Tag Archives: publication

Wang ZX, Lloyd AA, Donnelly E. Altered distributions of bone tissue mineral and collagen properties in women with fragility fractures. Bone. 2016

Abstract

Heterogeneity of bone tissue properties is emerging as a potential indicator of altered bone quality in pathologic tissue. The objective of this study was to compare the distributions of tissue properties in women with and without histories of fragility fractures using Fourier transform infrared (FTIR) imaging. We extended a prior study that examined the relationship of the mean FTIR properties to fracture risk by analyzing in detail the widths and the tails of the distributions of FTIR properties in biopsies from fracture and non-fracture cohorts. The mineral and matrix properties of cortical and trabecular iliac crest tissue were compared in biopsies from women with a history of fragility fracture (+Fx; n = 21, age: mean 54 ± SD 15 y) and with no history of fragility fracture (−Fx; n = 12, age: 57 ± 5 y). A subset of the patients included in the −Fx group were taking estrogen-plusprogestin hormone replacement therapy (HRT) (−Fx + HRT n = 8, age: 58 ± 5 y) and were analyzed separately from patients with no history of HRT (−Fx − HRT n = 4, age: 56 ± 7 y). When the FTIR parameter mean values were examined by treatment group, the trabecular tissue of −Fx−HRT patients had a lower mineral:matrix ratio (M:M) and collagen maturity (XLR) than that of −Fx + HRT patients (−22% M:M, −18% XLR) and +Fx patients (−17% M:M, −18% XLR). Across multiple FTIR parameters, tissue from the −Fx − HRT group had smaller lowtail (5th percentile) values than that from the −Fx + HRT or +Fx groups. In trabecular collagen maturity and crystallinity (XST), the −Fx − HRT group had smaller low-tail values than those in the –Fx + HRT group (−16% XLR, −5% XST) and the + Fx group (−17% XLR, −7% XST). The relatively low values of trabecular mineral:matrix ratio and collagen maturity and smaller low-tail values of collagen maturity and crystallinity observed in the −Fx − HRT group are characteristic of younger tissue. Taken together, our data suggest that the presence of newly formed tissue that includes small/imperfect crystals and immature crosslinks, as well as moderately mature tissue, is an important characteristic of healthy, fracture-resistant bone. Finally, the larger mean and low-tail values of mineral:matrix ratio and collagen maturity noted in our −Fx + HRT vs. −Fx−HRT biopsies are consistent with greater tissue age and greater BMD arising from decreased osteoclastic resorption in HRT-treated patients.

DOI: 10.1016/j.bone.2016.01.012

Lloyd AA, Wang ZX, Donnelly E. Multiscale Contribution of Bone Tissue Material Property Heterogeneity to Trabecular Bone Mechanical Behavior. J Biomech Eng. 2015.

Abstract

Heterogeneity of material properties is an important potential contributor to bone fracture resistance because of its putative contribution to toughness, but establishing the contribution of heterogeneity to fracture risk is still in an incipient stage. Experimental studies have demonstrated changes in distributions of compositional and nanomechanical properties with fragility fracture history, disease, and pharmacologic treatment. Computational studies have demonstrated that models with heterogeneous material properties predict apparent stiffness moderately better than homogeneous models and show greater energy dissipation. Collectively, these results suggest that microscale material heterogeneity affects not only microscale mechanics but also structural performance at larger length scales.

PMID:25383615

Donnelly E, Saleh A, Unnanuntana A, Lane JM. Atypical femoral fractures: epidemiology, etiology, and patient management. Curr Opin Support Palliat Care. 2012.

Abstract

Purpose of review: To review the definition, epidemiology, and putative pathophysiology of atypical femoral fractures and propose strategies for the management of patients with atypical fractures as well as patients on long-term bisphosphonates without atypical fractures.

Recent findings: Recent epidemiologic evidence shows that the absolute incidence of atypical femoral fractures is small compared with the incidence of typical hip fractures. However, long-term bisphosphonate use may be an important risk factor for atypical fractures, and minimal additional antifracture benefit has been demonstrated for treatment durations longer than 5 years for patients with postmenopausal osteoporosis. This review gives advice to aid clinicians in the management of patients with incipient or complete atypical fractures.

Summary: Extremely limited evidence is available for how best to manage patients with atypical fractures. A comprehensive metabolic approach for the management of patients on long-term bisphosphonates will help to prevent oversuppression of bone remodeling that is implicated in the pathogenesis of these fractures.

PMID: 22643705

Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DM, Lane JM, and Boskey AL. Reduced bone tissue compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res.

DOI

Abstract

Reduction of bone turnover with bisphosphonate treatment alters bone mineral and matrix properties. Our objective was to investigate the effect of bisphosphonate treatment on bone tissue properties near fragility fracture sites in the proximal femur in postmenopausal women with osteoporosis. The mineral and collagen properties of cortico-cancellous biopsies from the proximal femur were compared in bisphosphonate-naive (-BIS, n = 20) and bisphosphonate-treated (+BIS, n = 20, duration 7 ± 5 y) patients with intertrochanteric (IT) and subtrochanteric (ST) fractures using Fourier transform infrared imaging (FTIRI). The mean values of the FTIRI parameter distributions were similar across groups, but the widths of the parameter distributions tended to be reduced in the +BIS group relative to the -BIS group. Specifically, the distribution widths of the cortical collagen maturity and crystallinity were reduced in the +BIS group relative to those of the -BIS group by 28% (+BIS 0.45 ± 0.18 vs. -BIS 0.63 ± 0.28, p = 0.03) and 17% (+BIS 0.087 ± 0.012 vs. -BIS 0.104 ± 0.036, p = 0.05), respectively. When the tissue properties were examined as a function of fracture morphology within the +BIS group, the FTIR parameters were generally similar regardless of fracture morphology. However, the cortical mineral:matrix ratio was 8% greater in tissue from patients with atypical ST fractures (n =6) than that of patients with typical (IT or spiral ST) fractures (n = 14) (Atypical 5.6 ± 0.3 vs. Typical 5.2 ± 0.5, p = 0.03). Thus, although the mean values of the FTIR properties were similar in both groups, the tissue in bisphosphonate-treated patients had a more uniform composition than that of bisphosphonate-naïve patients. The observed reductions in mineral and matrix heterogeneity may diminish tissue-level toughening mechanisms. © 2011 American Society for Bone and Mineral Research

Keywords

Fourier transform infrared imaging; cortical bone; material properties; hip fracture; atypical subtrochanteric fracture

Donnelly E, Meredith DS, Nguyen JT, and Boskey AL. Bone tissue composition varies across anatomic sites in the proximal femur and the iliac crest. J Orthop Res.

DOI

Abstract

The extent to which bone tissue composition varies across anatomic sites in normal or pathologic tissue is largely unknown, although pathologic changes in bone tissue composition are typically assumed to occur throughout the skeleton. Our objective was to compare the composition of normal cortical and trabecular bone tissue across multiple anatomic sites. The composition of cadaveric bone tissue from three anatomic sites was analyzed using Fourier transform infrared imaging: iliac crest (IC), greater trochanter (GT), and subtrochanteric femur (ST). The mean mineral:matrix ratio was 20% greater in the subtrochanteric cortex than in the cortices of the iliac crest (p = 0.004) and the greater trochanter (p  = 0.02). There were also trends toward 30% narrower crystallinity distributions in the subtrochanteric cortex than in the greater trochanter (p = 0.10) and 30% wider crystallinity distributions in the subtrochanteric trabeculae than in the greater trochanter (p = 0.054) and the iliac crest (p  = 0.11). Thus, the average cortical tissue mineral content and the widths of the distributions of cortical crystal size/perfection differ at the subtrochanteric femur relative to the greater trochanter and the iliac crest. In particular, the cortex of the iliac crest has lower mineral content relative to that of the subtrochanteric femur and may have limited utility as a surrogate for subtrochanteric bone. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

Keywords

iliac crest; subtrochanteric femur; Fourier transform infrared imaging; cortical bone; material properties

Donnelly E. (2011) Methods for assessing bone quality. Clin Orthop Relat Res 469: 2128-2138.

DOI

Abstract

Bone mass, geometry, and tissue material properties contribute to bone structural integrity. Thus, bone strength arises from both bone quantity and quality. Bone quality encompasses the geometric and material factors that contribute to fracture resistance.This review presents an overview of the methods for assessing bone quality across multiple length scales, their outcomes, and their relative advantages and disadvantages.A PubMed search was conducted to identify methods related to bone mechanical testing, imaging, and compositional analysis. Using various exclusion criteria, articles were selected for inclusion.Methods for assessing mechanical properties include whole-bone, bulk tissue, microbeam, and micro- and nanoindentation testing techniques. Outcomes include structural strength and material modulus. Advantages include direct assessment of bone strength; disadvantages include specimen destruction during testing. Methods for characterizing bone geometry and microarchitecture include quantitative CT, high-resolution peripheral quantitative CT, high-resolution MRI, and micro-CT. Outcomes include three-dimensional whole-bone geometry, trabecular morphology, and tissue mineral density. The primary advantage is the ability to image noninvasively; disadvantages include the lack of a direct measure of bone strength. Methods for measuring tissue composition include scanning electron microscopy, vibrational spectroscopy, nuclear magnetic resonance imaging, and chemical and physical analytical techniques. Outcomes include mineral density and crystallinity, elemental composition, and collagen crosslink composition. Advantages include the detailed material characterization; disadvantages include the need for a biopsy.Although no single method can completely characterize bone quality, current noninvasive imaging techniques can be combined with ex vivo mechanical and compositional techniques to provide a comprehensive understanding of bone quality.

Boskey AL, Donnelly E, Kinnett JG. (2011) Bone quality: From bench to bedside: Opening editorial comment. Clin Orthop Relat Res 469: 2087-2089.

DOI

Abstract

The term ‘‘bone quality’’ is frequently used by clinicians,
basic scientists, and engineers. However, do they mean the
same thing? In this symposium, we asked the authors what
they meant by ‘‘bone quality,’’ and as the reader will discover,
there are many aspects of bone quality that vary in
importance and scope with the person providing the definition.
In recent years, numerous reviews have explored
and described bone quality (eg, [2–25, 29]) and some have
discussed therapies for fragility fractures [13], but none has
emphasized the transition from the bench to the bedside
(and the operating room). In fact, the majority of these
reviews of bone quality are either engineering or basic
bone biology articles [3–6, 10, 11, 16], including imaging
techniques [3, 8, 12, 17, 20, 25], or papers on how to treat
osteoporosis [5, 7, 9, 15, 18, 19, 21, 23, 24]. Here too we
review those topics, providing recent research data from
leaders in the field. This symposium reviews and makes
suggestions for appropriate management of individuals
with impaired bone quality because the orthopaedic surgeon
sees cases where the quality of the bone is abnormal,
whether in patients with osteoporosis, osteopetrosis, cancer
[14], or a metabolic problem, such as diabetes [22], kidney
disease [29], or rheumatoid arthritis, and because little
guidance is available on pre- and postsurgical management
of these cases.

Reumann MK, Strachna O, Lukashova L, Verdelis K, Donnelly E, Boskey AL, and Mayer-Kuckuk P. (2011) Early growth response gene-1 regulates bone properties in mice. Calcif Tissue Int 89:1-9.

DOI

Abstract

Transcriptional regulation of the postnatal skeleton is incompletely understood. Here, we determined the consequence of loss of early growth response gene 1 (EGR-1) on bone properties. Analyses were performed on both the microscopic and molecular levels utilizing micro-computed tomography (micro-CT) and Fourier transform infrared imaging (FTIRI), respectively. Mice deficient in EGR-1 (Egr-1 −/−) were studied and compared to sex- and age-matched wild-type (wt) control animals. Femoral trabecular bone in male Egr-1 −/− mice demonstrated osteopenic characteristics marked by reductions in both bone volume fraction (BV/TV) and bone mineral density (BMD). Morphological analysis revealed fewer trabeculae in these animals. In contrast, female Egr-1 −/− animals had thinner trabeculae, but BV/TV and BMD were not significantly reduced. Analysis of femoral cortical bone at the mid-diaphysis did not show significant osteopenic characteristics but detected changes in cross-sectional geometry in both male and female Egr-1 −/− animals. Functionally, this resulted in decreased resistance to three-point bending as indicated by a reduction in maximum load, failure load, and stiffness. Assessment of compositional bone properties, including mineral-to-matrix ratio, carbonate-to-phosphate ratio, crystallinity, and cross-linking, in femurs by FTIRI did not show any significant differences or an appreciable trend between Egr-1 −/− and wt mice of either sex. Unexpectedly, rib bone from Egr-1 −/− animals displayed distinct osteopenic traits that were particularly pronounced in female mice. This study provides genetic evidence that both sex and skeletal site are critical determinants of EGR-1 activity in vivo and that its site-specific action may contribute to the mechanical properties of bone.

Keywords

Transcription factor; Early growth response gene 1; Mice; Micro-computed tomography; Biomechanics

Donnelly E, Chen DX, Boskey AL, Baker SP, and van der Meulen MCH. (2010) Contribution of mineral to bone structural behavior and tissue mechanical properties. Calcif Tissue Int 87:450-460.

DOI

Abstract

Bone geometry and tissue material properties jointly govern whole-bone structural behavior. While the role of geometry in structural behavior is well characterized, the contribution of the tissue material properties is less clear, partially due to the multiple tissue constituents and hierarchical levels at which these properties can be characterized. Our objective was to elucidate the contribution of the mineral phase to bone mechanical properties across multiple length scales, from the tissue material level to the structural level. Vitamin D and calcium deficiency in 6-week-old male rats was employed as a model of reduced mineral content with minimal collagen changes. The structural properties of the humeri were measured in three-point bending and related to the mineral content and geometry from microcomputed tomography. Whole-cortex and local bone tissue properties were examined with infrared (IR) spectroscopy, Raman spectroscopy, and nanoindentation to understand the role of altered mineral content on the constituent material behavior. Structural stiffness (−47%) and strength (−50%) were reduced in vitamin D-deficient (−D) humeri relative to controls. Moment of inertia (−38%), tissue mineral density (TMD, −9%), periosteal mineralization (−28%), and IR mineral:matrix ratio (−19%) were reduced in −D cortices. Thus, both decreased tissue mineral content and changes in cortical geometry contributed to impaired skeletal load-bearing function. In fact, 97% of the variability in humeral strength was explained by moment of inertia, TMD, and IR mineral:matrix ratio. The strong relationships between structural properties and cortical material composition demonstrate a critical role of the microscale material behavior in skeletal load-bearing performance.

Keywords

Bone strength; Material property; Mineral; Rat; Fourier transform infrared spectroscopy

Unnanuntana A, Gladnick B, Donnelly E, and Lane JM. (2010) The assessment of fracture risk. J Bone Joint Surg Am 92:743-753.

DOI

Abstract

Bone mineral density is considered to be the standard measure for the diagnosis of osteoporosis and the assessment of fracture risk. The majority of fragility fractures occur in patients with bone mineral density in the osteopenic range.

The Fracture Risk Assessment Tool (FRAX) can be used as an assessment modality for the prediction of fractures on the basis of clinical risk factors, with or without the use of femoral neck bone mineral density. Treatment of osteoporosis should be considered for patients with low bone mineral density (a T-score of between -1.0 and -2.5) as well as a ten-year risk of hip fracture of =3% or a ten-year risk of a major osteoporosis-related fracture of =20% as assessed with the FRAX.

Biochemical bone markers are useful for monitoring the efficacy of antiresorptive or anabolic therapy and may aid in identifying patients who have a high risk of fracture.

An approach combining the assessment of bone mineral density, clinical risk factors for fracture with use of the FRAX, and bone turnover markers will improve the prediction of fracture risk and enhance the evaluation of patients with osteoporosis.

Keywords

fracture ; osteoporosis ; bone resorption ; bone mineral density ; hip fractures ; osteogenesis ; women