Collagen Resorption Research Articles

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

Serum levels of bone turnover markers including calculation of Z-scores: Data from a Dutch healthy reference cohort

IntroductionBone turnover markers (BTM) are biochemical compounds reflecting different stages of bone metabolism. Their levels change with age and differ between males and females. This makes clinical interpretation and comparison more difficult. Therefore, our aim was to establish BTM reference values which can be used to calculate Z-scores for use in daily clinical practice. MethodsSerum markers of collagen resorption, bone formation/regulation, collagen formation and bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured in non-fasting volunteers without bone-related abnormalities. Raw data was plotted and gender-specific age cohorts were established with their respective means and standard deviations (SD). Z-scores can be calculated using these reference values to correct for the influence of age and gender on BTM. ResultsIn total, 856 individuals were included of which 486 (57 %) were female. Individuals were aged between 7 and 70 years. Highest serum levels of BTM were found in childhood and puberty. Peak levels are higher in boys than girls and prevail at later ages. In adults, BTM levels decrease before reaching stable nadir levels. In adults, 10-year reference cohorts with means and SD were provided to calculate Z-scores. ConclusionWith our data, Z-scores of sCTX, OC, PINP and BALP can be calculated using reference categories (for age and gender) of Caucasian healthy volunteers. Clinicians can use BTM Z-scores to determine whether there are changes in bone turnover physiology beyond those expected during aging. BTM Z-scores facilitate harmonization of data interpretation in daily clinical practice and research.

After an initial balance favoring collagen formation and mineralization, bone turnover markers return to pre-treatment levels during long-term TNF-α inhibition in patients with ankylosing spondylitis.

Bone turnover balance favors bone formation, especially mineralization, during the first 3 years of treatment with TNF-α inhibitors (TNFi). Our aim was to evaluate the course of serum bone turnover markers (BTM) and to investigate if facilitation of mineralization reflected by BTM BALP continues to increase during 6 years of TNFi treatment in patients with ankylosing spondylitis (AS) in daily clinical practice. Included were outpatients from the University Medical Center Groningen (UMCG) participating in the Groningen Leeuwarden Axial SpA (GLAS) cohort who were treated with TNFi for at least 6 years. Serum markers of collagen resorption, bone regulation, collagen formation and facilitator of bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured at baseline, 3 and 6 months, 1, 2, 4 and 6 years. Z-scores were calculated to correct for age and gender. 53 AS patients were eligible for analyses (66% male, mean age 39±11 years). Disease activity showed rapid and sustained improvement after start of TNFi. Evaluating BTM, sCTX did not significantly change during 6 years of treatment. OC was only significantly increased at 3 months compared to baseline, with median change in Z-score of +0.5. PINP significantly increased at 3 and 6 months and 2 years of treatment, with maximum median change in Z-score of +0.3. Interestingly, BALP was significantly increased at all time points up to and including 2 years of TNFi treatment, with maximum change in median Z-score of +1.2, and decreased thereafter. In AS patients receiving long-term TNFi, bone turnover balance favored collagen formation and facilitation of mineralization during the first 2 years of treatment. Thereafter, at 4 and 6 years of follow-up, BTM Z-scores returned to pre-treatment levels.

Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice

Previously, we demonstrated that the administration of either geranylgeraniol (GGOH) or green tea polyphenols (GTP) improved bone health. This study examined the combined effects of GGOH and GTP on glucose homeostasis in addition to bone remodeling in obese mice. We hypothesized that GGOH and GTP would have an additive or synergistic effect on improving glucose homeostasis and bone remodeling possibly in part via suppression of proinflammatory cytokines. Forty-eight male C57BL/6J mice were assigned to a high-fat diet (control), HFD + 400 mg GGOH/kg diet (GG), HFD + 0.5% GTP water (TP), or HFD + GGOH + GTP (GGTP) diet for 14 weeks. Results demonstrated that GTP supplementation improved glucose tolerance in obese mice. Neither GGOH nor GTP affected pancreas insulin or bone formation procollagen type I intact N-terminal, bone volume at the lumbar vertebrae, or bone parameters at the trabecular bone and cortical bone of the femur. There was an interactive effect for serum bone resorption collagen type 1 cross-linked C-telopeptide concentrations, resulting in no-GGOH and no-GTP groups having the highest values. GGOH increased trabecular number and decreased trabecular separation at the lumbar vertebrae. GTP increased trabecular thickness at lumbar vertebrae. The GG group produced the greatest connectivity density and the lowest structure model index. Only GTP, not GGOH, decreased adipokines concentrations (resistin, leptin, monocyte chemoattractant protein-1, and interleukin-6). In an obese male mouse model, individual GGOH and GTP supplementation improved glucose homeostasis, serum CTX, and trabecular microstructure of LV-4. However, the combined GGOH and GTP supplementation compromises such osteoprotective effects on serum CTX and trabecular bone of obese mice.

Evaluation of the complex approach effectiveness of atrophic colpitis treatment in menopausal aged women from the pathogenetic view

Objectives: to determine the status of connective tissue and ionized magnesium value before and after complex treatment of atrophic colpitis with the CO2 laser in menopausal women. Materials and methods. 160 women with atrophic colpitis took part in this prospective study and were divided into three groups depending on the therapy. The main group included 55 patients who underwent CO2 laser therapy. The comparison group included 40 women who underwent CO2 laser therapy and local hormonal treatment with suppositories containing estriol and magnesium saturation by magnesium lactate dihydrate. The control group consisted of 65 women who received only suppositories containing estriol. The duration of treatment was 12 months. In addition to general clinical studies, markers of collagen synthesis (Total PINP, Total PІІІNP), collagen resorption marker (Pyriliks-D), as well as the ionized magnesium value in blood serum were determined in all patients.Results. A significant increase and steady retention at the physiological level of the average value of the Total PINP in the comparison group was revealed. The average level of the Total PIІІNP in patients of this group underwent a significant decrease and remained steadily at the upper limit of the physiological norm. A significant decrease and stable retention at the physiological level of the Pyriliks-D was noted in the comparison group against the background of the proposed therapy. Correction of magnesium status in the comparison group leads to a reliable and stable increase in the Mg+ ions concentration in blood serum.Conclusions. The inclusion CO2 laser in combination with local hormonal therapy and long-term correction of mineral metabolism in the treatment of the comparison group led to the stable normalization and prolonged retention at the physiological level for 12 months of the procollagen type I N-terminal propeptide, procollagen type III N-terminal propeptide, collagen resorption marker Pyriliks-D and a significant increase in magnesium concentration. This is confirms the effectiveness of the proposed complex.

Healing after tooth extraction and alveolar ridge preservation using demineralized cortical allograft particles in a dehiscence type defect: clinical, radiographic and histomorphometric case report

Aim The present article reports clinical, radiographic, and histological healing of a case of alveolar ridge preservation treated with a cortical bone allograft and a bioabsorbable collagen wound dressing membrane for the reconstruction of a damaged extraction socket with a buccal bone dehiscence. Case report In the case reported, alveolar ridge preservation technique was applied in an extraction site with a buccal dehiscence type defect, using an allograft bone substitute and a bioabsorbable collagen wound dressing membrane followed by a successful implant placement at a later stage. Conclusion This case report showed that alveolar ridge preservation technique in a damaged socket with buccal dehiscence, using a freeze dried bone allograft covered with a fast resorption collagen membrane, can lead to new bone formation, of up to 53.53%, and ultimately allow safe implant placement.

First person – Ana Diaz Espinosa

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Ana Diaz Espinosa is first author on ‘Dopamine D1 receptor stimulates cathepsin K-dependent degradation and resorption of collagen I in lung fibroblasts’, published in JCS. Ana conducted the research described in this article while a Post-baccalaureate Research Education Program (PREP) student in Daniel Tschumperlin's lab at the Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN. She is now a PhD student at the Mayo Clinic Graduate School for Biomedical Sciences, investigating how to restore cellular and tissue function by integrating fundamental principles of biology and biomaterials.

Dopamine D1 receptor stimulates cathepsin K-dependent degradation and resorption of collagen I in lung fibroblasts.

Matrix resorption is essential to the clearance of the extracellular matrix (ECM) after normal wound healing. A disruption in these processes constitutes a main component of fibrotic diseases, characterized by excess deposition and diminished clearance of fibrillar ECM proteins, such as collagen type I. The mechanisms and stimuli regulating ECM resorption in the lung remain poorly understood. Recently, agonism of dopamine receptor D1 (DRD1), which is predominantly expressed on fibroblasts in the lung, has been shown to accelerate tissue repair and clearance of ECM following bleomycin injury in mice. Therefore, we investigated whether DRD1 receptor signaling promotes the degradation of collagen type I by lung fibroblasts. For cultured fibroblasts, we found that DRD1 agonism enhances extracellular cleavage, internalization and lysosomal degradation of collagen I mediated by cathepsin K, which results in reduced stiffness of cell-derived matrices, as measured by atomic force microscopy. In vivo agonism of DRD1 similarly enhanced fibrillar collagen degradation by fibroblasts, as assessed by tissue labeling with a collagen-hybridizing peptide. Together, these results implicate DRD1 agonism in fibroblast-mediated collagen clearance, suggesting an important role for this mechanism in fibrosis resolution.This article has an associated First Person interview with the first author of the paper.

16465 Utility of 1565-nm nonablative fractional erbium laser in treatment of pediatric patients with acne scars measured by reflectance confocal microscopy

Background: Acne is a multifactorial inflammatory disease. It affects up to 80% of adolescents. It’s not a disabling disease, but it produces a high psychosocial impact. Acne resolves within an aberrant process with resorption of collagen, leaving scars. For acne scars there are multiple treatments. We use 1565-nm nonablative fractional erbium laser and confocal reflectance microscopy (CRM), which in real time offers the highest level of resolution (near histologic) of superficial skin lesions, to measure the depth of the acne scars before and after the treatment.

Features of the exchange of connective tissue and certain microelements in pregnant women with a risk of postterm pregnancy

Purpose of the study: to investigate the serum content of certain trace elements and synthesis markers (Total P1NP) and collagen resorption (β-CrossLaps) in pregnant women with a risk of postterm pregnancy and their role in this pathology.Materials and methods. Main group included 80 pregnant women with a risk of postterm pregnancy. Control group consisted of 34 pregnant women without a risk of postterm pregnancy demostrating physiologic cervical maturation. Enzyme immunoassay was used for measurement of synthesis markers (Total P1NP - N-terminal propeptide of type I collagen), connective tissue resorption (ß-CrossLaps), and trace elements - Na, K, Mg, P, total and ionized Ca.Results. Significant decrease in the concentration of Total P1NP was noted In pregnant women with a risk of postterm pregnancy compared with the control group (50.90 ± 4.27 ng/ml, p <0.05). The average value of connective tissue resorption marker β-CrossLaps in pregnant women of the main group was significantly higher than in the control ones (0.420 ± 0.02 ng/ml and 0.300 ± 0.02 ng/ml respectively). The total Ca was 1.98 ± 0.03 mmol/L that is 7.9% and 10.4% less than the lower limit of the physiological norm and in the control group (2.21 ± 0.04 mmol/l, p < 0.05) respectively. Mg in the main group was 0.68 ± 0.02 mmol/L, that is at the lower limit of the norm, and 20.9% less than in the control group (0.86 ± 0.03 mmol/L; < 0.05). The total serum vitamin D in pregnant women of the main group was 25.4% less than in the control group (23.62 ± 1.61 ng/ml, p <0.05).Conclusions. An imbalance of the most microelements significant for the normal functioning of connective tissue and processes of transmission of nervous excitation in combination with a deficiency of vitamin D contributes to a cascade of reactions that inhibit the timely restructuring of the cervix structure before childbirth. Pregnant women with a risk of overexposure are characterized by a predominance of type I collagen resorption processes over its synthesis processes, which is probably one of the reasons for the insufficient maturation of the cervix on the eve of childbirth.

A review on biomarkers of bone metabolism in camels (Camelus dromedarius)

Bone metabolism biomarkers of bone formation and bone resorption are released during the bone remodeling processes. In humans as well as in veterinary medicine, these bone biomarkers have attracted much attention in the last decade. However, there are few reports found in the application of bone metabolism biomarkers in camel medicine. In camels, the most commonly used bone formation biomarkers include osteocalcin (OC) and bone-specific alkaline phosphatase (b-ALP). Concerning the bone resorption biomarkers, the most commonly used one is pyridinoline cross-links (PYD). OC is synthesised mostly from by mature osteoblasts. It is believed that OC is associated with mineralisation of newly formed osteoid. Therefore it is considered as a putative biomarker of bone formation and mineralisation. b-ALP is an isoform of alkaline phosphatase and plays an important role in bone formation. With normal liver function in adults, about 50% of total b-ALP is produced from bone in serum. The PYD cross-links, indicators of type I collagen resorption, are found in the mature collagen of bone. It is not only found in mature type I collagen, which is the major type of collagen in bone tissues, but also in collagen types II and III (Eyre et al, 1984). Increased concentrations of PYD in the blood or urine are most commonly considered as indicators of bone resorption. This review article was written to emphasise the importance of commonly used bone formation (OC and b-ALP) and bone resorption (PYD) biomarkers in camels. It is believed that research on bone formation and bone resorption biomarkers in camels will be increasingly used in the future in the diagnosis and prognosis of bone diseases.

Effects of Tunable Keratin Hydrogel Erosion on Recombinant Human Bone Morphogenetic Protein 2 Release, Bioactivity, and Bone Induction.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) delivery from collagen sponges for bone formation is an important clinical example of growth factors in tissue engineering. Side effects from rhBMP-2 burst release and rapid collagen resorption have led to investigation of alternative carriers. Here, keratin carriers with tunable erosion rates were formulated by varying disulfide crosslinking via ratios of oxidatively (keratose) to reductively (kerateine) extracted keratin. In vitro rhBMP-2 bioactivity increased with kerateine content, reaching levels greater than with collagen. Heterotopic bone formation in a mouse model depended on the keratin formulation, highlighting the importance of the growth factor carrier.

Features of the non-alcoholic steatohepatitis and chronic kidney disease courses, pathogenetic correction efficiency

The aim of the study. To establish the mechanisms of mutual burden and progression of non-alcoholic steatohepatitis (NASH) and chronic kidney disease (CKD) in patients with obesity.Material and methods. 114 patients with NASH were examined against the background of І-ІІ degree obesity, including: 52 patients with NASH (group 1) (without accompanying CKD), 62 patients with NASH with a comorbid CKD І-ІІ degree (group 2). The average age of patients was (45.8 ± 3.81) years. The control group consisted of 20 practically healthy persons (PHPs) of the corresponding age and sex. Results. The obtained data testify that under the conditions of the H2S deficit and hyperproduction of homocysteine for the comorbidity of NASH from CKD I-II degree the synthesis and resorption of collagen are activated, but the anabolism processes predominate as a result of the activation of the fibroblasts system, with a significant hyperproduction of acute phase proteins, fibronectin, a higher degree of hyperthyroidism and dyslipidemia with predominance of proatherogenic lipoprotein fractions, and a higher degree of endothelium dysfunction.Conclusions. A significant increase in the synthesis of collagen and glycoproteins (fibronectin) in patients with NASH, which was observed on the background of obesity, was established, which is accompanied by an ineffective resorption of newly formed collagen due to inhibition of collagenolysis against activation of proteinase inhibitors (α2-MG), accompanied by hyperproduction of the fibroblast growth factor, homocysteine, endothelin‑1, deficiency in the liberation of hydrogen sulfide and nitrogen monoxide.

Bioresorption of Porous 3D Matrices Based on Collagen in Liver and Muscular Tissue

Highly porous cylinder-shaped 3D matrices with diameters of 1.3 and 3 mm were obtained by lyophilization of collagen solution. A study in vivo of the mechanism and rate of resorption of the resulting material showed that complete resorption of the matrix occurred 6 weeks after their implantation into liver tissue and 3 weeks after implantation into muscle tissue of animals. Surrounding tissues were not altered or damaged. Histological analysis revealed that, simultaneously with the resorption of matrix collagen, connective tissue and blood vessels were formed. This allows us to recommend the developed porous material based on collagen for use as matrices for tissue engineering and cellular transplantation.

MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases

Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM. First, we demonstrated that the release of lactate at the bone site is mediated by monocarboxylate transporter 4 (MCT4), as revealed by immunostaining and MCT4 localization at the plasma membrane of tumor cells in mouse model of BM and in human tissue sections of BM. Then, we showed that in vitro lactate is uptaken by osteoclasts to be used as a fuel for the oxidative metabolism of osteoclasts, ultimately enhancing Type I collagen resorption. The passive transport of lactate into osteoclasts was mediated by MCT1: MCT1 expression is significantly upregulated during osteoclast differentiation and Type I collagen resorption is significantly impaired when osteoclasts are treated with 7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid, an MCT-1 inhibitor. Together, these data demonstrate that lactate released by glycolytic breast carcinoma cells in the bone microenvironment promotes the formation of osteolytic lesions, and provide the rationale for further studies on the use of MCT1 targeting as a novel therapeutic approach in advanced cancer patients with BM.

Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases.

Loss Of Fatty Acid Synthase Increases The Severity Of Lung Fibrosis By Preventing Collagen Resorption

Loss Of Fatty Acid Synthase Increases The Severity Of Lung Fibrosis By Preventing Collagen Resorption

Abstract 3282: Host-derived MMP-13 mediates multiple myeloma-induced osteolysis

Abstract Myeloma cells promote osteolysis and suppress osteogenesis in the bone microenvironment by regulating osteoclasts (OCL) and osteoblasts (OBL), respectively. Patients often suffer painful, osteoporotic bone status as diseases progresses. Bone consists of 90% type-I collagen, which is degraded by OCL derived cathepsin K during regular bone remodeling. While bisphosphonates delay pathological fracture, they have little impact on overall survival; therefore, development of new therapies is crucial. Matrix metalloproteinase-13 (MMP-13) is an enzyme involved in type-I collagen degradation and resorption. Immunohistochemical staining of a panel of human myeloma biopsies (n = 15) show high MMP-13 expression predominantly in bone stroma and to a lesser extent in the myeloma compartment. Consistent with previous reports, MMP-13 expression localizes to mesenchymal stromal cells (MSC) and OBLs rather than OCLs. Further supporting these observations, analysis of publically available data sets revealed upregulation of MMP-13 expression in MSCs co-cultured with myeloma cells (1.81 LogFC, p<0.05). Based on this rationale, we examined whether stromal MMP-13 plays a role in myeloma progression. To test our hypothesis, we generated immune-compromised MMP-13-null mice on a C57BL/6 background for ex vivo and in vivo studies. Mouse myeloma cell line, 5TGM1, homes to the skeleton and progresses upon tail vein injection in this model. Our in vivo studies showed that 5TGM1-bearing MMP-13-null mice had significantly improved overall survival compared to wild-type controls (Mean 39 vs. 43 days; p<0.05). Interestingly, we detected no difference in tumor burden between wild-type and MMP-13-null groups, by bioluminescence or IgG2b quantification. We observed significantly less bone degradation in the MMP-13 null mice compared to controls as determined by μCT and histomorphometry. Surprisingly, however, tartrate-resistant acid phosphatase (TRAP) staining in bone sections showed no difference in OCL numbers and size in vivo, but ex vivo OCL differentiation cultures demonstrated fewer (Mean 89 vs. 16; p<0.05) and smaller (Mean 29 vs. 20 μm; p<0.05) OCLs in the MMP-13-null group. Furthermore, we note that OCLs derived from MMP-13-null bone marrow have a reduced capacity to resorb bone mimetic (24% reduction; p<0.05). Time course analyses indicate OCL formation is delayed in MMP-13-null cultures, and may partially explain observed differences between groups in vivo. Mechanistically, we are assessing MMP specific cross-linked carboxy-terminal telopeptide of type-I collage (ICTP) fragments in sera of tumor-bearing MMP-13-null and wild-type animals. Taken together, the data suggests that host stroma-derived MMP-13 contributes to myeloma progression and bone turnover, by regulating the formation and functionality of OCLs. The outcomes of our study provide rationale for the use of MMP-13 specific inhibitors in the treatment of multiple myeloma. Citation Format: Chen Hao Lo, Gemma Shay, Conor C. Lynch. Host-derived MMP-13 mediates multiple myeloma-induced osteolysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3282.

Short-term effects of teriparatide versus placebo on bone biomarkers, structure, and fracture healing in women with lower-extremity stress fractures: A pilot study

AimsIn this pilot, placebo-controlled study, we evaluated whether brief administration of teriparatide (TPTD) in premenopausal women with lower-extremity stress fractures would increase markers of bone formation in advance of bone resorption, improve bone structure, and hasten fracture healing according to magnetic resonance imaging (MRI). MethodsPremenopausal women with acute lower-extremity stress fractures were randomized to injection of TPTD 20-µg subcutaneous (s.c.) (n = 6) or placebo s.c. (n = 7) for 8 weeks. Biomarkers for bone formation N-terminal propeptide of type I procollagen (P1NP) and osteocalcin (OC) and resorption collagen type-1 cross-linked C-telopeptide (CTX) and collagen type 1 cross-linked N-telopeptide (NTX) were measured at baseline, 4 and 8 weeks. The area between the percent change of P1NP and CTX over study duration is defined as the anabolic window. To assess structural changes, peripheral quantitative computed topography (pQCT) was measured at baseline, 8 and 12 weeks at the unaffected tibia and distal radius. The MRI of the affected bone assessed stress fracture healing at baseline and 8 weeks. ResultsAfter 8 weeks of treatment, bone biomarkers P1NP and OC increased more in the TPTD- versus placebo-treated group (both p ≤ 0.01), resulting in a marked anabolic window (p ≤ 0.05). Results from pQCT demonstrated that TPTD-treated women showed a larger cortical area and thickness compared to placebo at the weight bearing tibial site, while placebo-treated women had a greater total tibia and cortical density. No changes at the radial sites were observed between groups. According to MRI, 83.3% of the TPTD- and 57.1% of the placebo-treated group had improved or healed stress fractures (p = 0.18). ConclusionsIn this randomized, pilot study, brief administration of TPTD showed anabolic effects that TPTD may help hasten fracture healing in premenopausal women with lower-extremity stress fractures. Larger prospective studies are warranted to determine the effects of TPTD treatment on stress fracture healing in premenopausal women.

Alteration in the Collagen Content of the Human Uterus During Pregnancy and Post Partum Involution

The physiological resorption of collagen during recoveryfrom experimental cirrhosis was demonstrated in1947 (1). Factors which influence the deposition anddisappearance of collagen in experimental cirrhosis,as well as the phenomenon of the regression of scartissue, were examined subsequently (2, 3). A strikingresorption of collagen from the rat uterus followingparturition was described by Harkness and Harknessin 1954 (4). Later these authors (5), and Harkness andMoralee (6), suggested that the post partum uterus isespecially suitable for investigation of the physiologicaldissolution and catabolism of endogenous collagen. Thepresent study was undertaken to determine the alterationsin the nature and content of collagen occurring inthe myometrium of the human uterus during pregnancyand the post partum involutionary period.