Fuller Albright and our current understanding of calcium and phosphorus regulation and primary hyperparathyroidism.

The major contributions of Fuller Albright to our understanding of calcium and phosphorus regulation and primary hyperparathyroidism are highlighted. Albright was the first investigator to initiate a systematic study of mineral metabolism. With resources limited to the measurement of serum calcium and phosphorus and the infusion of parathyroid extract, Albright used balance studies to establish a framework for our understanding of calcium and phosphorus regulation and primary hyperparathyroidism. Albright was the first to show that the etiology of primary hyperparathyroidism could be from either an adenoma or hyperplasia of the parathyroid glands and stone disease was a separate manifestation of primary hyperparathyroidism. Albright also showed that: 1) a renal threshold for calcium excretion was present in hypoparathyroid patients; 2) correction of hypocalcemia in hypoparathyroid patients with vitamin D had a phosphaturic action; 3) renal failure reduced the intestinal absorption of calcium in primary hyperparathyroidism; 4) the ''hungry bone'' syndrome developed after parathyroidectomy in severe primary hyperparathyroidism; and 5) a target organ can fail to respond to a hormone. He also suggested that a malignant tumor could be responsible for ectopic hormone production. Finally, our review integrates the observations of Albright with our current knowledge of calcium regulation and disorders.

Phosphate depletion in the rat: effect of bisphosphonates and the calcemic response to PTH.

BACKGROUND: The removal of phosphate from the diet of the growing rat rapidly produces hypercalcemia, hypophosphatemia, hypercalciuria, and hypophosphaturia. Increased calcium efflux from bone has been shown to be the important cause of the hypercalcemia and hypercalciuria. It has been proposed that the increased calcium efflux from bone is osteoclast mediated. Because bisphosphonates have been shown to inhibit osteoclast-mediated bone resorption, this study was performed to determine whether bisphosphonate-induced inhibition of osteoclast function changed the biochemical and bone effects induced by phosphate depletion. METHODS: Four groups of pair-fed rats were studied: (a) low-phosphate diet (LPD; phosphate less than 0.05%), (b) LPD plus the administration of the bisphosphonate Pamidronate (APD; LPD + APD), (c) normal diet (ND, 0.6% phosphate), and (d) ND + APD. All diets contained 0.6% calcium. A high dose of APD was administered subcutaneously (0.8 mg/kg) two days before the start of the study diet and on days 2, 6, and 9 during the 11 days of the study diet. On day 10, a 24-hour urine was collected, and on day 11, rats were either sacrificed or received an additional APD dose before a 48-hour parathyroid hormone (PTH) infusion (0.066 microgram/100 g/hr) via a subcutaneously implanted miniosmotic pump. RESULTS: Serum and urinary calcium were greater in the LPD and LPD + APD groups than in the ND and ND + APD groups [serum, 11.12 +/- 0.34 and 11.57 +/- 0.45 vs. 9.49 +/- 0.17 and 9.48 +/- 0.15 mg/dl (mean +/- SE), P < 0.05; and urine, 8.78 +/- 2.74 and 16.30 +/- 4.68 vs. 0.32 +/- 0.09 and 0.67 +/- 0.28 mg/24 hr, P < 0.05]. Serum PTH and serum and urinary phosphorus were less in the LPD and LPD + APD than in the ND and ND + APD groups (P < 0.05). The calcemic response to PTH was less (P < 0.05) in the LPD and LPD + APD groups than in the ND group and was less (P = 0.05) in the LPD + APD than in the ND + APD group. Bone histology showed that phosphate depletion increased the osteoblast and osteoclast surface, and treatment with APD reduced the osteoblast surface (LPD vs. LPD + APD, 38 +/- 4 vs. 4 +/- 2%, P < 0.05, and ND vs. ND + APD, 20 +/- 2 vs. 5 +/- 2%, P < 0.05) and markedly altered osteoclast morphology by inducing cytoplasmic vacuoles. CONCLUSIONS: (a) Phosphate depletion induced hypercalcemia and hypercalciuria that were not reduced by APD administration. (b) The calcemic response to PTH was reduced in phosphate-depleted rats and was unaffected by APD administration in normal and phosphate-depleted rats, and (c) APD administration markedly changed bone histology without affecting the biochemical changes induced by phosphate depletion.

Mineral metabolism in healthy geriatric dogs.

To study mineral metabolism in geriatric dogs, parathyroid hormone, calcitriol, ionised calcium, phosphorus, blood urea nitrogen and creatinine were evaluated in 35 geriatric dogs (> 10 years) and in 20 young adult dogs (2-5 years). Parathyroid hormone levels were within the normal range in both groups, but values (mean +/- SEM) were greater in the old dogs (34.8 +/- 3.6 vs 21.2 +/- 2.3 pg ml(-1), P=0.005). Calcitriol and ionised calcium were similar in the two groups, and the values for both parameters were within the normal reference range. Plasma phosphorus levels were in the normal range in both groups but tended to be greater in the older dogs (P=0.09). While blood urea nitrogen was similar in the two groups, creatinine levels (mean +/- SEM) were higher in the young dogs (82.2 +/- 3.5 vs 101.7 +/- 4.4 micromol litre(-1)). Even when the dogs were matched for weight, plasma creatinine concentration was still greater in the younger dogs. In conclusion, an increase in parathyroid hormone without changes in calcium, phosphorus and calcitriol has been identified in geriatric dogs.

The PTH-calcium relationship during a range of infused PTH doses in the parathyroidectomized rat.

To establish the PTH dosage that maintains normal mineral homeostasis in the PTX rat, a series of doses of rat 1-34 PTH were infused via a subcutaneously implanted miniosmotic pump. The doses were 0, 0.011, 0.022, 0.044, and 0.11 microg/100 g/hour. After 48 hours, serum calcium ranged from 5.56 +/- 0.02 to 16.29 +/- 0.25 mg/dl, ANOVA P < 0.001, and serum phosphorus from 12.49 +/- 0.03 to 5.33 +/- 0.34 mg/dl, ANOVA P < 0.001. By post hoc test, the serum calcium level was different (P < 0.05) at every PTH dose; the serum phosphorus level was different (P < 0.05) at every PTH dose except between the two highest doses. The PTH dosage that produced a normal serum calcium (10.09 +/- 0.10 mg/dl) and phosphorus (6.90 +/- 0.18 mg/dl) was 0.022 microg/100 g/hour. The relationship between increasing doses of PTH and both serum calcium and phosphorus was curvilinear and the calcium-phosphorus product was remarkably constant from a serum calcium of 7-13 mg/dl. The increase in serum calcium and the decrease in serum phosphorus were more rapid at lower than at higher PTH doses so that for both, an asymptote was reached. At the highest serum calcium values, the calcium-phosphorus product increased and in individual rats, an increase in serum phosphorus was associated with a decrease in serum calcium. In summary, this study shows that (1) for rat 1-34 PTH, the normal replacement dose in the PTX rat with normal renal function on a normal diet is 0.022 microg/100 g/hour; (2) the relationship between PTH and both serum calcium and phosphorus is curvilinear, and an asymptote is reached for both; and (3) the calcium-phosphorus product is remarkably constant as the serum calcium increases from 7 to 13 mg/dl and only increased during marked hypercalcemia when serum phosphorus did not decrease further or even tended to increase.

The interaction of PTH and dietary phosphorus and calcium on serum calcitriol levels in the rat with experimental renal failure.

BACKGROUND: Renal failure results in decreased calcitriol production, a key factor in the development of secondary hyperparathyroidism. Phosphorus accumulation and high parathyroid hormone (PTH) levels, both inherent to renal failure, have different effects on calcitriol production; moreover, dietary calcium loading may have a separate inhibitory effect on calcitriol production. This study was designed to evaluate the relative effects of PTH and dietary phosphorus and calcium on serum calcitriol levels. METHODS: Renal failure was surgically induced and rats were divided into normal, moderate renal failure, and advanced renal failure based on the serum creatinine. Each group was subdivided and received either a high-phosphorus diet (HPD, 0.6% Ca, 1.2% P) or high-calcium diet (HCaD, 1.2% Ca, 0.6% P) for 14-16 days to determine the relative effects of dietary calcium and phosphorus loading on serum calcitriol. In addition the effect of PTH and phosphorus on calcitriol stimulation was determined with a 48-h PTH infusion combined with either a low (0.16%) or high (1%) phosphorus diet; both diets had negligible calcium (< 0.05%). RESULTS: With decreasing renal function, PTH increased and was greater in rats fed the HPD than the HCaD; serum calcitriol decreased as renal function decreased and was lower in normal rats and rats with moderate renal failure fed a HCaD (P < 0.01). The calcitriol response to a PTH infusion decreased as renal function decreased (P < 0.05) but was greater on a low- (0.16%) than a high- (1%) phosphorus diet (P < 0.05). CONCLUSIONS: Dietary calcium loading either directly decreases serum calcitriol or acts by modifying the stimulatory effect of PTH; the stimulatory effect of PTH on serum calcitriol is modified by dietary phosphorus; in moderate renal failure, serum calcitriol levels depend on a complex interaction between PTH and dietary calcium and phosphorus; and in advanced renal failure, serum calcitriol levels are low and are difficult to stimulate, presumably because of the loss of renal mass.

Relative effects of PTH and dietary phosphorus on calcitriol production in normal and azotemic rats.

In moderate renal failure, the serum calcitriol level is influenced by the stimulatory effect of high PTH and the inhibitory action of phosphorus retention. Our goal was to evaluate the relative effect that high PTH levels and increased dietary phosphorus had on calcitriol production in normal rats (N) and rats with moderate renal failure (Nx). Normal and Nx (3/4 nephrectomy) rats were divided into two groups: (1) rats with intact parathyroid glands (IPTG) and (2) parathyroidectomized rats in which PTH was replaced (PTHR) by the continuous infusion of rat 1-34 PTH, 0.022 microgram/hr/100 g body wt, using a miniosmotic Alzet pump. To test the effect of dietary phosphorus, rats received either a moderate (MPD, 0.6% P) or a high phosphorus (HPD, 1.2%) diet for 14 days. The experimental design included pair-fed N and Nx rats with either IPTG or PTHR. Serum calcitriol and PTH levels in N rats fed a MPD were 69 +/- 3 and 40 +/- 5 pg/ml, respectively. In Nx rats on a MPD, serum calcitriol levels decreased only if hyperparathyroidism was not allowed to occur (76 +/- 4 vs. 62 +/- 4 pg/ml in Nx-IPTG-MPD and Nx-PTHR-MPD groups respectively, P < 0.05). Even in N rats on a HPD, high PTH levels (67 +/- 8 pg/ml in the N-IPTG-HPD group) were required to maintain normal serum calcitriol levels (69 +/- 4 vs. 56 +/- 6 pg/ml in Nx-IPTG-HPD and Nx-PTHR-HPD groups, respectively; P < 0.05). In Nx rats on a HPD, the development of secondary hyperparathyroidism (286 +/- 19 pg/ml in the Nx-IPTG-HPD group) prevented a decrease in serum calcitriol levels (68 +/- 7 pg/ml). In contrast, serum calcitriol levels were low in the Nx-PTHR-HPD group (52 +/- 4 pg/ml, P < 0.05), which were deprived of the adaptative increase in endogenous PTH production. In conclusion, our results in rats indicate that in moderate renal failure, an elevated PTH level maintains calcitriol production and overcomes the inhibitory action of phosphorus retention.

The set point of calcium and the reduction of parathyroid hormone in hemodialysis patients.

Since in some studies in hemodialysis patients calcitriol treatment has resulted in a reduction of both parathyroid hormone (PTH) levels and the set point of calcium, it has been suggested that that the set point of calcium reflects a reduction in the magnitude of hyperparathyroidism. However, others have maintained that the set point of calcium is primarily an indicator of the serum calcium at which PTH is secreted and may be dissociated form the magnitude of hyperparathyroidism. The present study was designed to evaluate how a reduction in PTH levels associated with an increase in the predialysis (basal) serum calcium would affect the set point of calcium. Two different treatments were used to produce a reduction in PTH that was associated with an increase in predialysis serum calcium. In the first group, hemodialysis patients received 2 micrograms of intravenous calcitriol and were dialyzed with a 3.5 mEq/liter calcium dialysate for six weeks; in the second group, hemodialysis patients were dialyzed with a 4 mEq/liter calcium dialysate and had oral calcium supplementation increased for six weeks. In both groups, low and high calcium studies were performed to determine the PTH-calcium relationship before treatment, at the end of six weeks of treatment, and six weeks after the discontinuation of treatment. In the calcitriol group the predialysis calcium increased form 9.62 +/- 0.34 to 10.56 +/- 0.31 mg/dl, P < 0.05 and the set point of calcium increased from 9.34 +/- 0.23 to 9.79 +/- 0.25 mg/dl, P < 0.05 at the same time as maximally stimulated PTH decreased from 2637 +/- 687 to 1555 +/- 617 pg/ml, P < 0.05. In the high calcium dialysate group, the predialysis serum calcium increased from 9.19 +/- 0.31 to 9.84 +/- 0.28 mg/dl, P < 0.05, and set point of calcium increased form 9.01 +/- 0.28 to 9.39 +/- 0.22 mg/dl, P < 0.05 at the same time as maximally stimulated PTH decreased from 1642 +/- 450 to 1349 +/- 513 pg/ml, P < 0.05. Discontinuation of treatment for six weeks resulted in a return to pretreatment values. In conclusion, our results would suggest that (1) the set point of calcium may not be a reliable indicator of the magnitude of hyperparathyroidism during calcitriol treatment, and (2) PTH secretion may adapt to the ambient serum calcium concentration.

Studies in a hemodialysis patient indicating that calcitriol may have a direct suppressive effect on bone.

Calcitriol putatively suppresses bone activity by decreasing parathyroid hormone (PTH) levels. Results of studies in a 52-year-old female maintenance hemodialysis patient suggest that calcitriol may also have a direct suppressive effect on bone. The PTH-calcium relationship was evaluated through the use of low (1 mEq/l) and high (4 mEq/l) calcium hemodialyses that were performed before the initiation of calcitriol treatment, at the end of 6 weeks of thrice-weekly intravenous calcitriol administration, and 6 weeks after the discontinuation of calcitriol. During the low-calcium dialysis, serum calcium decreased more rapidly and to a greater magnitude after calcitriol treatment despite no appreciable difference in basal and maximally stimulated PTH levels; during the high-calcium dialysis, calcitriol treatment resulted in a more rapid increase in serum calcium despite no appreciable difference in basal and maximally suppressed PTH levels. Discontinuation of calcitriol resulted in responses to the low and high calcium dialyses that were similar to those observed before calcitriol treatment. In conclusion, the results suggest that calcitriol may have a direct suppressive effect on bone that is independent of PTH.

Factors in the development of secondary hyperparathyroidism during graded renal failure in the rat.

Secondary hyperparathyroidism (2 degree HPT) develops as a result of renal failure. Hypocalcemia, phosphorus retention, calcitriol deficiency and skeletal resistance to the calcemic action of parathyroid hormone (PTH) are closely interrelated pathogenic factors important for the development of 2 degrees HPT in renal failure. Since previous studies have mainly focused on advanced renal failure, only limited data are available in early renal failure. The goal of the present study was to evaluate how alterations in the dietary calcium and phosphorus composition affect the factors known to contribute to the genesis of 2 degrees HPT in early and more advanced renal failure. To achieve this goal, graded differences in renal function were surgically induced in 453 rats while the dietary content of calcium and phosphorus was varied. Three different diets were used: (1) a high phosphorus diet (HPD), to induce phosphorus retention and stimulate 2 degrees HPT; (2) a high calcium diet (HCaD), to inhibit calcitriol synthesis; and (3) a moderate calcium-moderate phosphorus diet (MCaPD), to separate the effects of high dietary phosphorus and calcium. Based on the serum creatinine (SCr) concentration rats were assigned to one of four different groups: (1) normal renal function (SCr < or = 0.3 mg/dl); (2) mild renal failure (SCr 0.4 to 0.6 mg/dl); (3) moderate renal failure (SCr 0.7 to 0.8 mg/dl); or (4) advanced renal failure (SCr > or = 0.9 mg/dl). As the severity of renal failure increased, progressive 2 degrees HPT developed in each of the dietary groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of aluminium on the development of hyperparathyroidism and bone disease in the azotaemic rat.

Aluminium toxicity in dialysis patients is associated with a relative parathyroid hormone (PTH) deficiency as well as osteomalacia. In-vitro studies of parathyroid cells have shown that aluminium inhibits PTH secretion. However, only limited data are available on how aluminium affects the development of hyperparathyroidism in the azotaemic animal. Four groups of azotaemic rats were studied; in each group, renal failure was induced by a two-stage 5/6 nephrectomy, after which rats were studied for 40 days. In three groups hyperparathyroidism was stimulated by the use of a high phosphorus (1.2%) diet (HPD). The four groups were (1) HPD; (2) HPD + high-dose aluminium (HDAL)--1.5 mg of aluminium was administered intraperitoneally (IP) 5 days per week; (3) HPD + low-dose aluminium (LDAL)--0.5 mg of aluminium was administered IP 5 days per week; and (4) moderate phosphorus (0.6%) diet (MPD); the MPD group was used to control hyperparathyroidism and thus provide a comparison of PTH levels and azotaemic bone disease. After 40 days, the serum PTH level was higher (P < 0.05) in the HPD + HDAL group (37 +/- 2 pmol/l) than the HPD, HPD + LDAL, and MPD groups (24 +/- 3, 28 +/- 4, and 6 +/- 1 pmol/l respectively). The correlation between serum PTH and calcium, serum PTH and phosphorus, and serum calcium and phosphorus was significant for the four groups (P < 0.02); however, the relationship between serum PTH and calcium, and between serum calcium and phosphorus was altered in the HPD + HDAL group (serum aluminium 30.8 +/- 2 mumol/l). Aluminium administration induced a decrease (P < 0.05) in the bone formation rate and the adjusted apposition rate, and an increase (P < 0.05) in osteoid volume and the mineralization lag time. Despite aluminium administration, diet-induced hyperparathyroidism resulted in an increase (P < 0.05) in the osteoblast surface. In conclusion, in the azotaemic rat (1) aluminium did not slow the development nor decrease the magnitude of hyperparathyroidism; (2) aluminium appeared to alter the relationship between serum PTH and calcium, and between serum calcium and phosphorus; (3) hyperparathyroidism changed the expression of aluminium-induced bone disease and may afford the bone some protection against the toxic effects of aluminium.

Effect of parathyroidectomy on aluminum toxicity and azotemic bone disease in the rat.

In maintenance dialysis patients, low-turnover osteomalacia and aplastic bone disease are generally attributed to aluminum toxicity. Both groups of patients have a relative deficiency of PTH. The reason for the development of osteomalacia versus aplastic bone disease is unclear. The present study was performed to evaluate whether parathyroidectomy (PTX) modifies the effect of aluminum administration on bone histology in renal failure. Seven groups of pair-fed rats were studied: normals (N); renal failure (RF); RF + PTX; PTX; RF + aluminum (AL); RF + PTX + AL; and PTX + AL. Aluminum was administered intraperitoneally 5 days/week for 6 weeks. All groups were sacrificed at 6 weeks. Renal failure increased the serum calcium in both the parathyroid intact (RF versus N, 11 +/- 0.1 versus 10 +/- 0.3 mg/dl, X +/- SEM, P less than 0.05) and calcium-supplemented PTX groups (PTX + RF versus PTX, 9.7 +/- 0.2 versus 9.2 +/- 0.2 mg/dl, P less than 0.05). After PTX, aluminum administration increased the serum calcium (PTX + AL versus PTX, 9.8 +/- 0.3 versus 9.2 +/- 0.2, P less than 0.05, and PTX + RF + AL versus PTX + RF, 10.8 +/- 0.1 versus 9.7 +/- 0.2 mg/dl, P less than 0.05). In rats with renal failure receiving aluminum, PTX decreased osteoid volume and surface but not osteoid thickness. Rats receiving aluminum did not mineralize bone. Additionally, in PTX rats receiving aluminum, renal failure per se increased osteoblast surface, osteoid surface, osteoid volume, and osteoclast number.(ABSTRACT TRUNCATED AT 250 WORDS)

Aluminum administration in the rat separately affects the osteoblast and bone mineralization.

Aluminum administration in the experimental animal results in osteomalacia as characterized by osteoid accumulation and decreased mineralization. Previous in vivo and in vitro studies have indicated that either aluminum directly inhibits mineralization or is toxic to the osteoblast. In the present study, PTH was continuously infused in rats with aluminum-induced osteomalacia to evaluate whether aluminum administration decreased mineralization without a concomitant decrease in osteoblasts. Four groups of rats were studied: chronic renal failure (CRF); CRF + aluminum (AL); CRF + PTH; and CRF + PTH + AL. Rats were sacrificed 5 and 12 days after aluminum or diluent administration; in the PTH groups, bovine PTH (1-34) was administered at 2 units/h via a subcutaneously implanted Alzet pump. Aluminum administration decreased osteoblast surface, increased osteoid accumulation, and produced a cessation of bone formation. The infusion of PTH alone increased osteoblast surface and bone formation. The simultaneous administration of aluminum and PTH resulted in an osteoblast surface intermediate between aluminum and PTH alone; however, despite a PTH-induced restoration of osteoblast surface, bone formation did not increase. These findings indicate (1) aluminum is toxic to osteoblasts and also directly inhibits mineralization even when osteoblasts are not decreased; (2) PTH is capable of increasing osteoblasts even in the presence of aluminum; and (3) despite a PTH-induced increase in osteoblast surface, mineralization of osteoid was not improved.

Phosphorus administration in patients with profound hypophosphatemia.

The influence of severe hypophosphatemia (less than or equal to 1.0 mg/dl) on vitamin D metabolism was prospectively determined in 11 patients before and after intravenous phosphorus administration. Evidence of liver dysfunction was present in ten patients. The mean (+/- SE) plasma 25 hydroxycholecalciferol [25(OH)D] was significantly decreased before phosphorus therapy when compared to control subjects (9.4 +/- 1.3 vs. 17.8 +/- 1.3 ng/ml, P less than 0.001). With phosphorus administration, serum phosphorus increased from 0.59 +/- 0.07 to 2.58 +/- 0.09 mg/dl while 1,25 dihydroxycholecalciferol [1,25(OH)2D] decreased from 34.6 +/- 4.3 to 14.3 +/- 2.9 pg/ml (P less than 0.001). Plasma 25(OH)D, plasma immunoreactive PTH (both amino and carboxyterminal) and serum calcium did not change after phosphorus administration, suggesting that phosphorus alone was responsible for the change in plasma 1,25(OH)2D concentration. An inverse correlation was found between serum phosphorus and plasma 1,25(OH)2D (r = -0.62, P less than 0.005). In addition, a direct correlation was observed between plasma 25(OH)D and 1,25(OH)2D both before (r = 0.66, P less than 0.005) and after (r = 0.74, P less than 0.005) phosphorus administration. Thus, the decrease in 1,25(OH)2D levels with phosphorus therapy suggests a role of serum phosphate in the regulation of this sterol, and hypophosphatemia or phosphorus depletion may change the relationship of substrate [25(OH)D] to product [1,25(OH)2D].

Postparathyroidectomy hypocalcemia as an accurate indicator of preparathyroidectomy bone histology in the uremic patient.

19 chronic renal failure patients underwent iliac crest bone biopsy prior to total parathyroidectomy with autotransplantation. The preoperative serum calcium concentration did not correlate with the number of osteoclasts/mm2 present on the preparathyroidectomy iliac biopsy. However, the postparathyroidectomy decrement in serum calcium (mg/dl and percent change) and the osteoclasts/mm2 were strongly correlated (p less than 0.001). In addition, the postoperative fall in serum calcium also correlated with the postoperative change in serum alkaline phosphatase (p less than 0.001). The nadir in postparathyroidectomy serum calcium was attained in a mean of 4.4 +/- 2.7 days. Our results indicate that the preoperative serum calcium concentration does not necessarily reflect active bone resorption, but the postoperative decrement in serum calcium provides an accurate index of preoperative histologic activity. The available data do not provide information with respect to the mechanism of postparathyroidectomy hypocalcemia since either the cessation of bone resorption, continued bone deposition, or a combination of both may be operative.