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In Vivo Measurement of Apparent Trabecular Bone Structure of the Radius in Women With Low Bone Density Discriminates Patients with Recent Wrist Fracture from Those Without Fracture
Journal of Clinical Densitometry, vol. 6, no. 1, 35–43, 2003 © Copyright 2003 by Humana Press Inc. All rights of any nature whatsoever reserved. 1094-6950/03/6:35–43/$20.00
Original Article
In Vivo Measurement of Apparent Trabecular Bone Structure of the Radius in Women With Low Bone Density Discriminates Patients with Recent Wrist Fracture from Those Without Fracture Norma J. MacIntyre, PhD1, Jonathan D. Adachi, MD2, and Colin E. Webber, PhD3 1Human
Mobility Research Centre, Queen’s University, Kingston, Ontario; 2St. Joseph’s Hospital, Hamilton, Ontario; and 3Department of Nuclear Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Abstract The purpose of this cross-sectional case-control study was to determine whether indices of bone structure at the 4% site of the radius discriminate women who have sustained a recent low-energy fracture of the contralateral distal radius (n = 21) from women with similar bone density and no history of fracture (n = 21). Images of the distal forearm were acquired using peripheral quantitative computed tomography (pQCT) and were analyzed using in-house-developed software to determine indices of trabecular bone structure (average hole size [HA], maximum hole size, and connectivity index). The same images were analyzed using commercial software to determine bone density, mass, geometry, and torsional strength. The fracture group had significantly larger HA (p = 0.03). No other bone variable differed between groups. Individual HA values were compared to the mean value for young adult women (n = 42). The odds ratio (95% confidence interval) associated with an HA >2 SDs above the young adult mean was 5.4 (1.2–24.3). Thus, estimation of in vivo trabecular bone porosity by measuring the average diameter of the pQCT-imaged marrow spaces in the ultradistal radius identifies individuals with low bone mass most at risk for osteoporotic fracture. Key Words: Peripheral quantitative computed tomography; radius; in vivo bone structure; wrist fracture; osteoporosis.
Introduction
will break. Osteoporosis is a common condition that is characterized by loss of bone mass and structural integrity, which results in increased bone fragility and susceptibility to fracture (1). This has severe consequences for both the individual and the health care system. Therefore, considerable effort has been expended to identify those variables that determine bone strength and how they can be measured in order to target high-risk individuals for early intervention. Fracture of the distal radius is typically the earliest clinical manifestation of osteoporosis (2,3). Indeed, the distal forearm is the most common frac-
Skeletal fracture occurs when the strength of a bone is insufficient to withstand the forces to which the bone is subjected. Many factors contribute to fracture risk and anything that compromises bone strength will increase the likelihood that the bone
Address correspondence to Dr. Norma J. MacIntyre, Human Mobility Research Centre, Doran 2, Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7. E-mail: [email protected]
35
36 ture site among women under the age of 75, and lowenergy forearm fracture is predictive of underlying osteoporosis (2,4–6) and subsequent osteoporotic fracture (2,7). Since the peak incidence of forearm fracture occurs approx 15 yr prior to the peak incidence of hip fracture (3), identification of individuals at risk for radial fracture would permit much earlier intervention to prevent irreversible bone loss. A number of studies have shown that individuals with distal forearm fractures have significantly lower bone mineral density (BMD, g/cm2) at the hip, spine, and contralateral distal radius compared with healthy control subjects (4,5,8). On a population basis, the presence of osteoporosis can be determined using dual X-ray absorptiometry to measure BMD at fracture-prone sites (1,9). However, no suitable method is available for predicting which individuals with low BMD will experience osteoporotic fractures (9). In addition to BMD, bone architecture is an independent predictor of bone strength (10,11). That is, both the amount and the organization of bone mineral contribute to the regional competency of the skeleton. Previously, Gordon et al. (12) developed a technique to measure the apparent in vivo trabecular bone structure at the 4% site of the radius using peripheral quantitative computed tomography (pQCT). The indices of trabecular bone structure measured using this technique demonstrate the anticipated associations with age and gender (13) and between limbs (14). A cross-sectional study has shown an age-dependent increase in indices estimating the dimensions of the marrow spaces (average hole size [HA] and maximum hole size [HM]) and an age-dependent decrease in the connectivity index at the ultradistal radius (13). Moreover, an inverse relationship between intertrabecular spacing and compressive loading forces has been demonstrated in ex vivo radial bones (15). The extent to which structural changes in osteoporotic bone differ from those associated with normal aging is not clear. In osteoporosis, increased bone fragility may be associated with an accelerated rate of structural deterioration, or it may be associated with an altered pattern of structural deterioration. Identification of specific structural changes associated with osteoporotic wrist fracture may lead to the development of a screening tool capable of predicting an individual’s fracture risk. The purpose
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MacIntyre et al. of the present cross-sectional case-control study was to determine whether radial bone structure is different for individuals who have sustained a low-energy fracture of the distal radius compared with control subjects with low radial bone density but no history of fracture.
Materials and Methods Subjects Individuals who attended the St. Joseph’s Hospital Fracture Clinic with a recent (<8 wk) low-energy fracture of the distal radius were recruited. Volunteers (3 men, 32 women) who expressed an interest were contacted for further screening and to arrange an appointment. Of these, two volunteers were excluded because fracture resulted from a fall from higher than a standing height and six others did not attend the scheduled appointment. Informed consent was obtained from 1 man and 26 women. A control group was selected from a database of healthy individuals with no history of fracture recruited during the same time period from the same community to participate in a study of between-limb differences in trabecular bone structure (14). To have a comparison group with similar values for total bone density at the 4% site of the radius, the reference database was sorted according to ascending values for total bone density and the first 21 women were selected. All methods and procedures for the study were approved by the research ethics board at our institution.
Procedure Before performing pQCT scans, subjects completed a questionnaire to document age, gender, height, weight, hand dominance, and a general health/medical history profile. Menopausal status was determined by self-report, and natural menopause was defined as the age at which menses first ceased for a period of 12 mo. Height and weight were recorded to the nearest 0.1 cm and 0.1 kg, respectively, and body mass index (BMI, kg/m2) was calculated for each subject. In the nonfractured forearm, the length of the ulna from the olecranon process to the ulnar styloid was measured to the nearest 0.1 cm using a tape measure. Scans were performed on the nonfractured forearm of each subject. Care was taken to ensure that
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Trabecular Bone Structure and Radial Fracture the forearm being measured was well supported and positioned appropriately in the imaging field. Volunteers were instructed to remain motionless throughout the scanning procedure.
Equipment A second-generation Stratec XCT 960 pQCT scanner (manufactured by Stratec Medizintechnik, Germany, and distributed in North America by Norland, Fort Atkinson, WI) was used to acquire one high-resolution image in the transverse plane of each study subject’s wrist at the standard 4% site, which was located automatically by the system software. The image acquisition parameters, analyses protocol, and reproducibility of this method have been described previously (12–14). The transverse slice thickness is 2.5 mm and the in-plane voxel dimension is 0.33 mm2. The user sets a rectangular region of interest (ROI) around the cross-sectional image of the radial bone, and the commercial software (version 5.21A; Stratec) applies an iterative contour detection algorithm to determine material properties: volumetric bone density (total, cortical/subcortical, and trabecular bone compartments, ToBD, CoBD, and TrBD, respectively [mg/cm3], geometric properties (polar cross-sectional moment of inertia [mm4] and section modulus [mm3]) and torsional bone strength (stress-strain index [SSI] [mm3]). Bone mineral content (BMC) (total, cortical/subcortical, and trabecular bone compartments, ToBMC, CoBMC, and TrBMC, respectively, mg) was calculated as the product of density and slice volume. The same image of the radial bone was postprocessed using a segmentation algorithm developed in-house as previously described in detail (12). After the user sets a rectangular ROI around the cross-sectional image of the radial bone, the algorithm proceeds automatically to separate the bone from the marrow and soft-tissue background using a region grow step. A binary image of the trabecular compartment is created and the algorithm determines the number of holes and area of each hole. From these measurements, values for HA (mm2) and HM (mm2) are obtained. The next postprocessing step produces a skeletonized image and applies strut analysis to quantify the continuity of the trabecular network. The connectivity index is a mathematical construct that can take on positive or negative values. The
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37 number of free ends and isolated points is subtracted from the number of nodes, and this value is normalized to the length of the network and multiplied by 100. For example, when the number of nodes is higher relative to the number of free ends and isolated points, the connectivity index will be more positive and representative of a well-connected trabecular network. Conversely, a negative value reflects a highly disrupted network.
Statistical Analyses All statistical calculations were performed using Minitab (release 13; Minitab, State College, PA). Descriptive statistics were calculated for anthropometric measurements of the study subjects and all measured variables of bone density, mass, geometry, SSI, and structure. Comparisons between the group with low-energy wrist fractures and the control group were made using one-way analysis of variance, and differences were considered significant when p < 0.05. The odds ratio (OR) was calculated using binary logistic regression to assess the strength of the association between bone structure and fracture occurrence; in this case, if inferior bone structure is associated with fracture, the OR rises above 1. It has been suggested that radial bone density measurements are below normal and appropriate intervention is indicated when an individual value is >2 SDs below the young adult mean (YAM) (16). Guidelines are not available for interpreting measurements of radial bone structure so we have defined inferior bone structure similarly by comparing individual values to the YAM. That is, individuals with values for HA or HM >2 SDs above YAM or with a value for connectivity index >2 SDs below YAM would be identified as having inferior bone structure. The YAM for structure variables was determined for a group of healthy women (n = 42) between the ages of 20 and 40 who participated in a cross-sectional study to determine the relation between bone structure at the distal radius and normal aging (13).
Results In four images acquired from individuals with recent wrist fractures (one man), the software was unable to close the cortical ring; therefore, these scans were excluded from further analyses. Two vol-
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Table 1 Baseline Characteristics of Women With and Without Distal Radius Fracture
Variable Age (yr)a BMI (kg/m2)a Nondominant wrist imagedb Postmenopausalb Medication usageb Birth control pills Hormone replacement therapy Didrocal Thyroid hormone Dilantin Multivitamin Vitamin D Calcium Past medical historyb Premature menopausec Hypothyroidism Hyperthyroidism Prior low-energy fracture Family history of osteoporosis Cancer treated with chemotherapy
Fracture group (n = 21)
Control group (n = 21)
58.05 (12.28)d 26.18 (4.96)d 81 (17)d
57.26 (18.36) 23.7 (2.71) 86 (18)
62 (13)d
62 (13)
10 (2) 10 (2)
19 (4)e 10 (2)e
14 (3) 19 (4) 5 (1) 28 (6) 19 (4) 38 (8)
0 (0) 0 (0) 0 (0) 38 (8) 5 (1) 24 (5)
18 (4) 14 (3) 5 (1) 27 (6)
0 (0) 0 (0) 0 (0) 0 (0)
27 (6)
0 (0)
9 (2)
0 (0)
a
Data and expressed as mean (SD). Data expressed as percentage (n). c Before the age of 45 yr. d No significant difference between groups (p > 0.05). e Taken for reasons unrelated to bone loss. b
unteers in the fracture group reported a history of previous fracture in the currently nonfractured wrist. The previous fracture occurred within the 4% site of the radius, so the images from the two volunteers with previous wrist fractures were discarded. Images of the nonfractured distal radius for 21 women with recent wrist fractures were satisfactory for analyses and were included in the study. The characteristics of the group of women with recent wrist fractures and the control group with no
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Fig. 1. Indices of trabecular bone structure at 4% site of distal radius in nonfractured forearm for groups of control women with low bone density (n = 21; ■) and women with recent wrist fractures (n = 21; ). The left axis displays the values for the group means (SE) for mean hole size (HA) and connectivity index. The right axis displays the values for the group means (SE) for (HM). *HA is significantly larger in the fracture group (p = 0.03).
history of fracture are summarized in Table 1. There was no significant difference between the groups with respect to age, BMI, hand dominance, and menopausal status. However, when comparing medication usage and past medical history, the fracture group had a greater burden of illness. Figure 1 shows the group mean (SE) for each of the indices of apparent trabecular bone structure. HA was larger in the group of women with fracture than in the control group (p = 0.03). The connectivity index was lower and HM was larger in the fracture group, but these values were not significantly different between groups (Table 2). Typical structural differences between women with wrist fracture and women without fracture are shown in Fig. 2. The groups did not differ with respect to radial bone density, mass, geometry, and SSI (Table 2). More individuals with fractures had HA values >4.37 mm2 (i.e., more than 2 SDs above the YAM of 1.74 mm2) compared with individuals with no history of fracture (Fig. 3). The ability of HA to discriminate fracture cases from control subjects using this cut point is summarized in Table 3. When HA was >4.37 mm2, the sensitivity of this test was 47.6% and the specificity was 86%. There was a significant positive association between HA and lowVolume 6, 2003
Trabecular Bone Structure and Radial Fracture
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Table 2 pQCT Measurements of Bone Density, Mass, Geometry, Torsional Strength, and Apparent Trabecular Structure in Women With and Without Fracture of Distal Radius Variablea Density (mg/cm3) ToBD CoBD TrBD Mass (mg) ToBMC CoBMC TrBMC Geometry Polar moment of inertia (mm4) Section modulus (mm3) Torsional bone strength (mm3) SSIb Apparent trabecular structure HA (mm2) HM (mm2) Connectivity index
Fracture group (n = 21)
Control group (n = 21)
p Value
306.5 (67.2) 582.5 (108.0) 129.1 (40.8)
288.0 (42.5) 553.1 (108.9) 136.6 (40.8)
0.30 0.38 0.47
205.9 (38.2) 151.0 (24.0) 54.9 (21.8)
210.4 (39.4) 146.6 (29.4) 63.9 (15.8)
0.71 0.59 0.14
7302 (3118) 525.7 (141.3)
7852 (2315) 567.8 (113.9)
0.52 0.29
282.1 (69.5)
283.2 (88.3)
0.96
4.91 (3.86) 92.7 (44.8) –1.82 (9.25)
2.93 (1.50) 88.4 (32.1) 2.24 (6.16)
0.03 0.72 0.10
a
Data are expressed as mean (SD). SSI combines variables that represent geometric (section modulus) and material (cortical bone density) properties. b
Fig. 2. Representative binary images of trabecular compartment (with bone appearing black and marrow spaces appearing white) at 4% site of radius for women with recent fracture (A,B) and controls (C,D) matched for age and volumetric density of total bone compartment (ToBD). ToBD for (A) is 324 mg/cm3 and for (C) is 363 mg/cm3. ToBD for (B) and (D) is 287 and 244 mg/cm3, respectively.
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Fig. 3. Individual values for mean hole size (HA) at 4% site of distal radius in women with low bone density and no history of previous fracture (n = 21; ■) and women with recent fracture (n = 21; ◆) plotted with reference to YAM (1.74 mm2; ——) and 2 SDs above YAM (4.37 mm2; – – –). Table 3 Association Between Individual Values for HA, Bone Density, and Mass at 4% Site of Radius and Fracture of Distal Forearma Pairsb Bone variable
Concordant (%)
Discordant (%)
Ties (%)
O/R (95% CI)
p Value
40.0
7.5
51.7
5.4 (1.2–24.3)
0.03
21.8 14.7 16.3
17.0 14.7 16.3
61.2 56.2 53.1
1.28 (0.32–5.09) 0.51 (0.13–1.93) 1.87 (0.52–6.76)
0.73 0.32 0.34
25.4 24.5 31.7
15.9 10.2 3.2
58.7 65.3 65.1
1.6 (0.41–6.19) 0.42 (0.09–1.96) 10 (1.10–90.6)
0.50 0.27 0.04
HA (mm2) Bone density (mg/cm3) Compartments Total Cortical/subcortical Trabecular BMC (mg) Compartments Total Cortical/subcortical Trabecular a
Individual values for bone density and BMC >2 SDs below the YAM and individual values for HA >2 SDs above the YAM value were selected as cut points used for logistic regression analysis. As the OR rises above 1, the likelihood of distal radius fracture increases. b Observations are paired with different response values. A pair is concordant if the individual with low bone density or mass (<2 SDs below YAM) or high HA (> 2 SDs above YAM) has a higher probability of having a fracture, discordant if the opposite is true, and tied if the probabilities are equal.
energy fracture of the distal forearm (OR = 5.4 (95% CI: 1.2–24.3); p = 0.03). This suggests that a woman with an HA >4.37 mm2 was 5.4 times more likely to have sustained a recent wrist fracture. The discriminatory ability of HA was compared with that of bone density and mass (Table 3). Note that although there
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was no significant difference between groups with respect to TrBMC, TrBMC values >2 SDs below YAM were more likely to be associated with a wrist fracture (p = 0.04). However, the uncertainty in the OR was extremely large (95% CI: 1.1–90.6) and 65.1% of the observations were equally likely to be
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Trabecular Bone Structure and Radial Fracture cases in which fracture was associated with a TrBMC value <2 SDs below the YAM or cases in which no fracture was present but the TrBMC was >2 SDs below the YAM. Values >2 SDs from the YAM for either HA, connectivity index, or TrBMC were identified for 12 fracture subjects and 4 control subjects with low bone density but no history of fracture. For this combination of findings, the OR was 5.6 (95% CI: 1.4–22.8). Again, there was a significant association between the combination of HA (>2 SDs above YAM), connectivity index (>2 SDs below YAM), or trabecular BMC (<2 SDs below YAM) and low-energy fracture of the distal forearm (p = 0.01). Using this combination of diagnostic criteria, the sensitivity was increased and the specificity was decreased (52 and 81%, respectively) when compared to assessing HA values alone.
Discussion Previously, it has been shown that a BMD value 1 SD below the matched YAM is associated with a relative risk for fracture of 1.5 (95% CI: 1.4–1.6) (9). On a population basis, measurements of bone mass at the hip, spine, or radius represent a useful method of identifying individuals at risk for osteoporotic fracture (1,9). Currently, the ability to predict which individuals with low bone mass will experience a fracture is limited. When we compared the bone characteristics of women with similar bone density, apparent porosity of trabecular bone at the distal radius, estimated by means of pQCT-based in vivo measurements of HA, discriminates individuals with low-energy fracture of the distal forearm from individuals with no history of fracture. When HA was more than 2 SDs above the YAM, then the likelihood of this being associated with a low-energy fracture of the distal forearm was 5.4 (95% CI: 1.2–24.3). The specificity of the test was 86%. Thus, the measurement of apparent bone structure at the 4% site of the radius may prove to be useful in identifying individuals with low bone density whose risk of fracture is high. The primary distinction between the control group with low bone density and the group of women with recent wrist fracture was HA. Since no other estimate of radial bone quality discriminated between the groups, it appears that women who sustain lowenergy wrist fractures have larger average values for
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41 intertrabecular spacing at that site than women with no fracture. The average area of the hole size could be influenced by the thickness of the trabeculae as well as the number of trabeculae present. Ex vivo, it has been shown that radial bones with larger intertrabecular spacing fail under lower compressive loading forces (15). This concept is consistent with the findings of Mosekilde (17,18), who identified age-related increases in both intertrabecular spacing and thinning of the horizontally oriented vertebral trabeculae. In addition, an age-related increase in perforations of the trabecular elements was noted in the vertebrae of women over the age of 75 (18). If perforations of the trabecular struts occurred in our fracture group, it is likely that this would be observed as a decrease in connectivity and an increase in HM as compared with the control group. Such a gender-specific pattern is seen as a function of aging (13); Figure 1 shows this trend between the control and fracture groups that does not reach statistical significance. These data are consistent with the theory that structural deterioration associated with osteoporosis follows an accelerated pattern of age-related bone loss with increases in both intertrabecular spacing and thinning of the trabeculae. Our study characterized specific structural changes in the distal radius that distinguish fracture cases from those cases in which bone density is low but no fracture has occurred. Our findings are in agreement with those of others who have reported that trabecular structure in women with low vertebral bone density distinguishes between women with and without vertebral fracture (19,20). Oleksik et al. (19) have shown that cortical thinning and disruption of the trabecular network in biopsied iliac crest bone is associated with osteoporotic vertebral fracture in postmenopausal women with low bone density. In contrast to assessing biopsied bone from the iliac crest, Gordon et al. (20) used noninvasive imaging to study the relationship between site-specific trabecular structure and vertebral fracture in 61 women with low vertebral bone density. High-resolution computed tomography (CT) images of the spine were analyzed to quantify bone density and trabecular structure and, after adjusting for bone density, only HA distinguished women with vertebral fracture from those without fracture (20). Our data are the first to describe the association between
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42 HA and fracture at the distal radius in women with low bone density. Our study has several advantages over those previously reported. First, wrist fractures occur at an earlier age compared with vertebral fractures (2,3). Thus, identification of individuals at risk for radial fracture would permit early intervention to prevent bone loss. Second, the pQCT is dedicated to the assessment of a clinically relevant fracture site in the peripheral skeleton. By contrast, iliac crest bone biopsies are not taken from a fracture-prone site and the broad clinical applications of whole-body CT imaging limit its availability for general use in the diagnosis of osteoporosis. Third, pQCT imaging of the distal radius is noninvasive and the effective radiation dose (~1 µSv) is minimal (16). This is preferable to the invasive procedure required to obtain bone biopsies and the higher effective dose (~50 µSv) associated with whole-body CT imaging of the spine (16). Thus, pQCT-based assessment of apparent trabecular structure at the distal radius provides a noninvasive, accessible method of identifying early changes associated with osteoporotic wrist fracture in women with low bone density. A limitation of the case-control design used in our study and those studies previously mentioned is that a causal relationship between a more porous trabecular network and fragility fracture cannot be established. Whereas cortical bone quality has been identified as the chief determinant of bone strength at the distal radius (21), our study and many others (8,12,19,20) have found that estimates of trabecular bone quality are significant predictors of fracture. Perhaps pQCT-based estimates of trabecular structure at the 4% site of the radius provide an early indicator of changes in the whole-bone competency at the distal forearm. It would be ideal if it were possible to measure bone characteristics in the fractured radius just prior to the low-energy injury. Such a prospective study could demonstrate a causal relationship between trabecular structure and fracture. In our study, we assessed apparent trabecular bone porosity at the 4% site of the radius contralateral to the site of fracture. Previously, we have shown that there is no significant between-limb difference in measurements of HA, and that the bilateral measurements of HA are highly correlated within subjects (r = 0.87) (14).
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MacIntyre et al. Thus, the evaluation of HA in the nonfractured limb provides a satisfactory estimate of the trabecular bone structure in the fractured limb. This permits early measurement postinjury, thus avoiding the confounding influences that the fracture and subsequent changes in mechanical usage may introduce. The ability to determine differences in trabecular bone continuity using variables such as the connectivity index may be limited by the resolution of the pQCT. In healthy individuals, trabeculae are 0.1–0.4 mm thick and the average dimension of the bone marrow space is 0.75 mm (22,23). We acquire a twodimensional (2D) image with a voxel size of 0.33 mm and a slice thickness of 2.5 mm to characterize threedimensional (3D) structure. Clearly, this resolution is not sufficient for assessing true trabecular structure. The majority of work investigating the structural changes associated with osteoporosis has been based on 2D analysis of histomorphometric sections. Bone biopsies from osteoporotic patients demonstrate characteristics of poor structural integrity such as decreased trabecular number and plate density (24–26), and increased marrow star volume and trabecular separation (25,26). These findings are compatible with our observation of increased HA in women with recent wrist fracture even with the limited resolution in the 2D pQCT images. Recent advances in noninvasive imaging techniques make it possible to resolve individual trabeculae in vivo using high-resolution and micro CT or magnetic resonance microscopy (27). To date, technical challenges limit the resolution achieved in a clinical setting using these imaging methods given constraints such as field strength of clinical magnetic resonance magnets, acceptable radiation exposure during CT assessments, image acquisition time, and accessibility to equipment. More research using noninvasive, 3D, high-resolution imaging is needed to determine the merit of assessing bone structure in addition to BMD in order to predict an individual’s risk of osteoporotic fracture. In conclusion, our data suggest that a large value for average trabecular hole size is associated with wrist fracture and this structural property can be quantified noninvasively at the distal radius. In vivo assessment of apparent intertrabecular spacing at the distal radius in individuals with low bone density may improve the diagnostic ability to identify individuals at risk of osteoporotic fracture.
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Trabecular Bone Structure and Radial Fracture
Acknowledgments We thank the subject volunteers and Melanie Ackerman for assistance with recruitment. This work was supported in part by the Father Sean O’Sullivan Research Centre through an FSORC Studentship Award (NJM). Current support through The Arthritis Society/CIHR Health Research Partnership Fund Fellowship (NJM) is gratefully acknowledged.
References 1. World Health Organization (WHO) Study Group. 1994 Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 843. Geneva: WHO. 2. Owen RA, Melton LJ, Ilstrup DM, Johnson KA, Riggs BL. 1982 Colles’ fracture and subsequent hip fracture risk. Clin Orthop 171:37–43. 3. Melton LJ III. 1995 Epidemiology of Fractures. In: Osteoporosis: Etiology, Diagnosis and Management, 2nd ed. Riggs BL, Melton LJ III, eds. Lippincott-Raven, Philadelphia, PA, 225–247. 4. Ooms ME, Lips P, Van Lingen A, Valkenburg HA. 1993 Determinants of bone mineral density and risk factors for osteoporosis in healthy elderly women. J Bone Miner Res 8:669–674. 5. Mallmin H, Ljunghall S. 1994 Distal radius fracture is an early sign of general osteoporosis: bone mass measurements in a population-based study. Osteoporos Int 4:357–361. 6. Earnshaw SA, Cawte SA, Worley A, Hosking DJ. 1998 Colles’ fracture of the wrist as an indicator of underlying osteoporosis in postmenopausal women: a prospective study of bone mineral density and bone turnover rate. Osteoporos Int 8:53–60. 7. Cuddihy M-T, Gabriel SE, Crowson CS, O’Fallon WM, Melton LJ III. 1999 Forearm fractures as predictors of subsequent osteoporotic fractures. Osteoporos Int 9:469–475. 8. Schneider P, Reiners C, Cointry GR, Capozza RF, Ferretti JL. 2001 Bone quality parameters of the distal radius as assessed by pQCT in normal and fractured women. Osteoporos Int 12:639–646. 9. Marshall D, Johnell O, Wedel H. 1996 Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259. 10. Kleerekoper M, Villanueva AR, Stanciu J, Sudhaker D, Parfitt AM. 1985 The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 37:594–597. 11. Hui SL, Slemenda CW, Johnston CC. 1988 Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 81:1804–1809.
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43 12. Gordon CL, Webber CE, Adachi JD, Christoforou N. 1996 In vivo assessment of trabecular bone structure at the distal radius from high-resolution computed tomography images. Phys Med Biol 41:495–508. 13. MacIntyre NJ, Adachi JD, Webber CE. 1999 Gender differences in normal age-dependent patterns of radial bone structure and density: a cross-sectional study using peripheral quantitative computed tomography. J Clin Densitom 2:163–173. 14. MacIntyre NJ, Adachi JD, Webber CE. 1999 In vivo detection of structural differences between dominant and nondominant radii using peripheral quantitative computed tomography. J Clin Densitom 2:413–422. 15. Gordon CL, Webber CE, Nicholson PA. 1998 Relation between image-based assessment of distal radius trabecular structure and compressive strength. Can Assoc Radiol J 49:390–397. 16. Baran DT, Faulkner KG, Genant HK, Miller PD, Pacifici R. 1997 Diagnosis and management of osteoporosis: guidelines for the utilization of bone densitometry. Calcif Tissue Int 61:433–440. 17. Mosekilde L. 1988 Age-related changes in vertebral trabecular bone architecture—assessed by a new method. Bone 9:247–250. 18. Mosekilde L. 1989 Sex differences in age-related loss of vertebral trabecular bone mass and structure—biomechanical consequences. Bone 10:425–432. 19. Oleksik A, Ott SM, Vedi S, Bravenboer N, Compston J, Lips P. 2000 Bone structure in patients with low bone mineral density with and without vertebral fractures. J Bone Miner Res 15:1368–1375. 20. Gordon CL, Lang TF, Augat P, Genant HK. 1998 Imagebased assessment of spinal trabecular bone structure from high-resolution CT images. Osteoporos Int 8:317–325. 21. Spadaro JA, Werner FW, Brenner RA, Fortino MD, Fay LA, Edwards WT. 1994 Cortical and trabecular bone contribute strength to the osteopenic distal radius. J Orthop Res 12:211–218. 22. Amstutz HC, Sissons HA. 1969 The structure of the vertebral spongiosa. J Bone Joint Surg [Br] 51:540–550. 23. Whitehouse WJ. 1977 Cancellous bone in the anterior part of the iliac crest. Calcif Tissue Res 23:67–76. 24. Kleerekoper M, Villanueva AR, Stanciu J, Rao DS, Parfitt AM. 1985 The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 37:594–597. 25. Recker RR. 1993 Architecture and vertebral fracture. Calcif Tissue Int 53:S139–S142. 26. Legrand E, Chappard D, Pascaretti C, Duquenne M, Krebs S, Rohmer V, Basle MF, Audran M. 2000 Trabecular bone microarchitecture, bone mineral density and vertebral fractures in male osteoporosis. J Bone Miner Res 15:13–19. 27. Genant HK, Gordon C, Jiang Y, Lang TF, Link TM, Majumdar S. 1999 Advanced imaging of bone macro and micro structure. Bone 25:149–152.
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Original Article
In Vivo Measurement of Apparent Trabecular Bone Structure of the Radius in Women With Low Bone Density Discriminates Patients with Recent Wrist Fracture from Those Without Fracture Norma J. MacIntyre, PhD1, Jonathan D. Adachi, MD2, and Colin E. Webber, PhD3 1Human
Mobility Research Centre, Queen’s University, Kingston, Ontario; 2St. Joseph’s Hospital, Hamilton, Ontario; and 3Department of Nuclear Medicine, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Abstract The purpose of this cross-sectional case-control study was to determine whether indices of bone structure at the 4% site of the radius discriminate women who have sustained a recent low-energy fracture of the contralateral distal radius (n = 21) from women with similar bone density and no history of fracture (n = 21). Images of the distal forearm were acquired using peripheral quantitative computed tomography (pQCT) and were analyzed using in-house-developed software to determine indices of trabecular bone structure (average hole size [HA], maximum hole size, and connectivity index). The same images were analyzed using commercial software to determine bone density, mass, geometry, and torsional strength. The fracture group had significantly larger HA (p = 0.03). No other bone variable differed between groups. Individual HA values were compared to the mean value for young adult women (n = 42). The odds ratio (95% confidence interval) associated with an HA >2 SDs above the young adult mean was 5.4 (1.2–24.3). Thus, estimation of in vivo trabecular bone porosity by measuring the average diameter of the pQCT-imaged marrow spaces in the ultradistal radius identifies individuals with low bone mass most at risk for osteoporotic fracture. Key Words: Peripheral quantitative computed tomography; radius; in vivo bone structure; wrist fracture; osteoporosis.
Introduction
will break. Osteoporosis is a common condition that is characterized by loss of bone mass and structural integrity, which results in increased bone fragility and susceptibility to fracture (1). This has severe consequences for both the individual and the health care system. Therefore, considerable effort has been expended to identify those variables that determine bone strength and how they can be measured in order to target high-risk individuals for early intervention. Fracture of the distal radius is typically the earliest clinical manifestation of osteoporosis (2,3). Indeed, the distal forearm is the most common frac-
Skeletal fracture occurs when the strength of a bone is insufficient to withstand the forces to which the bone is subjected. Many factors contribute to fracture risk and anything that compromises bone strength will increase the likelihood that the bone
Address correspondence to Dr. Norma J. MacIntyre, Human Mobility Research Centre, Doran 2, Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7. E-mail: [email protected]
35
36 ture site among women under the age of 75, and lowenergy forearm fracture is predictive of underlying osteoporosis (2,4–6) and subsequent osteoporotic fracture (2,7). Since the peak incidence of forearm fracture occurs approx 15 yr prior to the peak incidence of hip fracture (3), identification of individuals at risk for radial fracture would permit much earlier intervention to prevent irreversible bone loss. A number of studies have shown that individuals with distal forearm fractures have significantly lower bone mineral density (BMD, g/cm2) at the hip, spine, and contralateral distal radius compared with healthy control subjects (4,5,8). On a population basis, the presence of osteoporosis can be determined using dual X-ray absorptiometry to measure BMD at fracture-prone sites (1,9). However, no suitable method is available for predicting which individuals with low BMD will experience osteoporotic fractures (9). In addition to BMD, bone architecture is an independent predictor of bone strength (10,11). That is, both the amount and the organization of bone mineral contribute to the regional competency of the skeleton. Previously, Gordon et al. (12) developed a technique to measure the apparent in vivo trabecular bone structure at the 4% site of the radius using peripheral quantitative computed tomography (pQCT). The indices of trabecular bone structure measured using this technique demonstrate the anticipated associations with age and gender (13) and between limbs (14). A cross-sectional study has shown an age-dependent increase in indices estimating the dimensions of the marrow spaces (average hole size [HA] and maximum hole size [HM]) and an age-dependent decrease in the connectivity index at the ultradistal radius (13). Moreover, an inverse relationship between intertrabecular spacing and compressive loading forces has been demonstrated in ex vivo radial bones (15). The extent to which structural changes in osteoporotic bone differ from those associated with normal aging is not clear. In osteoporosis, increased bone fragility may be associated with an accelerated rate of structural deterioration, or it may be associated with an altered pattern of structural deterioration. Identification of specific structural changes associated with osteoporotic wrist fracture may lead to the development of a screening tool capable of predicting an individual’s fracture risk. The purpose
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MacIntyre et al. of the present cross-sectional case-control study was to determine whether radial bone structure is different for individuals who have sustained a low-energy fracture of the distal radius compared with control subjects with low radial bone density but no history of fracture.
Materials and Methods Subjects Individuals who attended the St. Joseph’s Hospital Fracture Clinic with a recent (<8 wk) low-energy fracture of the distal radius were recruited. Volunteers (3 men, 32 women) who expressed an interest were contacted for further screening and to arrange an appointment. Of these, two volunteers were excluded because fracture resulted from a fall from higher than a standing height and six others did not attend the scheduled appointment. Informed consent was obtained from 1 man and 26 women. A control group was selected from a database of healthy individuals with no history of fracture recruited during the same time period from the same community to participate in a study of between-limb differences in trabecular bone structure (14). To have a comparison group with similar values for total bone density at the 4% site of the radius, the reference database was sorted according to ascending values for total bone density and the first 21 women were selected. All methods and procedures for the study were approved by the research ethics board at our institution.
Procedure Before performing pQCT scans, subjects completed a questionnaire to document age, gender, height, weight, hand dominance, and a general health/medical history profile. Menopausal status was determined by self-report, and natural menopause was defined as the age at which menses first ceased for a period of 12 mo. Height and weight were recorded to the nearest 0.1 cm and 0.1 kg, respectively, and body mass index (BMI, kg/m2) was calculated for each subject. In the nonfractured forearm, the length of the ulna from the olecranon process to the ulnar styloid was measured to the nearest 0.1 cm using a tape measure. Scans were performed on the nonfractured forearm of each subject. Care was taken to ensure that
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Trabecular Bone Structure and Radial Fracture the forearm being measured was well supported and positioned appropriately in the imaging field. Volunteers were instructed to remain motionless throughout the scanning procedure.
Equipment A second-generation Stratec XCT 960 pQCT scanner (manufactured by Stratec Medizintechnik, Germany, and distributed in North America by Norland, Fort Atkinson, WI) was used to acquire one high-resolution image in the transverse plane of each study subject’s wrist at the standard 4% site, which was located automatically by the system software. The image acquisition parameters, analyses protocol, and reproducibility of this method have been described previously (12–14). The transverse slice thickness is 2.5 mm and the in-plane voxel dimension is 0.33 mm2. The user sets a rectangular region of interest (ROI) around the cross-sectional image of the radial bone, and the commercial software (version 5.21A; Stratec) applies an iterative contour detection algorithm to determine material properties: volumetric bone density (total, cortical/subcortical, and trabecular bone compartments, ToBD, CoBD, and TrBD, respectively [mg/cm3], geometric properties (polar cross-sectional moment of inertia [mm4] and section modulus [mm3]) and torsional bone strength (stress-strain index [SSI] [mm3]). Bone mineral content (BMC) (total, cortical/subcortical, and trabecular bone compartments, ToBMC, CoBMC, and TrBMC, respectively, mg) was calculated as the product of density and slice volume. The same image of the radial bone was postprocessed using a segmentation algorithm developed in-house as previously described in detail (12). After the user sets a rectangular ROI around the cross-sectional image of the radial bone, the algorithm proceeds automatically to separate the bone from the marrow and soft-tissue background using a region grow step. A binary image of the trabecular compartment is created and the algorithm determines the number of holes and area of each hole. From these measurements, values for HA (mm2) and HM (mm2) are obtained. The next postprocessing step produces a skeletonized image and applies strut analysis to quantify the continuity of the trabecular network. The connectivity index is a mathematical construct that can take on positive or negative values. The
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37 number of free ends and isolated points is subtracted from the number of nodes, and this value is normalized to the length of the network and multiplied by 100. For example, when the number of nodes is higher relative to the number of free ends and isolated points, the connectivity index will be more positive and representative of a well-connected trabecular network. Conversely, a negative value reflects a highly disrupted network.
Statistical Analyses All statistical calculations were performed using Minitab (release 13; Minitab, State College, PA). Descriptive statistics were calculated for anthropometric measurements of the study subjects and all measured variables of bone density, mass, geometry, SSI, and structure. Comparisons between the group with low-energy wrist fractures and the control group were made using one-way analysis of variance, and differences were considered significant when p < 0.05. The odds ratio (OR) was calculated using binary logistic regression to assess the strength of the association between bone structure and fracture occurrence; in this case, if inferior bone structure is associated with fracture, the OR rises above 1. It has been suggested that radial bone density measurements are below normal and appropriate intervention is indicated when an individual value is >2 SDs below the young adult mean (YAM) (16). Guidelines are not available for interpreting measurements of radial bone structure so we have defined inferior bone structure similarly by comparing individual values to the YAM. That is, individuals with values for HA or HM >2 SDs above YAM or with a value for connectivity index >2 SDs below YAM would be identified as having inferior bone structure. The YAM for structure variables was determined for a group of healthy women (n = 42) between the ages of 20 and 40 who participated in a cross-sectional study to determine the relation between bone structure at the distal radius and normal aging (13).
Results In four images acquired from individuals with recent wrist fractures (one man), the software was unable to close the cortical ring; therefore, these scans were excluded from further analyses. Two vol-
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Table 1 Baseline Characteristics of Women With and Without Distal Radius Fracture
Variable Age (yr)a BMI (kg/m2)a Nondominant wrist imagedb Postmenopausalb Medication usageb Birth control pills Hormone replacement therapy Didrocal Thyroid hormone Dilantin Multivitamin Vitamin D Calcium Past medical historyb Premature menopausec Hypothyroidism Hyperthyroidism Prior low-energy fracture Family history of osteoporosis Cancer treated with chemotherapy
Fracture group (n = 21)
Control group (n = 21)
58.05 (12.28)d 26.18 (4.96)d 81 (17)d
57.26 (18.36) 23.7 (2.71) 86 (18)
62 (13)d
62 (13)
10 (2) 10 (2)
19 (4)e 10 (2)e
14 (3) 19 (4) 5 (1) 28 (6) 19 (4) 38 (8)
0 (0) 0 (0) 0 (0) 38 (8) 5 (1) 24 (5)
18 (4) 14 (3) 5 (1) 27 (6)
0 (0) 0 (0) 0 (0) 0 (0)
27 (6)
0 (0)
9 (2)
0 (0)
a
Data and expressed as mean (SD). Data expressed as percentage (n). c Before the age of 45 yr. d No significant difference between groups (p > 0.05). e Taken for reasons unrelated to bone loss. b
unteers in the fracture group reported a history of previous fracture in the currently nonfractured wrist. The previous fracture occurred within the 4% site of the radius, so the images from the two volunteers with previous wrist fractures were discarded. Images of the nonfractured distal radius for 21 women with recent wrist fractures were satisfactory for analyses and were included in the study. The characteristics of the group of women with recent wrist fractures and the control group with no
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Fig. 1. Indices of trabecular bone structure at 4% site of distal radius in nonfractured forearm for groups of control women with low bone density (n = 21; ■) and women with recent wrist fractures (n = 21; ). The left axis displays the values for the group means (SE) for mean hole size (HA) and connectivity index. The right axis displays the values for the group means (SE) for (HM). *HA is significantly larger in the fracture group (p = 0.03).
history of fracture are summarized in Table 1. There was no significant difference between the groups with respect to age, BMI, hand dominance, and menopausal status. However, when comparing medication usage and past medical history, the fracture group had a greater burden of illness. Figure 1 shows the group mean (SE) for each of the indices of apparent trabecular bone structure. HA was larger in the group of women with fracture than in the control group (p = 0.03). The connectivity index was lower and HM was larger in the fracture group, but these values were not significantly different between groups (Table 2). Typical structural differences between women with wrist fracture and women without fracture are shown in Fig. 2. The groups did not differ with respect to radial bone density, mass, geometry, and SSI (Table 2). More individuals with fractures had HA values >4.37 mm2 (i.e., more than 2 SDs above the YAM of 1.74 mm2) compared with individuals with no history of fracture (Fig. 3). The ability of HA to discriminate fracture cases from control subjects using this cut point is summarized in Table 3. When HA was >4.37 mm2, the sensitivity of this test was 47.6% and the specificity was 86%. There was a significant positive association between HA and lowVolume 6, 2003
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Table 2 pQCT Measurements of Bone Density, Mass, Geometry, Torsional Strength, and Apparent Trabecular Structure in Women With and Without Fracture of Distal Radius Variablea Density (mg/cm3) ToBD CoBD TrBD Mass (mg) ToBMC CoBMC TrBMC Geometry Polar moment of inertia (mm4) Section modulus (mm3) Torsional bone strength (mm3) SSIb Apparent trabecular structure HA (mm2) HM (mm2) Connectivity index
Fracture group (n = 21)
Control group (n = 21)
p Value
306.5 (67.2) 582.5 (108.0) 129.1 (40.8)
288.0 (42.5) 553.1 (108.9) 136.6 (40.8)
0.30 0.38 0.47
205.9 (38.2) 151.0 (24.0) 54.9 (21.8)
210.4 (39.4) 146.6 (29.4) 63.9 (15.8)
0.71 0.59 0.14
7302 (3118) 525.7 (141.3)
7852 (2315) 567.8 (113.9)
0.52 0.29
282.1 (69.5)
283.2 (88.3)
0.96
4.91 (3.86) 92.7 (44.8) –1.82 (9.25)
2.93 (1.50) 88.4 (32.1) 2.24 (6.16)
0.03 0.72 0.10
a
Data are expressed as mean (SD). SSI combines variables that represent geometric (section modulus) and material (cortical bone density) properties. b
Fig. 2. Representative binary images of trabecular compartment (with bone appearing black and marrow spaces appearing white) at 4% site of radius for women with recent fracture (A,B) and controls (C,D) matched for age and volumetric density of total bone compartment (ToBD). ToBD for (A) is 324 mg/cm3 and for (C) is 363 mg/cm3. ToBD for (B) and (D) is 287 and 244 mg/cm3, respectively.
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Fig. 3. Individual values for mean hole size (HA) at 4% site of distal radius in women with low bone density and no history of previous fracture (n = 21; ■) and women with recent fracture (n = 21; ◆) plotted with reference to YAM (1.74 mm2; ——) and 2 SDs above YAM (4.37 mm2; – – –). Table 3 Association Between Individual Values for HA, Bone Density, and Mass at 4% Site of Radius and Fracture of Distal Forearma Pairsb Bone variable
Concordant (%)
Discordant (%)
Ties (%)
O/R (95% CI)
p Value
40.0
7.5
51.7
5.4 (1.2–24.3)
0.03
21.8 14.7 16.3
17.0 14.7 16.3
61.2 56.2 53.1
1.28 (0.32–5.09) 0.51 (0.13–1.93) 1.87 (0.52–6.76)
0.73 0.32 0.34
25.4 24.5 31.7
15.9 10.2 3.2
58.7 65.3 65.1
1.6 (0.41–6.19) 0.42 (0.09–1.96) 10 (1.10–90.6)
0.50 0.27 0.04
HA (mm2) Bone density (mg/cm3) Compartments Total Cortical/subcortical Trabecular BMC (mg) Compartments Total Cortical/subcortical Trabecular a
Individual values for bone density and BMC >2 SDs below the YAM and individual values for HA >2 SDs above the YAM value were selected as cut points used for logistic regression analysis. As the OR rises above 1, the likelihood of distal radius fracture increases. b Observations are paired with different response values. A pair is concordant if the individual with low bone density or mass (<2 SDs below YAM) or high HA (> 2 SDs above YAM) has a higher probability of having a fracture, discordant if the opposite is true, and tied if the probabilities are equal.
energy fracture of the distal forearm (OR = 5.4 (95% CI: 1.2–24.3); p = 0.03). This suggests that a woman with an HA >4.37 mm2 was 5.4 times more likely to have sustained a recent wrist fracture. The discriminatory ability of HA was compared with that of bone density and mass (Table 3). Note that although there
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was no significant difference between groups with respect to TrBMC, TrBMC values >2 SDs below YAM were more likely to be associated with a wrist fracture (p = 0.04). However, the uncertainty in the OR was extremely large (95% CI: 1.1–90.6) and 65.1% of the observations were equally likely to be
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Trabecular Bone Structure and Radial Fracture cases in which fracture was associated with a TrBMC value <2 SDs below the YAM or cases in which no fracture was present but the TrBMC was >2 SDs below the YAM. Values >2 SDs from the YAM for either HA, connectivity index, or TrBMC were identified for 12 fracture subjects and 4 control subjects with low bone density but no history of fracture. For this combination of findings, the OR was 5.6 (95% CI: 1.4–22.8). Again, there was a significant association between the combination of HA (>2 SDs above YAM), connectivity index (>2 SDs below YAM), or trabecular BMC (<2 SDs below YAM) and low-energy fracture of the distal forearm (p = 0.01). Using this combination of diagnostic criteria, the sensitivity was increased and the specificity was decreased (52 and 81%, respectively) when compared to assessing HA values alone.
Discussion Previously, it has been shown that a BMD value 1 SD below the matched YAM is associated with a relative risk for fracture of 1.5 (95% CI: 1.4–1.6) (9). On a population basis, measurements of bone mass at the hip, spine, or radius represent a useful method of identifying individuals at risk for osteoporotic fracture (1,9). Currently, the ability to predict which individuals with low bone mass will experience a fracture is limited. When we compared the bone characteristics of women with similar bone density, apparent porosity of trabecular bone at the distal radius, estimated by means of pQCT-based in vivo measurements of HA, discriminates individuals with low-energy fracture of the distal forearm from individuals with no history of fracture. When HA was more than 2 SDs above the YAM, then the likelihood of this being associated with a low-energy fracture of the distal forearm was 5.4 (95% CI: 1.2–24.3). The specificity of the test was 86%. Thus, the measurement of apparent bone structure at the 4% site of the radius may prove to be useful in identifying individuals with low bone density whose risk of fracture is high. The primary distinction between the control group with low bone density and the group of women with recent wrist fracture was HA. Since no other estimate of radial bone quality discriminated between the groups, it appears that women who sustain lowenergy wrist fractures have larger average values for
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41 intertrabecular spacing at that site than women with no fracture. The average area of the hole size could be influenced by the thickness of the trabeculae as well as the number of trabeculae present. Ex vivo, it has been shown that radial bones with larger intertrabecular spacing fail under lower compressive loading forces (15). This concept is consistent with the findings of Mosekilde (17,18), who identified age-related increases in both intertrabecular spacing and thinning of the horizontally oriented vertebral trabeculae. In addition, an age-related increase in perforations of the trabecular elements was noted in the vertebrae of women over the age of 75 (18). If perforations of the trabecular struts occurred in our fracture group, it is likely that this would be observed as a decrease in connectivity and an increase in HM as compared with the control group. Such a gender-specific pattern is seen as a function of aging (13); Figure 1 shows this trend between the control and fracture groups that does not reach statistical significance. These data are consistent with the theory that structural deterioration associated with osteoporosis follows an accelerated pattern of age-related bone loss with increases in both intertrabecular spacing and thinning of the trabeculae. Our study characterized specific structural changes in the distal radius that distinguish fracture cases from those cases in which bone density is low but no fracture has occurred. Our findings are in agreement with those of others who have reported that trabecular structure in women with low vertebral bone density distinguishes between women with and without vertebral fracture (19,20). Oleksik et al. (19) have shown that cortical thinning and disruption of the trabecular network in biopsied iliac crest bone is associated with osteoporotic vertebral fracture in postmenopausal women with low bone density. In contrast to assessing biopsied bone from the iliac crest, Gordon et al. (20) used noninvasive imaging to study the relationship between site-specific trabecular structure and vertebral fracture in 61 women with low vertebral bone density. High-resolution computed tomography (CT) images of the spine were analyzed to quantify bone density and trabecular structure and, after adjusting for bone density, only HA distinguished women with vertebral fracture from those without fracture (20). Our data are the first to describe the association between
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42 HA and fracture at the distal radius in women with low bone density. Our study has several advantages over those previously reported. First, wrist fractures occur at an earlier age compared with vertebral fractures (2,3). Thus, identification of individuals at risk for radial fracture would permit early intervention to prevent bone loss. Second, the pQCT is dedicated to the assessment of a clinically relevant fracture site in the peripheral skeleton. By contrast, iliac crest bone biopsies are not taken from a fracture-prone site and the broad clinical applications of whole-body CT imaging limit its availability for general use in the diagnosis of osteoporosis. Third, pQCT imaging of the distal radius is noninvasive and the effective radiation dose (~1 µSv) is minimal (16). This is preferable to the invasive procedure required to obtain bone biopsies and the higher effective dose (~50 µSv) associated with whole-body CT imaging of the spine (16). Thus, pQCT-based assessment of apparent trabecular structure at the distal radius provides a noninvasive, accessible method of identifying early changes associated with osteoporotic wrist fracture in women with low bone density. A limitation of the case-control design used in our study and those studies previously mentioned is that a causal relationship between a more porous trabecular network and fragility fracture cannot be established. Whereas cortical bone quality has been identified as the chief determinant of bone strength at the distal radius (21), our study and many others (8,12,19,20) have found that estimates of trabecular bone quality are significant predictors of fracture. Perhaps pQCT-based estimates of trabecular structure at the 4% site of the radius provide an early indicator of changes in the whole-bone competency at the distal forearm. It would be ideal if it were possible to measure bone characteristics in the fractured radius just prior to the low-energy injury. Such a prospective study could demonstrate a causal relationship between trabecular structure and fracture. In our study, we assessed apparent trabecular bone porosity at the 4% site of the radius contralateral to the site of fracture. Previously, we have shown that there is no significant between-limb difference in measurements of HA, and that the bilateral measurements of HA are highly correlated within subjects (r = 0.87) (14).
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MacIntyre et al. Thus, the evaluation of HA in the nonfractured limb provides a satisfactory estimate of the trabecular bone structure in the fractured limb. This permits early measurement postinjury, thus avoiding the confounding influences that the fracture and subsequent changes in mechanical usage may introduce. The ability to determine differences in trabecular bone continuity using variables such as the connectivity index may be limited by the resolution of the pQCT. In healthy individuals, trabeculae are 0.1–0.4 mm thick and the average dimension of the bone marrow space is 0.75 mm (22,23). We acquire a twodimensional (2D) image with a voxel size of 0.33 mm and a slice thickness of 2.5 mm to characterize threedimensional (3D) structure. Clearly, this resolution is not sufficient for assessing true trabecular structure. The majority of work investigating the structural changes associated with osteoporosis has been based on 2D analysis of histomorphometric sections. Bone biopsies from osteoporotic patients demonstrate characteristics of poor structural integrity such as decreased trabecular number and plate density (24–26), and increased marrow star volume and trabecular separation (25,26). These findings are compatible with our observation of increased HA in women with recent wrist fracture even with the limited resolution in the 2D pQCT images. Recent advances in noninvasive imaging techniques make it possible to resolve individual trabeculae in vivo using high-resolution and micro CT or magnetic resonance microscopy (27). To date, technical challenges limit the resolution achieved in a clinical setting using these imaging methods given constraints such as field strength of clinical magnetic resonance magnets, acceptable radiation exposure during CT assessments, image acquisition time, and accessibility to equipment. More research using noninvasive, 3D, high-resolution imaging is needed to determine the merit of assessing bone structure in addition to BMD in order to predict an individual’s risk of osteoporotic fracture. In conclusion, our data suggest that a large value for average trabecular hole size is associated with wrist fracture and this structural property can be quantified noninvasively at the distal radius. In vivo assessment of apparent intertrabecular spacing at the distal radius in individuals with low bone density may improve the diagnostic ability to identify individuals at risk of osteoporotic fracture.
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Trabecular Bone Structure and Radial Fracture
Acknowledgments We thank the subject volunteers and Melanie Ackerman for assistance with recruitment. This work was supported in part by the Father Sean O’Sullivan Research Centre through an FSORC Studentship Award (NJM). Current support through The Arthritis Society/CIHR Health Research Partnership Fund Fellowship (NJM) is gratefully acknowledged.
References 1. World Health Organization (WHO) Study Group. 1994 Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report Series 843. Geneva: WHO. 2. Owen RA, Melton LJ, Ilstrup DM, Johnson KA, Riggs BL. 1982 Colles’ fracture and subsequent hip fracture risk. Clin Orthop 171:37–43. 3. Melton LJ III. 1995 Epidemiology of Fractures. In: Osteoporosis: Etiology, Diagnosis and Management, 2nd ed. Riggs BL, Melton LJ III, eds. Lippincott-Raven, Philadelphia, PA, 225–247. 4. Ooms ME, Lips P, Van Lingen A, Valkenburg HA. 1993 Determinants of bone mineral density and risk factors for osteoporosis in healthy elderly women. J Bone Miner Res 8:669–674. 5. Mallmin H, Ljunghall S. 1994 Distal radius fracture is an early sign of general osteoporosis: bone mass measurements in a population-based study. Osteoporos Int 4:357–361. 6. Earnshaw SA, Cawte SA, Worley A, Hosking DJ. 1998 Colles’ fracture of the wrist as an indicator of underlying osteoporosis in postmenopausal women: a prospective study of bone mineral density and bone turnover rate. Osteoporos Int 8:53–60. 7. Cuddihy M-T, Gabriel SE, Crowson CS, O’Fallon WM, Melton LJ III. 1999 Forearm fractures as predictors of subsequent osteoporotic fractures. Osteoporos Int 9:469–475. 8. Schneider P, Reiners C, Cointry GR, Capozza RF, Ferretti JL. 2001 Bone quality parameters of the distal radius as assessed by pQCT in normal and fractured women. Osteoporos Int 12:639–646. 9. Marshall D, Johnell O, Wedel H. 1996 Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259. 10. Kleerekoper M, Villanueva AR, Stanciu J, Sudhaker D, Parfitt AM. 1985 The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 37:594–597. 11. Hui SL, Slemenda CW, Johnston CC. 1988 Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 81:1804–1809.
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43 12. Gordon CL, Webber CE, Adachi JD, Christoforou N. 1996 In vivo assessment of trabecular bone structure at the distal radius from high-resolution computed tomography images. Phys Med Biol 41:495–508. 13. MacIntyre NJ, Adachi JD, Webber CE. 1999 Gender differences in normal age-dependent patterns of radial bone structure and density: a cross-sectional study using peripheral quantitative computed tomography. J Clin Densitom 2:163–173. 14. MacIntyre NJ, Adachi JD, Webber CE. 1999 In vivo detection of structural differences between dominant and nondominant radii using peripheral quantitative computed tomography. J Clin Densitom 2:413–422. 15. Gordon CL, Webber CE, Nicholson PA. 1998 Relation between image-based assessment of distal radius trabecular structure and compressive strength. Can Assoc Radiol J 49:390–397. 16. Baran DT, Faulkner KG, Genant HK, Miller PD, Pacifici R. 1997 Diagnosis and management of osteoporosis: guidelines for the utilization of bone densitometry. Calcif Tissue Int 61:433–440. 17. Mosekilde L. 1988 Age-related changes in vertebral trabecular bone architecture—assessed by a new method. Bone 9:247–250. 18. Mosekilde L. 1989 Sex differences in age-related loss of vertebral trabecular bone mass and structure—biomechanical consequences. Bone 10:425–432. 19. Oleksik A, Ott SM, Vedi S, Bravenboer N, Compston J, Lips P. 2000 Bone structure in patients with low bone mineral density with and without vertebral fractures. J Bone Miner Res 15:1368–1375. 20. Gordon CL, Lang TF, Augat P, Genant HK. 1998 Imagebased assessment of spinal trabecular bone structure from high-resolution CT images. Osteoporos Int 8:317–325. 21. Spadaro JA, Werner FW, Brenner RA, Fortino MD, Fay LA, Edwards WT. 1994 Cortical and trabecular bone contribute strength to the osteopenic distal radius. J Orthop Res 12:211–218. 22. Amstutz HC, Sissons HA. 1969 The structure of the vertebral spongiosa. J Bone Joint Surg [Br] 51:540–550. 23. Whitehouse WJ. 1977 Cancellous bone in the anterior part of the iliac crest. Calcif Tissue Res 23:67–76. 24. Kleerekoper M, Villanueva AR, Stanciu J, Rao DS, Parfitt AM. 1985 The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 37:594–597. 25. Recker RR. 1993 Architecture and vertebral fracture. Calcif Tissue Int 53:S139–S142. 26. Legrand E, Chappard D, Pascaretti C, Duquenne M, Krebs S, Rohmer V, Basle MF, Audran M. 2000 Trabecular bone microarchitecture, bone mineral density and vertebral fractures in male osteoporosis. J Bone Miner Res 15:13–19. 27. Genant HK, Gordon C, Jiang Y, Lang TF, Link TM, Majumdar S. 1999 Advanced imaging of bone macro and micro structure. Bone 25:149–152.
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