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Normative Data for Multisite Quantitative Ultrasound: The Canadian Multicenter Osteoporosis Study
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. -, no. -, 1e7, 2013 Ó Copyright 2013 by The International Society for Clinical Densitometry 1094-6950/-:1e7/$36.00 http://dx.doi.org/10.1016/j.jocd.2013.09.017
Original Article
Normative Data for Mulitsite Quantitative Ultrasound: The Canadian Multicenter Osteoporosis Study Wojciech P. Olszynski,*,1 Jacques P. Brown,2 Jonathan D. Adachi,3 David A. Hanley,4 George Ioannidis,3 and K. Shawn Davison5 The CaMos Research Group 1
Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Department of Medicine, Laval University, Quebec City, Quebec, Canada; 3Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 4Department of Medicine, University of Calgary, Calgary, Alberta, Canada; and 5Department of Graduate Studies, University of Victoria, Victoria, British Columbia, Canada
Abstract Multisite quantitative ultrasound (mQUS) machines are attractive tools for assessing fragility fracture risk as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS, in m/s) measures from a large sample of randomly selected community-based individuals. mQUS (BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S) measurements were obtained and assessed at the distal radius, tibia, and phalanx. All analyses were made separately for men and women and for each anatomical site. Scatterplots (SOS vs age) identified 30e39 yr of age as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated (30e96 yr of age; 2948 women and 1176 men) and, thus, was used as the ‘‘reference’’ population. For cross-sectional comparison of trends over aging, a number of age groupings were created: 30e39, 40e49, 50e59, 60e69, 70e79, and 80þ yr. In general, there were decreases in SOS over increasing age groupings. The normative data generated can be used to compare a given patient’s mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score. Key Words: Fracture; normative data; quantitative ultrasound. Although DXA-assessed BMD is of unquestionable value, machine availability or access can be limited in some regions and the release of low-dose radiation is a concern for some. Quantitative ultrasound (QUS) devices are attractive as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. QUS has been used to estimate the mechanical integrity, or strength, of bone with the intent of being able to identify those individuals who are at an increased risk for fracture. The hope is that the fracture risk estimate provided from QUS can be used as a surrogate for BMD or that information gleaned through QUS can be input into one of the new 10-yr fracture risk assessments to provide a better estimate of future fracture risk. For QUS to be able to assess a person’s risk for fragility fracture, 2 milestones must be met: there must be a significant
Introduction In the recent past, the assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) has served as an almost solitary pillar for the diagnosis of osteoporosis (1). However, with the realization that the majority of women who do experience a fracture have a BMD above that which would be considered osteoporotic (2,3), there has been a movement toward incorporating the valuable information provided by BMD with that of commonly assessed clinical risk factors to better estimate an individual’s 10-yr fracture risk (4,5). Received 06/12/13; Revised 09/13/13; Accepted 09/18/13. *Address correspondence to: Wojciech P. Olszynski, MD, PhD, 103-39 23rd Street East, Saskatoon, Saskatchewan S7K 0H6, Canada. E-mail: [email protected]
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relationship proven between the QUS measure of bone strength and future fracture risk, and there must be normative values available to compare a given individual’s current estimate of bone strength to those who would be deemed at low risk for fracture and those at high risk for fracture. A recent publication that assessed the 5-yr prospective utility of a multisite quantitative ultrasound (mQUS; BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S, Israel) concluded that mQUS was a significant predictor of clinical future risk in women, independent of BMD (6). Comparison of individuals to population norms allows the identification of those who may require intervention to minimize fracture risk. To establish a normative database for stratifying fracture risk, a reference population of sufficient sample size must be identified that has both the highest measure of bone strength and the lowest fragility fracture risk. Typically, these populations are selected to be around the age of attainment of peak bone mass during early adulthood (20e40 yr of age) (7) as this approximately coincides with the time of lowest fracture risk. Because osteoporotic fracture incidence increases with aging, the mQUS measures of bone strength should ideally decrease in a similar pattern to that of increasing fracture risk. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS) measures from a large sample of randomly selected communitybased individuals from the Canadian Multicentre Osteoporosis Study (CaMos). A secondary objective of this investigation was to assess whether mQUS SOS measures decreased in a pattern inverse to that of major osteoporotic fracture risks.
(clinical measures and questionnaires) occurred at baseline, after 3 yr (only for participants aged 40e60 yr at baseline), after 5 yr, and after 10 yr. In years that participants did not come to a study center, a self-administered fracture questionnaire was mailed out to identify incident fractures. At the 5-yr follow-up investigation, a number of the clinical sites expanded their protocol by assessing participants with an mQUS (at the 5-yr follow-up Sunlight Omnisense MultiSite Quantitative Ultrasound 7000 S and now BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S, Petah Tikva, Israel), in addition to the normal CaMos assessments (Calgary, Saskatoon, Hamilton, Quebec City, Halifax, St John’s). Because all participants were at least 25 yr of age at baseline, all the participants in this analysis were at least 30 yr of age (baseline plus and additional 5 yr).
Materials and Methods
mQUS Assessments
Participants This investigation used a subset of participants from the CaMos cohort. The methods and objectives of the CaMos study have been previously published (8). Briefly, CaMos is an ongoing, prospective cohort study involving 9423 randomly selected community-dwelling women (n 5 6539) and men (n 5 2884) aged 25 yr and older at baseline and who lived within 50 km of 9 major Canadian cities (St John’s, Newfoundland and Labrador; Halifax, Nova Scotia; Quebec City, Quebec; Toronto, Hamilton and Kingston, Ontario; Saskatoon, Saskatchewan; Calgary, Alberta; and Vancouver, British Columbia). Households were randomly selected from a list of residential phone numbers, and participants were randomly selected from eligible household members using standard protocol. Of those selected, 42% agreed to participate and had a baseline interview. All researches carried out in the CaMos have been approved by local university ethics boards in each of the cities the study had centers in and have satisfied the criteria of the World Medical Association Declaration of HelsinkidEthical Principles for Medical Research Involving Human Subjects. All participants provided informed consent. Data collection at baseline and each follow-up visit included an extensive, standardized interviewer-administered questionnaire and a clinical assessment. Full assessments
Table 1 Sample Sizes for Each Age Grouping by Gender and Site Women
Men
Age grouping
DR
TIB
PX
DR
TIB
PX
30e39 yr 40e49 yr 50e59 yr 60e69 yr 70e79 yr 80þ yr
79 104 509 723 856 250
80 102 502 731 857 242
81 115 568 794 932 276
67 86 246 272 316 92
68 88 260 278 311 91
69 89 266 278 312 96
Abbr: DR, distal radius; PX, phalanx; TIB, distal tibia.
mQUS measurements were obtained and assessed at the distal radius (DR), tibia (TIB), and phalanx (PX) on the nondominant side of the participant and were recorded as the SOS in meters per second. The mQUS was equipped with 2 handheld probes specifically designed for measurements of axial SOS along the surfaces of bone: 1 probe was suitable for measurements at the DRs and TIB, whereas the other assessed the PX. Details regarding the standard manufacturer-suggested techniques involved with bone measurement with the mQUS have been detailed previously, and these standards were employed in this investigation (9e13). Briefly, the mQUS emits and detects acoustic waves at a frequency of 1.25 MHz. The SOS measure acquired is the time taken for the sound wave to travel from the time of sound wave emission to its detection. Quality control measurements were performed daily following procedures recommended by the manufacturer. Intraobserver in vivo short-term precision has been reported as 0.76% for the radius, 0.47% for the TIB, and 1.54% for the phalanges and interobserver precision from 0.77% to 2.39% (14). Measures were taken by 1 technologist at each of the 6 study centers.
Analyses For the normative data creation, a number of calculations and analyses were conducted. All calculations and analyses
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A
B 4500
Distal radius speed of sound (m/s)
Distal radius speed of sound (m/s)
4600
4400
4200
4000
3800
3600
3400
20
30
40
50
60
70
80
90
4400 4300 4200 4100 4000 3900 3800 3700 3600 20
100
30
40
50
Age (years)
C
Tibia speed of sound (m/s)
Tibia speed of sound (m/s)
90
100
80
90
100
80
90
100
4300
4100 4000 3900 3800 3700 3600 3500 3400 30
40
50
60
70
80
90
4200 4100 4000 3900 3800 3700 3600 3500 20
100
30
40
50
E
60
70
Age (years)
Age (years)
F 4600
Phalanx speed of sound (m/s)
4600
Phalanx speed of sound (m/s)
80
4400
4200
4400 4200 4000 3800 3600 3400 3200 3000 20
70
D
4300
3300 20
60
Age (years)
30
40
50
60
70
80
90
100
4400 4200 4000 3800 3600 3400 3200 20
30
40
Age (years)
50
60
70
Age (years)
Fig. 1. (A) Scatterplot of women’s distal radius speed of sound vs age. (B) Scatterplot of men’s distal radius speed of sound vs age. (C) Scatterplot of women’s tibia speed of sound vs age. (D) Scatterplot of men’s tibia speed of sound vs age. (E) Scatterplot of women’s phalanx speed of sound vs age. (F) Scatterplot of men’s phalanx speed of sound vs age. were made separately for men and women and for each anatomical site (DR, TIB, and PX). Scatterplots of age vs SOS were generated to first examine if SOS did in fact decrease over age and to then estimate the age span at which there were the highest SOS measures to use as the reference value for the population. A Lowess regression curve was fitted to the data to allow for the best possible fit for trend. The scatterplots identified the ages of 30e39 yr as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated and, thus, was used as the ‘‘reference’’ population. The mean and standard deviation (SD) from both the men’s and women’s 30- to 39-yr group was used as the reference
point and assigned a T-score of 0. The means of all other groups were then reported as a T-score based on these sex-specific reference values. The calculations of individual T-scores were made with the following equation: ðIndividual SOS measure mean of sex specific SOS for 30 to 39 yr old groupÞ=SD of sex specific SOS for 30 to 39 yr old group: For cross-sectional comparison of trends over aging, a number of age groupings were created: 30e39, 40e49, 50e59, 60e69, 70e79, and 80þ yr. Basic descriptive
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Olszynski et al. Table 2 mQUS SOS Values at Various T-scores at the DR, TIB, and PX Sites by Gender
Assessment site Women DR TIB PX Men DR TIB PX
Reference popn SD
T-score 5 0 SOS m/s
T-score 5 1 SOS m/s
T-score 5 2 SOS m/s
T-score 5 3 SOS m/s
T-score 5 4 SOS m/s
111.75 162.61 192.53
4192 3877 3998
4080 3714 3805
3969 3552 3613
3857 3389 3420
3745 3227 3228
112.2 134.36 171.34
4137 3949 3958
4024 3814 3786
3913 3680 3615
3800 3546 3444
3688 3412 3273
Abbr: DR, distal radius; popn, population; PX, phalanx; SOS, speed of sound; TIB, tibia.
statistics were generated for each of the age grouping. Differences among groups for both men and women were assessed with analysis of variance, and significant differences among age groupings were determined with Tukey HSD (honestly significant difference) for unequal sample sizes (Spjotvoll/ Stoline method). Pearson product-moment correlations were conducted between each possible pair of sites, by gender, to explore the concordance between sites. The decrease in the DR SOS for both men and women over the cross-sectional age categories was compared with that increase in major osteoporotic 10-yr fracture risk from data previously published for the Canadian population (15). Because the original data for fracture estimates were not readily available, the comparison with the SOS values from this investigation were only made graphically. All analyses were completed on a Windows-based workstation with Statistica, Version 12 (Statsoft, Tulsa, OK). Statistical significance was considered to have occurred at an alpha of .05.
Results In this subset of CaMOS data, there were 2948 women and 1176 men included with a mean (SD) age of 66.5 (11.49) and 63.7 (13.04) yr, respectively and a range of 30e96 yr of age. Table 1 documents the sample size, by gender, for each age grouping. Figure 1AeC provides scatterplots of age vs SOS for each of the 3 sites. For each of the sites, the maximal SOS values were relatively stable through the age range of 30e39 yr and decreased with increasing age thereafter. As a result of these trends, the age range of 30e39 yr was used as the reference population for the development of the normative data generated in this article. Table 2 presents the SOS values for various T-score values for reference and the SD for the reference population. With the T-score of 0 and the SD of the reference population, it is possible to calculate the T-score of any given SOS value using the formula provided in the methods. Figure 2 presents the DR scatterplot vs age once more but has added the newly calculated T-scores for the women’s population.
Analysis of variance determined that there were statistically significant differences ( p ! 0.0001) among the different age groupings for all 3 skeletal sites assessed, for both genders. Figures 3 and 4 present graphs of the mean (SD) values for each age grouping for women and men, respectively. A matrix summary of the post hoc analyses denoting where statistically significant differences between age groupings occurred are presented in Table 3. In general, there were decreases in SOS over increasing age groupings. Pearson product-moment correlations demonstrated moderate, yet significant ( p ! 0.05), correlations between each possible site pairing for both women (r 5 .35e.51) and men (r 5 .27e.33). When the change in DR SOS was plotted with the increase in 10-yr fracture risk (Fig. 5), the trends showed convergence, lending support to the association of increasing fracture risk to decreasing SOS values.
Discussion The BeamMed mQUS device has been demonstrated to have the ability to prospectively stratify clinical fracture risk in women, independently from BMD (6). The next step
Fig. 2. Distal radius speed of sount scatterplot with women’s T-score ranges superimposed.
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Fig. 3. Comparison of age group mean (95% confidence interval) values for women’s distal radius, distal tibia, and phalanx sites.
Fig. 4. Comparison of age group mean (95% confidence interval) values for men’s distal radius, distal tibia, and phalanx sites.
in the development of the mQUS device for use as a diagnostic tool was to develop a robust normative database. This investigation used a large database of participants drawn from the general Canadian population to develop a normative scoring system for use with the BeamMed mQUS device. These data can be used to compare a given patient’s mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score. This T-score could then be used to aid in decisions about fracture risk either on its own or with the information provided from DXA and a 10-yr fracture risk assessment tool. Previous smaller investigations have assessed and reported normative mQUS SOS values for the investigated device in a North American population (11,16,17), and the values found in this investigation are largely similar to these investigations for both men and women. Drake et al (16) published North American normative mQUS SOS values for the DR, TIB, PX, and metatarsal sites from a population of 545 Canadian women aged 20 through 90 yr. The peak SOS was found to be at around 40 yr of age, similar to what was found in this investigation, although peak values in this investigation were observed as early as the youngest measures in this investigation. The maximal mean scores found were also similar to those found for the reference population in this investigation for the DR, TIB, and PX sites (4161 vs 4192, 3928 vs 3877, and 4092 vs 3998, respectively). The pattern of decline over age was very similar between both investigations as well, with losses in SOS manifesting after the age of 50 yr. Hayman et al (17) reported mean mQUS SOS values of the DR, TIB, PX, and metatarsal sites of 588 North American men (20e90 yr old). Similar to our findings, they reported that mQUS SOS began to decline in men after the age of 40 yr for the DR and PX. They also reported a relative preservation of SOS in the TIB site until very late adulthood, similar to what was observed in this study. At all 3 sites investigated, there were relative stability of the SOS measures from the ages 30e39 with gradual decreases
thereafter as the age groupings increased. The pattern of SOS loss, believed to be an index of strength, approximated the increase in 10-yr fracture risk in women and men, as was demonstrated in Fig. 5. The correlations between site pairings in this investigation were significant but only moderate in magnitude. The relative discordance between site pairing (O70% of the variance) suggests that the different sites may be affected in a manner that is not centrally controlled. At these differing sites, there may be local factors that are responsible for discordance between sites, such as differences in loading patterns. Njeh et al (11) reported similar correlations between investigated sites for women (n 5 334) assessed with the same mQUS device (r 5 .31e.56). In this investigation, the SOS values in the younger groups were higher in the women as compared with the men, but women tended to lose more SOS with aging resulting in higher SOS values in the men in later life (e.g., Fig. 5). This was the same trend that was observed when the data from the trials of Drake et al (16) and Hayman et al (17) were combined. The higher SOS values in men in later life are confirmatory of the value of mQUS as a diagnostic tool for estimating fracture risk as men have a lower fracture incidence as compared with women after the age of 50 yr. There were a few limitations in this investigation, most notably that it was a cross-sectional and that the youngest cohort may not have been young enough to capture the true peak in SOS. One limitation of QUS devices that has been often cited was the inability to assess bone at clinically important areas, such as the hip, spine, or radius. The mQUS has important clinical relevance as it incorporates a measurement of the radius, a site often fractured in those with osteoporosis. Because clinical trials of the efficacy of antifracture therapies used BMD as a inclusion criterion, it is not known whether these same therapies will have the same efficacy in a population selected by mQUS. Furthermore, mQUS has not yet
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Table 3 Matrices of Statistically Significant Differences Among Groups (Tukey HSD for Unequal Sample Sizes Using Spjotvoll/Stoline Method) Age grouping
30e39 yr
Women distal radius 30e39 yr 40e49 yr NS 50e59 yr *** 60e69 yr *** 70e79 yr *** 80þ yr *** Women distal tibia 30e39 yr 40e49 yr NS 50e59 yr NS 60e69 yr NS 70e79 yr * 80þ yr *** Women phalanx 30e39 yr 40e49 yr NS 50e59 yr * 60e69 yr *** 70e79 yr *** 80þ yr ***
40e49 yr
50e59 yr
60e69 yr
70e79 yr
80þ yr
NS
*** ***
*** *** ***
*** *** *** ***
*** *** *** *** ***
*** *** *** *** NS NS *** *** *** NS * *** *** ***
*** *** *** NS NS * *** *** * * *** *** ***
*** *** NS *** * *** *** *** *** *** *** ***
*** * *** *** ***
*** *** *** *** NS
NS *** *** *** *** ***
*** *** *** *** ***
30e39 yr
40e49 yr
Men distal radius * * NS NS * NS *** NS *** NS Men distal tibia NS NS NS NS NS NS NS NS * ** Men phalanx NS NS NS NS NS NS ** NS *** ***
50e59 yr
60e69 yr
70e79 yr
80þ yr
NS NS
* NS NS
*** NS *** NS
*** NS ** NS NS
NS *** ** NS NS NS NS NS NS NS * *** ***
NS NS NS NS NS * ** NS NS * ** ***
NS NS NS NS *
* ** NS ** NS
NS ** NS *** **
*** *** *** *** *
*
Abbr: NS, not statistically significant. *p ! 0.05; **p ! 0.01; ***p ! 0.001.
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Fig. 5. Distal radius SOS (m/s) and 10-yr major osteoporotic fracture incidence by age. SOS, speed of sound. shown that it is capable of monitoring response to treatment. This study had numerous strengths, including a randomly selected population from the general Canadian population, a very large sample size, and large span of included ages. The CaMos data set has allowed for the generation of a robust normative database. The CaMos mQUS normative data may be able to assist in the identification of those at an enhanced risk of fracture so that they may have opportunity to seek further diagnostic tests, clinical consultation, and if deemed necessary, treatment.
8. 9.
10. 11.
References 1. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. 1993 Am J Med 94:646e650. 2. Siris ES, Chen YT, Abbott TA, et al. 2004 Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108e1112. 3. Cranney A, Jamal SA, Tsang JF, et al. 2007 Low bone mineral density and fracture burden in postmenopausal women. CMAJ 177:575e580. 4. Kanis JA, McCloskey EV, Johansson H, et al. 2010 Development and use of FRAX in osteoporosis. Osteoporos Int 21(2 Suppl): S407eS413. 5. Leslie WD, Berger C, Langsetmo L, et al. 2011 Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts. Osteoporos Int 22:1873e1883. 6. Olszynski WP, Brown JP, Adachi JD, et al. 2013 Multisite quantitative ultrasound for the prediction of fractures over five years of follow-up: The Canadian Multicentre Osteoporosis Study. J Bone Miner Res 28:2027e2034. 7. Berger C, Goltzman D, Langsetmo L, et al. 2010 Peak bone mass from longitudinal data: implications for the prevalence,
12.
13. 14.
15.
16. 17.
pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 25:1948e1957. Kreiger N, Tenenhouse A, Joseph L, et al. 1999 The Canadian Multicentre Osteoporosis Study (CaMos): background, rationale, methods. Can J Aging 18:376e387. Weiss M, Ben-Shlomo AB, Hagag P, Rapoport M. 2000 Reference database for bone speed of sound measurement by a novel quantitative multi-site ultrasound device. Osteoporos Int 11: 688e696. Njeh CF, Hans D, Wu C, et al. 1999 An in vitro investigation of the dependence on sample thickness of the speed of sound along the specimen. Med Eng Phys 21:651e659. Njeh CF, Saeed I, Grigorian M, et al. 2001 Assessment of bone status using speed of sound at multiple anatomical sites. Ultrasound Med Biol 27:1337e1345. Knapp KM, Blake GM, Spector TD, Fogelman I. 2001 Multisite quantitative ultrasound: precision, age- and menopause-related changes, fracture discrimination, and T-score equivalence with dual-energy X-ray absorptiometry. Osteoporos Int 12:456e464. Knapp KM, Blake GM, Fogelman I, et al. 2002 Multisite quantitative ultrasound: Colles’ fracture discrimination in postmenopausal women. Osteoporos Int 13:474e479. Damilakis J, Papadokostakis G, Vrahoriti H, et al. 2003 Ultrasound velocity through the cortex of phalanges, radius, and tibia in normal and osteoporotic postmenopausal women using a new multisite quantitative ultrasound device. Invest Radiol 38:207e211. Leslie WD, Lix LM, Langsetmo L, et al. 2011 Construction of a FRAX((R)) model for the assessment of fracture probability in Canada and implications for treatment. Osteoporos Int 22: 817e827. Drake WM, McClung M, Njeh CF, et al. 2001 Multisite bone ultrasound measurement on North American female reference population. J Clin Densitom 4:239e248. Hayman SR, Drake WM, Kendler DL, et al. 2002 North American male reference population for speed of sound in bone at multiple skeletal sites. J Clin Densitom 5:63e71.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
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Original Article
Normative Data for Mulitsite Quantitative Ultrasound: The Canadian Multicenter Osteoporosis Study Wojciech P. Olszynski,*,1 Jacques P. Brown,2 Jonathan D. Adachi,3 David A. Hanley,4 George Ioannidis,3 and K. Shawn Davison5 The CaMos Research Group 1
Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Department of Medicine, Laval University, Quebec City, Quebec, Canada; 3Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 4Department of Medicine, University of Calgary, Calgary, Alberta, Canada; and 5Department of Graduate Studies, University of Victoria, Victoria, British Columbia, Canada
Abstract Multisite quantitative ultrasound (mQUS) machines are attractive tools for assessing fragility fracture risk as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS, in m/s) measures from a large sample of randomly selected community-based individuals. mQUS (BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S) measurements were obtained and assessed at the distal radius, tibia, and phalanx. All analyses were made separately for men and women and for each anatomical site. Scatterplots (SOS vs age) identified 30e39 yr of age as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated (30e96 yr of age; 2948 women and 1176 men) and, thus, was used as the ‘‘reference’’ population. For cross-sectional comparison of trends over aging, a number of age groupings were created: 30e39, 40e49, 50e59, 60e69, 70e79, and 80þ yr. In general, there were decreases in SOS over increasing age groupings. The normative data generated can be used to compare a given patient’s mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score. Key Words: Fracture; normative data; quantitative ultrasound. Although DXA-assessed BMD is of unquestionable value, machine availability or access can be limited in some regions and the release of low-dose radiation is a concern for some. Quantitative ultrasound (QUS) devices are attractive as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. QUS has been used to estimate the mechanical integrity, or strength, of bone with the intent of being able to identify those individuals who are at an increased risk for fracture. The hope is that the fracture risk estimate provided from QUS can be used as a surrogate for BMD or that information gleaned through QUS can be input into one of the new 10-yr fracture risk assessments to provide a better estimate of future fracture risk. For QUS to be able to assess a person’s risk for fragility fracture, 2 milestones must be met: there must be a significant
Introduction In the recent past, the assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) has served as an almost solitary pillar for the diagnosis of osteoporosis (1). However, with the realization that the majority of women who do experience a fracture have a BMD above that which would be considered osteoporotic (2,3), there has been a movement toward incorporating the valuable information provided by BMD with that of commonly assessed clinical risk factors to better estimate an individual’s 10-yr fracture risk (4,5). Received 06/12/13; Revised 09/13/13; Accepted 09/18/13. *Address correspondence to: Wojciech P. Olszynski, MD, PhD, 103-39 23rd Street East, Saskatoon, Saskatchewan S7K 0H6, Canada. E-mail: [email protected]
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relationship proven between the QUS measure of bone strength and future fracture risk, and there must be normative values available to compare a given individual’s current estimate of bone strength to those who would be deemed at low risk for fracture and those at high risk for fracture. A recent publication that assessed the 5-yr prospective utility of a multisite quantitative ultrasound (mQUS; BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S, Israel) concluded that mQUS was a significant predictor of clinical future risk in women, independent of BMD (6). Comparison of individuals to population norms allows the identification of those who may require intervention to minimize fracture risk. To establish a normative database for stratifying fracture risk, a reference population of sufficient sample size must be identified that has both the highest measure of bone strength and the lowest fragility fracture risk. Typically, these populations are selected to be around the age of attainment of peak bone mass during early adulthood (20e40 yr of age) (7) as this approximately coincides with the time of lowest fracture risk. Because osteoporotic fracture incidence increases with aging, the mQUS measures of bone strength should ideally decrease in a similar pattern to that of increasing fracture risk. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS) measures from a large sample of randomly selected communitybased individuals from the Canadian Multicentre Osteoporosis Study (CaMos). A secondary objective of this investigation was to assess whether mQUS SOS measures decreased in a pattern inverse to that of major osteoporotic fracture risks.
(clinical measures and questionnaires) occurred at baseline, after 3 yr (only for participants aged 40e60 yr at baseline), after 5 yr, and after 10 yr. In years that participants did not come to a study center, a self-administered fracture questionnaire was mailed out to identify incident fractures. At the 5-yr follow-up investigation, a number of the clinical sites expanded their protocol by assessing participants with an mQUS (at the 5-yr follow-up Sunlight Omnisense MultiSite Quantitative Ultrasound 7000 S and now BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S, Petah Tikva, Israel), in addition to the normal CaMos assessments (Calgary, Saskatoon, Hamilton, Quebec City, Halifax, St John’s). Because all participants were at least 25 yr of age at baseline, all the participants in this analysis were at least 30 yr of age (baseline plus and additional 5 yr).
Materials and Methods
mQUS Assessments
Participants This investigation used a subset of participants from the CaMos cohort. The methods and objectives of the CaMos study have been previously published (8). Briefly, CaMos is an ongoing, prospective cohort study involving 9423 randomly selected community-dwelling women (n 5 6539) and men (n 5 2884) aged 25 yr and older at baseline and who lived within 50 km of 9 major Canadian cities (St John’s, Newfoundland and Labrador; Halifax, Nova Scotia; Quebec City, Quebec; Toronto, Hamilton and Kingston, Ontario; Saskatoon, Saskatchewan; Calgary, Alberta; and Vancouver, British Columbia). Households were randomly selected from a list of residential phone numbers, and participants were randomly selected from eligible household members using standard protocol. Of those selected, 42% agreed to participate and had a baseline interview. All researches carried out in the CaMos have been approved by local university ethics boards in each of the cities the study had centers in and have satisfied the criteria of the World Medical Association Declaration of HelsinkidEthical Principles for Medical Research Involving Human Subjects. All participants provided informed consent. Data collection at baseline and each follow-up visit included an extensive, standardized interviewer-administered questionnaire and a clinical assessment. Full assessments
Table 1 Sample Sizes for Each Age Grouping by Gender and Site Women
Men
Age grouping
DR
TIB
PX
DR
TIB
PX
30e39 yr 40e49 yr 50e59 yr 60e69 yr 70e79 yr 80þ yr
79 104 509 723 856 250
80 102 502 731 857 242
81 115 568 794 932 276
67 86 246 272 316 92
68 88 260 278 311 91
69 89 266 278 312 96
Abbr: DR, distal radius; PX, phalanx; TIB, distal tibia.
mQUS measurements were obtained and assessed at the distal radius (DR), tibia (TIB), and phalanx (PX) on the nondominant side of the participant and were recorded as the SOS in meters per second. The mQUS was equipped with 2 handheld probes specifically designed for measurements of axial SOS along the surfaces of bone: 1 probe was suitable for measurements at the DRs and TIB, whereas the other assessed the PX. Details regarding the standard manufacturer-suggested techniques involved with bone measurement with the mQUS have been detailed previously, and these standards were employed in this investigation (9e13). Briefly, the mQUS emits and detects acoustic waves at a frequency of 1.25 MHz. The SOS measure acquired is the time taken for the sound wave to travel from the time of sound wave emission to its detection. Quality control measurements were performed daily following procedures recommended by the manufacturer. Intraobserver in vivo short-term precision has been reported as 0.76% for the radius, 0.47% for the TIB, and 1.54% for the phalanges and interobserver precision from 0.77% to 2.39% (14). Measures were taken by 1 technologist at each of the 6 study centers.
Analyses For the normative data creation, a number of calculations and analyses were conducted. All calculations and analyses
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A
B 4500
Distal radius speed of sound (m/s)
Distal radius speed of sound (m/s)
4600
4400
4200
4000
3800
3600
3400
20
30
40
50
60
70
80
90
4400 4300 4200 4100 4000 3900 3800 3700 3600 20
100
30
40
50
Age (years)
C
Tibia speed of sound (m/s)
Tibia speed of sound (m/s)
90
100
80
90
100
80
90
100
4300
4100 4000 3900 3800 3700 3600 3500 3400 30
40
50
60
70
80
90
4200 4100 4000 3900 3800 3700 3600 3500 20
100
30
40
50
E
60
70
Age (years)
Age (years)
F 4600
Phalanx speed of sound (m/s)
4600
Phalanx speed of sound (m/s)
80
4400
4200
4400 4200 4000 3800 3600 3400 3200 3000 20
70
D
4300
3300 20
60
Age (years)
30
40
50
60
70
80
90
100
4400 4200 4000 3800 3600 3400 3200 20
30
40
Age (years)
50
60
70
Age (years)
Fig. 1. (A) Scatterplot of women’s distal radius speed of sound vs age. (B) Scatterplot of men’s distal radius speed of sound vs age. (C) Scatterplot of women’s tibia speed of sound vs age. (D) Scatterplot of men’s tibia speed of sound vs age. (E) Scatterplot of women’s phalanx speed of sound vs age. (F) Scatterplot of men’s phalanx speed of sound vs age. were made separately for men and women and for each anatomical site (DR, TIB, and PX). Scatterplots of age vs SOS were generated to first examine if SOS did in fact decrease over age and to then estimate the age span at which there were the highest SOS measures to use as the reference value for the population. A Lowess regression curve was fitted to the data to allow for the best possible fit for trend. The scatterplots identified the ages of 30e39 yr as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated and, thus, was used as the ‘‘reference’’ population. The mean and standard deviation (SD) from both the men’s and women’s 30- to 39-yr group was used as the reference
point and assigned a T-score of 0. The means of all other groups were then reported as a T-score based on these sex-specific reference values. The calculations of individual T-scores were made with the following equation: ðIndividual SOS measure mean of sex specific SOS for 30 to 39 yr old groupÞ=SD of sex specific SOS for 30 to 39 yr old group: For cross-sectional comparison of trends over aging, a number of age groupings were created: 30e39, 40e49, 50e59, 60e69, 70e79, and 80þ yr. Basic descriptive
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Olszynski et al. Table 2 mQUS SOS Values at Various T-scores at the DR, TIB, and PX Sites by Gender
Assessment site Women DR TIB PX Men DR TIB PX
Reference popn SD
T-score 5 0 SOS m/s
T-score 5 1 SOS m/s
T-score 5 2 SOS m/s
T-score 5 3 SOS m/s
T-score 5 4 SOS m/s
111.75 162.61 192.53
4192 3877 3998
4080 3714 3805
3969 3552 3613
3857 3389 3420
3745 3227 3228
112.2 134.36 171.34
4137 3949 3958
4024 3814 3786
3913 3680 3615
3800 3546 3444
3688 3412 3273
Abbr: DR, distal radius; popn, population; PX, phalanx; SOS, speed of sound; TIB, tibia.
statistics were generated for each of the age grouping. Differences among groups for both men and women were assessed with analysis of variance, and significant differences among age groupings were determined with Tukey HSD (honestly significant difference) for unequal sample sizes (Spjotvoll/ Stoline method). Pearson product-moment correlations were conducted between each possible pair of sites, by gender, to explore the concordance between sites. The decrease in the DR SOS for both men and women over the cross-sectional age categories was compared with that increase in major osteoporotic 10-yr fracture risk from data previously published for the Canadian population (15). Because the original data for fracture estimates were not readily available, the comparison with the SOS values from this investigation were only made graphically. All analyses were completed on a Windows-based workstation with Statistica, Version 12 (Statsoft, Tulsa, OK). Statistical significance was considered to have occurred at an alpha of .05.
Results In this subset of CaMOS data, there were 2948 women and 1176 men included with a mean (SD) age of 66.5 (11.49) and 63.7 (13.04) yr, respectively and a range of 30e96 yr of age. Table 1 documents the sample size, by gender, for each age grouping. Figure 1AeC provides scatterplots of age vs SOS for each of the 3 sites. For each of the sites, the maximal SOS values were relatively stable through the age range of 30e39 yr and decreased with increasing age thereafter. As a result of these trends, the age range of 30e39 yr was used as the reference population for the development of the normative data generated in this article. Table 2 presents the SOS values for various T-score values for reference and the SD for the reference population. With the T-score of 0 and the SD of the reference population, it is possible to calculate the T-score of any given SOS value using the formula provided in the methods. Figure 2 presents the DR scatterplot vs age once more but has added the newly calculated T-scores for the women’s population.
Analysis of variance determined that there were statistically significant differences ( p ! 0.0001) among the different age groupings for all 3 skeletal sites assessed, for both genders. Figures 3 and 4 present graphs of the mean (SD) values for each age grouping for women and men, respectively. A matrix summary of the post hoc analyses denoting where statistically significant differences between age groupings occurred are presented in Table 3. In general, there were decreases in SOS over increasing age groupings. Pearson product-moment correlations demonstrated moderate, yet significant ( p ! 0.05), correlations between each possible site pairing for both women (r 5 .35e.51) and men (r 5 .27e.33). When the change in DR SOS was plotted with the increase in 10-yr fracture risk (Fig. 5), the trends showed convergence, lending support to the association of increasing fracture risk to decreasing SOS values.
Discussion The BeamMed mQUS device has been demonstrated to have the ability to prospectively stratify clinical fracture risk in women, independently from BMD (6). The next step
Fig. 2. Distal radius speed of sount scatterplot with women’s T-score ranges superimposed.
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Fig. 3. Comparison of age group mean (95% confidence interval) values for women’s distal radius, distal tibia, and phalanx sites.
Fig. 4. Comparison of age group mean (95% confidence interval) values for men’s distal radius, distal tibia, and phalanx sites.
in the development of the mQUS device for use as a diagnostic tool was to develop a robust normative database. This investigation used a large database of participants drawn from the general Canadian population to develop a normative scoring system for use with the BeamMed mQUS device. These data can be used to compare a given patient’s mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score. This T-score could then be used to aid in decisions about fracture risk either on its own or with the information provided from DXA and a 10-yr fracture risk assessment tool. Previous smaller investigations have assessed and reported normative mQUS SOS values for the investigated device in a North American population (11,16,17), and the values found in this investigation are largely similar to these investigations for both men and women. Drake et al (16) published North American normative mQUS SOS values for the DR, TIB, PX, and metatarsal sites from a population of 545 Canadian women aged 20 through 90 yr. The peak SOS was found to be at around 40 yr of age, similar to what was found in this investigation, although peak values in this investigation were observed as early as the youngest measures in this investigation. The maximal mean scores found were also similar to those found for the reference population in this investigation for the DR, TIB, and PX sites (4161 vs 4192, 3928 vs 3877, and 4092 vs 3998, respectively). The pattern of decline over age was very similar between both investigations as well, with losses in SOS manifesting after the age of 50 yr. Hayman et al (17) reported mean mQUS SOS values of the DR, TIB, PX, and metatarsal sites of 588 North American men (20e90 yr old). Similar to our findings, they reported that mQUS SOS began to decline in men after the age of 40 yr for the DR and PX. They also reported a relative preservation of SOS in the TIB site until very late adulthood, similar to what was observed in this study. At all 3 sites investigated, there were relative stability of the SOS measures from the ages 30e39 with gradual decreases
thereafter as the age groupings increased. The pattern of SOS loss, believed to be an index of strength, approximated the increase in 10-yr fracture risk in women and men, as was demonstrated in Fig. 5. The correlations between site pairings in this investigation were significant but only moderate in magnitude. The relative discordance between site pairing (O70% of the variance) suggests that the different sites may be affected in a manner that is not centrally controlled. At these differing sites, there may be local factors that are responsible for discordance between sites, such as differences in loading patterns. Njeh et al (11) reported similar correlations between investigated sites for women (n 5 334) assessed with the same mQUS device (r 5 .31e.56). In this investigation, the SOS values in the younger groups were higher in the women as compared with the men, but women tended to lose more SOS with aging resulting in higher SOS values in the men in later life (e.g., Fig. 5). This was the same trend that was observed when the data from the trials of Drake et al (16) and Hayman et al (17) were combined. The higher SOS values in men in later life are confirmatory of the value of mQUS as a diagnostic tool for estimating fracture risk as men have a lower fracture incidence as compared with women after the age of 50 yr. There were a few limitations in this investigation, most notably that it was a cross-sectional and that the youngest cohort may not have been young enough to capture the true peak in SOS. One limitation of QUS devices that has been often cited was the inability to assess bone at clinically important areas, such as the hip, spine, or radius. The mQUS has important clinical relevance as it incorporates a measurement of the radius, a site often fractured in those with osteoporosis. Because clinical trials of the efficacy of antifracture therapies used BMD as a inclusion criterion, it is not known whether these same therapies will have the same efficacy in a population selected by mQUS. Furthermore, mQUS has not yet
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Table 3 Matrices of Statistically Significant Differences Among Groups (Tukey HSD for Unequal Sample Sizes Using Spjotvoll/Stoline Method) Age grouping
30e39 yr
Women distal radius 30e39 yr 40e49 yr NS 50e59 yr *** 60e69 yr *** 70e79 yr *** 80þ yr *** Women distal tibia 30e39 yr 40e49 yr NS 50e59 yr NS 60e69 yr NS 70e79 yr * 80þ yr *** Women phalanx 30e39 yr 40e49 yr NS 50e59 yr * 60e69 yr *** 70e79 yr *** 80þ yr ***
40e49 yr
50e59 yr
60e69 yr
70e79 yr
80þ yr
NS
*** ***
*** *** ***
*** *** *** ***
*** *** *** *** ***
*** *** *** *** NS NS *** *** *** NS * *** *** ***
*** *** *** NS NS * *** *** * * *** *** ***
*** *** NS *** * *** *** *** *** *** *** ***
*** * *** *** ***
*** *** *** *** NS
NS *** *** *** *** ***
*** *** *** *** ***
30e39 yr
40e49 yr
Men distal radius * * NS NS * NS *** NS *** NS Men distal tibia NS NS NS NS NS NS NS NS * ** Men phalanx NS NS NS NS NS NS ** NS *** ***
50e59 yr
60e69 yr
70e79 yr
80þ yr
NS NS
* NS NS
*** NS *** NS
*** NS ** NS NS
NS *** ** NS NS NS NS NS NS NS * *** ***
NS NS NS NS NS * ** NS NS * ** ***
NS NS NS NS *
* ** NS ** NS
NS ** NS *** **
*** *** *** *** *
*
Abbr: NS, not statistically significant. *p ! 0.05; **p ! 0.01; ***p ! 0.001.
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Fig. 5. Distal radius SOS (m/s) and 10-yr major osteoporotic fracture incidence by age. SOS, speed of sound. shown that it is capable of monitoring response to treatment. This study had numerous strengths, including a randomly selected population from the general Canadian population, a very large sample size, and large span of included ages. The CaMos data set has allowed for the generation of a robust normative database. The CaMos mQUS normative data may be able to assist in the identification of those at an enhanced risk of fracture so that they may have opportunity to seek further diagnostic tests, clinical consultation, and if deemed necessary, treatment.
8. 9.
10. 11.
References 1. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. 1993 Am J Med 94:646e650. 2. Siris ES, Chen YT, Abbott TA, et al. 2004 Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108e1112. 3. Cranney A, Jamal SA, Tsang JF, et al. 2007 Low bone mineral density and fracture burden in postmenopausal women. CMAJ 177:575e580. 4. Kanis JA, McCloskey EV, Johansson H, et al. 2010 Development and use of FRAX in osteoporosis. Osteoporos Int 21(2 Suppl): S407eS413. 5. Leslie WD, Berger C, Langsetmo L, et al. 2011 Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts. Osteoporos Int 22:1873e1883. 6. Olszynski WP, Brown JP, Adachi JD, et al. 2013 Multisite quantitative ultrasound for the prediction of fractures over five years of follow-up: The Canadian Multicentre Osteoporosis Study. J Bone Miner Res 28:2027e2034. 7. Berger C, Goltzman D, Langsetmo L, et al. 2010 Peak bone mass from longitudinal data: implications for the prevalence,
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pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 25:1948e1957. Kreiger N, Tenenhouse A, Joseph L, et al. 1999 The Canadian Multicentre Osteoporosis Study (CaMos): background, rationale, methods. Can J Aging 18:376e387. Weiss M, Ben-Shlomo AB, Hagag P, Rapoport M. 2000 Reference database for bone speed of sound measurement by a novel quantitative multi-site ultrasound device. Osteoporos Int 11: 688e696. Njeh CF, Hans D, Wu C, et al. 1999 An in vitro investigation of the dependence on sample thickness of the speed of sound along the specimen. Med Eng Phys 21:651e659. Njeh CF, Saeed I, Grigorian M, et al. 2001 Assessment of bone status using speed of sound at multiple anatomical sites. Ultrasound Med Biol 27:1337e1345. Knapp KM, Blake GM, Spector TD, Fogelman I. 2001 Multisite quantitative ultrasound: precision, age- and menopause-related changes, fracture discrimination, and T-score equivalence with dual-energy X-ray absorptiometry. Osteoporos Int 12:456e464. Knapp KM, Blake GM, Fogelman I, et al. 2002 Multisite quantitative ultrasound: Colles’ fracture discrimination in postmenopausal women. Osteoporos Int 13:474e479. Damilakis J, Papadokostakis G, Vrahoriti H, et al. 2003 Ultrasound velocity through the cortex of phalanges, radius, and tibia in normal and osteoporotic postmenopausal women using a new multisite quantitative ultrasound device. Invest Radiol 38:207e211. Leslie WD, Lix LM, Langsetmo L, et al. 2011 Construction of a FRAX((R)) model for the assessment of fracture probability in Canada and implications for treatment. Osteoporos Int 22: 817e827. Drake WM, McClung M, Njeh CF, et al. 2001 Multisite bone ultrasound measurement on North American female reference population. J Clin Densitom 4:239e248. Hayman SR, Drake WM, Kendler DL, et al. 2002 North American male reference population for speed of sound in bone at multiple skeletal sites. J Clin Densitom 5:63e71.
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