Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of chronic GH and insulin-like growth factor-I (IGF-I) excess on bone metabolism were examined by measuring serum markers of bone formation and urine markers of bone resorption as well as vertebral bone densities in patients with active acromegaly. Fasting serum GH levels were elevated in all 27 patients (31 +/- 11 micrograms/L). Serum calcium levels were within the normal range, except in 3 of 27 (10%) patients with mild hypercalcemia. Urinary calcium excretion, however, was increased in 6 (22%) patients despite mainly normal serum PTH and 1,25-dihydroxyvitamin D levels, suggesting a direct renal GH and/or IGF-I-mediated calciuric effect. Urinary hydroxyproline/creatinine excretion was increased in all except 1 patient and correlated with plasma IGF-I levels (r = 0.49; P < 0.02; n = 22). A more specific indicator of bone collagen turnover, urinary type I collagen cross-linked N-telopeptide, was elevated in all except 1 patient and correlated with serum GH (r = 0.47; P < 0.02), IGF-I (r = 0.60; P < 0.005), and urinary hydroxyproline/creatinine excretion (r = 0.62; P < 0.001). Serum bone Gla protein (osteocalcin), a specific marker of osteoblastic activity, was also increased in 50% of the patients and correlated with urinary N-telopeptide (r = 0.47; P < 0.02), but not with serum GH or IGF-I concentrations. Trabecular bone density, as determined by quantitative computerized tomography of the lumbar spine, was increased in only 1 patient; 13 others had subnormal bone density. The results suggest that in long-standing acromegaly, osteoblastic and osteoclastic activities are increased. Vertebral trabecular bone mass is usually reduced. Urinary collagen cross-links may serve as a more specific marker of bone resorption in acromegaly.
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PMID:Biochemical assessment of bone formation and resorption in acromegaly. 850 Nov 50

In our previous double-blind trial, we reported that clodronate reduced the incidence of bone lesions, fractures, pain and hypercalcaemia in multiple myeloma. Recently, it has been assumed that the antiresorptive effect of bisphosphonates on the osteoclasts is mediated through the osteoblasts. We therefore determined, in 244 patients of the same trial, serum assays of aminoterminal propeptide of type I procollagen (PINP) and type I collagen degradation product (ICTP). PINP is an early synthesis product of proliferating osteoblasts, in comparison to the alkaline phosphatase (AP) which is secreted by differentiated osteoblasts during the maturation phase of collagen. ICTP circulates in serum when old bone is resorbed. Our results indicate that after 25 months, the PINP levels decreased in the clodronate group (from 68.9 +/- 4.4 micrograms/l to 37.2 +/- 3.5 micrograms/l; P < 0.001) but not in the control group (from 61.5 +/- 3.2 micrograms/l to 69.3 +/- 7.5 micrograms/l; P < NS). The fall in the ICTP levels was markedly steeper in the patients receiving clodronate (from 8.38 +/- 0.80 micrograms/l to 4.58 +/- 0.32 micrograms/l; P < 0.01) than placebo (from 7.84 +/- 0.53 micrograms/l to 6.45 +/- 0.95 micrograms/l; P = NS). A significant difference between the study groups was seen at 4 months in the PINP, at 7 months in the ICTP and at 13 months in the AP levels, suggesting that clodronate affected through the proliferating osteoblasts, the osteoclasts, and through the osteoclasts, the differentiated osteoblasts. High baseline ICTP, PINP and AP levels indicated a poor prognosis. The decrease of the markers by clodronate was more marked in survivors than in non-survivors.
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PMID:Monitoring the action of clodronate with type I collagen metabolites in multiple myeloma. 875 48

The goals of this study were to quantitate biochemical markers of bone metabolism on days 1-15 after bilateral tibial marrow ablation surgery in young adult rats and to determine the effect of a single dose of methylprednisolone (2 mg/kg) or deflazacort (2.5 mg/kg) given at the time of ablation. Unexpectedly, serum calcium levels rose to a maximum of 15.9 mg/dl on day 7 after marrow ablation and remained above normal through day 15. This increase was blocked by a single intramedullary injection of methylprednisolone or deflazacort immediately following ablation; however, the fact that both drugs produced a characteristic rapid 3- to 10-fold increase in the serum alpha 2-macroglobulin level demonstrates that the drugs rapidly reached the circulation. Both methylprednisolone and deflazacort also inhibited intramedullary deposition of collagen by 40-60% on day 7, a time near which operated control animals achieved maximal accumulation of new bone in this model. Histological comparisons among the three experimental groups were largely consistent with biochemical results. The urinary hydroxyproline/creatine ratio for the operated control group doubled on day 3 and then returned to presurgical levels on day 7 and later. The timing and size of the hydroxyproline/creatinine peak, as well as the fact that the intratibial osteoclastic response peaks on days 8-10 after ablation, suggests it results from extratibial bone resorption induced by marrow ablation. Consistent with this rationale, urinary calcium excretion in operated controls rose 9-fold from day 0 to day 3 and appeared to plateau over the period from day 3 to day 9, before returning to a near presurgical level on day 15. Elevated excretion of calcium noted on days 9-15 in deflazacort-treated animals, which occurs in the absence of a detectable increase in resorption marker hydroxyproline, may however be due to the known action of glucocorticoids in increasing kidney filtration of calcium. In summary, this is the first report to show that bilateral tibial marrow ablation in rats causes a rapid hypercalcemia and calciuria which is accompanied initially by a peak of bone resorption marker urinary hydroxyproline. We speculate that the source of calcium and hydroxyproline is extratibial osteoclastic bone resorption induced by circulating cytokines whose release from ablated tibias or osteoclastogenic action is inhibitable by methylprednisolone and deflazacort.
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PMID:Bilateral tibial marrow ablation in rats induces a rapid hypercalcemia arising from extratibial bone resorption inhibitable by methylprednisolone or deflazacort. 904 Oct 51

The process of bone resorption by osteoclasts involves the dissolution of mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix. Cysteine proteinases, which can efficiently degrade collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this enzyme can prevent bone resorption in vitro. The activity of acetyl-leu-leu-norleucinol (ALLN), a selective inhibitor of cathepsin L, was investigated in two models of bone resorption in vivo. In the first study, the ability of ALLN to inhibit bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a cathepsin L inhibitor to inhibit bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of cathepsin L-like cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on bone resorption in ovx rats. It is possible that in chronic bone resorption in ovx rats, the activity of other enzymes such as cathepsins OC-2 or K allows the process of resorption to continue even when cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of bone resorption which should be considered when investigating novel antiresorptive therapies.
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PMID:Effects of an inhibitor of cathepsin L on bone resorption in thyroparathyroidectomized and ovariectomized rats. 914 44

This chapter summarizes the many recent advances in our understanding of the principal heritable disorders of bone. In the course of little more than a decade many diseases that were recognizable only by their clinical and radiological features have become explicable in molecular terms. Large numbers of mutations of the genes coding for collagen, for alkaline phosphatase, for the cell surface receptors for parathyroid hormone and for calcium, and for a number of other proteins, are recognized. The chapter covers the many variants of osteogenesis imperfecta, the most common heritable cause of fractures. It also covers osteopetrosis, hypophosphatasia, pseudohypoparathyroidism (with Albright's hereditary osteodystrophy), familial benign hypercalcaemia, autosomal dominant hypocalcaemia and the molecular causes of some chondrodysplasias.
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PMID:Osteogenesis imperfecta and other heritable disorders of bone. 922 92

Gallium nitrate was originally developed as an antineoplastic agent; however, further studies have revealed that this drug has extremely potent effects on turnover of bone, and that low doses can be used to reduce bone resorption. Like the bisphosphonates, gallium nitrate has been studied in both malignant and in nonmalignant conditions. The results of randomized double blind studies have suggested that this drug has superior clinical efficacy relative to etidronate, calcitonin, and pamidronate for the acute control of cancer-related hypercalcemia. In patients with Paget's disease, low doses of gallium nitrate reduce biochemical parameters of accelerated bone turnover, including urinary excretion of calcium, hydroxyproline, and urinary collagen cross-linked N-telopeptides. Preliminary studies showed similar effects in patients with bone involvement from a wide variety of tumor types. Based on this high degree of clinical potency revealed in clinical studies, two randomized Phase III studies have been initiated in patients with bone metastases from breast carcinoma and bone involvement due to multiple myeloma. Both studies employ cyclic therapy with low dose gallium nitrate (i.e., 40 mg administered as a subcutaneous injection once daily for 2 weeks, followed by 2 weeks off treatment, recycled monthly). The endpoints of both studies are to document reductions in time to "morbid skeletal events," such as palliative skeletal radiotherapy, stabilizing orthopedic surgery, or pathologic fractures, as well as decreases in pain and analgesic requirements and improvements in mobility and other aspects of quality of life. These trials should provide definitive evidence of whether this agent is safe and effective as a treatment for bone metastases.
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PMID:Gallium nitrate for the treatment of bone metastases. 936 36

The immunomodulatory properties of the vitamin D analogue MC 1288 (20-epi-1alpha,25-dihydroxycholecalciferol) were investigated in CIA in rats. The analogue was administered systemically at three different time points; (i) for 10 consecutive days before collagen (CII) immunization; (ii) for 10 consecutive days after CII immunization; or (iii) for 7 consecutive days from disease onset. Treatment initiated either 10 days before CII immunization or at the day of collagen immunization effectively suppressed the development of arthritis. Treatment initiated at the day of the onset of arthritis reduced the severity of joint inflammation. Significantly, doses which did not induce hypercalcaemia decreased the incidence and severity of arthritis. In vivo treatment with the 20-epi analogue of 1alpha,25-dihydroxycholecalciferol diminished the serum levels of antibodies to rat CII. Similarly, mitogen-induced proliferation of lymph node cells from rat CII-immunized animals was reduced. The experiments demonstrate that the vitamin D analogue MC 1288 has the ability to prevent, and furthermore to suppress, already established CIA by its immunomodulatory properties without inducing hypercalcaemia.
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PMID:A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen-induced arthritis (CIA) without causing hypercalcaemia. 982 88

Hypercalcemia and hypercalciuria observed both in humans and in animals who were on long-term theophylline therapy, prompted us to investigate whether oral theophylline treatment at optimal doses causes any adverse side effects on bone metabolism in mild asthmatics. Therefore, serum osteocalcin (BGP) and total alkaline phosphatase (TALP, EC 3.1.3.1) as bone formation markers, serum prolidase I (EC 3.4.13.9) activity as a marker for collagen metabolism, urinary deoxypyridinoline (Dpd), hydroxyproline (Hyp) and fasting urinary calcium as bone resorption markers, were measured in 18 mild asthmatics who had been treated with theophylline over 1-10 years. Among measured bone turnover markers, BGP, TALP, and Hyp levels were found to be increased in mild asthmatics; and BGP showed the greatest percent mean increase (98%) over the healthy subjects. However, these increments did not exceed the upper reference limits. Serum prolidase I activity was also increased in mild asthmatics receiving theophylline. Our results indicate that theophylline therapy at optimal doses may not exert adverse side effects on bone homeostasis, but patients receiving supratherapeutic doses of theophylline should be under close examination in order to predict future bone mass status.
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PMID:Evaluation of the effect of low-dose oral theophylline therapy on some bone turnover markers and serum prolidase I activity in mild asthmatics. 1043 80

Advanced tumor osteopathy is characterized by abnormal bone turnover. Using a rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis, the aim of the present study was to define the sequential changes in, and the association between, biochemical and histomorphometric indices of bone metabolism during the early stages of developing tumor osteopathy. Eight-month-old Wistar rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or the bisphosphonate ibandronate until killing on day 8. Serum calcium (sCa), alkaline phosphatase (sTAP), and osteocalcin (sOC) and urinary calcium (uCa), deoxypyridinoline (uDPD), and pyridinoline (uPYD) were measured daily. In a second semilongitudinal experiment (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomorphometry. In untreated tumor-bearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2), p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%, p < 0.05). Both time course and magnitude of these changes were closely reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0. 31 +/- 0.15 nmol/12 h, p < 0.05) and uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h, p < 0.05), sCa (3.8 +/- 0.52 vs. 3.0 +/- 0. 13 mmol/L, p < 0.01), and uCa (0.13 +/- 0.08 vs. 0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/- 40 U/L, p < 0.001) on day 7 (mean +/- SD), whereas sOC remained unchanged until day 8. When combining the results of the two experiments, a high correlation was found between the number of osteoclasts and the urinary excretion of PYD (r = 0.91) and DPD (r = 0.89). Treatment with ibandronate delayed hypercalcemia, abolished hypercalciuria, and accelerated bone resorption. We conclude that osteoclast activation is an early event in PTHrP-mediated osteolysis, which is closely reflected by the renal excretion of pyridinium cross-links of type I collagen. Therefore, specific biochemical markers of collagen breakdown may be useful as early indicators of developing tumor osteopathy.
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PMID:Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis. 1077 87

We describe a new familial metabolic bone disease characterized by expanding hyperostotic long bones, early onset deafness, premature tooth loss, and episodic hypercalcemia. The condition affects a mother and daughter studied at the age of 36 years and 11 years, respectively. Both individuals lost all hearing in early childhood and suffered premature shedding of teeth. Skeletal pains began just before puberty. Swelling and aching of most middle phalanges in the hands is an especially troublesome manifestation. The mother also had episodes of symptomatic hypercalcemia first documented in late childhood and subsequently during intercurrent illness and postpartum lactation. Radiographs show hyperostosis and/or osteosclerosis predominantly in the skull and appendicular skeleton. Long bones also are expanded considerably, especially the middle phalanges in the fingers. The mother's skeletal abnormalities are more severe. Biochemical parameters of bone turnover, including serum alkaline phosphatase (ALP) activity, are elevated substantially. In the proposita, dynamic histomorphometry of nondecalcified sections of iliac crest revealed rapid skeletal remodeling. In the mother, who had been treated with bisphosphonates, electron microscopy (EM) showed disorganized collagen bundles as well as necrotic and apoptotic bone cells but no osteocytic osteolysis. Measles virus gene transcripts were not detected in peripheral blood monocytes. Karyotyping was normal, 46,XX. Hyperphosphatasia with bone disease previously has been reported as either a sporadic or autosomal recessive condition. Expansile skeletal hyperphosphatasia (ESH) is probably inherited as an autosomal dominant trait with a high degree of penetrance.
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PMID:Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease. 1112 98


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