Journal of the Endocrine Society, 2021, Vol. 5, No. 4, 1–8 doi:10.1210/jendso/bvaa179 Clinical Research Article Clinical Research Article Associations between Bone Material Strength Index, Calcaneal Quantitative Ultrasound, and Bone Mineral Density in Men Pamela Rufus-Membere,1 Kara L. Holloway-Kew,1 Adolfo Diez-Perez,2 Mark A. Kotowicz,1,3,4 and Julie A. Pasco1,3,4 1 Deakin University, IMPACT – Institute for Mental and Physical Health and Clinical Translation, Geelong, VIC, Australia; 2Department of Internal Medicine, Hospital del Mar-IMIM, Autonomous University of Barcelona and CIBERFES, Instituto Carlos III, Barcelona, Spain; 3Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia; and 4Barwon Health, Geelong, VIC, Australia ORCiD numbers: 0000-0002-8693-0457 (P. Rufus-Membere); 0000-0001-5064-2990 (K. L. Holloway-Kew); 0000-0001-8162-0209 (A. Diez-Perez); 0000-0002-8094-1411 (M. A. Kotowicz); 0000-0002-8968-4714 (J. A. Pasco). Abbreviations: 25OHD, 25-hydroxyvitamin D; BMD, bone mineral density; BMI, body mass index; BMSi, bone material strength index; BUA, broadband ultrasound attenuation; CKD, chronic kidney disease; DXA, dual-energy x-ray absorptiometry; eGFR, estimated glomerular filtration rate; IMI, impact micro-indentation; QUS, quantitative ultrasound; SOS, speed of sound; SI, stiffness index; T2DM, type 2 diabetes mellitus; TBS, trabecular bone score; UD, ultradistal. Received: 3 August 2020; Editorial Decision: 9 November 2020; First Published Online: 22 November 2020; Corrected and Typeset: 4 March 2021. Abstract Objectives: Impact micro-indentation (IMI) measures bone material strength index (BMSi) in vivo. This study investigated how IMI is associated with calcaneal quantitative ultrasound and bone densitometry parameters in men. Methods: BMSi was measured on the tibial plateau using the OsteoProbe in 377 men (age 33-96 years) from the Geelong Osteoporosis Study. Broadband ultrasound attenu- ation (BUA), speed of sound (SOS), and stiffness index (SI) were assessed at the calca- neus using an ultrasonometer. Areal BMD was measured at several skeletal sites using dual-energy x-ray absorptiometry. Linear associations between parameters were tested using Pearson’s correlation. Multivariable regression techniques were used to determine associations between BMSi and other measures of bone, independent of confounders. Results: BMSi was negatively correlated with age (r = –0.171, P = .001), weight (r = –0.100, P = .052), and body mass index (r = –0.187, P = .001), and positively with height (r = +0.109, P = .034). There was some evidence to support a positive association between BMSi and BUA (β = 0.052, P = .037), SOS (β = 0.013, P = .144), and SI (β = 0.036, P = .051). After age adjustment, this association was attenuated. No correlations were observed between BMSi and BMD at any skeletal site (r values ranged from –0.006 to +0.079, all P ≥ .13). Conclusion: There was a small positive association between BMSi and quantitative ultrasound (QUS) parameters, which were not independent of age. No associations ISSN 2472-1972 © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial- NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and https://academic.oup.com/jes   1 distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2 Journal of the Endocrine Society, 2021, Vol. 5, No. 4 were detected between BMSi and BMD. This suggests that BMSi and QUS are capturing common age-dependent properties of bone. Further research on the utility of IMI alone and complementary to conventional bone testing methods for predicting fracture risk is warranted. Key Words: impact microindentation, bone material strength index, fractures, osteoporosis, quantitative ultrasound With an increasingly aging population, fractures constitute correlated. Previous reports have demonstrated an associ- a major public health concern. This is because fractures are ation between low BMSi and low BMD [18], high preva- associated with significant morbidity and mortality [1-3], lence of fracture [19, 20], and increased cortical porosity particularly in cases of hip fracture, with the 1-year mor- [21]. Part of the evaluation of the clinical utility of the tality after sustaining a hip fracture estimated to be 14% OsteoProbe for assessing bone status is an appraisal of how to 58% [4-7]. its outcome, BMSi, relates to conventional bone measure- Bone fragility is determined by bone mass, bone archi- ment techniques. There are no previously published studies tecture, and bone material properties [8]. Hence, measuring investigating the associations between BMSi and QUS both the quantity and quality of bone is important in the parameters, and only a few have investigated associations assessment of fracture risk. The current gold standard for with BMD at multiple skeletal sites. assessment for fracture risk, areal bone mineral density In this study, we aimed to explore the associations be- (BMD) measured by dual-energy x-ray absorptiometry tween BMSi and bone parameters measured with QUS and (DXA), provides limited information on bone quality [8, DXA. Quantifying the relationship between BMSi and 9]. An existing complementary technique to DXA for as- other measures of bone will improve an understanding of sessing bone status is calcaneal (heel) quantitative ultra- how IMI might be used in the clinical assessment of bone sound (QUS), which provides information about bone fragility. density, architecture, and composition [9-12]. QUS measures broadband ultrasound attenuation (BUA), which reflects bone density and architecture, and Materials and Methods speed of sound (SOS), which reflects bone density and elas- Participants ticity; BUA and SOS are combined to calculate the stiff- Participants were men from the Geelong Osteoporosis ness index (SI) [10, 13]. BUA and SOS measured at the heel Study, a population-based cohort study situated in the have been reported to have weak correlations with DXA- Barwon Statistical Division, a geographically well-defined derived heel BMD [14] and femoral neck BMD [13]. The region in south-eastern Australia [22].The male arm of the QUS parameters have been associated with fracture risk, Geelong Osteoporosis Study commenced in 2001 with re- independently of BMD [15, 16]. cruitment of 1540 men aged 20 to 92 years. Participants are Recently, impact micro-indentation (IMI), using the reassessed every few years and data for this cross-sectional OsteoProbe, has been developed to measure bone material analysis were generated from the first 501 men who were strength index (BMSi), a property of cortical bone material measured in the current follow-up phase (ages 33-96 years), strength [17]. BMSi is defined as 100 times the ratio of the which commenced in 2016. The study was approved by the indentation distance from the impact to a calibration ma- Human Research Ethics Committee at Barwon Health. All terial, poly methyl methacrylate, divided by the indenta- participants provided written informed consent. tion distance from the impact into the bone. As the probe indents the bone, microfractures are induced. The more easily the bone is fractured, the deeper the probe indents Measurements and the lower the BMSi. IMI using the OsteoProbe RUO (Active Life Technologies, Elements like microporosity, collagen and noncollagen Santa Barbara, CA, USA), was conducted to measure BMSi protein properties, degree of mineralization, water con- on the anterior surface of the mid-tibia [23]. The indenta- tent, or tissue homogeneity, among others, contribute to tion site was located by measuring the midpoint from the the mechanical properties of the bone tissue and will be medial border of the tibial plateau to the distal edge of the reflected in the BMSi. Some of these properties of bone are medial malleolus. Following disinfection of the area and ad- more likely to be captured by QUS rather than by bone ministration of local anesthesia, the OsteoProbe tip was in- densitometry. Thus, we hypothesized that by virtue of such serted through the skin and periosteum until reaching the shared properties, BMSi, and QUS would be positively surface of the bone at the anterior face of the mid-tibia. The Journal of the Endocrine Society, 2021, Vol. 5, No. 4 3 right leg was measured, except in cases where some local and estimated glomerular filtration rate (eGFR) calcu- contraindication was present, in which case the left leg was lated. Diabetes was classified as fasting plasma glucose measured. Malgo et al. reported no difference in mean BMSi ≥ 7.0 mmol/L(126 mg/dL) and/or a self-report of dia- between the dominant and nondominant legs [24]. betes and/or use of antihyperglycemic agents. Type 2 dia- At least 11 indentations were performed for each par- betes mellitus (T2DM) was determined by examination ticipant, of which the first measurement was systematic- of medical records. Participants were classified as having ally disregarded followed by 10 valid test indentations. chronic kidney disease (CKD) if they had eGFR <60 mL/ The first measurement was disregarded to ensure sufficient min/1.73 m2, as previously described [27, 28] penetration of the probe tip through the periosteum. Two trained operators conducted the IMI measurements. The procedure was conducted according to internationally Statistical analysis recognized recommendations for using the OsteoProbe The distribution of continuous data was visually as- [23]. We have previously reported that it is feasible to use sessed for normality using histograms. Categorical the OsteoProbe in this research setting and that partici- data were considered as binary variables. Associations pants tolerate IMI measurements well [25]. between BMSi values and QUS and DXA parameters BUA (dB/MHz), SOS (m/sec), and SI (%) were as- were tested using Pearson’s correlation. Multiple linear sessed for the left heel using a Lunar Achilles Insight regression models were used to identify whether dif- ultrasonometer (GE Lunar, Madison, WI, USA). Areal ferences in BMSi were independent of other potential BMD (g/cm2) was measured at the total hip, femoral neck, confounders. The models were tested for interaction Ward’s triangle, trochanter, lumbar spine (posterior–an- terms. Age and BMI were classified as binary variables terior projection, L2-L4), whole body, ultradistal (UD) (age: <60 and ≥60 years; BMI: <30 and ≥30 kg/m2) to test forearm, and mid-third of the forearm using DXA (GE for interaction terms. Lunar, ProdigyPro, Madison, WI, USA). Trabecular bone Statistical analyses were performed using Minitab V.17 score (TBS) was determined from lumbar spine scans using (State College, Pennsylvania, USA). TBS iNsight software (Version 2.2). Quality control was maintained through daily measurements of a Lunar DXA phantom. Height and weight were measured to the nearest Results 0.1 cm and 0.1 kg, respectively, and body mass index (BMI; Of 510 participants in the current follow-up, 377 underwent kg/m2) was calculated. All clinical measures were per- IMI testing. Reasons for nonmeasurement in 153 men were formed by trained personnel. needle phobia (n = 20), existing skin infections (n = 41), excessive soft tissues around the mid-tibial region (n = 82), Questionnaire data discomfort (pressure, not pain) after the first indentation (n = 5), inability to provide informed consent (n = 2), and All participants completed comprehensive questionnaires 2 participants did not provide any reasons for declining. detailing medical history, medication use, and lifestyle Compared with participants, nonparticipants were older behaviors. A parental fracture referred to at least 1 ma- (mean ± SD, 70.3 ± 15.9 vs 64.2 ± 11.9 years, P < .001) ternal or paternal hip fracture. A participant’s prior frac- and had greater mean BMI (30.2 ± 5.4 vs 27.0 ± 3.2 kg/m2, ture was defined as any low-trauma fracture equivalent P < .001). to a fall from a standing height or less, excluding frac- tures of the toe, skull, finger, and face, occurring during adulthood (age ≥20 years). Fractures were radiologic- Associations between BMSi, anthropometrics, ally verified [26]. Secondary osteoporosis included cur- and TBS rent use of oral glucocorticoids (n = 3), anticonvulsants (n = 12), selective serotonin reuptake inhibitors (n = 12), Participant characteristics are presented in Table 1. BMSi androgen deprivation therapy, and history of hyper- was negatively correlated with age (r = –0.171, P = .001), parathyroidism (n = 4), rheumatoid arthritis (n = 5), or weight (r = –0.100, P = .052), and BMI (r = –0.187, gastrointestinal disease. P = .001), and positively correlated with height (r = +0.109, P = .034). A positive correlation was ob- served between BMSi and TBS (r = 0.200, P < .001). TBS Diabetes and vitamin D status was positively correlated with BUA (r = 0.370, P < .001), Blood samples were collected after an overnight fast and SOS (r = 0.288, P < .001), and SI (r = 0.345, P < .001). sera analyzed for serum 25-hydroxyvitamin D (25OHD) 4 Journal of the Endocrine Society, 2021, Vol. 5, No. 4 These associations were sustained after adjusting for Table 1. Participant characteristics (n = 377) other factors. Mean (± SD) Age (years) 62.7 ± 13.8 Associations between BMSi, anthropometrics, Weight (kg) 81.5 ± 11.1 QUS, and BMD parameters Height (cm) 174.2 ± 6.9 Body mass index (kg/m2) 26.8 ± 3.2 There was evidence to suggest a positive correlation be- BMSi 82.5 ± 6.8 tween BMSi and BUA (r = +0.108, P = .037), SI (r = +0.101, QUS P = .051), and SOS (r = +0.075, P = .144) (Fig. 1). These BUA (dB/MHz) 116.2 ± 13.9 associations were sustained after adjusting for potential SOS (m/sec) 1572.7 ± 40.5 confounders, including BMI, prior fracture, parental frac- SI (%) 97.2 ± 18.7 ture, alcohol consumption, secondary osteoporosis, CKD, BMD (g/cm2) and T2DM (Table 2). After age adjustment, this association Spine 1.314 ± 0.206 Femoral neck 0.958 ± 0.126 was attenuated. No interactions were identified. Ward’s triangle 0.748 ± 0.142 No correlations were detected between BMSi and BMD Trochanter 0.889 ± 0.137 at any skeletal site: spine (r = –0.027, P = .201), total Total femur 1.040 ± 0.139 femur (r = +0.006, P = .906), femoral neck (r = +0.012, UD forearm 0.511 ± 0.079 P = .822), Ward’s triangle (r = +0.036, P = .491), trochanter Mid-forearm 0.983 ± 0.099 (r = –0.012; P = .821), UD forearm (r = +0.079, P = .134), Whole body 1.248 ± 0.103 and mid-forearm (r = +0.068, P = .197).    Serum 25OHD (nmol/L) 63.867 ± 18.64    Prior fracture, n (%)a 41 (10.88)    Parental fracture, n (%) 42 (11.14) Discussion Alcohol consumption, n (%)b 63 (16.71)    Secondary osteoporosis, n (%)c 45 (11.94) Our data suggest that a higher BMSi is likely associated    T2DM, n (%) 45 (11.94) with higher QUS measures. This association was sustained    eGFR <60 mL/mm/1.73 m2, n (%)d 52 (13.79) after adjusting for most potential confounders but not in- dependent of age. We also observed positive relationships Abbreviations: 25OHD, 25-hydroxyvitamin D; QUS, quantitative ultrasound; BUA, broadband ultrasound attenuation; SOS, speed of sound; SI, stiffness between BMSi and TBS, and TBS and QUS parameters, in- index; BMD, bone mineral density; UD forearm, ultradistal forearm; T2DM, dependent of other factors. We found no evidence of an type 2 diabetes mellitus. association between BMSi and BMD. a Fractures were 5 vertebra, 2 hip, 2 foot, 3 elbow, 4 ankle, 5 humerus, 8 tibia, and 12 rib. To our knowledge, no previous studies have reported b Consumes 3 or more units of alcohol daily. how BMSi varies with parameters of QUS. Several studies c Current use of oral glucocorticoids, anticonvulsants, selective serotonin reup- have detected lower QUS values for people with fragility take inhibitors, androgen deprivation therapy, and presence of hyperparathy- fractures [29, 30, 31]. McCloskey et al. reported a relation- roidism, rheumatoid arthritis, or gastrointestinal diseases. d Chronic kidney disease (CKD) defined as estimated glomerular filtration rate ship between low heel QUS values and increased fracture (eGFR) <60 mL/min/1.73 m2. risk, that was independent of age [29]. While some studies have shown a correlation between IMI is a technique designed to determine bone material BMD and QUS measures [13, 14], others have reported properties, at a tissue level. Bone remodeling at the basic discordant results [30]. QUS and bone densitometry cap- multicellular units influences the material properties of ture different properties of bone. While the DXA measures bone by replacing old mineralized bone with new matrix, BMD by analyzing both cortical and trabecular bone, it increasing the heterogeneity of the skeleton, and increasing is limited in its ability to detect bone microarchitecture its resistance to the propagation of microdamage that ul- [32]. QUS parameters are related to properties of bone that timately leads to fracture. Additionally, the portability are influenced by the proportion of cortical to trabecular and absence of ionizing radiation of IMI and QUS tech- bone, trabecular orientation, and composition of organic niques make them a practicable alternative in clinical, re- and inorganic components [31] and thus reflect bone quan- search settings, and in certain populations, including those tity and bone quality (microarchitecture and strength) in rural and remote areas where access to densitometry [33]. Our finding that a higher BMSi is associated with a may be limited [34]. Bridges et al. [35] validated the use of higher TBS suggests that although TBS primarily reflects the OsteoProbe in measuring IMI. However, as with other trabecular microarchitecture, it may also be able to capture technologies, there are limitations. Some of the limitations differences in cortical bone. of IMI include the recommendation of 2 trained oper- ators and contraindications for the procedure such as local Journal of the Endocrine Society, 2021, Vol. 5, No. 4 5 Figure 1. Associations between BMSi and (A) BUA (dB/MHz); (B) SOS (m/sec) and (C) SI (%), r- and P values were calculated using Pearson correlation. oedema, severe obesity, local skin infection, and dermato- density increases with age [35], it seems plausible that the logical lesions in the area of measurement. Furthermore, BMSi should be negatively correlated with age [40]. there is a dearth of data confirming its potency in predicting BMSi was negatively correlated with weight and BMI, fractures. and positively correlated with height. The association be- Our finding that an association between BMSi and tween height and risk of fracture has been explored in BMD was not detected corroborates reports from some several studies, but the evidence is limited and inconclu- other studies. Malgo et al. [36] and Duarte Sosa et al. sive. Compston et al. [41] reported a positive association [37] reported no correlations between BMSi and BMD between height and vertebral fractures, but not wrist or in a study involving 90 patients (aged between 40.4 and hip fracture, while an inverse relationship was indicated 85.5 years) with low bone mass with or without fragility between height and clavicular and upper arm/shoulder fracture and in 66 women with osteoporotic fracture and fractures. Moreover, a decreased fracture risk in most 66 age- and sex-matched controls without fracture, re- sites has been described in men with obesity [42]. At this spectively. However, Rudäng et al. [18] observed a positive point, we have no clear explanation for the correlations association between BMSi and BMD of the total hip, fem- between BMSi and the anthropometric parameters in this oral neck, spine, and mid-third of the nondominant radius. population. This lack of consistency in in the literature may reflect life- Our study has several strengths and limitations. To the style and genetic differences between study populations or best of our knowledge, this is the first study to explore the biases resulting from study designs and participant selec- relationship between BMSi and QUS parameters and BMD tion. Our study involved unselected men drawn from the at the Ward’s triangle, trochanter, and UD forearm. Unlike general population, and with a wider age range and lower most of the previous studies, this study is population based mean age than the population examined by Rudäng et al. and unselected on the basis of disease status. However, we Our reported age-related decline in BMSi is similar to investigated men only and note that the sample was mainly the study by Malgo et al. [36] However, Duarte Sosa et al. Caucasian (~98%), and thus acknowledge that the obser- [37] observed no association between BMSi and age. Given vations may not be generalizable to women or other popu- that the strength of bone is inversely associated with density lations. Moreover, IMI, QUS, and DXA were measured at of microcracks in bone tissue [38, 39], and microcracks different parts of the skeleton and although the associations between BMSi and QUS parameters were independent of Table 2. Results for linear regression models with BMSi as the dependent variable and the QUS parameter (BUA, SOS, SI) as the independent variable, adjusting for BMI and 6 age Model BUA SOS SI 1 Variable β SE coefficient P value β SE coefficient P value β SE coefficient P value QUS 0.05 0.03 .037 0.01 0.01 .144 0.04 0.02 .051 Constant 76.43 2.92 <.001 62.70 13.50 <.001 78.98 1.84 <.001 2 QUS 0.06 0.02 .012 0.01 0.01 .093 0.04 0.02 .024 BMI –0.42 0.11 <.001 –0.40 0.11 <.001 –0.41 0.11 <.001 Constant 86.59 3.85 <.001 70.90 13.50 <.001 89.53 3.28 <.001 3 QUS 0.04 0.03 .167 0.01 0.01 .408 0.23 0.02 .225 Age –0.08 0.03 .003 –0.08 0.03 .002 –0.08 0.03 .003 Constant 83.16 3.68 <.001 76.20 14.10 <.001 85.05 2.74 <.001 4 QUS 0.05 0.02 .043 0.01 0.01 .203 0.03 0.02 .069 Previous fracture –1.94 1.11 .082 –1.87 1.12 .096 –1.86 1.11 .095 Constant 76.84 2.92 <.001 65.40 13.60 <.001 79.42 1.86 <.001 5 QUS 0.05 0.03 .046 0.01 0.01 .161 0.03 0.02 .06 Parental fracture –1.06 1.11 .338 –1.17 1.11 .292 –1.11 1.10 .316 Constant 76.79 2.95 <.001 63.6 13.6 <.001 79.22 1.86 <.001 6 QUS 0.05 0.03 .042 0.01 0.01 .145 0.04 0.02 .054 Alcohol consumption –0.64 0.97 .511 –0.77 0.97 .428 –0.71 0.97 .465 Constant 76.66 2.95 <.001 62.8 13.5 <.001 79.13 1.85 <.001 7 QUS 0.05 0.03 .04 0.02 0.01 .146 0.04 0.02 .053 Secondary osteoporosis –0.15 1.11 .891 –0.26 1.11 .812 –0.22 1.10 .842 Constant 76.47 2.94 <.001 62.8 13.6 <.001 79.01 1.85 <.001 8 QUS 0.06 0.03 .044 0.02 0.01 .065 0.04 0.02 .034 T2DM –2.09 1.08 .054 –2.27 1.07 .035 –2.14 1.07 .047 Constant 76.06 3.28 <.001 55.9 14.5 <.001 78.44 2.02 <.001 9 QUS 0.05 0.03 .052 0.01 0.01 .244 0.03 0.02 .087 eGFR –0.67 1.01 .505 –0.82 1.01 .420 –0.73 1.01 .468 Constant 76.49 3.16 <.001 66.1 14.2 <.001 79.28 1.98 <.001 10 QUS 0.05 0.002 <.001 0.01 0.00 <.001 0.04 0.01 <.001 Serum 25OHD 0.00 0.00 .996 0.00 0.00 .997 0.00 0.00 .996 Constant 76.06 0.27 <.001 64.62 1.14 <.001 78.97 0.19 <.001 1, unadjusted; 2, BMI adjusted; 3, age adjusted; 4, previous fracture; 5, parental fracture; 6, alcohol consumption; 7, secondary osteoporosis; 8, type 2 diabetes mellitus; 9, chronic kidney disease; 10, serum Vitamin D. Abbreviations: 25OHD, 25-hydroxyvitamin D; BMI, body mass index; eGFR, estimated glomerular filtration rate; QUS, quantitative ultrasound. Journal of the Endocrine Society, 2021, Vol. 5, No. 4 Journal of the Endocrine Society, 2021, Vol. 5, No. 4 7 BMI, we were not able to explore this across the full range References of BMI due to exclusions involving excessive soft tissue at   1. Pasco JA, Sanders KM, Hoekstra FM, Henry MJ, Nicholson GC, the measurement site. Kotowicz MA. The human cost of fracture. Osteoporos Int. We conclude that in this population-based sample of 2005;16(12):2046-2052. men, there was a small positive association between BMSi  2. Bliuc D, Nguyen ND, Nguyen TV, Eisman JA, Center JR. and measures of calcaneal QUS, which supports the hy- Compound risk of high mortality following osteoporotic frac- ture and refracture in elderly women and men. J Bone Miner pothesis that BMSi and QUS are capturing common age- Res. 2013;28(11):2317-2324. dependent properties of bone. The results of this study  3. Pande I, Scott DL, O’Neill TW, Pritchard C, Woolf AD, suggest that BMSi identifies unique properties of bone that Davis MJ. Quality of life, morbidity, and mortality after low are not captured by DXA. Hence, IMI may complement trauma hip fracture in men. Ann Rheum Dis. 2006;65(1):87-92. DXA for assessing fracture risk, predominantly in med-   4. Schnell S, Friedman SM, Mendelson DA, Bingham KW, Kates SL. ical disorders where BMD only partially explains fracture The 1-year mortality of patients treated in a hip fracture pro- propensity. This will be useful in targeting treatments since gram for elders. Geriatr Orthop Surg Rehabil. 2010;1(1):6-14. many patients with no or moderate deficits in BMD ex-   5. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA. perience fracture and not all patients with low BMD are 2009;302(14):1573-1579. destined to fracture. There were no associations found be-   6. Roche JJ, Wenn RT, Sahota O, Moran CG. Effect of comorbidities tween BMSi and BMD. Further studies are needed to es- and postoperative complications on mortality after hip fracture tablish the efficacy of BMSi alone, and in conjunction with in elderly people: prospective observational cohort study. BMJ. other measures of bone, for predicting fractures. 2005;331(7529):1374.   7. Bentler SE, Liu L, Obrizan M, et al. The aftermath of hip frac- ture: discharge placement, functional status change, and mor- Acknowledgments tality. Am J Epidemiol. 2009;170(10):1290-1299.   8. Felsenberg D, Boonen S. The bone quality framework: determin- Financial Support: The Geelong Osteoporosis Study was sup- ants of bone strength and their interrelationships, and implica- ported by grants from the National Health and Medical Research tions for osteoporosis management. Clin Ther. 2005;27(1):1-11. Council (NHMRC; projects 299831, 628582), Amgen-GSK OA- ANZBMS and Amgen Australia, but they played no role in the col-   9. Quiros Roldan E, Brianese N, Raffetti E, et al. Comparison be- lection or interpretation of data. tween the gold standard DXA with calcaneal quantitative ultra- Author Contributions: P.R.-M. performed the indentation meas- sound based-strategy (QUS) to detect osteoporosis in an HIV urements in the presence of another trained observer (K.L.H.-K.) infected cohort. Braz J Infect Dis. 2017;21(6):581-586. and drafted the manuscript. K.L.H.-K. assisted with taking meas- 10. Baroncelli GI. Quantitative ultrasound methods to assess bone urements. A.D.-P. assisted with training to use the OsteoProbe de- mineral status in children: technical characteristics, perform- vice and provided advice on measurement technique. M.A.K. and ance, and clinical application. Pediatr Res. 2008;63(3):220-228. J.A.P. conceived and designed the study. J.A.P. secured ethics ap- 11. Marín F, González-Macías J, Díez-Pérez A, Palma S, Delgado- proval. All authors interpreted the data, guided and reviewed the Rodríguez M. Relationship between bone quantitative ultra- manuscript. All authors read and approved the final manuscript. sound and fractures: a meta-analysis. J Bone Miner Res. 2006;21(7):1126-1135. 12. Pasco JA, Nicholson GC, Ng F, et al. Oxidative stress may be Additional Information a common mechanism linking major depression and osteopor- osis. Acta Neuropsychiatr. 2008;20(3):112-116. Correspondence: Pamela Rufus-Membere, Epi-Centre for Healthy 13. Njeh CF, Hans D, Li J, et al. Comparison of six calcaneal quan- Ageing, IMPACT Institute, School of Medicine, Deakin University titative ultrasound devices: precision and hip fracture discrim- (Barwon Health), Geelong, Australia. E-mail: pamela.r@deakin.edu. ination. Osteoporos Int. 2000;11(12):1051-1062. au. 14. Bouxsein ML, Radloff SE. Quantitative ultrasound of the calca- Disclosure Summary: P.R.-M., K.L.H.-K., M.A.K., and J.A.P. have nothing to disclose. A.D.-P. owns shares of Active Life neus reflects the mechanical properties of calcaneal trabecular Scientific, Inc., the manufacturer of the OsteoProbe. P.R.-M. is bone. J Bone Miner Res. 1997;12(5):839-846. supported by Deakin University Postgraduate Industry Research 15. Bauer DC, Glüer CC, Cauley JA, et al. Broadband ultrasound Scholarship. K.L.H.-K. is supported by an Alfred Deakin Post- attenuation predicts fractures strongly and independently of doctoral Research Fellowship. A.D.-P. owns shares of Active Life densitometry in older women. A prospective study. Study of Scientific, Inc., the manufacturer of the OsteoProbe. M.A.K. and Osteoporotic Fractures Research Group. Arch Intern Med. J.A.P. are recipients of grants from the NHMRC, and K.L.H.-K., 1997;157(6):629-634. M.A.K., and J.A.P. are recipients of grants from Amgen-GSK OA- 16. Moayyeri A, Kaptoge S, Dalzell N, et al. The effect of including ANZBMS and Amgen Australia. quantitative heel ultrasound in models for estimation of 10-year Data Availability: The datasets generated during and/or analyzed absolute risk of fracture. Bone. 2009;45(2):180-184. during the current study are not publicly available but are available 17. Randall C, Bridges D, Guerri R, et al. Applications of a new from the corresponding author on reasonable request. handheld reference point indentation instrument measuring bone material strength. J Med Device. 2013;7(4):410051-410056. 8 Journal of the Endocrine Society, 2021, Vol. 5, No. 4 18. Rudäng R, Zoulakis M, Sundh D, et al. Bone material strength ultrasound of the calcaneus in osteoporosis. Acta Reumatol is associated with areal BMD but not with prevalent fractures Port. 2011;36(4):327-335. in older women. Osteoporos Int. 2016;27(4):1585-1592. 31. Glüer CC, Wu CY, Jergas M, Goldstein SA, Genant HK. Three 19. Diez-Perez A, Güerri R, Nogues X, et al. Microindentation for quantitative ultrasound parameters reflect bone structure. in vivo measurement of bone tissue mechanical properties in Calcif Tissue Int. 1994;55(1):46-52. humans. J Bone Miner Res. 2010;25(8):1877-1885. 32. Schuit SC, Van der Klift M, Weel AE, et al. Fracture incidence 20. Sosa DD, Eriksen EF. Reduced bone material strength is asso- and association with bone mineral density in elderly men and ciated with increased risk and severity of osteoporotic frac- women: the Rotterdam Study. Bone. 2004;34(1):195-202. tures. An impact microindentation study. Calcif Tissue Int. 33. Chin KY, Ima-Nirwana S. Calcaneal quantitative ultrasound as 2017;101(1):34-42. a determinant of bone health status: what properties of bone 21. Sundh D, Rudäng R, Zoulakis M, Nilsson AG, Darelid A, does it reflect? Int J Med Sci. 2013;10(12):1778-1783. Lorentzon M. A high amount of local adipose tissue is associ- 34. Tucker KN, Schultz CG, Chatterton BE. Mobile bone densitom- ated with high cortical porosity and low bone material strength etry service in rural South Australia. ANZ Nuclear Medicine. in older women. J Bone Miner Res. 2016;31(4):749-757. 1997;28(3):41. 22. Pasco JA, Nicholson GC, Kotowicz MA. Cohort profile: Geelong 35. Bridges D, Randall C, Hansma PK. A new device for performing osteoporosis study. Int J Epidemiol. 2012;41(6):1565-1575. reference point indentation without a reference probe. Rev Sci 23. Diez-Perez A, Bouxsein ML, Eriksen EF, et al. Technical note: Instrum. 2012;83(4):044301. recommendations for a standard procedure to assess cortical 36. Malgo F, Hamdy NA, Papapoulos SE, Appelman-Dijkstra bone at the tissue-level in vivo using impact microindentation. NM. Bone material strength as measured by microindentation Bone Rep. 2016;5:181-185. in vivo is decreased in patients with fragility fractures inde- 24. Malgo F, Hamdy NT, Papapoulous SE, Appelman-Dijkstra. pendently of bone mineral density. J Clin Endocrinol Metab. Impact Microindentation: Consistency of serial measurements 2015;100(5):2039-2045. and alterations in patients with Paget’s Disease of the Tibia. J 37. Duarte Sosa D, Vilaplana L, Güerri R, et al. Are the high Bone Miner Res. 2017;32(12):2375-2380. hip fracture rates among Norwegian women explained 25. Rufus-Membere P, Holloway-Kew KL, Diez-Perez A, by impaired bone material properties? J Bone Miner Res. Kotowicz MA, Pasco JA. Feasibility and tolerability of bone 2015;30(10):1784-1789. impact microindentation testing: a cross-sectional, population- 38. Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, based study in Australia. BMJ Open. 2018;8(12):e023959. Turner CH. Bone microdamage and skeletal fragility 26. Pasco JA, Henry MJ, Gaudry TM, Nicholson GC, Kotowicz MA. in osteoporotic and stress fractures. J Bone Miner Res. Identification of incident fractures: the Geelong Osteoporosis 1997;12(1):6-15. Study. Aust N Z J Med. 1999;29(2):203-206. 39. Zioupos P. Accumulation of in-vivo fatigue microdamage and 27. Holloway-Kew KL, Betson A, Rufus PG, et al. Impact its relation to biomechanical properties in ageing human cor- microindentation in men with impaired fasting glucose and type tical bone. J Microsc. 2001;201(Pt 2):270-278. 2 diabetes. Bone. 2021;142:115685. 40. Schaffler MB, Choi K, Milgrom C. Aging and matrix 28. Holloway-Kew KL, Rufus-Membere P, Anderson KB, et al. microdamage accumulation in human compact bone. Bone. Bone material strength index is associated with prior fracture in 1995;17(6):521-525. men with and without moderate chronic kidney disease. Bone. 41. Compston JE, Flahive J, Hosmer DW, et al.; GLOW Investigators. 2020;133:115241. Relationship of weight, height, and body mass index with frac- 29. McCloskey EV, Kanis JA, Odén A, et al. Predictive ture risk at different sites in postmenopausal women: the Global ability of heel quantitative ultrasound for incident frac- Longitudinal study of Osteoporosis in Women (GLOW). J Bone tures: an individual-level meta-analysis. Osteoporos Int. Miner Res. 2014;29(2):487-493. 2015;26(7):1979-1987. 42. Premaor MO, Compston JE, Fina Avilés F, et al. The association 30. Flöter M, Bittar CK, Zabeu JL, Carneiro AC. Review of com- between fracture site and obesity in men: a population-based parative studies between bone densitometry and quantitative cohort study. J Bone Miner Res. 2013;28(8):1771-1777.