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Martin TJ, Seeman E. Bone Remodeling and Modeling: Cellular Targets for Antiresorptive and Anabolic Treatments, Including Approaches Through the Parathyroid Hormone (PTH)/PTH-Related Protein Pathway. Neurospine 2023; 20:1097-1109. [PMID: 38171279 PMCID: PMC10762382 DOI: 10.14245/ns.2346966.483] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Bone is continuously in a state of building and renewal, though the process of remodeling that takes place at many sites asynchronously throughout the skeleton, with bone formation and resorption equal at these sites (bone multicellular units). Remodeling takes place on bone surfaces, both on trabeculae and in the cortex, and serves the purposes of replacing old bone or that damaged by microfractures throughout the skeleton. The bone loss and consequent osteoporotic fractures that result from excess resorption over formation have mainly been prevented or treated by antiresorptive drugs that inhibit osteoclast formation and/or activity. Virtually all of the evidence leading to acceptance of antiresorptive drugs as treatment has depended upon their prevention of vertebral fractures. In recent decades, new prospects came of anabolic treatments that partly restore bone volume and microstructure restore bone that has been lost. The first of these was parathyroid hormone (PTH), shown by daily injection to increase markers of bone formation and prevent fractures. This field of interest enlarged with the discovery of PTH-related protein (PTHrP), so closely related in structure and action to PTH. The structural relationship between PTH and PTHrP is important in assessing their physiological and pharmacological roles, with the N-terminal domains of the 2 having virtually equal actions on target cells. Abaloparatide, a peptide analogue based on the structures of PTHrP and PTH, has been approved in some countries as a therapy for osteoporosis. Treatment through the PTH receptor activation pathway, and probably with any anabolic therapy, needs to be followed by antiresorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for antiresorptive drugs.
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Affiliation(s)
- Thomas John Martin
- Department of Medicine and St. Vincent’s Institute of Medical Research, University of Melbourne, Melbourne, Australia
| | - Ego Seeman
- Department of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Australia
- Mary MacKillop Institute of Health Research, Australian Catholic University, Melbourne, Australia
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Misof BM, Roschger P, Mähr M, Fratzl-Zelman N, Glorieux FH, Hartmann MA, Rauch F, Blouin S. Accelerated mineralization kinetics in children with osteogenesis imperfecta type 1. Bone 2023; 166:116580. [PMID: 36210024 DOI: 10.1016/j.bone.2022.116580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/24/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022]
Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria.
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Matthias Mähr
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Francis H Glorieux
- Shriners Hospital for Children and McGill University, Montreal, QC H4A 0A9, Canada
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Frank Rauch
- Shriners Hospital for Children and McGill University, Montreal, QC H4A 0A9, Canada
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
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3
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John Martin T. Aspects of intercellular communication in bone and implications in therapy. Bone 2021; 153:116148. [PMID: 34389478 DOI: 10.1016/j.bone.2021.116148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/18/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
Communication processes among the cells of bone are essential for the structure and function of the organ. After it was proposed that communication from the osteoblast lineage to hemopoietic cells initiated osteoclastogenesis, the molecular controls were identified to be the tumour necrosis factor ligand and receptor families. This was followed by revelation of very many signalling processes among the cells of bone that regulate the three phases of bone remodelling, the resorption, reversal and formation phases. In many instances the ways in which these mechanisms operate can determine how drugs act on bone, whether they be inhibitors of resorption or promoters of formation.
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Affiliation(s)
- T John Martin
- St Vincent's Institute of Medical Research, The University of Melbourne Department of Medicine at St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
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Hartmann MA, Blouin S, Misof BM, Fratzl-Zelman N, Roschger P, Berzlanovich A, Gruber GM, Brugger PC, Zwerina J, Fratzl P. Quantitative Backscattered Electron Imaging of Bone Using a Thermionic or a Field Emission Electron Source. Calcif Tissue Int 2021; 109:190-202. [PMID: 33837801 PMCID: PMC8273060 DOI: 10.1007/s00223-021-00832-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/25/2021] [Indexed: 12/21/2022]
Abstract
Quantitative backscattered electron imaging is an established method to map mineral content distributions in bone and to determine the bone mineralization density distribution (BMDD). The method we applied was initially validated for a scanning electron microscope (SEM) equipped with a tungsten hairpin cathode (thermionic electron emission) under strongly defined settings of SEM parameters. For several reasons, it would be interesting to migrate the technique to a SEM with a field emission electron source (FE-SEM), which, however, would require to work with different SEM parameter settings as have been validated for DSM 962. The FE-SEM has a much better spatial resolution based on an electron source size in the order of several 100 nanometers, corresponding to an about [Formula: see text] to [Formula: see text] times smaller source area compared to thermionic sources. In the present work, we compare BMDD between these two types of instruments in order to further validate the methodology. We show that a transition to higher pixel resolution (1.76, 0.88, and 0.57 μm) results in shifts of the BMDD peak and BMDD width to higher values. Further the inter-device reproducibility of the mean calcium content shows a difference of up to 1 wt% Ca, while the technical variance of each device can be reduced to [Formula: see text] wt% Ca. Bearing in mind that shifts in calcium levels due to diseases, e.g., high turnover osteoporosis, are often in the range of 1 wt% Ca, both the bone samples of the patients as well as the control samples have to be measured on the same SEM device. Therefore, we also constructed new reference BMDD curves for adults to be used for FE-SEM data comparison.
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Affiliation(s)
- Markus A. Hartmann
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Barbara M. Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Andrea Berzlanovich
- Unit of Forensic Gerontology, Center of Forensic Science, Medical University of Vienna, Sensengasse 2, 1090 Vienna, Austria
| | - Gerlinde M. Gruber
- Department of Anatomy and Biomechanics, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria
| | - Peter C. Brugger
- Center for Anatomy and Cell Biology, Department of Anatomy, Medical University of Vienna, Währingerstrasse 13, 1090 Vienna, Austria
| | - Jochen Zwerina
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Peter Fratzl
- Department of Biomaterials, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
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Martin TJ, Sims NA, Seeman E. Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R. Endocr Rev 2021; 42:383-406. [PMID: 33564837 DOI: 10.1210/endrev/bnab005] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Indexed: 12/13/2022]
Abstract
Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis.
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Affiliation(s)
- T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Ego Seeman
- The University of Melbourne, Department of Medicine at Austin Health, Heidelberg, Victoria, Australia
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Fratzl-Zelman N, Wesseling-Perry K, Mäkitie RE, Blouin S, Hartmann MA, Zwerina J, Välimäki VV, Laine CM, Välimäki MJ, Pereira RC, Mäkitie O. Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations. Bone 2021; 146:115900. [PMID: 33618074 DOI: 10.1016/j.bone.2021.115900] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 12/22/2022]
Abstract
CONTEXT Patients with osteoporosis-associated WNT1 or PLS3 mutations have unique bone histomorphometric features and osteocyte-specific hormone expression patterns. OBJECTIVE To investigate the effects of WNT1 and PLS3 mutations on bone material properties. DESIGN Transiliac bone biopsies were evaluated by quantitative backscattered electron imaging, immunohistochemistry, and bone histomorphometry. SETTING Ambulatory patients. PATIENTS Three pediatric and eight adult patients with WNT1 or PLS3 mutations. INTERVENTION Bone mineralization density distribution and osteocyte protein expression was evaluated in 11 patients and repeated in six patients who underwent repeat biopsy after 24 months of teriparatide treatment. MAIN OUTCOME MEASURE Bone mineralization density distribution and protein expression. RESULTS Children with WNT1 or PLS3 mutations had heterogeneous bone matrix mineralization, consistent with bone modeling during growth. Bone matrix mineralization was homogenous in adults and increased throughout the age spectrum. Teriparatide had very little effect on matrix mineralization or bone formation in patients with WNT1 or PLS3 mutations. However, teriparatide decreased trabecular osteocyte lacunae size and increased trabecular bone FGF23 expression. CONCLUSION The contrast between preserved bone formation with heterogeneous mineralization in children and low bone turnover with homogenous bone mineral content in adults suggests that WNT1 and PLS3 have differential effects on bone modeling and remodeling. The lack of change in matrix mineralization in response to teriparatide, despite clear changes in osteocyte lacunae size and protein expression, suggests that altered WNT1 and PLS3 expression may interfere with coupling of osteocyte, osteoblast, and osteoclast function. Further studies are warranted to determine the mechanism of these changes.
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Affiliation(s)
- Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Jochen Zwerina
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Ville-Valtteri Välimäki
- Department of Orthopaedics and Traumatology, Helsinki University Central Hospital and Helsinki University, Jorvi Hospital, Espoo, Finland
| | - Christine M Laine
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Endocrinology, Institute of Medicine, Sahlgrenska University Hospital and University of Gothenburg, Gothenburg, Sweden
| | - Matti J Välimäki
- Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Renata C Pereira
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Outi Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland; Department of Orthopedics, Institute of Clinical Sciences, Sahlgrenska University Hospital and University of Gothenburg, Gothenburg, Sweden; Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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Cosman F, Dempster DW. Anabolic Agents for Postmenopausal Osteoporosis: How Do You Choose? Curr Osteoporos Rep 2021; 19:189-205. [PMID: 33635520 DOI: 10.1007/s11914-021-00663-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW There are now three anabolic agents available for the treatment of postmenopausal women at high risk for fracture. The purpose of this review is to supply a rationale to aid in determining which agent should be used in which clinical settings. RECENT FINDINGS Studies over the last decade have shown that anabolic agents produce faster and larger effects against fracture than antiresorptive agents. Furthermore, trials evaluating anabolic antiresorptive treatment sequences have shown that anabolic first treatment strategies produce the greatest benefits to bone density, particularly in the hip region. However, there are no head-to-head evaluations of the three anabolic therapies with fracture outcomes or bone density, and these studies are not likely to occur. How to decide which agent to use at which time in a woman's life is unknown. We review the most significant clinical trials of anabolic agents which have assessed fracture, areal or volumetric bone density, microarchitecture, and/or bone strength, as well as information gleaned from histomorphometry studies to provide a rationale for consideration of one agent vs another in various clinical settings. There is no definitive answer to this question; all three agents increase bone strength and reduce fracture risk rapidly. Since the postmenopausal lifespan could be as long as 40-50 years, it is likely that very high-risk women will utilize different anabolic agents at different points in their lives.
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Affiliation(s)
- Felicia Cosman
- Department of Medicine, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY, 10032-3784, USA.
- Endocrinology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
| | - David W Dempster
- Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY, 10032-3784, USA
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Winzenrieth R, Ominsky MS, Wang Y, Humbert L, Weiss RJ. Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling. Osteoporos Int 2021; 32:575-583. [PMID: 33496831 PMCID: PMC7929959 DOI: 10.1007/s00198-020-05806-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/17/2020] [Indexed: 11/24/2022]
Abstract
UNLABELLED In postmenopausal osteoporotic women in ACTIVE, abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA. INTRODUCTION In ACTIVE, abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 μg, were significantly greater than with open-label teriparatide (TPTD), 20 μg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur. METHODS Hip DXA images from a subset of randomly selected patients in the ACTIVE trial (n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18. RESULTS Similar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains. CONCLUSION These results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.
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Affiliation(s)
- R Winzenrieth
- Galgo Medical, Carrer de París, 179 2°, Barcelona, 08036, Spain
| | - M S Ominsky
- Radius Health, Inc., 950 Winter Street, Waltham, MA, 02451, USA
| | - Y Wang
- Radius Health, Inc., 950 Winter Street, Waltham, MA, 02451, USA
| | - L Humbert
- Galgo Medical, Carrer de París, 179 2°, Barcelona, 08036, Spain
| | - R J Weiss
- Radius Health, Inc., 950 Winter Street, Waltham, MA, 02451, USA.
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Misof BM, Roschger P, Zhou H, Nieves JW, Bostrom M, Cosman F, Lindsay R, Klaushofer K, Dempster DW. No evidence for alteration in early secondary mineralization by either alendronate, teriparatide or combination of both in transiliac bone biopsy samples from postmenopausal osteoporotic patients. Bone Rep 2020; 12:100253. [PMID: 32215284 PMCID: PMC7090359 DOI: 10.1016/j.bonr.2020.100253] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022] Open
Abstract
The influence of treatment with alendronate (ALN), teriparatide (TPTD) or concurrent treatment with both on the human bone matrix mineralization has not yet been fully elucidated. For this purpose we analyzed quadruple fluorochrome labelled transiliac bone biopsy samples (n = 66) from postmenopausal osteoporotic women with prior and ongoing ALN (ALN-Rx arm) or without ALN (Rx-Naïve arm) after 7 months treatment with cyclic or daily TPTD or without TPTD using quantitative backscattered electron imaging and confocal scanning laser microscopy. Additionally to the bone mineralization density distribution (BMDD) of entire cancellous and cortical compartments, we measured the mineralization kinetics, i.e. the calcium concentration between the younger (Ca_DL2) and older double labels (Ca_DL1), and in interstitial bone (Ca_int) in a subset of the biopsy cohort. We found the BMDD from the patients with prior and ongoing ALN generally shifted to higher calcium concentrations compared to those without ALN (average degree of mineralization in cancellous bone Cn.CaMean + 3.1%, p<0.001). The typical BMDD changes expected by cyclic or daily TPTD treatment due to the increased bone turnover/formation, e.g. an increase in low mineralized bone area were not observed. Additionally, we found no influence of treatment with ALN or TPTD or combination thereof on Ca_DL2, Ca_DL1, or Ca_int. Pooling the information from all groups, Ca_DL1 was +5.9% (p<0.001) higher compared to Ca_DL2, corresponding to a mineralization rate of 0.18 wt% Ca per week during the early secondary mineralization process. Our data suggest that the patients in the ALN-Rx arm had more highly mineralized bone matrix than those without ALN due to their lower bone turnover. The reason for the unexpected BMDD findings in the TPTD treated remain unknown and cannot be attributed to altered mineralization kinetics as no differences in the time course of early secondary mineralization were observed between the treatment groups.
Quadruple fluorescence labeling provided analysis of early secondary bone mineralization rate in osteoporotic patients. Alendronate, teriparatide or combination of both had no influence on early secondary bone mineralization in patients. The early secondary mineralization rate (increase in mineral content with time) was found to be 0.18 wt% Ca per week. Patients in the ALN-Rx arm had higher average bone matrix mineralization than the patients in the Rx-naïve arm.
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Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Hua Zhou
- Regional Bone Center and Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY, USA
| | - Jeri W Nieves
- Department of Epidemiology, Columbia University, New York, NY, USA.,Hospital for Special Surgery, New York, NY, USA
| | - Mathias Bostrom
- Regional Bone Center and Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY, USA.,Hospital for Special Surgery, New York, NY, USA
| | - Felicia Cosman
- Department of Medicine, Columbia University, New York, NY, USA
| | - Robert Lindsay
- Regional Bone Center and Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - David W Dempster
- Regional Bone Center and Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY, USA.,Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Abstract
Numerous safe and efficient drug therapies are currently available to decrease risk of low trauma fractures in patients with osteoporosis including postmenopausal, male, and secondary osteoporosis. In this chapter, we give first an overview of the most important outcomes regarding fracture risk reduction, change in bone mineral density (BMD by DXA) and/or bone markers of the phase III clinical studies of well-established therapies (such as Bisphosphonates, Denosumab or Teriparatide) and also novel therapies (such as Romosozumab or Abaloparatide) and highlight their mechanisms of action at bone tissue/material level. The latter understanding is not only essential for the choice of drug, duration and discontinuation of treatment but also for the interpretation of the clinical outcomes (in particular of eventual changes in BMD) after drug administration. In the second part of this chapter, we focus on the management of different forms of osteoporosis and give a review of the respective current guidelines for treatment. Adverse effects of treatment such as atypical femoral fractures, osteonecrosis of the jaw or influence of fracture healing are considered also in this context.
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Ramchand SK, Seeman E. Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy. Handb Exp Pharmacol 2020; 262:423-450. [PMID: 32232792 DOI: 10.1007/164_2020_354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume.Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling - fewer BMUs remodel, "turn over," the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50-60% but only reduce nonvertebral fractures by 20-30%.Restoring bone volume, microstructure, and material composition, "curing" bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested.
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Affiliation(s)
- Sabashini K Ramchand
- Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA.
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia.
| | - Ego Seeman
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia
- Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC, Australia
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12
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Farlay D, Bala Y, Rizzo S, Bare S, Lappe JM, Recker R, Boivin G. Bone remodeling and bone matrix quality before and after menopause in healthy women. Bone 2019; 128:115030. [PMID: 31404670 DOI: 10.1016/j.bone.2019.08.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 07/18/2019] [Accepted: 08/03/2019] [Indexed: 01/23/2023]
Abstract
Acceleration of remodeling activity after menopause leads to bone loss and fragility, however, whether this is associated with modifications of bone matrix quality has been less studied. The impact of variation in bone remodeling rate on bone matrix has been studied mainly in pathologies or anti-osteoporotic treatments. However, in healthy women this has been less studied. We analyzed, at the global level, bone matrix quality in bone biopsies from 3 groups of healthy women (20 per group): 1) before menopause (PreM), 2) 1 year after menopause (PostM, paired biopsies with preM), and 3) 14 (±9) years after menopause (LT-PostM). The mean degree of mineralization (DMB) and heterogeneity index (HI) of mineralization were assessed by X-ray microradiography on whole bone matrix; intrinsic properties (mineral/organic ratio, mineral maturity, mineral crystallinity, collagen maturity) were assessed by Fourier Transform Infrared microspectroscopy, microhardness by microindentation, both at a global level and calculated by mean of several measurements over the whole tissue area. In PostM compared to PreM (bone remodeling rate had doubled), mean DMB measured on the entire bone plane (whole bone matrix) of the sample was not different. HI was increased in trabecular bone indicating a higher heterogeneity of mineralization. However, in PostM, mineral/organic ratio (trabecular) and microhardness (cortical and trabecular) were decreased, whereas mineral/collagen maturation or crystal size/perfection were unchanged. Thus, in PostM, the local mineral content and microhardness were first affected. In LT-PostM (bone remodeling rate was 3 times higher), the mean DMB was still not different. However, the mineral/organic ratio, microhardness, mineral maturity, crystallinity all were lower compared to PreM and PostM, in both cortical and trabecular bone. Bone remodeling rate was negatively correlated with microhardness, DMB, mineral/organic and crystallinity. This suggests that increases in bone remodeling rates after menopause have a direct impact on bone quality by inducing the formation of more extensive "immature" bone areas, but the amount of immature bone does not cause modification of the global DMB.
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Affiliation(s)
- D Farlay
- INSERM, Université de Lyon, UMR 1033, F-69008 Lyon, France.
| | - Y Bala
- INSERM, Université de Lyon, UMR 1033, F-69008 Lyon, France
| | - S Rizzo
- INSERM, Université de Lyon, UMR 1033, F-69008 Lyon, France
| | - S Bare
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - J M Lappe
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - R Recker
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA
| | - G Boivin
- INSERM, Université de Lyon, UMR 1033, F-69008 Lyon, France
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13
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Hofstaetter JG, Misof BM, Jones DC, Zoehrer R, Blouin S, Schueler C, Paschalis EP, Erben RG, Weinkamer R, Klaushofer K, Roschger P. Biomechanical and Bone Material Properties of Schnurri-3 Null Mice. JBMR Plus 2019; 3:e10226. [PMID: 31768487 PMCID: PMC6874182 DOI: 10.1002/jbm4.10226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/01/2019] [Accepted: 07/04/2019] [Indexed: 12/31/2022] Open
Abstract
Schnurri‐3 (Shn3) is an essential regulator of postnatal skeletal remodeling. Shn3‐deficient mice (Shn3–/–) have high bone mass; however, their bone mechanical and material properties have not been investigated to date. We performed three‐point bending of femora, compression tests of L3 vertebrae. We also measured intrinsic material properties, including bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics by quantitative backscatter electron imaging, as well as collagen cross‐linking by Fourier transform infrared microspectroscopy of femora from Shn3–/– and WT mice at different ages (6 weeks, 4 months, and 18 months). Moreover, computer modeling was performed for the interpretation of the BMDD outcomes. Femora and L3 vertebrae from Shn3–/– aged 6 weeks revealed increased ultimate force (2.2‐ and 3.2‐fold, p < .01, respectively). Mineralized bone volume at the distal femoral metaphysis was about twofold (at 6 weeks) to eightfold (at 4 and 18 months of age) in Shn3–/– (p < .001). Compared with WT, the average degree of trabecular bone mineralization was similar at 6 weeks, but increased at 4 and 18 months of age (+12.6% and +7.7%, p < .01, respectively) in Shn3–/–. The analysis of OLS characteristics revealed a higher OLS area for Shn3–/– versus WT at all ages (+16%, +23%, +21%, respectively, p < .01). The collagen cross‐link ratio was similar between groups. We conclude that femora and vertebrae from Shn3–/– had higher ultimate force in mechanical testing. Computer modeling demonstrated that in cases of highly increased bone volume, the average degree of bone matrix mineralization can be higher than in WT bone, which was actually measured in the older Shn3–/– groups. The area of 2D osteocyte lacunae sections was also increased in Shn3‐deficiency, which could only partly be explained by larger remnant areas of primary cortical bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Jochen G Hofstaetter
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria.,Orthopaedic Hospital Vienna Speising Vienna Austria
| | - Barbara M Misof
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
| | - Dallas C Jones
- Department of Immunology and Infectious Diseases Harvard School of Public Health Boston MA USA
| | - Ruth Zoehrer
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
| | - Stéphane Blouin
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
| | - Christiane Schueler
- Department of Biomedical Sciences University of Veterinary Medicine Vienna Austria
| | - Eleftherios P Paschalis
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
| | - Reinhold G Erben
- Department of Biomedical Sciences University of Veterinary Medicine Vienna Austria
| | - Richard Weinkamer
- Department of Biomaterials Max Planck Institute of Colloids and Interfaces Potsdam Germany
| | - Klaus Klaushofer
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
| | - Paul Roschger
- 1st Medical Department Hanusch Hospital Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling Vienna Austria
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14
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Deluiz D, Delcroix GJR, D'Ippolito G, Grau-Monge C, Bonnin-Marquez A, Reiner T, Tinoco EMB, Amadeu T, Pires FR, Schiller PC. Human Bone Marrow-Derived Mesenchymal Stromal Cell-Seeded Bone Biomaterial Directs Fast and Superior Mandibular Bone Augmentation in Rats. Sci Rep 2019; 9:11806. [PMID: 31413279 PMCID: PMC6694159 DOI: 10.1038/s41598-019-48236-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/29/2019] [Indexed: 01/11/2023] Open
Abstract
Atrophic maxillary ridges present a challenge in the field of oral implantology. Autologous bone is still considered the gold standard grafting material, but the increased morbidity and surgical complications represent a major drawback for its use. The aim of this study was to assess the efficacy of an off-the-shelf cell-seeded bone biomaterial for mandibular bone augmentation, compared to its acellular counterpart. We used a rat model to test the osteogenic properties of bone marrow-derived mesenchymal stromal cells (MSCs)-seeded bone microparticles compared to acellular bone microparticles alone. Rats were euthanized at 4 and 8 weeks, and results analyzed using micro-CT imaging, histology (H&E, Masson's Trichrome), histomorphometry and immunohistology (Tartrate-Resistant Acid Phosphatase-TRAP, Osteocalcin and human specific anti-mitochondria antibodies). Micro-CT analysis demonstrated that the cell-seeded biomaterial achieved significantly more bone volume formation at 4 weeks (22.75 ± 2.25 mm3 vs 12.34 ± 2.91 mm3, p = 0.016) and at 8 weeks (64.95 ± 5.41 mm3 vs 42.73 ± 10.58 mm3, p = 0.029), compared to the acellular bone microparticles. Histology confirmed that the cell-seeded biomaterial was almost completely substituted at 8 weeks, in opposition to the acellular biomaterial group. Immunohistochemical analysis showed a significantly higher number of TRAP and Osteocalcin positive cells at 4 weeks in the cell-seeded group compared to the acellular group, thereby demonstrating a higher rate of bone remodeling in the presence of MSCs. The grafted human cells remained viable and were detected up to at least 8 weeks, as observed using the human specific anti-mitochondria antibody. This off-the-shelf material available in unlimited quantities could therefore represent a significant advance in the field of mandibular bone augmentation by providing a larger volume of new bone formation in a shorter time.
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Affiliation(s)
- Daniel Deluiz
- Department of Periodontology, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA.
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Gaëtan J-R Delcroix
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
- Nova Southeastern University, College of Allopathic Medicine, Fort Lauderdale, FL, USA
| | - Gianluca D'Ippolito
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
- Department of Biomedical Engineering, College of Engineering, University of Miami, Miami, FL, USA
| | - Cristina Grau-Monge
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andrea Bonnin-Marquez
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
| | - Teresita Reiner
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA
| | - Eduardo M B Tinoco
- Department of Periodontology, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Thaís Amadeu
- Department of Pathology and Laboratories, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Fabio R Pires
- Department of Oral Pathology, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Paul C Schiller
- Geriatric Research, Education, and Clinical Center, and Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA.
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, FL, USA.
- Department of Biochemistry & Molecular Biology and Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
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15
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Eugster PJ, Chtioui H, Herren A, Dunand M, Cappelle D, Bourquin J, Buclin T, Grouzmann E. Sub-picomolar quantification of PTH 1-34 in plasma by UHPLC-MS/MS after subcutaneous injection of teriparatide and identification of PTH 1-33, its degradation product. J Pharm Biomed Anal 2019; 166:205-212. [PMID: 30660035 DOI: 10.1016/j.jpba.2019.01.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/07/2019] [Accepted: 01/08/2019] [Indexed: 01/01/2023]
Abstract
Teriparatide (PTH 1-34, Forsteo®) is a bioactive N-terminal fragment of the native endogenous parathyroid hormone (PTH 1-84) recommended for the treatment of osteoporosis in patients with high risk of fracture. Since PTH 1-34 may undergo proteolysis we have validated an ultra-high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for unambiguously measuring intact PTH 1-34 with the same sensitivity as ELISA, at subpicomolar level (LLOQ at 0.4 pM). The full chromatographic run was achieved in 16.5 min. The method validation showed satisfactory intra- and inter-assay precision (CV < 13%) and excellent trueness (<5%), and almost no matrix effect (recoveries 78-92%). We found that after subcutaneous injection in two volunteers, PTH 1-34 half-life was shorter with UHPLC-MS/MS and that ELISA was overestimating PTH 1-34 late concentrations in both volunteers. Qualitative mass spectrometry was performed and led to the discovery of PTH 1-33, a fragment of PTH 1-34 with unknown function. This study emphasized the importance of switching from immunoassays to mass spectrometry when measuring bioactive peptides prompt to proteolysis into fragments that may exhibit altered bioactivity and duration of action.
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Affiliation(s)
- Philippe J Eugster
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
| | - Haithem Chtioui
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Adeline Herren
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Marielle Dunand
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Delphine Cappelle
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Julien Bourquin
- Waters Corporation, Stamford Avenue, Altrincham Road, Wilmslow, SK9 4AX, United Kingdom
| | - Thierry Buclin
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Eric Grouzmann
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
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16
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Vrahnas C, Buenzli PR, Pearson TA, Pennypacker BL, Tobin MJ, Bambery KR, Duong LT, Sims NA. Differing Effects of Parathyroid Hormone, Alendronate, and Odanacatib on Bone Formation and on the Mineralization Process in Intracortical and Endocortical Bone of Ovariectomized Rabbits. Calcif Tissue Int 2018; 103:625-637. [PMID: 30019315 DOI: 10.1007/s00223-018-0455-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 07/10/2018] [Indexed: 02/02/2023]
Abstract
Bone is formed by deposition of a collagen-containing matrix (osteoid) that hardens over time as mineral crystals accrue and are modified; this continues until bone remodeling renews that site. Pharmacological agents for osteoporosis differ in their effects on bone remodeling, and we hypothesized that they may differently modify bone mineral accrual. We, therefore, assessed newly formed bone in mature ovariectomized rabbits treated with the anti-resorptive bisphosphonate alendronate (ALN-100µ g/kg/2×/week), the anabolic parathyroid hormone (PTH (1-34)-15µ g/kg/5×/week), or the experimental anti-resorptive odanacatib (ODN 7.5 µM/day), which suppresses bone resorption without suppressing bone formation. Treatments were administered for 10 months commencing 6 months after ovariectomy (OVX). Strength testing, histomorphometry, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone strength, bone formation, and mineral accrual, respectively, in newly formed endocortical and intracortical bone. In Sham and OVX endocortical and intracortical bone, three modifications occurred as the bone matrix aged: mineral accrual (increase in mineral:matrix ratio), carbonate substitution (increase in carbonate:mineral ratio), and collagen molecular compaction (decrease in amide I:II ratio). ALN suppressed bone formation but mineral accrued normally at those sites where bone formation occurred. PTH stimulated bone formation on endocortical, periosteal, and intracortical bone surfaces, but mineral accrual and carbonate substitution were suppressed, particularly in intracortical bone. ODN treatment did not suppress bone formation, but newly deposited endocortical bone matured more slowly with ODN, and ODN-treated intracortical bone had less carbonate substitution than controls. In conclusion, these agents differ in their effects on the bone matrix. While ALN suppresses bone formation, it does not modify bone mineral accrual in endocortical or intracortical bone. While ODN does not suppress bone formation, it slows matrix maturation. PTH stimulates modelling-based bone formation not only on endocortical and trabecular surfaces, but may also do so in intracortical bone; at this site, new bone deposited contains less mineral than normal.
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Affiliation(s)
- Christina Vrahnas
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
| | - Pascal R Buenzli
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Thomas A Pearson
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | | | - Mark J Tobin
- The Australian Synchrotron, Clayton, VIC, Australia
| | - Keith R Bambery
- The Australian Synchrotron, Clayton, VIC, Australia
- Australian Nuclear Science and Technology Organisation, The Australian Synchrotron, Lucas Heights, NSW, Australia
| | - Le T Duong
- MRL, Merck & Co., Inc., West Point, PA, USA
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
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17
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Paschalis EP, Krege JH, Gamsjaeger S, Eriksen EF, Burr DB, Disch DP, Stepan JJ, Fahrleitner-Pammer A, Klaushofer K, Marin F, Pavo I. Teriparatide Treatment Increases Mineral Content and Volume in Cortical and Trabecular Bone of Iliac Crest: A Comparison of Infrared Imaging With X-Ray-Based Bone Assessment Techniques. J Bone Miner Res 2018; 33:2230-2235. [PMID: 30102789 DOI: 10.1002/jbmr.3565] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 07/25/2018] [Accepted: 08/05/2018] [Indexed: 11/11/2022]
Abstract
Teriparatide increases bone mass primarily through remodeling of older or damaged bone and abundant replacement with new mineralizing bone. This post hoc analysis investigated whether dual-energy X-ray absorptiometric (DXA) areal bone mineral density (aBMD) measurement adequately reflects changes of mineral and organic matrix content in cortical and trabecular bone. Paired biopsies and aBMD measurements were obtained before and at end of 2 years of teriparatide treatment from postmenopausal women with osteoporosis who were either alendronate pretreated (mean, 57.5 months) or osteoporosis-treatment naive. Biopsies were assessed by micro-computed tomography (μCT) to calculate mean cortical width (Ct.Wi), cortical area (Ct.Ar), and trabecular bone volume fraction (BV/TV). Fourier transformed infrared imaging (pixel size ∼6.3 × 6.3 μm2 ) was utilized to calculate mineral and organic matrix density (mean absorption/pixel), as well as total mineral and organic contents of cortical and cancellous compartments (sum of all pixels in the compartment). Effect of pretreatment over time was analyzed using mixed model repeated measures. μCT derived Ct.Wi and BV/TV increased, accompanied by similar increases in the overall mineral contents of their respective bone compartments. Mineral density did not change. Marked increases in the total content of both mineral and organic matrix associated with volumetric growth in both compartments consistently exceeded those of aBMD. Increases in organic matrix exceeded increases in mineral content in both cortical and trabecular compartments. For percent changes, only change in Ct.Wi correlated to change in femoral neck aBMD (r = .38, p = 0.043), whereas no other significant correlations of Ct.Wi or BV/TV with lumbar spine, total hip, or femoral neck aBMD were demonstrable. These data indicate that 2 years of teriparatide treatment leads to an increased bone organic matrix and mineral content in the iliac crest. The magnitude of these increases in the iliac crest were not detected with conventional aBMD measurements at other skeletal sites. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Eleftherios P Paschalis
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK), Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Sonja Gamsjaeger
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK), Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Erik F Eriksen
- Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Insititute of Clinical Medicine, Oslo University, Oslo, Norway
| | - David B Burr
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Jan J Stepan
- Institute of Rheumatology and Faculty of Medicine 1, Charles University, Prague, Czech Republic
| | - Astrid Fahrleitner-Pammer
- Department of Internal Medicine, Division of Endocrinology and Diabetes, Medical University of Graz, Graz, Austria
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of Wiener Gebietskrankenkasse (WGKK), Allgemeine Unfallversicherungsanstalt (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Imre Pavo
- Eli Lilly and Company, Indianapolis, IN, USA
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18
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Eastell R, Szulc P. Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol 2017; 5:908-923. [PMID: 28689768 DOI: 10.1016/s2213-8587(17)30184-5] [Citation(s) in RCA: 354] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 05/07/2017] [Accepted: 05/08/2017] [Indexed: 12/30/2022]
Abstract
Bone turnover comprises two processes: the removal of old bone (resorption) and the laying down of new bone (formation). N-terminal propeptide of type I procollagen (PINP) and C-telopeptide of type I collagen (CTX-I) are markers of bone formation and resorption, respectively, that are recommended for clinical use. Bone turnover markers can be measured on several occasions in one individual with good precision. However, these markers are subject to several sources of variability, including feeding (resorption decreases) and recent fracture (all markers increase for several months). Bone turnover markers are not used for diagnosis of osteoporosis and do not improve prediction of bone loss or fracture within an individual. In untreated women, very high bone turnover marker concentrations suggest secondary causes of high bone turnover (eg, bone metastases or multiple myeloma). In people with osteoporosis, bone turnover markers might be useful to assess the response to anabolic and antiresorptive therapies, to assess compliance to therapy, or to indicate possible secondary osteoporosis. Much remains to be learnt about how bone turnover markers can be used to monitor the effect of stopping bisphosphonate therapy (eg, to identify a threshold above which restarting therapy should be considered). More studies are needed to investigate the use of bone turnover markers for assessment of the bone safety of new medications.
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Affiliation(s)
- Richard Eastell
- Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
| | - Pawel Szulc
- INSERM UMR 1033, University of Lyon, Hôpital Edouard Herriot, Lyon, France
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19
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Miyaoka D, Imanishi Y, Ohara M, Hayashi N, Nagata Y, Yamada S, Mori K, Emoto M, Inaba M. Effects of Teriparatide and Sequential Minodronate on Lumbar Spine Bone Mineral Density and Microarchitecture in Osteoporosis. Calcif Tissue Int 2017; 101:396-403. [PMID: 28589205 DOI: 10.1007/s00223-017-0295-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 06/01/2017] [Indexed: 12/19/2022]
Abstract
The trabecular bone score (TBS) is a new surrogate for trabecular bone microarchitecture assessment, independent of bone mineral density (BMD), calculated from pixel gray-level variations in the lumbar spine (LS) dual-energy X-ray absorptiometry (DXA) image. Although Teriparatide (TPTD) increased LS-BMD as well as TBS in 2 years, the precise time-course of these parameters was not well known. The aim of this study was to determine the changes in LS-BMD and the TBS in osteoporotic patients treated with TPTD, followed by minodronate (MINO). Primary osteoporotic patients with a low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with TPTD subcutaneously at 20 µg/day for 12-24 months, followed by MINO (orally at 50 mg/once monthly) for 12 months. LS-BMD and the TBS were measured at 0, 3, 6, 12, and 24 months after the initiation of TPTD treatment, and 12 months after the initiation of MINO. The increments of LS-BMD, significant at 6 months, increased until 12 months, whereas the increments of TBS, significant at 3 months (0.035 ± 0.011; p = 0.045 vs. the baseline), stabilized until 12 months. TPTD treatment, followed by 12 months of MINO, maintained both BMD and the TBS. Comparing the increments of the TBS to those of LS-BMD, our results indicate that TPTD treatment improved trabecular microarchitecture faster than mineralization. TPTD treatment, followed by MINO, can maintain both BMD and the TBS.
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Affiliation(s)
- Daichi Miyaoka
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yasuo Imanishi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Masaya Ohara
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Noriyuki Hayashi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yuki Nagata
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shinsuke Yamada
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Katsuhito Mori
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Masanori Emoto
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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Lovato C, Lewiecki EM. Emerging anabolic agents in the treatment of osteoporosis. Expert Opin Emerg Drugs 2017; 22:247-257. [DOI: 10.1080/14728214.2017.1362389] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Affiliation(s)
- Christina Lovato
- Division of Endocrinology, Diabetes and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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Vrahnas C, Pearson TA, Brunt AR, Forwood MR, Bambery KR, Tobin MJ, Martin TJ, Sims NA. Anabolic action of parathyroid hormone (PTH) does not compromise bone matrix mineral composition or maturation. Bone 2016; 93:146-154. [PMID: 27686599 DOI: 10.1016/j.bone.2016.09.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/23/2016] [Accepted: 09/25/2016] [Indexed: 02/04/2023]
Abstract
Intermittent administration of parathyroid hormone (PTH) is used to stimulate bone formation in patients with osteoporosis. A reduction in the degree of matrix mineralisation has been reported during treatment, which may reflect either production of undermineralised matrix or a greater proportion of new matrix within the bone samples assessed. To explore these alternatives, high resolution synchrotron-based Fourier Transform Infrared Microspectroscopy (sFTIRM) coupled with calcein labelling was used in a region of non-remodelling cortical bone to determine bone composition during anabolic PTH treatment compared with region-matched samples from controls. 8week old male C57BL/6 mice were treated with vehicle or 50μg/kg PTH, 5 times/week for 4weeks (n=7-9/group). Histomorphometry confirmed greater trabecular and periosteal bone formation and 3-point bending tests confirmed greater femoral strength in PTH-treated mice. Dual calcein labels were used to match bone regions by time-since-mineralisation (bone age) and composition was measured by sFTIRM in six 15μm2 regions at increasing depth perpendicular to the most immature bone on the medial periosteal edge; this allowed in situ measurement of progressive changes in bone matrix during its maturation. The sFTIRM method was validated in vehicle-treated bones where the expected progressive increases in mineral:matrix ratio and collagen crosslink type ratio were detected with increasing bone maturity. We also observed a gradual increase in carbonate content that strongly correlated with an increase in longitudinal stretch of the collagen triple helix (amide I:amide II ratio). PTH treatment did not alter the progressive changes in any of these parameters from the periosteal edge through to the more mature bone. These data provide new information about how the bone matrix matures in situ and confirm that bone deposited during PTH treatment undergoes normal collagen maturation and normal mineral accrual.
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Affiliation(s)
- Christina Vrahnas
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Thomas A Pearson
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Athena R Brunt
- School of Medical Science, Griffith University, Gold Coast, Queensland, Australia
| | - Mark R Forwood
- School of Medical Science, Griffith University, Gold Coast, Queensland, Australia
| | | | - Mark J Tobin
- Australian Synchrotron, Clayton, Victoria, Australia
| | - T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Victoria, Australia.
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Abstract
Antiresorptive agents for osteoporosis are a cornerstone of therapy, but anabolic drugs have recently increased our options. By directly stimulating bone formation, anabolic agents reduce fracture incidence by improving bone qualities as well as increasing bone mass. The anabolic agent currently approved for osteoporosis, teriparatide (recombinant human parathyroid hormone[1–34]), has emerged as a major approach for selected patients with osteoporosis. Parathyroid hormone(1–84) is also available in Europe. Teriparatide increases bone density and bone turnover, improves microarchitecture and changes bone size. The incidence of vertebral and nonvertebral fractures is reduced. A current concept in the mechanism of teriparatide action is related to its effect of stimulating processes associated with bone formation before processes associated with bone resorption. This sequence of events has led to the concept of the anabolic window, the period of time when teriparatide is maximally anabolic. Newer approaches to the use of teriparatide alone and in combination with antiresorptive agents has led to ways in which the anabolic window can be expanded.
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Affiliation(s)
- John P Bilezikian
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032 USA, Tel.: +1 212 305 6238, Fax: +1 212 305 6486,
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Dempster DW, Roschger P, Misof BM, Zhou H, Paschalis EP, Alam J, Ruff VA, Klaushofer K, Taylor KA. Differential Effects of Teriparatide and Zoledronic Acid on Bone Mineralization Density Distribution at 6 and 24 Months in the SHOTZ Study. J Bone Miner Res 2016; 31:1527-35. [PMID: 26931279 DOI: 10.1002/jbmr.2825] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 02/18/2016] [Accepted: 02/26/2016] [Indexed: 12/24/2022]
Abstract
The Skeletal Histomorphometry in Patients on Teriparatide or Zoledronic Acid Therapy (SHOTZ) study assessed the progressive effects of teriparatide (TPTD) and zoledronic acid (ZOL) on bone remodeling and material properties in postmenopausal women with osteoporosis. Previously, we reported that biochemical and histomorphometric bone formation indices were significantly higher in patients receiving TPTD versus ZOL. Here we report bone mineralization density distribution (BMDD) results based on quantitative backscattered electron imaging (qBEI). The 12-month primary study was randomized and double blind until the month 6 biopsy, then open label. Patients (TPTD, n = 28; ZOL, n = 31) were then eligible to enter a 12-month open-label extension with their original treatment: TPTD 20 μg/d (subcutaneous injection) or ZOL 5 mg/yr (intravenous infusion). A second biopsy was collected from the contralateral side at month 24 (TPTD, n = 10; ZOL, n = 10). In cancellous bone, ZOL treatment was associated at 6 and 24 months with significantly higher average degree of mineralization (CaMEAN, +2.2%, p = 0.018; +3.9%, p = 0.009, respectively) and with lower percentage of low mineralized areas (CaLOW , -34.6%, p = 0.029; -33.7%, p = 0.025, respectively) and heterogeneity of mineralization CaWIDTH (-12.3%, p = 0.003; -9.9%, p = 0.012, respectively), indicating higher mineralization density and more homogeneous mineral content versus TPTD. Within the ZOL group, significant changes were found in all parameters from month 6 to 24, indicating a progressive increase in mineralization density. In sharp contrast, mineralization density did not increase over time with TPTD, reflecting ongoing deposition of new bone. Similar results were observed in cortical bone. In this study, TPTD stimulated new bone formation, producing a mineralized bone matrix that remained relatively heterogeneous with a stable mean mineral content. ZOL slowed bone turnover and prolonged secondary mineralization, producing a progressively more homogeneous and highly mineralized bone matrix. Although both TPTD and ZOL increase clinical measures of bone mineral density (BMD), this study shows that the underlying mechanisms of the BMD increases are fundamentally different. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- David W Dempster
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Barbara M Misof
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, USA
| | - Eleftherios P Paschalis
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
| | | | | | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept. Hanusch Hospital, Vienna, Austria
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Burr DB. Bone Biomechanics and Bone Quality: Effects of Pharmaceutical Agents Used to Treat Osteoporosis. Clin Rev Bone Miner Metab 2016. [DOI: 10.1007/s12018-016-9217-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Mansur SA, Mieczkowska A, Flatt PR, Bouvard B, Chappard D, Irwin N, Mabilleau G. A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus. Bone 2016; 87:102-13. [PMID: 27062994 DOI: 10.1016/j.bone.2016.04.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 03/30/2016] [Accepted: 04/04/2016] [Indexed: 12/25/2022]
Abstract
Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala(2)]GIP-Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala(2)]GIP-Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala(2)]GIP-Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM.
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Affiliation(s)
- Sity Aishah Mansur
- Universiti Tun Hussein Onn Malaysia, Johor, Malaysia; School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Aleksandra Mieczkowska
- GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France
| | - Peter R Flatt
- Universiti Tun Hussein Onn Malaysia, Johor, Malaysia
| | - Beatrice Bouvard
- GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France
| | - Daniel Chappard
- GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France
| | - Nigel Irwin
- Universiti Tun Hussein Onn Malaysia, Johor, Malaysia
| | - Guillaume Mabilleau
- GEROM Groupe Etudes Remodelage Osseux et bioMatériaux - LHEA, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France; SCIAM, Service Commun d'Imagerie et Analyses Microscopiques, IRIS-IBS Institut de Biologie en Santé, CHU d'Angers, LUNAM Université, 49933 ANGERS Cedex, France.
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27
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Eriksen EF, Brown JP. Commentary: Concurrent administration of PTH and antiresorptives: Additive effects or DXA cosmetics. Bone 2016; 86:139-42. [PMID: 26944033 DOI: 10.1016/j.bone.2016.02.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 02/15/2016] [Accepted: 02/20/2016] [Indexed: 01/08/2023]
Abstract
Osteoanabolic therapy with parathyroid hormone (PTH(1-84)) or the PTH analogues teriparatide (PTH(1-34), TPTD) and abaloparatide induces a positive remodeling balance and increases modeling and remodeling activity on bone surfaces. As the anabolic action of PTH is primarily remodeling based increased bone turnover maximizes bone accrual. Increased remodeling, however, also increases cortical porosity and reduces mineralization of newly formed bone, which may cause initial reductions in BMD, particularly at sites rich in cortical bone. Increased cortical porosity may also have negative consequences for bone strength. Consequently, an interest developed in concurrent therapies offsetting the potential early negative cortical bone effects developed, and several studies using varying concurrent combinations of TPTD or PTH(1-84) with various antiresorptive (anti-catabolic) agents (estrogen, SERMs, bisphosphonates and denosumab) have been published. This commentary addresses the discrepancy between changes in areal bone mineral density (BMD) and bone turnover markers (BTM) in concurrent therapy studies leading to possible misinterpretations of the results. In studies of concurrent therapies increases in BMD are generally accompanied by decreases in biochemical markers of bone turnover. This includes Procollagen Type I N-Terminal Propetide (PINP), which has emerged as a reliable marker of bone formation during osteoanabolic therapy. We therefore want to submit, that the larger increases in BMD seen initially in patients on concurrent therapy mask the potential for later reduced osteoanabolic action of PTH. This notion is corroborated by: 1) the lesser impairment of bone anabolism seen with milder antiresorptive modalities like hormone replacement therapy (HRT) or Selective Estrogen Receptor Modulators (SERMs); 2) the changes in BMD seen in extension studies where treatment naïve patients previously treated with PTH alone are crossed over to antiresorptive drugs. We therefore advise against a general use of concurrent therapy with PTH and antiresorptive agents, as it entails blunting of osteoanabolic action of PTH in the long run.
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Affiliation(s)
- Erik Fink Eriksen
- Dept. of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway
| | - Jacques P Brown
- Dept. of Rheumatology, Laval University and CHU de Québec (CHUL) Research Centre, Quebec City, Canada
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Misof BM, Roschger P, Blouin S, Recker R, Klaushofer K. Bone matrix mineralization is preserved during early perimenopausal stage in healthy women: a paired biopsy study. Osteoporos Int 2016; 27:1795-803. [PMID: 26650378 DOI: 10.1007/s00198-015-3446-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 11/30/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED Bone matrix mineralization based on quantitative backscatter electron imaging remained unchanged during the first year of menopause in paired transiliac biopsy samples from healthy women. This suggests that the reported early perimenopausal reductions in bone mineral density are caused by factors other than decreases in the degree of mineralization. INTRODUCTION It is unknown whether perimenopausal loss of bone mass is associated with a drop in bone matrix mineralization. METHODS For this purpose, we measured the bone mineralization density distribution (BMDD) by quantitative backscatter electron imaging (qBEI) in n = 17 paired transiliac bone biopsy samples at premenopausal baseline and 12 months after last menses (obtained at average ages of 49 ± 2 and 55 ± 2 years, respectively) in healthy women. For interpretation of BMDD outcomes, previously measured bone mineral density (BMD) and biochemical and histomorphometric markers of bone turnover were revisited for the present biopsy cohort. RESULTS Menopause significantly decreased BMD at the lumbar spine (-4.5 %) and femoral neck (-3.8 %), increased the fasting urinary hydroxyproline/creatinine ratio (+60 %, all p < 0.01) and histomorphometric bone formation rate (+25 %, p < 0.05), but affected neither cancellous nor cortical BMDD variables (paired comparison p > 0.05). Mean calcium concentrations of cancellous (Cn.CaMean) and cortical bone (Ct.CaMean) were within normal range (p > 0.05 compared to established reference data). Ct.CaMean was significantly correlated with Cn.CaMean before (R = 0.81, p < 0.001) and after menopause (R = 0.80, p < 0.001) and to cortical porosity of mineralized tissue (Ct.Po.) after menopause (R = -0.57, p = 0.02). CONCLUSIONS Surprisingly, the BMDD was found not affected by the changes in bone turnover rates in this cohort. This suggests that the substantial increase in bone formation rates took place shortly before the second biopsy, and the bone mineralization changes lag behind. We conclude that during the first year after the last menses, the degree of bone matrix mineralization is preserved and does not contribute to the observed reductions in BMD.
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Affiliation(s)
- B M Misof
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Kundratstr. 37, A-1120, Vienna, Austria.
| | - P Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Kundratstr. 37, A-1120, Vienna, Austria
| | - S Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Kundratstr. 37, A-1120, Vienna, Austria
| | - R Recker
- Osteoporosis Research Center, Creighton University, Omaha, Nebraska, USA
| | - K Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Kundratstr. 37, A-1120, Vienna, Austria
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Tsai JN, Uihlein AV, Burnett-Bowie SM, Neer RM, Derrico NP, Lee H, Bouxsein ML, Leder BZ. Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture and Strength (DATA-HRpQCT study). J Clin Endocrinol Metab 2016; 101:2023-30. [PMID: 26964731 PMCID: PMC4870854 DOI: 10.1210/jc.2016-1160] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT In postmenopausal osteoporosis, combining denosumab and teriparatide increases hip and spine bone mineral density more than either monotherapy. OBJECTIVE The objective of the study was to determine the effects of 2 years of combination therapy on bone microarchitecture and estimated strength. DESIGN This was an open-label, randomized controlled trial. PARTICIPANTS AND METHODS We performed high-resolution peripheral quantitative computed tomography at the distal tibia and radius in 94 postmenopausal osteoporotic women randomized to 2 years of teriparatide 20 μg sc daily, denosumab 60 mg sc every 6 months, or both. RESULTS Total volumetric bone mineral density (vBMD) at the radius and tibia, trabecular vBMD at the radius, and cortical vBMD at the tibia all increased more in the combination group than both monotherapy groups (P < .002 for all comparisons with combination). Cortical thickness at the tibia also increased more in the combination group (8.1% ± 4.3%) than both other groups (P < .001). Cortical porosity at both the radius and tibia increased progressively over the 24-month treatment period in the teriparatide group but was stable in both other groups (P < .001 teriparatide vs both other groups). Trabecular vBMD at the tibia increased similarly in all groups, whereas radius trabecular vBMD increased more in the combination group than the other groups (P < .01 for both comparisons). Finite element analysis-estimated strength improved or was maintained by all treatments at both the radius and tibia. CONCLUSIONS Two years of combined teriparatide and denosumab improves bone microarchitecture and estimated strength more than the individual treatments, particularly in cortical bone. These findings suggest that this regimen may be beneficial in postmenopausal osteoporosis.
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Affiliation(s)
- J N Tsai
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - A V Uihlein
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - S M Burnett-Bowie
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - R M Neer
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - N P Derrico
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - H Lee
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - M L Bouxsein
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
| | - B Z Leder
- Endocrine Unit (J.N.T., A.V.U., S.M.B.-B., R.M.N., N.P.D., M.L.B., B.Z.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Orthopedic Surgery (M.L.B.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
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30
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Ross RD, Mashiatulla M, Robling AG, Miller LM, Sumner DR. Bone Matrix Composition Following PTH Treatment is Not Dependent on Sclerostin Status. Calcif Tissue Int 2016; 98:149-57. [PMID: 26514840 PMCID: PMC7391132 DOI: 10.1007/s00223-015-0074-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 10/09/2015] [Indexed: 12/28/2022]
Abstract
Sclerostin and parathyroid hormones are strong negative and positive regulators of bone formation, respectively. The anabolic response induced by intermittent (iPTH) treatment is sclerostin status-dependent. However, the interaction between sclerostin and iPTH at the matrix level is unknown. The goal of the current study was to determine if iPTH treatment affects matrix composition and, if so, whether these effects are dependent on sclerostin status. Humeral trabecular and cortical bone sites from 16 week old male wild-type (WT) and sclerostin knockout (KO) mice, which had been treated with vehicle or iPTH from age 10-16 weeks, were examined by micro-computed tomography (µCT) to measure bone volume, backscatter scanning electron microscopy (bSEM) to assess global mineralization, and Fourier transform infrared microspectroscopy (FTIRM) to examine matrix composition (mineral-to-matrix ratio, crystallinity, collagen cross-link ratio, and carbonate substitution). The FTIRM measurements were restricted to the tissue formed during the 6-week treatment period. iPTH treatment led to increased trabecular bone volume (p < 0.001) and this effect was much greater in KO mice than WT mice (interaction effect, p < 0.001). iPTH treatment led to reduced trabecular crystallinity (p = 0.047), increased cortical bone area (p < 0.001), decreased cortical bone crystallinity (p = 0.002) and increased cortical bone collagen cross-linking (p = 0.028) to similar degrees in both WT and KO mice. Compared to WT mice, sclerostin KO mice had higher trabecular and cortical bone mass (p < 0.001) and lower mineral-to-matrix ratio in the trabecular (p = 0.010) and cortical (p = 0.016) compartments. Thus, iPTH-induced changes in bone mass are dependent upon sclerostin status in the trabecular compartment, but not in the cortical compartment. In contrast, iPTH-induced changes in matrix composition are sclerostin-independent in both trabecular and cortical compartments.
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Affiliation(s)
- Ryan D Ross
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA.
| | - Maleeha Mashiatulla
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA
- Department of Bioengineering, University of Illinois Chicago, Chicago, IL, USA
| | - Alexander G Robling
- Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Lisa M Miller
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
- National Synchrotron Light Source-II, Brookhaven National Laboratory, Upton, NY, USA
| | - D Rick Sumner
- Department of Anatomy and Cell Biology, Rush University Medical Center, 600 South Paulina, Suite 507, Chicago, IL, 60612, USA.
- Department of Bioengineering, University of Illinois Chicago, Chicago, IL, USA.
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.
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31
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Misof BM, Roschger P, Dempster DW, Zhou H, Bilezikian JP, Klaushofer K, Rubin MR. PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization. J Bone Miner Res 2016; 31:180-9. [PMID: 26111772 PMCID: PMC4830900 DOI: 10.1002/jbmr.2588] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 06/20/2015] [Accepted: 06/23/2015] [Indexed: 11/07/2022]
Abstract
Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1-84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1-year or 2-year PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn.BMDD and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1 year; 16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p < 0.001) compared to reference BMDD. After 1-year PTH(1-84), Cn.CaMean was significantly lower than that at baseline (-6.3%, p < 0.001), whereas in the 2-year PTH(1-84) group Cn.CaMean did not differ from baseline. Significant changes of Ct.BMDD were observed in the 1-year treatment group only. The change in histomorphometric bone formation (mineralizing surface) was predictive for Cn.BMDD outcomes in the 1-year PTH(1-84) group, but not in the 2-year PTH(1-84) group. Our findings suggest higher baseline bone matrix mineralization consistent with the decreased bone turnover in hypoparathyroidism. PTH(1-84) treatment caused differential effects dependent on treatment duration that were consistent with the histomorphometric bone formation outcomes. The greater increase in bone formation during the first year of treatment was associated with a decrease in bone matrix mineralization, suggesting that PTH(1-84) exposure to the hypoparathyroid skeleton has the greatest effects on BMDD early in treatment.
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Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Paul Roschger
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - David W Dempster
- Regional Bone Center Helen Hayes Hospital, West Haverstraw, New York, NY, USA.,Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Hua Zhou
- Regional Bone Center Helen Hayes Hospital, West Haverstraw, New York, NY, USA
| | - John P Bilezikian
- Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University New York, NY, USA
| | - Klaus Klaushofer
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of Social Health Insurance Vienna (WGKK) and Austrian Social Insurance for Occupational Risk (AUVA) Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Mishaela R Rubin
- Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University New York, NY, USA
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Kaynia N, Soohoo E, Keaveny TM, Kazakia GJ. Effect of intraspecimen spatial variation in tissue mineral density on the apparent stiffness of trabecular bone. J Biomech Eng 2015; 137:1944612. [PMID: 25412197 DOI: 10.1115/1.4029178] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 12/10/2014] [Indexed: 11/08/2022]
Abstract
This study investigated the effects of intraspecimen variations in tissue mineral density(TMD) on the apparent-level stiffness of human trabecular bone. High-resolution finite element (FE) models were created for each of 12 human trabecular bone specimens,using both microcomputed tomography (lCT) and “gold-standard” synchrotron radiation lCT (SRlCT) data. Our results confirm that incorporating TMD spatial variation reduces the calculated apparent stiffness compared to homogeneous TMD models. This effect exists for both lCT- and SRlCT-based FE models, but is exaggerated in lCT based models. This study provides a direct comparison of lCT to SRlCT data and is thereby able to conclude that the influence of including TMD heterogeneity is overestimated in lCT-based models.
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33
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Gafni RI, Guthrie LC, Kelly MH, Brillante BA, Christie CM, Reynolds JC, Yovetich NA, James R, Collins MT. Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism. J Bone Miner Res 2015; 30:2112-8. [PMID: 25990370 DOI: 10.1002/jbmr.2555] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 05/05/2015] [Accepted: 05/11/2015] [Indexed: 11/06/2022]
Abstract
Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.
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Affiliation(s)
- Rachel I Gafni
- Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Lori C Guthrie
- Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Marilyn H Kelly
- Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Beth A Brillante
- Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
| | | | - James C Reynolds
- Clinical Center (CC)/Nuclear Medicine Department (NMD), National Institutes of Health (NIH), Bethesda, MD, USA
| | | | | | - Michael T Collins
- Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA
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34
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Bala Y, Seeman E. Bone's Material Constituents and their Contribution to Bone Strength in Health, Disease, and Treatment. Calcif Tissue Int 2015; 97:308-26. [PMID: 25712256 DOI: 10.1007/s00223-015-9971-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/11/2015] [Indexed: 12/24/2022]
Abstract
Type 1 collagen matrix volume, its degree of completeness of its mineralization, the extent of collagen crosslinking and water content, and the non-collagenous proteins like osteopontin and osteocalcin comprise the main constituents of bone's material composition. Each influences material strength and change in different ways during advancing age, health, disease, and drug therapy. These traits are not quantifiable using bone densitometry and their plurality is better captured by the term bone 'qualities' than 'quality'. These qualities are the subject of this manuscript.
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Affiliation(s)
- Y Bala
- Laboratoire Vibrations Acoustique, Institut National des Sciences Appliquées de Lyon, Campus LyonTech la Doua, Villeurbanne, France
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Whitmarsh T, Treece GM, Gee AH, Poole KES. Mapping Bone Changes at the Proximal Femoral Cortex of Postmenopausal Women in Response to Alendronate and Teriparatide Alone, Combined or Sequentially. J Bone Miner Res 2015; 30:1309-18. [PMID: 25639838 DOI: 10.1002/jbmr.2454] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/16/2014] [Accepted: 01/10/2015] [Indexed: 11/06/2022]
Abstract
Combining antiresorptive and anabolic drugs for osteoporosis may be a useful strategy to prevent hip fractures. Previous studies comparing the effects of alendronate (ALN) and teriparatide (TPTD) alone, combined or sequentially using quantitative computed tomography (QCT) in postmenopausal women have not distinguished cortical bone mineral density (CBMD) from cortical thickness (CTh) effects, nor assessed the distribution and extent of more localized changes. In this study a validated bone mapping technique was used to examine the cortical and endocortical trabecular changes in the proximal femur resulting from an 18-month course of ALN or TPTD. Using QCT data from a different clinical trial, the global and localized changes seen following a switch to TPTD after an 18-month ALN treatment or adding TPTD to the ALN treatment were compared. Ct.Th increased (4.8%, p < 0.01) and CBMD decreased (-4.5%, p < 0.01) in the TPTD group compared to no significant change in the ALN group. A large Ct.Th increase could be seen for the switch group (2.8%, p < 0.01) compared to a significantly smaller increase for the add group (1.5%, p < 0.01). CBMD decreased significantly for the switch group (-3.9%, p < 0.01) and was significantly different from no significant change in the add group. Ct.Th increases were shown to be significantly greater for the switch group compared to the add group at the load bearing regions. This study provides new insights into the effects of ALN and TPTD combination therapies on the cortex of the proximal femur and supports the hypothesis of an increased bone remodeling by TPTD being mitigated by ALN.
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Affiliation(s)
| | - Graham M Treece
- Department of Engineering, University of Cambridge, Cambridge, UK
| | - Andrew H Gee
- Department of Engineering, University of Cambridge, Cambridge, UK
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Acerbo AS, Kwaczala AT, Yang L, Judex S, Miller LM. Alterations in collagen and mineral nanostructure observed in osteoporosis and pharmaceutical treatments using simultaneous small- and wide-angle X-ray scattering. Calcif Tissue Int 2014; 95:446-56. [PMID: 25190190 DOI: 10.1007/s00223-014-9913-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 08/22/2014] [Indexed: 12/27/2022]
Abstract
The influence of the macroscale material properties of bone on its mechanical competence has been extensively investigated, but less is known about possible contributions from bone's nanoscale material properties. These nanoscale properties, particularly the collagen network and the size and shape of hydroxyapatite mineral crystals, may be affected by aging, mechanical loading, and diseases including osteoporosis. Here, changes to the collagen and mineral properties of cortical bone induced by osteoporosis and subsequent pharmaceutical treatments were investigated by simultaneous small- and wide-angle X-ray scattering (SAXS/WAXS) microbeam mapping. Adult rats (6 months old) were ovariectomized and treated with alendronate, parathyroid hormone, or sodium fluoride, and compared to untreated ovariectomized and age-matched controls. Scattering data from tibial cortical bone showed that osteoporosis increased collagen alignment in existing intracortical bone, while this effect was mitigated in the alendronate and sodium fluoride groups though by different mechanisms. Further, mineral crystal lengths in newly formed cortical bone were smaller in animals with osteoporosis, but existing cortical bone was not altered. Subsequent treatment with alendronate mitigated changes in crystal lengths. Together, these results suggest that osteoporosis may alter the collagen alignment and mineral geometry in bone formed before and after the onset of this disease, and that osteoporosis treatments may differentially rescue these changes.
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Affiliation(s)
- Alvin S Acerbo
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA
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Amugongo SK, Yao W, Jia J, Dai W, Lay YAE, Jiang L, Harvey D, Zimmermann EA, Schaible E, Dave N, Ritchie RO, Kimmel DB, Lane NE. Effect of sequential treatments with alendronate, parathyroid hormone (1-34) and raloxifene on cortical bone mass and strength in ovariectomized rats. Bone 2014; 67:257-68. [PMID: 25016965 PMCID: PMC4157684 DOI: 10.1016/j.bone.2014.04.033] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 04/03/2014] [Accepted: 04/16/2014] [Indexed: 01/10/2023]
Abstract
UNLABELLED Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. METHODS Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. RESULTS Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. SUMMARY Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.
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Affiliation(s)
- Sarah K Amugongo
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Wei Yao
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Junjing Jia
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Weiwei Dai
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Yu-An E Lay
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Li Jiang
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA
| | - Danielle Harvey
- Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA 95616, USA
| | - Elizabeth A Zimmermann
- Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Eric Schaible
- Experimental Systems Group, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Neil Dave
- Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Robert O Ritchie
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA; Department of Materials Science and Engineering, University of California, Berkeley, CA 94720, USA
| | - Donald B Kimmel
- Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE 68131, USA
| | - Nancy E Lane
- Musculoskeletal Research Unit, Department of Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA.
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Misof BM, Dempster DW, Zhou H, Roschger P, Fratzl-Zelman N, Fratzl P, Silverberg SJ, Shane E, Cohen A, Stein E, Nickolas TL, Recker RR, Lappe J, Bilezikian JP, Klaushofer K. Relationship of bone mineralization density distribution (BMDD) in cortical and cancellous bone within the iliac crest of healthy premenopausal women. Calcif Tissue Int 2014; 95:332-9. [PMID: 25134800 PMCID: PMC4464772 DOI: 10.1007/s00223-014-9901-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 07/18/2014] [Indexed: 02/04/2023]
Abstract
Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25-48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.Ca(Width)), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.Ca(Mean)). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.Ca(High)) and positively with the percentage of lowly mineralized bone areas (Ct.Ca(Low)). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD.
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Affiliation(s)
- B. M. Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin-Str. 30, 1140 Vienna, Austria
| | - D. W. Dempster
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA
- College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA
| | - P. Roschger
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin-Str. 30, 1140 Vienna, Austria
| | - N. Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin-Str. 30, 1140 Vienna, Austria
| | - P. Fratzl
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
| | - S. J. Silverberg
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - E. Shane
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - A. Cohen
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - E. Stein
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - T. L. Nickolas
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - R. R. Recker
- Creighton University Osteoporosis Research Center, Omaha, NE, USA
| | - J. Lappe
- Creighton University Osteoporosis Research Center, Omaha, NE, USA
| | - J. P. Bilezikian
- Department of Medicine and Pathology, Columbia University, New York, NY, USA
| | - K. Klaushofer
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin-Str. 30, 1140 Vienna, Austria
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Abstract
Bone fragility is a major health concern, as the increased risk of bone fractures has devastating outcomes in terms of mortality, decreased autonomy, and healthcare costs. Efforts made to address this problem have considerably increased our knowledge about the mechanisms that regulate bone formation and resorption. In particular, we now have a much better understanding of the cellular events that are triggered when bones are mechanically stimulated and how these events can lead to improvements in bone mass. Despite these findings at the molecular level, most exercise intervention studies reveal either no effects or only minor benefits of exercise programs in improving bone mineral density (BMD) in osteoporotic patients. Nevertheless, and despite that BMD is the gold standard for diagnosing osteoporosis, this measure is only able to provide insights regarding the quantity of bone tissue. In this article, we review the complex structure of bone tissue and highlight the concept that its mechanical strength stems from the interaction of several different features. We revisited the available data showing that bone mineralization degree, hydroxyapatite crystal size and heterogeneity, collagen properties, osteocyte density, trabecular and cortical microarchitecture, as well as whole bone geometry, are determinants of bone strength and that each one of these properties may independently contribute to the increased or decreased risk of fracture, even without meaningful changes in aBMD. Based on these findings, we emphasize that while osteoporosis (almost) always causes bone fragility, bone fragility is not always caused just by osteoporosis, as other important variables also play a major role in this etiology. Furthermore, the results of several studies showing compelling data that physical exercise has the potential to improve bone quality and to decrease fracture risk by influencing each one of these determinants are also reviewed. These findings have meaningful clinical repercussions as they emphasize the fact that, even without leading to improvements in BMD, exercise interventions in patients with osteoporosis may be beneficial by improving other determinants of bone strength.
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40
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Roschger P, Misof B, Paschalis E, Fratzl P, Klaushofer K. Changes in the degree of mineralization with osteoporosis and its treatment. Curr Osteoporos Rep 2014; 12:338-50. [PMID: 24947951 DOI: 10.1007/s11914-014-0218-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The diagnosis of osteoporosis is based on low bone mineral density (BMD) and/or the occurrence of fragility fractures. The majority of patients, however, have also abnormally low bone matrix mineralization. The latter is indicative of alterations in bone turnover rates and/or in kinetics of mineral accumulation within the newly formed bone matrix. Osteoporosis therapies can alter the bone matrix mineralization according to their action on bone turnover and/or mineralization kinetics. Antiresorptives, including the most widely used bisphosphonates, reduce the bone turnover rate resulting in a decrease in heterogeneity and an increase in the degree of mineralization toward to or even beyond normal values. Anabolic agents increase the bone volume and the amount of newly formed bone resulting in a likely transient decrease in mean degree and homogeneity of mineralization. Hence, the measurement of bone matrix mineralization is a sensitive tool to evaluate the response to therapy.
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Affiliation(s)
- Paul Roschger
- 1st Medical Department, Hanusch Hospital, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Heinrich Collin Str. 30, A-1140, Vienna, Austria,
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Koehne T, Vettorazzi E, Küsters N, Lüneburg R, Kahl-Nieke B, Püschel K, Amling M, Busse B. Trends in trabecular architecture and bone mineral density distribution in 152 individuals aged 30-90 years. Bone 2014; 66:31-8. [PMID: 24859568 DOI: 10.1016/j.bone.2014.05.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 05/12/2014] [Accepted: 05/15/2014] [Indexed: 01/22/2023]
Abstract
The strength of trabecular bone depends on its microarchitecture and its tissue level properties. However, the interrelation between these two determinants of bone quality and their relation to age remain to be clarified. Iliac crest bone cores (n=152) from individuals aged 30-90 years were analyzed by quantitative backscattered electron imaging. Univariate and multivariate analyses were conducted to determine whether epidemiological parameters (age, sex or BMI), structural histomorphometrical variables (BV/TV, Tb.Th, Tb.N and Tb.Sp) and osteoid-related indices (OV/BV, OS/BS or O.Th) predict the degree of bone mineralization. While sex and BMI were not associated with bone mineralization, age was positively correlated with the most frequently occurring calcium concentrations (Ca peak), the percentage of highly mineralized bone areas (Ca high) and, in the case of adjusted covariates, also the mean calcium content (Ca mean). Bone volume fraction and trabecular thickness were both negatively correlated with Ca mean. However, trabecular thickness was additionally associated with Ca peak, Ca high as well as the amount of low mineralized bone (Ca low) and was the only structural parameter predicting bone mineralization independent of age. Furthermore, our analyses demonstrated that osteoid variables - within a normal range (<2% OV/BV) - were significantly associated with all mineralization parameters and represent the only predictor for the mineralization heterogeneity (Ca width). Taken together, we showed that elevated trabecular bone mineralization correlates with aging and bone loss. However, these associations are attributable to trabecular thinning that comes along with high bone mineralization due to the loss of low mineralized bone surfaces. Therefore, we demonstrated that the degree of areally resolved bone mineral is primarily associated with the amount of physiological osteoid present and the thickness of mineralized bone in trabeculae.
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Affiliation(s)
- Till Koehne
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Orthodontics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eik Vettorazzi
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalie Küsters
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rike Lüneburg
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bärbel Kahl-Nieke
- Department of Orthodontics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Püschel
- Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Ross RD, Edwards LH, Acerbo AS, Ominsky MS, Virdi AS, Sena K, Miller LM, Sumner DR. Bone matrix quality after sclerostin antibody treatment. J Bone Miner Res 2014; 29:1597-607. [PMID: 24470143 DOI: 10.1002/jbmr.2188] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 01/21/2014] [Accepted: 01/22/2014] [Indexed: 11/10/2022]
Abstract
Sclerostin antibody (Scl-Ab) is a novel bone-forming agent that is currently undergoing preclinical and clinical testing. Scl-Ab treatment is known to dramatically increase bone mass, but little is known about the quality of the bone formed during treatment. In the current study, global mineralization of bone matrix in rats and nonhuman primates treated with vehicle or Scl-Ab was assayed by backscattered scanning electron microscopy (bSEM) to quantify the bone mineral density distribution (BMDD). Additionally, fluorochrome labeling allowed tissue age-specific measurements to be made in the primate model with Fourier-transform infrared microspectroscopy to determine the kinetics of mineralization, carbonate substitution, crystallinity, and collagen cross-linking. Despite up to 54% increases in the bone volume after Scl-Ab treatment, the mean global mineralization of trabecular and cortical bone was unaffected in both animal models investigated. However, there were two subtle changes in the BMDD after Scl-Ab treatment in the primate trabecular bone, including an increase in the number of pixels with a low mineralization value (Z5) and a decrease in the standard deviation of the distribution. Tissue age-specific measurements in the primate model showed that Scl-Ab treatment did not affect the mineral-to-matrix ratio, crystallinity, or collagen cross-linking in the endocortical, intracortical, or trabecular compartments. Scl-Ab treatment was associated with a nonsignificant trend toward accelerated mineralization intracortically and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment (p < 0.001). These findings suggest that Scl-Ab treatment does not negatively impact bone matrix quality.
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Affiliation(s)
- Ryan D Ross
- Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA
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Kleerekoper M, Greenspan SL, Lewiecki EM, Miller PD, Kendler DL, Maricic M, Keaveny TM, Kopperdahl DL, Ruff VA, Wan X, Janos B, Krohn K. Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength. J Bone Joint Surg Am 2014; 96:e90. [PMID: 24897747 PMCID: PMC6948798 DOI: 10.2106/jbjs.l.01757] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 μg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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Affiliation(s)
- Michael Kleerekoper
- Division of Endocrinology, Department of Medicine, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614. E-mail address:
| | - Susan L Greenspan
- Osteoporosis Treatment and Prevention Center, University of Pittsburgh, 3459 Fifth Avenue, 4th Floor, Pittsburgh, PA 15213
| | - E Michael Lewiecki
- New Mexico Clinical Research & Osteoporosis Center, 300 Oak Street N.E., Albuquerque, NM 87106
| | - Paul D Miller
- Colorado Center for Bone Research, University of Colorado Health Sciences Center, 3190 South Wadsworth Boulevard, Lakewood, CO 80227
| | - David L Kendler
- University of British Columbia, 150-943 West Broadway, Vancouver, BC V5Z 4E1, Canada
| | - Michael Maricic
- Catalina Pointe Rheumatology, 7520 North Oracle Road, Suite 100, Tucson, AZ 85724
| | - Tony M Keaveny
- Departments of Mechanical Engineering and Bioengineering, 6175 Etcheverry Hall, MC 1740, University of California, Berkeley, CA 94720-1740
| | | | - Valerie A Ruff
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285
| | - Xiaohai Wan
- Novartis Pharmaceuticals Corporation, One Health Plaza East, East Hanover, NJ 07936
| | - Boris Janos
- Eli Lilly Canada Inc., 3650 Danforth Avenue, Toronto, ON M1N 2E8, Canada
| | - Kelly Krohn
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285
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Ng KW, Martin TJ. New therapeutics for osteoporosis. Curr Opin Pharmacol 2014; 16:58-63. [PMID: 24699340 DOI: 10.1016/j.coph.2014.03.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 03/12/2014] [Accepted: 03/12/2014] [Indexed: 12/11/2022]
Abstract
Two new approaches for the treatment of osteoporosis are summarized, each having arisen out of important new discoveries in bone biology. Odanacatib (ODN) inhibits the enzyme, cathepsin K, that is essential for the resorbing activity of osteoclasts. It is effective in preventing ovariectomy-induced bone loss in preclinical studies, and a phase II clinical study has shown inhibition of resorption sustained over five years. Outcome of a phase III study is awaited. The finding from mouse and human genetics that Wnt signaling is a powerful inducer of bone formation led to developments aimed at enhancing this pathway. Of the several approaches towards this, the most advanced is with a neutralizing antibody against sclerostin, the osteocyte-derived inhibitor of Wnt signaling. Preclinical studies show a powerful bone anabolic effect, and a clinical phase II study shows dose-dependent increases in bone formation and decreases in bone resorption markers.
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Affiliation(s)
- Kong Wah Ng
- University of Melbourne, Department of Medicine, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia
| | - T John Martin
- University of Melbourne, Department of Medicine, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia.
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Martin TJ. Bone biology and anabolic therapies for bone: current status and future prospects. J Bone Metab 2014; 21:8-20. [PMID: 24707463 PMCID: PMC3970295 DOI: 10.11005/jbm.2014.21.1.8] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 02/03/2014] [Accepted: 02/03/2014] [Indexed: 12/20/2022] Open
Abstract
Bone is continuously remodelled at many sites asynchronously throughout the skeleton, with bone formation and resorption balanced at these sites to retain bone structure. Negative balance resulting in bone loss and osteoporosis, with consequent fractures, has mainly been prevented or treated by anti-resorptive drugs that inhibit osteoclast formation and/or activity, with new prospects now of anabolic treatments that restore bone that has been lost. The anabolic effectiveness of parathyroid hormone has been established, and an exciting new prospect is presented of neutralising antibody against the osteocyte protein, sclerostin. The cellular actions of these two anabolic treatments differ, and the mechanisms will need to be kept in mind in devising their best use. On present evidence it seems likely that treatment with either of these anabolic agents will need to be followed by anti-resorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for safe, effective anti-resorptive drugs.
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Affiliation(s)
- T John Martin
- Department of Medicine, St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia
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Abstract
Teeth are mineralized organs composed of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of rickets, which traditionally referred to skeletal disease associated with vitamin D deficiency but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate-regulating endopeptidase homolog, X-linked, fibroblast growth factor 23, and dentin matrix protein 1. Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase are necessary for proper mineralization, where rickets can result from loss of activity of tissue nonspecific alkaline phosphatase. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the rachitic tooth will be revealed.
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Affiliation(s)
- Brian L Foster
- National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Jeon YK, Kim KM, Kim KJ, Kim IJ, Lim SK, Rhee Y. The anabolic effect of teriparatide is undermined by low levels of high-density lipoprotein cholesterol. Calcif Tissue Int 2014; 94:159-68. [PMID: 23907724 DOI: 10.1007/s00223-013-9772-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 07/17/2013] [Indexed: 02/07/2023]
Abstract
Intermittent parathyroid hormone (PTH) administration has a potent ability to increase bone mass, regardless of underlying conditions or species. A recent study using LDLR(-/-) mice showed that the anabolic effect of PTH was blunted by hyperlipidemia, whereas PTH anabolism was rescued by enhancement of high-density lipoprotein cholesterol (HDL-C) function. We conducted a retrospective longitudinal study to determine whether lipid profiles also affect the anabolic effect of intermittent PTH treatment in humans. Fifty-two patients (8 males and 44 females, ages 38-85 years) with severe osteoporosis who had been treated with teriparatide (TPTD, recombinant human PTH(1-34) for 12 months were studied at Severance Hospital, Yonsei University. C-telopeptide (CTX) and osteocalcin (OCN) were measured at 0, 3, and 12 months; and total cholesterol, triglycerides, and HDL-C were measured at baseline. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at 0 and 12 months. Lumbar spine BMD increased significantly after 12 months of treatment with TPTD (10.0 ± 9.3%, p < 0.001). Initial 3-month changes in CTX and OCN levels revealed positive correlations with the increase in lumbar BMD (r = 0.546, p = 0.001 and r = 0.500, p = 0.006, respectively). Moreover, percentage change in lumbar BMD at 12 months showed a negative correlation with baseline total cholesterol (r = -0.438, p = 0.009) and a positive correlation with HDL-C (r = 0.498, p = 0.016). A smaller 3-month increase in OCN and a lower HDL-C level at baseline were associated with a smaller lumbar BMD increase after TPTD treatment, even after adjustment for age, sex, and other confounding factors (β = 0.462, p = 0.031 for ΔOCN and β = 0.670, p = 0.004 for HDL-C). Plasma levels of lipids, especially HDL-C, seem to be associated with the extent of osteoanabolic effects of TPTD in humans.
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Affiliation(s)
- Yun Kyung Jeon
- Division of Endocrinology, Department of Internal Medicine, Pusan National University, Busan, Korea,
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48
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Wan X, Zhao Y, Burge R, Jiang Y. Actions of osteoporosis treatments on bone histomorphometric remodeling: a two-fold principal component analysis. Osteoporos Int 2013; 24:3011-9. [PMID: 23881284 DOI: 10.1007/s00198-013-2414-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 05/14/2013] [Indexed: 10/26/2022]
Abstract
UNLABELLED This was the first study to apply principal component analysis method to bone histomorphometric parameters. The results corroborated teriparatide's distinct, yet different, mechanisms of action, which stimulate both bone formation and resorption. INTRODUCTION This study consolidated bone histomorphometric parameters and compared the effects of two osteoporosis treatments on bone remodeling by using a principal component analysis (PCA). METHODS Included in this analysis were postmenopausal women with osteoporosis who were treated with either teriparatide or alendronate and who completed transiliac bone biopsy at either 6 or 18 months in the randomized, double-blind Forteo Alendronate Comparator Trial. Eighteen histomorphometric parameters were grouped into formation and resorption categories. The first principal component of each category was estimated through the PCA. The summation of principal formation component (PFC) and principal resorption component (PRC) was calculated to represent the overall level of bone turnover. The difference between PFC and PRC was computed to determine the balance between formation and resorption. RESULTS The PFC was significantly higher in the teriparatide group than in the alendronate group (P < 0.0001), while the PRC was numerically lower in the alendronate group (P = 0.18). The mean difference between the PFC and PRC was positive in the teriparatide group and negative in the alendronate group. CONCLUSIONS Our approach of consolidating bone histomorphometric remodeling parameters corroborated the idea that the distinct, yet different, mechanisms of action of teriparatide treatment stimulate both bone formation and resorption, and alendronate treatment suppresses both bone formation and resorption.
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Affiliation(s)
- X Wan
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA,
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Qiu Z, Wei L, Liu J, Sochacki KR, Liu X, Bishop C, Ebraheim M, Yang H. Effect of intermittent PTH (1-34) on posterolateral spinal fusion with iliac crest bone graft in an ovariectomized rat model. Osteoporos Int 2013; 24:2693-700. [PMID: 23756875 DOI: 10.1007/s00198-013-2385-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 03/13/2013] [Indexed: 10/26/2022]
Abstract
SUMMARY Intermittent treatment with high-dose parathyroid hormone (PTH) enhances the quantity and quality of the fusion callus and reduces healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague-Dawley rats. Intermittent PTH (1-34) could be an appropriate adjunctive therapy for osteoporotic patients undergoing posterolateral intertransverse process fusion. INTRODUCTION The study was designed to test the hypothesis that intermittent administration of PTH improves spinal fusion rates in a randomized controlled, ovariectomized osteoporotic rat spinal fusion model. METHODS Thirty-six 10-week-old Sprague-Dawley rats were ovariectomized and underwent bilateral posterolateral L4-L5 spinal fusion with autologous iliac bone graft 6 weeks later. The experimental (PTH) group (18 rats) received daily subcutaneously administered injections of PTH (1-34) at 30 μg/kg/day starting on the day of operation. The control group (18 rats) received a subcutaneously administered injection of normal saline of the same volume. Nine rats from each group were sacrificed at 4 and 6 weeks. After sacrifice, the L4-L5 vertebral segments were removed and analyzed by plain radiographs, μ-CT, histomorphometry, and serum bone metabolism marker. RESULTS The PTH group had a significantly higher fusion rate and X-ray fusion score than the control group at 4 and 6 weeks (p < 0.05). μ-CT and histological analysis showed that the fusion bone volume and cortical thickness for the PTH group were significantly higher than those for the control group at 4 and 6 weeks (p < 0.05). Metabolic marker analysis also showed significant difference between the two groups. The serum osteocalcin was significantly higher in the PTH group at 4 and 6 weeks, and levels of N-terminal peptide of type I collagen were significantly higher at 4 weeks (p < 0.05). CONCLUSION Intermittent treatment with high-dose PTH enhances the quantity of the fusion callus and reduces the healing time of posterolateral spinal fusion with autologous iliac bone grafts in ovariectomized osteoporotic female Sprague-Dawley rats.
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Affiliation(s)
- Z Qiu
- The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, China
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50
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Bala Y, Farlay D, Boivin G. Bone mineralization: from tissue to crystal in normal and pathological contexts. Osteoporos Int 2013; 24:2153-66. [PMID: 23229470 DOI: 10.1007/s00198-012-2228-y] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 11/12/2012] [Indexed: 10/27/2022]
Abstract
Bone is a complex and structured material; its mechanical behavior results from an interaction between the properties of each level of its structural hierarchy. The degree of mineralization of bone (bone density measured at tissue level) and the characteristics of the mineral deposited (apatite crystals) are major determinants of bone strength. Bone remodeling activity acts as a regulator of the degree of mineralization and of the distribution of mineral at the tissue level, directly impacting bone mechanical properties. Recent findings have highlighted the need to understand the underlying process occurring at the nanostructure level that may be independent of bone remodeling itself. A more global comprehension of bone qualities will need further works designed to characterize what are the consequences on whole bone strength of changes at nano- or microstructure levels relative to each other.
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Affiliation(s)
- Y Bala
- Endocrine Center, Austin Health, University of Melbourne, Melbourne, Australia.
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