Publications by authors named "David B Burr"

113 Publications

Effects of anti-resorptive treatment on the material properties of individual canine trabeculae in cyclic tensile tests.

Bone 2021 May 1;150:115995. Epub 2021 May 1.

Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria. Electronic address:

Osteoporosis is defined as a decrease of bone mass and strength, as well as an increase in fracture risk. It is conventionally treated with antiresorptive drugs, such as bisphosphonates (BPs) and selective estrogen receptor modulators (SERMs). Although both drug types successfully decrease the risk of bone fractures, their effect on bone mass and strength is different. For instance, BP treatment causes an increase of bone mass, stiffness and strength of whole bones, whereas SERM treatment causes only small (4%) increases of bone mass, but increased bone toughness. Such improved mechanical behavior of whole bones can be potentially related to the bone mass, bone structure or material changes. While bone mass and architecture have already been investigated previously, little is known about the mechanical behavior at the tissue/material level, especially of trabecular bone. As such, the goal of the work presented here was to fill this gap by performing cyclic tensile tests in a wet, close to physiologic environment of individual trabeculae retrieved from the vertebrae of beagle dogs treated with alendronate (a BP), raloxifene (a SERM) or without treatments. Identification of material properties was performed with a previously developed rheological model and of mechanical properties via fitting of envelope curves. Additionally, tissue mineral density (TMD) and microdamage formation were analyzed. Alendronate treatment resulted in a higher trabecular tissue stiffness and strength, associated with higher levels of TMD. In contrast, raloxifene treatment caused a higher trabecular toughness, pre-dominantly in the post-yield region. Microdamage formation during testing was not affected by either anti-resorptive treatment regimens. These findings highlight that the improved mechanical behavior of whole bones after anti-resorptive treatment is at least partly caused by improved material properties, with different mechanisms for alendronate and raloxifene. This study further shows the power of performing a mechanical characterization of trabecular bone at the level of individual trabeculae for better understanding of clinically relevant mechanical behavior of bone.
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http://dx.doi.org/10.1016/j.bone.2021.115995DOI Listing
May 2021

Skeletal Protection and Promotion of Microbiome Diversity by Dietary Boosting of the Endogenous Antioxidant Response.

J Bone Miner Res 2021 Apr 30;36(4):768-778. Epub 2020 Dec 30.

Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

There is an unmet need for interventions with better compliance that prevent the adverse effects of sex steroid deficiency on the musculoskeletal system. We identified a blueberry cultivar (Montgomerym [Mont]) that added to the diet protects female mice from musculoskeletal loss and body weight changes induced by ovariectomy. Mont, but not other blueberries, increased the endogenous antioxidant response by bypassing the traditional antioxidant transcription factor Nrf2 and without activating estrogen receptor canonical signaling. Remarkably, Mont did not protect the male skeleton from androgen-induced bone loss. Moreover, Mont increased the variety of bacterial communities in the gut microbiome (α-diversity) more in female than in male mice; shifted the phylogenetic relatedness of bacterial communities (β-diversity) further in females than males; and increased the prevalence of the taxon Ruminococcus1 in females but not males. Therefore, this nonpharmacologic intervention (i) protects from estrogen but not androgen deficiency; (ii) preserves bone, skeletal muscle, and body composition; (iii) elicits antioxidant defense responses independently of classical antioxidant/estrogenic signaling; and (iv) increases gut microbiome diversity toward a healthier signature. These findings highlight the impact of nutrition on musculoskeletal and gut microbiome homeostasis and support the precision medicine principle of tailoring dietary interventions to patient individualities, like sex. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4231DOI Listing
April 2021

Fifty years of bisphosphonates: What are their mechanical effects on bone?

Authors:
David B Burr

Bone 2020 09 3;138:115518. Epub 2020 Jul 3.

Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, United States of America; Department of Biomedical Engineering, Indiana University-Purdue University, Indianapolis, Indianapolis, IN 46202, United States of America. Electronic address:

After fifty years of experience with several generations of bisphosphonates (BPs), and 25 years after these drugs were approved for use in humans, their mechanical effects on bone are still not fully understood. Certainly, these drugs have transformed the treatment of osteoporosis in both men and women. There is no question that they do prevent fractures related to low bone mass, and there is widespread agreement that they increase strength and stiffness of the vertebrae. There is less consensus, however, about their effects on cortical bone, or on bone tissue properties in either trabecular or cortical bone, or their effects with longer periods of treatment. The consensus of most studies, both those based on ovariectomized and intact animal models and on testing of human bone, is that long-term treatment and/or high doses with certain BPs make the bone tissue more brittle and less tough. This translates into reduced energy to fracture and potentially a shorter bone fatigue life. Many studies have been done, but Interpretation of the results of these studies is complicated by variations in which BP is used, the animal model used, dose, duration, and methods of testing. Duration effects and effects on impact properties of bone are gaps that should be filled with additional testing.
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http://dx.doi.org/10.1016/j.bone.2020.115518DOI Listing
September 2020

Preface to the special issue of BONE in honor of John D. Currey.

Bone 2020 04 25;133:115246. Epub 2020 Jan 25.

Institute of Technology Berlin, Materials Science and Engineering, Berlin, Germany.

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http://dx.doi.org/10.1016/j.bone.2020.115246DOI Listing
April 2020

The Importance of Biologically Active Vitamin D for Mineralization by Osteocytes After Parathyroidectomy for Renal Hyperparathyroidism.

JBMR Plus 2019 Nov 23;3(11):e10234. Epub 2019 Oct 23.

Department of Medicine, Kidney Center Tokyo Women's Medical University Shinjuku-ku, Tokyo Japan.

Hypomineralized matrix is a factor determining bone mineral density. Increased perilacunar hypomineralized bone area is caused by reduced mineralization by osteocytes. The importance of vitamin D in the mineralization by osteocytes was investigated in hemodialysis patients who underwent total parathyroidectomy (PTX) with immediate autotransplantation of diffuse hyperplastic parathyroid tissue. No previous reports on this subject exist. The study was conducted in 19 patients with renal hyperparathyroidism treated with PTX. In 15 patients, the serum calcium levels were maintained by subsequent administration of alfacalcidol (2.0 μg/day), i.v. calcium gluconate, and oral calcium carbonate for 4 weeks after PTX (group I). This was followed in a subset of 4 patients in group I by a reduced dose of 0.5 μg/day until 1 year following PTX; this was defined as group II. In the remaining 4 patients, who were not in group I, the serum calcium (Ca) levels were maintained without subsequent administration of alfacalcidol (group III). Transiliac bone biopsy specimens were obtained in all groups before and 3 or 4 weeks after PTX to evaluate the change of the hypomineralized bone area. In addition, patients from group II underwent a third bone biopsy 1 year following PTX. A significant decrease of perilacunar hypomineralized bone area was observed 3 or 4 weeks after PTX in all group I and II patients. The area was increased again in the group II patients 1 year following PTX. In group III patients, an increase of the hypomineralized bone area was observed 4 weeks after PTX. The maintenance of a proper dose of vitamin D is necessary for mineralization by osteocytes, which is important to increase bone mineral density after PTX for renal hyperparathyroidism. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874232PMC
November 2019

Voluntary Chronic Heavy Alcohol Consumption in Male Rhesus Macaques Suppresses Cancellous Bone Formation and Increases Bone Marrow Adiposity.

Alcohol Clin Exp Res 2019 12 17;43(12):2494-2503. Epub 2019 Oct 17.

Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon.

Background: Chronic heavy alcohol consumption is an established risk factor for bone fracture, but comorbidities associated with alcohol intake may contribute to increased fracture rates in alcohol abusers. To address the specific effects of alcohol on bone, we used a nonhuman primate model and evaluated voluntary alcohol consumption on: (i) global markers of bone turnover in blood and (ii) cancellous bone mass, density, microarchitecture, turnover, and microdamage in lumbar vertebra.

Methods: Following a 4-month induction period, 6-year-old male rhesus macaques (Macaca mulatta, n = 13) voluntarily self-administered water or ethanol (EtOH; 4% w/v) for 22 h/d, 7 d/wk, for a total of 12 months. Control animals (n = 9) consumed an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice to label mineralizing bone surfaces. Global skeletal response to EtOH was evaluated by measuring plasma osteocalcin and carboxyterminal collagen cross-links (CTX). Local response was evaluated in lumbar vertebra using dual-energy X-ray absorptiometry, microcomputed tomography, static and dynamic histomorphometry, and histological assessment of microdamage.

Results: Monkeys in the EtOH group consumed an average of 2.8 ± 0.2 (mean ± SE) g/kg/d of EtOH (30 ± 2% of total calories), resulting in an average blood EtOH concentration of 88.3 ± 8.8 mg/dl 7 hours after the session onset. Plasma CTX and osteocalcin tended to be lower in EtOH-consuming monkeys compared to controls. Significant differences in bone mineral density in lumbar vertebrae 1 to 4 were not detected with treatment. However, cancellous bone volume fraction (in cores biopsied from the central region of the third vertebral body) was lower in EtOH-consuming monkeys compared to controls. Furthermore, EtOH-consuming monkeys had lower osteoblast perimeter and mineralizing perimeter, no significant difference in osteoclast perimeter, and higher bone marrow adiposity than controls. No significant differences between groups were detected in microcrack density (2 lumbar vertebra).

Conclusions: Voluntary chronic heavy EtOH consumption reduces cancellous bone formation in lumbar vertebra by decreasing osteoblast-lined bone perimeter, a response associated with an increase in bone marrow adiposity.
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http://dx.doi.org/10.1111/acer.14202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904502PMC
December 2019

Stress concentrations and bone microdamage: John Currey's contributions to understanding the initiation and arrest of cracks in bone.

Authors:
David B Burr

Bone 2019 10 22;127:517-525. Epub 2019 Jul 22.

Dept. of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States of America; Dept. of Biomedical Engineering, Indiana University-Purdue University, Indianapolis (IUPUI), Indianapolis, IN 46202, United States of America. Electronic address:

The microarchitecture of bone tissue presents many features that could act as stress concentrators for the initiation of bone microdamage. This was first identified by John Currey in a seminal paper in 1962 in which he presented the mechanical and biological evidence for stress concentrations at the bone surface, within the bone through the action of stiffness differentials between architectural features including between lamellae, and at the level of the lacunar and canalicular walls. Those early observations set the stage to consider how microscopic damage to bone tissue might affect the properties of bone at a time when most in the scientific community dismissed microcracks in bone as artifact. Evidence collected in the nearly 60 years since those important initial observations suggest that some of these architectural features in bone tissue are more effective as crack arrestors than as crack initiators. Sites of higher mineralization in the bone matrix, particularly interstitial sites in both cortical and trabecular bone, may serve preferentially as locations for crack initiation, whereas those boundaries identified by Currey as both stress concentrators and stress arrestors are more effective at stopping cracks than at initiating them.
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http://dx.doi.org/10.1016/j.bone.2019.07.015DOI Listing
October 2019

Loss of optimizes osteogenic metabolism and secretion to enhance bone quality.

Am J Physiol Endocrinol Metab 2019 05 15;316(5):E749-E772. Epub 2019 Jan 15.

Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana.

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor nuclear matrix protein 4 (, , , ) respond to several classes of osteoporosis drugs with enhanced bone formation compared with wild-type (WT) animals. mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyperanabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that MSPCs exhibited an enhanced capacity for glycolytic conversion: a key step in bone anabolism. cells showed elevated collagen translation and secretion. The expression of matrix genes that contribute to bone material-level mechanical properties was elevated in cells, an observation that was supported by biomechanical testing of bone samples from and WT mice. We conclude that loss of increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.
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http://dx.doi.org/10.1152/ajpendo.00343.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580174PMC
May 2019

Changes in bone matrix properties with aging.

Authors:
David B Burr

Bone 2019 03 10;120:85-93. Epub 2018 Oct 10.

Dept. of Anatomy and Cell Biology, Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, United States of America; Dept. of Biomedical Engineering, Indiana University-Purdue University, Indianapolis (IUPUI), United States of America. Electronic address:

It is well known that bone loss accompanies aging in both men and women and contributes to skeletal fragility in the older population, but changes that occur to the bone tissue matrix itself are less well known. These changes in bone quality aggravate the skeletal fragility associated with loss of bone mass. Bone tissue quality is affected by age-related changes in bone mineral, collagen and its cross-linking profiles, water compartments and even non-collagenous proteins. It is commonly assumed that greater tissue mineralization accompanies aging as bone turnover slows down in elderly individuals, but the data for this are weak. However, there may be changes in the quality of the mineral crystals, and the substitutions found within the crystal. Both enzymatically-mediated and non-enzymatically-mediated collagen cross-links multiply with age. The former tend to make the bone stiffer and stronger, but the latter, while making the bone stiffer can also make it more brittle and more likely to fracture. Bone pore water that is not bound to collagen or mineral increases with age as bone mass is lost, but water that is bound to collagen and mineral declines with age. These changes contribute to skeletal fragility by reducing the amount that bone can deform before fracturing. Finally, non-collagenous proteins have physical properties that can alter matrix mechanical properties and can also have molecular signaling functions that regulate bone remodeling. Whether these change with age, how they change, and how this affects skeletal fragility with aging is still largely a black box, and requires much more investigation. The roles of any of these factors in skeletal fragility are difficult to assess clinically as there is no easy or economical way to evaluate them, but a picture of fragility in the aging skeleton is incomplete without them.
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http://dx.doi.org/10.1016/j.bone.2018.10.010DOI Listing
March 2019

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 12 14;33(12):2230-2235. Epub 2018 Sep 14.

Eli Lilly and Company, Indianapolis, IN, USA.

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 μm ) 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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http://dx.doi.org/10.1002/jbmr.3565DOI Listing
December 2018

Microcrack-associated bone remodeling is rarely observed in biopsies from athletes with medial tibial stress syndrome.

J Bone Miner Metab 2019 May 31;37(3):496-502. Epub 2018 Jul 31.

Bergman Clinics, Naarden, The Netherlands.

The pathology of medial tibial stress syndrome (MTSS) is unknown. Studies suggest that MTSS is a bony overload injury, but histological evidence is sparse. The presence of microdamage, and its potential association with targeted remodeling, could provide evidence for the pathogenesis of MTSS. Understanding the pathology underlying MTSS could contribute to effective preventative and therapeutic interventions for MTSS. Our aim was to retrospectively evaluate biopsies, previously taken from the painful area in athletes with MTSS, for the presence of linear microcracks, diffuse microdamage and remodeling. Biopsies, previously taken from athletes with MTSS, were evaluated at the Department of Anatomy and Cell Biology at the Indiana University. After preparing the specimens by en bloc staining, one investigator evaluated the presence of linear microcracks, diffuse microdamage and remodeling in the specimens. A total of six biopsies were evaluated for the presence of microdamage and remodeling. Linear microcracks were found in 4 out of 6 biopsies. Cracking in one of these specimens was artefactual due to the biopsy procedure. No diffuse microdamage was seen in any of the specimens, and only one potential remodeling front in association with the microcracks. We found only linear microcracks in vivo in biopsies taken from the painful area in 50% of the athletes with MTSS, consistent with the relationship between linear cracks and fatigue-associated overloading of bone. The nearly universal absence of a repair reaction was notable. This suggests that unrepaired microdamage accumulation may underlie the pathophysiological basis for MTSS in athletes.
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http://dx.doi.org/10.1007/s00774-018-0945-9DOI Listing
May 2019

Osteocytic perilacunar/canalicular turnover in hemodialysis patients with high and low serum PTH levels.

Bone 2018 08 5;113:68-76. Epub 2018 May 5.

Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.

Osteocytic perilacunar/canalicular turnover in hemodialysis patients has not yet been reported. Osteocyte lacunae in lamellar bone and woven bone were classified as eroded surface-, osteoid surface-, and quiescent surface-predominant osteocyte lacunae (ES-Lc, OS-Lc, QS-Lc, respectively) in 55 hemodialysis patients with either high- (n = 45) or low- (n = 10) parathyroid hormone levels, and 19 control subjects without chronic kidney disease. We calculated the area and number of ES-Lc, OS-Lc, and QS-Lc. The mineralized surface on the osteocyte lacunar walls was measured in each group, and compared among the three groups. The shapes of the osteocyte lacunar walls were validated by backscattered electron microscopy. While the number of ES-Lc per bone area (N.ES-Lc/B.Ar) was higher than the number of OS-Lc per bone area (N.OS-Lc/B.Ar) in all groups, N.ES-Lc/B.Ar and N.OS-Lc/B.Ar were greater in high-parathyroid hormone group than in low-parathyroid hormone and control groups. The total volume of ES-Lc per bone area (ES-Lc.Ar/B.Ar) was greater than the total volume of OS-Lc per bone area (OS-Lc.Ar/B.Ar) in both parathyroid hormone groups. However, both lacunar erosion and lacunar formation increased proportionally, suggesting that global coupling between them was maintained. N.ES-Lc/B.Ar was higher in woven bone than in lamellar bone. The rate of OS-Lc stained by tetracycline hydrochloride, the mineralized lacunar surface and the mean area of OS-Lc with Tc obtained from both parathyroid hormone groups were greater than those in the control group. We conclude that osteocytic perilacunar/canalicular turnover is increased in hemodialysis patients with high parathyroid hormone levels. Osteocytic perilacunar/canalicular turnover depends, at least in part, on serum parathyroid hormone level. However, the ideal PTH level for osteocytic perilacunar/canalicular turnover could not be determined but osteocytic osteolysis was predominant in both the high- and low-PTH groups in this study. Thus, attention should be paid to bone loss from the viewpoint of osteocytic perilacunar/canalicular turnover in hemodialysis patients.
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http://dx.doi.org/10.1016/j.bone.2018.05.002DOI Listing
August 2018

Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification.

J Bone Miner Res 2018 05 5;33(5):930-944. Epub 2018 Feb 5.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

Approximately 10% of all bone fractures do not heal, resulting in patient morbidity and healthcare costs. However, no pharmacological treatments are currently available to promote efficient bone healing. Inhibition of Ca /calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) reverses age-associated loss of trabecular and cortical bone volume and strength in mice. In the current study, we investigated the role of CaMKK2 in bone fracture healing and show that its pharmacological inhibition using STO-609 accelerates early cellular and molecular events associated with endochondral ossification, resulting in a more rapid and efficient healing of the fracture. Within 7 days postfracture, treatment with STO-609 resulted in enhanced Indian hedgehog signaling, paired-related homeobox (PRX1)-positive mesenchymal stem cell (MSC) recruitment, and chondrocyte differentiation and hypertrophy, along with elevated expression of osterix, vascular endothelial growth factor, and type 1 collagen at the fracture callus. Early deposition of primary bone by osteoblasts resulted in STO-609-treated mice possessing significantly higher callus bone volume by 14 days following fracture. Subsequent rapid maturation of the bone matrix bestowed fractured bones in STO-609-treated animals with significantly higher torsional strength and stiffness by 28 days postinjury, indicating accelerated healing of the fracture. Previous studies indicate that fixed and closed femoral fractures in the mice take 35 days to fully heal without treatment. Therefore, our data suggest that STO-609 potentiates a 20% acceleration of the bone healing process. Moreover, inhibiting CaMKK2 also imparted higher mechanical strength and stiffness at the contralateral cortical bone within 4 weeks of treatment. Taken together, the data presented here underscore the therapeutic potential of targeting CaMKK2 to promote efficacious and rapid healing of bone fractures and as a mechanism to strengthen normal bones. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549722PMC
May 2018

Editorial: Wnt Signaling Related to Subchondral Bone Density and Cartilage Degradation in Osteoarthritis.

Arthritis Rheumatol 2018 02 9;70(2):157-161. Epub 2018 Jan 9.

Indiana University School of Dentistry, Indianapolis, Indiana.

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http://dx.doi.org/10.1002/art.40382DOI Listing
February 2018

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

PLoS One 2017 9;12(8):e0181750. Epub 2017 Aug 9.

Department of Orthopedics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1-2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549927PMC
October 2017

Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism.

Endocrinology 2017 09;158(9):2722-2740

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.

Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.
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http://dx.doi.org/10.1210/en.2017-00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659666PMC
September 2017

Response to PD Miller, Underdiagnosis and Undertreatment of Osteoporosis: The Battle To Be Won.

J Clin Endocrinol Metab 2017 03;102(3):1088-1089

Department of Medicine, Monash University, Melbourne, Victoria 3800, Australia.

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http://dx.doi.org/10.1210/jc.2016-2189DOI Listing
March 2017

STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice.

Arthritis Rheumatol 2017 Feb;69(2):460-471

University of Massachusetts Medical School, Worcester.

Objective: Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN-α/β/ω receptor (IFNAR) (DNase II /IFNAR double-knockout [DKO] mice) compared with controls.

Methods: Bone parameters were evaluated by micro-computed tomography and histomorphometry in DKO mice in comparison with mice triple deficient in STING, DNase II, and IFNAR and control mice. Cell culture techniques were employed to determine the parameters of osteoclast and osteoblast differentiation and function. NanoString and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation.

Results: Despite the expression of proinflammatory cytokines that would be expected to induce bone loss in the skeleton of DKO mice, the results, paradoxically, demonstrated an accumulation of bone in the long bones and spleens, sites of erythropoiesis and robust DNA accrual. In addition, factors promoting osteoblast recruitment and function were induced. Deficiency of STING significantly inhibited bone accrual.

Conclusion: These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. The results demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in human autoimmune diseases.
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http://dx.doi.org/10.1002/art.39863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274601PMC
February 2017

Corrigendum to "The resistance of cortical bone tissue to failure under cyclic loading is reduced with alendronate"[Bone 64 (2014) 57-64].

Bone 2016 02 27;83:283. Epub 2015 Mar 27.

Department of Orthopaedics, New Jersey Medical School, Rutgers University, 205S. Orange Avenue, Newark NJ 07103, USA; Department of Biomedical Engineering, New Jersey Institute of Technology, 323 Martin Luther King, Jr. Boulevard, Newark, NJ, 07102, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bone.2015.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811041PMC
February 2016

Structural features underlying raloxifene's biophysical interaction with bone matrix.

Bioorg Med Chem 2016 02 29;24(4):759-67. Epub 2015 Dec 29.

Lilly Research Laboratories, Indianapolis, IN, United States.

Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.
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http://dx.doi.org/10.1016/j.bmc.2015.12.045DOI Listing
February 2016

Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone.

Bone 2015 Dec 5;81:352-363. Epub 2015 Aug 5.

Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA. Electronic address:

Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.
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http://dx.doi.org/10.1016/j.bone.2015.08.002DOI Listing
December 2015

Microbial osteolysis in an Early Pleistocene hominin (Paranthropus robustus) from Swartkrans, South Africa.

J Hum Evol 2015 Aug 18;85:126-35. Epub 2015 Jun 18.

Plio-Pleistocene Palaeontology Section, Department of Vertebrates, Ditsong National Museum of Natural History, Pretoria 0002, South Africa.

Microbiological degradation is one of the most important factors responsible for the destruction of bone in archaeological contexts. Microscopic focal destruction (MFD) is the most prevalent form of microbial tunneling and is encountered very commonly in human bones from archaeological sites, whereas animal bones from these same sites show significantly better preservation if they were deposited in a fragmentary (e.g., butchered) state. Similarly, most fossils show either no evidence or only minor traces of bacterial osteolysis. These observations and experimental evidence point to an endogenous origin for osteolytic bacteria, suggesting that bone bioerosion could potentially aid in reconstructing early taphonomic events. We here report extensive MFD in the mandibular corpus of a small (presumptive female) individual of the hominin Paranthropus robustus from the Early Pleistocene site of Swartkrans, South Africa. The specimen (SKX 5013) derives in situ from the Member 2 deposit, which is dated to ca. 1.5-1.0 Ma. Examination of sections from the corpus by backscattered electron microscopy reveals numerous small linear longitudinal and budded tunneling cavities, which tend to be concentrated around Haversian canals and are more abundant closer to the endosteal aspect of the section. The taphonomy of Swartkrans has been the subject of intense investigation, and given the possibility that different agents of accumulation may have been responsible for the faunal and hominin fossils in the different members at the site, the observation that a specimen of P. robustus from Member 2 displays significant microbial osteolysis is of potential interest. A study of the prevalence of this process in adequately large samples of the animal bones from these units may yield novel insights and provide refinement of our understanding of their taphonomic histories. Such observations might well reveal differences among the various members that could provide another valuable source of osteoarchaeological information for the site.
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http://dx.doi.org/10.1016/j.jhevol.2015.05.004DOI Listing
August 2015

Foreword: Calcified Tissue International and Musculoskeletal Research Special Issue: Bone Material Properties and Skeletal Fragility.

Calcif Tissue Int 2015 Sep 13;97(3):199-200. Epub 2015 May 13.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA,

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http://dx.doi.org/10.1007/s00223-015-0012-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527876PMC
September 2015

Understanding the etiology of the posteromedial tibial stress fracture.

Bone 2015 Sep 28;78:11-4. Epub 2015 Apr 28.

Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA, USA.

Previous human in vivo tibial strain measurements from surface strain gauges during vigorous activities were found to be below the threshold value of repetitive cyclical loading at 2500 microstrain in tension necessary to reduce the fatigue life of bone, based on ex vivo studies. Therefore it has been hypothesized that an intermediate bone remodeling response might play a role in the development of tibial stress fractures. In young adults tibial stress fractures are usually oblique, suggesting that they are the result of failure under shear strain. Strains were measured using surface mounted unstacked 45° rosette strain gauges on the posterior aspect of the flat medial cortex just below the tibial midshaft, in a 48year old male subject while performing vertical jumps, staircase jumps and running up and down stadium stairs. Shear strains approaching 5000 microstrain were recorded during stair jumping and vertical standing jumps. Shear strains above 1250 microstrain were recorded during runs up and down stadium steps. Based on predictions from ex vivo studies, stair and vertical jumping tibial shear strain in the test subject was high enough to potentially produce tibial stress fracture subsequent to repetitive cyclic loading without necessarily requiring an intermediate remodeling response to microdamage.
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http://dx.doi.org/10.1016/j.bone.2015.04.033DOI Listing
September 2015

Response to Courtney et al.

Bone 2016 08 24;89:77-79. Epub 2015 Mar 24.

Department of Orthopaedics, New Jersey Medical School, Rutgers University, 205 S. Orange Avenue, Newark, NJ 07103, USA; Department of Biomedical Engineering, New Jersey Institute of Technology, 323 Martin Luther King, Jr. Boulevard, Newark, NJ 07102, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bone.2015.03.007DOI Listing
August 2016

In Vivo UTE-MRI Reveals Positive Effects of Raloxifene on Skeletal-Bound Water in Skeletally Mature Beagle Dogs.

J Bone Miner Res 2015 Aug 21;30(8):1441-4. Epub 2015 May 21.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Raloxifene positively affects mechanical properties of the bone matrix in part through modification of skeletal-bound water. The goal of this study was to determine if raloxifene-induced alterations in skeletal hydration could be measured in vivo using ultra-short echotime magnetic resonance imaging (UTE-MRI). Twelve skeletally mature female beagle dogs (n = 6/group) were treated for 6 months with oral doses of saline vehicle (VEH, 1 mL/kg/d) or raloxifene (RAL, 0.5 mg/kg/d). After 6 months of treatment, all animals underwent in vivo UTE-MRI of the proximal tibial cortical bone. UTE-MRI signal intensity versus echotime curves were analyzed by fitting a double exponential to determine the short and long relaxation times of water with the bone (dependent estimations of bound and free water, respectively). Raloxifene-treated animals had significantly higher bound water (+14%; p = 0.05) and lower free water (-20%) compared with vehicle-treated animals. These data provide the first evidence that drug-induced changes in skeletal hydration can be noninvasively assessed using UTE-MRI.
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http://dx.doi.org/10.1002/jbmr.2470DOI Listing
August 2015

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone.

Proc Natl Acad Sci U S A 2015 Feb 20;112(5):E478-86. Epub 2015 Jan 20.

Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center and Division of Endocrinology, Department of Medicine, Indiana University School of Medicine;

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat(Ot) mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat(Ot) mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat(Ot) mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat(Ot) mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.
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http://dx.doi.org/10.1073/pnas.1409857112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321271PMC
February 2015

Repair mechanisms for microdamage in bone.

Authors:
David B Burr

J Bone Miner Res 2014 Dec;29(12):2534-6

Department of Anatomy and Cell Biology, Indiana University School of Medicine, and Department of Biomedical Engineering, Indiana University-Purdue University, Indianapolis, IN, USA.

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http://dx.doi.org/10.1002/jbmr.2366DOI Listing
December 2014

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone.

Bone 2015 Apr 5;73:8-15. Epub 2014 Dec 5.

Medical Science Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6 months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0 mg/mL) and low-density (<2.0 mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality.
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http://dx.doi.org/10.1016/j.bone.2014.11.025DOI Listing
April 2015