Bone Fragility and Collagen Cross-Links

Paschalis, Eleftherios P.; Shane, Elizabeth; Lyritis, George P.; Skarantavos, G.; Mendelsohn, Richard; Boskey, Adele L.

doi:10.1359/jbmr.040820

Cited by 235 publications

(196 citation statements)

References 49 publications

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“…Genotype differences in serum pyridinoline content were not seen in this study. The significance of this finding is unclear as previous studies have found both increased and decreased crosslinking in oim/oim animals, although crosslinking characteristics are unique to the tissue containing them [13,53,54]. The combination of age-associated accumulation of both mineral and organic phases of the bone and a decrease in bone turnover may account for the increase in biomechanical integrity of bone with age.…”

Section: Discussionmentioning

confidence: 84%

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

Carleton¹,

McBride²,

Carson³

et al. 2008

Bone

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Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disease characterized by extreme bone fragility. Although fracture numbers tend to decrease post-puberty, OI patients can exhibit significant variation in clinical outcome, even among related individuals harboring the same mutation. OI most frequently results from mutations in type I collagen genes, yet how genetic background impacts phenotypic outcome remains unclear. Therefore, we analyzed the phenotypic severity of a known proα2(I) collagen gene defect (oim) on two genetic backgrounds (congenic C57BL/6J and outbred B6C3Fe) throughout postnatal development to discern the phenotypic contributions of the Col1a2 locus relative to the contribution of the genetic background.To this end, femora and tibiae were isolated from wildtype (Wt) and homozygous (oim/oim) mice of each strain at 1, 2 and 4 months of age. Femoral geometry was determined via µCT prior to torsional loading to failure to assess bone structural and material biomechanical properties. Changes in mineral composition, collagen content and bone turnover were determined using neutron activation analyses, hydroxyproline content and serum pyridinoline crosslinks.Corresponding Author: Charlotte L. Phillips, Ph.D., Associate Professor, Departments of Biochemistry and Child Health, University of Missouri-Columbia, 1 Hospital Dr., M743 Medical Sciences Bldg., Columbia, MO 65212, Phone: (573) 882-5122, Fax: (573) 884-4597, Email: PhillipsCL@missouri.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. µCT analysis demonstrated genotype-, strain-and age-associated changes in femoral geometry as well as a marked decrease in the amount of bone in oim/oim mice of both strains. Oim/oim mice of both strains, as well as C57BL/6J (B6) mice of all genotypes, had reduced femoral biomechanical strength properties compared to Wt at all ages, although they improved with age. Mineral levels of fluoride, magnesium and sodium were associated with biomechanical strength properties in both strains and all genotypes at all ages. Oim/oim animals also had reduced collagen content as compared to Wt at all ages. Serum pyridinoline crosslinks were highest at two months of age, regardless of strain or genotype. NIH Public AccessStrain differences in bone parameters exist throughout development, implicating a role for genetic background in determining biomechanical strength. Age-associated improvements indicate that oim/ oim animals partially compensate for their weaker bone material, but never attain Wt levels. These studies indicate the importance of genetic back...

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Section: Discussionmentioning

confidence: 84%

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

Carleton¹,

McBride²,

Carson³

et al. 2008

Bone

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“…These samples also showed increased osteoid thickness and volume fraction in the histomorphometric measurements compared with the normal samples. Indeed, the trabecular edges were less mineralized than normal bone.Previously, FTIRI has been employed to study osteoporotic bone (17,19,27) or bone from patients with fragility fractures, (15) as well as bone from patients with ostemalacia. (18) However, to our knowledge, no previous studies have employed FTIRI to investigate bone from patients with ROD.…”

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confidence: 99%

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Isaksson

Turunen

Rieppo

et al. 2010

Journal of Bone and Mineral Research

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Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high-turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n ¼ 11) and patients with renal osteodystrophy (ROD, n ¼ 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate-toamide I ratio (mineral-to-matrix ratio), carbonate-to-phosphate ratio, and carbonate-to-amide I ratio (turnover rate/remodeling activity), as well as the collagen cross-link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate-to-phosphate ( p < .01) and carbonate-to-amide I ( p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization ( p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone-remodeling activity and number of bone cells and FTIRI-calculated parameters based on carbonate-to-phosphate and carbonate-to-amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone. ß 2010 American Society for Bone and Mineral Research.KEY WORDS: BONE COMPOSITION; HISTOMORPHOMETRY; FOURIER TRANSFORM; INFRARED; RENAL OSTEODYSTROPHY; CARBONATE B one is a composite material consisting of a mineral phase (hydroxyapatite), an organic phase (collagen), noncollagenous proteins, lipids, and water. (1,2) Metabolic bone disease is a common term referring to a number of abnormalities caused by a broad spectrum of disorders. Most disorders lead to weakening of the bone or impaired bone function and are followed most often by altered bone mechanical properties. Renal osteodystrophy (ROD) is a chronic kidney disease that can be accompanied by different types of bone pathologies. ROD can lead to defective mineralization, altered bone morphology, and/or bone turnover. (3,4) Commonly, it is accompanied by hyperparathyroid disease, which is characterized by increased bone turnover. Patients with renal osteodystrophy may exhibit bone and joint pain, bone deformation, and spontaneous bone fractures. Bone biopsies followed by quantitative histomorphometry prevail as the ''gold standard'' for the diagnosis of renal osteodystrophy. (5)(6)(7) Histomorphometric analysis emphasizes increased amounts of osteoid and erosion surface and a larger amount of bone cells than what is present in normal bone. (8) However, the invasive nature of obtaining the biopsies, the required experience of the pathologists to identify the abnormalities, as well as the lack of standardized normal limits remain problematic.ROD also commonly results in lower bone ...

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“…Additionally, in the previously published study no strict tissue age normalization was employed, thus the reported results are expected to be dependent on bone turnover. (11) Finally, it has been previously reported that there are significant differences in the intrinsic material properties between normal and osteoporotic human bone, (36)(37)(38) thus extrapolation from normal canine to osteoporotic human bone, although informative, may not be conclusive.…”

Section: Discussionmentioning

confidence: 99%

“…(10,11,37,38) It should be noted that in cases for which bone strength and BMD exhibit divergent trends, the mineral maturity/crystallinity and collagen cross-links ratio correlate with the former rather than the latter. (38,57) It has recently been shown in animals that alterations in collagen cross-links (most notably the pyr/divalent cross-link ratio), coupled with changes in microarchitecture, are sufficient to adversely affect bone biomechanical performance in the absence of any concomitant changes in mineral quantity and quality, even when these changes are anatomically confined to bone-forming surfaces. (61) Both shorter-term and longer-term RIS use resulted in significantly lower pyr/divalent collagen cross-link ratios compared to ALN, in agreement with a recent publication.…”

Section: Discussionmentioning

confidence: 99%

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Effects of alendronate and risedronate on bone material properties in actively forming trabecular bone surfaces

Hofstetter

Gamsjaeger

Phipps³

et al. 2012

Journal of Bone and Mineral Research

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We used Raman and Fourier transform infrared microspectroscopy (FTIRM) analysis to examine the intrinsic bone material properties at actively bone-forming trabecular surfaces in iliac crest biopsies from women with postmenopausal osteoporosis (PMO) who were treated with either alendronate (ALN) or risedronate (RIS). At eight study sites, women were identified who had postmenopausal osteoporosis (PMO), were at least 5 years postmenopause, and had been on long-term therapy (either 3-5 years or >5 years) with daily or weekly ALN or RIS. Following standard tetracycline labeling, biopsies were collected from 102 women (33 treated with ALN for 3-5 years , 35 with ALN for >5 years , 26 with RIS for 3-5 years , and 8 with RIS for >5 years ) and were analyzed at anatomical areas of similar tissue age in bone-forming areas (within the fluorescent double labels). The following outcomes were monitored and reported: mineral to matrix ratio (corresponding to ash weight), relative proteoglycan content (regulating mineralization commencement), mineral maturity (indicative of the mineral crystallite chemistry and stoichiometry, and having a direct bearing on crystallite shape and size), and the ratio of two of the major enzymatic collagen cross-links (pyridinoline/divalent). In RIS-5 there was a significant decrease in the relative proteoglycan content (À5.83% compared to ALN-5), while in both RIS-3 and RIS-5 there was significantly lower mineral maturity/ crystallinity (À6.78% and À13.68% versus ALN-3 and ALN-5, respectively), and pyridinoline/divalent collagen cross-link ratio (À23.09% and À41.85% versus ALN-3 and ALN-5, respectively). The results of the present study indicate that ALN and RIS exert differential effects on the intrinsic bone material properties at actively bone-forming trabecular surfaces. ß

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Bone Fragility and Collagen Cross-Links

Cited by 235 publications

References 49 publications

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Effects of alendronate and risedronate on bone material properties in actively forming trabecular bone surfaces

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