Urinary Collagen Crosslinks Research Articles

Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

PurposePathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII.MethodsWe analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma.ResultsThe analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption.ConclusionThe gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Factors Influencing Serum Homocysteine Levels in Postmenopausal Osteoporotic Females – Comparison to Urinary Collagen Crosslinks –

ABSTRACTPurpose: The correlation between serum levels of homocysteine and bone mineral density remains controversial. The aim of this study was to identify the potential factors associated with the levels of serum total homocysteine (S-Hcy) and urinary N-terminal telopeptide of type I collagen (U-NTX) in female osteoporotic patients.Materials and Methods: This cross-sectional study included 163 female osteoporotic patients, aged between 48 and 91 years, who had never been treated with anti-osteoporosis therapy. Background data including spine and hip bone mineral density, ongoing therapy for the metabolic disease, aortic calcification score as evaluated by lateral lumbar X-ray film, and recent fragility fracture history were obtained. S-Hcy, U-NTX levels, and creatinine clearance were measured.Results: Multiple linear regression analysis revealed a significant correlation between S-Hcy levels and aortic calcification score (p = 0.022), creatinine clearance (p = 0.004), and recent fracture history (within 1 year after fracture) (p = 0.028); conversely, U-NTX levels correlated significantly with total hip bone mineral density (p < 0.0001) and recent fracture history (p = 0.0007).Conclusions: S-Hcy levels had no correlation with bone mineral density, but were associated with the degree of aortic calcification, renal function, and fracture events. These confounding factors should be taken into consideration when the relationship between S-Hcy and bone mineral density is discussed.

Effects of a physical activity program on the urinary collagen crosslinks in pre- and postmenopausal women.

This study analyzes the effects of physical exercise on urinary collagen crosslinks, pyridinoline (PYD) and deoxipyridinoline (DPD), in women. Thirty premenopausal (PRE) and 40 postmenopausal (PST) women took part in a six month randomized controlled trial of moderate physical exercise. Moreover, skinfold thickness, muscle strength and flexibility were evaluated. Basal values of urinary PYD and DPD were higher in postmenopausal women versus premenopausal women (P<0.01). Physical exercise increased in both groups urinary PYD levels (P<0.05) and urinary DPD levels in postmenopausal women (P<0.05). After the exercise program, no changes were observed in the levels of urinary DPD in premenopausal women. Significant improvements in flexibility, muscle strength and decrease in skinfolds thickness were observed in the exercise group. No changes were observed in non-exercise group. In conclusion, the physical activity program produced beneficial effects on muscle strength and flexibility and changes in the musculoskeletal system. Also, the physical activity program led to a non-pathological increase in the urinary elimination of bone reabsorption and collagen metabolism biomarkers.

BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy

Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD). To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH. A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured. Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum β-CrossLaps (0.37 ± 0.34 μg/l; P < 0.05) and urinary collagen crosslinks (NTX, 68.1 ± 32.4 nmol/g; P < 0.005) despite receiving the lowest average daily hydrocortisone dose of 9.9 ± 3.7 mg/m(2) (P < 0.05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6.7, 95% CI = 1.78-25.38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes. Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity.

Bone Mineral Density Is Not Significantly Reduced in Adult Patients on Low-Dose Glucocorticoid Replacement Therapy

Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis. Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women? We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients. BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured. PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m(2) (range, 4.9-19.1) and 15.5 ± 7.8 mg/m(2) (range, 5.7-33.7), respectively. BMD varied within the normal reference range (-2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Ward's region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAI women treated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Ward's region compared to non-DHEA-treated women. Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addison's women.

A pilot study of copper supplementation effects on plasma F 2α isoprostanes and urinary collagen crosslinks in young adult women

Marginal copper deficiency has been proposed to occur frequently, but the benefits of correction remain largely uncharacterized. Two benefits could be reduced oxidant stress and better crosslinking of collagen in bone. Copper intake was increased in 8 female university students by supplementation with copper glycinate (2 mg copper/day) for 8 weeks. Supplementation improved copper status based on serum activity of two copper enzymes, ceruloplasmin and diamine oxidase (9% and 75% mean increase, respectively). No effect was seen for erythrocyte copper–zinc superoxide dismutase. Supplementation produced a 39% mean decrease in plasma for F 2α-isoprostanes (a marker of oxidant stress), and gave a 62% increase in the urine ratio of collagen crosslinks to a measure of total collagen. None of the supplementation effects were duplicated for 8 women given placebo. In conclusion, this pilot study found that in young adult women, increased copper intake can alter biochemical parameters relevant to copper function.

Automated HPLC Assay for Urinary Collagen Cross-links: Effect of Age, Menopause, and Metabolic Bone Diseases

The pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) are established markers of bone resorption. We evaluated the analytical and clinical performance of a commercially available PYD HPLC assay and established reference intervals in children and adults. We used a commercially available reagent set (Chromsystems Instruments & Chemicals) to measure PYD and DPD in 319 healthy controls (156 premenopausal women, 80 healthy men, and 83 healthy children age 1 month to 14 years) and 397 patients with metabolic bone diseases (postmenopausal osteoporosis, n = 175; male osteoporosis, n = 176; hyperparathyroidism, n = 17; hyperthyroidism, n = 19; Paget disease, n = 10). The mean intraassay and interassay CVs were <6% and <8% for both PYD and DPD, respectively. The reference interval was constant for premenopausal women in the age group 20-49 years. In men, cross-link values peaked at 20-29 years and decreased thereafter. Women with postmenopausal osteoporosis had significantly higher PYD (51%) and DPD (58%) values compared to premenopausal women. Similar results were found in osteoporotic men. In children the highest values were found in the first weeks and months after birth, followed by a decrease of 50%-60% at age 11-14 years. In metabolic bone diseases cross-link concentrations were significantly increased. The DPD:PYD ratio (mean value approximately 0.2) was remarkably constant in all populations evaluated. The automated HPLC assay is a precise and convenient method for PYD and DPD measurement. We established reference intervals for adult women and men and for children up to 14 years old. The cross-link concentrations we determined by use of this HPLC method confirm its clinical value in enabling identification of increased bone resorption in patients with metabolic bone diseases.

Effect of different doses of vitamin D on osteocalcin and deoxypyridinoline in preterm infants

Metabolic bone disease of prematurity is a common problem in preterm infants. The aim of the present paper was to measure the effect of vitamin D, in order to see the relation between vitamin D and urinary excretion of deoxypyridinoline (DPD), serum osteocalcin (OC), calcium (Ca), inorganic phosphorus (P), and alkaline phosphatase (ALP). Three different doses of vitamin D, 200 IU/kg (group 1, 11 infants), 400 IU/kg (group 2, 15 infants) and 800 IU/kg bodyweight/day (group 3, 11 infants), were administered to a total of 37 preterm infants between 15th day of birth until the 30th day of birth. There were no significant differences in levels of serum Ca and P before and after vitamin D supplementation in all groups. Serum ALP levels were increased in all but significantly only in groups 1 and 3. Serum OC levels were also increased in each group by the treatment. Urinary DPD excretion was increased gradually by the increase in vitamin D intake, but it was significant only in group 3. High dose of vitamin D supplementation might accelerate bone turnover and increased urinary DPD levels might reflect increased bone resorption. To the best of the authors' knowledge this is the first study comparing the effects of different vitamin D dose, by the means of urinary collagen cross-links, on bone turnover in preterm infants.

65: Hypovitaminosis D is associated with accelerated bone loss in lung transplant recipients

Osteoporosis may result in significant morbidity in lung transplant recipients and is also considered a relative contraindication for transplant in severe cases. The etiology of post-transplant osteoporosis is likely multi-factorial, compounded by steroid use and chronic medical illness. We reviewed the records of all lung transplant recipients at Emory University Hospital and performed a cross-sectional analysis using data on bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and urinary collagen crosslinks (N-telopeptide and pyridinolines) from 73 recipients who had at least one year follow-up.

Bone Markers, Calcium Metabolism, and Calcium Kinetics During Extended-Duration Space Flight on the Mir Space Station

Bone loss is a current limitation for long-term space exploration. Bone markers, calcitropic hormones, and calcium kinetics of crew members on space missions of 4-6 months were evaluated. Spaceflight-induced bone loss was associated with increased bone resorption and decreased calcium absorption. Bone loss is a significant concern for the health of astronauts on long-duration missions. Defining the time course and mechanism of these changes will aid in developing means to counteract these losses during space flight and will have relevance for other clinical situations that impair weight-bearing activity. We report here results from two studies conducted during the Shuttle-Mir Science Program. Study 1 was an evaluation of bone and calcium biochemical markers of 13 subjects before and after long-duration (4-6 months) space missions. In study 2, stable calcium isotopes were used to evaluate calcium metabolism in six subjects before, during, and after flight. Relationships between measures of bone turnover, biochemical markers, and calcium kinetics were examined. Pre- and postflight study results confirmed that, after landing, bone resorption was increased, as indicated by increases in urinary calcium (p < 0.05) and collagen cross-links (N-telopeptide, pyridinoline, and deoxypyridinoline were all increased >55% above preflight levels, p < 0.001). Parathyroid hormone and vitamin D metabolites were unchanged at landing. Biochemical markers of bone formation were unchanged at landing, but 2-3 weeks later, both bone-specific alkaline phosphatase and osteocalcin were significantly (p < 0.01) increased above preflight levels. In studies conducted during flight, bone resorption markers were also significantly higher than before flight. The calcium kinetic data also validated that bone resorption was increased during flight compared with preflight values (668 +/- 130 versus 427 +/- 153 mg/day; p < 0.001) and clearly documented that true intestinal calcium absorption was significantly lower during flight compared with preflight values (233 +/- 87 versus 460 +/- 47 mg/day; p < 0.01). Weightlessness had a detrimental effect on the balance in bone turnover such that the daily difference in calcium retention during flight compared with preflight values approached 300 mg/day (-234 +/- 102 versus 63 +/- 75 mg/day; p < 0.01). These bone marker and calcium kinetic studies indicated that the bone loss that occurs during space flight is a consequence of increased bone resorption and decreased intestinal calcium absorption.

Bone disease after kidney transplantation

Kidney transplantation is the optimal form of renal replacement therapy for many with end-stage kidney disease. However, kidney transplantation comes with a unique set of medical complications, important among them is bone disease. Posttransplant bone disorders are manifestations of pathologic processes occurring posttransplant that are superimposed on preexisting disorders of bone and mineral metabolism secondary to kidney failure and/or diabetes mellitus. As a consequence of early rapid bone loss, which is seen commonly within the first 3 to 6 months of transplant, the fracture risk posttransplant increases and has been reported as high as 5% to 44%. Posttransplant fractures occur more commonly at peripheral than central sites. Patients with a history of diabetes mellitus are at particular risk for fracture. Parathyroid hormone (PTH) and osteocalcin levels generally decrease after transplantation. Alkaline phosphatase and urinary collagen cross-links are unpredictable. Bone histology varies. No single biomarker unequivocally distinguishes between the various bone disorders found on biopsy examination. Immunosuppression is a major cause of posttransplant bone disorders. Glucocorticoids lead to decreased bone formation whereas the calcineurin inhibitors appear to cause increased bone turnover. Evaluating and managing posttransplant bone disease is an integral part of posttransplant medical care.

Response to alendronate in osteoporotic women previously treated with pamidronate

Introduction: Different bisphosphonates have been shown to increase bone mineral density (BMD) and reduce the risk of fracture in osteoporotic patients. It is unclear how shifting from a treatment with one bisphosphonate to another will influence the evolution of BMD and bone turnover. Methods: In the present study, we followed BMD (DXA, Hologic QDR1000) of the lumbar spine (BMDL) and of the total hip (BMDH), bone alkaline phosphatase (Ostase, Hibritech), and urinary collagen cross links (pyridinoline, deoxypyridinoline, Biorad) in 39 patients treated with IV pamidronate (60 mg/3 months) since at least 2 years and who were shifted to oral alendronate (10 mg/day, n=18) or left to IV pamidronate ( n=21) for 2 more years. Results: BMD increased similarly and significantly in both groups after 2 additional years of treatment as compared to baseline ( P<0.05, sign test). BMDL: +3.8% in the alendronate group vs +4.1% in the pamidronate group; BMDH: +4.3% in alendronate group vs +3.6% in pamidronate group, There was no significant change in the biological parameters of bone turnover in any group. Conclusion: The increase of BMD with both bisphosphonates in these previously treated patients was as expected after a 2 more years of treatment. Alendronate administration did not induce a larger gain in BMD as compared to cyclic pamidronate. Bone turnover was no longer affected by switching the bisphosphonate treatment.

Urinary Collagen Cross-Links as Biochemical Markers of Growth: An Evaluation of Biological Variables

Aim: To investigate the validity of urinary pyridinium cross-links (pyridinoline and deoxypyridinoline) as markers of growth in healthy children. Methods: Three pilot studies (P1–P3) were conducted to investigate the time of day, the minimal duration within a day, and how many times per week urine samples needed to be collected to obtain representative values of cross-link excretion in normal children 3–5 years of age. The results were used to design a 4-month longitudinal protocol to evaluate whether pyridinium cross-links could be used as markers of growth velocity. Results: Mean differences from 24-hour values were only between 1 and 4% for urinary cross-links (nmol/h) in overnight 12-hour collections. Three consecutive collections were required for weekly output estimates with a maximum error of 10% in >90% of the children. During the 4-month longitudinal study, the regression equation of height velocity on pyridinoline and deoxypyridinoline excretion explained approximately 60% of the variance in the subgroup of subjects who provided three complete urinary collections per observation period. No relationship was observed when the cases with fewer or incomplete collections were included in the analysis. Cross-link values collected at baseline were of no use to predict height velocity at 4 months. Conclusions: Urinary pyridinium cross-links correlate with the growth velocity in healthy children when using an appropriate urinary collection protocol. However, their predictive value in this population is negligible.

Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease

There is considerable debate as to the optimum schedule of bisphosphonate treatment in advanced malignancy. Short term studies using symptomatic response and biochemical markers of bone resorption may provide useful insight into differences between agents. Fifty-one patients with metastatic bone disease were randomly allocated to either oral clodronate 1,600 mg daily (group 1), intravenous clodronate followed by the same schedule of oral clodronate (group 2). or intravenous pamidronate 90 mg monthly (group 3). No radiotherapy was delivered or other systemic anticancer treatments were allowed except for long term endocrine therapy. Bone resorption was assessed by measurement of urinary collagen crosslinks. At each visit a pain score was recorded. Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate. Nine of sixteen patients experienced a sustained improvement in pain score in the pamidronate-treated group, in contrast to only 4 of 16 and 2 of 11 patients in groups 1 and 2, respectively. There was a significant improvement in pain scores in the pamidronate arm compared with the clodronate treated patients after both three months of treatment (P <0.01) and at the last measurement (P <0.05). Biochemical changes correlated with changes in the pain score (P = 0.01). Intravenous pamidronate appears to be more effective than oral clodronate in both controlling symptoms and suppressing bone resorption.

Effect of high doses of oral risedronate (20 mg/day) on serum parathyroid hormone levels and urinary collagen cross-link excretion in postmenopausal women with spinal osteoporosis

The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were −46.9% and −58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover.

Collagen cross-links and early postnatal growth in newborns with intrauterine growth retardation

This study assessed growth and skeletal metabolism in full-term newborns with intrauterine growth retardation (IUGR) and determined the value of the urinary excretion of collagen cross-links in predicting postnatal catch-up growth. We studied 38 newborns (16 females) born at term with a birth weight less than the 10th centile of the reference and a ponderal index ([PI] 100 × weight in g/length in cm3) of 2.27 ± 0.19. The sample was divided into 23 children with proportionate ([P] PI ≥ 10th centile of the reference) and 15 with nonproportionate ([NP] PI < 10th centile of the reference) IUGR. The weight, head circumference, length, and knee-heel length of the newborns at days 7, 14, 30, 60, and 90 were measured. The height of 23 of the 38 children was also assessed at 27 ± 6 months of life. Urinary collagen cross-links were analyzed by high-performance liquid chromatography at day 14 and day 60. Most of the infants (68%) underwent catch-up growth, and the growth performance at 3 months was independent of the proportions at birth. Children who did not show catch-up growth in the first trimester of life failed to normalize in height in the following 2 years. The urinary excretion of pyridinoline (Pyd) was not related to the anthropometric measurements. In P children, urinary excretion of deoxypiridinoline (Dpd) at day 14 significantly correlated with the gain in length during the first 3 months, accounting for 25% of the variance. In NP children, these correlations between urinary Dpd and the gain in length were not significant. The evaluation of urinary Dpd excretion at 2 weeks of age might help to determine the therapeutic regimen in IUGR children. Copyright © 2000 by W.B. Saunders Company

Prevention of early postmenopausal bone loss with cyclical etidronate

Cyclical etidronate has been shown to be effective in the treatment of established postmenopausal osteoporosis but less is known about its effects on early menopausal bone loss. The aim of the study was to establish the effects of cyclic etidronate therapy on spinal and proximal femoral bone mineral loss in early postmenopausal women. One hundred and seven women who were within 6 months to 3 years of the menopause were recruited into a 2-year, randomised, placebo-controlled, double-blind trial. Spinal bone mineral density was within 2 SD of the age-matched mean reference value at baseline. Bone mineral density in the lumbar spine and proximal femur was assessed by dual energy X-ray absorptiometry at baseline and thereafter at 6 monthly intervals for 2 years. Urinary collagen cross-links (deoxypyridinoline and pyridinoline) were measured at the same time points. Seventy-seven women completed the study. At the end of the treatment period, the mean bone mineral density change from baseline in the treated group was +0.14% and -0.06% in the lumbar spine and femoral neck, respectively, compared to -1.49 and -2.22 in the control group. Overall, there was a significant difference between the two groups at both these sites (p=0.01 and 0.001, respectively). No significant differences between the groups were demonstrated at the greater trochanter or Ward's triangle. The conclusion was that cyclical etidronate therapy prevents bone loss in the spine and femoral neck in early postmenopausal women. It provides a safe and effective therapeutic option for the prevention of postmenopausal osteoporosis in women who are unwilling or unable to tolerate hormone replacement therapy.

Immediate changes in biochemical markers of bone turnover and circulating interleukin-6 after parathyroidectomy for primary hyperparathyroidism.

The time course of the immediate change in bone turnover after parathyroidectomy (PTX) for primary hyperparathyroidism (PHPT) is not clear. It is uncertain whether circulating interleukin-6 (IL-6) plays a role in mediating the acute withdrawal of the effects of parathyroid hormone (PTH) on bone turnover after PTX. The aims of this study were to determine the time course of immediate changes in biochemical markers of bone turnover after PTX and whether circulating IL-6 is involved in the immediate changes of bone turnover after PTX. IL-6 and bone turnover markers were measured in eight women (aged 55+/-11 years, mean+/-s.d. ) with PHTP at baseline and at 1-2h, and 1, 2, 5, 7 and 12 days after PTX. We compared the results with those from eight individually matched women (healthy controls) and five subjects undergoing major surgery (surgical controls). At baseline, serum levels of IL-6 and bone turnover markers were higher in PHPT than those in healthy controls (P<0.05). Serum levels of procollagen propeptides increased by 22 and 27% at days 2 and 5, respectively, compared with baseline (P<0.05). Serum tartrate-resistant acid phosphatase decreased by 2 days after PTX, and urinary collagen crosslinks decreased significantly by 21-41% within 24h (P<0.05). Serum IL-6 levels increased immediately in both PHPT and surgical controls at postoperative follow-up (repeated measures ANOVA). (1) PTX decreases bone resorption immediately and (2) circulating IL-6 is not involved in the changes in bone turnover immediately after PTX.

Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study.

The aim of this study was to assess the ability of serum bone-specific alkaline phosphatase (bone ALP), creatinine-corrected urinary collagen crosslinks (CTx) and calcaneus bone mineral density (BMD) to identify postmenopausal women who have an increased risk of osteoporotic fractures. Calcaneus BMD and biochemical markers of bone turnover (serum bone ALP and urinary CTx) were measured in 512 community-dwelling postmenopausal women (mean age at baseline 69 years) participating in the Hawaii Osteoporosis Study. New spine and nonspine fractures subsequent to the BMD and biochemical bone markers measurements were recorded over an average of 2.7 years. Lateral spinal radiographs were used to identify spine fractures. Nonspine fractures were identified by self-report at the time of each examination. During the 2.7-year follow-up, at least one osteoporotic fracture occurred in 55 (10.7%) of the 512 women. Mean baseline serum bone ALP and urinary CTx were significantly higher among women who experienced an osteoporotic fracture compared with those women who did not fracture. In separate age-adjusted logistic regression models, serum bone ALP, urinary CTx and calcaneus BMD were each significantly associated with new fractures (odds ratios of 1.53, 1.54 and 1.61 per SD, respectively). Multiple variable logistic regression analysis identified BMD and serum bone ALP as significant predictors of fracture (p = 0.002 and 0.017, respectively). The results from this investigation indicate that increased bone turnover is significantly associated with an increased risk of osteoporotic fracture in postmenopausal women. This association is similar in magnitude and independent of that observed for BMD.

A new spin on an old model: in vivo evaluation of disease progression by magnetic resonance imaging with respect to standard inflammatory parameters and histopathology in the adjuvant arthritic rat.

To noninvasively examine the pathogenesis of rat adjuvant-induced arthritis (AIA) by magnetic resonance imaging (MRI), and to correlate MRI indices of disease progression with classic inflammatory parameters and histologic evaluation. AIA was established in male Lewis rats following subcutaneous injection in the right hindpaw with 0.5 mg of heat-killed Mycobacterium butyricum suspended in light mineral oil. In vivo MRI evaluations of soft tissue and bony changes in AIA rats with matched histopathology were correlated with changes in left hindpaw volumes, circulating leukocytes, acute-phase reactants, and urinary collagen crosslinks throughout the disease process. MRI of arthritic tibiotarsal joints of the uninjected left hindpaws from AIA rats demonstrated 2 distinct phases of disease activity. The first phase, apparent between days 10 and 18, was characterized by periarticular inflammation with marked synovitis, synovial fibroplasia, and distension of the joint capsule into the surrounding tissue. The secondary phase, occurring between days 18 and 30, was marked by continued soft tissue inflammation, periostitis with osteolysis, and periosteal new bone formation progressing to a state of near complete ankylosis by day 30. These 2 phases of disease activity observed by MRI paralleled biochemical, cellular, and histologic markers of disease progression. MRI can be used to noninvasively detect, monitor, and quantify the chronic synovitis and progressive destruction of soft tissue and bone in live AIA rats, thereby improving the ability to evaluate disease progression in this preclinical animal model of rheumatoid arthritis.