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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 220-228

Noninvasive screening of osteoporosis using bio-impedance and quantitative ultrasound


1 Department of Biomedical Engineering, MGM’s College of Engineering and Technology, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra, India
2 Department of Imaging Radiology, Nanavati Super Speciality Hospital, Swami Vivekanand Rd, near LIC colony, Vile Parle (W), Mumbai, 400056, Maharashtra, India

Date of Submission24-May-2022
Date of Acceptance25-May-2022
Date of Web Publication17-Jun-2022

Correspondence Address:
Ghanshyam D Jindal
Department of Biomedical Engineering, MGM’s College of Engineering and Technology, Sector 1, Kamothe, Navi Mumbai-410209, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_75_22

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  Abstract 

Bone mineral loss is a serious health issue all over the globe resulting in osteoporosis, without showing any pre-indication of its occurrence. Dual Energy X-ray Absorptiometry test is a widely accepted method for its diagnosis which gives areal information about the bone mineral. Other methods like Quantitative Computed Tomography (QCT) and Peripheral QCT give volumetric information. Application of these methods for mass screening is not recommended due to the use of ionizing radiations. Few non-ionizing methods, namely Bioelectric Impedance Analysis and Quantitative Ultrasound, have evolved in the past few decades. Bioelectric Impedance Analysis, a non-invasive and low-cost tool, has been immensely recognized for its promising use in estimating body composition and body fluids. Similarly, Quantitative Ultrasound is another non-invasive technique for determining bone density at fixed locations, making noninvasive assessment much faster, easier to use, and portable. A multi-parametric approach combining these two modalities has yielded higher efficiency for the detection of bone mineral loss. These developments are briefly reviewed in this paper.

Keywords: Bioelectrical impedance analysis, bone mineral, osteopenia, osteoporosis, quantitative ultrasound


How to cite this article:
Jethe JV, Patkar D, Jindal GD. Noninvasive screening of osteoporosis using bio-impedance and quantitative ultrasound. MGM J Med Sci 2022;9:220-8

How to cite this URL:
Jethe JV, Patkar D, Jindal GD. Noninvasive screening of osteoporosis using bio-impedance and quantitative ultrasound. MGM J Med Sci [serial online] 2022 [cited 2022 Jul 6];9:220-8. Available from: http://www.mgmjms.com/text.asp?2022/9/2/220/347704




  Introduction Top


Bone is the hardest tissue forming the skeletal system of the human body, providing shape and mechanical strength. It is composed of a collagen-protein-rich organic matrix filled with minerals; especially calcium and phosphate formulations.[1] It is a growing tissue that undergoes a process called remodeling including resorption (breakdown or removal of bone) and formation when new bone tissue is formed. This process helps the body to repair and rebuild the skeleton during growth and also balance calcium levels.[2] The remodeling process is regulated by various hormones like calcitonin, vitamin D, parathyroid hormone (PTH), estrogen in women, and testosterone in men.[3] The process of remodeling stops when skeletal maturity is achieved, typically, during the early 20s in women and late 20s in men. Advancement in age leads to bone loss in terms of mineral and organic matter.[4] In women, bone mass decreases briskly compared to men, as their peak-bone mass is attained earlier than men. Hormonal imbalance following menopause in women is another factor reducing bone mass rapidly. Decrease in bone mass results in a high risk of bone fractures known as osteoporosis, a condition in which bone becomes porous and bone mineral is reduced either due to disturbed remodeling of bone or deficiency of calcium and vitamin D. Since this condition has no symptoms, an early diagnosis, and regular follow-ups are essential for preventing unnecessary fractures.

Accurate testing of bone strength is to measure bone mineral density (BMD) that yields mineral concentration in the bone. Standard methods for measurement of BMD are Dual Energy X-ray Absorptiometry (DEXA), Quantitative Computed Tomography (QCT), or their derivatives. QCT gives BMD in mg/cm3 (typical value 120 mg/cm3 at spine level), whereas DEXA gives the same in g/cm2 (typical value 1.3g/cm2). As per World Health Organization (WHO) recommendations, BMD measurements are converted into T-scores for describing the status of bone minerals. These indices are derived from control values of BMD in the female group (age 20–25 yrs) and male group (age 25–30 yrs). Deviation of BMD value observed in a person from the mean value of the population (µ) in units of standard deviation (σ) gives the T-score of the individual. For instance, if O is the observed value in a particular subject, (O - µ)/σ gives the T-score in the individual. Z-score is another index, which compares the test value of BMD with age and sex-matched control values. In this case, µ and σ values are taken from the age and gender-matched populations. DEXA machines feature special software that computes and display the bone density measurements on a computer monitor in terms of T-score and Z-score as per WHO standards; with Caucasian and Hispanic populations as references. DEXA measurements for bone density are currently the gold standard for the clinical diagnosis of osteoporosis.

QCT is based on the differential absorption of ionizing radiation by calcified tissue and gives accurate estimates of BMD for trabecular and cortical bone as true volumetric mineral density in mg/cm3. QCT of the spine reflects three-dimensional bone mineral density. It is generally used to assess the lumbar spine but has been adapted for other skeletal areas. Peripheral QCT (pQCT) gives a detailed examination of bone parameters of the peripheral skeleton (e.g. radius, tibia, and femur). It advocates the calculation of volumetric BMD (vBMD), in place of the projected areal BMD obtained by DEXA. In comparison to DEXA, QCT or pQCT provide a more refined characterization of bone, including measures of vBMD, and quantifies the distribution of minerals within the cross-section, thus providing a better understanding of skeletal deficits associated with fracture risk.

The above-described methods involve ionizing radiation which curtail mass screening of bone mineral density and regular post-therapeutic follow-ups. Few non-ionizing techniques, namely bio-electric impedance analysis (BIA) and quantitative ultrasound densitometry (QUD) have evolved during the past few decades for the assessment of bone mineral density. These methods make use of the physical properties of the body tissues like density, electrical resistivity, and speed of sound as given in [Table 1]. Manifold contrast in their values from one tissue to another makes them attractive for their employment in bone mineral determination. These, being non-invasive and cost-effective, have been studied prolifically. This review article briefly describes these assessment methods for the assessment of bone minerals noninvasively.
Table 1: Typical SOS values in different media

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  BIO-ELECTRIC IMPEDANCE ANALYSIS Top


Bioelectric impedance analysis is based on the electrical property of biological matter such as body tissue/cell, body fluids, etc. As shown in [Table 1], electrical resistivity varies nearly 50 times from muscle to bone. Therefore, any abnormality in any of the tissues gets reflected in the electrical impedance value of the body segment. Since its invention in 1940 by Jan Nyboer, it has been used for the assessment of central and peripheral blood flow for nearly 8 decades. Presently it is the only non-invasive method for continuous monitoring of cardiac output in critical patients. It’s another desirable application is measurement of body composition and body fluid status. Bio-Impedance Analyzer introduces a small amount of sinusoidal current (800µA) into the body and outputs resistance and reactance values of any segment along the current path, by measuring electrical impedance and phase angle respectively. [Figure 1] shows the electrode placement of the current injecting and sensing electrodes for the measurement of electrical impedance of different parts of the body. [Table 2] shows, various permutations of electrodes for this segmental assessment.
Figure 1: Shows placement of carrier electrodes (C1 & C2) and sensing electrodes (S1 & S2) for the whole body as well as segmental body impedance measurement

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Table 2: Location of carrier electrodes and sensing electrodes for segmental BIA

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Conventionally it has been used for the measurement of fat mass and fat-free mass noninvasively. Since osteoporosis causes a reduction in bone mineral content (BMC), which increases electrical resistivity, bio-impedance parameters of the body can therefore provide quantitative information about BMC.[5] Though manufacturers use proprietary equations for estimating BMC, Patil et al[6] for the first time, have described an empirical BIA prediction equation for estimation of BMC and have validated the same against DEXA in 113 Indian healthy adults in the age group of 23–81 years as follows.

[INLINE 1]

where, H = height, Zbody250 = impedance at 250 Khz, A = age, Rbody250 = resistance at 250 Khz, Xcbody250 = reactance at 250 Khz, Zbody5 = impedance at 5 Khz, Φbody250 = phase angle at 250 Khz.

This equation yielded a correlation of 0.9136 against DEXA with a standard error of estimate at 0.168 kg and a total error of 0.162 kg. Mean ± SD values of BMC in control, osteopenic and osteoporotic subjects obtained by BIA and DEXA are shown in [Table 3]. Statistical analysis shows no significant difference (P > 0.05) between BIA and DEXA estimations.
Table 3: Mean and SD values of bone mineral density obtained from BIA and DEXA

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Cvetko et al[7] carried out a comparative study between DEXA and BIA for the calculation of bone minerals in 11 males and 16 females. Using proprietary equations, they have shown that T-scores correlate well in females (0.726) than that in males (0.427). In 2017, Peppa et al.[8] studied the presence of osteosarcopenia in postmenopausal women and compared the results obtained from DEXA and BIA with correlations ranging from 0.98 to 0.96. Fujimoto et al[9] performed DEXA and BIA in patients with lower back pain. The measurements were carried out in 130 patients and adequate correlations were observed in males and females (r = 0.73, r = 0.9 respectively). These studies express the merit of BIA as a potential technique for screening osteoporosis.


  Quantitative ultrasound densitometry Top


As given in [Table 1], there is a considerable difference in the tissue densities as well as the speed of sound through them. These features have led to the use of ultrasound not only in imaging but also in emerging bone status assessment.[10],[11] Ultrasound densitometer uses either a single transducer in reflection mode or two transducers in transmission mode for the assessment of bone density. The measurement site generally used in this system is the heel because of the presence of calcaneus bone which shows the first sign of osteoporosis or loss of bone minerals in the body. The patient’s heel is kept either in a water bath system or dry contact is made between the transducers and the heel, as shown in [Figure 2].
Figure 2: Shows ultrasound measurement at calcaneus with the help of a water bath system (left) and dry contact system (right)

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In ultrasound (US) densitometry, the transmission mode is used. In this case, two transducers are used; one for transmitting the US pulse and the other for receiving the transmitted US pulse.[12] Recent developments show the speed of sound (SOS; typical values in different media are given in [Table 1] and broadband ultrasound attenuation (BUA) are discriminating parameters for the detection of osteoporosis. Measurement of SOS is based upon the calculation of transit time (∆t) which is the total time taken by ultrasound waves to travel between the onset of transmitted wave pulse on one side of the heel to the onset of received wave pulse on the other side of the heel. This time is measured using a high-frequency crystal-controlled clock. SOS value is related to bone mineral density.

BUA expresses the attenuation of the individual frequency component of the passing wave through the measuring site. BUA is calculated by recording the amplitude spectrum of an ultrasound pulse through a reference material Aref, generally water, and through the bone Abone, as shown in [Figure 3]. At each frequency (f), generally between 0.2 and 0.6 MHz, attenuation (in dB) is calculated from the amplitude through water and through the sample to be plotted as a function of frequency. The slope of this plot gives BUA index with units of dB/MHz. The specific frequency range of 0.2 to 0.6 MHz provides the greatest sensitivity to osteoporosis, i.e., the greatest slope difference between healthy and osteoporotic subjects.[12]
Figure 3: (a) shows amplitude spectrum of received US pulse through reference and sample and (b) attenuation plotted against frequency to give slope as BUA parameter (Courtesy: Langton et al[12])

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Floter et al,[13] have published a review article comparing the results of DEXA and QUD reported during the first decade of the 21st century. All studies have been evaluated by comparing calcaneus QUD to the lumbar spine or femoral neck DEXA (as the gold standard). QUD sensitivity ranged from 79% to 93% with a specificity of 28% to 90%, when at the lower threshold. Gold-standard threshold (T-score < -2.5, DEXA) could not be used for QUD without errors in osteoporosis diagnosis. All studies had a threshold determined by the authors’ criteria, with a T-score variability of -2.4 to -3.65 for QUD corresponding to -1.7 to -2.5 for DEXA. Further research conducted in this area has helped to improve the diagnostic yield by varying the cut-off T-score. QUD of the calcaneus has proved to be a helpful tool for assessing pathological fractures, whether or not they were associated with osteoporosis.

Beerhorst et al,[14] who have compared QUD with DEXA in 205 patients with epilepsy have reported a high correlation (p = 0.01) between QUD and DEXA. Although some studies have suggested a weaker correlation[15],[16] others have shown a better correlation[17],[18] between QUD with DEXA. Young et al[19] in their study used mean ultrasound values to predict moderately low DEXA in post-menopausal women with a sensitivity of 68–70%. Herd et al[20] also reported similar result by using lower quartile ultrasound parameter values to predict osteopenia as defined by DEXA (T or Z score of -1), in which sensitivity ranged from 68–69% for lumbar spine and 63–70% for femoral neck osteopenia.

Shenoy et al. in 2014[21] performed QUD measurements on three groups of women comprising young normals (20-40yrs), healthy pre-menopausal (41-50yrs), and post-menopausal (51-65yrs). QUD parameters SOS and BUA were compared to the BMD value of DEXA which showed a very strong correlation in all three groups. Their results confirmed QUD to be an accurate screening tool in identifying patients at risk of osteoporosis and can differentiate between young, pre-and post-menopausal females, and can serve as an alternative to the traditional radiation-based technologies. Quiros et al. in 2017[22] carried out a BMD assessment in 73 HIV patients and compared the results of DEXA and QUD. They have concluded that the use of calcaneal quantitative ultrasound for screening is a reasonable alternative to DEXA.

A lot of studies report the ability of QUD to predict fractures and have also scrutinized the significance of predictive factors. These include the age of the patient, weight, and BMD as measured by DEXA. Taking these factors into account, the studies suggest that the predictive value of QUD is still significant. Most of the investigators have concluded that QUD measures something different than DEXA, especially the structural quality of bone. Based on this fact scientist recommends that the combined investigations of DEXA and QUD would provide stronger predictive information.


  Bia and qud combined Top


As described above, the detection efficiency of osteoporosis is seen to improve by combining two techniques; in described case QUD with DEXA. DEXA being invasive and prohibitive for mass screening, Jethe JV[23] has combined QUD with BIA. The former measures BMD at the peripheral site and the latter measuring for the whole body. She developed BIA for multi-frequency and multi-lead provision using an application-specific integrated circuit (AFE4300) giving bone mineral content in kg and QUD using MOSFET fired pulse-receiver system. Both the developments are combined as shown in [Figure 4] and run by a graphic user interface (GUI) developed in Lab-Windows to capture and calculate the above parameters.
Figure 4: Shows a block diagram of the Bone Mineral Analyser system, which combines both the modalities, namely BIA and QUD. BIA module comprises the application-specific integrated circuit AFE4300 and a few assorted components. Electrodes from IOUT and VSENSE terminals are connected to the extremities of the subject as shown in the figure. The module is connected to the laptop PC through an interfacing circuit. QUD module comprises ultrasonic transducers, a pulsar-receiver circuit, and a digital storage oscilloscope. The lower extremity is placed in a water bath as shown in the figure

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AFE4300 is programmed to provide a sine-wave current of different frequencies from 0 to 255 KHz, which is passed through the body with the help of current leads (IOUT1 to IOUT4). Sensing leads (VSENSE1 to VSENSE4) feed the voltage to AFE4300 for calculating impedance and phase value respectively of the desired body segment. The interfacing circuit (Arduino Uno) connects AFE4300 with Laptop PC through serial peripheral interface (SPI) pins for programming and measurement as described elsewhere.[24]

Impedance (Z) of the body segment is measured by connecting the current leads to the right palm, left palm, right toe, and left toe, while VSENSE leads are connected to the right wrist, left wrist, right ankle, and left ankle, by reading the output of AFE4300 in detector mode. Similarly, the phase (Φ) is measured by reading the I/Q demodulator output of AFE4300 with electrodes connected as above. Thus, Z and Φ are measured for the right arm (RA), left arm (LA), right leg (RL), left leg (LL), right side (RS), and left side (LS) respectively as shown in GUI of [Figure 5]. After inputting the physical parameters like age, weight, gender, and height, BMC is computed and displayed.
Figure 5: Shows the graphic user interface of BIA. Detector and I/Q output values are displayed in the Table for different lead configurations and different frequencies. Subject details and anthropological variables are entered manually. BMC value computed from this data using Patil’s regression equation is displayed in the right bottom corner of the panel

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QUD data generated by pulse-receiver[25] and digital storage oscilloscope (DSO) is read by laptop. Two ultrasonic transducers used as transmitter and receiver are placed on either side of a water bath in which the subject places his/her heel as shown in [Figure 4]. QUD parameters SOS, BUA, and a newly introduced transmitted energy (TE) are calculated from this data as follows.

For calculating SOS, time of flight (∆t in seconds) is obtained by subtracting the sample number of starting transmitted signal from the sample number of the first peak value in the received signal and multiplying the difference by 100 nanoseconds. The subject’s heel width (w in meters) is physically measured. Both these values (∆t and w) yield SOS for the given experimental settings using the following formula.

[INLINE 2]

where constants 1545 and 0.133 represent the velocity of ultrasound in water and the width of the water bath in meters respectively.

For calculating BUA, transmitted pulse through reference material (water) and sample in-situ are used. Prominent peaks in the neighborhood of 0.3, 0.4, and 0.5 MHz are measured and the sample value is subtracted from the reference value to obtain attenuation for respective frequencies. The slope of the regression line between attenuation and frequency gives the value of BUA. Amplitude data of the received pulse is used to find transmitted energy. Mean amplitude is subtracted from the instantaneous value, the difference is squared and all such squares about the received pulse are added to obtain the total TE.

[Figure 6] shows GUI for QUD measurements. Clicking A-scan pops up a window in the GUI and selected data is displayed in the adjoining window in this panel. A received pulse is seen around the central line. Initial pulses are transients generated by the transmitted pulse. The frequency spectrum of the received pulse, TE, SOS, and BUA are displayed by clicking on respective buttons.
Figure 6: Shows the graphic user interface of QUD. A-scan and its fast Fourier transform are displayed on the top and middle panels. TE, SOS, and BUA are displayed at the right bottom after keying in anthropological information

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[Table 4] gives the bone mineral measurements in 11 subjects using the combined Bone Mineral Analyzer (BMA) along with the T-score of DEXA. Observations are arranged in the ascending order of T-score values for ease of understanding. It can be observed that a T-score lower than -2.5 yields deviated values of 3 parameters and 2 parameters in 3 and 4 subjects respectively. T-scores between -2.49 and -1.51 has yielded a deviated value of 1 parameter in 2 subjects. T-score less than -1.5 has not yielded any deviated value of the BMA parameter. The observations have revealed that two or more deviated BMA parameters indicate the diagnosis of osteoporosis and that one parameter may indicate osteopenia. Abnormal values for BMA parameters are empirically taken to be <500, >13.9, and <1600 for TE, BUA, and SOS respectively. The expected value of BMC is empirically derived from the height of the subject as used in most commercial BIA equipment from overseas. Cut-off values for BMC are therefore less than BMC (expected).
Table 4: Bone mineral measurements in 11 subjects. Data arranged in ascending values of DEXA T-score in the subjects

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As described above, all BMA parameters in a subject in the normal range suggest bones to be healthy. Subjects with one or more abnormal values of BMA parameters can be selectively subjected to DEXA or QCT for confirming the diagnosis of osteopenia or osteoporosis. Thus BMA combining BIA and QUD offers an effective screening procedure for the assessment of bone health. Furthermore, BMA, being fully non-invasive, can be performed on a given subject any number of times without causing any harm or discomfort to the patient. Thus it can be a method of choice in the screening and management of osteoporosis.

The multi-parameter approach in place of derived T-score and combining BIA and QUD in place of any one of them, has led to the increase in sensitivity from 68% to 88.8% for the detection of osteopenia/osteoporosis. In the combined approach of Jyoti V Jethe, it is not necessary to obtain a T-score of BIA or QUD for arriving at a diagnosis. This is an added advantage of this approach since the detection is independent of the ethnic group. Sensitivity can further be enhanced by adjusting the thresholds of BMA parameters using neural networks.


  Conclusion Top


BIA and QUD being non-invasive methods, are radiation-free and inexpensive techniques for assessing bone minerals in the body. Commercial BIA instruments measure whole-body bone mineral content in kg and do not convert the same into T or Z scores. The advantage of such systems is that no measurement is necessary for the reference population and the output is not dependent on the topography of the place. QUD is a technique for determining bone density at fixed locations and has shown the ability to estimate bone quality and provide information about its elastic properties. Commercially available QUD systems give T-score, again based on reference observations from Caucasian and Hispanic populations. The latest study combining BIA and QUD and making assessments through observed parameters in place of derived parameters (using Hispanic and Caucasian populations as references) has increased the non-invasive detection efficiency of osteoporosis.

Acknowledgement

The authors are grateful to Dr. Geeta S Lathkar, Director, and Dr. VG Sayagavi, Vice Principal, MGM’s College of Engineering and Technology (MGMCET), Navi Mumbai, Maharashtra, India for their guidance and encouragement. The authors thank Dr. T. S. Ananthakrishnan, Ex-Head Electronics Division, Bhabha Atomic Research Center (BARC), Trombay, Maharashtra, India for his valuable guidance. The authors are also grateful to Ms. Aparna Lakhe, Ms. Manasi S Sawant, Mr. Nishant Patil, Mr. Nazim Momin, and Mr. B.V. Gaikwad, MGMCET, Navi Mumbai, Maharashtra, India for their continuous help and support during the execution of this work.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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