Arnold J. Felsenfeld

Calcium Deficiency Reduces Circulating Levels of FGF23

Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia.

Effect of Phosphate on Parathyroid Hormone Secretion In Vivo

Alterations in phosphate homeostasis play an important role in the development of secondary hyperparathyroidism in renal failure. Until recently, it was accepted that phosphate retention only increased parathyroid hormone (PTH) secretion through indirect mechanisms affecting calcium regulation and calcitriol synthesis. However, recent in vitro studies have suggested that phosphate may directly affect PTH secretion. Our goal was to determine whether in vivo an intravenous phosphate infusion stimulated PTH secretion in the absence of changes in serum calcium. Three different doses of phosphate were infused intravenously during 120 minutes to increase the serum phosphate concentration in dogs. Sulfate was also infused intravenously as a separate experimental control. A simultaneous calcium clamp was performed to maintain a normal ionized calcium concentration throughout all studies. At the lowest dose of infused phosphate (1.2 mmol/kg), serum phosphate values increased to ∼3 mM, but PTH values did not increase. At higher doses of infused phosphate (1.6 mmol/kg and 2.4 mmol/kg), the increase in serum phosphate to values of ∼4 mM and 5 mM, respectively, was associated with increases in PTH, even though the ionized calcium concentration did not change. Increases in PTH were not observed until 30–60 minutes into the study. These increases were not sustained, since by 120 minutes PTH values were not different from baseline or controls despite the maintenance of marked hyperphosphatemia. During the sulfate infusion, serum sulfate values increased by ∼3‐fold, but no change in PTH values were observed. In conclusion, an acute elevation in serum phosphate stimulated PTH secretion in the intact animal, but the magnitude of hyperphosphatemia exceeded the physiologic range. Future studies are needed to determine whether PTH stimulation is more sensitive to phosphate loading in states of chronic phosphate retention. Moreover, the mechanisms responsible for the delay in PTH stimulation and the failure to sustain the increased PTH secretion need further evaluation.

Milk Alkali Syndrome and the Dynamics of Calcium Homeostasis

Intensive treatment with calcium-containing antacids and milk first was used in the early 20th century for the treatment of peptic ulcer disease and sometimes was associated with toxicity, eventually known as the milk alkali syndrome. Despite the introduction of H2 blockers and proton pump inhibitors for the treatment of peptic ulcer disease, the milk alkali syndrome continues to occur but is seen more frequently in older women who are receiving treatment for osteoporosis. The milk alkali syndrome provides a unique opportunity to discuss calcium homeostasis in a setting in which the primary calcium regulatory hormones, parathyroid hormone (PTH) and calcitriol, are not overtly abnormal. A thorough understanding of the pathophysiology of the milk alkali syndrome, including its generation and maintenance, requires knowledge of intestinal calcium absorption, bone influx and efflux of calcium, and renal calcium excretion and also how these processes change with age. In this review, the pathophysiology of the milk alkali syndrome is discussed in light of recent advances in our understanding of calcium homeostasis, particularly the role of the calcium-sensing receptor (CaSR) and epithelial calcium channels that are present in various tissues such as the parathyroid gland, kidney, and intestine. The contributions of alkalosis, per se , to the generation and maintenance of hypercalcemia are discussed in detail. Almost 100 years ago, Sippy (1) developed a calcium-laden milk and antacid regimen for the treatment of peptic ulcer disease. His rationale was to neutralize the hyperacidity that was deemed responsible for peptic ulcer disease. The Sippy regimen was used for the treatment of peptic ulcer disease, a disorder that was most common in middle-aged men, until the 1970s, when nonantacid treatment first was introduced (2–4). The original recommendation by Sippy consisted of the hourly administration of milk and cream together with what became known as …

Dynamics of Parathyroid Hormone Secretion in Health and Secondary Hyperparathyroidism

This review examines the dynamics of parathyroid hormone secretion in health and in various causes of secondary hyperparathyroidism. Although most studies of parathyroid hormone and calcium have focused on the modification of parathyroid hormone secretion by serum calcium, the relationship between parathyroid hormone and serum calcium is bifunctional because parathyroid hormone also modifies serum calcium. In normal animals and humans, factors such as phosphorus and vitamin D modify the basal parathyroid hormone level and the maximal parathyroid hormone response to hypocalcemia. Certain medications, such as lithium and estrogen, in normal individuals and sustained changes in the serum calcium concentration in hemodialysis patients change the set point of calcium, which reflects the serum calcium concentration at which parathyroid hormone secretion responds. Hypocalcemia increases the basal/maximal parathyroid hormone ratio, a measure of the relative degree of parathyroid hormone stimulation. The phenomenon of hysteresis, defined as a different parathyroid hormone value for the same serum calcium concentration during the induction of and recovery from hypo- and hypercalcemia, is discussed because it provides important insights into factors that affect parathyroid hormone secretion. In three causes of secondary hyperparathyroidism--chronic kidney disease, vitamin D deficiency, and aging--factors that affect the dynamics of parathyroid hormone secretion are evaluated in detail. During recovery from vitamin D deficiency, the maximal parathyroid hormone remains elevated while the basal parathyroid hormone value rapidly becomes normal because of a shift in the set point of calcium. Much remains to be learned about the dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism.

Evidence for Both Abnormal Set Point of PTH Stimulation by Calcium and Adaptation to Serum Calcium in Hemodialysis Patients with Hyperparathyroidism

In vitro studies of parathyroid glands removed from dialysis patients with secondary hyperparathyroidism and hypercalcemia have demonstrated the presence of an increased set point of parathyroid hormone (PTH) stimulation by calcium (set point [PTHstim]), suggesting an intrinsic abnormality of the hyperplastic parathyroid cell. However, clinical studies on dialysis patients have not observed a correlation between the set point (PTHstim) and the magnitude of hyperparathyroidism. In the present study, 58 hemodialysis patients with moderate to severe hyperparathyroidism (mean PTH 780 ± 377 pg/ml) were evaluated both before and after calcitriol treatment to establish the relationship among PTH, serum calcium, and the set point (PTHstim) and to determine whether changes in the serum calcium, as induced by calcitriol treatment, modified these relationships. Calcitriol treatment decreased serum PTH levels and increased the serum calcium and the setpoint (PTHstim); however, the increase in serum calcium was greater than the increase in the setpoint (PTHstim). Before treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium was r = 0.82, p < 0.001, and between the set point (PTHstim) and PTH was r = 0.39, p = 0.002. After treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium remained significant (r = 0.70, p < 0.001), but the correlation between the set point (PTHstim) and PTH was no longer significant (r = 0.09); moreover, a significant correlation was present between the change in the set point (PTHstim) and the change in serum calcium that resulted from calcitriol treatment (r = 0.73, p < 0.001). The correlation between the residual values (deviation from the regression line) of the set point (PTHstim), derived from the correlation between PTH and the set point (PTHstim), and serum calcium was r = 0.77, p < 0.001 before calcitriol and r = 0.72, p < 0.001 after calcitriol. In conclusion, the set point (PTHstim) increased after a sustained increase in the serum calcium, suggesting an adaptation of the set point to the existing serum calcium; the increase in serum calcium resulting from calcitriol treatment was greater than the increase in the set point (PTHstim); the set point (PTHstim) was greater in hemodialysis patients with higher serum PTH levels; and the correlation between PTH and the set point (PTHstim) may be obscured because the serum calcium directly modifies the set point (PTHstim).

Dynamics of skeletal resistance to parathyroid hormone in the rat : Effect of renal failure and dietary phosphorus

UNLABELLED Secondary hyperparathyroidism develops in renal failure and is generally ascribed to factors directly affecting parathyroid hormone (PTH) production and/or secretion. These include hypocalcemia, phosphorus retention, and a calcitriol deficiency. However, not often emphasized is that skeletal resistance to PTH is an important factor. Our study evaluated: (1) the relative effects of uremia and dietary phosphorus on the skeletal resistance to PTH; and (2) how, during a PTH infusion, the dynamics of skeletal resistance to PTH were affected by renal failure. Renal failure was surgically induced and, based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure. In each group, three diets with the same calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2%, LPD) phosphorus. The study diet was given for 14-16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 microg/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphorus (0.2%) diet. In both moderate and advanced renal failure, the PTH level was greatest in the HPD group (p < 0.05) and, despite normal serum calcium values, PTH was greater in the MPD than the LPD group (p < 0.05). Despite phosphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater (p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less (p < 0.05) in all groups as renal function declined. Furthermore, despite normal and similar serum phosphorus values at the end of PTH infusion, the serum calcium concentration was less (p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups. IN CONCLUSION (1) uremia and phosphorus each had separate and major effects on skeletal resistance to PTH; (2) skeletal resistance to PTH was an important cause of secondary hyperparathyroidism, even in moderate renal failure; (3) during PTH infusion, the dynamics of skeletal resistance to PTH changed because all groups received a low phosphorus diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during states of disequilibrium.

Direct Effect of Acute Metabolic and Respiratory Acidosis on Parathyroid Hormone Secretion in the Dog

Because both metabolic (Met Acid) and respiratory acidosis (Resp Acid) have diverse effects on mineral metabolism, it has been difficult to establish whether acidosis directly affects parathyroid hormone (PTH) secretion. Our goal was to determine whether acute Met Acid and Resp Acid directly affected PTH secretion. Three groups of dogs were studied: control, acute Met Acid induced by HCl infusion, and acute Resp Acid induced by hypoventilation. EDTA was infused to prevent acidosis‐induced increases in ionized calcium, but more EDTA was needed in Met Acid than in Resp Acid. The PTH response to EDTA‐induced hypocalcemia was evaluated also. Magnesium needed to be infused in groups receiving EDTA to prevent hypomagnesemia. The half‐life of intact PTH (iPTH) was determined during hypocalcemia when PTH was measured after parathyroidectomy. During normocalcemia, PTH values were greater (p < 0.05) in Met Acid (92 ± 19 pg/ml) and Resp Acid (77 ± 22 pg/ml) than in controls (27 ± 5 pg/ml); the respective pH values were 7.23 ± 0.01, 7.24 ± 0.01, and 7.39 ± 0.02. The maximal PTH response to hypocalcemia was greater (p < 0.05) in Met Acid (443 ± 54 pg/ml) than in Resp Acid (267 ± 37 pg/ml) and controls (262 ± 48 pg/ml). The half‐life of PTH was greater (p < 0.05) in Met Acid than in controls, but the PTH secretion rate also was greater (p < 0.05) in Met Acid than in the other two groups. In conclusion, (1) both acute Met Acid and Resp Acid increase PTH secretion when the ionized calcium concentration is normal; (2) acute Met Acid may increase the bone efflux of calcium more than Resp Acid; (3) acute Met Acid acts as a secretogogue for PTH secretion because it enhances the maximal PTH response to hypocalcemia.

Approach to Treatment of Hypophosphatemia

Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole.

Direct suppressive effect of Acute metabolic and respiratory alkalosis on parathyroid hormone secretion in the dog

Acute alkalosis may directly affect PTH secretion. The effect of acute metabolic and respiratory alkalosis was studied in 20 dogs. PTH values were lower in the metabolic (5.6 ± 0.8 pg/ml) and respiratory (1.8 ± 0.6 pg/ml) alkalosis groups than in the control group (27 ± 5 pg/ml). Acute alkalosis is an independent factor that decreases PTH values during normocalcemia and delays the PTH response to hypocalcemia.

Effect of a Low Calcium Dialysate on Parathyroid Hormone Secretion in Diabetic Patients on Maintenance Hemodialysis

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty‐three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126 ± 20 vs. II, 108 ± 19 pg/ml) and maximal (I, 269 pg/ml ± 40 pg/ml vs. II, 342 pg/ml ± 65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98 ± 18 vs. II, 200 ± 34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml ± 37 pg/ml vs. II, 529 pg/ml ± 115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12‐month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0,6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = −0.59; p < 0.001) and the basal PTH (r = −0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady‐state PTH level is largely determined by the prevailing serum calcium concentration. (J Bone Miner Res 2000;15:927–935)