P Garnero

Publications (110)594.11 Total impact

• Article: Early effects of zoledronic acid and teriparatide on bone microarchitecture, remodeling and collagen crosslinks: comparison between iliac crest and lumbar vertebra in ewes.

  N R Portero-Muzy, P M Chavassieux, M L Bouxsein, E Gineyts, P Garnero, R D Chapurlat
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  ABSTRACT: Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short-term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20 μg/d) for 3 months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (p<0.0001). This was associated with a trend of higher Tb.N, Tb.Th, DA, an inferior Conn.D and a lower bone turnover as shown by the decreases of osteoid parameters, MS/BS, Ac.f in LV1 when compared to IC. In addition, the ratio PYD/DPD was 4 times higher in LV1 than IC. After 3 months, significant decreases of sALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from -94 to -98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3 months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly only in LV1 (p<0.05) with a trend of increases in MS/BS and BFR/BS, compared to LV1-CTRL. In conclusion, in adult ewes, the bone mass, microarchitecture, remodeling and collagen crosslink content differ according to the bone site (iliac crest and vertebra). Furthermore, after 3 months, the responses to ZOL and TPTD were of different magnitude and delay between the two bone sites. The distinction of bone sites to study the early effects of anti-osteoporotic therapies appears meaningful in order to approach their site-specific anti-fracture efficacy.
  Bone 07/2012; 51(4):714-9. · 4.02 Impact Factor
• Article: Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study.

  P Garnero, E Sornay-Rendu, F Munoz, O Borel, R D Chapurlat
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  ABSTRACT: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects. INTRODUCTION: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk. METHODS: We investigated 572 postmenopausal women (mean age, 67 ± 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum β-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture. RESULTS: Serum sclerostin correlated positively with spine (r = 0.35, p < 0.0001) and total hip (r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r = -0.10, p = 0.014) and CTX (r = -0.13, p = 0.0026) and with intact PTH (r = -0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture. CONCLUSION: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association.
  Osteoporosis International 04/2012; · 4.58 Impact Factor
• Article: Quantification of immature and mature collagen crosslinks by liquid chromatography-electrospray ionization mass spectrometry in connective tissues.

  E Gineyts, O Borel, R Chapurlat, P Garnero
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  ABSTRACT: We describe a novel high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) method for the simultaneous quantification of enzymatic immature (dihydroxylysinonorleucine DHLNL, hydroxylysinonorleucine HLNL) and mature (pyridinoline PYD, deoxypyridinoline DPD) collagen crosslinks in connective tissues. The crosslinks were separated on a C18 Atlantis T3 reversed-phase column with heptafluorobutyric acid (HFBA) as volatile ion-pairing reagent in an acetonitrile-water mobile phase. Detection was carried out by electrospray ionization mass spectrometry in a positive ion mode with selected ion recording (SIR). This method is more sensitive and selective than ion exchange chromatography with post-column ninhydrin detection which is the reference method used for the simultaneous quantification of collagen enzymatic divalent and trivalent crosslinks. The intra and inter-day precision errors were less than 3.4 and 7.7%, respectively for DHLNL, 3.5 and 5.9%, respectively for HLNL, 4.0 and 5.2%, respectively for PYD, 8.2 and 10.7%, respectively for DPD. This novel technique should be useful to quantify simultaneously DHLNL, HLNL, PYD and DPD in connective tissues and to evaluate the maturation of collagen by determination of the ratio between immature and mature enzymatic crosslinks.
  Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 06/2010; 878(19):1449-54. · 2.78 Impact Factor
• Article: Opposite relationships between circulating Dkk-1 and cartilage breakdown in patients with rheumatoid arthritis and knee osteoarthritis.

  N Voorzanger-Rousselot, N Charni Ben-Tabassi, P Garnero
  Annals of the rheumatic diseases 10/2009; 68(9):1513-4. · 8.11 Impact Factor
• Article: Nitrated type III collagen as a biological marker of nitric oxide-mediated synovial tissue metabolism in osteoarthritis.

  P Richardot, N Charni-Ben Tabassi, L Toh, H Marotte, A-C Bay-Jensen, P Miossec, P Garnero
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  ABSTRACT: Nitric oxide (NO) is a major mediator of joint tissue inflammation and damage in osteoarthritis (OA) and mediates the nitration of tyrosine (Y*) residues in proteins. We investigated the nitration of type III collagen, a major constituent of synovial membrane, in knee OA. A polyclonal antibody directed against the nitrated QY*DSY*DVKSG sequence from type III collagen N-telopeptide was generated. Synovial tissues from patients with knee OA (n=4) and rheumatoid arthritis (RA, n=4) were analyzed by immunohistochemistry for IIINys. Serum IIINys levels were measured by enzyme-linked immunosorbent assay in 87 patients with painful knee OA (mean age: 63.0+/-8.0 years, Kellgren-Lawrence score II-III) and in 40 sex and age-matched healthy controls. Competition experiments using various nitrated and un-nitrated type III collagen and derived sequences, showed that the antibody was highly specific for the nitrated IIINys sequence. High IIINys immunoreactivity was detected in the synovial tissues from all patients with OA and RA with a preferential localization in the intimal layer. Serum IIINys levels were on average 1.5-fold higher (P<0.0001) in patients with knee OA than in healthy controls and significantly correlated with C-reactive protein values (r=0.40, P<0.005). Nitration of tyrosine residues of type III collagen N-telopeptide is increased in the synovial tissue of patients with knee OA. Measurements of serum IIINys level may be useful for the clinical investigation of oxidative-related alterations of synovial tissue metabolism in OA.
  Osteoarthritis and Cartilage 05/2009; 17(10):1362-7. · 3.90 Impact Factor
• Article: Circulating nitrated N-telopeptide of type III collagen (IIINys) as a biochemical marker of oxidative-related synovial tissue metabolism in rheumatoid arthritis.

  N Charni-Ben Tabassi, P Richardot, L Toh, H Marotte, A-C Bay-Jensen, P Miossec, P Garnero
  Annals of the rheumatic diseases 04/2009; 68(3):451-2. · 8.11 Impact Factor
• Article: Is bone quality associated with collagen age?

  D J Leeming, K Henriksen, I Byrjalsen, P Qvist, S H Madsen, P Garnero, M A Karsdal
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  ABSTRACT: The World Health Organization defines osteoporosis as a systemic disease characterized by decreased bone tissue mass and microarchitectural deterioration, resulting in increased fracture risk. Since this statement, a significant amount of data has been generated showing that these two factors do not cover all risks for fracture. Other independent clinical factors, such as age, as well as aspects related to qualitative changes in bone tissue, are believed to play an important role. The term "bone quality" encompasses a variety of parameters, including the extent of mineralization, the number and distribution of microfractures, the extent of osteocyte apoptosis, and changes in collagen properties. The major mechanism controlling these qualitative factors is bone remodeling, which is tightly regulated by the osteoclast/osteoblast activity. We focus on the relationship between bone remodeling and changes in collagen properties, especially the extent of one posttranslational modification. In vivo, measurements of the ratio between native and isomerized C-telopeptides of type I collagen provides an index of bone matrix age. Current preclinical and clinical studies suggests that this urinary ratio provides information about bone strength and fracture risk independent of bone mineral density and that it responds differently according to the type of therapy regulating bone turnover.
  Osteoporosis International 04/2009; 20(9):1461-70. · 4.58 Impact Factor
• Article: Biochemical markers of type II collagen breakdown and synthesis are positioned at specific sites in human osteoarthritic knee cartilage.

  A-C Bay-Jensen, T L Andersen, N Charni-Ben Tabassi, P W Kristensen, P Kjaersgaard-Andersen, L Sandell, P Garnero, J-M Delaissé
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  ABSTRACT: To investigate whether type II collagen turnover markers used for osteoarthritis (OA) activity evaluation in body fluids can be detected at the level of specific histological features of OA cartilage tissue, as well as how they relate with each other at this level. Adjacent sections were obtained from full-depth cartilage biopsies from 32 OA knees. Immunohistochemistry was performed for Helix-II and CTX-II, which are type II collagen fragments originating from the triple helix and the telopeptide region, respectively, and believed to reflect distinct breakdown events, as well as for type IIA N propeptide (PIIANP), a biochemical marker reflecting synthesis of type IIA collagen. Helix-II and CTX-II were detected in areas where collagen damage was reported previously, most frequently around chondrocytes, but also frequently in regions not previously investigated such as the margin area and close to subchondral bone, including vascularization sites and bone-cartilage interface. The latter is CTX-II's prevailing position and shows rarely Helix-II. PIIANP co-localized with Helix-II and CTX-II on a limited number of features, mainly in deep zone cartilage. Overall, our analysis highlights clear patterns of association of the markers with specific histological features, and shows that they spread to these features in an ordered way. Helix-II and CTX-II show to some degree differential selectivity for specific features in cartilage tissue. CTX-II detection close to bone may be relevant to the possible role of subchondral bone in OA. The restricted co-localization of breakdown markers and PIIANP suggests that collagen fragments can result only partially from newly synthesized collagen. Our study strengthens the interest for the question whether combining several markers reflecting different regional cartilage contributions or metabolic processes should allow a broader detection of OA activity.
  Osteoarthritis and Cartilage 06/2008; 16(5):615-23. · 3.90 Impact Factor
• Article: The type II collagen fragments Helix-II and CTX-II reveal different enzymatic pathways of human cartilage collagen degradation.

  N Charni-Ben Tabassi, S Desmarais, A-C Bay-Jensen, J M Delaissé, M D Percival, P Garnero
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  ABSTRACT: Cartilage degradation in osteoarthritis (OA) generates the type II collagen fragments, Helix-II and CTX-II that can be used as clinical biological markers. Helix-II and C-telopeptide of type II collagen (CTX-II) levels are associated independently with progression of OA suggesting that they may be generated through different collagenolytic pathways. In this study we analyzed the release of Helix-II and CTX-II from human cartilage collagen by the proteinases reported to play a role in cartilage degradation. In vitro, human articular cartilage extract was incubated with activated human recombinant cathepsins (Cats) and matrix-metalloproteases (MMPs). Next, we analyzed the spontaneous release of Helix-II and CTX-II from cartilage sections of patients with knee OA who were immediately deep frozen after joint replacement to preserve endogenous enzyme activity until assay. Cartilage sections were then incubated for up to 84 h in the presence or absence of E-64 and GM6001, inhibitors of cysteine proteases and MMPs, respectively. In vitro, Cats K, L and S generated large amount of Helix-II, but not CTX-II. Cat B generated CTX-II fragment, but destroyed Helix-II immunoreactivity. Cat D was unable to digest intact cartilage. MMPs-1, -3, -7, -9, and -13 efficiently released CTX-II, but only small amount of Helix-II. Neither CTX-II nor Helix-II alone was able to reflect accurately the collagenolytic activity of Cats and MMPs as reflected by the release of hydroxyproline. In OA cartilage explants, E-64 blunted the release of Helix-II whereas the release of CTX-II could be completely abrogated by GM6001 and only partly by E-64. These in vitro and ex vivo experiments of human cartilage suggest that Helix-II and CTX-II could be released in part by different enzymatic pathways. Helix-II and CTX-II alone reflect only partially overall cartilage collagen degradation. These findings may explain why these two biological markers could provide complementary information on disease progression in OA.
  Osteoarthritis and Cartilage 05/2008; 16(10):1183-91. · 3.90 Impact Factor
• Article: PIIANP and HELIXII diurnal variation.

  D J Quintana, P Garnero, J L Huebner, N Charni-Ben Tabassi, V B Kraus
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  ABSTRACT: Serum levels of procollagen type IIA N-terminal propeptide (sPIIANP) and type-II collagen helical peptide (sHELIXII) biomarkers were evaluated for variation diurnally and with physical activity and food in participants with osteoarthritis (OA) of the knee. Forty participants with OA of at least one knee were admitted overnight to the General Clinical Research Center for serial serum sampling. Samples were obtained on the evening (6-8 pm) of Day 1 (T3, n=40); prior to rising (8 am) from bed (T0, n=40); 1 h after rising (9 am) without food consumption (T1a, n=20); 1-2 h after rising (9-10 am) with food consumption (T1, n=40); and additionally at noon, 4 h after rising (T2, n=20). sPIIANP and sHELIXII were measured by enzyme-linked immunosorbent assay. Results were analyzed using non-parametric Freidman's test with Dunn's post-hoc multiple comparison test. Normalized mean concentrations for sPIIANP and sHELIXII increased significantly from T0 to T1 (P<0.05). This is the first study to demonstrate diurnal variation of these collagen-II biomarkers in individuals with knee OA. These results suggest that serum sampling for these markers should be standardized for purposes of clinical trials.
  Osteoarthritis and Cartilage 04/2008; 16(10):1192-5. · 3.90 Impact Factor
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  Available from: John Richard Kirwan

  Article: Can biochemical markers serve as surrogates for imaging in knee osteoarthritis?

  C R Davis, J Karl, R Granell, J R Kirwan, J Fasham, J Johansen, P Garnero, M Sharif
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  ABSTRACT: Osteoarthritis (OA) is a complex heterogeneous joint disease affecting more than 35 million people worldwide. The current gold standard diagnostic investigation is the plain radiograph, which lacks sensitivity. Biochemical markers have the potential to act as adjunct markers for imaging in the assessment of knee OA. We undertook this study to determine the association between individual biochemical markers and radiographic features, and to establish whether the association is strengthened when selected biochemical markers are combined into a single factor (a theoretical marker). Twenty serum and urinary biochemical markers were analyzed in 119 patients with predominantly tibiofemoral knee OA. Pearson's correlation was performed, and corresponding coefficients of determination (R(2)) were calculated to determine the association between biochemical markers and a range of imaging features from radiographs and dual x-ray absorptiometry of the knee. Biochemical markers demonstrating a significant association (P < 0.05) with a specific imaging feature were combined by principal components analysis (PCA). Pearson's correlation was repeated to establish whether the combined panel of biochemical markers showed a stronger association with imaging than the best single marker. Fourteen biochemical markers showed significant associations with one or more imaging features. By combining specific panels of biochemical markers to form factors, the association of markers with imaging features (R(2)) increased from 11.9% to 22.7% for the Kellgren/Lawrence (K/L) score, from 5.9% to 9.2% for joint space width (JSW), from 6.6% to 10.8% for sclerosis, from 13.5% to 22.6% for osteophytes, and from 12.0% to 14.2% for bone mineral density (BMD). Biochemical markers identifying patients with osteophytes overlapped with those correlated with a high K/L score, while markers of subchondral BMD formed a completely separate group. Biochemical markers of JSW included markers associated with both osteophytes and BMD. The PCA results suggest that biochemical marker combinations may be more sensitive than individual biochemical markers for reflecting structural damage in patients with knee OA. The differences in biochemical marker profiles associated with osteophytes compared with those associated with subchondral BMD raise the possibility that these 2 processes, commonly seen in bone in knee OA, have underlying biologic differences.
  Arthritis & Rheumatism 01/2008; 56(12):4038-47. · 7.87 Impact Factor
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  Available from: PubMed Central

  Article: Increased Dickkopf-1 expression in breast cancer bone metastases.

  N Voorzanger-Rousselot, D Goehrig, F Journe, V Doriath, J J Body, P Clézardin, P Garnero
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  ABSTRACT: The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.
  British Journal of Cancer 10/2007; 97(7):964-70. · 5.04 Impact Factor
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  Available from: academielouvain.be

  Article: Zoledronic acid efficacy and safety over five years in postmenopausal osteoporosis.

  J P Devogelaer, J P Brown, P Burckhardt, P J Meunier, S Goemaere, K Lippuner, J J Body, G Samsioe, D Felsenberg, T Fashola, L Sanna, C E Ortmann, U Trechsel, J Krasnow, E F Eriksen, P Garnero
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  ABSTRACT: In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. BMD increased significantly. Bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges. After completion of the core study, two consecutive, 2-year, open-label extensions investigated the efficacy and safety of zoledronic acid 4 mg over 5 years in postmenopausal osteoporosis. In the core study, patients received 1 to 4 mg zoledronic acid or placebo. In the first extension, most patients received 4 mg per year and then patients entered the second extension and received 4 mg per year or calcium only. Patients were divided into three subgroups according to years of active treatment received (2, 3 or 5 years). Changes in BMD and bone turnover markers (bone ALP and CTX-I) were assessed. All subgroups showed substantial increases in BMD and decreases in bone markers. By the end of the core study, 37.5% of patients revealed a suboptimal reduction (< 30%) of bone ALP levels. After subsequent study drug administration during the extensions, there was no evidence of progressive reduction of bone turnover markers. Furthermore, increased marker levels after treatment discontinuation demonstrates preservation of bone remodelling capacity. This study showed that zoledronic acid 4 mg once-yearly was well tolerated and effective in reducing biomarkers over 5 years. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodelling activity in one third of patients.
  Osteoporosis International 10/2007; 18(9):1211-8. · 4.58 Impact Factor
• Article: A 5-yr longitudinal study of type IIA collagen synthesis and total type II collagen degradation in patients with knee osteoarthritis--association with disease progression.

  M Sharif, J Kirwan, N Charni, L J Sandell, C Whittles, P Garnero
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  ABSTRACT: The 5-yr longitudinal study tested the hypothesis that serum and urinary markers of type II collagen metabolism would be associated with radiological progression of disease in patients with mild-to-moderate knee osteoarthritis (OA). Synthesis of type IIA collagen and degradation of total type II collagen were assessed in 135 patients with mild-to-moderate knee OA over 5 yrs using serum concentration of the N-propeptide of collagen type IIA (PIIANP) and urinary excretion of crosslinked C-telopeptide (CTX-II), respectively. The markers were measured at baseline, 2, 3 and 5 yrs' follow-up corresponding to X-ray time points. Analysis of variance (ANOVA) was performed to determine longitudinal changes over 5 yrs in the biomarkers in all patients and between progressors and non-progressors. Complete X-ray progression data over 5 yrs, serum PIIANP and urinary CTX-II were available for 84/135 patients. There were 24 progressors and 60 non-progressors. Overall, over the 5-yr study period average PIIANP and CTX-II levels were higher in progressors compared with non-progressors (P < 0.05 for both, ANOVA). The patients with serum PIIANP in the highest quartile of 5-yr levels of PIIANP had a significantly higher risk of progression than the other patients [relative risk (95% CI): 3.2 (1.1-9.2)]. Increased levels of urinary CTX-II were also associated with a higher risk of progression with a relative risk (95% CI) of 3.4 (1.2-9.4) in patients with 5-yr levels above the median. The risk of progression was highest in patients with 5-yr levels of PIIANP in the highest quartile and/or CTX-II in the two highest quartiles with a relative risk (95% CI) of progression, 11.8 (2.5-54). The data presented here suggest that progression of knee OA is associated with alterations of systemic levels of biological markers of type II collagen metabolism. The data also suggest that the combined measurement of serum PIIANP and urinary CTX-II may be useful to identify patients with knee OA at increased risk of disease progression.
  Rheumatology 07/2007; 46(6):938-43. · 4.06 Impact Factor
• Article: Biochemical markers in oncology. Part I: molecular basis. Part II: clinical uses.

  N Voorzanger-Rousselot, P Garnero
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  ABSTRACT: The investigation of the molecular mechanisms involved in carcinogenesis and tumor progression has led to the development of numerous biochemical markers. Biochemical markers may serve for early prediction of tumor recurrence, progression and development of metastases including bone metastases and for prediction of response to therapy. Tumor antigens have been used for more than a decade and although they have shown promising clinical results, their sensitivity and specificity remain limited. A lot of knowledge on the key molecules which control cell cycle, apoptosis and angiogenesis has been acquired during recent years, but their clinical value remains uncertain. Molecular markers which are linked to malignant transformation may provide a non-surgical therapeutic approach by targeting these molecules through gene therapy or antisense molecules. Because of the complexity of the physiopathogical processes involved in tumorogenesis and metastases, we first provide a review on the molecular basis of the various tumor markers and then discuss their potential clinical utility for the major cancers. The review of the current literature indicates that at the exception of a few examples, such as the use of Her-2 to predict response of the targeted Herceptin therapy, no single marker is sensitive and specific enough to perform an accurate diagnosis, predict disease progression or response to treatment. A combination of different biochemical and imaging markers appears to be the most promising strategy to monitor patients with cancer.
  Cancer Treatment Reviews 06/2007; 33(3):230-83. · 6.05 Impact Factor
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  Available from: cof.cn

  Article: Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study.

  P Garnero, F Munoz, E Sornay-Rendu, P D Delmas
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  ABSTRACT: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.
  Bone 03/2007; 40(3):716-22. · 4.02 Impact Factor
• Article: Increased urinary type II collagen helical and C telopeptide levels are independently associated with a rapidly destructive hip osteoarthritis.

  P Garnero, N Charni, F Juillet, T Conrozier, E Vignon
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  ABSTRACT: Biochemical markers reflecting the degradation of the type II collagen helical (Helix-II) and type II collagen C telopeptides (CTX-II) have been developed. Aim: To investigate the association of rapidly destructive hip osteoarthritis with urinary Helix-II and urinary CTX-II. 12 patients (mean age 70 years) meeting the criteria for rapidly destructive hip osteoarthritis and 28 patients with slowly progressive hip osteoarthritis (mean age 63 years) defined as <0.20 mm joint space loss/year were included in a case-control study. In each patient, urinary Helix-II and CTX-II were measured at the end of the follow-up period, with retrospective evaluation of x rays. Helix-II levels were 41% (p = 0.002) higher in the 40 patients with hip osteoarthritis than in 75 healthy controls. Increased Helix-II levels were associated with decreased minimum joint space width of the hip (r = -0.57, p = 0.001). Mean urinary Helix-II levels were 71% higher in rapidly destructive than in slowly progressive disease (mean (standard deviation (SD)) ng/mmol Cr: 396 (160) v 232 (118) ng/mmol; p = 0.002). When levels of Helix-II and CTX-II in the highest tertile were both included in a multivariate logistic regression model, high Helix-II level (OR; (95% CI) 5.73 (1.01 to 32.8)) after adjustment for age and body mass index and high CTX-II level (6.67 (1.14 to 39.0)) were, independently of each other, associated with a rapidly destructive disease. Increased urinary Helix-II levels are associated with rapidly destructive hip osteoarthritis, independently of urinary CTX-II. Measurement of Helix-II, alone or in combination with CTX-II, could be useful for the clinical investigation of patients with hip osteoarthritis.
  Annals of the Rheumatic Diseases 12/2006; 65(12):1639-44. · 8.73 Impact Factor
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  Available from: PubMed Central

  Article: Association of 12 serum biochemical markers of angiogenesis, tumour invasion and bone turnover with bone metastases from breast cancer: a crossectional and longitudinal evaluation.

  N Voorzanger-Rousselot, F Juillet, E Mareau, J Zimmermann, T Kalebic, P Garnero
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  ABSTRACT: Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BM-), 28 patients with breast carcinoma and BM (BC/BM+) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFbeta1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b (+95%, P=0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P=0.006), MMP-7 (P=0.004) and TIMP-1 (P=0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients.
  British Journal of Cancer 09/2006; 95(4):506-14. · 5.04 Impact Factor
• Article: Urinary CTX-II and glucosyl-galactosyl-pyridinoline are associated with the presence and severity of radiographic knee osteoarthritis in men.

  K M Jordan, H E Syddall, P Garnero, E Gineyts, E M Dennison, A A Sayer, P D Delmas, C Cooper, N K Arden
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  ABSTRACT: To investigate the association between biochemical markers of bone, cartilage, and synovial turnover with the presence and severity of knee osteoarthritis (OA) in men. 176 men aged 59-70 years from the MRC Hertfordshire Cohort were studied. Weightbearing anteroposterior and lateral semiflexed radiographs were taken of both knees. A lifestyle questionnaire including basic demographic details and a questionnaire detailing knee pain was completed. This random sample was stratified based on the Kellgren and Lawrence (K&L) score, and the following biochemical markers were analysed: serum osteocalcin, serum C-terminal crosslinked telopeptide of type I collagen (CTX-I), urinary C-terminal crosslinked telopeptide of type II collagen (CTX-II), and urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-Pyd). Age, body mass index (BMI), social class, smoking, and alcohol consumption were similar across K&L grades. Only one subject had a grade 4 K&L score, and was amalgamated with grade 3 subjects. A strong significant association was found between the presence of knee OA and urinary CTX-II and urinary Glc-Gal-Pyd (p=0.0001 and p=0.009), which persisted after adjustment for age and BMI. A significant positive association was also found between urinary CTX-II and urinary Glc-Gal-Pyd and the severity of K&L grade, joint space narrowing, and osteophytes scores, which persisted after adjustment for age and BMI. No associations between the presence and severity of knee OA were found for serum CTX-I or serum osteocalcin. Urinary CTX-II and Glc-Gal-Pyd, but not systemic markers of bone turnover, are strongly associated with disease severity and the presence of OA at the tibiofemoral and patellofemoral joints in men.
  Annals of the Rheumatic Diseases 07/2006; 65(7):871-7. · 8.73 Impact Factor
• Article: Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis.

  D C Bauer, P Garnero, J P Bilezikian, S L Greenspan, K E Ensrud, C J Rosen, L Palermo, D M Black
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  ABSTRACT: Treatment of osteoporotic women with PTH increases biochemical markers of bone turnover, increases axial bone mineral density (BMD), and reduces fracture risk. Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD. We conducted a randomized, placebo-controlled trial at four academic centers. Patients included 238 postmenopausal women with low hip or spine BMD. Subjects were randomized to sc PTH (1-84), 100 mug/d (119 women), for 1 yr. Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy. Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each sd increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD. Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.
  Journal of Clinical Endocrinology &amp Metabolism 05/2006; 91(4):1370-5. · 6.50 Impact Factor