The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

Denosumab-Induced Hypocalcemia and Hyperparathyroidism in de novo Kidney Transplant Recipients.

INTRODUCTION: Denosumab represents a realistic treatment option to increase bone mineral density in kidney transplant recipients (KTRs). It is still unknown how and at what extent posttransplantation bone disease and graft function influence the effects of denosumab on mineral metabolism indexes. In this study, we analyze risk factors of hypocalcemia and parathyroid hormone (PTH) increase after denosumab administration in eighteen de novo KTRs and its management before and after this treatment. METHODS: We conducted a monocentric, observational, prospective study on de novo KTRs. All KTRs enrolled received a single 60 mg subcutaneous dose of denosumab every 6 months. Before kidney transplantation, no patients were treated with calcio-mimetic. After kidney transplantation and before antiresorptive therapy, no patients were treated with calcio-mimetic drugs and/or vitamin D receptor agonists, while all patients received nutritional vitamin D supplementation (from 1,000 IU to 1,500 IU daily). RESULTS: Hypocalcemia was related to the degree of lumbar osteoporosis (p = 0.047); the increase in the PTH level was correlated to baseline bone turnover markers (bone alkaline phosphatase, serum osteocalcin, and ß-C-terminal telopeptide), the 25 OH status, and eGFR. The introduction of calcitriol, after the PTH increase, in addition to cholecalciferol was necessary to ensure an adequate control of serum calcium and PTH during a follow-up of 15 months. Following the treatment with denosumab, it was observed an improvement of areal bone mineral density both at lumbar and femoral sites with a mean percentual increase of 1.74% and 0.25%, respectively. CONCLUSIONS: Denosumab is an effective treatment for bone disease in KTRs. In our study, the increase in PTH is not a transient event but prolonged throughout the follow-up period and requires continuous supplementation therapy with calcitriol.

Mono- and polyphosphates have similar effects on calcium and phosphorus metabolism in healthy young women.

PURPOSE: Phosphate (Pi) salts, often mono- (MP) or polyphosphates (PP), are commonly used as additives in the food industry. Previous studies have shown that the effects of MP and PP on calcium (Ca) and phosphorus (P) metabolism may differ. The aim of this study was to determine whether the effects of MP and PP salts differ on markers of Ca and P metabolism in young women. METHODS: Fourteen healthy women 19-31 years of age were randomized into three controlled 24-h study sessions, each subject serving as her own control. During each session, the subjects received three doses of MP, PP or a placebo with meals in randomized order. Both Pi salts provided 1,500 mg P/d, and the diet during each session was identical. Markers of Ca and P metabolism were followed six times over 24 h. RESULTS: During both MP and PP sessions, we found an increase in serum phosphate (S-Pi, p = 0.0001), urinary phosphate (U-Pi, p = 0.0001) and serum parathyroid hormone (S-PTH, p = 0.048 MP, p = 0.012 PP) relative to the control session. PP decreased U-Ca more than did MP (p = 0.014). CONCLUSIONS: The results suggest that PP binds Ca in the intestine more than does MP. Based on the S-Pi, U-Pi and S-PTH results, both Pi salts are absorbed with equal efficiency. In the long run, increased S-PTH, caused by either an MP or PP salt, could have negative effects on bone metabolism.

Vitamin D and primary hyperparathyroidism (PHPT).

Vitamin D deficiency and primary hyperparathyroidism (PHPT) are two common conditions, especially in postmenopausal women. Vitamin D deficiency is said to be even more frequent in PHPT patients than in the general population due to an accelerated conversion of 25-hydroxy vitamin D (25OHD) into calcitriol or 24-hydroxylated compounds. Although several studies have reported worsening of PHPT phenotype (larger tumours, higher parathyroid hormone [PTH] levels, more severe bone disease) when vitamin D deficiency coexists whereas vitamin D supplementation in PHPT patients with a serum calcium level less than 3 mmol/L has been shown to be safe (no increase in serum or urinary calcium) and to decrease serum PTH concentration, many physicians are afraid to give vitamin D to already hypercalcemic PHPT patients. It is possible that, in some patients, a persistent vitamin D deficiency induces, in the long-term, an autonomous secretion of PTH (i.e. tertiary hyperparathyroidism). The mechanism by which this could occur is unclear however. Finally, as many, otherwise normal, subjects with vitamin D insufficiency may have an increased serum PTH level we believe that those with vitamin D insufficiency should be excluded from a reference population for serum PTH levels. By doing that, we found that the upper normal limit for serum PTH was 25-30% lower than in the whole population.

Tertiary hyperparathyroidism attributable to long-term oral phosphate therapy.

OBJECTIVE: To report a rare case of tertiary hyperparathyroidism (HPT) as a result of long-term oral phosphate therapy. METHODS: We present a case report, with a focus on clinical manifestations and biochemical findings during the course of tertiary HPT, and discuss the pathophysiologic features of this disorder and the therapeutic strategies. RESULTS: A 35-year-old woman, 22 years after the initial diagnosis of familial hypophosphatemic rickets and initiation of treatment with phosphate and vitamin D, underwent assessment for recurrent symptomatic kidney stones, bone pain, and fatigue. Laboratory studies performed 10 months before this presentation showed findings consistent with secondary HPT. Examination was notable for short stature, and pertinent laboratory results were as follows: intact parathyroid hormone 602 pg/mL, calcium 10.9 mg/dL, and phosphorus 3.6 mg/dL. Tertiary HPT was diagnosed, and she underwent subtotal parathyroidectomy and transcervical thymectomy. Postoperatively, she had hypocalcemia and was treated with calcitriol, phosphate, and calcium carbonate; the last agent was discontinued when the serum calcium normalized. Despite multiple dosage alterations in the phosphate and calcitriol therapy, the patient had recurrent tertiary HPT and another kidney stone (treated by lithotripsy). Three years after the subtotal parathyroidectomy, treatment consisted of cinacalcet, calcitriol, and elemental phosphate. CONCLUSION: Long-term follow-up of patients with tertiary HPT is critical, with careful dosage adjustments in phosphate and vitamin D therapy and monitoring of serum levels of phosphorus, calcium, and parathyroid hormone.

[Hyperparathyroidism associated with hypophosphatemic osteomalacia: case report and review of the literature]. / Hiperparatireoidismo associado à osteomalacia hipofosfatêmica do adulto: relato de caso e revisão da literatura.

Adult-onset hypophosphatemic osteomalacia is a rare disease characterized by hypophosphatemia, increased levels of alkaline phosphatase and decreased bone mass. Oral supplementation with phosphate and vitamin D is the main treatment and, in cases of oncogenic osteomalacia, tumor resection is mandatory. We report the case of a patient with hypophosphatemic osteomalacia of an unknown cause. Despite extensive search, no tumor was found. The patient was treated with phosphate for a long period and developed tertiary hyperparathyroidism. Serum PTH levels did not return to normal after surgical excision of three parathyroids and the patient refused to continue clinical investigation and treatment. After ten years absent from the hospital, during which medications were used irregularly, she was admitted with multiple fractures and respiratory insufficiency caused by severe thoracic deformities, and died. The authors discuss the relationship between osteomalacia and hyperparathyroidism and the aggressive course of the disease.

Effect of dietary magnesium supplementation on bone loss in rats fed a high phosphorus diet.

The purpose of this study was to investigate the effect of dietary magnesium (Mg) supplementation on bone loss in rats fed a high phosphorus (P) diet. Weanling Wistar strain rats were randomly divided into four dietary groups of 6 rats each and fed their respective diets; a diet containing 0.3% P and 0.05% Mg (C), a diet containing 1.5% P and 0.05% Mg (HP), a diet containing 0.3% P and 0.15% Mg (HMg), or a diet containing 1.5% P and 0.15% Mg (HPMg), for 21 days. Compared to the C and HMg groups, serum parathyroid hormone (PTH) concentration was significantly higher in the HP and HPMg groups. Serum osteocalcin concentration and urinary excretion of C-terminal telopeptides of type I collagen (CTx), markers of bone turnover, were significantly higher in the HP and HPMg groups than in the C and HMg groups. Dietary Mg supplementation had no significant effects on serum PTH and osteocalcin concentrations, while urinary excretion of CTx was significantly lower in the HPMg group than in the HP group. These results suggested that dietary Mg supplementation suppressed bone resorption due to high P diet.

Relative hypoparathyroidism induced by interferon treatment in a hemodialysis patient.

Several authors have documented beneficial effects of interferon (IFN) in chronic hepatitis C virus (HCV) infection among the dialysis population. Reports about mineral metabolism disturbances during IFN treatment are scarce, especially in dialysis patients. We report the case of a 49-year-old woman on hemodialysis with chronic HCV infection who developed significant decrease in serum calcium (Ca) and phosphorus (P) levels accompanied by relative hypoparathyroidism while being under treatment with alpha-IFN. These changes were closely related to IFN treatment, because they disappeared after INF was discontinued, reaching Ca and P levels which were similar to those of the pre-IFN period. Because IFN may induce immune disorders, several autoimmune markers were analyzed. All of them were negative or within the normal range. To further explore these mineral metabolism disturbances, a number ofparathyroid hormone (PTH) secretion-inhibiting factors, such as aluminum, magnesium, 25-hydroxyvitamin D, and calcitriol were excluded as a cause for these changes. We suggest that mineral metabolism should be carefully observed during interferon treatment in dialysis patients.

Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia.

Oncogenic osteomalacia is a rare paraneoplastic syndrome. It is characterized by bone pain, muscle weakness, gait disturbance, fractures and skeletal deformities. Hypophosphatemia, diminished renal phosphate reabsorption, decreased 1,25 dihydroxy Vitamin D and elevated alkaline phosphatase are the biochemical hallmarks of this disorder. Most tumors are of mesenchymal origin. We report the case of a 39-year-old woman with oncogenic osteomalacia caused by osteosarcoma of the right scapula which was unrecognized for several years. She subsequently developed tertiary hyperparathyroidism after treatment with oral phosphate and Vitamin D. This case illustrates that oncogenic osteomalacia may persist for many years before the tumor is discovered. This is because the tumors are frequently very small and are in obscure locations. The uniqueness of this case is the coexistence of hyperparathyroidism and oncogenic osteomalacia. Five other cases have been reported up to date. All patients had received phosphate supplement, ranging from 10 to 14 years prior to their diagnosis. Interestingly, our patient was on the treatment for only 2 years. The proposed mechanism is that exogenous phosphate stimulates parathyroid activity through sequestration of calcium.

Effect of growth hormone (GH) therapy on parathyroid hormone metabolism in a girl with GH deficient short stature and chronic renal failure.

During GH treatment of a 14 year-old girl with chronic renal failure and short stature, she developed hyperparathyroidism which was successfully treated by the oral agent 26,27-F6-1, 25-dihydroxyvitamin D3 (26,27-F6-1,25(OH)2vit D3). It is hypothesized that the elevation of serum PTH level was induced either by the rise in phosphorus levels induced by GH or by a direct stimulatory effect of IGF-I on PTH production. This seems to be the first report of this kind.

Tertiary hyperparathyroidism after long-term phosphate supplementation in adult-onset hypophosphataemic osteomalacia.

We report the development of tertiary hyperparathyrodism in a patient with a sporadic form of adult-onset hypophosphataemic osteomalacia who had been treated with vitamin D or calcitriol and large doses of phosphate. This observation suggests that even with concomitant vitamin D or calcitriol therapy, long-term oral phosphate supplementation may lead to the development of hypercalcaemic hyperparathyrodism. Caution is recommended when relatively large doses of phosphate are used to treat hypophosphataemic osteomalacia of diverse causes.

Effect of parathyroid hormone on rat skeletal muscle in vivo.

The secondary hyperparathyroidism of chronic renal failure has been implicated in the pathogenesis of metabolic abnormalities in skeletal muscle. We studied the muscle metabolism in a model of hyperparathyroidism (Wistar rats injected with parathyroid hormone or saline for 4 days). 31P magnetic resonance spectroscopy allowed measurements of the concentration of cytosolic metabolically active inorganic phosphate [Pi] at rest and the rates of oxidative and anaerobic adenosine triphosphate turnover during exercise and recovery. Parathyroid hormone caused significant reductions in plasma [Pi] and intracellular [Pi], but had no effect upon oxidative or glycogenolytic adenosine triphosphate turnover.

[Tertiary hyperparathyroidism induced by the treatment of hypophosphatemic osteomalacia]. / Hyperparathyroïdie tertiaire induite par le traitement d'une ostéomalacie hypophosphorémique.

Tertiary hyperparathyroidism developed after a 30-year treatment of low phosphorus osteomalacia with phosphorus supplementation. Parathormone stimulation by exogenous phosphorus would result from sequestration of calcium leading to low plasma levels of both ionized and total calcium. In this case, decreased calcium level was favoured by renal failure. Addition of calcitriol (1.25 hydroxyvitamin D3) to the phosphorus supplementation could avoid secondary hyperparathyroidism in patients with low phosphorus osteomalacia by increasing intestinal absorption of phosphorus and inhibiting, though not totally, parathyroid stimulation. Tertiary hyperparathyroidism is thus a potential complication of long-term phosphorus supplementation in vitamin D-resistant osteomalacia. Parathormone and phosphorus should be measured regularly in order to diagnose induced hyperparathyroidism early since this state is reversible with calcitriol and reduced doses of phosphorus.

Chronic nephropathy and renal carcinogenicity of o-benzyl-p-chlorophenol in F344/N rats and B6C3F1 mice.

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluated in male and female F344/N rats and B6C3F1 mice in a series of subchronic and 2-year toxicity and carcinogenicity studies. Kidney was the primary target of toxicity in the 13-week gavage studies in rats and mice, with increased nephropathy noted as low as 240 mg/kg in male rats. Considering the nephropathy to be doselimiting, the chronic (2-year) study was conducted at lower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60, 120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg; in corn oil; n = 50/group). Survival and body weights of dosed rats were similar to controls in the 2-year study. Survival of high-dose male and female mice, and body weights of all dosed male and mid- and high-dose female mice, were lower than controls. The incidence and severity of nephropathy increased with dose and length of treatment in both rats and mice. There was an increased incidence of renal tubule adenomas or carcinomas in both the mid- and high-dose male mice. Despite similar evidence of nephropathy, however, there were no increased incidences of neoplasms in female mice or in male or female rats. This study suggests therefore that while nephrotoxicity may have been a necessary component, factors other than the marked nephrotoxicity of o-benzyl-p-chlorophenol were critical to the development of renal carcinogenesis induced in only male mice.

Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets.

We report the development of severe tertiary hyperparathyroidism in three girls treated for familial hypophosphatemic rickets and characterize parathyroid function in vivo and in vitro. All patients had been previously treated with relatively large doses of inorganic phosphorus (125 mm/day) and ergocalciferol or calcitriol for several years and had radiographic evidence of long-standing hyperparathyroidism. Even in the presence of extremely elevated PTH levels, oral phosphate lowered serum calcium levels in vivo and further stimulated PTH secretion. Profound multiglandular parathyroid hyperplasia was found in each patient at surgery. Examination of the secretory characteristics of the excised parathyroid tissue revealed that either relatively high calcium concentrations were generally needed to suppress PTH secretion or PTH secretion was not suppressible. Caution is recommended when relatively large doses of phosphate are used to treat familial hypophosphatemic rickets.

High phosphate diet-induced primary hyperparathyroidism: an animal model.

Primary hyperparathyroidism (PHPT) is increasing in incidence and detection, primarily because of the aging of our population and the widespread use of automated serum calcium determination. As a result, a substantial number of "early" cases or "biochemical" PHPT are being detected. The indications for parathyroidectomy in such early cases of PHPT are currently under debate, primarily because of economic issues. These factors underscore the importance of research into the basic mechanisms and natural history of PHPT. We investigated an animal model of diet-induced PHPT that retains two crucial aspects of PHPT: elevation of endogenously produced parathyroid hormone (PTH), accompanied by gross and microscopic changes in the native parathyroid glands. Female Long-Evans rats were divided into six groups of 15 each and fed a control diet (Ca/P of 1:2) or a high-phosphate diet (Ca/P of 1:7) for 1-, 2-, or 3-month intervals. Compared with the control animals, serum PTH levels were elevated at all three time intervals in the experimental group, whereas serum calcium levels were decreased at all time intervals. Serum creatine levels were also elevated at all time intervals, whereas serum phosphorus levels did not change. Parathyroid histopathologic studies demonstrated no change at 1 month, whereas nine of 15 experimental animals showed mild hyperplasia at 2 months and 13 of 14 showed mild to moderate hyperplasia with gland enlargement at 3 months compared with control animals. Histopathologic examination of the kidneys showed no change at 1 month but focal parenchymal inflammation with calcium deposition at 2 and 3 months in the experimental groups. In conclusion, the high-phosphate diet successfully induced the earliest changes of PHPT: elevated PTH levels and parathyroid hyperplasia. However, because renal function was mildly compromised early on, some element of early secondary (renal) hyperparathyroidism may have supervened quickly. Because this model is simple, it may be useful to investigate this complex syndrome further, as well as its natural history and the complications it produces in other organs such as the kidneys.

Morphometric analysis of osteosclerotic bone resulting from hexachlorobenzene exposure.

Hexachlorobenzene (HCB) exposure has been shown to induce hyperparathyroidism and osteosclerosis in rats. Experiments were undertaken to investigate the effects of HCB-induced hyperparathyroidism and osteosclerosis on femur morphometry as well as femur breaking strength. Fischer 344 rats were dosed 5 d/wk for 15 wk with 0, 0.1, 1, 10, or 25 mg HCB/kg body weight. Hyperparathyroidism was produced in the two higher dose groups as reported previously (Andrews et al., 1989). Femur weight was significantly increased in the rats receiving 0.1, 1, and 25 mg HCB/kg body weight, whereas density was increased significantly at 1, 10, and 25 mg HCB/kg dose levels. Bone strength was also significantly increased at the three higher dose levels. Cross-sectional area of the midpoint of the femur was significantly increased at the 1 mg/kg HCB dose level. Cortical area and the proportion of the total area of the bone that the cortex occupied were significantly increased at the three higher dose levels. Medullary cavity area was significantly increased at the 0.1 mg/kg dose level but significantly decreased at the 2 higher dose levels of HCB. The right femur was significantly predominant to the left femur in weight, volume, and density through all dosing regimens. HCB exposure significantly altered bone morphometry and strength characteristics in the Fischer 344 rat.

Clinical experience with desferrioxamine in dialysis patients with aluminium toxicity.

A desferrioxamine (DFO) infusion test, using a DFO dose of 36.9 +/- 11.2 mg/kg (mean +/- SD), was performed in 50 consecutive dialysis patients undergoing diagnostic bone biopsy. In 30 patients whose bones stained positively for aluminium the serum aluminium level increased by an average of 373 +/- 250.4 ng/ml. The increase in 20 aluminium-negative patients was 231 +/- 179.2 ng/ml (p less than 0.05). Aluminium-positive patients had lower levels of immunoreactive parathyroid hormone (336 +/- 442 muleq/ml) than aluminium-negative patients (1278 +/- 1400 muleq/ml; p less than 0.05). A change in serum aluminium level of greater than 200 ng/ml after the administration of DFO was 73 percent sensitive and 50 percent specific, and had a positive predictive value of 69 percent for detecting positive bone aluminium staining. The combination of a baseline immunoreactive parathyroid hormone level less than 200 muleq/ml and a change in serum aluminium of greater than 200 ng/ml after DFO was 90 percent specific and had a positive predictive value of 85 percent. In the second phase of our study, 28 dialysis patients with aluminium toxicity received long-term therapy (11.0 +/- 4.3 months) with DFO at an average starting dose of 41.7 +/- 17.1 mg/kg, administered once weekly. The four deaths which occurred during this treatment involved the only patients who had advanced dialysis dementia. Seven patients with less severe neurological symptoms responded favourably. Fractures decreased from 1.7 fractures/patient/year to 0.1 fracture/patient/year. Muscular strength and overall functional class were improved or stable in 25 patients; myalgias and arthralgias were also stable or improved in 19 patients. After 5-7 months of treatment, serum aluminium levels decreased from 401 +/- 262 ng/ml to 245 +/- 217 ng/ml (p less than 0.01); erythrocyte mean corpuscular volume increased from 86.3 +/- 10.91 fl to 94.1 +/- 9.23 fl (p less than 0.02); and serum calcium decreased from 10.4 +/- 0.94 mg/dl to 9.9 +/- 0.70 mg/dl (p less than 0.02). Serum immunoreactive parathyroid hormone levels remained stable in 25 patients, but severe hyperparathyroidism developed rapidly in three patients. Eight patients with transfusional iron overload had no change in serum ferritin levels. Iron depletion developed in six patients, with a decrease in serum ferritin from 251 +/- 229.8 micrograms/l to 45 +/- 29.3 micrograms/l, and they required parenteral iron supplementation. Significant side-effects occurring during long-term DFO administration were hypotension (11 patients), gastrointestinal upset (seven patients), porphyria cutaneous tarda-like lesions (three patients), and transient visual disturbance (one patient). There was a decrease in stainable bone aluminium in all nine patients with paired bone biopsy specimens (pre- and post-DFO).(ABSTRACT TRUNCATED AT 400 WORDS)

Furosemide effect on mineral status of parenterally nourished premature neonates with chronic lung disease.

In this study, the effect of prolonged furosemide administration on calcium and phosphorus homeostasis was examined in 16 parenterally nourished very low birth weight infants with chronic lung disease. Patients received one of three different dosages of phosphorus: low, 0.91 +/- 0.06 mmol/kg per day; moderate, 1.24 +/- 0.02 mmol/kg per day; and high, 1.64 +/- 0.06 mmol/kg per day. All furosemide-treated patients had high levels of urinary calcium (12.1 +/- 2.2 mg/kg per day), phosphate (19.1 +/- 2.7 mg/kg per day), and cyclic 3'5'-adenosine monophosphate (76.8 +/- 6.7 nmol/kg per day) excretion, independent of their phosphorus intake. Parathyroid hormone concentrations were high in furosemide-treated patients (0.95 +/- 0.15 ng/mL) compared with patients not treated with furosemide and receiving either moderate (0.49 +/- 0.05 ng/mL) or low (0.42 +/- 0.07 ng/mL) phosphorus intakes. Furosemide administration may lead to secondary hyperparathyroidism.

Hexachlorobenzene-induced hyperparathyroidism and osteosclerosis in rats.

Hexachlorobenzene (HCB) exposure has been shown to alter the normal concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D3 in rats and to result in osteoporosis in humans. Experiments were undertaken to investigate the effects of HCB on the homeostatic mechanism of calcium metabolism and to determine its effect on bone in rats. Fischer 344 rats were dosed 5 days/week for 5, 10, or 15 weeks with 0, 0.1, 10.0, or 25.0 mg HCB/kg body wt. Body weight was not affected by any of the exposure conditions. Liver weight was significantly elevated above control values at the two higher dose levels at all three time periods. Kidney weight and kidney-to-body weight ratio were significantly elevated at the highest dose level after 10 weeks and at the two higher dose levels after 15 weeks of exposure. Serum alkaline phosphatase was significantly decreased at the two higher dose levels after both 10 and 15 weeks of exposure. 1,25-Dihydroxyvitamin D3 was measured in the 5-week exposure group only and was significantly elevated in the three higher dose levels. After 5 and 15 weeks of HCB exposure, parathyroid hormone concentration was significantly elevated at the two higher dose levels at both time periods. Wet femur density was significantly increased at the two higher dose levels of HCB after 10 weeks of exposure and the three higher dose levels after 15 weeks of exposure. Dry femur density was also increased in the cases where wet femur density was increased. However, femur weight was not affected at any dose level. The results from this study indicate that HCB induces hyperparathyroidism in rats, as demonstrated by increased serum parathyroid hormone levels and osteosclerosis of the femur.(ABSTRACT TRUNCATED AT 250 WORDS)