V. Carnevale

Clinical usefulness of serum tartrate-resistant acid phosphatase activity determination to evaluate bone turnover

The study was carried out to evaluate the clinical validity and usefulness of serum tartrate-resistant acid phosphatase (TRAP) activity determined using an improved spectrophotometric assay. Enzyme activity was measured in 84 normal subjects and in 109 patients with common metabolic bone diseases. Mean values of serum TRAP activity in male subjects (n = 19; 10.4 +/- 2.15 U l-1) were not significantly different from those found in female subjects (n = 65; 10.8 +/- 1.8 U l-1). In the latter group mean values were significantly raised in post-menopausal subjects (10.5 +/- 2.0 U l-1; p less than 0.01) compared with mean values in pre-menopausal women (8.45 +/- 1.8 U l-1). We found a significant inverse correlation between serum TRAP activity values and bone mineral density (BMD) measured both at an ultradistal radial point (n = 33, r = -0.506; p less than 0.01), and at the lumbar spine (n = 57, r = -0.261; p less than 0.05). Mean serum TRAP activity values in patients with metabolic bone diseases were: primary hyperparathyroidism, n = 30: 14.2 +/- 4.89 U l-1, p less than 0.001 vs normal subjects; chronic maintenance haemodialysis, n = 19: 17.4 +/- 6.7, p less than 0.001; metastatic cancer, n = 13: 21.2 +/- 6.3, p less than 0.001; post-surgical hypoparathyroidism, n = 10: 9.9 +/- 1.8, NS; involutional osteoporosis, n = 20: 12.5 +/- 2.3 p less than 0.001; Pagets disease, n = 10: 16.8 +/- 3.5, p less than 0.001; osteomalacia, n = 7: 19.5 +/- 3.31, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of estrogen deficiency on IGF-I plasma levels: Relationship with bone mineral density in perimenopausal women

SummaryBone tissue is a source of growth factors; among them, insulin-like growth factor I (IGF-I) is probably an important local regulator of bone formation. This study has been carried out in order to assess the effects of natural menopause on plasma concentrations of IGF-I in the first 6 years after the cessation of gonadal function independent of age. We also examined the relationship between plasma IGF-1 levels and bone mineral density (BMD) measured at the lumbar spine (LS), at the ultradistal radius (UDR), and at the junction of the distal and middle thirds of the radius (MR). Sixty-seven healthy nonobese women, aged 45–55, were studied (premenopausal n = 21; postmenopausal n = 46, from 1 to 6 years since menopause). Plasma IGF-I levels were measured by RIA, after acid-ethanol extraction. BMD of the forearm was measured by dual-photon densitometer and BMD of the LS was assessed by quantitative digital radiography. Mean values of IGF-I plasma levels were significantly reduced in postmenopausal women compared to the premenopausal group. Menopausal duration did not influence IGF-I plasma levels in postmenopausal women. We also found a positive correlation between IGF-I levels and BMD measured at MR both in pre- and postmenopausal women, while a correlation with LS and UDR-BMD was found only in fertile subjects. The results show that IGF-I plasma levels decrease immediately after menopause, since significantly lower levels are reached in the first years. The correlations found between plasma IGF-I levels and BMD suggest a possible role of reduced IGF-I in bone loss at particular skeletal sites.

Serum ionized calcium, parathyroid hormone and related variables: effect of age and sex.

This study was carried out in order to determine interrelationships of age and sex on parameters within the parathyroid endocrine system in healthy men and women. One hundred and fifteen normal subjects (70 females and 45 males) subdivided into three groups aged 25-35, 45-55 and 65-75 years were studied. Female subjects aged between 45 and 55 were further subdivided into two age-matched groups in relation to gonadal functional status. Serum intact parathyroid hormone (PTH) concentrations were measured using a two-site immunoradiometric assay. We found that there was a significant decrease of serum ionized calcium with ageing only in men (r = -0.666, P < 0.001) and a significant increase of serum PTH with age in both men (r = 0.488, P < 0.001) and women (r = 0.279, P < 0.019). A significant inverse correlation was found between serum ionized calcium and PTH in male subjects (r = -0.661, P < 0.001) and in fertile females (r = -0.353, P < 0.037) but not in postmenopausal women or in the entire female population. Furthermore, we found a significant decline of serum phosphate (r = -0.484, P < 0.001) and TmP/GFR (r = -0.492, P < 0.001) with advancing age in men, but not in women. We believe that the decrease of serum ionized calcium, as a likely consequence of the physiological reduction of intestinal calcium absorption, is the pivotal factor responsible for the increased PTH levels we observed with advancing age. The phenomenon is clear in men and in premenopausal women, but is masked in the female sex at menopause by the effects of a shortage of oestrogen on the calcium-phosphorus metabolism. These may also be responsible for the differences observed between the two sexes as far as phosphate metabolism is concerned. In conclusion, this study has, for the first time, taken relationships between serum ionized calcium and PTH, over a wide age range, into consideration. The results obtained show a marked difference of serum ionized calcium values between sexes with ageing, while serum parathyroid hormone levels increase in both men and women. Important differences also exist, as far as phosphate metabolism is concerned, between males and females.

Trabecular bone mineral density in primary hyperparathyroidism : relationship to clinical presentation and biomarkers of skeletal turnover

This study was carried out in order to investigate the entity of trabecular bone involvement in 62 patients with primary hyperparathyroidism (PHPT). Bone mineral density (BMD) was measured in all patients at the ultradistal radius (UDR) of the non-dominant arm by a dual photon densitometer and also at the lumbar spine (L) in 40 of the patients by means of quantitative dual energy radiography. Mean Z score values of UDR-BMD (-2.4 +/- 0.4) and L-BMD (-3.5 +/- 0.2) in patients with the skeletal variety of the disease (n = 6) were significantly reduced in respect to values of both asymptomatic (n = 31) and kidney stone patients (n = 25). As far as the comparison between the two sites of trabecular bone mass measurement in each hyperparathyroid subgroup of patients was concerned, a significant difference (P < 0.05) was found in patients with skeletal manifestations of the disease. Either serum total alkaline phosphatase activity, or osteocalcin and the 24-h hydroxyproline/creatinine ratio were significantly inversely related to the entity of bone mass evaluated at these two sites. Z score changes following surgery in 14 patients showed a positive trend in 13 of them at L compared to 7 out of 14 at UDR (P < 0.036 by chi square analysis). There was a very good inverse correlation between basal Z score values and the changes following surgery at the L (r = -0.851; P < 0.001) but not at the UDR. Our results demonstrate firstly that, in PHPT skeletal sites with almost similar composition of trabecular bone are differently involved in patients with more severe skeletal damage and that different skeletal sites may be divergently affected by the cessation of parathyroid gland hyperfunction.

Effects of ipriflavone on bone remodeling in primary hyperparathyroidism

The aim of this study was to evaluate the effects of ipriflavone treatment on bone remodeling in primary hyperparathyroidism. Nine patients, 6 females and 3 males (mean +/- SD age 56 +/- 12.5 years) were treated with 1200 mg/day of ipriflavone by oral administration divided in 3 daily doses. All patients were treated for 21 days; in 5 patients treatment was prolonged to 42 days. In all patients the main serum and urinary parameters of bone remodeling were evaluated. The results suggest that ipriflavone affects bone remodeling by inhibiting bone resorption without affecting bone formation. Ipriflavone is, therefore, indicated in the treatment of metabolic bone diseases characterized by a high bone turnover.

Temporal relationship between bone loss and increased bone turnover: A longitudinal study following natural menopause

We report the results of a longitudinal study aimed at better defining concomitant changes of both bone mineral density (BMD) and of four independent markers of bone turnover (serum osteocalcin, serum alkaline phosphatase activity, fasting urinary hydroxyproline/creatinine and calcium/creatinine ratio) following natural menopause. The results obtained indicate that, within a relatively short period of time since cessation of gonadal function, conventional markers of bone turnover behave differently. In fact, while the mean values of hydroxyproline/creatinine ratio ( felt to be a marker of bone résorption) rise immediately at the first control (19.7±11.7 months), the bone formation markers gradually increase and, as far as serum osteocalcin levels are concerned, this increment appears to be long-lasting. As a result of these changes, a negative skeletal balance follows, which is documented by the prolonged reduction of bone mineral density during the entire observation period. Mean±SD % measured yearly bone loss was −2.83±2.6. There was a highly significant correlation between initial and final BMD values (r= 0.908, p<0.001; r2= 82.5) and a weak inverse correlation (r= −0.298, p<0.046) between initial serum alkaline phosphatase values and % yearly bone loss. In conclusion, measurement of the biological indices of bone remodelling following natural menopause indicate that the increase in osteogenesis is delayed compared to that of bone résorption; furthermore, in the immediate postmenopausal period, the actual bone massshould be considered the best predictor of future bone mass. The inverse correlation found between % yearly bone loss and serum alkaline phosphatase values seems to emphasize the importance of increased bone turnover as an independent predictor of bone loss.

Circulating levels of insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor I (IGF-I) in perimenopausal women

The study investigated possible menopause-related changes in circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and their relationship with insulin-like growth factor I (IGF-I) plasma levels. Forty-three healthy women, aged 45–55 years, were studied (22 premenopausal and 21 postmeno-pausal, matched for age and body mass index); in all subjects plasma IGF-I and IGFBP-3 levels were measured by radioimmunoassay. No difference was found between mean IGFBP-3 plasma levels in the two groups studied (premenopausal 3.42±0.49 v postmenopausal 3.46±0.58 mg/l), while mean IGF-I levels were significantly lower in postmenopausal as compared with premenopausal women (136.7±37.86 v 175.7±51.91 ng/ml,p<0.02). Multiple regression analysis showed no significant effect of age, body mass index and years since menopause on IGFBP-3 levels; however, considering the IGF-I/IGFBP-3 ratio as a possible parameter of circulating free somatomedin C, an inverse correlation was found with years since menopause (n=43,r=−0.499,p<0.001). We conclude that lack of oestrogen induces different effects on circulating IGF-I and IGFBP-3, possibly reflecting a real decrease in IGF-I activity.

The effects of oophorectomy on skeletal metabolism.

The effects of oophorectomy on the biological indices of bone remodelling and the time-course of their changes are described. In the first few months following surgical menopause the measurement of the markers of bone remodelling indicates that the increase in osteogenesis is delayed compared with that of bone resorption; this prevalence of destruction over new bone deposition justifies the deficiency of skeletal balance, shortly after acute oestrogen deficiency. The changes in bone remodelling are accompanied by an increase in serum calcium while serum immunoreactive parathyroid hormone levels remain unchanged or even decrease, suggesting a shift to right of the parathyroid gland set-point. The reasons for the negative skeletal balance after oophorectomy might be sought therefore at bone tissue level, even if changes in responsiveness and/or of the parathyroid gland set-point could also be contributory.

Two-site assay of intact parathyroid hormone in primary hyperparathyroidism: studies in basal conditions, following adenoma removal and during calcium and EDTA infusion

This study has been carried out in order to investigate parathyroid hormone secretion in patients with primary hyperparathyroidism in basal conditions, during stimulation and suppression tests and following successful surgery. Parathyroid gland secretory activity has been evaluated by a highly sensitive immunoradiometric assay (IRMA) which detects only the biologically intact active hormone and with a well established midmolecule (MM) PTH RIA. There was a good correlation between the two assays in basal state (r = 0.779); however the correlation found between serum PTH levels and total calcium values was better for the intact hormone (P less than 0.001) than for the radioimmunoassay (P less than 0.05). Twenty-four hours following surgery, serum intact PTH levels were in all patients less than 10 pg/ml while midmolecule PTH was still detectable, thereafter remaining at a higher level during the next six days. Serum IRMA PTH levels fell rapidly in response to the increase in serum calcium, then there was a trend to reach a plateau; serum midregion PTH levels fell, although slower than those of intact hormone. The percent increase obtained for serum intact hormone levels was higher than that observed for MM RIA, following EDTA stimulation. The results obtained indicate that the assays of intact and midmolecule parathyroid hormone clearly reflect different aspects of hormone metabolism in vivo and may prove therefore to be useful for its investigation in various calcium disorders.

Clinical value of the measurement of bone remodelling markers in primary hyperparathyroidism

This study was performed in order to evaluate the clinical usefulness of the measurement of total serum alkaline phosphatase activity (AP), serum osteocalcin (BGP) and urinary hydroxyproline (OHPr) in assessing bone remodelling in primary hyperparathyroidism. Thirty-two patients with primary hyperparathyroidism were included in the study. No statistically significant differences were observed between the mean values of Z-scores obtained for each marker. Furthermore, an inverse correlation was found between percentage of bone mineral content at the distal radius and both BGP (r = −0.57; p < 0.05) and AP (r = −0.49; p < 0.05). The results obtained demonstrate that, contrary to other metabolic bone diseases (e.g. Paget’s disease of bone), all three markers examined may be used in clinical practice to evaluate the entity of skeletal turnover in primary hyperparathyroidism.