R. Dorizzi

The Acute-Phase Response after Bisphosphonate Administration

SummaryIn patients who have never previously received bisphosphonate therapy, the intravenous administration of 4-amino-1-hydroxybuthilidene-1,1-bisphosphonate (AHButBP), 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP), or 6-amino-1-hydroxyhexylidene-1,1-bisphosphonate (AHHexBP) induced an acute-phase response (APR) irrespective of the underlying disease, manifested by a fall in circulating lymphocyte number and serum zinc concentration and in a rise in C-reactive protein (CRP); a febrile reaction occurred in 30% of the patients. The APR was maximally expressed within 28–36 hours of i.v. administration of the bisphosphonates and disappeared 2–3 days later despite continuous treatment. These effects were dose dependent and the lowest doses necessary for an APR were 10 mg of AHButBP and AHPrBP and 75 mg of AHHexBP. Doses up to 1,000 mg/day i.v. of dichloromethanebisphosphonate (Cl2MBP) were devoid of these side effects. In patients treated with either a single i.v. dose of amino-bisphosphonates which resulted in an APR or with a suboptimal dose, a subsequent challenge 12–160 days later of the high dose failed to cause a rise in CRP or a fall in the lymphocyte count. The desensitization to AHButBP or AHPrBP was also seen following pretreatment with Cl2MBP. These findings suggest that bisphosphonates interact with macrophage-like cells resident in the skeleton and stimulate interleukin-1 release which is responsible for the appearance of the APR. At the same time, however, the bisphosphonates render these cells insensitive to further stimulation for several months. This latter observation might be relevant to the long-lasting suppression of bone resorption observed after bisphosphonate therapy.

Dichloromethylene-Diphosphonate in Patients with Prostatic Carcinoma Metastatic to the Skeleton

A total of 17 patients with multiple osteoblastic bone metastases owing to prostatic carcinoma was treated with 2-dichloromethylene-diphosphonate, a powerful inhibitor of bone resorption. The drug was given intravenously (300 mg.) for 2 weeks and then orally (3,200 mg.) or intramuscularly (100 mg.) for 4 to 11 weeks. A definite improvement in pain, assessed by daily consumption of analgesic drugs and by an analogic scale, was observed within 10 days in 16 of the 17 patients. Four patients confined to bed rest for pain were able to walk after 2 weeks and reversal of paralysis also was noted in 1 patient. Transient changes in serum calcium (decreasing) and alkaline phosphatase (increasing) were observed in most patients. In the 3 patients in whom it was performed, repeated bone scanning showed a partial regression of pathological areas in 2 and the complete disappearance of most pathological areas in 1. Our results suggest that 2-dichloromethylene-diphosphonate may represent an important supportive treatment in patients with bone metastases owing to prostatic carcinoma, providing sustained relief of pain and regression of bone destruction without undesirable side effects.

Duration of the effects of intravenous alendronate in postmenopausal women and in patients with primary hyperparathyroidism and Paget's disease of bone

The effect of a single intravenous (i.v.) infusion of 5 mg alendronate was studied in ten patients with Pagets disease, six patients with primary hyperparathyroidism and ten osteopenic postmenopausal women. Urinary hydroxyproline excretion significantly decreased within few days in all patients (from 113 +/- 67.9 to 58 +/- 35 mmol/mol Cr in Pagets disease, from 21.8 +/- 9 to 12.9 +/- 6 mmol/mol Cr in hyperparathyroidism, from 18.7 +/- 9.5 to 8.5 +/- 4.3 mmol/mol Cr in postmenopausal women). In the patients with Pagets disease urinary hydroxyproline remained suppressed over the 6 months of follow-up, whereas it rose toward pretreatment values within 4 and 6 weeks in the patients with primary hyperparathyroidism and in postmenopausal osteopenic women, respectively. Plasma alkaline phosphatase significantly fell only after 4-6 weeks in patients with primary hyperparathyroidism and in Pagetic patients. In the latter group alkaline phosphatase continued to decline thereafter and a plateau became apparent after 2 months. In postmenopausal women the serum alkaline phosphatase remained unchanged. Thus, the same dose of alendronate induces comparable fractional decreases of bone resorption in the three groups of patients, but the effect is persistent only in Pagets disease. This is consistent with the hypothesis that alendronate inhibits osteoclastic activity only at the level of the existing resorption sites. In osteoporotic and primary hyperparathyroid patients, as soon as the treatment is withdrawn, the appearance of new sites of resorption is not inhibited and bone turnover is resumed to pre-treatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 micrograms/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 +/- 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.

Measurement of Urine Relative Density Using Refractometer and Reagent Strips

Abstract The relative density of urine is the ratio of its density to that of water and depends on both the number and weight of solute particles in the sample, while osmolality depends only on the number of solute particles. Water metabolism is regulated by the interaction of the renal medullary countercurrent system with the circulating levels of antidiuretic hormone and thirst. The concentration of solids in urine can be measured by weighing, hydrometry, oscillations of a capillary tube, refractometry and reagent strip. These techniques, interrelated but not identical, are commonly used in hospital laboratories and in clinical wards. We compared the results obtained in 1725 urine samples of inpatients and outpatients using an automated refractometer to those obtained using two visually read dip stick tests. The correlation coefficients (Super Aution analyser vs. Aution Sticks 10 EA, Aution Sticks 10 EA vs. N-Multistix, Super Aution analyser vs. N-Multisticks were 0.663, 0.645 and 0.514, respectively) and the great dispersion of mountain plots demonstrates that different techniques are not interchangeable in the measurement of relative density. Since the results obtained after discarding the samples with pH higher than 7 and those containing glucose or protein were very similar to the ones reported above, the role of these interferents appears negligible in inducing the discrepancy.

Simultaneous measurement of 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D from a single two milliliters serum specimen. Preliminary clinical application

A simple method for extraction, purification and separation of the principal vitamin D metabolites from a single serum sample is described. The method involved extraction of serum with acetonitrile followed by a first purification employing C-18 Sep-pak cartridges eluted with methanol/water and acetonitrile. Final separation before assay was carried out by high pressure liquid chromatography. 1.25-dihydroxy-vitamin D was measured with radioimmunoassay using an antiserum (S11) with high selectivity for 1α-OH function of the hormone at a final dilution of 1:100,000. 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D were measured employing a competitive binding assay with normal rat serum at a final dilution of 1:10,000 as source of binding protein. The mean (± SD) serum 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D concentrations for a group of healthy subjects were 50.4 ± 17.3 pg/ml, 2.3 ±2.6 ng/ml and 20.8 ± 12.3ng/ml, respectively. 1.25-dihydroxy-vitamin D concentrations were low or undetectable in patients on dialysis or with mild renal failure. High 1.25-dihydroxy-vitamin D levels were found in 2 out of 17 patients with primary hyperparathyroidism. In 4 normal subjects treated for two weeks with large doses of 25-hydroxy-vitamin D, serum 25-hydroxy-vitamin D rose from 12.5 ng/ml to 119 ng/ml and from 0.89 ng/ml to 15 ng/ml, respectively; no changes in the 1.25-dihydroxy-vitamin D assay were found.

Clinical Utility of a Wheat-Germ Precipitation Assay for Determination of Bone Alkaline Phosphatase Concentrations in Patients with Different Metabolic Bone Diseases

Bone alkaline phosphatase was evaluated by wheat-germ lectin precipitation in several clinical conditions. The study included 33 premenopausal healthy women, 46 postmenopausal apparently healthy women, 19 growing children, 24 patients with Pagets disease, 31 patients with primary hyperparathyroidism and 66 patients with hepatobiliary diseases. In postmenopausal women the mean T score (i.e.: the number of SD below or above the mean for premenopausal women) was 2.6 +/- 1.3 (SD) for bone alkaline phosphatase and 1.61 +/- 1.21 for total alkaline phosphatase (p < 0.001). The T score for bone alkaline phosphatase provided a better discrimination from normals for both Pagets disease (22.1 +/- 27.8 versus 12.8 +/- 16 p < 0.001) and primary hyperparathyroidism (8.2 +/- 4.3 versus 4.6 +/- 3.7 p < 0.005 for bone alkaline phosphatase and total alkaline phosphatase respectively). After treatment with intravenous bisphosphonate the percent decrease of bone alkaline phosphatase was larger than that of total alkaline phosphatase both in patients with Pagets disease (-46% versus -72% p < 0.01) and in patients with primary hyperparathyroidism (-21% versus -47% p < 0.02) and an estimate of the precision (delta mean/SD of the delta mean) for bone alkaline phosphatase was 1.9-3.7 times higher than that of total alkaline phosphatase. In twelve osteoporotic patients treated for six months with oral alendronate the decrease in bone turnover was detected with significantly higher precision with bone alkaline phosphatase than with total alkaline phosphatase (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)