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The vertebral fracture cascade in osteoporosis: a review of aetiopathogenesis. A. M. Briggs & A. M. Greig & J. D. Wark. Received: 11 June 2006 /Accepted: 28 ...
Osteoporos Int (2007) 18:575–584 DOI 10.1007/s00198-006-0304-x

REVIEW

The vertebral fracture cascade in osteoporosis: a review of aetiopathogenesis A. M. Briggs & A. M. Greig & J. D. Wark

Received: 11 June 2006 / Accepted: 28 November 2006 / Published online: 6 January 2007 # International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Abstract Once an initial vertebral fracture is sustained, the risk of subsequent vertebral fracture increases significantly. This phenomenon has been termed the “vertebral fracture cascade”. Mechanisms underlying this fracture cascade are inadequately understood, creating uncertainty in the clinical environment regarding prevention of further fractures. The cascade cannot be explained by low bone mass alone, suggesting that factors independent of this parameter contribute to its aetiopathogenesis. This review explores physiologic properties that may help to explain the vertebral fracture cascade. Differences in bone properties, including bone mineral density and bone quality, between individuals with and those without osteoporotic vertebral fractures are discussed. Evidence suggests that non-bone parameters differ between individuals with and those without osteoporotic vertebral fractures. Spinal properties, including vertebral macroarchitecture, intervertebral disc integrity, spinal curvature and spinal loading are compared in these groups of individuals. Cross-sectional studies also indicate that neurophysiologic properties, particularly trunk control and balance, are affected by the presence of a vertebral fracture. This review provides a synthesis of the literature to highlight the multi-factorial aetiopathogenesis A. M. Briggs : A. M. Greig Centre for Health, Exercise and Sports Medicine, School of Physiotherapy, University of Melbourne, Melbourne, Victoria 3010, Australia A. M. Briggs e-mail: [email protected] A. M. Briggs : A. M. Greig : J. D. Wark (*) Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3010, Australia e-mail: [email protected]

of the vertebral fracture cascade. With a more comprehensive understanding of the mechanisms underlying this clinical problem, more effective preventative strategies may be developed to offset the fracture cascade. Keywords Balance . Bone mineral density . Bone quality . Kyphosis . Loading . Neuromuscular control . Osteoporosis . Review . Vertebral fracture

Introduction Osteoporotic vertebral fractures are recognised as a significant health problem facing the aged population. They account for almost half of all fracture presentations due to osteoporosis and impact significantly on health-related quality of life [1]. However, this estimate may underestimate their true prevalence, considering that only one in four come to clinical attention, either due to a lack of radiographic attention or absence of recognised classical symptoms [2], and their under-diagnosis [3]. Of particular concern is the alarmingly high rate of individuals suffering subsequent vertebral fractures after an initial vertebral fracture is sustained—termed here the “vertebral fracture cascade”. In the first year after sustaining an initial vertebral fracture, the risk of sustaining a second vertebral fracture is reported to be 20% [4]. Other studies report the risk of subsequent vertebral fracture to increase by 4–7-fold after an initial fracture, and then exponentially with greater numbers of prior vertebral fractures [5–7]. The physical, psychosocial and public health sequelae of vertebral fractures are significant, yet become more pronounced with each subsequent vertebral fracture sustained [8–11]. Therefore, identification of patients at risk of further fractures and the prevention thereof is a priority for

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clinicians. Although measurement of areal bone mineral density (BMD) is the most widely used index of skeletal integrity and bone strength, the risk of subsequent fracture is poorly predicted from measurements of areal BMD derived from dual-energy X-ray absorptiometry (DXA). Minimal trauma failure of one vertebral body is indicative of critical weakness at multiple other vertebral levels, leading to the vertebral fracture cascade unless bone strength is improved with treatment. A key question is why does one vertebral fracture predispose to more fractures, independently of areal BMD? Clearly, a more comprehensive understanding of mechanisms underlying this fracture cascade is needed to develop more appropriate strategies to prevent subsequent vertebral fractures. The aetiopathogenesis of the vertebral fracture cascade is complex and poorly understood, and thus medical and allied health professionals are faced with uncertainty regarding appropriate preventative measures for subsequent fractures in a population who have sustained an initial fracture. Therefore, the purpose of this paper is to review relevant literature highlighting differences between individuals who have osteoporosis with and those without

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vertebral fractures as a means of highlighting evidencebased mechanisms underlying this complex and worrying clinical problem. The aetiology of the vertebral fracture cascade may be explained with a dynamic systems model, where the properties of several domains are considered as well as their interactions (Fig. 1). Domains recognised in the literature as potentially important in the aetiology of the vertebral fracture cascade include bone, spinal and neurophysiologic properties. This review is divided into three parts, each focussing on one of these domains.

Bone properties Bone properties encompass BMD and bone quality, both of which are important determinants of bone strength. Areal BMD measured with DXA is widely accepted as the most efficient and clinically suitable measure of skeletal status and surrogate of bone strength [12]. Ex vivo studies confirm that BMD accounts for up to 70–90% of the variance observed in vertebral bone strength [13], with the

Fig. 1 Dynamic systems framework for conceptualising factors influencing the vertebral fracture cascade

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remaining variance attributed to bone geometry and parameters defined under the umbrella term of “bone quality”, such as microarchitecture, microdamage, bone turnover, bone mineralisation, cortical porosity, osteocyte health and density, bone marrow cellularity, and other aspects of the bone micro-environment [14–17]. BMD alone cannot provide a complete picture of bone strength, highlighting the drawback of relying on BMD as a predictor of fracture risk and the need to also consider bone quality. Although a combination of bone mass and architecture can account for a greater proportion of variance in bone strength than bone mass alone, some variance still remains unaccounted for [18, 19], and this may reflect the component of fatigue damage accumulation through physiologic loading and other extra-osseous factors. The relationship between BMD and bone quality is unclear. For example, studies examining the efficacy of pharmacologic agents demonstrate reductions in fracture risk before increases in BMD are apparent [20, 21], while associations between BMD and microarchitectural parameters are weak [22, 23]. These data suggest that BMD and bone quality are likely to operate with some independence in determining fracture risk and fracture mechanics, stimulating research in both areas to identify differences between individuals with and those without fractures to provide a clearer understanding of the vertebral fracture cascade. Therefore, the following sections discuss BMD and bone quality in further detail. Bone mineral density The strong relationship between bone mass and bone strength underlines the rationale for the use of densitometry in assessing fracture risk and skeletal status. However, evidence from epidemiologic studies suggests a lack of discriminant power of standard BMD measurements derived from DXA in differentiating between individuals with and those without vertebral fractures. Marked differences exist in the prevalence rate of vertebral fracture among individuals with comparable BMD [23–28]. Certainly, this may reflect differences between cohorts in factors other than BMD and the stochastic nature of vertebral fractures, but it is also likely that a differential bone mass component exists given the unequivocal relationship between BMD and the compressive strength of trabecular bone. Recently, Ciarelli et al. [29] used back-scattered electron microscopy to examine mineralisation levels in cancellous bone of the iliac crest in individuals with and without osteoporotic vertebral fractures. They found that although the fracture group had a similar mean bone formation rate to the controls, the distribution of mineralisation differed markedly between groups as evidenced by standard deviations of the mineralisation measures in the fracture group being 2.0–

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2.4 times that of the normal group. This finding supports the hypothesis that vertebral fracture aetiology is influenced by the distribution of bone mineralisation, thus creating a greater variability of mechanical properties in the trabecular bone of individuals with vertebral fractures. The intra-vertebral distribution of bone mass may be a defining characteristic between individuals with and those without vertebral fractures. Indeed, the inability to accurately identify BMD differences between osteoporotic individuals with and those without vertebral fractures may be attributable, in part, to limitations in the measurement approach, particularly anteroposterior (AP) projection DXA, and failure to consider the distribution of bone mass within vertebrae. Standard measures of lumbar areal BMD are derived from the whole vertebral body DXA scan (or mean of several lumbar vertebrae), thereby obscuring any intra-vertebral BMD differences. Variance in areal BMD within vertebral subregions may be a defining characteristic between individuals with and those without vertebral fractures who have comparable BMD. Ex vivo research has identified heterogeneity in the distribution of bone mass within the vertebral body using tools such as histomorphometry, quantitative computed tomography (QCT) and DXA. In general, histomorphometry studies indicate relatively greater trabecular separation and lower bone volume, trabecular thickness and trabecular number in central and anterior vertebral subregions [30– 32]. Similarly, studies utilising QCT report lower volumetric bone density in central and anterior regions of vertebral bodies [33, 34], while studies using DXA report lower BMD anteriorly and centrally compared with measures of gross bone mass [35, 36]. Jergas et al. [27] found that the greatest percentage difference in BMD between 331 postmenopausal women with and those without vertebral fractures was obtained when using a subregion in a lateral DXA scan. Similarly, Sandor et al. [37] reported that subregional analysis of lumbar BMD using QCT could discriminate between fracture and non-fracture cases with 90% accuracy, while conventional BMD analysis resulted in a significant overlap of BMD values between the groups. It would seem plausible that considering vertebral subregions when using DXA may help to resolve the issue of poor discriminant power of standard DXA assessment between individuals with and those without a vertebral fracture. Collectively, the above studies suggest that individuals with and without vertebral fractures are likely to differ in intra-vertebral BMD profiles. This observation may partly account for the vertebral fracture cascade. Notably, a recent study provided some evidence to confirm this hypothesis. Subregional areal BMD was compared in osteoporotic women with and without vertebral fractures. Although not reaching statistical significance possibly due to the low

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sample size, strong and clinically important trends were identified showing differences between fracture and nonfracture cases [38]. Differences in BMD between groups ranged from 0.7–5.4% based on standard DXA parameters, while appreciably larger differences were noted (13.1– 16.3%) when comparing the groups using a subregional protocol. Although there is preliminary evidence to suggest that investigation of intra-vertebral BMD may help to overcome the inability to reliably identify BMD differences between osteoporotic individuals with and those without vertebral fractures, the stochastic nature of vertebral fragility fractures should be kept in mind. Indeed, the often unpredictable nature of the vertebral fracture cascade is also likely to account for the inability to discriminate between osteoporotic individuals with and without fractures. Physical characteristics other than areal BMD such as bone quality, spine properties and neurophysiologic properties may also contribute to the fracture cascade. Bone quality The importance of bone quality in determining bone strength is now widely recognised. Indeed, the condition of osteoporosis has been re-defined to include aspects of bone quality in its definition [14], thus stimulating debate surrounding the usefulness of current WHO diagnostic criteria for osteoporosis. Many studies provide evidence that bone quality parameters, particularly trabecular microarchitecture, differ between individuals with and those without osteoporotic vertebral fractures, thus explaining one component of the vertebral fracture cascade. However, not all studies match participants for bone mass, precluding generalisability of the findings to populations with comparable BMD. In studies where individuals with and without fractures had comparable BMD or bone volume, significant differences in microarchitecture at different skeletal sites were reported. Generally, individuals with fractures had greater trabecular thickness, greater trabecular spacing, greater free end-to-end struts, a greater number of trabecular termini, increased marrow space star volume, fewer trabeculae, fewer node-to-node struts, lower osteocyte density and reduced cortical thickness as determined from histomorphometric analysis of bone from the iliac crest [15, 23, 39–42]. Hordon et al. [26] reported similar trends for trabecular bone also removed from the iliac crest, although their data failed to reach statistical significance, likely attributable to an inadequate sample size. Similar findings of microarchitectural anisotropy (variability in physical properties along axes of different directions) have been reported in femoral bone among individuals with and without femoral fractures [43, 44]. Notably, Legrand and colleagues [23] reported a range of iliac crest trabecular

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microarchitectural parameters as significant predictors of vertebral fracture while hip and spine BMD were not, highlighting the importance of bone quality in fracture pathogenesis. The microarchitectural anisotropy in trabecular bone noted among individuals who have suffered vertebral fractures is likely to increase the risk of subsequent fracture. This aspect of bone quality is not captured by conventional bone densitometry. However, microarchitectural disruption renders the bone biomechanically less competent [40]. Indeed, architectural anisotropy has been associated with mechanical anisotropy, resulting in bone less able to withstand mechanical loads in directions other than the primary load axis [45]. A loss of trabecular connectivity is likely to result in increased strain, fatigue and accumulation of microdamage in the trabecular network [15]. Previous research has found that a 2–3-fold elevation in microdamage accumulation is associated with a 20% reduction in bone toughness [46], thus increasing the propensity to fracture. Moreover, an inverse association between trabecular microdamage and the percentage of live osteocytes has been reported [47, 48]. Thus, the relative deficit in osteocyte density reported in individuals with vertebral fracture [42] may predispose to trabecular microdamage leading to increased fracture risk. Evidence from epidemiologic research supports this hypothesis where black individuals sustain a significantly lower rate of vertebral fractures than comparable whites [49], and osteocyte density is higher among blacks, which may contribute to greater bone strength in the black population [50]. A limitation of findings from histological studies mentioned above is that bone specimens are commonly derived from the iliac crest, which does not experience the same functional loads as vertebral bone. In addition, iliac bone has a curved plate morphology and is rarely involved in nontraumatic fractures. Thus, the validity of extrapolating results to vertebral or femoral bone is sometimes questionable [44]. However, some studies indicate that iliac bone parameters are associated with vertebral bone characteristics [51]. Although bone quality is recognised as an important differentiating factor between individuals with and those without fractures, clinicians are still faced with the problem of measuring it in the clinical context with adequate precision, accuracy, patient comfort and financial legitimacy. The clinical method most widely used to quantify microarchitecture is transiliac bone biopsy taken in vivo, with subsequent histologic analysis. The discomfort involved and invasive nature of bone biopsy procedures precludes their use in routine clinical practice for identifying patients at risk of fracture. Ultrasound parameters measured at the calcaneum and phalanges reflect components of bone independent of bone mass. Indeed, ultrasound parameters are reported to be independent predictors of

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vertebral fracture [52, 53]. Although ultrasound parameters can differentiate reliably between normal and osteoporotic bone [54, 55], they are unable to differentiate between osteoporotic individuals with and without fractures [56]. Fortunately, other imaging technologies such as quantitative MRI [57], micro-CT [58], multi-detector row CT (MDCT) [59] and pQCT show promising results for examining trabecular microarchitecture in axial and appendicular skeletal structures in individuals with and without fractures. Ultimately, these technologies may become available for clinical practice to enable quantification of bone quality parameters and better discrimination of patients at increased risk of fracture.

Spine properties A cascade of fractures occurs in the spine, and less often at other skeletal sites. One reason that this phenomenon occurs predominantly in the spine may be the spinal structure changes introduced by the first fracture. However, it may also be that the spine is the best site in which to observe a fracture cascade due to its unique structural organisation. That is, multiple bones in close proximity that may fail readily in a cascade fashion. However, the fracture cascade phenomenon observed in osteoporosis may also occur in sites other than the spine, but to a lesser extent. For example, a vertebral fracture also increases the risk of subsequent hip fracture [60] and one hip fracture is associated with a high risk of another hip fracture in the next 1–2 years [61]. In terms of the vertebral fracture cascade, local and global spinal properties and structural changes are important in explaining its aetiopathogenesis. Local spine properties Vertebral macroarchitecture differs between individuals with and those without vertebral fractures, and these differences are likely to account for some of the increased risk of subsequent vertebral fractures among individuals with prevalent fracture(s). Vertebral size and cross-sectional area (CSA) are directly related to bone strength. Notably, women with vertebral fractures are reported to have 7% smaller vertebrae compared with age- and height-matched women with no history of vertebral fracture [62], and similar data exist for males [63]. Vertebral volume is also lower (by 15%) in women who have sustained vertebral fractures when matched with controls for age, height, mass and BMD [64]. However, matching participants for height may be inappropriate in the context of vertebral fractures, since patients who have experienced multiple vertebral fractures invariably lose height. Smaller vertebral dimensions increase the mechanical stresses (σ) imposed on the

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vertebral body, thus decreasing its compressive force (Fc) threshold (σ = Fc/CSA). In a study comparing women with osteoporosis with and those without vertebral fracture, vertebral CSA in T12–L4 was significantly less in the fracture group by 5–12% when matched to control women with regard to age, height, mass and trabecular and cortical BMD [65]. In addition to smaller vertebral CSA, the women with vertebral fractures had smaller lever arms (distance between the erector spinae and vertebral centroids) in the order of 5.8%. The combination of reduced vertebral CSA and a shorter lever arm (r) resulted in increased vertebral mechanical loading by 8% during erect stance and by 15% during trunk flexion in the fracture cohort. Therefore, in order to maintain the moment equilibrium, muscle force (Fm) must increase proportionally (moment = Fm × r). Under normal conditions, the musculoskeletal system can make this adjustment safely. However, in the presence of underlying bone fragility, vertebral bone may be incapable of sustaining the resultant increase in compressive and shear loads, thus leading to vertebral failure. To compound the problem, lever arms from vertebrae to the erector spinae decrease with spinal flexion [66], which is a common outcome of vertebral fracture. This biomechanical factor may help to explain the vertebral fracture cascade and provide some insight into why there is a fracture cascade in the spine but not at other sites. In addition to differences in stress magnitude imposed on vertebral bodies between individuals with and those without fractures, the nature of the load distribution may also differ. Load distribution through the vertebral centrum is largely influenced by intervertebral disc integrity. Disc degeneration is not uncommon in a population with osteoporosis [67] and may be more prevalent in a population with vertebral fractures compared with osteoporosis alone considering the increased spinal loading associated with vertebral fractures [68]. Both vertebral damage and increased spinal loading are established risk factors for disc degeneration [69, 70]. A recent study of 559 postmenopausal women examined the relationship between vertebral fracture risk and spinal degeneration [71]. Disc space narrowing, a sign of degenerative changes, was associated with an increased risk of vertebral fracture after adjusting for age, body mass index and BMD, highlighting the contribution of disc degeneration to vertebral fragility. As the disc degenerates, axial load is distributed to the lateral areas of the endplates and cortical rim instead of the centre of the endplate [72]. Consequently, different areas of the vertebral body become highly loaded, while other areas remain “stress-shielded” [73]. Resorption of bone may occur in areas that are stress-shielded, decreasing the threshold to failure in these areas [36]. Evidence from histological studies supports this theory since intervertebral

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disc degeneration was associated with changes in subregional trabecular microarchitecture in the lumbar spine [31]. Therefore, the likely increased incidence of intervertebral disc degeneration in a population with vertebral fractures may itself be a risk factor for further fracture through stress shielding effects on vertebral bone, changes in subregional trabecular architecture leading to regional variability in biomechanical competence [74], and greater muscle forces required to achieve active movement in motion segments that contain degenerated discs. Although differences in vertebral structure between individuals with and those without vertebral fractures may provide some explanation of the vertebral fracture cascade, the risk of future fracture is also influenced by specific features of the initial fracture. Local spinal structural changes introduced by an initial fracture are likely to help explain why there is a fracture cascade in the spine in particular. Data from the European Prospective Osteoporosis Study suggest that subsequent fracture risk varies according to the location, type and severity of the baseline deformity [5]. Subsequent fracture risk was increased when baseline fractures occurred at T5, when anterior and middle vertebral heights were reduced, and with increased severity of the baseline fracture. In addition, vertebrae close to the baseline deformity level were at greater risk of subsequent fracture than more distant vertebrae. Collectively, these structural changes introduced by an initial fracture are likely to increase vertebral loading through changes in vertebral morphology. Notably, a recent biomechanical study provided evidence indicating significantly increased compression and shear loads imposed on vertebrae directly adjacent to the fractured level, highlighting the potential for increased fracture risk at these levels [68]. The effects of vertebral fracture extend beyond the local vertebral and contiguous levels, and influence biomechanics of the entire (global) spine. Global spine properties Vertebrae fail when loads exceed their structural capacity, and in the case of osteoporotic vertebral fractures, these loads are generally minimal trauma. Therefore, characterisation of loads imposed throughout the spine is important in this population. When accounting for body mass, physiologic loading through the spine is directly dependent on spinal posture, since this variable determines the distribution of the mass within the trunk. Many authors speculate that osteoporotic vertebral fractures are associated with increases in thoracic curvature. However, the relationship between vertebral fracture and thoracic kyphosis remains unclear in the literature. Discrepancies between studies may be due to differences in the criteria used to diagnose the presence of fracture and variability in the way

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kyphosis was measured. Studies that describe measurement of these variables in detail report conflicting findings, with some studies reporting significantly greater kyphosis in fracture groups compared with non-fracture groups [75– 77], while others do not [78–80]. It seems that the positive relationship between thoracic kyphosis and vertebral fracture becomes clearer as the number of vertebral fractures (or severity of vertebral deformities) increases [8, 81]. Irrespective of this relationship, thoracic kyphosis is a significant and independent predictor of vertebral fracture [82], highlighting the importance of considering thoracic spine posture in a population with osteoporosis, and in particular with vertebral fracture. A recent biomechanical study using a complex anatomic model driven by optimisation found that individuals with a single vertebral fracture had significantly greater spinal loads compared with individuals with no history of vertebral fracture [68]. The increased shear and compression forces reported from T2–L5 in the fracture group may explain part of the mechanism underlying the fracture cascade. Greater loads in the fracture group were attributed to a subtle increase in thoracic curvature, undetected radiographically. Similar findings for vertebral loading were reported by Keller et al. [76]. Thus, interventions aimed at minimising thoracic kyphosis may be of benefit in reducing spinal loading and the risk of future fracture; however, prospective studies should be conducted to explore this issue. Interventions such as vertebroplasty and kyphoplasty are being more widely performed due to their positive effects in restoring vertebral shape and volume and possibly reducing pain for individuals who have sustained a vertebral fracture [83]. However, single-level kyphoplasty procedures do not significantly change overall spinal curvature [84], and thus may not have a clinically significant benefit in reducing spinal loading. Notably, multi-level procedures are required to change overall spinal posture [84]. Vertebroplasty procedures may provide short-term benefit to patients in terms of pain and function [85], but some concern exists regarding the risk of fracture in vertebrae adjacent to those treated with vertebroplasty post-fracture [86].

Neurophysiologic properties The central nervous system (CNS) is recognised as an important component in the control of body movement and responses to perturbations. In the context of vertebral fracture, the performance of the CNS in trunk muscle recruitment and balance is of interest when considering the contribution of muscle force in spinal loading and the high incidence of vertebral fractures with falls [87]. However, little research has been devoted to examining trunk muscle

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recruitment and balance characteristics in individuals with osteoporotic vertebral fractures. Several studies have identified differences in balance parameters between individuals with normal bone mass and those with osteoporosis, noting deficits, predominantly increased sway, in the osteoporosis groups [88, 89]. However, the effect of vertebral fracture was not examined independently in the groups with osteoporosis. A recent study compared balance characteristics among postmenopausal women with and without vertebral fractures yet with comparable BMD. Greater shear forces and AP centre-of-pressure displacement were found in the fracture group, suggesting a greater reliance on hip strategy for postural control in the fracture group [79]. This finding clearly indicates the negative effect of vertebral fracture on balance control in individuals who have sustained fractures and may therefore increase the risk of falls and subsequent fracture in this group. Compromised balance and fear of falling have also been associated with increased trunk muscle activity [90]. Indeed, compared with osteoporotic women with no history of vertebral fracture, those who had sustained a vertebral fracture demonstrated a reliance on trunk muscle co-contraction [79]. Co-contraction of the trunk musculature, defined as a simultaneous contraction of agonist and antagonist muscles, causes increased spinal loading [91]. This places osteoporotic vertebrae at increased risk of failure, and prevents coordinated movements of the trunk necessary to restore balance during high magnitude perturbations [92]. Differences in trunk muscle recruitment among women with and without vertebral fractures have also been reported [79]. In a study examining muscle recruitment with intramuscular electromyography (EMG) in the thoracic erector spinae at commonly fractured vertebral levels, individuals who had sustained fractures demonstrated a longer time to initiate a postural response to a perturbation, yet a shorter time to reach maximum EMG amplitude [93]. Certainly, this response may be viewed as an adaptive mechanism of the CNS to minimise verbal loading time. However, a faster loading rate is likely to increase intra-vertebral strains and may increase the risk of subsequent vertebral fracture [94]. Further research in this area is needed using EMG-driven models to clarify differences in loading strategies. The mechanisms explaining the differential balance and muscle recruitment patterns between individuals with and those without vertebral fractures are uncertain. Inhibition of muscle function due to pain may be attributable to symptomatic fractures, while subtle changes in thoracic kyphosis may have altered the mechanical properties of the muscles. Previous research has confirmed changes in trunk muscle recruitment as a consequence of pain [95]. Other factors related to vertebral fractures such as decreased mobility [11], fear of falling [96], depression [97], pulmonary compromise [98] and reduced muscle strength

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[99] could also influence muscle activation and balance characteristics, while generalised deconditioning effects attributable to these sequelae may increase risk of falls and therefore propensity to further fracture.

Conclusion and summary Vertebral fractures due to osteoporosis are associated with a number of negative psychosocial, physical and public health outcomes. Once an initial vertebral fracture is sustained, the risk of subsequent vertebral fracture rises sharply compared with individuals with osteoporosis and no history of vertebral fracture. However, the mechanisms underlying this fracture cascade are uncertain. While several medications that are effective in treating osteoporosis appear to be able to interrupt the fracture cascade, clinicians are faced with the problem of not knowing the optimal comprehensive strategy to prevent recurrent fractures from occurring with minimal trauma. We have proposed a dynamic systems framework to conceptualise the many factors that are likely to contribute to the vertebral fracture cascade. Evidence from the literature suggests that the intra-vertebral distribution of bone mass, bone quality parameters, vertebral macroarchitecture, intervertebral disc degeneration, prevalent fracture characteristics, trunk neuromuscular control, balance and other health-related factors differ significantly between individuals with and those without vertebral fractures, yet with comparable BMD. These differences are likely to represent defining characteristics between these groups. It is hoped that a more cohesive understanding of the many factors explaining the fracture cascade and impairments in individuals who have sustained fractures may help to optimise management and target research aimed at the prevention of future fractures in patients who have sustained an initial fracture. Research and interventions should be directed towards each domain of the dynamic systems framework.

References 1. Oleksik A, Ewing S, Shen W et al (2005) Impact of incident vertebral fractures on health related quality of life (HRQOL) in postmenopausal women with prevalent vertebral fractures. Osteoporos Int 16:861–870 2. Ensrud KE, Nevitt MC, Palermo L et al (1999) What proportion of incident morphometric vertebral fractures are clinically diagnosed and vice versa. J Bone Miner Res 14:S138 3. Delmas PD, van de Langerijt L, Watts NB et al (2005) Underdiagnosis of vertebral fracture is a worldwide problem: the IMPACT study. J Bone Miner Res 20:557–563 4. Lindsay R, Silverman SL, Cooper C et al (2001) Risk of new vertebral fracture in the year following a fracture. JAMA 285:320–323

582 5. Lunt M, O’Neill TW, Felsenberg D et al (2003) Characteristics of a prevalent vertebral deformity predict subsequent vertebral fracture: results from the European prospective osteoporosis study (EPOS). Bone 33:505–513 6. Ross PD, Davis JW, Epstein RS et al (1991) Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 114:919–923 7. Ross PD, Genant HK, Davis JW et al (1993) Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women. Osteoporos Int 3:120–126 8. Ensrud KE, Black DM, Harris F et al (1997) Correlates of kyphosis in older women. J Amer Geriat Soc 45:682–687 9. Gabriel SE, Tosteson ANA, Leibson CL et al (2002) Direct medical costs attributable to osteoporotic fractures. Osteoporos Int 13:323–330 10. Lindsay R, Burge RT, Strauss DM (2005) One year outcomes and costs following a vertebral fracture. Osteoporos Int 16:78–85 11. Pluijm SFM, Tromp AM, Smit JH et al (2000) Consequences of vertebral deformities in older men and women. J Bone Miner Res 15:1564–1572 12. Kleerekoper M, Nelson DA (1997) Which bone density measurement? J Bone Miner Res 12:712–714 13. Singer K, Edmondston S, Day R et al (1995) Prediction of thoracic and lumbar vertebral body compressive strength. Correlations with bone mineral density and vertebral region. Bone 17:167–174 14. NIH Consensus Development Panel on Osteoporosis Prevention (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795 15. Recker RR (1993) Architecture and vertebral fracture. Calcif Tissue Int 53:S139–S142 16. Seeman E, Delmas PD (2006) Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 354:2250–2261 17. Watts NB (2002) Bone quality: getting closer to a definition. J Bone Miner Res 17:1148–1150 18. Borah B, Dufresne TE, Chmielewski PI et al (2002) Risedronate preserves trabecular architecture and increases bone strength in vertebrae of ovariectomized minipigs as measured by threedimensional micro-computed tomography. J Bone Miner Res 17:1139–1147 19. Kabel J, Van-Rietbergen B, Odgaard A et al (1999) Constitutive relationships of fabric density, and elastic properties in cancellous bone architecture. Bone 25:481–486 20. Black DM, Cummings SR, Karpf DB et al (1996) Randomised trial of the effect of alendronate on risk of fracture in women without existing vertebral fractures. Lancet 348:1535–1541 21. Ettinger B, Black DM, Mitlak BH et al (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282:637–645 22. Fazzalari NL, Forwood MR, Smith K et al (1998) Assessment of cancellous bone quality in severe osteoarthrosis: bone mineral density, mechanics, and microdamage. Bone 22:381–388 23. Legrand E, Chappard D, Pascaretti C et al (2000) Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner Res 15:13–19 24. Eastell R, Cedel SL, Wahner HW et al (1991) Classification of vertebral fractures. J Bone Miner Res 6:207–215 25. Grey C, Young R, Bearcroft PWP et al (1996) Vertebral deformity in the thoracic spine in post-menopausal women: value of lumbar spine bone density. Br J Radiol 69:137–142 26. Hordon LD, Raisi M, Aaron JE et al (2000) Trabecular architecture in women and men of similar bone mass with and without vertebral fracture. I. Two-dimensional histology. Bone 27:271–276

Osteoporos Int (2007) 18:575–584 27. Jergas M, Breitenseher M, Gluer CC et al (1995) Which vertebrae should be assessed using lateral dual-energy x-ray absorptiometry of the lumbar spine. Osteoporos Int 5:196–204 28. Mitra D, Elvins DM, Speden DJ et al (2000) The prevalence of vertebral fractures in mild ankylosing spondylitis and their relationship to bone mineral density. Rheumatology 39:85–89 29. Ciarelli TE, Fyhrie DP, Parfitt AM (2003) Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females. Bone 32:311–315 30. Cvijanovic O, Bobinac D, Zoricic S et al (2004) Age and region dependent changes in human lumbar vertebral bone. A histomorphometric study. Spine 24:2370–2375 31. Simpson EK, Parkinson IH, Manthey B et al (2001) Intervertebral disc disorganisation is related to trabecular bone architecture in the lumbar spine. J Bone Miner Res 16:681–687 32. Thomsen JS, Ebbesen EN, Mosekilde LI (2002) Zone-dependent changes in human vertebral trabecular bone: clinical implications. Bone 30:664–669 33. Banse X, Devogelaer JP, Munting E et al (2001) Inhomogeneity of human vertebral cancellous bone: systematic density and structure patterns inside the vertebral body. Bone 28:563–571 34. Sandor TA, Felsenberg D, Kalender WA et al (1991) Global and regional variations in the spinal trabecular bone: single and dual energy examinations. J Clin Endocrinol Metab 72:1157–1168 35. Briggs AM, Wark JD, Kantor S et al (2006) Bone mineral density distribution in thoracic and lumbar vertebrae: an ex vivo study using dual energy x-ray absorptiometry. Bone 38:286–288 36. Pollintine P, Tobias JH, McNally DS et al (2002) Intervertebral disc degeneration increases load-bearing by the neural arch and reduces BMD in the anterior vertebral body. J Bone Miner Res 17:F9 37. Sandor T, Felsenberg D, Brown E (1997) Discriminability of fracture and non-fracture cases based on the spatial distribution of spinal bone mineral. J Comp Assist Tomog 21:498–505 38. Briggs A, Wark J, Phillips B et al (2005) Subregional bone mineral density characteristics in the lumbar spine: an in vivo pilot study using dual energy x-ray absorptiometry. Annual Scientific Meeting of the Australian and New Zealand Bone and Mineral Society, Perth, Australia 39. Aaron JE, Shore PA, Shore RC et al (2000) Trabecular architecture in women and men of similar bone mass with and without vertebral fracture. II. Three-dimensional histology. Bone 27:277–282 40. Kleerekoper M, Villaneueva AR, Stanciu J et al (1985) The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 37:594–597 41. Oleksik A, Ott SM, Vedi S et al (2000) Bone structure in patients with low bone mineral density with or without vertebral fractures. J Bone Miner Res 15:1368–1375 42. Qui SJ, Rao DS, Palnitkar S et al (2003) Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res 18:1657–1663 43. Bell KL, Loveridge N, Power J et al (1999) Intracapsular hip fracture: increased cortical remodeling in the thinned and porous anterior region of the femoral neck. Osteoporos Int 10:248–257 44. Ciarelli TE, Fyhrie DP, Schaffler MB et al (2000) Variations in threedimensional cancellous bone architecture of the proximal femur in female hip fractures and controls. J Bone Miner Res 15:32–40 45. Homminga J, McCreadie BR, Ciarelli TE et al (2002) Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structural level, not on the bone hard tissue level. Bone 30:759–764 46. Burr D (2003) Microdamage and bone strength. Osteoporos Int 14:S67–S72 47. Qui SJ, Rao DS, Fyhrie DP et al (2005) The morphological association between microcracks and osteocyte lacunae in human cortical bone. Bone 37:10–15

Osteoporos Int (2007) 18:575–584 48. Vashishth D, Verborgt O, Divine G et al (2000) Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 26:375–380 49. Tracy JK, Meyer WA, Grigoryan M et al (2006) Racial differences in the prevalence of vertebral fractures in older men: the Baltimore men’s osteoporosis study. Osteoporos Int 17:99–104 50. Qui SJ, Rao DS, Palnitkar S et al (2006) Differences in osteocyte density between black and white American women. Bone 38:130–135 51. Mosekilde L, Mosekilde L (1988) Iliac crest trabecular bone volume as a predictor for vertebral compressive strength, ash density, and trabecular bone volume in normal individuals. Bone 9:195–199 52. Heaney RP, Avioli LV, Chesnut CHI et al (1995) Ultrasound velocity through bone predicts incident vertebral deformity. J Bone Miner Res 10:341–345 53. Stewart A, Kumar V, Reid DM (2006) Long-term fracture prediction by DXA and QUS: a 10-year prospective study. J Bone Miner Res 21:413–418 54. Fiore CE, Pennisi P, Gibilaro M et al (1999) Correlation of quantitative ultrasound of bone with biochemical markers of bone resorption in women with osteoporotic fractures. J Clin Densitom 2:231–239 55. Gonnelli S, Cepollaro C, Agnusdei D et al (1995) Diagnostic value of ultrasound analysis and bone densitometry as predictors of vertebral deformity in postmenopausal women. Osteoporos Int 5:413–418 56. Di Stefano M, Isaia GC (2002) Ability of ultrasound bone profile score (UBPS) to discriminate between fractured and not fractured osteoporotic women. Ultrasound Med Biol 28:1485–1489 57. Wehrli FW, Hilaire L, Fernandez-Seara M et al (2002) Quantitative magnetic resonance imaging in the calcaneus and femur of women with varying degrees of osteopenia and vertebral deformity status. J Bone Miner Res 17:2265–2273 58. Teo JCM, Si-Hoe KM, Keh JEL et al (2006) Relationship between CT intensity, micro-architecture and mechanical properties of porcine vertebral cancellous bone. Clin Biomech 21:235–244 59. Ito M, Ikeda K, Nishiguchi M et al (2005) Multi-detector row CT imaging of vertebral microstructure for evaluation of fracture risk. J Bone Miner Res 20:1828–1836 60. Black DM, Arden NK, Palermo L et al (1999) Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res 14:821–828 61. Chapurlat RD, Bauer DC, Nevitt M et al (2003) Incidence and risk factors for a second hip fracture in elderly women. The study of osteoporotic fractures. Osteoporos Int 14:130–136 62. Mazess RB, Barden H, Mautalen C et al (1994) Normalization of spine densitometry. J Bone Miner Res 9:541–548 63. Vega E, Ghiringhelli G, Mautalen C et al (1998) Bone mineral density and bone size in men with primary osteoporosis and vertebral fractures. Calcif Tissue Int 62:465–469 64. Duan YB, Parfitt AM, Seeman E (1999) Vertebral bone mass, size, and volumetric density in women with spinal fractures. J Bone Miner Res 14:1796–1802 65. Gilsanz V, Loro LM, Roe TF et al (1995) Vertebral size in elderly women with osteoporosis: mechanical implications and relationships to fractures. J Clin Invest 95:2332–2337 66. Tveit P, Daggfeldt K, Hetland S et al (1994) Erector spinae lever arm length variations with changes in spinal curvature. Spine 19:199–204 67. Margulies JY, Payzer A, Nyska M et al (1996) The relationship between degenerative changes and osteoporosis in the lumbar spine. Clin Orthop Relat Res 324:145–152 68. Briggs AM, Wrigley TV, van Dieën JH et al (2006) The effect of osteoporotic vertebral fracture on predicted spinal loads in vivo. Eur Spine J 15:1785–1795 69. Adams MA, Freeman BJC, Morrison HP et al (2000) Mechanical initiation of intervertebral disc degeneration. Spine 25:1625–1636

583 70. Adams MA, McMillan DW, Green TP et al (1996) Sustained loading generates stress concentrations in lumbar intervertebral discs. Spine 21:434–438 71. Sornay-Rendu E, Munoz F, Duboeuf F et al (2004) Disc space narrowing is associated with increased vertebral fracture risk in postmenopausal women: the OFELY study. J Bone Miner Res 19:1994–1999 72. Kurowski P, Kubo A (1986) The relationship of degeneration of the intervertebral disc to mechanical loading conditions on lumbar vertebrae. Spine 11:726–731 73. Pollintine P, Dolan P, Tobias JH et al (2004) Intervertebral disc degeneration can lead to “stress-shielding” of the anterior vertebral body—a cause of osteoporotic vertebral fracture? Spine 29:774–782 74. McCubbery DA, Cody DD, Peterson EL et al (1995) Static and fatigue failure properties of thoracic and lumbar vertebral bodies and their relation to regional density. J Biomech 28:891–899 75. Cortet B, Roches E, Logier G et al (2002) Evaluation of spinal curvatures after a recent osteoporotic vertebral fracture. Joint Bone Spine 69:201–208 76. Keller TS, Harrison DE, Colloca CJ et al (2003) Prediction of osteoporotic spinal deformity. Spine 28:455–462 77. Lombardi I, Oliveira LM, Mayer AF et al (2005) Evaluation of pulmonary function and quality of life in women with osteoporosis. Osteoporos Int 16:1247–1253 78. De Smet AA, Robinson RG, Johnson BE et al (1988) Spinal compression fractures in osteoporotic women: patterns and relationship to hyperkyphosis. Radiology 166:497–500 79. Greig AM (2006) Relationships between vertebral fracture, thoracic kyphosis and postural control in individuals with osteoporosis. Doctoral thesis, University of Melbourne 80. Schneider DL, von Muhlen DG, Barrett-Connor E et al (2004) Kyphosis does not equal vertebral fractures: the Rancho Bernardo study. J Rheumatol 31:747–752 81. Shipp KM, Guess HA, Ensrud KE et al (2002) Thoracic kyphosis and rate of incident vertebral fracture. J Bone Miner Res 17:S174 82. Huang MH, Barrett-Connor E, Greendale GA et al (2006) Hyperkyphotic posture and risk of future osteoporotic fractures: the Rancho Bernado study. J Bone Miner Res 21:419–423 83. Komemushi A, Tanigawa N, Kariya S et al (2005) Percutaneous vertebroplasty for compression fracture: analysis of vertebral body volume by CT volumetry. Acta Radiol 46:276–279 84. Pradhan B, Bae HW, Kropf MA et al (2006) Kyphoplasty reduction of osteoporotic vertebral compression fractures: correction of local kyphosis versus overall sagittal alignment. Spine 31:435–441 85. Garfin SR, Yuan HA, Reiley MA (2001) New technologies in spine: kyphoplasty and vertebroplasty for the treatment of painful osteoporotic compression fractures. Spine 26:1511–1515 86. Fribourg D, Tang C, Delamarter R et al (2004) Incidence of subsequent vertebral fracture after kyphoplasty. Spine 29:2270– 2276 87. Cooper C, Atkinson EJ, O’Fallon WM et al (1992) Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989. J Bone Miner Res 7:221–227 88. Lynn SG, Sinaki M, Westerlind KC (1997) Balance characteristics of persons with osteoporosis. Arch Phys Med Rehabil 78:273–277 89. Sinaki M, Brey RH, Hughes CA et al (2005) Balance disorder and increased risk of falls in osteoporosis and kyphosis: significance of kyphotic posture and muscle strength. Osteoporos Int 16:1004– 1010 90. Carpenter MG, Frank JS, Silcher CP et al (2001) The influence of postural threat on the control of upright stance. Exp Brain Res 138:210–218 91. Marras W, Davis KG, Ferguson SA et al (2001) Spine loading characteristics of patients with low back pain compared with asymptomatic individuals. Spine 26:2566–2574

584 92. Horak FB, Nashner LM (1986) Central programming of postural movements: adaptations to altered support-surface configurations. J Neurophysiol 55:1369–1381 93. Briggs AM, Greig AM, Bennell KL et al (2007) Paraspinal muscle control in people with osteoporotic vertebral fracture. Eur Spine J. DOI 10.1007/s00586-006-0276-8 94. Kopperdahl DL, Pearlman JL, Keaveny TM (2000) Biomechanical consequences of an isolated overload on the human vertebral body. J Orthop Res 18:685–690 95. Hodges PW, Richardson CA (1999) Altered trunk muscle recruitment in people with low back pain with upper limb movement at different speeds. Arch Phys Med Rehabil 80:1005–1012

Osteoporos Int (2007) 18:575–584 96. Cook DJ, Guyatt GH, Adachi JD et al (1993) Quality of life issues in women with vertebral fractures due to osteoporosis. Arthritis Rheum 36:750–756 97. Balzini L, Vannucchi L, Benvenuti F et al (2003) Clinical characteristics of flexed posture in elderly women. J Amer Geriatr Soc 51:1419–1426 98. Schleich C, Minne HW, Bruckner T et al (1998) Reduced pulmonary function in patients with spinal osteoporotic fractures. Osteoporos Int 8:261–267 99. Dixon WG, Lunt M, Pye SR et al (2005) Low grip strength is associated with bone mineral density and vertebral fracture in women. Rheumatology 44:642–646