Paraneoplastic hypercalcemia associated with bladder carcinoma: report of 2 cases

Hypercalcemia associated with bladder carcinoma is rare. We report on 2 patients with hypercalcemia and bladder tumor without bone metastases. In both patients serum calcium returned to normal after removal of the tumor. Serum immunoreactive parathyroid hormone levels were normal in both patients. In 1 case a high gradient of immunoreactive parathyroid hormone across the tumor was demonstrated but the secretion of nephrogenous cyclic adenosine monophosphate was normal. Urinary excretion of prostaglandins also was normal in this case. These data show that hypercalcemia was caused by the tumoral production of some humoral factor different from parathyroid hormone.     

The effects of dichloromethylene diphosphonate on hypercalcemia and other parameters of the humoral hypercalcemia of malignancy in the rat leydig cell tumor

Summary There is a high frequency of Leydig cell tumors associated with hypercalcemia in the aged Fischer 344 rat. We studied a transplantable tumor cell line (Rice D-6) which is associated with hypercalcemia, hypercalciuria, hypophosphatemia, renal phosphate wasting, increased urinary cyclic adenosine monophosphate (AMP) excretion, absence of bone metastases, increased osteoclastic bone resorption, and suppressed immunoreactive parathyroid hormone (iPTH) concentrations. We examined the ability of dichloromethylene diphosphonate (Cl₂MDP) to lower serum calcium and decrease the parameters of increased bone resorption. We used this drug also as a pharmacologic tool to determine the relationship of hypercalcemia and increased bone resorption to the abnormalities in renal tubular function associated with the humoral hypercalcemia of malignancy. Daily administration of Cl₂MDP before development of hypercalcemia, in doses from 2.5–40 mg/kg body weight subcutaneously, delayed and suppressed both the hypercalcemia and hypercalciuria. There was an increase in bone mass and decrease in both osteoclast number and activity compared with bones from untreated tumor-bearing animals. The urinary hydroxyproline excretion in treated animals declined towards the normal range. There were no significant effects on serum phosphorus, urine phosphorus, or urine cyclic AMP excretion. These data suggest that Cl₂MDP reverses the increased bone resorption that occurs in the humoral hypercalcemia of malignancy, and confirms that diphosphonates are effective agents in the prevention and treatment of increased bone resorption associated with malignant disease. They also suggest that renal phosphate wasting and increased urinary cyclic AMP excretion are not directly related to the hypercalcemia.     

A case report: primary hyperparathyroidism--comparison before and after parathyroidectomy by oral calcium tolerance test

To evaluate the cause of hypercalciuria, we carried out the oral calcium tolerance test before and after parathyroidectomy in a patient with primary hyperparathyroidism who had recurrent and multiple nephrolithiasis. Preoperative laboratory examination showed hypercalcemia, hypophosphetamia, hypercalciuria, decrease in % tubular reabsorption of phosphorus and strikingly elevated urinary cyclic AMP excretion. The oral calcium tolerance test indicated a significantly greater increase in serum calcium (delta serum calcium: 1.4 mg/dl vs 0.8 mg/dl) and a significantly greater suppression of urinary cyclic AMP excretion (delta U-cyclic AMP:-3.56 moles/gCre vs-1.17 moles/gCre) before parathyroidectomy than after. These results showed that hypercalciuria in this case was induced not only by the significant increase in the filtrated load of calcium but by the reduction in the resorption of calcium in the distal tubule caused by the significantly suppressed parathyroid hormone effect.     

Kidney stones as a manifestation of hypercalcemic disorders. Hyperparathyroidism and sarcoidosis

When hypercalcemia is detected in a kidney stone formation, an intact parathyroid hormone measurement should be made. Detection of hyperparathyroidism (HPT) is important to prevent further stone episodes and to avoid the complications of high serum calcium in other organ systems. Stones in patients with HPT often contain apatite salts in addition to calcium oxalate because parathyroid excess may create a renal tubular acidosis. The calculi seen in patients with sarcoidosis, another hypercalcemic state that may cause stone formation, however, are usually pure calcium oxalate. Excess generation of 1,25-dihydroxyvitamin D results in intestinal hyperabsorption of calcium and secondary hyperoxaluria.     

Possible mechanism of impaired calcium and vitamin D metabolism in nephrotic rats.

Patients who have nephrotic syndrome and normal renal function are hypocalcemic in spite of the elevated levels of serum parathyroid hormone (PTH) caused by a low serum concentration of 1,25-dihydroxyvitamin D[1,25(OH)2D], presumably because of its loss in urine. However, it has not been established whether the conversion of 25-hydroxyvitamin D[25(OH)D] into 1,25(OH)2D is impaired in the kidney. In this study, we examined the serum levels of vitamin D metabolites, and kinetics of renal 25(OH)D-1-hydroxylase activity in vitro, and nephrogenous cyclic AMP excretion in response to exogenous PTH administration in puromycin aminonucleoside-induced nephrosis in rats. Plasma ionized calcium and the serum levels of vitamin D metabolites were lower, and conversely, the serum PTH level was higher, in nephrotic rats than in controls. Serum 1,25(OH)2D levels were higher in 25(OH)D3-treated nephrotic rats than in untreated nephrotic rats, indicating that the low 1,25(OH)2D level in nephrotic rats is partially due to the low concentration of 25(OH)D. Although PTH levels were higher in nephrotic rats than in control rats, the Vmax of renal 25(OH)D-1-hydroxylase and nephrogenous adenosine 3',5'-monophosphate (cyclic AMP) excretion in response to exogenous PTH were significantly lower in nephrotic animals than in controls. These results suggest that abnormalities in calcium and vitamin D metabolism in nephrotic rats are partially attributable to impaired proximal tubular function.     

Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease

Disorders of mineral metabolism develop early in chronic kidney disease, but it appears that Blacks with stage-5 disease have more severe secondary hyperparathyroidism than other races. We measured levels of parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in 227 Black and 1633 non-Black participants in the SEEK study, a multi-center cohort of patients with early chronic kidney disease. Overall, Blacks had similar 1,25D levels compared with non-Blacks, but significantly lower levels of 25D with higher levels of calcium, phosphorus, and parathyroid hormone, and were significantly more likely to have hyperphosphatemia than non-Blacks. In multivariable analyses adjusted for age, gender, estimated glomerular filtration rate, body mass index, and diabetes, Blacks had significantly lower 25D and higher parathyroid hormone levels than non-Blacks, with the latter parameter remaining significant after further adjustment for calcium, phosphorus, 25D, and 1,25D. The association between Black race and secondary hyperparathyroidism, independent of known risk factors, suggests that novel mechanisms contribute to secondary hyperparathyroidism in Blacks with chronic kidney disease.     

The 'oral 1,25-dihydroxyvitamin D3 pulse therapy' in hemodialysis patients with severe secondary hyperparathyroidism

Many hemodialysis patients are still suffering from secondary hyperparathyroidism although 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been used to treat renal osteodystrophy for the last two decades. The main reason for its failure to correct the secondary hyperparathyroidism is that in patients, hypercalcemia occurs before adequate parathyroid hormone (PTH) suppression is obtained when a large daily dose of 1,25(OH)2D3 is started. In this study, the oral dose of 1,25(OH)2D3 (4.0 micrograms) was administered only twice a week at the end of hemodialysis ('oral 1,25(OH)2D3 pulse therapy'), in 19 patients with severe secondary hyperparathyroidism. Serum immunoreactive PTH started to decrease after 6 weeks of therapy, and the original level of 41.2 +/- 7.24 was reduced to 24.4 +/- 6.12 ng/ml by the end of the 6-month therapy (p less than 0.001). Serum alkaline phosphatase also was reduced by 64.4%. Three out of 19 patients suffered from hypercalcemia during the 4th month of therapy. Calcium supplement given to 6 other patients with severe secondary hyperparathyroidism did not lower serum PTH levels significantly after 6 weeks of therapy, although serum calcium levels increased and were sustained above 10 mg/dl for the last 5 weeks. These findings strongly suggest that the suppressive effect of the oral 1,25(OH)2D3 pulse therapy was attained by a direct action of 1,25(OH)2D3 on the parathyroid gland rather than by its ability to elevate serum calcium levels. In conclusion, the oral 1,25(OH)2D3 pulse therapy effectively lowered PTH levels in hemodialysis patients who cannot tolerate large daily doses of 1,25(OH)2D3.     

Reduced plasma concentration of 1,25-dihydroxyvitamin D in children with moderate renal insufficiency

We measured the plasma concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) in 39 children comprising three groups; eight with moderate renal insufficiency (GFR of 25 to 50 ml/min/1.73 M2, seven of whom had tubulointerstitial disease), eight with severe renal insufficiency (on chronic hemodialysis), and 23 healthy control subjects. The mean plasma concentration of 1,25-(OH)2D was reduced by some 40% (P less than 0.002) in the children with moderate renal insufficiency, and by some 80% (P less than 0.001) in the children with severe renal insufficiency. In the children with moderate renal insufficiency, the reduced concentration of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of 1,25-(OH)2D was associated with increased serum concentrations of immunoreactive parathyroid hormone (iPTH) and reduced serum concentrations of calcium and phosphorus. When analyzed over the range of renal function from normal through severely impaired, values of iPTH correlate inversely and significantly with those of 1,25-(OH)2D. Growth was impaired in four of the eight children with moderate renal insufficiency. The results of the current study suggest that in children with moderate renal insufficiency, a reduction in the renal synthesis and in the plasma concentration of 1,25-(OH)2D may be important pathogenetic events in disordered metabolism of calcium and phosphorus, including secondary hyperparathyroidism.     

Clodronate in hypercalcemia of malignancy

Of the many compounds belonging to the diphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis of malignancy. All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients, clodronate, given intravenously either as a single infusion or as repeated daily administrations, can normalize serum calcium, usually 3–5 days after the onset of therapy. In these good responders, long-term maintenance treatment should be individually adjusted since relapse appears to depend upon the type of tumor, the extent of malignancy and the administration of anticancer therapy. In a subset of well-rehydrated hypercalcemic patients in whom increased tubular calcium reabsorption represents the prevailing disturbed calcium flux, the acute effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be experimentally reproduced in diphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from lung, kidney and breast carcinomas. This indicates that, in addition to antiosteolytic drugs, such as clodronate, patients with hypercalcemia of malignancy would benefit from the development of agents that can selectively reduce the renal tubular reabsorption of calcium. In patients displaying a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D₃. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate-treated patients. No serious side effects have been reported in cancer patients receiving oral clodronate, except for the occasional occurrence of mild and transient gastrointestinal upset. A large number of clinical studies indicate that clodronate is a safe and efficacious drug in the treatment of hypercalcemia of malignancy, particularly in cases in which increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.     

Human lactation: forearm trabecular bone loss, increased bone turnover, and renal conservation of calcium and inorganic phosphate with recovery of bone mass following weaning

The calcium (Ca) metabolism of established human lactation was studied in 40 adult women (mean age 32.4 years) who had been breast-feeding for 6 months (Lac) and in 40 age-matched controls (Con) using fasting urine and blood biochemistry and forearm single-photon bone mineral densitometry (BMD). Serial studies were performed up to 6 months after weaning in Lac women and repeated once in Con women. During lactation the significant findings were (1) a selective reduction (7.1%, P less than 0.03) in BMD at the ultradistal site containing 60% trabecular bone, but not at two more proximal, chiefly cortical bone sites; (2) increased bone turnover affecting bone resorption [fasting hydroxyproline excretion, Lac 2.22 +/- 0.12 mumol/liter GF (mean +/- SEM), Con 1.19 +/- 0.04, P less than 0.001] and affecting bone formation (plasma alkaline phosphatase, Lac 81.9 +/- 2.5 IU/liter, Con 53.5 +/- 2.7, P less than 0.001, and serum osteocalcin, Lac 14.0 +/- 0.7 microgram/liter, Con 7.3 +/- 0.4, P less than 0.001); and (3) renal conservation in the fasting state of both Ca and inorganic phosphate (Pi) with a resultant moderate increase in plasma Pi but not in plasma Ca (total or ionized). There were no differences between the groups in serum parathyroid hormone (PTH, intact and midmolecule assays), 25-hydroxy- and 1,25-dihydroxyvitamin D, nephrogenous cyclic AMP production, or plasma creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary hyperparathyroidism. Preoperative evaluation and correlation with surgical findings

The clinical and operative findings in 101 patients with the diagnosis of primary hyperparathyroidism are reviewed, with particular emphasis on the current methods of preoperative evaluation.Of these patients seventy-two (72 per cent) underwent neck exploration. The twenty-nine patients who did not have an operation either refused operative treatment or were not granted an operation because of medical reasons (multiple system disease in elderly patients). Fourteen of the surgical patients (20 per cent) required re-exploration. Two patients had negative neck explorations.Preoperative evaluation included routine serum calcium (X3), serum phosphorus, and alkaline phosphatase determinations, and appropriate radiologic evaluation. Urinary cyclic AMP levels were helpful in differentiating primary hyperparathyroidism from nonparathyroid hypercalcemia.Phosphorus clearance studies were helpful as were twenty-four hour urinary calcium determinations. Parathyroid scans and arteriography were not helpful diagnostically and intravenous toluidine blue was of no benefit intraoperatively.Eleven patients had selective neck vein catheterizations for parathyroid hormone immunoassays with 63 per cent localization.Of seventy patients with positive surgical findings, eleven had chief cell hyperplasia, six had adenomatous hyperplasia, and fifty-three had adenoma(s).     

Evidence that obesity does not influence the vitamin D-endocrine system in blacks

As compared to nonobese white men and women, age-matched nonobese black subjects and obese white individuals show alterations in the vitamin D-endocrine system that are characterized by increases in mean serum immunoreactive parathyroid hormone (PTH), serum 1,25-dihydroxyvitamin D [1,25-(OH)2D], and urinary cyclic adenosine 3,5-monophosphate (cAMP) and by decreases in mean serum 25-hydroxyvitamin D (25 OHD) and in urinary calcium. Thus, both groups show secondary hyperparathyroidism which is associated with increased renal tubular reabsorption of calcium and increased renal synthesis of 1,25-(OH)2D. In view of these findings, studies were conducted in 10 obese black subjects (3 men and 7 women) and in 12 nonobese black individuals (7 men and 5 women), ranging in age from 20 to 35 yr, to determine whether obesity influences the vitamin D-endocrine system in blacks. Body weight averaged 99 +/- 4 kg in the obese and 73 +/- 3 kg in the nonobese subjects (p less than .001). All of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium, 900 mg of phosphorus, 110 meq of sodium, 65 meq of potassium, and 18 meq of magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)     

A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy

Summary Tumors causing humoral hypercalcemia of malignancy (HHM) were implanted to athymic nude rats. In one of these rat models transplanted with uterine cancer (UCC), a complete reproduction of human HHM syndrome was achieved: hypercalcemia, hypophosphatemia with increased urinary phosphate and cyclic AMP excretion, and suppressed serum 1,25-dihydroxy-vitamin D (1,25(OH)₂D) level. In another hypercalcemic nude rat model implanted with oral cavity cancer (OCC), all the features were similar except for markedly elevated serum 1,25(OH)₂D. Hypercalcemia disappeared by surgical removal of the tumors in both models, confirming the humoral mechanisms for causing these features. Furthermore, in UCC tumor-bearing rats, hypophosphatemia, increased renal phosphate excretion, and reduced serum 1,25(OH)₂D concentration were already present when these rats were only marginally hypercalcemic. These results raise the possibility that the changes in renal tubular phosphate handling and vitamin D metabolism in HHM are not secondary to hypercalcemia but are due to direct effects of the humoral factor(s) that cause this syndrome. Extracts of both tumors exhibited stimulation of cyclic AMP production in osteoblastlike cells, UMR 106, which could be almost completely inhibited by parathyroid hormone (PTH) antagonist, human PTH(3–34). By comparing the nature and characteristics of humoral factor(s) from UCC and OCC models, mechanisms responsible for causing these abnormalities can be explored. Thus, these nude rat models can be useful for elucidating the underlying mechanism of the development of HHM.     

Urinary excretion of parathyroid hormone-related protein fragments in patients with humoral hypercalcemia of malignancy and hypercalcemic tumor-bearing nude mice

To investigate whether parathyroid hormone-related protein (PTHrP), a hypercalcemia-inducing factor responsible for malignancy-associated hypercalcemia (MAH), is excreted into urine of these patients, radioimmunoassay was established using antiserum specific for the C-terminal region of PTHrP-(127-141). Immunoreactive PTHrP (iPTHrP) was detected in the urine of all patients with MAH (n = 6) in whom nephrogenous cyclic AMP excretion was elevated. However, iPTHrP was not detected in the urine of normal subjects (n = 25) or hypercalcemic patients with primary hyperparathyroidism (n = 8). In normocalcemic patients with malignant disorders iPTHrP was not detected in the urine in most cases (24 of 25 patients) but was detectable in 1 of 25 patients. iPTHrP was also detected in the urine of hypercalcemic nude mice transplanted with PTHrP-producing tumors, but not in the urine of control and normocalcemic nude mice transplanted with PTHrP-nonproducing tumor. Furthermore, size-exclusion high-performance liquid chromatography revealed that the molecular weight of iPTHrP is about 2000-6000 daltons in the urine of patients as well as tumor-bearing nude mice. These data indicate that the fragments of the C-terminal region of PTHrP are excreted into the urine of patients with MAH and in a few normocalcemic patients with malignancies, suggesting that the measurement of iPTHrP in the urine is potentially useful in the differential diagnosis of hypercalcemia, particularly in differentiating humoral hypercalcemia of malignancy and primary hyperparathyroidism.     

Influence of 1,25-dihydroxycholecalciferol on parathyroid activity in patients with primary hyperparathyroidism.

Parathyroid morphology and blood chemistry were studied in five patients with primary hyperparathyroidism treated with 1,25-dihydroxycholecalciferol (1,25-DHCC) for 2 to 11 days before planned operation. Before the institution of treatment all patients were hypercalcemic, whereas the serum immunoreactive parathyroid hormone (iPTH) concentration either was elevated or normal. During the treatment the urinary phosphate excretion was significantly increased, whereas the calcium excretion and the serum concentrations of calcium and phosphate were unaffected or only slightly changed. Serum iPTH decreased during the first days of treatment, but returned then to increased levels close to the pretreatment ones. The treatment was tolerated well by the patients. Light and electron microscopy of the removed parathyroid glands disclosed one adenoma in each of the five patients, the other glands exhibiting either a slight hyperplasia or a normal appearance. Both the adenomatous and the non-adenomatous parathyroid tissue showed a predominance of dark chief cells and three of the adenomas exhibited a varying number of atrophic and oxyphil cells. The non-adenomatous glands were composed of atrophic and dark chief cells. Signs of low functional activity were ultrastructurally observed in the parathyroid parenchymal cells. It is suggested that 1,25-DHCC treatment of patients with primary hyperparathyroidism inhibits parathyroid hormone secretion.     

Metabolic and skeletal effects of low and high doses of calcium acetate in patients with preterminal chronic renal failure

BACKGROUND: Secondary hyperparathyroidism commonly evolves, as the glomerular filtration rate falls. The metabolic and skeletal effects of a possible remedy, calcium acetate, have not been studied in patients with preterminal chronic renal failure. METHODS: Men with a mean creatinine clearance of approximately 30 ml/min took calcium acetate for 24 weeks at doses which provided 507 or 1,521 mg calcium/day with meals. Metabolic determinations were made at intervals of 4-8 weeks, and the bone mineral density (BMD) was measured at the beginning and at the end of the trial. RESULTS: The low-dose regimen produced no metabolic or skeletal effect. In subjects prescribed the high-dose regimen, the 24-hour urine phosphorus excretion fell from 0.53 mg/mg creatinine to values ranging from 0.34 to 0.41 mg/mg creatinine. The theoretical phosphorus threshold concentration rose by a maximum of 38.6%, and the serum phosphorus concentration did not change. The mean serum calcium concentration rose by a maximum of 7.2%. The mean fractional changes in parathyroid hormone and 1,25-dihydroxyvitamin D concentrations ranged from -27.0 to -39.6% and from -5.0 to -20.3%, respectively. The BMD increased at L1, L3, and L4. CONCLUSION: Calcium acetate prescribed to deliver 1,521 mg calcium/day with meals reduced parathyroid hormone and 1,25-dihydroxyvitamin D concentrations and increased lumbar BMD in men with preterminal chronic renal failure.     

Milk alkali syndrome. Does it exist and can it be differentiated from primary hyperparathyroidism?

Four patients with milk-alkali syndrome (MAS) presented with many of the characteristics of primary hyperparathyroidism including hypercalcemia, low or normal serum phosphorus levels, normal or increased urinary calcium levels, and inappropriately high or elevated serum parathyroid hormone levels. These laboratory findings differ from those classically described in MAS, i.e., hypercalcemia without hypercalciuria and a normal or high plasma phosphate level. Because the serum calcium level failed to return to normal after two weeks of hydration and a low calcium diet, and because of the inability to distinguish this syndrome from primary hyperparathyroidism, two of the four patients underwent neck exploration. Four normal parathyroid glands were histologically proven in each, and at autopsy in a third patient, there was no evidence of parathyroid hyperplasia or adenoma. Hypercalcemia eventually resolved in all patients with a low-calcium diet for as long as six months. Of the several features of MAS, hypercalcemia, alkalosis in the presence of azotemia, a history of increased calcium and alkali intake, and a response to dietary calcium restriction are helpful in differentiating this syndrome from primary hyperparathyroidism. Laboratory tests in patients with MAS may be confusing and the return to normocalcemia in response to a calcium deficient diet may be delayed.     

Nonautonomy of parathyroid hormone and urinary cyclic AMP in primary hyperparathyroidism.

This study demonstrates that appreciable changes in serum parathyroid hormone and urinary cyclic AMP occur during experimentally induced hyper- and hypocalcemia in almost all patients with primary hyperparathyroidism regardless of histology. A single patient with tertiary hyperparathyroidism also demonstrated a significant elevation of serum parathyroid hormone and urinary cyclic AMP in response to EDTA induced reduction in ionized calcium. Thus, total autonomy of hormone secretion was not present in the great majority of the patients with a parathyroid adenoma, parathyroid hyperplasia, or the single patient with tertiary hyperparathyroidism. Therefore, preoperative evaluation of the rsponse of urinary cyclic AMP and serum parapthyroid hormone to EDTA or calcium infusion will not distinguish parathyroid adenomas from hyperplasia on the basis of total autonomy of hormone secretion. If a difference in secretory control is present between parathyroid adenomas and parathyroid hyperplasia, it is more subtle than total autonomy for adenomas and nonautonomy for hyperplasia.     

Dissociation of renal cyclic AMP and phosphate responses to parathyroid hormone in uremia

Summary Various investigators have shown that chronic uremia is associated with a normal or exaggerated phosphaturic response to parathyroid hormone (PTH). To explore the relationship between progressive uremia, renal tubular cyclic AMP (cAMP), and inorganic phosphate (Pi) response to PTH and acidosis, in vivo and in vitro experiments were designed in rats with experimental uremia of 4–6 weeks’ duration. Both uremic and pair-fed control rats were treated with 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃) and/or chronic NH₄Cl feeding. Urinary Pi and cAMP and plasma immunoreactive PTH (iPTH) were measured as well as PTH- and NaF-stimulated cAMP from isolated renal tubules. Excretion of cAMP decreased by 30% in uremic as compared to control rats despite a 3-fold rise in Pi excretion. Acidosis superimposed on uremia did not further decrease cAMP excretion, nor did it significantly alter the elevated Pi excretion. 1,25(OH)₂D₃ treatment of uremic rats further lowered cAMP excretion although Pi excretion rose, hypercalcemia occurred, and plasma iPTH fell. In nonuremic control rats, 1,25(OH)₂D₃ treatment led to hypercalcemia, a progressive decrease in cAMP, and increase in Pi excretion. Isolated renal tubules from uremic or acidotic uremic rats revealed a 50% reduction in both PTH- and NaF-stimulated cAMP generation compared to control rat renal tubules. This observation was unchanged by 1,25(OH)₂D₃ treatment. Renal tubules of 1,25(OH)₂D₃-treated control rats demonstrated a decreased cAMP production in response to both PTH and NaF which was inversely related to the calcium content of the renal tubules. Renal tubular calcium levels of uremic rats, initially 3-fold elevated, also increased during 1,25(OH)₂D₃ treatment. These results are consistent with the hypothesis that progressive uremia results in a dissociation between PTH, urinary cAMP, and Pi excretion which cannot be explained by either metabolic acidosis or 1,25(OH)₂D₃ deficiency.     

Role of parathyroid hormone and 1,25-dihydroxyvitamin D3 in the development of osteopenia in oophorectomized rats

Summary The effect of ovarian insufficiency on calcium metabolism has been thought to involve an increased bone resorptive effect of parathyroid hormone and possible impaired synthesis of 1,25-dihydroxyvitamin D₃. In the present study a rat model allowing for controlled serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D₃ was used. Oophorectomy in this species is associated with increased serum levels of 1,25-dihydroxyvitamin D₃ and decreased bone mass. Although thyroparathyroidectomy increased bone mass, an increased sensitivity of bone to parathyroid hormone in oophorectomized rats was not observed. Thus the development of the osteopenia did not seem to be related to increased parathyroid hormone sensitivity or to reduced levels of 1,25-dihydroxyvitamin D₃. Exogenous 1,25-dihydroxyvitamin D₃ increased bone mass in oophorectomized as well as intact rats. Intestinal calcium transport was increased by moderate doses of 1,25-dihydroxyvitamin D₃. Intestinal calcium transport was also reduced by thyroparathyroidectomy and increased by the administration of parathyroid extract. A tendency for increased accumulation of 1,25-dihydroxyvitamin D₃ in blood in oophorectomized rats has been noted. It is suggested that the tendency to hypercalcemia in ovarian-insufficient females given 1-hydroxylated vitamin D compounds may be related to a diminished metabolism of 1,25-dihydroxyvitamin D₃.