with disappearance of symptoms referrable to hypocalcemia. Such a favorable effect of a small dose of 1alphaOH-vitamin D3 in a patient with typical hypoparathyroidism suggests an important role of disturbance of 1alpha-hydroxylation of vitamin D3 by the kidney in the pathogenesis of calcium and phosphorus abnormality in this disease. Forty-four cases of pseudohypoparathyroidism in the Japanese literature were briefly reviewed.     

Plasma monomeric calcitonin as a marker of disease activity in multiple myeloma patients with osteolysis.

Circulating monomeric human calcitonin (hCT-M), parathyroid hormone, osteocalcin, alkaline phosphatase, urinary hydroxyproline, corrected serum calcium and inorganic phosphate were measured in 49 multiple myeloma patients and 49 matched controls. In patients with Durie-Salmon stage III disease hCT-M levels (16.9 +/- 5.8 ng/l, mean +/- SD) were significantly higher than controls and stage I patients (P less than 0.01), and correlated directly with corrected serum calcium (r = 0.74; P less than 0.001). In the same subgroup 14 of 15 patients had plasma hCT-M concentrations higher than the mean + 2SD of the controls. The calcium infusion test induced an increase of hCT-M in normocalcemic patients which was significantly greater in patients with advanced disease than in either controls or stage I patients. These findings suggest that hCT-M may be a biochemical index of bone resorption and disease activity in myeloma patients with osteolysis. In fact, its plasma concentrations were elevated in a large proportion (93%) of patients with severe bone involvement, and correlated directly with serum calcium. Moreover, our findings suggest the presence of a calcitonin-dependent calcium homeostatic mechanism, that protects against hypercalcemia due to tumor osteolysis.     

1-alpha-hydroxycholecalciferol for renal osteodystrophy.

Fourteen patients with renal osteodystrophy were treated for at least one year with 1-alpha-hydroxycholecalciferol (1-alpha-OHD3) in a dose varying from 1 microgram/week to 3 microgram/day. Plasma calcium and inorganic phosphorus concentrations increased significantly. The plasma alkaline phosphatase concentration fell in 11 of the 12 patients in whom it was initially raised and returned to normal in seven. Serum parathyroid hormone concentrations were initially raised in all patients, but they decreased significantly with treatment and became normal in eight patients within one year. The 10 patients with radiological abnormalities showed some improvement. Hypercalcaemia occurred in 11 patients, and necessitated a reduction in the dose of 1-alpha-OHD3 in some. 1-alpha-OHD3 was effective in reducing the biochemical and radiological abnormalities of renal osteodystrophy, but it should be used wtih care, and plasma calcium concentrations should be monitored.     

The Role of Overweight and Obesity in Calcium Oxalate Stone Formation

Objective: The aim of the study was to assess the influence of overweight and obesity on the risk of calcium oxalate stone formation. Research Methods and Procedures: BMI, 24‐hour urine, and serum parameters were evaluated in idiopathic calcium oxalate stone formers (363 men and 164 women) without medical or dietetic pretreatment. Results: Overweight and obesity were present in 59.2% of the men and in 43.9% of the women in the study population. Multiple linear regression analysis revealed a significant positive relationship between BMI and urinary uric acid, sodium, ammonium, and phosphate excretion and an inverse correlation between BMI and urinary pH in both men and women, whereas BMI was associated with urinary oxalate excretion only among women and with urinary calcium excretion only among men. Serum uric acid and creatinine concentrations were correlated with BMI in both genders. Because no association was established between BMI and urinary volume, magnesium, and citrate excretion, inhibitors of calcium oxalate stone formation, the risk of stone formation increased significantly with increasing BMI among both men and women with urolithiasis (p = 0.015). The risk of calcium oxalate stone formation, median number of stone episodes, and frequency of diet‐related diseases were highest in overweight and obese men. Discussion: Overweight and obesity are strongly associated with an elevated risk of stone formation in both genders due to an increased urinary excretion of promoters but not inhibitors of calcium oxalate stone formation. Overweight and obese men are more prone to stone formation than overweight women.     

Pseudohypoparathyroidism showing positive phosphaturic and negative cyclic AMP excretion response to parathyroid hormone

We report a patient with pseudohypoparathyroidism (PHP) in whom parathyroid hormone (PTH) infusion failed to produce an increase in urinary adenosine 3', 5' monophosphate (cAMP) excretion in spite of the positive urinary phosphate excretion. The dbcAMP infusion test showed almost the same increase in phosphate as in the E-H test, although high urinary cAMP excretion was detected. Furthermore, a PTH infusion test in combination with calcium antagonist (diltiazem) administration markedly increased phosphate excretion, whereas the response of urinary cAMP excretion also remained negative. After treatment with 1 alpha(OH)D3, phosphaturic response increased by at least 14.3 mg/2 h compared with that in the pretreatment period. Therefore, intra and extra cellular calcium seem to affect the phosphaturic response induced by PTH.     

Parathyroid hormone, cAMP, electrolytes and uric acid after high dose CaCl2 in patients with idiopathic stone formation

High dose levels of calcium chloride significantly decrease serum level of parathyroid hormone (PTH) in both patients with history of idiopathic stone formation and healthy controls. Suppressibility of parathyroid glands is obtained by injection of 10 ml 10% calcium chloride without any restriction in calcium diet. Serum levels of calcium measured 14 mg/dl 10 min. after high dose calcium chloride injection and distinctly affect cAMP in urine in patients when compared to healthy controls. The elimination of electrolytes and uric acid is elevated 40 min. after calcium application in both patients and controls and returns to normal values 120 min. later. No stone formation has been observed in an eighteen mouth follow up of all subjects studied.