Excess PTH Research Articles

Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism

Patients with chronic renal failure (CRF) display impaired phagocytosis by the polymorphonuclear leucocytes (PMNL), and these cells have elevated basal levels of cytosolic calcium ([Ca2+]i) and reduced ATP content. It has been suggested that these changes in PMNL metabolism and function are mediated by the state of secondary hyperparathyroidism of CRF. To examine the role of excess PTH in these derangements of PMNL, we studied [Ca2+]i, ATP and phagocytic ability of PMNL in five groups of rats including: CRF, CRF normocalcemic parathyroidectomized (CRF-PTX), CRF and normal animals treated with verapamil (CRF-V), and normal-V, respectively. The level of [Ca2+]i in the PMNL of CRF rats (149 +/- 2.7 nM) was significantly (P less than 0.01) higher and the ATP content (4.2 +/- 0.17 nmol/5 x 10(6) PMNL) significantly lower (P less than 0.01) than in normal (108 +/- 2.4 nM; 9.5 +/- 0.15 nmol/5 x 10(6) PMNL), CRF-PTX (103 +/- 2.9 nM; 9.2 +/- 0.19 nmol/5 x 10(6) PMNL), CRF-V (107 +/- 2.2 nM; 9.0 +/- 0.2 nmol/5 x 10(6) PMNL) and normal-V (106 +/- 1.8 nM; 9.2 +/- 0.2 nmol/5 x 10(6) PMNL), despite sustained elevation in blood PTH in the CRF-V group. Phagocytosis was significantly (P less than 0.01) impaired in CRF animals (5.6 +/- 0.25 micrograms oil/10(7) PMNL/min) but was normal in CRF-PTX (9.3 +/- 0.21 micrograms oil/10(7) PMNL/min) and CRF-V (9.5 +/- 0.22 micrograms oil/10(7) PMNL/min) rats. The values of phagocytosis in normal and normal-V rats were 9.6 +/- 44 and 9.6 +/- 0.18 micrograms oil/10(7) PMNL/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired potassium-induced insulin secretion in chronic renal failure

Extrarenal disposal of potassium load is impaired in chronic renal failure (CRF). This has been attributed to excess PTH since extrarenal disposition of potassium is normal in CRF-PTX animals. Insulin augments potassium entry into cells and hyperkalemia stimulates insulin secretion. Since glucose-induced insulin secretion is impaired in CRF and normal in CRF-PTX, it is possible that K(+)-induced insulin secretion is also impaired in CRF due to excess PTH. Such a defect would contribute to the abnormality in extrarenal disposal of potassium in CRF. We examined K(+)-induced insulin secretion, cytosolic calcium ([Ca2+]i) and the changes in [Ca2+]i in response to 20 mM KCl of islets from normal, CRF, and CRF-PTX rats; and normal and CRF animals treated with verapamil (normal-V and CRF-V). K(+)-induced insulin secretion by islets isolated from CRF rats was significantly (P less than 0.01) lower than that from normal, CRF-PTX, CRF-V and normal-V rats. Basal level of [Ca2+]i in islets of CRF rats was significantly (P less than 0.01) higher than in islets of the other four groups of animals. The calcium signal (delta [Ca2+]i) and the delta [Ca2+]i/basal [Ca2+]i ratio in response to 20 mM KCl observed in islets from CRF rats were significantly lower than in the other four groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)

On the Transforming Growth Factor β-Like Activity of Synthetic Polypeptides Comprising the Amino-Terminal Sequence of Human Parathyroid Hormone-Related Peptide

Purified native forms of human parathyroid hormone-related peptide (PTHrp) have recently been reported to display biological activities characteristic of transforming growth factor beta (TGF-beta). The TGF-beta-like property of PTHrp may reside within the amino N-terminal PTH-receptor binding region of the polypeptide, since a synthetic analog corresponding to amino acids 1-36 of human PTHrp is as active as purified native PTHrp in bioassays specific to TGF-beta. Complete lack of structural similarity between PTHrp and TGF-beta prompted us to address the question whether copresence of the TGF-beta-like and PTH-like biological activities in the N-terminal sequence of the PTHrp molecule is a general phenomenon observable with different N-terminal PTHrp peptides of varying amino acid chain length in a variety of target cells that respond in defined ways to TGF-beta in vitro. Two forms of synthetic N-terminal human PTHrp, PTHrp-(1-34) and [Tyr40]PTHrp-(1-40), which are fully active in conventional assays for PTH/PTHrp, were tested for effects in three in vitro bioassay systems for TGF-beta: 1) stimulation, and 2) inhibition, respectively, of epidermal growth factor-dependent soft-agar colony formation of either normal rat kidney-derived fibroblasts (NRK 49F) or human lung carcinoma cells (A549); and 3) biosynthesis of metabolically labeled fibronectin in both NRK 49F cells and clonal osteoblastic rat osteosarcoma cells (ROS 17/2.8). Human TGF-beta over the dose range of 2.5-80 pM significantly stimulated or inhibited soft-agar colony formation of either NRK 49F or A549 cells, respectively, and caused a severalfold increase in biosynthetically labeled [35S]fibronectin in NRK 49F and ROS 17/2.8 cells. In contrast, none of PTHrp-(1-34), [Tyr40]PTHrp-(1-40), and synthetic human PTH-(1-34), each tested at 0.1-10 nM, displayed detectable biological activity in any of the three assay systems. In addition, covalent cross-linking of intact NRK 49F and ROS 17/2.8 cells with either [125I]TGF-beta or 125I-[Tyr40] PTHrp-(1-40) revealed the presence of several distinct affinity-labeled receptor species for TGF-beta in both cell types and the 80K PTH/PTHrp receptors in ROS 17/2.8 cells. The affinity-labeled TGF-beta receptor species were insensitive to excess PTHrp and PTH peptides, and the 80K PTH/PTHrp receptors were insensitive to excess TGF-beta, indicating that PTHrp and TGF-beta do not cross-react with respect to receptor binding for interaction with these cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Impaired Activity of Alpha-Ketoglutarate Dehydrogenase of Heart Mitochondria in Chronic Renal Failure: Role of Secondary Hyperparathyroidism

Chronic renal failure (CRF) is associated with impaired oxidation of alpha-ketoglutarate (alpha-KG) by heart mitochondria, and previous data indicated that this derangement is due to the state of secondary hyperparathyroidism of CRF. A reduction in the utilization of alpha-KG by heart mitochondria implies that the activity of mitochondrial alpha-ketoglutarate dehydrogenase (alpha-KGDH) is impaired; however, direct evidence for such an abnormality is not available. We examined the Vmax and the Km of alpha-KGHD of heart mitochondria obtained from normal rats, CRF animals and normocalcemic parathyroidectomized (PTX) CRF rats. Our data showed that CRF has no effect on the Km of alpha-KGDH for alpha-KG. However, Vmax of the enzyme was significantly (p less than 0.01) reduced and this abnormality was prevented by PTX of CRF rats. Our results provide the evidence that the impaired utilization of alpha-KG by myocardial mitochondria of CRF rats is due to reduced Vmax of alpha-KGDH and that both derangements are mediated by excess PTH or a metabolic consequence of the secondary hyperparathyroidism of CRF.

Fatty acid oxidation in the myocardium: Effects of parathyroid hormone and CRF

Fatty acids constitute an important substrate utilized by the myocardium as a major fuel for energy production; certain data suggest that oxidation of long chain fatty acids (LCFA) may be impaired in uremia, and such a derangement could, in part, contribute to the myocardiopathy of uremia. The latter is associated with secondary hyperparathyroidism and PTH has been shown to affect myocardial metabolism. The present study evaluated in rats the effects of four days administration of PTH and 21 days of chronic renal failure (CRF) with and without excess PTH on oxidation of alpha-ketoglutarate, beta-hydroxybutyric acid, LCFA and short chain fatty acids (SCFA). PTH impaired oxidation of alpha-ketoglutarate, LCFA, SCFA, but not of beta-hydroxybutyric acid and reduced the activity of carnitine palmitoyl transferase (CPT). Inactivation of the PTH abolished its effects. CRF rats with intact parathyroid glands also had impaired oxidation of LCFA and CTP activity. Carnitine contents of myocardium were not altered. The data show that PTH excess in normal rats is associated with impaired oxidation of LCFA and SCFA, and secondary hyperparathyroidism in CRF animals impairs oxidation of LCFA. This effect is due to: 1) reduction in the activity of CPT, a key enzyme for the transport of LCFA to mitochondrial matrix for beta-oxidation; and 2) impairment in beta-oxidation. The data provide for new and additional pathway through which excess PTH and CRF can affect myocardial metabolism.

Chronic renal failure, parathyroid hormone and fatty acids oxidation in skeletal muscle

Fatty acids are an important source of skeletal muscle energy, and certain data suggest oxidation of long-chain fatty acids (LCFA) may be impaired in uremia. This abnormality may in part be responsible for uremic myopathy. Uremia is associated with hyperparathyroidism and PTH affects muscle metabolism; PTH enhances muscle proteolysis and impairs muscle bioenergetics, and it is possible that PTH also affects fatty acids oxidation. The present study examined in rats the effects of 4 days administration PTH and of 21 days of chronic renal failure (CRF) with and without excess PTH on oxidation of LCFA and short-chain fatty acids (SCFA). Both 1-84 and 1-34 PTH impaired oxidation of LCFA but not of a SCFA (beta-hydroxybutyric acid) and reduced the activity of carnitine palmitoyl transferase (CPT). Inactivation of the PTH abolished its effects. CRF rats with intact parathyroid glands had also impaired oxidation of LCFA and of CPT activity. Parathyroidectomy in CRF rats normalized these abnormalities. Carnitine contents of muscle were not altered. The data show that PTH excess in normal or in CRF rats is associated with impaired oxidation of LCFA and this effect is due to reduction in the activity of CPT, a key enzyme for the transport of LCFA to mitochondrial matrix for beta-oxidation. The data demonstrate another toxic effect of PTH on muscle in CRF and provide an additional pathogenic mechanism for uremic myopathy.

Effects of parathyroidectomy on circulating levels of 1 alpha,25-dihydroxyvitamin D and bone Gla protein in dialyzed patients.

The effects of decreasing serum levels of PTH after parathyroidectomy on circulating levels of 1 alpha,25-dihydroxyvitamin D [1,25-(OH)2D] and bone Gla protein (BGP) were studied in seven patients treated with chronic maintenance dialysis. Before surgery, all patients had extremely elevated levels of PTH, low normal or low levels of 1,25-(OH)2D, high levels of BGP, and histological signs of excess PTH action on bone. The fall in PTH levels after surgery resulted in a further decline in 1,25-(OH)2D concentrations and a reduction in circulating BGP levels. This fall in serum 1,25-(OH)2D and BGP levels was not related to serum calcium or phosphorus. Administration of 1,25-(OH)2D3 from 4-6 months after surgery did not significantly affect serum levels of BGP or PTH. These data indicate that 1,25-(OH)2D is still under regulatory control of PTH in patients without excretory kidney function. This might reflect some remaining endocrine activity of the kidneys in these dialyzed patients or extrarenal production of 1,25-(OH)2D. In addition, the data show that serum BGP levels in renal failure are elevated due not only to impaired clearance but also to PTH-mediated acceleration in bone turnover. Therapy with 1,25-(OH)2D3 in these patients resulted in supraphysiological serum 1,25-(OH)2D levels which did not stimulate BGP production.

Impaired mineral metabolism in Cushing's syndrome: parathyroid function, vitamin D metabolites and osteopenia.

To clarify the mechanism for the impaired mineral metabolism in Cushing's syndrome, the clinical features, biochemical parameters before and after oral calcium load, and vitamin D metabolism were compared between two groups of patients of endogenous Cushing's syndrome (17 cases) with and without osteopenia. The patients with osteopenia [OP (+): 7 cases, all female] were older (42.7 +/- 8.3 y. o.) and had a longer duration (117 +/- 75 M) of the syndrome than those without osteopenia [OP (-): 33.8 +/- 8.9 y. o., 36 +/- 25 M]. OP (-) showed a blunted hypercalciuria after oral calcium load (63.7 +/- 20.4 to 90.9 +/- 36.1 mg/g X Cr), while OP (+) had higher levels of urinary excretion of calcium (fasting: 120.4 +/- 37.5, and after oral calcium load: 235.6 +/- 72.6 mg/g X Cr), of cyclic AMP (7.6 +/- 1.1 nmol/dl X GF), and of plasma 1.25(OH)2D (76.6 +/- 34.0 pg/ml) than OP (-) (u-cAMP: 3.2 +/- 2.0 nmol/dl X GF, 1,25(OH)2D: 27.9 +/- 16.3 pg/ml). These results indicate that 1) elderly female patients with Cushing's syndrome of long duration are susceptible to OP, 2) during the early phases of the syndrome, reduced intestinal calcium absorption with sustained calciuria (probably through the inhibition of calcium reabsorptive effect of PTH by glucocorticoid) induces negative calcium balance, leading to 3) a development of secondary hyperparathyroidism which stimulates 1,25(OH)2D synthesis. Thus, the mechanism involving bone resorption stimulated by excess PTH along with the direct inhibition of bone formation by glucocorticoid seems to play an important role in a progressive development of OP in Cushing's syndrome.

Acid-base homeostasis during chronic PTH excess in humans

The chronic renal and systemic acid-base effects of hyperparathyroidism in humans remain controversial and unresolved. The present studies evaluated the acid-base response of normal human subjects to a 13-day intravenous infusion of synthetic b(1-34) PTH sufficient to result in sustained hypercalcemia and hypophosphatemia. The acid-base response was biphasic: an initial transient renal acidosis developed on the first day of PTH infusion, followed by a prompt increase in net acid excretion and plasma [HCO3-] of sufficient magnitude to result in a steady state of mild metabolic alkalosis. The results indicate that: 1) sustained, continuous, experimentally produced hyperparathyroidism results in a steady state of mild metabolic alkalosis; 2) the alkalosis is both generated and maintained, at least in part, by renal mechanisms; and 3) reported renal acidosis in sustained clinical conditions of primary hyperparathyroidism is not attributable to either direct or indirect effects of PTH excess when present for a 2-week period, an interval sufficient to re-establish a new steady state of renal and systemic acid-base equilibrium.

Postmenopausal osteoporosis as a manifestation of renal hypercalciuria with secondary hyperparathyroidism.

An apparently unique presentation of osteoporosis was encountered in eight postmenopausal women (mean age, 56.8 yr). They had renal hypercalciuria, since they had fasting hypercalciuria [0.17 +/- 0.04 (+/- SD) mg/100 ml glomerular filtrate (GF)] in the setting of normocalcemia and parathyroid stimulation (high serum immunoreactive PTH and/or urinary cAMP). Serum 1,25-dihydroxyvitamin D was not significantly different (28 +/- 7 vs. 34 +/- 2 pg/ml) from that in a nonelderly control group, but fractional intestinal calcium (Ca) absorption was significantly lower (0.382 +/- 0.123 vs. 0.49 +/- 0.06; P less than 0.025). Thus, the patients did not have compensatory intestinal hyperabsorption of Ca despite PTH excess. Treatment with hydrochlorothiazide (50 mg/day) produced a decline in fasting urinary Ca (to 0.07 +/- 0.02 mg/100 ml GF; P less than 0.01), serum PTH (from 39 +/- 19 to 21 +/- 1 microliters eq/ml; P less than 0.05), and urinary cAMP excretion (from 5.30 +/- 0.57 to 3.57 +/- 0.59 nmol/100 ml GF; P less than 0.0025). The results suggested that hyperparathyroidism was secondary. Histomorphometric analysis of bone showed reduced trabecular bone volume without mineralization defect, compatible with osteoporosis. Four of eight patients had high or high normal fractional resorption surfaces, fractional formation surfaces, and fractional osteoid volumes. That these abnormalities may reflect PTH-dependent osteoclastic resorption and bone turnover was supported by the reduction of these indices after correction of secondary hyperparathyroidism with hydrochlorothiazide therapy. The remaining four patients, however, had normal histomorphometric results. In summary, postmenopausal osteoporosis may occur sometimes with renal hypercalciuria and secondary hyperparathyroidism. The lack of compensatory intestinal hyperabsorption of Ca predisposes to negative Ca balance, and the hyperparathyroid state may be manifested by stimulated osteoclastic and osteoblastic activities.

Evidence for a role of PTH in the reduced pressor response to norepinephrine in chronic renal failure

Reduced pressor response to norepinephrine (NE) is present in patients with chronic renal failure (CRF) and is responsible partly for some of the manifestations of autonomic nervous system dysfunction in these patients. PTH blunts the pressor response to NE in normal rats, suggesting that excess PTH in CRF may be responsible for this abnormality. However, the relative roles of uremia and of excess PTH in the uremic state in the genesis of this abnormality are not defined. The present study examines this question. Rats with chronic renal failure display reduced pressor response to NE administration, but this derangement can be prevented by prior parathyroidectomy and abolished by administration of indomethacin. The role of PTH in the genesis of this abnormality can also be demonstrated in the hind limb preparation obtained from rats with CRF. Our data show that excess PTH and not other consequences of CRF plays a paramount pathogenetic role in the reduced pressor response to NE and that this effect of PTH is due to a direct action on the blood vessels. Further, this hormone action is most likely mediated through increased production of vasodilating prostaglandins. These observations are constant with the idea that PTH would contribute to the pathogenesis of some of the manifestations of autonomic nervous system dysfunction in CRF.

1574 MULTICENTER STUDY OF SERUM ERYTHROPOIETIN AND PTH LEVELS IN CHILDREN WITH CHRONIC RENAL FAILURE

The relative roles of erythropoietin (Ep) deficiency and PTH excess in the development of anemia in children with chronic renal failure (CRF) have been assessed. Serum Ep in 71 patients (PTS) was determined by radioimmunoassay (RIA). Seven were studied in the predialysis stage, 32 on hemodialysis, 16 on CAPD and 16 on CCPD. The mean serum Ep was 38.1±3.5 mu/ml with anemia of renal disease (predialysis and dialysis PTS) compared to 19.6±1.5 mu/ml in normals. However, when compared to 30 children with anemia of non-renal origin, the elevation in Ep (range 28.7-327 mu/ml) was significantly below that expected for the degree of anemia in these renal disease PTS. We also found a direct inhibitory effect of uremic serum on both immunologic and biologic activity of Ep itself. Co-incubation of Ep (50, 100, or 200 mu/ml) with uremic serum resulted in markedly lower RIA values for these three concentrations of Ep compared to normal serum. Biologic activity as assessed in the fetal mouse liver CFU-E assay was also decreased with uremic serum. Serum PTH levels, although elevated, did not correlate with the degree of anemia. In conclusion although relative Ep deficiency plays a primary role in the anemia of CRF other factors which alter Ep itself and inhibit erythroid progenitors appear to be involved.

Increased renal responses to exogenous parathyroid hormone in postsurgical hypoparathyroidism.

Prior exposure to excess PTH desensitizes the kidney to subsequent doses of the hormone. We tested the hypothesis that prior deficiency of PTH would increase renal responsiveness to the agent. Ten normal subjects and nine patients with treated chronic postsurgical hypoparathyroidism received infusions of synthetic human PTH fragment 1-34 [hPTH-(1-34), Armour], 200 U over 10 min. All subjects responded to hPTH-(1-34) infusion with marked increases in plasma and urinary cAMP and phosphaturia. Mean (and median) urinary cAMP responses in the hypoparathyroid subjects were 62% (and 91%) above the responses in normal subjects, while mean (and median) nephrogenous cAMP responses were 65% (and 88%) higher than those in normal subjects. Mean (and median) phosphaturic responses to hPTH-(1-34) in hypoparathyroidism were 49% (and 52%) above normal subjects' responses. All of these differences were statistically significant. These data and others from the literature suggest that chronic hypoparathyroidism enhances renal responses to PTH, consistent with the concept of hormonal regulation of tissue sensitivity to the hormone.

Renal and systemic magnesium metabolism during chronic continuous PTH infusion in normal subjects

Renal and systemic magnesium metabolism has not been adequately characterized in states of prolonged PTH excess in humans. Whereas acute experimental PTH administration uniformly results in enhanced renal magnesium reabsorption in many species, including humans, numerous clinical reports have documented renal magnesium wasting in human primary hyperparathyroidism. The possibility has been raised, therefore, that secondary consequences of sustained hyperparathyroidism (eg, hypercalcemia, nephrocalcinosis) might override the direct renal effects of PTH. Accordingly, the present studies assessed the effects of chronic (12 days) continuous intravenous (IV) b-(1–34)-PTH infusion in four normal human subjects on plasma, urinary, and intestinal magnesium and calcium homeostasis under metabolic balance conditions. Chronic PTH infusion resulted in a steady-state of hypercalcemia, hypercalciuria, and persistent negative calcium balance, which returned to baseline values in a recovery period. In contrast to plasma calcium concentration, plasma magnesium concentration was not altered by PTH infusion. Significant hypermagnesuria was observed during the period of PTH administration (control, 8.21 ± 0.43 mEq/24 hours; PTH days 7–12, 10.75 ± 0.74 mEq/24 hours, P < 0.05) resulting in an initial, but transient, negative magnesium balance. During days 7–12 of PTH administration, net intestinal magnesium absorption increased sufficiently to result in a return to control magnesium balance. These findings suggest that hypermagnesuria associated with clinical primary hyperparathyroidism results from either direct or indirect effects of PTH excess, per se, and does not require the long-term consequences or complications of the clinical disorder (eg, nephrocalcinosis, renal insufficiency, acidosis).

Serum Thyroid Hormone Indexes in Patients With Primary Hyperparathyroidism

Serum total reverse triiodothyronine (rT3) levels are normal in patients with renal diseases with and without renal insufficiency but elevated in nonrenal nonthyroidal illnesses. To evaluate the role of secondary hyperparathyroidism of renal diseases in this difference, serum thyroid hormone levels were studied in 27 patients with primary hyperparathyroidism (PHP) and normal renal function. In PHP, total T3 levels were reduced (118 +/- 6 ng/dL, normal: 147 +/- 3 ng/dL) and correlated with PTH levels. Serum rT3 levels were also decreased (27 +/- 3 ng/dL, normal: 34 +/- 2 ng/dL). Values for serum total thyroxine (T4), T3 uptake ratio, free T4 index, and thyrotrophin were not altered. Serum rT3 levels were increased (63 +/- 13 ng/dL) in patients with hypercalcemia due to malignant neoplasms who had low T3 levels, undetectable PTH and normal renal function. Thus, PTH excess may be the factor responsible for the failure of rT3 levels to increase in PHP and secondary hyperparathyroidism.

Anatomy and physiology of the parathyroids: a practical discussion for surgeons.

AbstractNormal parathyroid glands vary in macroscopic appearance, number, and location. Adequate surgical treatment of hyperparathyroidism often depends on identification of all glands, which requires precise knowledge of the normal anatomy and embryology of organs derived from the third and fourth branchial pouches. The following questions form the basis of surgical strategy: (a) Is this a normal parathyroid gland? (b) Where should the surgeon look for a normal gland? (c) How many parathyroid glands are there? (d) Where should the surgeon look for a missing gland? About 80% of patients have 4 glands. The upper pair is usually near the point where the recurrent nerve enters the larynx. The lower pair is more variable in location and may be found between the inferior thyroid artery and the thymus. Normal glands may be ectopically located along the path of embryologic migration, adjacent to or embedded in organs of similar origin.Parathyroid hormone (PTH), vitamin D, and calcitonin maintain calcium levels which modify intestinal absorption, renal excretion, and bone turnover. PTH secretion responds promptly to calcium changes acting upon vitamin D synthesis, tubular reabsorption of phosphates, calcium renal excretion, and bone reabsorption. Vitamin D controls intestinal calcium absorption. Calcitonin stimulates bone accretion. Excess PTH tilts this balance toward hypercalcemia, hypercalciuria, and bone décalcification; hypercalcemia and detectable PTH levels coincide only in hyperparathyroidism.In treating patients with hyperparathyroidism, delicate surgical technique is essential, but the ingenuity of the surgeon in developing a plan of action based on thorough knowledge of normal anatomy and embryology is the key to successful therapy.

Hypercalcemia as a presenting manifestation of leukemia: Evidence of excessive PTH secretion

Hypercalcemia as a presenting manifestation of leukemia: Evidence of excessive PTH secretion

Parathyroid hormone as a possible causal factor in osteopetrosis of the tl rat.

The possibility of parathyroid dysfunction as a causal factor in the osteopetrosis of the tl rats was explored by evaluating serum calcium (Ca) and immunoreactive parathyroid hormone (iPTH) concentrations in this strain of rats, as compared with those of phenotypically normal littermate (LM) and non-littermate (NLM) control groups. The mean serum Ca concentration in the tl rat was not significantly different from that of the NLM group, although it was less than that of the LM group. However, all Ca values were within the normal range. The mean serum iPTH concentration in the tl rats was not significantly different from those of either control group. The data indicate that the adult tl rat has adequate but not excessive PTH secretion. Therefore, osteopetrosis and its manifestations in the adult tl are not caused by an abnormality of parathyroid function.