Effects of inflammation and treatment on bone turnover and bone mass in polymyalgia rheumatica

Objective. Polymyalgia rheumatica (PMR) has an abrupt onset of inflammatory symptoms, making it a useful model for studying the effects of inflammation in bone. PMR requires corticosteroid treatment, which may itself have a detrimental effect on bone. This study used serially measured biochemical markers of bone turnover and bone density to address the relative contributions of systemic inflammation and corticosteroid therapy to bone loss. Methods. Fifty untreated patients with PMR were randomized to receive oral prednisolone or intramuscular methylprednisolone. Biochemical bone markers (pyridinoline [PYR], deoxypyridinoline [DPYR], procollagen type I carboxy-terminal peptide [PICP]) and bone mineral density (BMD) were measured at baseline and at 6, 12, and 24 months. Results. The median disease duration at presentation was 12 weeks (range 5–32 weeks). Levels of urinary crosslinks were increased in patients with untreated PMR compared with controls (PYR 74.9 ± 30.0 nmole/mmole creatinine, DPYR 14.6 ± 6.4 nmoles/mmole creatinine [mean ± SD]; P = 0.0001); the PICP level was normal (115.0 ± 39.0 μg/liter). With treatment, the crosslinks levels fell and PICP levels rose within 6 months (P = 0.01). Bone resorption (PYR) correlated with untreated disease activity (erythrocyte sedimentation rate [ESR]) (r = 0.5, P = 0.003) and with interleukin-6 levels (r = 0.48, P = 0.05). There was a significant reduction in BMD of both the hip and the spine after 12 months of treatment (P = 0.0002), with no difference between treatment groups. As the steroid dosage was reduced, bone mass improved. Initial ESR influenced the percent change in BMD at 1 year (r = 0.35, P = 0.05), while cumulative steroid dose, mean ESR, and type of steroid used did not. Conclusion. Inflammation in PMR increases bone resorption and appears to have a more detrimental effect on bone than does low-dose corticosteroid. If corticosteroids can be tapered and discontinued, bone loss in PMR can be a transient phenomenon.     

The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab

Rheumatoid arthritis is a systemic disease that causes inflammation and joint destruction. As a result of pathological destruction in bone and cartilage, crosslinks in collagen are resorbed more rapidly. This causes a rise in circulating collagen crosslink levels and their urinary excretion. In RA, apart from the crosslink resorption at the site of inflamed joints, there may be increased resorption due to general bone loss associated with disease activity. The aim of this study was to evaluate the influence of therapy with infliximab on urinary excretion of pyridinoline (PYD) and deoxypyridinoline (DPYR) as a markers of collagen degradation and its correlation with clinical and biochemical parameters of disease activity. Seventeen patients with active rheumatoid arthritis treated with infliximab were recruited into the study. The therapy resulted in the reduction in the symptoms of RA and urinary excretion of PYD and DPYR. The urinary excretion of PYD correlated with a number of swollen joints, morning stiffness, CRP and ESR. The urinary excretion of DPYR correlated during infliximab therapy with the number of swollen and tender joints and morning stiffness. The measurement of urinary excretion of PYR and DPYR may give insight into bone metabolism and help us to better understand the actual changes in bone and cartilage caused by RA and its treatment.Abbreviations DPYR Deoxypyridinoline - PYR Pyridinoline - RA Rheumatoid arthritis     

Increased levels of urinary collagen crosslinks in females with rheumatoid arthritis

Summary Bone loss is a feature of RA, but the exact mechanisms involved are not clear. The collagen crosslinks deoxypyridinoline (DPYR) and pyridinoline (PYR) are specific indices of mature collagen breakdown and reflect increased bone turnover. The aims of the study were to examine crosslink levels in RA and their association with disease activity and the effect of steroids. Urinary crosslinks corrected for creatinine were measured on morning fasting samples by HPLC in 70 postmenopausal women with rheumatoid arthritis (RA) aged 45–65 and compared with 169 postmenopausal healthy age-matched controls from the population. Mean levels of PYR were significantly higher in RA cases than in controls (52.4 versus 37.5 nmols/mmolCr) although mean levels of DPYR did not differ significantly. A weak correlation was found with ESR and PYR (r=0.35) but not with other markers of disease activity. Thirteen of the RA cases were current steroid users and their levels of DPYR and PYR even with low doses, were significantly elevated above those of non-users, ex-users and controls. The finding of raised urinary PYR but not the bone specific DPYR in nonsteroid using RA cases suggests that the increased collagen breakdown does not primarily come from bone but from other sources such as cartilage and synovium. The large increases in collagen excretion in low dose steroid users, may reflect the higher risk of osteoporosis in this group.     

Evidence of impaired cartilage/bone turnover in patients with active ankylosing spondylitis.

OBJECTIVES--To compare serum markers of bone formation with the urinary excretion of pyridinium crosslinks (PYR) as a possible measure of bone and cartilage degradation which would detect changes in bone metabolism in patients with ankylosing spondylitis (AS) and to relate them to influences of inflammatory disease activity, and to treatment. METHODS--In 62 patients with AS, serum osteocalcin, alkaline phosphatase (ALP), and skeletal ALP isoenzyme levels were evaluated concurrently in comparison with urinary excretion of pyridinium cross links and were compared with values in 50 healthy controls. RESULTS--Osteocalcin concentrations in AS patients were in the middle normal range (3.5 (SD 1.2) ng/ml) and did not differ significantly from those in control subjects (4.2 (1.3) ng/ml); the same was true for ALP and skeletal ALP isoenzyme fraction (AS: ALP 149 (50.3) U/l, skeletal ALP 12.8 (4.1) micrograms/l; controls: ALP 133 (25.2) U/l, skeletal ALP 11.9 (4.3) micrograms/l). The urinary levels of PYR in AS (51.2 (25.2) nmol PYR/mmol creatinine) were significantly increased compared with controls (33.9 (12.4) nmol PYR/mmol creatinine (p < 0.001)). In the AS group there was a positive correlation between urinary excretion of PYR and inflammatory disease activity (erythrocyte sedimentation rate (ESR)) (r = 0.6, p < 0.0001) and C reactive protein (CRP) (r = 0.3, p = 0.02), but no significant correlation was found with ESR, CRP, and markers of bone formation. CONCLUSIONS--Bone metabolism in patients with AS is characterised by normal bone formation and enhanced cartilage/bone degradation, suggesting that impaired bone turnover is pronounced in active disease. The results clearly indicate that this comparison can be used to demonstrate impairment of cartilage/bone metabolism which correlates with disease activity. The data obtained further emphasise the importance of measuring both serum variables and urinary excretion of PYR crosslinks to obtain adequate evaluation of cartilage/bone metabolism in patients with AS.     

Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.     

Protective effect of an aldose reductase inhibitor against bone loss in galactose-fed rats: possible involvement of the polyol pathway in bone metabolism.

Many patients with diabetes mellitus show a moderate reduction in bone mass. Our recent in vitro studies showed that sustained exposure of osteoblast-like MG-63 cells to high glucose by itself impairs their functions partly via the polyol pathway. To investigate the role of hyperglycemia in the etiology of diabetic osteopenia in vivo separately from insulin deficiency, we determined whether epalrestat, an aldose reductase (AR) inhibitor (ARI), lessens the abnormalities in calcium (Ca) metabolism in galactose-fed rats. Weight gain was impaired in the rats, which was not altered by epalrestat. Galactose feeding temporarily enhanced bone resorption as reflected by increased biochemical markers for bone resorption (urinary excretion of pyridinoline [PYR] and deoxypyridinoline [DPYR]) at 1 to 3 months, which were significantly decreased by epalrestat. Epalrestat also restored the positive correlation between a bone-formation marker (serum osteocalcin [OC]) and a bone-resorption marker (urinary DPYR excretion) at 6.5 months. Histomorphometric analysis of bone performed 6.5 months after galactose feeding showed that both the bone volume and osteoblast numbers in the tibia, which were significantly suppressed by galactose feeding, were partly restored to a significant extent by the simultaneous administration of epalrestat. In summary, epalrestat partially protected against the development of osteoblast dysfunction and reduced the temporary increase in biochemical markers for bone resorption induced by galactose feeding, with a resultant increase in bone volume, suggesting that the polyol pathway may be intimately involved in the development of abnormal bone metabolism in galactose-fed rats.     

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.     

First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

BACKGROUND: Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. METHODS: In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). RESULTS: At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing 相似文献   

Comparison of IgA-alpha1-antitrypsin levels in rheumatoid arthritis and seronegative oligoarthritis: complex formation is not associated with inflammation per se

Serum complexes between IgA and alpha1-antitrypsin (IgA alpha1AT) have been found at raised levels in early rheumatoid arthritis (RA), where they appear to be associated with more erosive disease. We have now measured the levels of these complexes in the sera and synovial fluid of patients with RA and seronegative oligoarthritis to determine whether there is a relationship between complex levels and joint inflammation, and if bacterial stimulation of the mucosa is associated with complex formation in seronegative oligoarthritis. IgA-alpha1AT complexes were measured in patients with RA (n = 75) and seronegative oligoarthritis, with or without definite reactive arthritis (n = 28), using a newly developed sandwich ELISA. The results were compared with serum levels from healthy volunteers (n = 30). IgA and alpha1AT were also measured using ELISA and radial immunodiffusion (RID) techniques, respectively. IgA-alpha1AT complex levels in the sera of RA patients [mean = 25.6 arbitrary units (au)] were significantly higher (P = 0.0034) than those in patients with seronegative oligoarthritis (mean = 12.36 au) and healthy controls (mean = 8.08 au). There was no evidence for the inflamed joint being the source of IgA-alpha1AT complexes since synovial fluid levels were lower than corresponding serum levels, although higher amounts were found in RA than seronegative oligoarthritis (12.84 au vs 4.11 au, P = 0.01). Serum levels of IgA and alpha1AT were similar in RA and seronegative oligoarthritis patients, and were higher than in normals. There was a significant correlation between complex and serum IgA levels in RA (r = 0.49, P < 0.001) and seronegative oligoarthritis (r = 0.53, P < 0.001) patients, although no relationship was found with alpha1AT levels. There was no correlation with other markers of the acute-phase response (C-reactive protein, erythrocyte sedimentation rate), nor with any clinical markers. In RA patients, serum complex levels were significantly higher in seropositive than seronegative patients (30.75 vs 16.48 au, P = 0.03), and we have demonstrated that a small amount of alpha1AT may be complexed with IgA rheumatoid factor. Our data suggest that the formation of IgA-alpha1AT complexes is not associated with inflammation per se, and does not appear to be related to bacterial stimulation of the mucosal immune system in patients with seronegative oligoarthritis.      

Does active treatment of rheumatoid arthritis limit disease-associated bone loss?

OBJECTIVE: Generalized bone loss in rheumatoid arthritis (RA) is multi-factorial, with the inflammatory disease itself thought to contribute to bone loss. To study the extent to which control of disease activity affects bone turnover in RA and whether treatment with disease-modifying anti-rheumatic drugs (DMARDs) reduces bone turnover and loss of bone mass, we measured bone density and biochemical markers of bone resorption in a group of patients with active RA starting on DMARDS. METHODS: Patients with active RA were enrolled on starting a new DMARD. Patients were mobile and none took steroids or any treatment for osteoporosis. Clinical and laboratory measures of disease activity were made at 3-monthly intervals and an index of disease activity (DAS) calculated. Bone density was assessed at 0, 1 and 2 yr (Hologic QDR 4500c). Urinary deoxypyridinoline (D-PYR) and pyridinoline (PYR) were measured by ELISA at 0, 3, 6, 9 and 12 months. RESULTS: Forty patients were enrolled, mean age 59.5 (range 31-76), 26 female, 14 male, 25 had established RA, 15 had RA for <2 yr. Baseline D-PYR was elevated (8.4+/-4.55 nmol/mmol creatinine) and correlated with ESR (r=0.6, P<0.01) and DAS (r=0.4, P<0.05). On treatment ESR and DAS fell by 38.5 and 29.3%, respectively. D-PYR was reduced by 12.3% by 9 months (P<0.01). Spearman rank order correlation showed ESR to be the most significant determinant of D-PYR over 1 yr (r=0.43, P<0.001). Serial bone density was available on 21 patients. There was no significant change in BMD over the 2 yr. The change in DAS over 0-3 months showed an inverse relationship with the percent change in spine over 1 yr (r=-0.5, P=0.05). The change in D-PYR over 0-3 months was not closely related to the change in BMD at hip or spine at 1 yr. CONCLUSION: Disease activity is a significant determinant of bone turnover in RA. Bone resorption markers fall on treatment of RA with DMARDs and no change in BMD was demonstrated at 2 yr. This study suggests the need to control disease activity in RA in order to prevent systemic bone loss.     

Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers

The administration of moderate to high doses of corticosteroids is associated with bone loss. This probably results from the uncoupling of bone formation (decreased) and bone resorption (unchanged or increased). We examined the effect of low-dose (10 mg/day) prednisone (LDP) and the possible mitigating effects of calcium and 1.25 (OH)2 vitamin D (calcitriol) on calcium and bone metabolism in eight healthy, young male volunteers. The study consisted of four observation periods: in the first period, LDP was prescribed during 1 week; in the second, third and fourth periods, calcium (500 mg/day), calcitriol (0.5 micrograms b.i.d.) and calcium in combination with calcitriol, respectively, were added to LDP. Bone formation was measured by means of serum osteocalcin, carboxy-terminal propeptide of type 1 procollagen (P1CP) and alkaline phosphatase, bone resorption by means of urinary excretion of calcium, hydroxyproline, (free and total) pyridinoline, (free and total) deoxypyridinoline and serum carboxy-terminal cross- linked telopeptide of type 1 collagen (1CTP). Dietary calcium and sodium intake were maintained at a stable level during the entire study period. Treatment with LDP led to a decrease in osteocalcin, P1CP and alkaline phosphatase (all P < 0.01). Urinary excretion of pyridinolines, hydroxyproline and serum 1CTP did not increase, but remained unchanged or slightly reduced (P < 0.05), depending on the time of measurement and the marker of bone resorption. Parathyroid hormone (PTH) (insignificantly) increased during LDP (+19%) and LDP plus calcium (+14%), but decreased during supplementation with calcitriol (-16%) and calcium/calcitriol (-44%; P < 0.01). Urinary excretion of calcium increased during treatment with LDP and calcitriol (P < 0.05) and calcium/calcitriol (P < 0.05). It is concluded that LDP has a negative effect on bone metabolism, since bone formation decreased while bone resorption remained unchanged or decreased slightly. The increase in PTH during LDP could be prevented by calcitriol combined with calcium supplementation.      

Effect of granulocyte colony-stimulating factor on bone metabolism during peripheral blood stem cell mobilization

Granulocyte colony-stimulating factor (G-CSF) has been shown to affect the biochemical markers of bone metabolism, including serum bone alkaline phosphatase (BALP), serum osteocalcin, and urine deoxypyridinoline. To determine the association between bone resorption and formation and the G-CSF-induced mobilization of peripheral blood stem cells (PBSC), we examined these markers during mobilization in 19 healthy donors. The average (+/- SEM) serum BALP level before treatment was 81.6 +/- 17.0 IU/dL, and the level increased significantly to 117.7 +/- 15.8 IU/dL on day 5 of G-CSF administration (P < .0001). The urine deoxypyridinoline level before treatment was 12.3 +/- 2.4 nmol/mmol creatinine, and this level also increased significantly to 19.4 +/- 3.0 nmol/mmol creatinine on day 5 of G-CSF administration (P < .0001). In contrast, the average level of serum osteocalcin significantly decreased from 8.07 +/- 2.88 ng/mL to 1.53 +/- 0.18 ng/mL on day 5 (P = .0353). During G-CSF administration, we also studied the serum levels of various cytokines (IL-1beta, osteoclastogenesis inhibitory factor [OCIF], IL-6, tumor necrosis factor alpha, transforming growth factor beta, interferon-gamma, macrophage colony-stimulating factor) related to bone metabolism. Only the kinetics of OCIF were significantly affected. The serum level of OCIF increased immediately after the start of G-CSF administration and remained high during G-CSF administration. These results demonstrate that high-dose G-CSF affects bone metabolism and that OCIF may play a role in bone metabolism. Consistent with the notion that G-CSF affects bone metabolism, a significant correlation was observed between CD34+ cell yield and the increase in urine deoxypyridinoline but not for the changes in serum BALP and osteocalcin levels. This result suggests that bone resorption is either directly or indirectly related to the mobilization of PBSC by G-CSF.     

Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy

CONTEXT: Biochemical markers of bone turnover may reflect bone structure during anabolic treatment. OBJECTIVE: The objective was to evaluate associations between changes in biochemical markers and structural and dynamic bone parameters during teriparatide treatment. DESIGN: This study was a randomized, multicenter, double-blind, placebo-controlled fracture prevention trial, with 20-month median treatment duration for biopsy subset. SETTING: The trial was conducted at 11 clinical study sites. PATIENTS: Sixty-one postmenopausal women with osteoporosis who had paired transiliac biopsy specimens participated in the study. INTERVENTIONS: Once-daily sc injections of either placebo or teriparatide (20 or 40 microg) were administered. MAIN OUTCOME MEASURES: The study measured: 1) serum and urinary biochemical markers of bone formation [bone alkaline phosphatase and procollagen I C-terminal propeptide (PICP)] and resorption (N-telopeptide and deoxypyridinoline); and 2) structural and dynamic analyses of bone biopsies, including two-dimensional (2D) histomorphometry and three-dimensional (3D) micro-computed tomography evaluations measured at baseline (n = 57) and 12 (n = 21) or 22 (n = 36) months. RESULTS: U-N-telopeptide/creatinine and serum-PICP correlated with bone structure and dynamic indices at baseline, respectively. Changes in bone alkaline phosphatase at 1 month correlated with changes at 22 months in 2D wall thickness (r = 0.73; P = 0.001), trabecular bone volume (trabecular bone volume per total volume, BV/TV) (r = 0.58; P < 0.05), marrow star volume (r = -0.51; P = 0.05); 3D trabecular thickness (r = 0.49; P < 0.05), and BV/TV (r = 0.54; P < 0.05). Changes in PICP at 1 month correlated with changes in wall thickness (r = 0.60; P = 0.01), and 2D BV/TV (r = 0.51; P < 0.05) at 22 months. Changes in markers at 6 or 12 months were not associated with changes in structural or dynamic parameters. CONCLUSIONS: Early (1-month) changes in biochemical markers of bone formation, but not resorption, correlated with improvements in bone structure after 22 months of teriparatide therapy.     

Osteoporosis and beta-thalassemia major: role of the IGF-I/IGFBP-III axis

Patients with beta-thalassaemia major are susceptible to osteopenia due to several factors which interfere with bone remodeling. It is known that bone metabolism and skeletal consolidation result from a complex sequence of hormonal changes, where the concerted actions of GH, IGF-I and sex hormones and their receptors, are responsible for the timing and attainment of skeletal consolidation. IGF-I and the corresponding binding protein (IGFBP-III), markers of bone metabolism and lumbar and femoral neck BMD were measured in 28 adult patients, undergoing hormonal replacement and chelation therapy and a hypertransfusion program, with beta-thalassaemia major (12 males with mean age 22.5+/-3.1 and 16 females with mean age 27.5+/-8.2), and in 28 healthy volunteers matched for age, anthropometric features and sex to the patients. BMD values, both at lumbar and femoral neck level were significantly lower (p<0.001 and p<0.05) by 18.7 and 4.2% respectively, in patients than in the controls. Markers of bone resorption [pyridinoline (Pyr) 78.1+/-15.7 vs 47.5+/-11.2 pmol/pmol urinary creatinine, p<0.001 and deoxypyridinoline (D-Pyr) 21.9+/-3.5 vs 14.5+/-5.4 pmol/ micromol urinary creatinine, p<0.001] were higher in patients than in controls, whereas the marker of bone formation was slightly lower [osteocalcin (BGP) 3.8+/-0.6 vs 4.6+/-1.7 pmol/ml, p<0.05]. Plasma levels of IGF-I (21.07+/-5.12 vs 35.25+/-8.33 nmol/ml, p<0.001) and IGF binding protein III (IGFBP-III) (1.9+/-0.4 vs 2.5+/-0.1 mg/ml, p<0.001) were lower in patients than in controls and positively correlated with BMD L2-L4 (r=0.57, p<0.05 and r=0.47, p<0.05 respectively), BMD neck (r=0.40, p<0.05 and r=0.34, p<0.05 respectively) and BGP (r=0.52, p<0.05 and r=0.34, p<0.05 respectively). Our beta-thalassaemic patients, in spite of normalizing hemoglobin levels, adequate hormone replacement and chelation therapies, showed osteopenia and an unbalanced bone turnover with an increased resorptive phase and a decreased formation phase probably correlated to low levels of IGF-I and IGFBP-III observed in our study.     

Serum leptin level is a predictor of bone mineral density in postmenopausal women

To assess whether leptin is an independent predictor of bone mineral density (BMD) in postmenopausal women, we studied the relationships of BMD to serum leptin, 25(OH)D, 1,25(OH)(2)D, PTH, E2, dehydroepiandrosterone sulfate, GH, IGF-I, creatinine clearance, calcium intake, fat mass, and lean mass in 107 women aged 50-90 yr. We also related serum leptin to markers of bone formation [serum bone alkaline phosphatase and osteocalcin (OC)] and resorption (urine C-telopeptide of type I collagen). In stepwise multiple linear regression, lean mass explained 28.5%, age 10.3%, and leptin 7.2% of the whole body BMD variance. Age explained 21.1%, lean mass 12.8%, and leptin 3.7% of the femoral neck BMD variance. After adjustment for fat mass and creatinine clearance, correlations between leptin and bone alkaline phosphatase (positive) and OC (negative) disappeared but, remained significant with urine C-telopeptide of type I collagen (r = -0.27, P < 0.01). Markers of bone formation and resorption were strongly intercorrelated. These data demonstrate that leptin is an independent predictor of whole body and femoral neck BMD in postmenopausal women. Although the relationships between leptin and markers of bone formation appear complex, leptin may exert a protective effect on bone by limiting the excessive bone resorption coupled to bone formation associated with bone loss after menopause.     

Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women

The aim of this study was to determine whether early changes in serum markers of bone resorption could predict long-term responses in bone mineral density (BMD) after alendronate therapy in elderly women. One hundred and twenty women (mean age, 70 yr) were randomized to alendronate or placebo in this double blind, placebo-controlled clinical trial for 2.5 yr. Outcome measures were hip and spine BMD and biochemical markers of bone resorption, including serum N-telopeptide and C-telopeptide cross-linked collagen type I (NTx and CTx, respectively). Serum NTx and CTx were highly correlated at baseline (r = 0.73; P < 0.001) and remained so throughout the study (range, r = 0.36-0.56; all P < 0.05). After treatment with alendronate, serum NTx decreased 30.4+/-16.0% at 6 months, reaching a nadir of -36.7+/-18.0% by 24 months (P < 0.001). Serum CTx decreased 43.5+/-67.0% at 6 months and continued to decrease to 67.3+/-19.3% at 2.5 yr (P < 0.001). Moreover, decreases in serum NTx and CTx at 6 months were correlated with long-term improvements in vertebral BMD at 2.5 yr in patients receiving alendronate therapy (NTx: r = -0.42; CTx: r = -0.31; both P < 0.05). We conclude that early changes in serum NTx and CTx, markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving alendronate therapy and provide a useful tool to assess skeletal health.     

Serum concentrations of interleukin 6, osteocalcin, intact parathyroid hormone, and markers of bone resorption in patients with rheumatoid arthritis.

OBJECTIVE: To analyze serum concentrations of interleukin 6 (IL-6), osteocalcin, intact parathyroid hormone (PTH), and type 1 collagen carboxyterminal telopeptide (ICTP) as well as the urinary concentrations of crosslinked N-telopeptides of type 1 collagen (NTx) and deoxypyridinoline (Dpd) in patients with rheumatoid arthritis (RA) to investigate their role in the etiology of the osteopenia in this disease. METHODS: Using ELISA and radioimmunoassay methods, we estimated serum concentrations of IL-6, osteocalcin, ICTP, intact PTH, and spot urine concentrations of NTx and Dpd in 25 female patients with active RA, 25 female patients with suppressed disease, and 25 age matched healthy female controls. RESULTS: Patients with active RA had significantly higher (p < 0.001) concentrations of IL-6 (94.0+/-12.1 pg/ml) compared to patients with suppressed disease (13.2+/-0.8 pg/ml) and healthy controls (12.3+/-0.8 pg/ml). Serum osteocalcin was significantly lower (p < 0.001) in patients with active RA (1.9+/-0.2 ng/ml) compared to patients with suppressed disease (2.7+/-0.2 ng/ml) and the controls (2.9+/-0.2 ng/ml). Similarly, serum intact PTH was significantly lower (p < 0.001) in patients with active disease (29.9+/-1.5 ng/ml) compared to patients with suppressed RA (38.0+/-1.6 ng/ml) and controls (49.8+/-2.4 ng/ml). Serum ICTP was also significantly higher (p < 0.01) in patients with active RA (9.5+/-0.3 microg/l) versus patients with suppressed disease (4.1+/-0.2 microg/l) and controls (3.4+/-0.2 microg/l). In patients with active disease, spot urine concentrations of NTx (123.1+/-5.1 nmol bone collagen equivalent/mmol creatinine) and Dpd (15.1+/-0.7 nmol/mmol creatinine) were significantly higher (p < 0.001) than in patients with suppressed disease (58.4+/-2.5 nmol bone collagen equivalent/mmol creatinine and 10.1+/-0.5 nmol/mmol creatinine, respectively) and healthy controls (53.4+/-2.1 nmol bone collagen equivalent/mmol creatinine and 9.7+/-0.5 nmol/mmol creatinine, respectively). There were no significant correlations between serum IL-6 and serum ICTP (r = 0.2357, p = 0.257) or urinary NTx (r = 0.1436, p = 0.494) or between serum intact PTH and ICTP (r = 0.0206, p = 0.922) in patients with active RA. CONCLUSION: There are no significant correlations between bone resorption markers and serum IL-6 and intact PTH in patients with RA.     

Biochemical markers of bone turnover following high-dose chemotherapy and autografting in multiple myeloma

The effect of high-dose chemotherapy and autografting on bone turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), expressed as a ratio of the urinary creatinine concentration. Bone formation was assessed by serum concentration of procollagen 1 extension peptide (P1CP) and bone-specific alkaline phosphatase (BSAP). Eighteen cases had normal fPyr and fDPyr at transplant, and in all but one of these cases the level remained normal throughout subsequent follow-up. In contrast, in 14 cases urinary fPyr and fDPyr levels were increased at transplant. In these cases, both fPyr and fDPyr fell to normal levels over the next few months (P = .0009 and.0019, respectively). fPyr and fDPyr levels at transplant and their trends post-BMT were unrelated to the use of pre-BMT or post-BMT bisphosphonate or post-BMT interferon. Nine cases had elevated P1CP or BSAP at transplant, which rapidly normalized. In most patients there was an increase in P1CP and/or BSAP several months post-transplant. In conclusion, increased osteoclast activity may be present even in apparent plateau phase of myeloma. High-dose chemotherapy with autografting may normalize abnormal bone resorption, although the effect may take several weeks to emerge and may be paralleled by increased osteoblast activity. The findings provide biochemical evidence that autografting may help normalize the abnormal bone turnover characteristic of myeloma. (Blood. 2000;96:2697-2702)     

Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology

The objective was to evaluate the prevalence and severity of osteopenia in patients with uncomplicated insulin-dependent diabetes mellitus (IDDM) and to obtain more information on the pathophysiology of diabetic osteopenia. In 35 patients with uncomplicated IDDM (21 men and 14 women; age 37.6+/-9.9 yr; duration of disease 8.5+/-3.5 years) bone mineral density was measured by dual energy X-ray absorptiometry (DEXA). In addition, markers of bone formation [plasma insulin-like growth factor I (IGF-I), serum alkaline phosphatase (ALP), serum bone alkaline phosphatase (BAP) and serum osteocalcin] and bone resorption [urinary excretion of calcium and of the cross-linked N-telopeptide of type 1 collagen, both corrected for the excretion of creatinine] were measured in the diabetic patients and in 33 healthy controls, matched for sex, age, height, weight and body mass index (BMI). In 67% of the diabetic men and 57% of the diabetic women osteopenia of the femoral neck and/or the lumbar spine (T-value < or = -1 SD) was present. Fourteen percent of the male patients, but none of the female patients, met the criteria for osteoporosis (T-value < or = -2.5 SD). In the whole group of diabetic patients the mean plasma IGF-I level tended to be lower (p<0.10) as compared to that in the controls. In the diabetic patients with femoral neck osteopenia, the mean plasma IGF-I level was significantly lower (p<0.05) than in those without osteopenia at this site. There were no differences in the mean serum ALP, BAP and osteocalcin levels between the diabetic patients and the controls, nor between the diabetic patients with and without femoral neck osteopenia. Considering only the male diabetic patients, significantly lower mean plasma IGF-I (-26%), serum ALP (-24%) and serum osteocalcin (-38%) levels were present in the patients with femoral neck osteopenia than in those without osteopenia at this site, suggesting lowered bone formation. The bone resorption markers were similar in all (sub)groups of diabetic patients and not different between diabetic patients and controls. Bone mineral density (BMD) did not correlate with plasma levels of glycosylated hemoglobin (HbA1c). BMD values were not related to any of the bone resorption or formation markers, except for plasma IGF-I both in the femoral neck (r=+0.38, p=0.026) and the lumbar spine (r=+0.34, p=0.043). Our data demonstrate that at least in male patients with IDDM, osteopenia is the consequence of a lowered bone formation with a predominance of bone resorption over formation.     

Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover

Background The aim of this exploratory study was to establish whether we could improve skeletal health with a physiological regimen of SSR in young women with premature ovarian failure (POF). Patients and Methods In an open‐label randomized controlled crossover trial, 34 women with POF were randomized to 4‐week cycles of pSSR (transdermal oestradiol, 100 μg daily for week 1, 150 μg for weeks 2–4; vaginal progesterone, 200 mg twice daily for weeks 3–4) or standard hormone replacement treatment (sHRT) (oral ethinyloestradiol 30 μg and 1·5 mg norethisterone daily for weeks 1–3, week 4 ‘pill‐free’) for 12 months. Bone mineral density (BMD) was measured by DEXA at study entry and after each 12‐month treatment period. Blood samples for hormones and markers of bone formation (bone alkaline phosphatase, BALP and type I collagen N‐terminal propeptide, PINP) and bone resorption (CrossLaps) were collected pre‐/postwashout and after 3, 6 and 12 months of each treatment. Results Eighteen women, mean 27 (range 19–39) years, completed the study. Both regimens caused similar suppression of LH and FSH. Mean baseline lumbar spine BMD z‐score was ?0·89 (95% CI ?1·27 to ?0·51) and increased by +0·17 (CI +0·07 to +0·27) in response to pSSR (P = 0·003), compared with +0·07 (CI ?0·03 to +0·18) during standard HRT (P = 0·2). During pSSR, the increment in lumbar spine BMD z‐score was related positively to oestradiol (r = +0·49, P = 0·04) and inversely to FSH (r = ?0·65, P = 0·004). Bone formation markers, BALP and P1NP increased in the pSSR arm (anova P < 0·001) but decreased in the sHRT arm (P < 0·01). Both treatments suppressed the bone resorption marker, CrossLaps (P < 0·001). Conclusion We conclude that pSSR over 12 months has a beneficial affect on bone mass acquisition on the lumbar spine in women with POF, mediated by increased bone formation and decreased bone resorption.