Eve Donnelly

The Assessment of Fracture Risk

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 > or = 3% or a ten-year risk of a major osteoporosis-related fracture of > or = 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.

Methods for Assessing Bone Quality: A Review

BackgroundBone 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.Questions/purposesThis review presents an overview of the methods for assessing bone quality across multiple length scales, their outcomes, and their relative advantages and disadvantages.MethodsA 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.ResultsMethods 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.ConclusionsAlthough 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.

Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures.

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 corticocancellous biopsies from the proximal femur were compared in bisphosphonate‐naive (−BIS, n = 20) and bisphosphonate‐treated (+BIS, n = 20, duration 7 ± 5 years) 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 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 versus −BIS 0.63 ± 0.28, p = 0.03) and 17% (+BIS 0.087 ± 0.012 versus −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 versus 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‐naive patients. The observed reductions in mineral and matrix heterogeneity may diminish tissue‐level toughening mechanisms.

Effects of tissue age on bone tissue material composition and nanomechanical properties in the rat cortex.

Although osteoporosis is known to alter bone tissue composition, the effects of such compositional changes on tissue material properties have not yet been examined. The natural gradient in tissue mineral content arising from skeletal appositional growth provides a basic model for investigation of relationships between tissue composition and mechanical properties. The purpose of this study was to examine the effects of tissue age on bone tissue composition and nanomechanical properties. The nanomechanical properties and composition of regions of differing tissue age were characterized in the femoral cortices of growing rats using nanoindentation and Raman spectroscopy. In addition, spatial maps of the properties of periosteal tissue were examined to investigate in detail the spatial gradients in the properties of newly formed tissue. Newly formed tissue (0-4 days) was 84% less stiff and had 79% lower mineral:matrix ratio than older intracortical (15-70 days) tissue. Tissue modulus, hardness, mineral:matrix ratio, and carbonate:phosphate ratio increased sharply with distance from the periosteum and attained the properties of intracortical tissue within 4 days of formation. The mineral: matrix ratio explained 54% and 62% of the variation in tissue indentation modulus and hardness, respectively. Our data demonstrate significant variations in tissue mechanical properties with tissue age and relate mechanical properties to composition at the microscale.

Contribution of Mineral to Bone Structural Behavior and Tissue Mechanical Properties

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.

Primary Cilia Are Highly Oriented with Respect to Collagen Direction and Long Axis of Extensor Tendon

Skeletal tissues adapt to their mechanical environments by modulating gene expression, cell metabolism, and extracellular matrix (ECM) architecture; however, the mechanosensory mechanisms for these processes are incompletely understood. Primary cilia have emerged as critical components of the cellular mechanosensory apparatus and have been hypothesized to participate in establishment of cellular and ECM orientation, but their function in skeletal tissues is just beginning to be examined. Here we focused on tendon, a tissue with an oriented matrix that is ideal for analysis of spatial relationships between primary cilia and the ECM. The objective of this study was to characterize the incidence and orientation of tenocyte primary cilia in their native ECM. Primary cilia, nuclei, and collagen were analyzed three‐dimensionally in immunofluorescently labeled rat extensor tendon using multiphoton microscopy and semiautomated morphometry. Primary cilia were observed in 64% of tenocytes. The cilia were highly oriented with respect to the ECM: cilia were aligned parallel to the collagen fibers and the long axis of the tendon. This study represents the first quantification of the in situ incidence and orientation of primary cilia in tendon.

Bone tissue composition varies across anatomic sites in the proximal femur and the iliac crest

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.

Examining the relationships between bone tissue composition, compositional heterogeneity and fragility fracture: a matched case controlled FTIRI study.

Fourier transform infrared imaging (FTIRI) provides information on spatial distribution of the chemical composition of thin tissue specimens at ∼7 µm spatial resolution. This study of 120 age‐ and bone mineral density (BMD)‐matched patients was designed to investigate the association of FTIRI variables, measured in iliac crest biopsies, with fragility fractures at any site. An earlier study of 54 women found hip BMD to be a significant explanatory variable of fracture risk for cortical bone but not for cancellous bone. In the current study, where age and BMD were controlled through matching, no such association was observed, validating the pairing scheme. Our first study of unmatched iliac crest biopsies found increases in collagen maturity (cancellous and cortical bone) and mineral crystal size (cortical bone only) to be a significant explanatory variable of fracture when combined with other covariates. The ratio for collagen maturity has been correlated to the amount of enzymatic collagen cross‐links. To assess the impact of other FTIRI variables (acid phosphate substitution, carbonate‐to‐phosphate ratio, and the pixel distribution [heterogeneity] of all relevant FTIRI variables), we examined biopsies from a matched case‐controlled study, in which 60 women with fractures were each paired with an age‐ and BMD‐matched female control. With the matched data set of 120 women, conditional logistic regression analyses revealed that significant explanatory variables of fracture were decreased carbonate‐to‐phosphate ratio in both cancellous (odds ratio [OR] = 0.580, 95% confidence interval [CI] 0.37–0.909, p = 0.0176) and cortical bone (OR = 0.519, 95% CI 0.325–0.829, p = 0.0061), and increased heterogeneity (broadened pixel distribution) of collagen maturity for cancellous bone (OR = 1.549, 95% CI 1.002–2.396, p = 0.0491). The observation that collagen maturity was no longer linked to fracture in age‐ and BMD‐matched samples suggests that age‐dependent variation in collagen maturity may be a more important contributory factor to fragility fractures than previously thought.

Atypical Femoral Fractures: Epidemiology, Etiology, and Patient Management

Purpose of reviewTo 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 findingsRecent 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. SummaryExtremely 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.

Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance

Significance Since the first reports of atypical femoral fractures (AFFs), a clinical phenomenon in which patients experience catastrophic brittle fractures of the femoral shaft with minimal trauma, the risk associated with bisphosphonates, the most widely prescribed pharmaceuticals for osteoporosis, has become increasingly well-established. However, the underlying cause of AFFs and their causal relationship to bisphosphonates is unknown. Here we examine bone tissue from women with AFFs and show that long-term bisphosphonate treatment degrades the fracture-resistance toughening mechanisms that are inherent to healthy bone. Our work resolves the apparent paradox of AFFs as a side effect of the most common osteoporosis treatment by clarifying the differing effects of bisphosphonates on bone tissue structure and mechanical properties across multiple length scales. Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; −BIS Typical: n = 11; −BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonate-treated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.