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Research Papers

Enhanced Individual Trabecular Repair and Its Mechanical Implications in Parathyroid Hormone and Alendronate Treated Rat Tibial Bone

[+] Author and Article Information
Allison R. Altman

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: alaltman@mail.med.upenn.edu

Chantal M. J. de Bakker

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: chantald@seas.upenn.edu

Wei-Ju Tseng

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: weits@mail.med.upenn.edu

Abhishek Chandra

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: abhic@mail.med.upenn.edu

Ling Qin

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
424A Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: qinling@mail.med.upenn.edu

X. Sherry Liu

McKay Orthopaedic Research Laboratory,
Department of Orthopaedic Surgery,
University of Pennsylvania,
426C Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104
e-mail: xiaoweil@mail.med.upenn.edu

1Corresponding author.

Manuscript received June 16, 2014; final manuscript received September 30, 2014; accepted manuscript posted October 16, 2014; published online December 10, 2014. Assoc. Editor: Ara Nazarian.

J Biomech Eng 137(1), 011004 (Jan 01, 2015) Paper No: BIO-14-1266; doi: 10.1115/1.4028823 History: Received June 16, 2014; Revised September 30, 2014; Accepted October 16, 2014; Online December 10, 2014

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.

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Topics: Maintenance , Bone , Stiffness
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Figures

Grahic Jump Location
Fig. 1

(a) Precisely registered trabecular bone subvolumes from day 0 and day 12 treated by 12 days of PTH. (b) Individual rods and plates were isolated using ITS analysis, and occurrences of (c) rod disconnection, plate perforation, rod connection, and plate perforation filling (from left to right) were located and quantified by ITD analysis.

Grahic Jump Location
Fig. 2

2D schematics for the 3D μFE analysis performed on the day 0 (left), day 12 (right), and simulated day 12 image (middle). The simulated image was created by deleting the effects of changed connectivity over the treatment period identified by ITD analysis. Circles indicate examples of locations where altered connectivity was returned to baseline. The arrows below describe how each structural contribution was delineated, numbers correspond to Eqs. (1)–(3).

Grahic Jump Location
Fig. 3

Standard trabecular microstructural evaluation on precisely registered subvolumes: (a) BV/TV, (b) stiffness, (c) Tb.Th, and (d) Conn.D. Bar graphs represent the percent difference from baseline to day 12 of each parameter. “*” Indicates a significant difference between groups at day 12, and “&” indicates a significant increase from baseline.

Grahic Jump Location
Fig. 4

(Top) Representative images of ITD: (a) rod disconnection; (b) plate perforation; (c) rod connection; and (d) perforation filling. Each brick represents an image voxel (10.5 × 10.5 × 10.5 μm3). Red/darker shading indicates the bone tissue lost at day 12 in (a) and (b) and green/lighter shading indicates the bone tissue gained at day 12 in (c) and (d). (Bottom) percent of (a) rod disconnection, (b) plate perforation, (c) rod connection, and (d) perforation filling over total number of trabeculae were compared among Veh, ALN, PTH, and PTH+ALN groups. “*” Significant difference between treatment groups; “#” trend difference (p < 0.1) between treatment groups.

Grahic Jump Location
Fig. 5

Linear correlation between standard Conn.D measurement and (a) ITD measures of net connectivity gain (connectivity deterioration subtracted from connectivity repair) and (b) ITD measures of simulated Conn.D (%plate perforation − %plate perforation filling + %rod connection − %rod disconnection). “*” Indicates a significant correlation.

Grahic Jump Location
Fig. 6

Linear correlation of percent increase in stiffness and percent increase in (a) BV/TV, (b) Tb.Th, and (c) ITD measures of net connectivity gain (connectivity deterioration subtracted from connectivity repair). “*” Indicates a significant correlation.

Grahic Jump Location
Fig. 7

Percent increase in BV and stiffness attributed to (a) thickening and (b) connectivity repair in each treatment group. Numbers over bars indicate the efficiency ratio for a particular treatment and mechanism.

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