Short-term metabolic effects of pamidronate in patients with prostatic carcinoma and bone metastases.
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Bone Neoplasms↗
Biomedical subjects
S E Papapoulos
Publications and source records attributed to S E Papapoulos.
[Alkaline phosphatase level in bone diseases; frequently too high, sometimes too low].
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Alkaline Phosphatase↗
Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis.
Osteogenic cells mediate PTH-stimulated osteoclastic bone resorption by a yet unidentified mechanism. We show that primairy rat osteoblast-like cells and the clonal osteogenic sarcoma cell line UMR-106 produce interleukin-6 (IL-6) and that bPTH(1-84) and synthetic hPLP(1-34) stimulate this production dose-dependently. With both peptides a close relation between IL-6 and cyclic-AMP production was found, though for PTH concentrations higher than 2.10(-8) M a clear dissociation was observed. Significant IL-6 activity was also detected in media of cultures of 17-day-old fetal mouse radii and metacarpals which was clearly stimulated by PTH. The source of IL-6 in these bone explants seems to be the osteogenic (cartilage) cells. Treatment of bone explants with IL-6 induced osteoclastic resorption which, however, depended on the bone resorption system used. This bone resorbing action of IL-6 is exerted probably through an effect on the formation of osteoclasts (osteoclastogenesis) rather than on the activation of already existing mature osteoclasts. We suggest that IL-6 produced by osteogenic cells may be a mediator in PTH-stimulated osteoclastic bone resorption.
Animals↗
Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate.
The development of new bisphosphonates for clinical use requires congruence between the results of basic and clinical investigations. We have previously shown that this can be achieved with the use of an in vitro coculture mouse metacarpal resorption system sensitive to the activation of osteoclast precursors together with a clinical protocol in which the rate of decrease in urinary hydroxyproline excess with bisphosphonate treatment is assessed in patients with Paget's disease. In these studies bisphosphonates of known potencies were used. In the present study we have evaluated these approaches prospectively in the assessment of the antiresorptive potency of the new bisphosphonate (3-dimethylamino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). A total of 42 patients with Paget's disease of bone received dimethyl-APD in doses predicted from the in vitro system. A total of 24 patients received the bisphosphonate intravenously (2, 4, and 8 mg/day) in groups of 8 patients each and 18 orally (100, 200, and 400 mg/day) in groups of 6 patients each for 10 days. Dimethyl-APD therapy was highly effective in inhibiting bone resorption. Urinary hydroxyproline excretion reached 30.9 +/- 5.6, 17.1 +/- 3.1, and 2.1 +/- 5.3% of initial excess after 10 days treatment with intravenous dimethyl-APD, 2, 4, and 8 mg/day, and 37.4 +/- 18, 10.4 +/- 8.5, and 13 +/- 4.1% with oral therapy, 100, 200, and 400 mg/day, respectively. Comparison of the antiresorptive potency of dimethyl-APD with that of APD showed that the former is roughly five times more potent, as predicted in the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Precision of dual photon absorptiometry measurements: comparison of three different methods of selection of the region of interest.
To determine the short-term reproducibility of bone mass calculations with dual photon absorptiometry of the lumbar spine (L2-L4), duplicate measurements in healthy subjects were used. Three different methods for selection of region of interest were compared: a rectangular region with variable height and width, an irregular region to be drawn freely by the operator and the standard calculation software supplied with the bone densitometer. Contributions of changes in size and location of the region of interest on calculated bone mineral mass were also investigated. An increase in height of the region by 2 scan lines caused an increase in bone mineral content (BMC) of 8.4% +/- 1.8%. Enlargement in width by 2 pixels in each scan line caused an increase in BMC of 2.5% +/- 1.3%. The difference between these region of interest changes was significant (P less than 0.0005). The use of a rectangular region, optimized to enclose L2-L4 in each person but of the same size in both measurements, resulted in a reproducibility of 1.4% and 0.7% respectively for 2 observers, with an inter observer variation of 1.2%. The reproducibility of the duplicate measurements was worse for the other methods of region of interest selection. A further series of duplicate DPA measurements in normal subjects, but with a standard meal between the measurements, showed a larger variation in the results. Again the reproducibility of the calculations using the rectangular region was better than with the other methods, with much less inter observer variation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The reproducibility of single photon absorptiometry in a clinical setting.
The reproducibility of single photon absorptiometry (SPA) results for detection of changes in bone mineral content (BMC) was evaluated in a clinical setting. During a period of 18 months with 4 different sources, the calibration scans of an aluminium standard had a variation of less than 1% unless the activity of the 125I source was low. The calibration procedure was performed weekly and this was sufficient to correct for drift of the system. The short term reproducibility in patients was assessed with 119 duplicate measurements made in direct succession. The best reproducibility (CV = 1.35%) was found for fat corrected BMC results expressed in g/cm, obtained at the site proximal to the 8 mm space between the radius and ulna. Analysis of all SPA scans made during 1 year (487 scans) showed a failure of the automatic procedure to detect the space of 8 mm between the forearm bones in 19 scans (3.9%). A space adjacent to the ulnar styloid was taken as the site for the first scan in these examinations. This problem may be recognized and corrected relatively easy. A significant correlation was found between BMC of the lower arm and BMC of the lumbar spine assessed with dual photon absorptiometry. However, the error of estimation of proximal BMC (SEE = 20.0%) and distal BMC (SEE = 19.4%) made these measurements of little value to predict BMC at the lumbar spine in individuals. The short term reproducibility in patients combined with the long term stability of the equipment in our clinical setting showed that SPA is a reliable technique to assess changes in bone mass at the lower arm of 4% between 2 measurements with a confidence level of 95%.
Bone and Bones↗
Facial dysmorphia, parathyroid and thymic dysfunction in the father of a newborn with the DiGeorge complex.
A boy born at full-term died after 14 days from cardiac failure. At autopsy DiGeorge complex was diagnosed. The father was found to have facial dysmorphia and hypocalcaemia. Investigations revealed no cause other than hypoparathyroidism associated with normal serum 1,25-dihydroxyvitamin D concentrations and normal renal handling of phosphate. Immunological tests, performed on two occasions with an interval of 9 months, revealed a decrease in the number of CD8+ lymphocytes, compatible with a partial thymus deficiency. The combination of facial dysmorphia with dysfunction of the thymus and the parathyroid glands can constitute a partial DiGeorge complex. The findings in this family are compared with reports of four other families with DiGeorge complex in two generations. In genetic counseling DiGeorge complex should be considered a heterogenous disorder. Screening of the parents for somatic stigmata, hypocalcaemia, disturbed cellular immunity, cardiac and chromosomal abnormalities is essential.
Adult↗
Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD.
The effects of the (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in osteoporosis were investigated in a series of open studies. Seven patients received a high dose of 600 mg/day of APD orally and showed an increase in calcium balance of 5.5 mmol/day (P less than 0.01) within a period of 10 days. In a group of 14 patients with osteoporosis, receiving a low dose of 150 mg/day of APD continuously, the mean calcium balance rose from -0.72 +/- 0.59 mmol/day before treatment to 1.33 +/- 0.87 mmol/day (P less than 0.005) after 1 year. In 24 patients treated with APD 150 mg/day for a mean period of 3.7 years (range 1.4-6.2) repeated dual photon absorptiometry measurements of the lumbar spine showed a mean rate of increase in bone mineral content of 3.1 +/- 1.0% per year (P less than 0.005). This yearly gain in bone mineral content appeared continuous for several years of treatment. In a comparable group of 19 patients with osteoporosis who also received conventional care and treatment but no APD, no significant changes in bone mineral content were found. Addition of a low dose of APD to conventional treatment of osteoporosis does not only prevent bone loss but induces a continuous gain in bone mass. These results justify long-term prospective studies with uninterrupted low dose APD treatment in osteoporosis.
Adult↗
Renal responsiveness to synthetic human parathyroid hormone 1-38 in healthy subjects.
Renal responsiveness to synthetic human parathyroid hormone (HPTH) 1-38 was examined in seven healthy volunteers. Each subject received three different doses (35 micrograms, 17.5 micrograms, 8.75 micrograms) as bolus intravenous injections. Rapid, transient, dose-dependent decreases in diastolic blood pressure and increases in heart rate were observed, as reported previously in animal studies, suggesting an acute vasodilatory effect of the hormone. The extracellular cyclic AMP responses were brisk and dose-dependent in the group as a whole as well as in the individual subjects. In contrast, the phosphaturic responses, though statistically significant with all three doses, were of a lesser magnitude and showed an individual variability. Nearly maximal decreases in TmP/GFR were found even after the lowest dose with minimal increases in cyclic AMP in some subjects. The injections of HPTH 1-38 also induced a dose-dependent natriuresis which was accompanied by an increase in excreted calcium. It seems that under these experimental conditions the sodium-dependent renal calcium transport cannot be compensated by the effects of the hormone on the distal tubule. HPTH 1-38 can be safely and predictably used for the assessment of renal responsiveness to PTH in routine clinical practice.
Adult↗
Modulation of calcium oxalate monohydrate crystallization kinetics in vitro.
The effects of several low and high molecular weight (mol wt) compounds on the kinetics of calcium oxalate crystallization were examined using a seeded crystal growth method in which the solubility, the growth and the agglomeration of calcium oxalate crystals were measured as three separate and system-independent parameters. Citrate, magnesium, phosphate, pyrophosphate, chondroitinsulphate, pentosanpolysulphate and heparin were tested in a wide range of concentrations. The solubility of calcium oxalate crystals was increased only by citrate and magnesium. The crystal growth was inhibited by all compounds tested, but those with the high mol wt had the greatest effect at low concentrations. In contrast, inhibition of crystal agglomeration was achieved only by the low mol wt compounds; citrate was found to be the most potent inhibitor at concentrations likely to be present in normal urine. The high mol wt substances, despite their potent crystal growth inhibitory activity, had no effect on agglomeration. The results show that growth and agglomeration of calcium oxalate crystals are separate processes which are differently modulated by various compounds. They further provide a possible explanation for the pathogenetic role of citrate in hypocitraturic renal stone disease.
Calcium Oxalate↗
Circulating 1,25-dihydroxycholecalciferol after intravenous injections of 1 alpha-hydroxycholecalciferol in patients on regular haemodialysis.
The formation of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) after single intravenous injections of 1 alpha-hydroxycholecalciferol (1 alpha-OHD3) was examined in four patients with chronic renal failure on regular haemodialysis. Following 1-3 micrograms 1 alpha-OHD3, administered at weekly intervals, 1,25-(OH)2D3 appeared in the circulation within 1 h, and peak concentrations were reached between 2 h and 5 h. By 8 h serum 1,25-(OH)2D3 concentrations had started declining and by 44 h they had returned to baseline after 1 microgram 1 alpha-OHD3, but they were still above basal after 2 and 3 micrograms by an average of 30 pmol/l. One week after injections, concentrations were back to basal in all patients studied. The serum 1,25-(OH)2D3 dose response to injected 1 alpha-OHD3 was linear, indicating ample capacity of the liver 25-hydroxylase to further hydroxylate 1 alpha-OHD3. However, examination of the individual responses revealed lower increments in serum 1,25-(OH)2D3 concentrations in the patients with the highest basal serum 25-hydroxyvitamin D concentrations. Intravenous 1 alpha-OHD3 may be useful in the further study of the interactions between 1,25-(OH)2D3, calcium and PTH in chronic renal failure, as well as of the hepatic metabolism of vitamin D.
Aged↗
Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD).
Early and late responses to treatment with either oral (600 mg/day) or intravenous (20 mg/day) (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (aminohydroxypropylidene bisphosphonate; APD) were studied in 142 patients with Paget's disease of bone who had not previously been treated with bisphosphonate. The efficacy of three therapeutic regimens was compared: (a) oral aminohydroxypropylidene bisphosphonate given continuously until six months after the serum alkaline phosphatase activity had returned to normal (long term); (b) oral aminohydroxypropylidene bisphosphonate given until urinary hydroxyproline excretion had returned to normal (short term); (c) intravenous aminohydroxypropylidene bisphosphonate for 10 days. With either oral or intravenous treatment the decrease in urinary hydroxyproline excretion was rapid and always preceded the fall in serum alkaline phosphatase activity. Normal urinary hydroxyproline excretion is essential for return of the serum alkaline phosphatase activity to normal. Complete biochemical remission, defined as return of the serum alkaline phosphatase activity to normal, was obtained in 129 patients (91%). The median duration of remission as assessed by actuarial analysis was 2.7 years. This study found no difference in the long term among the three modes of treatment, suggesting that for most patients with Paget's disease a short course of intravenous aminohydroxypropylidene bisphosphonate will produce longlasting, complete remission without need for maintenance treatment.
Administration, Oral↗
Ectopic production of 1,25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcemia.
A patient with long-standing rheumatoid arthritis developed hypercalcemia (3.13 mmol/l) and was subsequently found to have a B-cell lymphoma (centroblastic type). The hypercalcemia was associated with high circulating concentrations of 1,25-dihydroxyvitamin D (235 pmol/l) and both abnormalities were corrected with treatment. A lymph node was excised before treatment and was incubated in vitro with either labeled or unlabeled 25-hydroxyvitamin D3. After purification of the extract and chromatography on three different HPLC systems, material comigrating with authentic 1,25-dihydroxyvitamin D3 was identified. This was shown to bind to a specific chick intestinal cytosol receptor and to dilute in parallel with synthetic 1,25-dihydroxyvitamin D3 in the receptor binding assay. In conclusion, hypercalcemia in malignant B-cell lymphoma can be due to extrarenal production of 1,25-dihydroxyvitamin D by lymphomatous tissue.
Arthritis, Rheumatoid↗
Low inhibition of crystal agglomeration and citrate excretion in recurrent calcium oxalate stone formers.
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Bicarbonates↗
Serum osteocalcin in Paget's disease of bone: basal concentrations and response to bisphosphonate treatment.
Serum osteocalcin concentrations were measured in 42 patients with Paget's disease of bone and elevated serum alkaline phosphatase (AP) levels. High serum osteocalcin levels were found in only 22 patients. Serum osteocalcin was significantly correlated with urinary hydroxyproline excretion (r = 0.747; P less than 0.001) and, to a lesser extent, with serum AP levels (r = 0.483; P less than 0.01). In 23 patients who were followed during treatment with iv (3-amino-1-hydroxypropylidene) 1,1-bisphosphonate (APD) for 10 days, a dissociation among these 3 biochemical parameters was found. Urinary hydroxyproline excretion fell significantly (P less than 0.001), serum AP levels decreased, but not significantly, and serum osteocalcin concentrations increased progressively (P less than 0.001). This increase was greater when initial levels were lower than expected for the activity of the disease. The rise in serum osteocalcin correlated significantly with the concomitant increase in serum 1,25-dihydroxyvitamin D concentrations. Three months after initiation of treatment, all 3 parameters, urinary OHP excretion, serum AP, and serum osteocalcin levels, were near or within the normal range. These results indicate that serum osteocalcin is not a clinically useful parameter for assessment of the activity of Paget's disease. Its basal concentrations lag behind those expected from the activity of the disease, suggesting defective osteocalcin production. It appears that the functions of osteocalcin and AP as well as their initial expression by the osteoblasts are different and that this difference may be important for the quality of bone formed in Paget's disease. APD can modulate the release of osteocalcin, possibly through stimulation of 1,25-dihydroxyvitamin D production, although other factors may be involved.
Adult↗
A tumour-like bone lesion as a manifestation of vitamin D-resistant hypophosphataemic osteomalacia.
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Adult↗
Excessive crystal agglomeration with low citrate excretion in recurrent stone-formers.
In 7 highly recurrent calcium oxalate stone-formers and 10 healthy subjects the effects of urine on three processes of calcium oxalate monohydrate crystallisation--solubility, crystal growth, and crystal agglomeration--were studied. The urine of the stone-formers showed low calcium oxalate solubility and normal crystal growth inhibition, but lacked the ability to inhibit crystal agglomeration. As the sole metabolic abnormality, all stone-formers showed hypocitraturia. Normalisation of urinary citrate concentration resulted both in vitro and in vivo in a significant rise in agglomeration inhibition. These results show that inhibition of agglomeration is a very important, probably citrate-regulated, process in calcium oxalate stone formation.
Adult↗
Evidence for extrarenal metabolism of 25-hydroxyvitamin D3 in man.
Metabolites of vitamin D3 were measured in the circulation of four patients on chronic haemodialysis (three of whom were surgically anephric) before and during daily ingestion of 40 000 i.u. of cholecalciferol. Circulating 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] was measurable, but abnormally low before treatment; its circulating concentration rose in a substrate dependent manner when serum 25-hydroxyvitamin D3 (25-OHD3) increased, but the response was reduced when compared with the normal relationship. Serum 1,25-hydroxyvitamin D3 [1,25-(OH)2D3] and calcidiol lactone (25-OHD3-lactone) were consistently unmeasurable in sera from these patients before administration of cholecalciferol. However, when serum 25-OHD3 rose with treatment, 1,25-(OH)2D3 became detectable in the sera of three of the four patients and 25-OHD3-lactone could be measured in all of them. These data indicate that extrarenal sites of synthesis of 24,25-(OH)2D3, 25-OHD3-lactone and 1,25-(OH)2D3 exist in chronically dialysed patients but require large amounts of substrate to be significant.
Adult↗