Biochemical markers of bone turnover as predictors of osteoporosis and osteoporotic fractures in men and women: 10-year follow-up of the Taiji cohort

We aimed to assess the capacity of biochemical markers of bone turnover (BTMs) to predict bone loss, osteoporosis (OP), and osteoporotic fractures. We randomly selected 400 individuals (age 40–79 years in 1993; 50 of each gender and age stratum) from a list of registered residents. In the years 1993, 1996, 2000, and 2003, bone mineral density (BMD) of the spine and hip were measured by dual-energy X-ray absorptiometry. The BTMs assessed at baseline were serum intact osteocalcin (OC), total OC, bone-specific alkaline phosphatase, C-terminal propeptide of type I procollagen, N-terminal propeptide of type I procollagen (PINP), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinase, C-terminal cross-linking telopeptide of type I collagen (beta-CTX), N-terminal cross-linking telopeptide of type I collagen (NTX), urinary pyridinoline, and deoxypyridinoline (DPD). For 307 completers, multivariate analysis after adjusting for confounders revealed that serum PINP levels in men [hazard ratio (HR) 2.80, P < 0.05] and serum PINP (HR 1.65, P < 0.05), beta-CTX (HR 1.80, P < 0.001), NTX (HR 1.96, P < 0.01), and urinary DPD levels (HR 1.40, P < 0.05) in women were significantly related to the occurrence of spinal OP. In addition to adjustment for the baseline status of BMD, i.e., osteopenia or normal range, PINP, beta-CTX, and NTX in women could significantly predict the future occurrence of spinal OP. BTMs were not significant predictors of bone loss, femoral OP, or osteoporotic fractures. In conclusion, various BTMs in women can predict the occurrence of spinal OP.     

Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity

Objective. To evaluate the relationship between biochemical markers of bone turnover and bone scan indices of disease activity, as well as to analyze their variations based on skeletal involvement, in Paget's disease. Methods. Serum samples were obtained from 51 patients with Paget's disease to determine the levels of total alkaline phosphatase (total AP), bone alkaline phosphatase (bone AP), propeptide carboxyterminal of type I procollagen (PICP), propeptide aminoterminal of type I procollagen (PINP), osteocalcin, tartrate-resistant acid phosphatase, and telopeptide carboxyterminal of type I collagen. Urine samples were analyzed for levels of hydroxyproline (HYP), pyridinoline (PYR), deoxypyridinoline (DPYR), C-terminal telopeptide of type I collagen (CTx), and N-terminal telopeptide of type I collagen (NTx). In addition, 2 semiquantitative scintigraphic indices, disease activity (AI) and disease extent (EI), were obtained. Pagetic skeletal locations were evaluated individually, with special attention to skull involvement. Results. All biochemical markers correlated with the AI and the EI. Serum PINP, bone AP, and total AP showed the highest proportions of increased values among the bone formation markers (94%, 82%, and 76%, respectively). Among the bone resorption markers, urinary NTx showed the highest proportion of increased values in patients with Paget's disease (96%), compared with PYR (69%), DPYR (71%), CTx (65%), and HYP (64%). In patients with mild disease activity, serum PINP was the marker with the highest proportion of increased values (71%). In contrast, serum PICP and urinary CTx were the most discriminative markers for skull involvement. Except for higher values for most of the biochemical markers of bone turnover in flat bones, no major differences in other skeletal locations were observed. Conclusion. The determination of serum PINP as a marker of bone formation and urinary NTx as a marker of bone resorption provided the best biochemical profile to ascertain the extent and activity of Paget's disease. In patients with skull involvement, serum PICP and urinary CTx were shown to be the most discriminative markers.     

Very low birth weight survivors have reduced peak bone mass and reduced insulin sensitivity

Context Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long‐term effects through reprogramming of metabolic systems. Objective To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. Design Cross‐sectional, observational, case‐control study. Participants Thirty‐seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). Measurements Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual‐energy X‐ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N‐terminal telopeptide of type I collagen (NTX), serum C‐terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF‐1, PTH and 25‐OH vitamin D) and insulin sensitivity (HOMA‐IR and oral glucose tolerance testing). Results VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS‐30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls. Conclusions Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.     

Connective tissue components in serum in multiple myeloma: Analyses of propeptides of type I and type III procollagens,type I collagen telopeptide,and hyaluronan

The present study was performed to evaluate whether information concerning synthesis and degradation of type I collagen in multiple myeloma (MM) as obtained by serum analyses of C-terminal propeptide of type I procollagen (PICP) and the C-terminal telopeptide of type I collagen (ICTP) may be useful in evaluating the development of osteolytic bone destruction. Serum N-terminal propeptide of type III procollagen (PIIINP) may give information about marrow fibrosis in MM. No data are available about MM and serum hyaluronan, another important component of bone marrow stroma. We examined 15 consecutive patients before treatment and 15 sex- and age-matched controls. We found highly significant elevations in serum ICTP (median 6.2 vs. 2.4 μg/L; P < 0.01), PIIINP (median 5.2 vs. 2.9 μ/L; P < 0.01) and hyaluronan (median 122 vs. 45 μ/L; P < 0.01). ICTP in serum correlated closely to bone morbidity (r = 0.69; P < 0.01). Furthermore, serum ICTP correlated highly significantly to serum PIIINP (P < 0.01) and serum β₂-microglobulin (P < 0.01), whereas there was no correlation between hyaluronan and any of the collagen-derived peptides or β₂-microglobulin. The MM group was followed for 9–25 months and analysis of survival data suggested that serum ICTP may be of predictive value (P < 0.05). We conclude that important changes in connective tissue metabolism occur in MM. ICTP in serum seems to be a noninvasive marker of bone morbidity and may be of prognostic value. Furthermore, elevation of hyaluronan in serum is common in MM, the significance of which is unknown. © 1994 Wiley-Liss, Inc.     

Effects of teriparatide versus alendronate for treating glucocorticoid‐induced osteoporosis: Thirty‐six–month results of a randomized,double‐blind,controlled trial

Objective

To compare the bone anabolic drug teriparatide (20 μg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid‐induced osteoporosis (OP).

Methods

This was a 36‐month, randomized, double‐blind, controlled trial in 428 subjects with OP (ages 22–89 years) who had received ≥5 mg/day of prednisone equivalent for ≥3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety.

Results

Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N‐terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C‐terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001).

Conclusion

Our findings indicate that subjects with glucocorticoid‐induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

     

Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy

OBJECTIVE:To compare the effects of tiludronate and risedronate on Paget's disease activity assessed by biochemical markers of bone turnover and quantitative bone scintigraphy. METHODS: An open-labeled non-randomized study was performed in 49 patients with Paget's disease who had completed treatment with tiludronate (400 mg/d) for 3 months (28 patients) or risedronate (30 mg/d) for 2 months (21 patients). Biochemical markers of bone turnover, including serum total alkaline phosphatase (TAP), bone alkaline phosphatase (BAP), procollagen type I N propeptide (PINP) and urinary N-terminal cross-linking telopeptide of type I collagen (NTX) were measured at baseline and at 6 and 12 months after the end of treatment. Quantitative bone scintigraphy at baseline and 6 months after the end of treatment was performed in all patients obtaining a scintigraphic activity index (SAI). RESULTS: At baseline there were no significant differences in disease activity between both groups of patients, since markers of bone turnover as well as SAI were similar in both groups. The effects of tiludronate and risedronate in reducing the biochemical markers of bone turnover were comparable at 6 months (tiludronate vs risedronate: TAP -52% vs -43%; BAP -69% vs -56%; PINP -68% vs -63%; NTX -62% vs -59%) and at 12 months after the end of treatment (tiludronate vs risedronate: TAP -47% vs -36%; BAP -57% vs -46%; PINP -57% vs -52%; NTX -51% vs -52%). The effects of tiludronate and risedronate on SAI were also similar 6 months after the discontinuation of treatment. In addition, the percentage of patients who showed normalized serum TAP levels at 6 months after treatment were similar with both agents (74% with tiludronate and 70% with risedronate). CONCLUSION: Tiludronate and risedronate given at the currently recommended dosages induce similar responses in Paget's disease activity.     

Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide,osteocalcin, bone-specific alkaline phosphatase and propeptides of type I and type III procollagens

Abstract: The main difference between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is the presence of lytic bone destructions in the latter. About 20% of MGUS patients develop MM, and histomorphometric studies have shown disturbed bone turnover rates in some of these patients. This study was performed in order to evaluate whether serum analyses of the C-terminal telopeptide of type I collagen (ICTP), as a reflector of bone degradation, and of osteocalcin, bone-specific alkaline phosphatase (bAP) and the C-terminal propeptide of type I procollagen (PICP), as markers of bone formation, might give information on disturbancies of bone metabolism in MGUS. Furthermore, serum N-terminal propeptide of procollagen III (PIIINP) might give information on disturbances in collagen III metabolism in the bone marrow. In the 35 patients examined, serum ICTP was elevated in 12 patients (34%), serum PIIINP elevated in 6 patients (17%), serum osteocalcin elevated in 11 patients (31%), serum bAP elevated in 6 patients (17%), and serum PICP elevated in 4 patients (11%). Serum ICTP correlated significantly with PIIINP (r=0.72, p<0.001), and with serum osteocalcin (r=0.57, p<0.001) and serum bAP (r=0.51, p=0.002). These findings indicate disturbancies of bone turnover and affected collagen metabolism in some MGUS patients. Follow-up observation may reveal any prognostic value of these findings.     

Bone mineral density and bone remodelling in Tunisian patients with ankylosing spondylitis: A cross-sectional study

Aim of the workTo assess the bone turnover markers and bone mineral density (BMD) in ankylosing spondylitis (AS) patients and to evaluate their association with clinical variables.Patients and methodsForty-seven AS patients were compared with 47 matched control. Clinical features and inflammatory parameters were assessed. C-terminal telopeptide fragments of type I collagen (CTX), alkaline phosphatases (ALP), N-terminal propeptide of type I procollagen (PINP) serum levels, and BMD of the lumbar spine and femoral neck were evaluated. The Bath AS disease activity and functional indices (BASDAI and BASFI) were assessed.ResultsMean serum levels of C-reactive protein, ALP and CTX were higher in AS patients than control (p = 0.001, p = 0.001 and p = 0.027 respectively). Osteopenia and osteoporosis were significantly more frequent in AS patients (57.4%) than control (21.3%) (p < 0.001). The PINP and ALP significantly correlated with disease duration (r = 0.33, p = 0.02 and r = 0.3, p = 0.04 respectively). BMD of the femoral neck was significantly lower in AS patients with history of coxitis than AS patients without (p = 0.02). Patients on anti-tumour necrosis factor (TNFα) therapy had higher T score (lumbar spine) compared to those not. Multivariate regression showed that CRP levels and disease activity were independently associated with low BMD and T score (lumbar) was significantly associated with anti-TNF use (p = 0.007).ConclusionsAn increase in bone turnover markers and decrease of BMD were observed in AS patients. Inflammatory activity of AS was associated to hyper bone remodelling and decrease of BMD. Anti-TNF use seems to be beneficial on AS inflammation and therefore on the BMD.     

Acute effects of a single session of aerobic exercise with or without weight-lifting on bone turnover in healthy young women

This study aimed to investigate the acute effects of exercise on bone turnover and to determine whether brisk walking with or without weight-lifting makes a difference on bone metabolism. Nine healthy women performed two exercise bouts: brisk walking on a treadmill for 30 min (E), and similar exercise carrying 5 kg of weight in a backpack (WE). Serum parathyroid hormone (PTH), osteocalcin (OC), calcitonin (CT), procollagen type 1 carboxy terminal propeptide (PICP), procollagen type 1 amino terminal propeptide (PINP), type 1 collagen carboxy terminal telopeptide (ICTP), total alkaline phosphatase (ALP), and urine deoxypyridinoline (D-Pyr) levels were studied. Resting values served as control. Significant variances were observed only in serum ALP and PTH values. Variances in ALP values within subjects after exercise were statistically significant (analysis of variance in repeated measurements [AVRM], P = 0.000). E caused a significant decrease, while WE caused a significant increase in ALP values at the 24th h (Bonferroni pairwise comparisons tests [BPC t-test]: P = 0.028, P = 0.000, respectively). Variances in PTH values within subjects after exercise were statistically significant (AVRM, P = 0.029), while diurnal variation was not significant (P = 0.981). E caused significant alterations in PTH levels (an increase at the 30th min, turned towards baseline at the 45th min) (BPC t-test, P = 0.007). WE also caused alterations in PTH levels, though insignificant (BPC t-test, P = 1.00). Brisk walking for 30 min has stimulating effects on bone turnover by various mechanisms without any additive effect of weight bearing.     

Interferon‐αα treatment decreases serum cross‐linked C‐terminal telopeptide of type I collagen in haematological diseases

Interferon‐α (IFN‐α) is used in the treatment of many haematological diseases and it is known that IFN‐α may affect bone turnover. The effect of IFN‐α on bone metabolism was studied in 10 haematological patients. The mean duration of the treatment was 4 (range: 2.8–7.2) months. Besides the usual markers of bone metabolism, levels of the cross‐linked C‐terminal telopeptide of type I collagen (ICTP), the N‐terminal propeptide of type I procollagen (PINP) and the bone‐specific alkaline phosphatase were measured. The bone mineral density was measured by computed tomography. During IFN‐α treatment, serum ICTP decreased from a mean of 5.4 (range: 1.8–12.4) to 3.6 (range: 1.4–8.8) μg/l (P= 0.017). All other variables reflecting bone metabolism remained unaltered during IFN‐α treatment. The bone mineral density remained unchanged. It was concluded that the observed decrease in ICTP may be an indicator of a beneficial therapeutic effect of IFN‐α on bone turnover, resulting in decreased bone resorption. However, it is possible that elevated pretreatment ICTP values reflected disease of the bone marrow.     

Acute effects of a single session of aerobic exercise with or without weight-lifting on bone turnover in healthy young women

Abstract

This study aimed to investigate the acute effects of exercise on bone turnover and to determine whether brisk walking with or without weight-lifting makes a difference on bone metabolism. Nine healthy women performed two exercise bouts: brisk walking on a treadmill for 30?min (E), and similar exercise carrying 5?kg of weight in a backpack (WE). Serum parathyroid hormone (PTH), osteocalcin (OC), calcitonin (CT), procollagen type 1 carboxy terminal propeptide (PICP), procollagen type 1 amino terminal propeptide (PINP), type 1 collagen carboxy terminal telopeptide (ICTP), total alkaline phosphatase (ALP), and urine deoxypyridinoline (D-Pyr) levels were studied. Resting values served as control. Significant variances were observed only in serum ALP and PTH values. Variances in ALP values within subjects after exercise were statistically significant (analysis of variance in repeated measurements [AVRM], P = 0.000). E caused a significant decrease, while WE caused a significant increase in ALP values at the 24th h (Bonferroni pairwise comparisons tests [BPC t-test]: P = 0.028, P = 0.000, respectively). Variances in PTH values within subjects after exercise were statistically significant (AVRM, P = 0.029), while diurnal variation was not significant (P = 0.981). E caused significant alterations in PTH levels (an increase at the 30th min, turned towards baseline at the 45th min) (BPC t-test, P = 0.007). WE also caused alterations in PTH levels, though insignificant (BPC t-test, P = 1.00). Brisk walking for 30?min has stimulating effects on bone turnover by various mechanisms without any additive effect of weight bearing.     

Growth hormone response to GHRH, GHRP-6 and GHRH+GHRP-6 in patients with polycystic ovary syndrome

OBJECTIVE A number of long-term research studies are in progress to evaluate the effects of treatment with GH on growth and final height in children with short stature but no demonstrable abnormality of GH secretion. Such treatment is invasive, expensive and carries some risk to the child. An early indication of growth response would allow restriction of treatment to those children most likely to benefit, but anthropometric measurements are relatively subjective, insensitive and imprecise. The aim of this study was to evaluate bone alkaline phosphatase, procollagen Type I C-terminal propeptide, procollagen Type III N-terminal propeptide and the cross-linked carboxyterminal telopeptide of Type I collagen as early biochemical predictors of height velocity response to growth-promoting treatments in short normal children. DESIGN A prospective intervention study, partially placebo controlled on a double blind basis. PATIENTS Fifty healthy children with familial short stature or constitutional delay in growth and puberty (8 girls, 42 boys, ages 5.5–16.5 years and all either prepubertal (45) or in very early puberty (5 boys) at the start of treatment) were treated with placebo (6), GH alone (32), GH plus oxandrolone (8) or GH plus testosterone (4). MEASUREMENTS Bone alkaline phosphatase and the collagen markers were measured at the start of treatment and 3 months later. Height velocity was calculated at the start of treatment and again after one year. RESULTS Pre-treatment biochemical marker concentrations did not predict height velocity response after one year. Increments in all markers after 3 months were significantly correlated with height velocity increments after one year of treatment, the highest correlations being observed for bone alkaline phosphatase (r = 0.67, P < 0.0001) and procollagen Type III N-terminal propeptide (r = 0.57, P < 0.0001). Highly significant correlations (P < 0.0001) were also observed between bone alkaline phosphatase and procollagen Type I C-terminal propeptide (r = 0.55) and between procollagen Type III N-terminal propeptide and the cross-linked carboxyterminal telopeptide of Type I collagen (r = 0.62). Multiple linear regression with stepwise selection of variables identified bone alkaline phosphatase and procollagen Type III N-terminal propeptide as the only two independent variables that contributed significantly to the prediction of height velocity response after one year (analysis of variance, P < 0.0001). Together they predicted 59% of the variability in height velocity response after a year. CONCLUSIONS The best early predic tors of height velocity response were bone alkaline phosphatase (a protein found in hypertrophic chondrocytes in the epiphyseal growth plate, in calcifying matrix vesicles and in mature osteoblasts) and procollagen Type III N-terminal propeptide, a marker of interstitial fibril biosynthesis in soft tissues. Using these markers, GH treatment could be targeted to those children most likely to benefit in the medium term.     

Type 2 diabetes mellitus is associated with increased axial bone density in men and women from the Hertfordshire Cohort Study: evidence for an indirect effect of insulin resistance?

Aims/hypothesis Previous studies have suggested that the high bone density often observed in type 2 diabetic patients may be explained by insulin resistance. We explored this hypothesis in the Hertfordshire Cohort Study.Methods A total of 465 men and 444 women aged 59 to 71 years and with no prior diagnosis of diabetes attended a clinic where a glucose tolerance test was performed and bone density measured at the femoral neck and lumbar spine. Biochemical markers of bone turnover (serum osteocalcin and urinary mean c-terminal cross-linking telopeptide of type II collagen) were measured in 163 men.Results According to WHO criteria, 83 men and 134 women were diagnosed with impaired glucose tolerance and a further 33 men and 32 women were diagnosed as having type 2 diabetes. Bone density was higher in newly diagnosed diabetic subjects, with relationships stronger in women (p<0.001) than men (p<0.05) and attenuated by adjustment for body mass index. In both sexes, we observed positive correlations between the total femur and femoral neck bone mineral density with measures of insulin resistance (r=0.17–0.22), with stronger results observed in women. These relationships did not apply after adjustment for body mass index. Glucose status did not lead to differences in osteocalcin level or c-terminal cross-linking telopeptide of type II collagen levels.Conclusions/interpretation Our findings suggest that hyperinsulinaemia may affect bone mineral density through indirect effects, e.g. body weight.     

Clinical application of bone turnover markers in treating osteoporotic vertebral compression fractures and their role in predicting fracture progression

This study aimed to investigate whether changes in the bone turnover markers (BTMs) during teriparatide therapy for osteoporotic vertebral compression fractures could reflect therapeutic effects by analyzing the relationship between clinical and radiological features and BTMs.A total of 33 patients with 51 osteoporotic vertebral compression fracture segments were included. Plain radiographs and BTM levels were evaluated at the pretreatment and at 3 months after teriparatide treatment. Based on serial vertebral compression ratio analysis, the progression of fracture was defined as a vertebral compression ratio decrease of ≥10%, relative to the pretreatment values.All segments were divided into 2 groups: the “maintain” group with 32 (62.7%) segments and the “progression” group with 19 (37.3%) segments. After the teriparatide treatment, serum osteocalcin and serum C-terminal telopeptide of type I collagen levels (P = .028 and .008, respectively), and change amounts of them were significantly larger, increasing (P = .001) in the progression group. The vitamin D (25OH-D) levels were significantly lower (P = .038) in the progression group; however, the relative changes in the 25OH-D levels between the 2 groups, before and after the treatment, were not significantly different (P = .077). The parathyroid hormone (PTH) levels were reduced by the teriparatide treatment in both groups, while the decrease in PTH concentration after the treatment was significantly more pronounced in the progression group (P = .006). Significant increase in the osteocalcin and serum C-terminal telopeptide of type I collagen levels and a simultaneous decrease in the PTH levels during the teriparatide treatment suggest that clinicians should assume the progression of fracture.     

Biochemical markers of types I and III collagen and limited joint mobility in type 1 diabetic patients

Abstract. Limited joint mobility (LJM), a long-term complication of diabetes, has been shown to be associated with microvascular complications of diabetes. Connective tissue alterations may contribute to the development of LJM and other diabetic complications. We tested whether biochemical markers of types I and III collagen metabolism are associated with LJM in type 1 diabetes. We studied 28 male patients of mean age 43.4 years (SD=9.5) and with a duration of diabetes of 25.2 years (SD=9.7) years. LJM assessment included goniometric measurements of the joints and classification by Rosenblooms method. We measured serum concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal crosslinked telopeptide of type I collagen (ICTP); urinary excretion of crosslinked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) was also measured. Although average serum PIIINP tended to be higher in subjects with moderatesevere LJM (3.1±1.3 µg/l) than in subjects with mild LJM (2.5±0.7 µg/l) or without LJM (2.6±0.4 µg/l), no significant association was found (p<0.27). Concentrations of the other collagen markers were not different in subjects with or without LJM. We conclude that synthesis and degradation of types I and III collagen in diabetic subjects with LJM did not differ from those without LJM to reflect changes in the biochemical markers of these proteins.     

Increased bone resorption is implicated in the pathogenesis of bone loss in hemophiliacs: correlations with hemophilic arthropathy and HIV infection

Osteoporosis has been recently recognized as a severe comorbidity factor in hemophilia. However, its pathogenesis is still obscure. We evaluated the incidence of osteoporosis in 90 hemophilia patients and investigated possible correlations with clinical and laboratory data. Out of the 90 patients, 80 (89%) had severe hemophilia, and 35 (38.9%) were human immunodeficiency virus (HIV)-positive. Hemophilic arthropahty was assessed using World Federation of Hemophilia clinical score and Petterson radiological score. Bone mineral density of the lumbar spine (LS) and femoral neck (FN) were measured using dual-energy X-ray absortiometry. Bone turnover was evaluated by the measurement of: (1) bone resorption markers [N-terminal cross-linking telopeptide of collagen type I (NTX), C-terminal cross-linking telopeptide of collagen type I (CTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], (2) bone formation markers [bone-alkaline phosphatase (bALP) and osteocalcin], and (3) osteoclast stimulators (receptor activator of nuclear factor-κB ligand, osteoprotegerin, and tumor necrosis factor-alpha). Osteopenia or osteoporosis was observed in 86% and 65% of the patients in FN and LS, respectively. Osteoporosis was more common among HIV-positive patients in both FN (65.3% vs 41.6%; p = 0.007) and LS (17.86% vs 5.41%, p = 0.004). The severity of osteoporosis in FN correlated with the patients' total clinical and radiological score (p = 0.001). Hemophilia patients showed increased osteoclastic activity (significant increase of TRACP-5b, NTX, and CTX), which was not accompanied by a comparable increased bone formation (reduced osteocalcin and borderline increase of bALP). In multivariate analysis, HIV infection (p = 0.05) and total clinical score (p = 0.001) were independent risk factors for osteoporosis development. We conclude that there is a high prevalence of osteoporosis among hemophiliacs, which is related to the severity of arthropathy and is enhanced by HIV infection. We report for the first time a high bone resorption that seems not to be balanced by a comparable bone formation.     

Abstracts

Patients with glycogen storage disease (GSD) types I, III and IX show reduced bone mineral content, but there is scarce data on new serum and urine markers of bone turnover or their relationship to bone densitometry. Six GSD I, four GSD III and four GSD IX patients underwent bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry. Free pyridinoline (fPYD):creatinine and free deoxypyridinoline (fDPD):creatinine ratios were analysed on random urines. Procollagen type I C-terminal propeptide, procollagen type I N-terminal propeptide (PINP), carboxyterminal telopeptide of type I collagen and bone-specific alkaline phosphatase were analysed in serum. Some GSD I and GSD III patients had low or very low BMD. There was no difference in total body BMD z-score between the GSD types after adjusting for height (p=0.110). Bone marker analysis showed no consistent pattern. Urine fPYD:creatinine ratio was raised in four GSD I and two GSD III patients, while serum PINP was inappropriately low in some of these patients. There was no clear correlation between any markers of bone destruction and total body z-score, but the patient with the lowest total body z-score showed the highest concentrations of both urinary fPYD:creatinine and fDPD:creatinine ratios. We conclude that some GSD I and GSD III patients have very low bone mineral density. There is no correlation between mineral density and bone markers in GSD patients. The inappropriately low concentration of PINP in association with the raised urinary fPYD:creatinine and fDPD:creatinine ratios seen in two GSD I patients reflect uncoupling of bone turnover. All these findings taken together suggest that some GSD I and GSD III patients may be at an increased risk of osteoporosis.     

Serum estradiol, testosterone, and sex hormone-binding globulin as regulators of peak bone mass and bone turnover rate in young Finnish men

To study the role of serum testosterone (T), estradiol (E(2)), and SHBG as regulators of peak bone mass and bone turnover rate in males, a cross-sectional study with data on lifestyle factors collected retrospectively was performed in 204 young Finnish men, 18.3-20.6 yr old. One hundred fifty-four men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content, density, and scan area were measured in lumbar spine and upper femur by dual-energy x-ray absorptiometry. Blood was sampled for determination of serum total and free T, total and free E(2), SHBG, type I procollagen aminoterminal propeptide (PINP), total osteocalcin (TOC) and carboxylated osteocalcin (COC), and tartrate-resistant acid phosphatase 5b (TRACP5b); and urine was collected for determination of type I collagen aminoterminal telopeptide (NTX). Serum sex steroid concentrations did not associate with bone mineral content, scan area, or bone mineral density, adjusted for anthropometric and lifestyle factors at any measurement site. Instead, serum total (r = 0.23; P = 0.008) and free (r = 0.15; P = 0.023) T were positive predictors of serum TOC, whereas serum free E(2) correlated inversely with serum PINP (r = -0.20; P = 0.0039), TOC (r = -0.12; P = 0.086), COC (r = -0.14; P = 0.036), and urinary NTX (r = -0.15; P = 0.041). Interestingly, serum SHBG correlated positively with all the bone markers studied, the correlation coefficients being 0.18 for serum PINP (P = 0.012), 0.24 for TOC (P = 0.0006), 0.24 for COC (P = 0.0005), 0.27 for serum TRACP5b (P < 0.0001), and 0.21 for urine NTX (P = 0.0031). Serum SHBG was also a positive predictor of serum 25-hydroxyvitamin-D level (r = 0.20; P = 0.0036). The correlations of SHBG persisted after adjusting for weight, free E(2), and free T. We conclude that single measurements of serum E(2) and T were not determinants of peak bone mass in this population of young men. However, E(2) and T contributed to bone turnover rate, with serum T increasing bone formation, and serum E(2) suppressing both bone formation and resorption. Moreover, serum SHBG appeared to be an independent positive predictor of bone turnover rate, which also positively associated with serum 25-hydroxyvitamin-D levels.     

Octreotide abolishes the acute decrease in bone turnover in response to oral glucose

Feeding or oral intake of glucose results in an acute suppression of bone turnover. This does not appear to be mediated by insulin. Several gastrointestinal hormones modulate bone turnover in vitro and may mediate this response. We examined whether inhibiting the production of gastrointestinal hormones using octreotide could block glucose-mediated suppression of bone turnover. Fifteen subjects were each studied on four occasions in a randomized, single-blind, crossover study after receiving 1) oral placebo, iv saline; 2) oral glucose, iv saline; 3) oral glucose, iv octreotide; or 4) iv octreotide alone. We measured serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen, osteocalcin, procollagen type I N-terminal propeptide, PTH, insulin, ionized calcium, and glucose over 4 h. All bone turnover markers decreased significantly after oral glucose (P < 0.001). At 120 min serum C-terminal telopeptide decreased by 45 +/- 2%, urinary N-terminal telopeptide by 31 +/- 7%, osteocalcin by 16 +/- 1%, and procollagen type I N-terminal propeptide by 8 +/- 1%. There was no significant decrease in bone turnover in response to oral glucose during octreotide infusion. Octreotide alone resulted in a significant increase in all bone turnover markers (P < 0.05) and PTH (P < 0.01). We conclude that octreotide completely abolishes the bone turnover response to glucose intake and increases PTH secretion. The apparent bone turnover response to feeding is probably mediated by an octreotide-inhibitable endocrine factor.     

Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies

Bone turnover is acutely suppressed after feeding or oral glucose. Insulin infusion suppresses bone turnover and might mediate this effect, but this is confounded by a possible direct effect of hypoglycemia. We examined the effect of euglycemic hyperinsulinemia and hypoglycemic hyperinsulinemia on bone turnover using an insulin clamp. Sixteen men participated in this double-blind crossover study. Clamp induction involved infusion of insulin (80 mU/m(2).min) while maintaining euglycemia (5 mmol/liter) for 40 min with a variable rate dextrose infusion. Glucose was lowered to 2.5 mmol/liter (hypoglycemic clamp) or maintained at 5 mmol/liter (euglycemic clamp) for a further 105 min. Nine controls received a matched saline infusion. Measurements included serum C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide, osteocalcin, and PTH. Induction of hyperinsulinemia resulted in a reduction in PTH (27% +/- 5; P < 0.01), but no significant change in bone turnover from baseline. Hypoglycemic clamp resulted in suppression of serum C-terminal telopeptide of type I collagen by 34% +/- 3, procollagen type I N-terminal propeptide by 15% +/- 1, osteocalcin by 5% +/- 1, and PTH by a further 12% +/- 5 (all P < 0.05). By contrast, there was no significant change in any marker of bone turnover during euglycemic clamp. Postprandial hyperinsulinemia is unlikely to explain the acute suppression of bone turnover with feeding. The reduction in bone turnover during hypoglycemia may be related to hypoglycemia itself, acute changes in PTH, or other hormones released in response to hypoglycemia.