The use of bone markers in a 6-week study to assess the efficacy of oral clodronate in patients with metastatic bone disease.

Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind, multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen (S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of >or=1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P=0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other (mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients but may be suboptimal for the other tumors studied.

Recovery of bone mass and normalization of bone turnover in long-term survivors of allogeneic bone marrow transplantation.

Osteoporotic fractures are potential long-term complications of bone marrow transplantation (BMT). We previously reported that bone mineral density (BMD) of patients undergoing allogeneic BMT decreased by 6% to 9% during the first 6 months after BMT and that bone turnover rate was still increased 1 year after BMT. BMT patients do not need lifelong immunosuppressive treatment, which should offer favorable circumstances for the recovery of BMD. Thus, 27 (14 women, 13 men) of 29 long-term survivors of our previous study were invited to a follow-up study at a median of 75 months after BMT. From 12 months after BMT the BMD of the lumbar spine had increased by 2.4% (P = 0.002). The respective changes in femoral sites were +4.1% in the femoral neck (P = 0.087), 4.0% in the trochanter (P = 0.095), +4.7% in Ward's triangle (P = 0.072) and +1.4% in the total hip (P = 0.23). The markers of bone formation, serum osteocalcin and type I procollagen aminoterminal propeptide (PINP) had returned to control levels, but out of the markers of bone resorption the mean level of serum type I carboxyterminal telopeptide (ICTP) was 41% higher (P = 0.0001) and that of urinary type I collagen N-terminal telopeptide/creatinine (NTx) 41% lower (P = 0.0002) in patients than in controls. The mean serum 25-hydroxyvitamin D [25(OH)D] was 33% lower in patients (P = 0.0002), most of whom had hypovitaminosis D [serum 25(OH)D < or = 37 nmol/l]. Except for two, males had serum testosterone level lower than before BMT and four men had hypogonadism. In conclusion, in long-term survivors of allogeneic BMT BMD recovers and bone turnover state normalizes as compared to the situation 1 year after BMT. More attention should be paid to the vitamin D status of all recipients and to possible hypogonadism of male patients.

A high prevalence of hypovitaminosis D in Finnish medical in- and outpatients.

OBJECTIVE: To study the prevalence of hypovitaminosis D [serum 25(OH)D < or = 37 nmol L-1)] in Finnish medical in- and outpatients in a cross-sectional study. METHODS: The subjects were 106 consecutive medical inpatients (57 females, 49 males with mean ages of 65 and 58 years) from the Peijas Hospital, Vantaa, Finland, and 99 ambulatory patients (48 females, 51 males with mean ages of 42 and 46 years) contacting a private outpatient centre in Helsinki, Finland. Serum 25(OH)D, vitamin D binding protein (DBP), free vitamin D index (FDI), intact PTH (iPTH), and albumin-corrected calcium were measured. RESULTS: Serum 25-hydroxyvitamin D [25(OH)D] was 37 nmol L(-1) or less in 70% of female and in 61% of male inpatients and in 44% of female and in 37% of male outpatients. In the whole population, a statistically significant inverse association (P < 0.0001) was detected between iPTH and 25(OH)D levels; the iPTH concentration appeared to start increasing when 25(OH)D concentration was 50 nmol L(-1) or less. The association remained the same (P < 0.0001) when FDI was used instead of 25(OH)D in the calculations. When the sexes were analysed separately, the statistically significant association was found only in females (P < 0.0001 for iPTH versus 25(OH)D; P < 0.0001 for iPTH versus FDI) but not in males. CONCLUSION: Hypovitaminosis D is very common amongst Finnish in- and outpatients in both sexes, causing secondary hyperparathyroidism in females. More extensive studies are warranted to elucidate the vitamin D status of the Finnish population.

Relation of collagen type I alpha 1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people.

Background: In a previous study, we showed an association between the vitamin D receptor (VDR) gene BsmI restriction fragment polymorphism and peak bone mass in young Finnish adults. Design: The previous finding prompted us to study the relationship of the same polymorphism, as well as of the polymorphism in the Sp1 binding site of the collagen type I alpha 1 (COLIA 1) gene, to bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry and adjusted for age, weight, height, and lifestyle factors. Also studied was the relationship of VDR and COLIA 1 genotypes to markers of bone turnover [serum osteocalcin, type I procollagen carboxy- (PICP), and aminoterminal (PINP) propeptide, and type I collagen carboxyterminal telopeptide (ICTP)] and bone fractures in 513 early postmenopausal women (1-5 years postmenopausal), as well as hip fractures in 172 very old people. Results: The BB, Bb, and bb genotypes of the VDR gene, as well as the SS, Ss, and ss genotypes of the COLIA 1 gene, were distributed similarly among 402 early postmenopausal women with osteopenia in the lumbar spine and among 111 women with normal BMD (P=0.12 for VDR, P=0.53 for COLIA 1). There was no relation between the VDR and COLIA 1 genotypes and lumbar spine BMD among osteopenic women, among normal women, or in the combined study population. Among the women with vertebral osteopenia, the femoral neck BMD did not associate significantly with the VDR or COLIA 1 polymorphisms. The frequencies of the different VDR and COLIA 1 genotypes were similar among women with or without a history of a low-energy fracture. There was a borderline association between the VDR genotype and serum osteocalcin concentrations, with the Bb genotype associated with the highest median level (P=0.037). In a population-based sample of very old individuals (>85 years), the frequencies of the different VDR and COLIA 1 genotypes were similar among those with (n=64) and without (n=108) a history of hip fracture. Conclusion: The present data suggest that, in the Finnish population, the VDR and COLIA 1 genotypes do not determine the bone mass of early postmenopausal women or their bone turnover rate. The polymorphisms are not associated with risk of hip fractures in elderly people or with low-energy fractures in early postmenopausal women.

Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1,25-dihydroxyvitamin D (Calcitriol) for four years.

To evaluate the long-term effect of calcitriol treatment on bone mineral density (BMD) of the femoral neck and lumbar spine and the parameters of calcium and bone metabolism in elderly women, 55 healthy, postmenopausal women, all aged 66 years, were enrolled in the study. Eighteen started a 4-year supplementation with 0.5 microg of calcitriol daily and 37 served as controls. Calcium intake of all the subjects was adjusted to 800 mg daily. In 4 years femoral neck BMD increased by 3.0% in the calcitriol group, but decreased by 1.6% in the control group (P = 0.009). The respective changes in lumbar spine BMD were +2.3% and +0.9% (P = 0.067). Two years' treatment with calcitriol increased the intestinal absorption of strontium by 57% (P < 0.001), doubled the urinary excretion of calcium (P < 0. 001), and decreased the mean parathyroid hormone (PTH) level by 32% (P < 0.01). In the calcitriol group the marker of bone formation, serum osteocalcin, decreased by 27% (P < 0.01), and the marker of bone resorption, serum C-telopeptide of type I collagen (CTx), by 33% (P = 0.05) after 2 years. In two subjects the calcitriol dose had to be reduced because of hypercalciuria. We conclude that calcitriol treatment increases bone mass at the femoral neck and lumbar spine, the increases being maintained for up to 4 years. The gain in bone mass results from reduced bone turnover which is partly a consequence of the enhanced intestinal absorption of calcium and suppressed serum PTH levels.

A prospective study of bone loss and turnover after cardiac transplantation: effect of calcium supplementation with or without calcitonin.

Cardiac transplantation exposes recipients to osteoporosis and increased risk of consequent fractures. The purpose of the present study was to examine the magnitude, timing and mechanism of bone loss following cardiac transplantation, and to establish whether bone loss can be prevented by calcium with or without calcitonin. Thirty patients (29 men, 1 woman), aged 26-68 years (mean 48 years), were randomized into three groups of 10 to receive either no additional treatment, oral calcium 1 g twice daily for 12 months or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months. Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA) at the time of transplantation and 6 and 12 months later. Markers of bone formation [serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal propeptide (PICP) and aminoterminal propeptide (PINP)] and resorption [serum type I collagen carboxyterminal telopeptide (ICTP)], as well as serum testosterone in men, were assayed before transplantation and at 1 week and 1, 3, 6 and 12 months after transplantation. During the first 6 post-transplant months BMD calculated as a percent change from baseline decreased in the control group by 6.4% (p = 0.014) in the lumbar spine, by 6.0% (p = 0.003) in the femoral neck, by 5.0% (p = 0.003) in the trochanter and by 5.5% (p = 0.130) in Ward's triangle. Between 6 and 12 months a further decline in BMD occurred only at the three femoral sites, ranging from 2.2% to 9.8% (p = 0.004-0.079). In comparison with the control group, the group receiving calcium alone lost less bone in the trochanter between 0 and 6 months (p = 0.019), and the group receiving calcium together with calcitonin lost less bone in the femoral neck (p = 0.068) and Ward's triangle (p = 0.076) between 0 and 12 months. Seven (28%) of 25 assessable patients experienced vertebral compression fractures. Calcium with or without calcitonin had no effect on changes in biochemical parameters; consequently, the three study groups were combined. The markers of bone formation increased, the elevations in mean values being 59% for B-ALP at 1 month (p = 0.009), 152% for PICP at 1 week (p < 0. 0001) and 27% for PINP at 1 week (p = 0.021). After a temporary decline at 3 months B-ALP (p = 0.0002) and PINP (p < 0.0001) at 1 year were nearly doubled compared with baseline values. Throughout the study the marker of bone resorption, serum ICTP, was above normal, with a peak (mean values 67-69% above baseline) at 1 week (p = 0.0002) to 1 month (p < 0.0001). The mean concentration of total testosterone was decreased by 48% (p < 0.0001) 1 week and by 28% (p = 0.0005) 1 month after transplantation, but this was mainly explained by the concomitant drop in serum albumin. High bone turnover underlies bone loss after cardiac transplantation. Bone loss is most rapid during the first 6 post-transplant months. In the upper femur this bone loss may be reduced by treatment with calcium and calcitonin.

A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin.

Transplantation of solid organs including heart, kidney, and liver is associated with rapid bone loss and increased rate of fracture; data on bone marrow transplantation recipients (BMT) are scarce. The purpose of the present study was to examine the magnitude, timing, and mechanism of bone loss following allogeneic BMT, and to study whether bone loss can be prevented by calcium with or without calcitonin. Sixty-nine patients undergoing allogeneic BMT for malignant blood diseases were enrolled into the study. Forty-four (22 women, 22 men) completed 6 months, and 36 patients 1 year follow-up. They were randomized to receive either no additional treatment (n = 22), or oral calcium 1 g twice daily for 12 months (n = 12) or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months (n = 10). Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward's triangle) was measured by dual-energy X-ray absorptiometry (DXA). Bone turnover rate was followed with markers of bone formation and resorption (serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal (PICP) and aminoterminal propeptide (PINP), serum type I collagen carboxyterminal telopeptide (ICTP)). Serum testosterone was assayed in men. Calcium with or without calcitonin had no effect on bone loss or bone markers; consequently the three study groups were combined. During the first 6 post-transplant months BMD decreased by 5.7% in the lumbar spine and by 6.9% to 8.7% in the three femoral sites (P < 0.0001 for all); no significant further decline occured between 6 and 12 months. Four out of 25 assessable patients experienced vertebral compression fractures. Markers of bone formation reduced: B-ALP by 20% at 3 weeks (P = 0.027), PICP by 40% (P < 0.0001) and PINP by 63% at 6 weeks (P < 0.0001), with a return to baseline by 6 months. The marker of bone resorption, serum ICTP was above normal throughout the whole observation period, with a peak at 6 weeks (77% above baseline, P < 0.0001). In male patients serum testosterone decreased reaching a nadir (57% below baseline) at 6 weeks (P = 0.0003). In conclusion, significant bone loss occurs after BMT. It results from imbalance between reduced bone formation and increased bone resorption; hypogonadism may be a contributing factor in men. Bone loss can not be prevented by calcium with or without calcitonin.

Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy.

OBJECTIVE: To study whether levothyroxine (LT4) suppressive therapy exposes patients with differentiated thyroid cancer (TC) to an increased risk of osteoporosis. DESIGN AND METHODS: Markers of bone formation (serum alkaline phosphatase (ALP), osteocalcin (OC), type I procollagen carboxyterminal (PICP) and aminoterminal (PINP) propeptide) and resorption (serum type I collagen carboxyterminal telopeptide (ICTP) and urine hydroxyproline (HOP)), as well as serum intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25(OH)2-D) were measured in 29 patients (25 women, 4 men) with a median age of 45 years, and in 38 age- and sex-matched controls. In a subgroup of 14 patients the measurements were repeated after 5 weeks' interruption of LT4 therapy. Since the primary treatment of TC the patients had used TSH suppressive doses of LT4 (a mean daily dose of 215 microg) for 9 to 11 years. The bone mineral density (BMD) of patients and controls was measured by dual energy X-ray absorptiometry. RESULTS: When on T4 therapy, patients had significantly higher mean levels of ALP (+21%, P < 0.05), OC (+35%, P < 0.01), PICP (+10%, P < 0.05), PINP (+46%, P < 0.001), ICTP (+21%, P < 0.05), and HOP (+37%, P < 0.001) compared with controls. After stopping treatment, OC (-42%, P < 0.001), PINP (-7%, P < 0.05), and ICTP (-54%, P < 0.001) decreased, whereas PICP (+24%, P < 0.001) and 1,25(OH)2D (+29%, P < 0.01) increased. BMD of the lumbar spine and the upper femur was similar in patients and controls. CONCLUSIONS: Patients with differentiated TC have high bone turnover when on LT4 suppressive therapy, After withdrawing treatment both bone formation and resorption decrease acutely. During development of hypothyroidism, serum PICP and PINP, which form from the same type I procollagen molecule and should change similarly, behaved differently. This may be due to different effects of hypothyroidism on their removal through separate receptors in the liver.

Serum gelsolin and rhabdomyolysis.

We measured the serum gelsolin, actin-modulating protein, levels in five patients after rhabdomyolysis. We observed a tendency of serum gelsolin (83 kDa) to increase during the study period of 11 days. No intracellular gelsolin (80 kDa) was found in the serum, although it is abundant in muscle, and the destruction was severe as judged by other parameters. Serum gelsolin thus behaves differently in rhabdomyolysis than after acute tissue damage in other organs, such as liver necrosis and adult respiratory distress syndrome.

Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age.

We investigated whether levels of serum collagen markers and serum osteocalcin are related to pubertal growth and development in a cross-sectional study of 57 healthy boys at 14 y of age. The level of the soft tissue marker, serum amino-terminal propeptide of type III procollagen (PIIINP) was higher in boys at Tanner stages G3 versus G2 (p < 0.01). The levels of the markers of bone collagen matrix differed only at a more advanced pubertal stage: the formation markers, carboxy-terminal and amino-terminal propeptides of type I procollagen, and the degradation marker, carboxy-terminal telopeptide of type I collagen were higher only at stage G4 versus G3 (p < 0.01). The marker of bone mineralization, serum osteocalcin was also higher only at stage G4 versus G3 (p < 0.01). Stage G4 was associated with the pubertal growth spurt. The results demonstrate that pubertal development should be taken into account when serum levels of collagen markers and osteocalcin are evaluated, and suggest that an increase in serum PIINP in boys at G3 might predict a normal pubertal growth spurt, but the finding remains to be confirmed in longitudinal studies.

The aminoterminal propeptide of type I procollagen: evaluation of a commercial radioimmunoassay kit and values in healthy subjects.

OBJECTIVES: Evaluation of the performance of a radioimmunoassay kit for measuring serum concentrations of the aminoterminal extension peptide of human type I procollagen, S-PINP. DESIGN AND METHODS: S-PINP concentrations in 229 healthy subjects, 140 females, aged 3.8-81 years, and 89 males, aged 0.9-71 years, were measured with the kit. Because PINP and PICP (the carboxy-terminal propeptide of type I procollagen) are formed in equimolar concentrations, we also calculated the PICP/PINP ratio and compared the S-PINP values to those of S-PICP, which have been shown to correlate with bone formulation rate. RESULTS: The sensitivity of the assay was 2.3 micrograms/L, the spiking recovery ranged from 95.5 to 100.3%, the dilution recovery from 79.3 to 103.1%. The intra-assay imprecision was 2.3 to 3.5% (CV), the interassay imprecision within one reagent lot 2.5-5.2% and, between several reagent lots, 2.7 to 6.1% (CV). S-PINP in females over 20 years old ranged from 12 to 90 micrograms/L (x = 39.7, SD = 14.7), in males over 25 years old, from 22 to 89 micrograms/L (x = 49.9, SD = 15.8); the PICP/PINP ratio ranged from 1.5 to 5.2 and from 1.8 to 4.9, respectively. In females under 20 years old, S-PINP ranged from 52 to 820 micrograms/L, in males aged 25 years or younger from 35 to 1404 micrograms/L; the PICP/PINP ratio was 0.44-2.3 and 0.38-2.8. In females under 20 years and males under 25 years, there was a significant negative correlation between S-PINP and age: r = -0.70, p < 0.001 for females, r = -0.52, p = 0.004 for males. In different groups of healthy subjects, the correlation of S-PINP and S-PICP was significant (r = 0.67-0.86, p < 0.001). CONCLUSION: The assay performance is good. The significant positive relationship between S-PINP and S-PICP suggests that S-PINP also reflects bone formation rate. Because the clearance of PINP is probably less sensitive to hormonal changes, PINP may prove to be superior to PICP as a marker of bone formation.

Effects of short-term treatment with clodronate on parameters of bone metabolism and their diurnal variation.

The goal of the present study was to answer the question whether the diurnal variation of markers of bone turnover is abolished by inhibition of osteoclasts by bisphosphonates and to assess the effects of short-term treatment with clodronate on parameters of calcium and bone metabolism. Nine healthy, postmenopausal women, all aged 68 years, were studied before and after oral administration of clodronate, first 800 mg daily for 2 weeks and then 1600 mg daily for 2 weeks. During the two-study sessions of 24 hours, the subjects received exactly similar meals and were recumbent from 10:00 P.M. to 6:00 A.M. Blood was sampled every 2 hours and urine was collected in 4-hour aliquots. On each study occasion, three markers of bone resorption (ICTP, serum type-I collagen carboxyterminal telopeptide; F-Pyr, urinary-free pyridinoline; and NTx, crosslinked N-telopeptide of type I collagen) and one marker of bone formation (PICP, serum type I procollagen carboxyterminal propeptide) showed a diurnal variation; only that of NTx was lessened by treatment with clodronate. Mean area under curve (AUC) values for the 24-hour study periods decreased by 41% (P = 0.0002) and 4.7% (P = 0.016) for urinary NTx and F-Pyr, but remained unchanged for serum ICTP (P = 0.41) and PICP (P = 0.99). Treatment with clodronate decreased mean AUC for the serum concentration of total calcium by 1.4% (P = 0.030) and that for the urinary excretion of calcium by 33% (P = 0.021). Mean AUC for serum-intact PTH increased by 19% (P = 0.004). We conclude that short-term treatment with clodronate lowers serum and urine calcium levels and causes compensatory hyperparathyroidism. Treatment also clearly decreases the urinary excretion of NTx and lessens its diurnal variation. As assessed by sensitive markers such as NTx, the nocturnal rise in bone resorption is greatly blunted by inhibition of osteoclasts with bisphosphonates.

Aggressive breast cancer leads to discrepant serum levels of the type I procollagen propeptides PINP and PICP.

The propeptides PICP and PINP are derived from the synthesis of type I collagen, a major matrix protein of bone and soft tissues. The aim of this cross-sectional study was to investigate their value as indicators of the aggressivity of breast cancer. Serum PINP, PICP, and total alkaline phosphatase were determined from 89 breast cancer patients. Forty had major bone and/or soft tissue metastases with an aggressive disease course: the progressive disease (PD) group. Forty-nine had either none or minor bone and/or soft tissue metastases with a stable clinical course: the stable disease group (SD). The mean value of PINP in the PD group was 7.2 times higher than that in the SD group (276 +/- 79 microg/l versus 38 +/- 3 microg/l, respectively; P = 0.005), whereas PICP mean value was only 1.7 times higher in the PD group (174 +/- 20 microg/l versus 100 +/- 5 microg/l; P = 0.001). The ratio of PICP to PINP was 1.02 +/- 0.07 in the PD group and 3.07 +/- 0.18 in the SD group (P < 0.001). The correlation between PICP and PINP was linear in the SD group and nonlinear in the PD group. The results indicate that high serum PICP and PINP concentrations and a low PICP:PINP ratio are associated with a highly aggressive nature of breast cancer. Determination of PINP, in particular, may be valuable when evaluating the clinical status of a breast cancer patient.

High doses of alcohol increase urinary testosterone-to-epitestosterone ratio in females.

The effect of alcohol (1.2 and 2.0 g/kg) on the urinary testosterone-to-epitestosterone (T/E) ratio was studied by two experiments each conducted with four healthy females and males. The intake of 2.0 g/kg of ethanol within 5 h in the evening significantly increased plasma testosterone concentration and ratio of T/E in urine collected next morning in females. The results suggest that alcohol increases the T/E ratio more in females than in males. The effect of high doses of alcohol on urinary T/E ratio must be kept in mind when doping tests are performed during training periods.

Changes in bone markers in children with asthma during inhaled budesonide and nedocromil treatments.

We evaluated serum and urinary markers of bone turnover in 14 children with asthma during inhaled budesonide and nedocromil treatments. Both the markers of formation (serum carboxy- and amino-terminal propeptides of type I procollagen and serum osteocalcin) and the markers of degradation (serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-links) decreased (p < 0.05) during budesonide treatment for 6 months. During inhaled nedocromil treatment (for the following 6 months), the markers returned to the normal levels. These transient decreases in the markers of both formation and degradation of bone suggest that inhaled budesonide may slightly decrease the bone turnover rate. However, normal "coupling" between formation and degradation seemed to operate, e.g. a change in one resulted in a corresponding change in the other, so that net bone loss did not necessarily occur.

Serum concentrations of type I collagen carboxyterminal telopeptide (ICTP) and type I procollagen carboxy-and aminoterminal propeptides (PICP, PINP) as markers of metastatic bone disease in breast cancer.

The most abundant protein in bone is type I collagen. During type I collagen formation two extension peptides from both ends of the procollagen molecule, carboxy- and aminoterminal propeptides (PICP and PINP), are liberated in equimolar concentrations into the circulation. Type I collagen carboxyterminal telopeptide (ICTP) is formed during bone collagen breakdown and is liberated into the circulation. Serum concentration of the propeptides reflect bone formation, and the concentration of the telopeptide, bone resorption. We evaluated the usefulness of these bone remodelling markers in diagnosing and monitoring metastatic bone disease in breast cancer patients. Serum concentrations of ICTP, PICP and PINP were measured and the PICP/PINP-ratio calculated in 25 patients with bone metastases, 12 patients without metastases and their age matched healthy controls. S-ICTP and S-PINP were significantly higher in metastatic patients (p = 0.0001 and 0.02 respectively), and the S-PICP/PINP-ratio lower (p = 0.002) than in controls. S-PICP in metastatic patients did not differ significantly from that of controls. ICTP values in patients without metastases also differed from those of controls (p = 0.01). The clinical sensitivity for diagnosing metastatic bone disease was 56% for ICTP, 24% for PICP, 30% for PINP and 52% for PICP/PINP ratio. The clinical specifities were 93%, 100%, 98% and 91% respectively. During follow-up the changes in the marker values were parallel to the behaviour of the disease. We conclude that these markers alone are not sensitive enough for diagnosis, but they seem to be of use in detecting bone metastases and monitoring the activity of bone disease.

Myosin heavy-chain fragments and cardiac troponins in the serum in rhabdomyolysis. Diagnostic specificity of new biochemical markers.

BACKGROUND: Myosin is the major structural protein in muscle. Antibodies to beta-type heavy meromyosin react with cardiac and slow-twitch skeletal muscle. Cardiac TnT and TnI were developed as tissue-specific indicators. OBJECTIVES: To study myosin heavy-chain fragments as a delayed marker of previous rhabdomyolysis. To examine the cardiac specificity of cardiac troponin T (TnT) and cardiac troponin I (TnI) in patients with severe skeletal muscle damage. DESIGN AND METHODS: Serum myosin heavy-chain fragments, TnT, and TnI were studied up to 12 days after diagnosis in relationship to the serum creatine kinase level in 20 patients with rhabdomyolysis. The mean peak serum creatine kinase activity was 91,300 U/L. Myosin heavy-chain fragments were measured by an immunoradiometric assay, TnT by a one-step immunoenzymometric assay, and TnI by an immunoenzymometric assay. RESULTS: Values for serum myosin heavy-chain fragments were greater than the upper limit of normal in all patients. The peak value (70 times the upper normal limit, on average) was usually achieved 4 to 7 days after the diagnosis of rhabdomyolysis, and it was increased up to 12 days. The peak level of TnT was increased in 95% of the patients, and it correlated strongly with the peak activity of serum creatine kinase. The highest TnI value was above the detection limit of myocardial infarction in 30% of the patients. Half of these patients were the only patients with ischemic changes observed on an electrocardiogram performed on admission to the hospital. CONCLUSIONS: The measurement of myosin heavy-chain fragments was useful in the diagnosis of previous rhabdomyolysis up to 12 days. The role of TnT was negligible as an indicator of cardiac muscle damage in patients with severe rhabdomyolysis. Cardiac TnI is a more tissue-specific marker for myocardial damage even with concurrent rhabdomyolysis.

Role of plasma vasopressin in changes of water balance accompanying acute alcohol intoxication.

Acute alcohol intoxication causes diuresis presumably resulting from inhibition of vasopressin (also called antidiuretic hormone) release from the posterior pituitary gland. In contrast, in alcoholics during withdrawal from alcohol, vasopressin release is stimulated, resulting in water retention (antidiuresis) and dilutional hyponatremia. The purpose of this study was to evaluate the role of this biphasic response of vasopressin secretion to alcohol in normal persons. We studied eight healthy men who took part in two study sessions: one involving the ingestion of ethanol (1.2 g/kg of body weight) and the other the ingestion of the same volume of fruit juice during 3 hr from 6 to 9 PM. Starting at 6 AM the following morning, subjects were loaded with water (20 ml/kg of body weight within 15 min). During the first 3 hr of the study, ethanol intake increased diuresis, whereas from midnight to 6 AM, a phase of antidiuresis was obtained. Antidiuresis continued during water loading when the retention of water was 44 +/- 6% during the alcohol experiment and 12 +/- 4% during the control session (p < 0.05). During the alcohol-induced diuresis, the plasma arginine vasopressin levels did not differ from the control experiment, but were higher during the phase of antidiuresis from 10 PM to 6 AM (p < 0.05- < 0.01). Also, after water loading at 8 and 9 AM, they were higher in the alcohol study than in the control experiment (p < 0.05). After alcohol ingestion, serum osmolality was higher than the corresponding control values from 8 PM to 2 AM (p < 0.01- < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)