Determination of isosorbide-5-mononitrate in human serum by gas chromatography-mass spectrometry.
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Gas Chromatography-Mass Spectrometry↗
Biomedical subjects
R Pacifici
Publications and source records attributed to R Pacifici.
Antacid and sucralfate-induced hypophosphatemic osteomalacia: a case report and review of the literature.
A 42-year-old woman presented to our institution with a 2-week history of bone pain in the lower extremities. Her history was remarkable for duodenal ulcer and long-term treatment with a magnesium-aluminum hydroxide antacid (Maalox) and sucralfate. Initial laboratory studies showed severe hypophosphatemia and elevated alkaline phosphatase and serum 1,25-dihydroxyvitamin D levels. Bone scan showed multiple areas of increased uptake consistent with osteomalacia and microfractures. The patient recovered completely following withdrawal of antacids and sucralfate and short-term treatment with phosphate. Although hypophosphatemia induced by aluminum-containing antacids is rare, treatment of peptic ulcer disease with a combination of two aluminum-containing agents may increase the risk of clinically significant hypophosphatemia. Awareness of this condition is important, because early recognition can prevent morbidity and lead to safe and effective treatment.
Adult↗
Vertebral cortical bone mass measurement by a new quantitative computer tomography method: correlations with vertebral trabecular bone measurements.
Previous studies comparing axial and appendicular skeleton have shown that trabecular bone loss is greater than cortical bone loss. However, whether the same difference exists between the trabecular and the cortical compartments of the vertebral body remains to be determined. In this study, we used quantitative computer tomography (QCT) to simultaneously measure the cortical rim of the vertebral body as well as trabecular bone. In 99 Caucasian women (mean age 53.8 +/- 13.0 years, range 26-79 years) we found a significant correlation between cortical mineral content (BMCC) and both single (SE) and dual energy (DE) trabecular mineral content (BMCT) (r = 0.62, P less than 0.0001 for both regressions). The cross-sectional rates of bone loss per year were 1.32%, 1.16%, and 0.59% for SE-BMCT, DE-BMCT, and BMCC, respectively. BMCC decreased at a rate that was 45-51% that of SE-BMCT and DE-BMCT, respectively. Our results indicate that (1) QCT may provide a useful means to selectively measure cortical density in vertebral bodies; (2) the decrease of cortical density over time in the spine appears to have been underestimated previously by extrapolation from appendicular bone measurements; (3) because measurements of the entire vertebral body (exclusive of the posterior elements) may provide information that is more representative of spine changes with age, a measurement that includes both areas might be more useful than one measuring only the trabecular region.
Adult↗
The role of interleukin-1 in postmenopausal bone loss.
Interleukin-1 (IL-1), a cytokine best known for its ability to stimulate lymphocyte proliferation, has recently been shown to stimulate bone resorption and modulate bone formation in vivo. Consequently, the authors have devised a series of studies to investigate the relationship between bone remodeling, menopause, and monocyte IL-1-secretion. In a first study, monocytes from osteoporotic patients were found to produce more IL-1 than monocytes from control subjects. IL-1 activity was also found to reflect histomorphometric indices of bone formation, but not of bone resorption. In a second study, devised to assess the effect of menopause on the relationship between IL-1 and bone turnover, a significant correlation was found between IL-1 and BGP in premenopausal osteoporotic women and osteoporotic men, but not in both postmenopausal osteoporotic subjects and normal subjects of either sex. In a third study, IL-1 from untreated postmenopausal women was found to be higher than in either untreated premenopausal or estrogen/progesterone-treated postmenopausal women. A significant negative correlation was found between IL-1 and years since menopause in both the healthy and osteoporotic postmenopausal women. Premenopausal IL-1 levels were achieved within eight years of menopause in the healthy but not in the osteoporotic subjects. In osteoporotic women, high IL-1 levels were evident as long as 15 years after menopause. IL-1 also correlated inversely with mineral density as measured by quantitative computer tomography. In prospective study, treatment with estrogen/progesterone caused a significant increase in IL-1 activity. This data indicates that monocyte IL-1 production mirrors the rate of bone turnover in both the healthy and osteoporotic patient, and that alteration in IL-1 production may underlie the postmenopausal acceleration of bone loss and its inhibition by ovarian steroids.
Bone Density↗
Dual energy radiography versus quantitative computer tomography for the diagnosis of osteoporosis.
In this study we compared dual energy radiography (DER), a new, highly precise x-ray densitometric technique recently devised for measurements of vertebral mineral density and quantitative computer tomography (QCT), a densitometric technique that selectively measures the trabecular compartment of the vertebra. DER and QCT measurements were obtained in 56 healthy (H) and 48 fractured osteoporotic (OP) women using a Hologic QDR 1000 bone densitometer and a GE 9800 scanner, respectively. DER was significantly correlated with QCT in both the H (r = 0.75; P less than 0.0001) and the OP subjects (r = 0.58; P less than 0.0001). DER decreased significantly with age in the H (P less than 0.05), but not in the OP women, whereas QCT was related to age in both the H (P less than 0.0001) and the OP subjects (P less than 0.01). The rate of bone loss with age was also higher with QCT than with DER in both normal and osteoporotic women. The difference in bone density between the H and the OP subjects was larger (P less than 0.05) with QCT than with DER. Receiver operating characteristic analysis revealed that QCT was a better predictor of vertebral fractures than DER. A larger percentage of OP subjects were 2 SD or more below the normal predicted value with QCT (41%) than with DER (29%). Furthermore, the slopes of the regressions of bone density with age for normal and osteoporotic women were significantly different (P less than 0.05) with QCT but not with DER. These findings are consistent with a disproportionate loss of trabecular bone with age in osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorptiometry, Photon↗
Lateral dual energy radiography: a new method for measuring vertebral bone density: a preliminary study.
Dual energy radiography (DER) is a new technique for non-invasive measurement of vertebral bone mineral density, which because of its high precision (1%), is particularly suitable for prospective analyses of time-related changes in bone mass. However, we recently found that DER is less sensitive to demineralization of trabecular bone than quantitative computed tomography (QCT). Since the compact bone of the posterior vertebral elements are included in the standard anterior-posterior DER (APDER), but not in QCT measurements, changes in trabecular bone mass attending the early phases of the osteoporotic process go undetected with the APDER technique due to the preponderance of cortical mass. Lateral-view DER (LDER), however, would minimize the contribution of vertebral compact bone as well as intra-abdominal calcifications to the trabecular component. To determine the in vivo short-term precision of the LDER method, we obtained three measurements in 18 healthy women, aged 23 to 76, during a four-week period. In addition, both APDER and LDER measurements were obtained in 53 healthy women, aged 23 to 80. The coefficient of variation for LDER was 2.8%. LDER density values accounted for a higher percentage of the variance of bone mass measurements with age (47%) than APDER (23%). Moreover, LDER declined significantly with age in both premenopausal (r = -0.42, p less than 0.05) and post-menopausal women (r = -0.50, p less than 0.005), whereas the age-related changes in APDER values failed to reach statistical significance in either group. The rate of bone loss with age in the premenopausal group was 0.45% per year with LDER, and 0.10% per year with APDER. Postmenopausal women showed a 0.78% loss of bone mass per year with LDER and 0.47% per year with APDER. The correlation between APDER and LDER was significant (r = 0.78, p less than 0.01). The accumulated data indicate that LDER may be a more appropriate technique than APDER for detecting the initial loss of vertebral trabecular bone that characterizes early subclinical osteoporotic syndrome.
Adult↗
Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria.
Idiopathic hypercalciuria (IH) is a heterogeneous disorder frequently observed in patients with nephrolithiasis. At one extreme of its clinical spectrum is fasting hypercalciuria (FH), a condition characterized by increased bone resorption and turnover. In previous studies we have shown that monocytes from patients with high turnover osteoporosis and from women in early postmenopause elaborate increased amounts of interleukin-1 (IL-1), a cytokine that stimulates bone resorption in vitro and in vivo. Since IL-1 could also mediate the resorptive mechanism of FH and cause a clinically significant bone loss, we have studied the relationship of IH, vertebral mineral density, bone turnover, and monocyte IL-1 activity in 47 patients with absorptive hypercalciuria (AH), 23 with FH, and 38 nonhypercalciuric subjects with recurrent nephrolithiasis (controls). Vertebral mineral density, as measured by quantitative computer tomography, was decreased in each of the three patient groups, but was significantly lower in FH patients than in AH patients or control subjects. Twenty-four-hour total urinary hydroxyproline excretion was increased in FH patients compared to that in AH patients or controls, but blood levels of osteocalcin were not. Monocytes from FH subjects yielded significantly more IL-1 (alpha + beta) activity than those from AH patients or controls; levels of IL-1 activity in monocytes of AH and control patients were similar. In IH subjects, significant correlations were found between IL-1 and hydroxyproline (r = 0.70; P less than 0.0001), IL-1 and quantitative computer tomography values (r = -0.49; P less than 0.005), and IL-1 and urinary calcium (r = -0.36; P less than 0.05). Serum PTH levels were within normal limits in all subjects and were similar in the three study groups, 1,25-Dihydroxyvitamin D3 levels, although higher in IH patients than in controls, were not significantly different in FH and AH subjects. Increased IL-1 activity and decreased vertebral mineral density are features of a subset of patients with IH. Although a cause-effect relationship remains to be established, increased monocytic IL-1 activity, rather than elevated PTH or 1,25-dihydroxyvitamin D3 levels, could underlie the resorptive component of FH.
Adult↗
Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release.
In previous studies, we showed that blood monocyte elaboration of interleukin 1 (IL-1), a known stimulator of bone resorption, was higher in osteoporotic patients with rapid bone turnover than in those with slow turnover and in nonosteoporotic subjects. Since an acceleration of bone loss following menopause contributes to the risk of osteoporosis in women, we have studied the effects of menopause and ovarian steroid treatment on IL-1 release by monocytes obtained from nonosteoporotic and osteoporotic women. IL-1 activity in the monocyte culture medium derived from untreated postmenopausal women (nonosteoporotic and osteoporotic) was higher than in the medium derived from either untreated premenopausal or estrogen/progesterone-treated postmenopausal women. A significant negative correlation was found between IL-1 and years since menopause in both the healthy (r = -0.75; P less than 0.005) and the osteoporotic (r = -0.61; P less than 0.01) untreated postmenopausal women. The difference between the two slopes was significant at P less than 0.05. Premenopausal IL-1 levels were achieved within 8 years of menopause in the nonosteoporotic, but not in the osteoporotic, subjects in whom increases were evident as long as 15 years after menopause. IL-1 also correlated inversely with vertebral mineral density (r = -0.37; P less than 0.05), as measured by quantitative computed tomography. In prospective studies, treatment with estrogen/progesterone for 1 month caused a substantial highly significant decrease in IL-1 activity in each of three nonosteoporotic and five osteoporotic women, confirming the apparent effect of hormone therapy observed in the cross-sectional analysis. Although a cause-effect relationship has not been established, it is our hypothesis, based on these data, that alterations in IL-1 production may underlie the postmenopausal acceleration in bone loss and its inhibition by ovarian steroids. Persistent elevation of IL-1 secretion appears to be a feature of postmenopausal osteoporosis.
Adult↗
Influence of antacids on the bioavailability of glibenclamide.
A single oral dose of glibenclamide (2.5 mg) was given to eight healthy volunteers in a randomized cross-over study after a standardized fasting and breakfast (374 kcal), with or without a concomitant intake of 10 ml of antacid suspension. Serum glibenclamide levels were determined by means of a specific radioimmunoassay method. The areas under the blood concentration-time curves (AUC0-infinity), with or without antacid, were 408.17 +/- 168.25 and 307.9 +/- 84.13 ng/ml (p less than 0.05), respectively. The peak concentrations of 96.88 +/- 49.9 and 66.19 +/- 32.35 ng/ml/h (p less than 0.05) with or without antacid, were reached in 4.13 and 3.81 h, respectively. Values of tmax, Vd and t1/2 were not affected by the presence of the antacid. A 33% increase in bioavailability of glibenclamide emerged, as seen from the respective AUC values, but no clinically remarkable effect was observed in the subjects.
Adult↗
Does interleukin-1 affect intracellular calcium in osteoblast-like cells (UMR-106)?
Interleukin-1 (IL-1) enhances bone resorption and formation in vitro, presumably through a primary action on osteoblasts, but the mechanism by which IL-1 activates bone cells is unknown. We investigated the possibility that the effect of IL-1 on osteoblasts is mediated through an increase in intracellular calcium [Ca++]i by studying the effects of purified human monocyte-derived IL-1 (hIL-1) and recombinant human IL-1 alpha (rhIL alpha) and beta (rhIL-1 beta) on [Ca++]i in the rat osteogenic sarcoma cell line UMR 106 using indo-1, a new-generation fluorescent Ca++-sensitive probe. hIL-1 (1 U/ml) resulted in an 85.5% rise in [Ca++]i over baseline that reached a peak after 30 seconds and returned to basal levels within 60 seconds. A similar transient rise in calcium was obtained upon exposure of the UMR cells to both the hIL-1 suspension buffer and to the concentration of fetal bovine serum present in the hIL-1 buffer. This effect was not abolished either by heat inactivation of both hIL-1 and serum or by pretreatment of hIL-1 with specific rabbit antihuman-IL-1 antibody. Moreover, exposure of the UMR cells to either rhIL-1 alpha or rhIL-1 beta or to a mixture of both at concentrations of 1 to 100 U/ml was not followed by any change in [Ca++]i. Our data do not support the idea that IL-1 can stimulate osteoblasts through a calcium-mediated pathway.
Animals↗
Evidence for a prostaglandin-mediated bone resorptive mechanism in subjects with fasting hypercalciuria.
This study was performed to assess whether treatment with prostaglandin synthesis inhibitors decreases calcium excretion in patients with idiopathic hypercalciuria. Nineteen hypercalciuric (12 with fasting hypercalciuria (FH), 7 with nonfasting hypercalciuria (NFH) and 8 control non-hypercalciuric stone formers were treated with sodium diclofenac, 50 mg t.i.d. for 2 weeks. After a washout phase, 7 FH patients received 200 mg/day of sulindac (a nonsteroidal antiinflammatory agent (NSAID) inactive on renal prostaglandin synthetase) for 14 more days. Diclofenac reduced urine calcium excretion in subjects with idiopathic hypercalciuria with either normal or elevated fasting urinary calcium (from 387 +/- 26 to 240 +/- 23 mg/day, P less than 0.001; and from 370 +/- 39 to 246 +/- 40 mg/day, P less than 0.05, respectively), whereas it was ineffective in normocalciuric stone formers. Similar antihypercalciuric effectiveness was exerted by sulindac in the seven FH patients. The antihypercalciuric action exerted by diclofenac in subjects with FH was associated with a significant increment in serum PTH (48 +/- 4 vs, 70 +/- 9 pmol/liter, P less than 0.05), whereas in NFH subjects, the antihypercalciuric effect of diclofenac on NFH was not associated with a change in parathyroid activity. Since the major effect of NSAIDs is to decrease prostaglandin synthesis, these data suggest that prostaglandins may play a pathogenetic role in idiopathic hypercalciuria. Furthermore, they suggest that PTH is suppressed in patients with FH, possibly due to stimulation of prostaglandin-mediated bone resorption process.
Adolescent↗
Dual energy radiography (DER): a preliminary comparative study.
Dual energy radiography (DER) has been recently proposed as a new technique for the non invasive measurement of vertebral mineral density. This preliminary study was undertaken to assess the short-term precision of DER and to compare DER to dual photon absorptiometry (DPA) measurements. Three DER measurements were obtained in 19 healthy volunteers (mean age 34.7 +/- 9.3 years) over a 3 week period. In addition, both DER and DPA measurements were obtained in 52 women (mean age 54.3 +/- 12.5 years). The coefficient of variation for the DER measurements was 1.00%. A highly significant correlation (r = 0.94; p less than 0.0001) was found between DPA and DER. Using this curve a conversion factor of -6.8% was calculated to convert DER to DPA values. Both DER and DPA were significantly and similarly correlated with age (r = -0.43, p less than 0.005; r = -0.38, p less than 0.05, respectively). The rates of bone loss, 0.66% per year for DER and 0.57% per year for DPA, were also similar with the two techniques. From these data, it is concluded that DER is a precise new method for vertebral bone mass measurements.
Adult↗
Coherence therapy does not prevent axial bone loss in osteoporotic women: a preliminary comparative study.
Coherence therapy, also known as ADFR (activate, depress, free, repeat) therapy, has been proposed as a new form of treatment for osteoporosis. We compared the effects of this therapy with those of gonadal steroid and calcium and of calcium alone in 93 osteoporotic women. Thirty women were treated for 1 yr with ADFR, in the form of K-phosphate (1.5 g/day), for 3 days followed by etidronate, (400 mg/day) for 14 days, followed by 8 weeks of neither drug, plus continuous calcium carbonate therapy (1 g/day). Thirty-six women received conjugated estrogens (0.625 mg/day) for 25 days/month plus medroxyprogesterone acetate (10 mg/day) for 10 days/month and calcium, while 27 women received calcium carbonate (500 mg, twice daily). Sixteen women in the ADFR group, 15 in the calcium group, and 19 in the hormone-calcium group completed 2 yrs of treatment. Spinal bone mineral density was measured by single energy quantitative computerized tomography (QCT) and in the proximal and distal radius by single energy photon absorptiometry. The 3 groups were similar in age, initial bone mass, years since menopause, and dietary calcium intake. After 2 yrs, the mean women in the ADFR therapy group had a mean reduction of 8.0% in spinal QCT (P less than 0.05), and no change in proximal radius mineral content/bone width (BMC), and distal radius BMC. The group treated with calcium only had a decrease of 3.8% in QCT (P less than 0.05), of 5.6% in proximal BMC (P less than 0.05), and of 4.9% in distal BMC (P less than 0.05). The group treated with hormonal replacement and calcium had no change in any of their measurements. The relative bone loss in the spine at the end of the study was greater in the ADFR group than in the hormone-calcium group (P less than 0.05). Bone loss in the calcium group was slightly but not significantly greater than that in the hormone group and lower than that in the ADFR group. In conclusion, these preliminary results indicate that the ADFR regimen using phosphate and etidronate in doses of 1.5 g/day for 3 days and 400 mg/day for 14 days, respectively, is not as effective as hormonal replacement in preventing trabecular bone loss in osteoporosis, nor it is any more effective than calcium supplementation alone.
Adult↗
Calcium supplementation and postmenopausal bone loss.
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Calcium↗
Adrenal responses to subtotal parathyroidectomy for primary hyperparathyroidism.
Although it is well known that hypertension is often associated with primary hyperparathyroidism and that parathyroidectomy reverses or reduces this abnormality, the etiology of elevated blood pressure in hyperparathyroidism is still conjectural. We have analyzed serum calcium, blood pressure, and metabolites of adrenal cortical hormones before and after surgical therapy for hyperparathyroidism in 10 normotensive and six hypertensive patients with primary hyperparathyroidism. Successful parathyroidectomy lowered serum calcium (P less than 0.01) and diastolic blood pressure (P less than 0.05) in all subjects. Mean urinary aldosterone and Porter-Silber chromagens were within normal limits preoperatively in normotensive as well as hypertensive subjects. After parathyroidectomy, aldosterone levels as well as Porter-Silber chromagens decreased significantly in all patients (P less than 0.01). However, when normotensive and hypertensive subjects were analyzed separately, the decrease in aldosterone levels was significant only in the normotensive group (P less than 0.05) whereas the decrease in Porter-Silber chromagens reached significancy only in the hypertensive group (P less than 0.01). The results indicate that surgical therapy for hyperparathyroidism lowers serum calcium and blood pressure and is associated with a decrease in the excretion of adrenal steroid metabolites. It is suggested that the temporal relationship which exists between ionized calcium and steroidogenesis in hyperparathyroid patients contributes at least in part to the generalized decrease in blood pressure observed after successful parathyroidectomy.
17-Hydroxycorticosteroids↗
Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis.
Osteoporosis is a state of reduced skeletal mass characterized by various rates of bone remodeling. Multiple locally elaborated factors have been identified that appear to influence the cellular events in bone remodeling. The possible role(s) of these factors in the pathogenesis of osteoporosis is unknown. One such factor, interleukin 1 (IL-1), is of particular interest, as this protein is known to stimulate bone resorption and perhaps formation. Consequently, we have measured the spontaneous secretion of IL-1 activity by cultured peripheral blood monocytes obtained from 22 osteoporotic patients and 14 age-matched control subjects. Monocytes from osteoporotic patients produced more IL-1 than did monocytes from control subjects. When patients were grouped according to monocyte-produced IL-1 activity, dynamic parameters of bone formation, as judged by quantitative histomorphometric analysis of iliac crest bone biopsies and by circulating levels of bone 4-carboxyglutamic acid protein (BGP)--a marker of bone formation--were higher in subjects with elevated IL-1 activity; whereas, indices of bone resorption and static indices of bone formation were similar in subjects with either high or normal IL-1 activity. IL-1 activity released by peripheral blood monocytes appears to reflect bone formation rate in osteoporotic patients and may be of pathogenetic significance in a subset of individuals with osteoporosis.
Adult↗
Single and dual energy tomographic analysis of spinal trabecular bone: a comparative study in normal and osteoporotic women.
To investigate the effects of age on rates of bone loss and the relationship between amount of trabecular bone and clinical severity of osteoporosis, trabecular mineral density of the lumbar spine (VMD) was measured in 55 osteoporotic women and 133 healthy women with both single energy (SE) and dual energy (DE) quantitative computed tomography (QCT). The amount of marrow fat was indirectly estimated by the difference (delta) between DE and SE VMD values. The rate of bone loss in the normal women was 1.14%/yr with SE and 1.03%/yr with DE QCT. Osteoporotic patients had a VMD decline of 1.62%/yr with SE and 1.17%/yr with DE QCT. Osteoporotic patients had significantly lower (P less than 0.0001) mean SE and DE VMD at any age, but VMD was not significantly different among groups characterized by different number of fractures or different radiographic severity of fractures. The threshold values of VMD below which the risk of having fractures was increased were 99.8 and 118.7 mg/cm3, respectively, for SE and DE QCT. Dispersion around the mean, overlap between osteoporotic and healthy women, and the incidence of asymptomatic osteoporosis were greater with DE than SE QCT. Osteoporotic women had higher delta values (P less than 0.05) compared to normal women, but delta did not correlate with clinical severity of osteoporosis. The results indicate that factors in addition to the amount of spinal trabecular bone determine the number and severity of fractures in osteoporotic women; DE QCT reduce the VMD underestimation due to intravertebral fat content, but not the overlap between osteoporotic and normal women; and further anatomical studies of osteoporotic vertebrae are necessary to investigate the effect of age on intravertebral fat.
Adult↗
Serum bone gla protein (BGP) and other markers of bone mineral metabolism in postmenopausal osteoporosis.
Bone gla protein, the vitamin K-dependent protein synthesized by osteoblasts and measured in blood by radioimmunoassay, has been used as an index of the rate of bone turnover. The relationship of bone gla protein with other markers of bone mineral metabolism was determined in 31 untreated postmenopausal women with the osteoporotic syndrome. In addition to serum osteocalcin (BGP) we measured parathyroid hormone (PTH) (carboxyl and mid-molecule fragments), 25(OH)D, alkaline phosphatase, estradiol (E2), estrone (E1), dietary calcium intake, 24 hour urinary calcium excretion, and bone mineral density by CT scan of the lumbar vertebrae. Significant osteopenia was present on CT in untreated postmenopausal osteoporotic women (bone density in 18 out of 31 was below the critical value of 60 mg/cm3). Serum BGP correlated positively with CT scan (r + 0.647, P less than 0.001). CT and age were negatively correlated (r - 0.661, P less than 0.001) while CT and E2 showed a positive correlation (r + 0.554, P less than 0.01). Unexpectedly, BGP and age revealed a significant negative correlation (r - 0.421, P less than 0.05). These findings suggest a state of low bone turnover in this group with untreated postmenopausal osteoporosis.
Adult↗