Combined parathyroid hormone (PTH) and bisphosphonate (alendronate—ALN) therapy has recently been shown to increase bone volume fraction and plate-like trabecular structure beyond either monotherapy. To identify the mechanism through which plate-like structure was enhanced, we used in vivo microcomputed tomography (μCT) of the proximal tibia metaphysis and individual trabecular dynamics (ITD) analysis to quantify connectivity repair (incidences of rod connection and plate perforation filling) and deterioration (incidences of rod disconnection and plate perforation). Three-month-old female, intact rats were scanned before and after a 12 day treatment period of vehicle (Veh, n = 5), ALN (n = 6), PTH (n = 6), and combined (PTH+ALN, n = 6) therapy. Additionally, we used computational simulation and finite element (FE) analysis to delineate the contributions of connectivity repair or trabecular thickening to trabecular bone stiffness. Our results showed that the combined therapy group had greater connectivity repair (5.8 ± 0.5% connected rods and 2.0 ± 0.3% filled plates) beyond that of the Veh group, resulting in the greatest net gain in connectivity. For all treatment groups, increases in bone volume due to thickening (5–31%) were far greater than those due to connectivity repair (2–3%). Newly formed bone contributing only to trabecular thickening caused a 10%, 41%, and 69% increase in stiffness in the ALN, PTH, and PTH+ALN groups, respectively. Moreover, newly formed bone that led to connectivity repair resulted in an additional improvement in stiffness, with the highest in PTH+ALN (by an additional 12%), which was significantly greater than either PTH (5.6%) or ALN (4.5%). An efficiency ratio was calculated as the mean percent increase in stiffness divided by mean percent increase in BV for either thickening or connectivity repair in each treatment. For all treatments, the efficiency ratio of connectivity repair (ALN: 2.9; PTH: 3.4; PTH+ALN: 4.4) was higher than that due to thickening (ALN: 2.0; PTH: 1.7; PTH+ALN: 2.2), suggesting connectivity repair required less new bone formation to induce larger gains in stiffness. We conclude that through rod connection and plate perforation filling PTH+ALN combination therapy improved bone stiffness in a more efficient and effective manner than either monotherapy.
References
1.
Bone
, H. G.
, Hosking
, D.
, Devogelaer
, J. P.
, Tucci
, J. R.
, Emkey
, R. D.
, Tonino
, R. P.
, Rodriguez-Portales
, J. A.
, Downs
, R. W.
, Gupta
, J.
, Santora
, A. C.
, and Liberman
, U. A.
, 2004
, “Ten Years’ Experience With Alendronate for Osteoporosis in Postmenopausal Women
,” N. Engl. J. Med.
, 350
(12
), pp. 1189
–1199
.10.1056/NEJMoa0308972.
McClung
, M.
, Harris
, S. T.
, Miller
, P. D.
, Bauer
, D. C.
, Davison
, K. S.
, Dian
, L.
, Hanley
, D. A.
, Kendler
, D. L.
, Yuen
, C. K.
, and Lewiecki
, E. M.
, 2013
, “Bisphosphonate Therapy for Osteoporosis: Benefits, Risks, and Drug Holiday
,” Am. J. Med.
, 126
(1
), pp. 13
–20
.10.1016/j.amjmed.2012.06.0233.
Baron
, R.
, and Hesse
, E.
, 2012
, “Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives
,” J. Clin. Endocrinol. Metab.
, 97
(2
), pp. 311
–325
.10.1210/jc.2011-23324.
Datta
, N. S.
, and Abou-Samra
, A. B.
, 2009
, “PTH and PTHrP Signaling in Osteoblasts
,” Cell. Signalling
, 21
(8
), pp. 1245
–1254
.10.1016/j.cellsig.2009.02.0125.
Goltzman
, D
., 2008
, “Studies on the Mechanisms of the Skeletal Anabolic Action of Endogenous and Exogenous Parathyroid Hormone
,” Arch. Biochem. Biophys.
, 473
(2
), pp. 218
–224
.10.1016/j.abb.2008.03.0036.
Jilka
, R. L.
, 2007
, “Molecular and Cellular Mechanisms of the Anabolic Effect of Intermittent PTH
,” Bone
, 40
(6
), pp. 1434
–1446
.10.1016/j.bone.2007.03.0177.
Qin
, L.
, Raggatt
, L. J.
, and Partridge
, N. C.
, 2004
, “Parathyroid Hormone: A Double-Edged Sword for Bone Metabolism
,” Trends Endocrinol. Metab.
, 15
(2
), pp. 60
–65
.10.1016/j.tem.2004.01.0068.
Black
, D. M.
, Greenspan
, S. L.
, Ensrud
, K. E.
, Palermo
, L.
, McGowan
, J. A.
, Lang
, T. F.
, Garnero
, P.
, Bouxsein
, M. L.
, Bilezikian
, J. P.
, and Rosen
, C. J.
, 2003
, “The Effects of Parathyroid Hormone and Alendronate Alone or in Combination in Postmenopausal Osteoporosis
,” N. Engl. J. Med.
, 349
(13
), pp. 1207
–1215
.10.1056/NEJMoa0319759.
Cosman
, F.
, Eriksen
, E. F.
, Recknor
, C.
, Miller
, P. D.
, Guanabens
, N.
, Kasperk
, C.
, Papanastasiou
, P.
, Readie
, A.
, Rao
, H.
, Gasser
, J. A.
, Bucci-Rechtweg
, C.
, and Boonen
, S.
, 2011
, “Effects of Intravenous Zoledronic Acid Plus Subcutaneous Teriparatide [rhPTH(1–34)] in Postmenopausal Osteoporosis
,” J. Bone Miner. Res.
, 26
(3
), pp. 503
–511
.10.1002/jbmr.23810.
Cosman
, F.
, Keaveny
, T. M.
, Kopperdahl
, D.
, Wermers
, R. A.
, Wan
, X.
, Krohn
, K. D.
, and Krege
, J. H.
, 2013
, “Hip and Spine Strength Effects of Adding Versus Switching to Teriparatide in Postmenopausal Women With Osteoporosis Treated With Prior Alendronate or Raloxifene
,” J. Bone Miner. Res.
, 28
(6), pp. 1328
–1336
.11.
Cosman
, F.
, Nieves
, J.
, Zion
, M.
, Woelfert
, L.
, Luckey
, M.
, and Lindsay
, R.
, 2005
, “Daily and Cyclic Parathyroid Hormone in Women Receiving Alendronate
,” N. Engl. J. Med.
, 353
(6
), pp. 566
–575
.10.1056/NEJMoa05015712.
Cosman
, F.
, Wermers
, R. A.
, Recknor
, C.
, Mauck
, K. F.
, Xie
, L.
, Glass
, E. V.
, and Krege
, J. H.
, 2009
, “Effects of Teriparatide in Postmenopausal Women With Osteoporosis on Prior Alendronate or Raloxifene: Differences Between Stopping and Continuing the Antiresorptive Agent
,” J. Clin. Endocrinol. Metab.
, 94
(10
), pp. 3772
–3780
.10.1210/jc.2008-271913.
Finkelstein
, J. S.
, Hayes
, A.
, Hunzelman
, J. L.
, Wyland
, J. J.
, Lee
, H.
, and Neer
, R. M.
, 2003
, “The Effects of Parathyroid Hormone, Alendronate, or Both in Men With Osteoporosis
,” N. Engl. J. Med.
, 349
(13
), pp. 1216
–1226
.10.1056/NEJMoa03572514.
Finkelstein
, J. S.
, Wyland
, J. J.
, Lee
, H.
, and Neer
, R. M.
, 2010
, “Effects of Teriparatide, Alendronate, or Both in Women With Postmenopausal Osteoporosis
,” J. Clin. Endocrinol. Metab.
, 95
(4
), pp. 1838
–1845
.10.1210/jc.2009-170315.
Muschitz
, C.
, Kocijan
, R.
, Fahrleitner-Pammer
, A.
, Lung
, S.
, and Resch
, H.
, 2013
, “Antiresorptives Overlapping Ongoing Teriparatide Treatment Result in Additional Increases in Bone Mineral Density
,” J. Bone Miner. Res.
, 28
(1
), pp. 196
–205
.10.1002/jbmr.171616.
Schafer
, A. L.
, Burghardt
, A. J.
, Sellmeyer
, D. E.
, Palermo
, L.
, Shoback
, D. M.
, Majumdar
, S.
, and Black
, D. M.
, 2013
, “Postmenopausal Women Treated With Combination Parathyroid Hormone (1–84) and Ibandronate Demonstrate Different Microstructural Changes at the Radius vs. Tibia: The PTH and Ibandronate Combination Study (PICS)
,” Osteoporos. Int.
, 24
(10
), pp. 2591
–2601
.10.1007/s00198-013-2349-y17.
Altman
, A. R.
, Tseng
, W. J.
, de Bakker
, C. M.
, Huh
, B. K.
, Chandra
, A.
, Qin
, L.
, and Liu
, X. S.
, 2014
, “A Closer Look at the Immediate Trabecula Response to Combined Parathyroid Hormone and Alendronate Treatment
,” Bone
, 61C
, pp. 149
–157
.10.1016/j.bone.2014.01.00818.
Liu
, X. S.
, Bevill
, G.
, Keaveny
, T. M.
, Sajda
, P.
, and Guo
, X. E.
, 2009
, “Micromechanical Analyses of Vertebral Trabecular Bone Based on Individual Trabeculae Segmentation of Plates and Rods
,” J. Biomech.
, 42
(3
), pp. 249
–256
.10.1016/j.jbiomech.2008.10.03519.
Liu
, X. S.
, Sajda
, P.
, Saha
, P. K.
, Wehrli
, F. W.
, Bevill
, G.
, Keaveny
, T. M.
, and Guo
, X. E.
, 2008
, “Complete Volumetric Decomposition of Individual Trabecular Plates and Rods and Its Morphological Correlations With Anisotropic Elastic Moduli in Human Trabecular Bone
,” J. Bone Miner. Res.
, 23
(2
), pp. 223
–235
.10.1359/jbmr.07100920.
Liu
, X. S.
, Zhang
, X. H.
, and Guo
, X. E.
, 2009
, “Contributions of Trabecular Rods of Various Orientations in Determining the Elastic Properties of Human Vertebral Trabecular Bone
,” Bone
, 45
(2
), pp. 158
–163
.10.1016/j.bone.2009.04.20121.
Shi
, X.
, Liu
, X. S.
, Wang
, X.
, Guo
, X. E.
, and Niebur
, G. L.
, 2010
, “Type and Orientation of Yielded Trabeculae During Overloading of Trabecular Bone Along Orthogonal Directions
,” J. Biomech.
, 43
(13
), pp. 2460
–2466
.10.1016/j.jbiomech.2010.05.03222.
Shi
, X.
, Liu
, X. S.
, Wang
, X.
, Guo
, X. E.
, and Niebur
, G. L.
, 2010
, “Effects of Trabecular Type and Orientation on Microdamage Susceptibility in Trabecular Bone
,” Bone
, 46
(5
), pp. 1260
–1266
.10.1016/j.bone.2010.02.00523.
Liu
, X. S.
, Sajda
, P.
, Saha
, P. K.
, Wehrli
, F. W.
, and Guo
, X. E.
, 2006
, “Quantification of the Roles of Trabecular Microarchitecture and Trabecular Type in Determining the Elastic Modulus of Human Trabecular Bone
,” J. Bone Miner. Res.
, 21
(10
), pp. 1608
–1617
.10.1359/jbmr.06071624.
Guo
, X. E.
, and Kim
, C. H.
, 2002
, “Mechanical Consequence of Trabecular Bone Loss and Its Treatment: A Three-Dimensional Model Simulation
,” Bone
, 30
(2
), pp. 404
–411
.10.1016/S8756-3282(01)00673-125.
Boyd
, S. K.
, Davison
, P.
, Muller
, R.
, and Gasser
, J. A.
, 2006
, “Monitoring Individual Morphological Changes Over Time in Ovariectomized Rats by In Vivo Micro-Computed Tomography
,” Bone
, 39
(4
), pp. 854
–862
.10.1016/j.bone.2006.04.01726.
Brouwers
, J. E.
, van Rietbergen
, B.
, and Huiskes
, R.
, 2007
, “No Effects of In Vivo Micro-CT Radiation on Structural Parameters and Bone Marrow Cells in Proximal Tibia of Wistar Rats Detected After Eight Weekly Scans
,” J. Orthop. Res.
, 25
(10
), pp. 1325
–1332
.10.1002/jor.2043927.
Buie
, H. R.
, Moore
, C. P.
, and Boyd
, S. K.
, 2008
, “Postpubertal Architectural Developmental Patterns Differ Between the L3 Vertebra and Proximal Tibia in Three Inbred Strains of Mice
,” J. Bone Miner. Res.
, 23
(12
), pp. 2048
–2059
.10.1359/jbmr.08080828.
Lan
, S.
, Luo
, S.
, Huh
, B. K.
, Chandra
, A.
, Altman
, A. R.
, Qin
, L.
, and Liu
, X. S.
, 2013
, “3D Image Registration is Critical to Ensure Accurate Detection of Longitudinal Changes in Trabecular Bone Density, Microstructure, and Stiffness Measurements in Rat Tibiae by in vivo Micro Computed Tomography (μCT)
,” Bone
, 56
(1
), pp. 83
–90
.10.1016/j.bone.2013.05.01429.
Schulte
, F. A.
, Lambers
, F. M.
, Kuhn
, G.
, and Muller
, R.
, 2011
, “In Vivo Micro-Computed Tomography Allows Direct Three-Dimensional Quantification of Both Bone Formation and Bone Resorption Parameters Using Time-Lapsed Imaging
,” Bone
, 48
(3
), pp. 433
–442
.10.1016/j.bone.2010.10.00730.
Waarsing
, J. H.
, Day
, J. S.
, van der Linden
, J. C.
, Ederveen
, A. G.
, Spanjers
, C.
, De Clerck
, N.
, Sasov
, A.
, Verhaar
, J. A.
, and Weinans
, H.
, 2004
, “Detecting and Tracking Local Changes in the Tibiae of Individual Rats: A Novel Method to Analyse Longitudinal In Vivo Micro-CT Data
,” Bone
, 34
(1
), pp. 163
–169
.10.1016/j.bone.2003.08.01231.
Chandra
, A.
, Lan
, S.
, Zhu
, J.
, Lin
, T.
, Zhang
, X.
, Siclari
, V. A.
, Altman
, A. R.
, Cengel
, K. A.
, Liu
, X. S.
, and Qin
, L.
, 2013
, “PTH Prevents the Adverse Effects of Focal Radiation on Bone Architecture in Young Rats
,” Bone
, 55
(2
), pp. 449
–457
.10.1016/j.bone.2013.02.02332.
Ibanez
, L.
, Schroeder
, W.
, Ng
, L.
, and Cates
, J.
, 2005
, The ITK Software Guide
, 2nd ed., Kitware, New York.33.
Collignon
, A.
, Maes
, F.
, Delaere
, D.
, Vandermeulen
, D.
, Suetens
, P.
, and Marchal
, G.
, 1995
, “Automated Multi-Modality Image Registration Based on Information Theory
,” Information Processing in Medical Imaging
, Y.
Bizais
, C.
Barillot
, and R.
di Paola
, eds., Kluwer Academic Publishers
, Dordrecht, The Netherlands
, pp. 263
–274
.34.
Viola
, P.
, and Wells
, W. M.
, III, 1997
, “Alignment by Maximization of Mutual Information
,” Int. J. Comput. Vis.
, 24
(2
), pp. 137
–154
.10.1023/A:100795890491835.
Saha
, P. K.
, and Chaudhuri
, B. B.
, 1994
, “Detection of 3D Simple Points for Topology Preserving
,” IEEE Trans. Pattern Anal. Mach. Intell.
, 16
(10
), pp. 1028
–1032
.10.1109/34.32900736.
Saha
, P. K.
, and Chaudhuri
, B. B.
, 1996
, “3D Digital Topology Under Binary Transformation With Applications
,” Comput. Vis. Image Understanding
, 63
(3
), pp. 418
–429
.10.1006/cviu.1996.003237.
Saha
, P. K.
, Chaudhuri
, B. B.
, and Majumder
, D. D.
, 1997
, “A New Shape Preserving Parallel Thinning Algorithm for 3D Digital Images
,” Pattern Recognit.
, 30
(12
), pp. 1939
–1955
.10.1016/S0031-3203(97)00016-238.
Liu
, X. S.
, Zhang
, X. H.
, Sekhon
, K. K.
, Adams
, M. F.
, McMahon
, D. J.
, Bilezikian
, J. P.
, Shane
, E.
, and Guo
, X. E.
, 2010
, “High-Resolution Peripheral Quantitative Computed Tomography Can Assess Microstructural and Mechanical Properties of Human Distal Tibial Bone
,” J. Bone Miner. Res.
, 25
(4
), pp. 746
–756
.10.1359/jbmr.09082239.
Guo
, X. E.
, and Goldstein
, S. A.
, 1997
, “Is Trabecular Bone Tissue Different From Cortical Bone Tissue?
,” Forma
, 12
, pp. 185
–196
.40.
Hollister
, S. J.
, Brennan
, J. M.
, and Kikuchi
, N.
, 1994
, “A Homogenization Sampling Procedure for Calculating Trabecular Bone Effective Stiffness and Tissue Level Stress
,” J. Biomech.
, 27
(4
), pp. 433
–444
.10.1016/0021-9290(94)90019-141.
Feldkamp
, L. A.
, Goldstein
, S. A.
, Parfitt
, A. M.
, Jesion
, G.
, and Kleerekoper
, M.
, 1989
, “The Direct Examination of Three-Dimensional Bone Architecture In Vitro by Computed Tomography
,” J. Bone Miner. Res.
, 4
(1
), pp. 3
–11
.10.1002/jbmr.565004010342.
Kabel
, J.
, Odgaard
, A.
, van Rietbergen
, B.
, and Huiskes
, R.
, 1999
, “Connectivity and the Elastic Properties of Cancellous Bone
,” Bone
, 24
(2
), pp. 115
–120
.10.1016/S8756-3282(98)00164-143.
Kinney
, J. H.
, and Ladd
, A. J.
, 1998
, “The Relationship Between Three-Dimensional Connectivity and the Elastic Properties of Trabecular Bone
,” J. Bone Min. Res.
, 13
(5
), pp. 839
–845
.10.1359/jbmr.1998.13.5.83944.
Odgaard
, A
., 1997
, “Three-Dimensional Methods for Quantification of Cancellous Bone Architecture
,” Bone
, 20
(4
), pp. 315
–328
.10.1016/S8756-3282(97)00007-045.
Kostenuik
, P. J.
, Capparelli
, C.
, Morony
, S.
, Adamu
, S.
, Shimamoto
, G.
, Shen
, V.
, Lacey
, D. L.
, and Dunstan
, C. R.
, 2001
, “OPG and PTH-(1–34) Have Additive Effects on Bone Density and Mechanical Strength in Osteopenic Ovariectomized Rats
,” Endocrinology
, 142
(10
), pp. 4295
–4304
.10.1210/endo.142.10.843746.
Pierroz
, D. D.
, Bonnet
, N.
, Baldock
, P. A.
, Ominsky
, M. S.
, Stolina
, M.
, Kostenuik
, P. J.
, and Ferrari
, S. L.
, 2010
, “Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone? A Study of Intermittent Parathyroid Hormone With Denosumab or Alendronate in Knock-in Mice Expressing Humanized RANKL
,” J. Biol. Chem.
, 285
(36
), pp. 28164
–28173
.10.1074/jbc.M110.10196447.
Samadfam
, R.
, Xia
, Q.
, and Goltzman
, D.
, 2007
, “Co-Treatment of PTH With Osteoprotegerin or Alendronate Increases Its Anabolic Effect on the Skeleton of Oophorectomized Mice
,” J. Bone Miner. Res.
, 22
(1
), pp. 55
–63
.10.1359/jbmr.06091548.
Campbell
, G. M.
, Bernhardt
, R.
, Scharnweber
, D.
, and Boyd
, S. K.
, 2011
, “The bone Architecture is Enhanced With Combined PTH and Alendronate Treatment Compared to Monotherapy While Maintaining the State of Surface Mineralization in the OVX Rat
,” Bone
, 49
(2
), pp. 225
–232
.10.1016/j.bone.2011.04.00849.
Tsai
, J. N.
, Uihlein
, A. V.
, Lee
, H.
, Kumbhani
, R.
, Siwila-Sackman
, E.
, McKay
, E. A.
, Burnett-Bowie
, S. A.
, Neer
, R. M.
, and Leder
, B. Z.
, 2013
, “Teriparatide and Denosumab, Alone or Combined, in Women With Postmenopausal Osteoporosis: The DATA Study Randomised Trial
,” Lancet
, 382
(9886
), pp. 50
–56
.10.1016/S0140-6736(13)60856-950.
Giuliani
, N.
, Pedrazzoni
, M.
, Negri
, G.
, Passeri
, G.
, Impicciatore
, M.
, and Girasole
, G.
, 1998
, “Bisphosphonates Stimulate Formation of Osteoblast Precursors and Mineralized Nodules in Murine and Human Bone Marrow Cultures In Vitro and Promote Early Osteoblastogenesis in Young and Aged Mice In Vivo
,” Bone
, 22
(5
), pp. 455
–461
.10.1016/S8756-3282(98)00033-751.
Duque
, G.
, and Rivas
, D.
, 2007
, “Alendronate has an Anabolic Effect on Bone Through the Differentiation of Mesenchymal Stem Cells
,” J. Bone Miner. Res.
, 22
(10
), pp. 1603
–1611
.10.1359/jbmr.07070152.
Fu
, L.
, Tang
, T.
, Miao
, Y.
, Zhang
, S.
, Qu
, Z.
, and Dai
, K.
, 2008
, “Stimulation of Osteogenic Differentiation and Inhibition of Adipogenic Differentiation in Bone Marrow Stromal Cells by Alendronate Via ERK and JNK Activation
,” Bone
, 43
(1
), pp. 40
–47
.10.1016/j.bone.2008.03.00853.
Tu
, X.
, Rhee
, Y.
, Condon
, K. W.
, Bivi
, N.
, Allen
, M. R.
, Dwyer
, D.
, Stolina
, M.
, Turner
, C. H.
, Robling
, A. G.
, Plotkin
, L. I.
, and Bellido
, T.
, 2012
, “Sost Down Regulation and Local Wnt Signaling are Required for the Osteogenic Response to Mechanical Loading
,” Bone
, 50
(1
), pp. 209
–217
.10.1016/j.bone.2011.10.02554.
Bruel
, A.
, Vegger
, J. B.
, Raffalt
, A. C.
, Andersen
, J. E.
, and Thomsen
, J. S.
, 2013
, “PTH (1–34), But Not Strontium Ranelate Counteract Loss of Trabecular Thickness and Bone Strength in Disuse Osteopenic Rats
,” Bone
, 53
(1
), pp. 51
–58
.10.1016/j.bone.2012.11.03755.
Turner
, C. H.
, Warden
, S. J.
, Bellido
, T.
, Plotkin
, L. I.
, Kumar
, N.
, Jasiuk
, I.
, Danzig
, J.
, and Robling
, A. G.
, 2009
, “Mechanobiology of the Skeleton
,” Sci. Signaling
, 2
(68
), p. pt3
.10.1126/scisignal.268pt3Copyright © 2015 by ASME
You do not currently have access to this content.
