MCCUE CUBACLINICAL ULTRASONIC BONE SONOMETRY SYSTEM WITH CUBAPLUS+ V4.1.0
Device Facts
| Record ID | P990016 |
|---|---|
| Device Name | MCCUE CUBACLINICAL ULTRASONIC BONE SONOMETRY SYSTEM WITH CUBAPLUS+ V4.1.0 |
| Applicant | CooperSurgical, Inc. |
| Product Code | MUA · Radiology |
| Decision Date | Jan 7, 2000 |
| Decision | APRL |
| Regulation | 21 CFR 892.1180 |
| Device Class | Class 2 |
Intended Use
The intended use of the McCue CUBA Clinical Ultrasonic Bone Sonometry System is to perform a quantitative ultrasound measurement of the calcaneus (heel bone), the results of which can be used in conjunction with other clinical risk factors as an aid for the diagnosis of osteoporosis and other medical conditions leading to reduced bone density and, ultimately, for the determination of fracture risk.
Device Story
Device performs quantitative ultrasound measurement of calcaneus; uses non-audible, high-frequency sound waves. Operator applies coupling gel to patient heel; secures foot in footwell with Velcro straps; transducer heads contact opposite sides of heel. One transducer transmits; one receives. System calculates Broadband Ultrasound Attenuation (BUA) and Velocity of Sound (VOS). Results displayed on user-supplied PC; includes BUA, T-Score, Z-Score, and percent expected. Used in clinical settings by healthcare professionals. Output aids clinicians in diagnosing osteoporosis and assessing fracture risk; provides non-ionizing radiation alternative to X-ray based methods (DEXA/SXA). Benefits include assessment of skeletal status without ionizing radiation exposure.
Clinical Evidence
Five clinical studies (n=1343) evaluated safety, effectiveness, and precision. Studies compared CUBAClinical BUA to DEXA/SXA BMD measurements. Results showed moderate correlations (0.42-0.82) between BUA and BMD. ROC analysis demonstrated AUCs ranging from 0.63 to 0.93 for discriminating osteoporotic subjects. Precision (CV%) reported between 2.5% and 4.4%. No adverse effects reported in 5775 total subjects.
Technological Characteristics
Ultrasonic bone sonometer; uses two silicone elastomer-covered transducer heads. Measures BUA (dB/MHz) and VOS (m/s). Portable unit (10 kg); connects to PC via serial cable. Power: standard outlet. Materials: medical grade silicone (transducers), acrylic-capped ABS plastic (case/supports). Software: CUBAPlus+ V4.1.0. Non-sterile; low-level disinfection recommended.
Indications for Use
Indicated for use in patients with intact skin to assess bone quality and fracture risk in individuals at risk for osteoporosis. Used as an aid for diagnosis of osteoporosis and conditions leading to reduced bone density.
Regulatory Classification
Identification
A bone sonometer is a device that transmits ultrasound energy into the human body to measure acoustic properties of bone that indicate overall bone health and fracture risk. The primary components of the device are a voltage generator, a transmitting transducer, a receiving transducer, and hardware and software for reception and processing of the received ultrasonic signal.
Special Controls
*Classification.* Class II (special controls). The special control for this device is FDA's “Guidance for Industry and FDA Staff; Class II Special Controls Guidance Document: Bone Sonometers.” See § 892.1(e) for the availability of this guidance document.
Reference Devices
- Lunar DPX-1
- Lunar Achilles
- OsteoAnalyzer
- QDR-1500/2000
Related Devices
- P010058 — OSTEOSPACE · Medilink · Mar 15, 2004
- P980010 — DTU-ONE ULTRASOUND SCANNER · Osteometer Meditech A/S · Sep 19, 2000
- P000055 — UBIS 5000 BONE SONOMETER · Diagnostic Medical Systems · Jul 17, 2001
- P990035 — THE SUNLIGHT OMNISENSE(TM) ULTRASOUND BONE SONOMETER · Beam-Med, Ltd. · Jan 20, 2000
- P990039 — QUS-2 (TM) CALCANEAL ULTRASONOMETER · Quidel Corp. · Aug 1, 2000
Submission Summary (Full Text)
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# SUMMARY OF SAFETY AND EFFECTIVENESS INFORMATION
## I. GENERAL INFORMATION
Device Generic Name(s): Ultrasonic Bone Sonometer
Device Trade Name: McCue CUBA Clinical Ultrasonic Bone Sonometry System with CUBAPlus+ V4.1.0 Software
Applicant Name and Address: McCue Corporation, Inc.
Harbor Towers, Apt.729
5855 Midnight Pass Road
Sarasota, FL 34242
Premarket Approval Application Number: P990016
Date of Panel Recommendation: N/A
Date of Notice of Approval to the Applicant: January 7, 2000
## II. INDICATIONS FOR USE
The intended use of the McCue CUBA Clinical Ultrasonic Bone Sonometry System is to perform a quantitative ultrasound measurement of the calcaneus (heel bone), the results of which can be used in conjunction with other clinical risk factors as an aid for the diagnosis of osteoporosis and other medical conditions leading to reduced bone density and, ultimately, for the determination of fracture risk.
The CUBA Clinical measures two parameters, Broadband Ultrasound Attenuation (BUA in dB/MHz) which is used for the clinical measurement and Velocity of Sound (VOS in m/s) which is used for QA purposes only. The BUA output is expressed both as an absolute value and, with reference to the embedded Normative Data, as a T-Score, Z-Score, and the percent expected (age-matched).
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# III. CONTRAINDICATIONS
There are no known contraindications associated with the use of the McCue CUBAClinical system.
# IV. WARNINGS AND PRECAUTIONS
See labeling for warnings and precautions.
# V. DEVICE DESCRIPTION
The McCue CUBAClinical Ultrasonic Bone Sonometry System performs quantitative ultrasound measurement of the calcaneus by passing non-audible, high frequency sound waves through the heel. The System is small, lightweight (10 Kg), and portable. It plugs into a standard power outlet. Ultrasound measurements are performed with the patient seated, and the foot positioned and secured. Use of Foot Positioning Inserts is determined by patient foot size.
After the patient’s foot is secured, using Velcro® straps, and coupling gel is applied, a pair of silicone elastomer covered transducer heads is brought into contact with opposite sides of the patient’s heel. One transducer transmits the sound wave and the other, on the opposite side of the patient’s heel, receives the sound wave. The results are then analyzed and displayed on the screen of the computer. The ultrasound power levels used by the CUBAClinical are lower than the limits for standard imaging ultrasound devices set forth in the 1997 FDA Guidance Document, “Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers”.
## A. System Components
The McCue CUBAClinical Ultrasonic Bone Sonometry System consists of the following components: CUBAClinical Unit with carrying case, the serial cable, the power cable, the hybrid phantom for routine quality assurance testing (in its own carrying case), the User Manual, a set of Foot Positioning Inserts, the CUBAplus+ V4.1.0 software on one 3.5" diskette (1.44 MB diskette), and ultrasound coupling gel. Additional equipment
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necessary for operation includes a user-supplied desktop or portable computer (PC) with display and printer.
## B. System Operation
The McCue CUBAClinical is controlled by push buttons on the unit and by a user-supplied PC. Operator instructions and results are displayed on the screen of the PC. A hard copy printout of measurement results can be obtained using the user-supplied printer. The printout reports the subject’s BUA, T-Score, Z-Score, and as a percentage expected (age matched) (%exp). In addition, the printout displays the subject’s results graphically. Additional information entered in the patient record is the patient identification information and demographic information (age, sex, etc.).
For measurement, the operator applies ultrasound coupling gel to the subject’s heel. The subject then places the designated foot into the footwell. Labels inside the footwell indicate if and which size Foot Positioning Insert should be used. Once the foot is positioned, the operator secures the calf into position with the Velcro® straps and activates the transducers by pushing a button. Following a settling period of 30 seconds, the CUBAClinical takes a minimum of three separate readings of BUA and providing that they are within a defined tolerance, the mean value is calculated and reported as the result. Results are displayed on the PC screen, retained on hard disk, and are available for printing.
The McCue CUBAClinical is provided non-sterile and is not intended to be sterilized. The User Manual provides instructions for post-use decontamination. The System is indicated for use with intact skin only. Low level disinfection using hospital-grade solutions is recommended.
## C. Principles of Operation
For ultrasonic measurements of the calcaneus, the CUBAClinical uses two ultrasound transducers: one as the transmitter, and one as the receiver. The measurement provided by the CUBAClinical, broadband ultrasound attenuation (BUA) is defined as the slope (dB/MHz) between attenuation (dB) and frequency, typically between 0.2 MHz and 0.6 MHz.
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VOS (velocity of sound, in m/s) is used in the QA test with the Phantom. For calculation of VOS, a linear transducer measures the distance between the two-ultrasound transducers. Transit time is calculated from the point source of the ultrasound signal to the leading edge of its detection with adjustment for the transit time through the transducer face-plates and the silicone pads.
## VI. ALTERNATIVE PRACTICES AND PROCEDURES
Traditional methods for assessing bone quality use x-rays to estimate bone mineral density (BMD) and expose the patient and operator to ionizing radiation. These methodologies include single energy X-ray absorptiometry (SXA), dual energy X-ray absorptiometry (DEXA or DXA), quantitative computed tomography (QCT), single photon absorptiometry (SPA), and dual photon absorptiometry (DPA). Of these techniques, SXA, DXA, and SPA have been used specifically for the estimation of BMD of the calcaneus.
Of the traditional X-ray based methods for assessing bone density, the dual energy X-ray absorptiometry (DXA) and single energy X-ray absorptiometry (SXA) techniques are the most widely used. These established techniques estimate BMD at a variety of anatomical sites, including the heel, by measuring the attenuation of X-rays due to passing through the bone.
FDA has recently approved several quantitative ultrasound devices, which measure BUA and VOS for the assessment of bone quality for osteoporosis and determination of fracture risk.
## VII. MARKETING HISTORY
CUBAClinical Systems have been sold in 21 countries, including the United Kingdom, Ireland, Australia, Argentina, Japan, Korea, Taiwan, Singapore, New Zealand, Italy, Spain, Switzerland, Holland, Sweden, Greece, Turkey, the Czech Republic, Iceland, Hong Kong, Syria, and Austria. No McCue CUBAClinical System has been withdrawn from the market for any reason related to safety and effectiveness.
## VIII. POTENTIAL ADVERSE EFFECTS ON HEALTH
There are no known potential adverse effects of this device on health. The McCue CUBAClinical uses ultrasound power levels lower than standard ultrasound
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imaging devices, which are widely used and accepted. No adverse events of any kind have been reported.
## IX. SUMMARY OF NON-CLINICAL STUDIES
The McCue CUBAClinical is a non-critical, reusable medical device with contact to intact patient skin for approximately two minutes per measurement. Areas of patient risk associated with system operation were evaluated in non-clinical studies.
### A. Electrical Safety
The CUBAClinical is in compliance with EN60601-1 Medical Electrical Equipment: General Requirements for Safety.
### B. Electromagnetic Compatibility
The CUBAClinical complies with IEC 60601-1-2 (1993) and FCC Part 15 Subpart B, Class A (1996) for electromagnetic compatibility.
### C. Software
Software verification tests used for the CUBAClinical were submitted by McCue PLC. A hazards analysis indicated that all software and hardware patient and user concerns were adequately addressed. Verification, validation, and unit testing demonstrate that the device operates in a manner described in the System Specification.
### D. Acoustic Output
McCue PLC provided testing to demonstrate the acoustic output of the CUBAClinical transducers. Intensities are within the limits specified in CDRH Guidance, “Information for Manufacturers seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers” (1997). Global Maximum Value of MI (mechanical index) = 0.27(±17%), I$_{apta3}$ = 5.3(±31%) μW/cm², and I$_{appa3}$ = 1.9(±32%) W/cm².
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# E. Biological/Sterility
The materials used for silicone pads covering the ends of the transducers are medical grade silicones for which FDA has Master Files. McCue PLC has submitted authorization from the manufacturer to reference these files.
The material for the Calf Plate Support and Foot Positioning Inserts, acrylic-capped ABS plastic, was tested for toxicity (in vitro and in vivo). The in vivo sensitization study of the material used for the CUBAClinical case and external parts (acrylic capped ABS plastic) suggests that this material may be a potential sensitizer. The CUBAClinical is intended for use in patients with intact skin and without evidence of skin irritation. The acute cutaneous irritation test, which most closely replicates clinical conditions of use, showed no evidence of irritation after four hours of exposure over freshly shaved skin.
# F. Evaluation of Design Variation
To demonstrate that the CUBAClinical intended for marketing in the U.S. is equivalent to the design that was used for the collection of clinical data, a side-by-side comparison was conducted using the Hybrid Phantom. The coefficient of variation (CV%) for the proposed device was 0.626 for BUA and 0.2458 for VOS. CV% specifications for BUA and VOS are 1% and 0.5% respectively. The CV% values for BUA and VOS for the previous model were 1.7467 and 0.1836 respectively.
# X. SUMMARY OF CLINICAL STUDIES
## A. Introduction
Clinical studies of the McCue CUBAClinical were submitted in support of the PMA to:
(1) support the safety, effectiveness, and clinical utility of the McCue CUBAClinical. Results from five studies performed at six international clinical sites involving 1343 subjects were provided to demonstrate that the CUBAClinical is safe, to compare CUBAClinical BUA results to bone mineral density results obtained at the calcaneus, femoral neck, and spine,
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and to assess the ability of the CUBAClinical BUA to predict risk of osteoporotic fractures in the elderly.
(2) demonstrate the precision of the CUBAClinical
(3) describe the reference population used by the CUBAClinical
(4) demonstrate that the performance of the proposed device model is equivalent to that of the model used in the clinical studies
## B. Safety, Effectiveness, and Clinical Utility
Five studies performed at six sites in the U.S. and Europe were used to support the safety, effectiveness, and clinical utility of the McCue CUBAClinical.
Table 1. Summary of Clinical Studies
| Clinical Center | Testing Area | Number of Study Subjects | Study Design (Btu) |
| --- | --- | --- | --- |
| Beth Israel Deaconess Medical Center Boston, Massachusetts | S. L. Greenspan M.L. Bouxsein | 159 females | Study A |
| Oregon Health Sciences University Portland, Oregon | K. G. Faulkner E. S. Orwoll | | |
| Vrije Universiteit, Amsterdam, Netherlands | S. M. F. Pluijm W. C. Graafmans L. M. Bouter P. Lips | 583 females 132 males | Study B |
| Centre for Metabolic Bone Disease Hull Royal Infirmary, Hull, UK | C. M. Langton | 105 females | Study C |
| University of Aberdeen, UK | D. M. Reid A. Stewart | 246 females | Study D |
| | | 118 females | Study E |
Objectives of the studies included an assessment of the performance of the CUBAClinical, and a comparison of its performance to bone mineral densitometry systems. The studies were designed to assess the following:
(1) the relationship of CUBAClinical BUA to specific patient characteristics, such as age and sex;
(2) use of CUBAClinical BUA for predicting fracture risk;
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(3) the ability of CUBAClinical BUA to discriminate osteoporotic subjects from non-osteoporotic subjects, and subjects with fractures from non-fracture subjects;
(4) the correlation of CUBAClinical BUA with results obtained using other ultrasound techniques; and
(5) the correlation of CUBAClinical BUA results with results obtained using radiological methods.
## STUDY A: Fosamax Protocol 349
This study was conducted at two clinical sites in the United States to determine if measuring skeletal status at the calcaneus is a useful technique for diagnosis of osteoporosis. It was designed to evaluate precision, correlation, and discrimination ability of five calcaneal bone assessment instruments. The study enrolled a total of
161 Caucasian women: 53 were "young normal" women between the ages of 20 and 35 (mean age: 30.2); and 52 were osteoporotic women with no history of fracture; and 56 were osteoporotic women without a history of fracture. The 108 osteoporotic women were all between the age of 55 and 92 (mean age: 72.5). Subjects were considered to be osteoporotic if they had a femoral neck or trochanter BMD T-Score of -2.5 or lower. CUBAClinical BUA measurements were performed on the subjects using the CUBAClinical as well as DEXA and SEXA of the calcaneus, hip, and spine. In addition, measurements were performed using three other calcaneal ultrasound devices, but these devices were not included in the analysis presented in the PMA. Complete results for all devices tested are provided in a report published by Greenspan, et al (1997).
Femoral neck and trochanter BMD T-Scores using device-specific reference populations were used to qualify subjects for enrollment in the osteoporotic cohorts. T-Scores for all instruments for all other analyses were determined using the young normal subjects, thereby providing a common reference population.
Pearson's product moment correlation coefficients were determined for age and CUBAClinical BUA measurements and for the DEXA and SEXA devices. For all study subjects, the correlation between subject age and the instrument measurements ranged from -0.677 (BMD calcaneus) to -0.836 (BMD femoral neck). The correlation coefficient for CUBAClinical BUA was approximately in the middle of this range at -0.743.
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The correlation of the CUBAClinical BUA T-Scores to the T-Scores for the BMD measurements was determined. Pearson's correlation coefficients for BUA versus each of the DEXA and SEXA devices ranged from 0.696 (BUA versus DEXA of the trochanter) to 0.821 (BUA versus DEXA of the calcaneus). Correlations among the different BMD measurements ranged from 0.729 (DEXA calcaneus versus DEXA femoral neck) to 0.908 (DEXA calcaneus versus SEXA calcaneus).
T-Scores for fracture and non-fracture cohorts for CUBAClinical BUA measurements, DEXA measurements, and SEXA measurements at different anatomical sites are given in Table 2. For all of the devices studied, the mean T-Scores for the fracture groups were significantly lower than the mean T-Scores for the non-fracture groups (p<02). Duncan's Multiple Range Test was used to compare the mean T-Scores for the CUBAClinical BUA and the SEXA and DEXA measurements for all osteoporotic subjects. This test found that the mean T-Score for CUBAClinical BUA was not significantly different from the mean BMD T-Scores for DEXA calcaneus and DEXA trochanter. BMD T-Scores for DEXA femoral neck and SEXA calcaneus were also not significantly different.
Table 2. Summary of T-Scores for Study A Osteoporotic Subjects
| Instrument | Osteoporotic
No Fracture
(n=12) | Fracture
(n=15) | All
(n=104) |
| --- | --- | --- | --- |
| CUBAClinical BUA | Mean | -1.77 | -2.24 | -2.02 |
| SD | 0.837 | 0.859 | 0.877 |
| OsteoAnalyzer (BMC) | Mean | -1.99 | -2.62 | -2.32 |
| (SEXA calcaneus) | SD | 1.015 | 1.186 | 1.148 |
| QDR-1500/2000 (BMD) | Mean | -1.76 | -2.305 | -2.05 |
| (DEXA calcaneus) | SD | 1.141 | 1.219 | 1.208 |
| QDR-1500/2000 (BMD) | Mean | -1.71 | -2.13 | -1.93 |
| (DEXA trochanter) | SD | 0.698 | 0.810 | 0.783 |
| QDR-1500/2000 (BMD) | Mean | -2.30 | -2.54 | -2.43 |
| (DEXA femoral neck) | SD | 0.413 | 0.592 | 0.527 |
The ability of CUBAClinical BUA, DEXA calcaneus BMD, and SEXA calcaneus BMD to discriminate between osteoporotic and non-osteoporotic controls was assessed for T-Score thresholds of -2.5 and -2.0. For a T-Score threshold of -2.5, the proportion of subjects classified as osteoporotic by CUBAClinical BUA was 31 percent. This compares to 39 percent and 47 percent for DEXA calcaneus and
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SEXA calcaneus, respectively. For a T-Score threshold of -2.0, the number of subjects correctly classified as osteoporotic ranged from 53 to 69 percent, with CUBAClinical BUA at 58 percent.
Receiver-Operator Characteristic (ROC) curves were generated to determine the ability of CUBAClinical BUA and DEXA and SEXA of the calcaneus to discriminate osteoporotic subjects from the young normal control group. In addition, ROCs and the areas under the ROC curves were generated to discriminate between osteoporotic subjects with fractures from those without fractures. The area under an ROC curve provides a figure of merit for comparing one curve to another. The AUC must be greater than 0.5 if the diagnostic ability is better than chance. A summary of the AUCs obtained for the three instruments is provided in Table 3.
Table 3. Areas Under the ROC Curves for Study A
| Instrument | Counselor
Osteoporotic
AUC (95% CI) | Osteoporotic Men
Osteoporotic (95% CI) |
| --- | --- | --- |
| CUBAClinical BUA | 0.93 (0.89, 0.97) | 0.63 (0.53, 0.73) |
| OsteoAnalyzer (SEXA calcaneus) | 0.93 (0.89, 0.97) | 0.65 (0.55, 0.75) |
| QDR 1500/2000 (DEXA calcaneus) | 0.90 (0.86, 0.94) | 0.62 (0.52, 0.72) |
| QDR 1500/2000 (DEXA trochanter) | 0.93 (0.89, 0.97) | 0.65 (0.52, 0.75) |
| QDR 1500/2000 (DEXA femoral neck) | 0.98 (0.96, 1.00) | 0.60 (0.48, 0.72) |
To further compare the discriminatory ability of CUBAClinical BUA to the X-ray absorptiometry instruments, the sensitivity and specificity of each instrument was determined for T-Score thresholds of -1.5, -2.0, and -2.5. The results, summarized in Table 4, indicate that the sensitivity and specificity of CUBAClinical BUA is comparable to that of SEXA of the calcaneus and DEXA of the calcaneus.
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Table 4. Comparison of Sensitivity and Specificity of Calcaneal Instruments in Study A
| Instrument | 1.25 mV
1000 mA | 1.5 mV
1000 mA | Specificity (%) |
| --- | --- | --- | --- |
| CUBAClinical BUA | -1.5 | 77 % | 96 % |
| | -2.0 | 58 % | 96 % |
| | -2.5 | 31 % | 100 % |
| QDR-1500/2000
(DEXA calcaneus) | -1.5 | 69 % | 92 % |
| | -2.0 | 54 % | 98 % |
| | -2.5 | 36 % | 98 % |
| OsteoAnalyzer
(SEXA calcaneus) | -1.5 | 77 % | 94 % |
| | -2.0 | 67 % | 96 % |
| | -2.5 | 44 % | 100 % |
STUDY B: Netherlands Study of Fracture Risk
This prospective longitudinal study was conducted to determine the possible contribution of CUBAClinical BUA for assessing risk of osteoporotic fracture in the elderly. The study was conducted at the Institute of Research in Extramural Medicine Academic Hospital, Vrije University, Amsterdam, Netherlands. Dr. S.M.F. Pluijm was the Principle Investigator. A total of 710 Caucasian subjects between the ages of 70 and 99 were enrolled in the study, of whom 578 were women and 132 were men. Subjects were excluded if they were unable to give informed consent, had a history of calcaneal fracture, were confined to bed, or used a wheelchair.
CUBAClinical measurements were performed at time of enrollment. Subjects were contacted every six months by telephone or self-administered mail questionnaire to determine if they had a fall or fracture during the previous month. Fractures were verified with the subject’s primary physician. During the time of the study, 168 subjects died and 5 were lost to follow-up. The study accumulated 1844 person-years of follow-up (median: 2.8 years, maximum: 3.7 years).
During the period of follow-up, 77 of the subjects (73 females and 4 males) sustained a total of 96 fractures (31 hip and 65 other non-spinal fractures). Table 5 compares the baseline CUBAClinical BUA measurement for the 77 subjects with fractures and the subjects without fractures. The differences in BUA between the females with and without fracture were statistically significant.
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Table 5. Summary of Baseline CUBAClinical BUA Measurements by Fracture Status and Sex for Study B
| | CUBAClinical BUA (SD) | | |
| --- | --- | --- | --- |
| | Fracture | Non-Fracture | p value* |
| Female | n=73 | n=503 | 0.010 |
| Mean (SD) | 51.27 (15.88) | 56.92 (17.52) | |
| Male | n=4 | n=128 | 0.194 |
| Mean (SD) | 66.81 (16.56) | 81.05 (21.57) | |
| Combined | n=77 | n=631 | <0.001 |
| Mean (SD) | 52.08 (16.18) | 61.81 (20.80) | |
Significance level for paired t-test comparing mean for fracture versus non-fracture subjects.
Relative hazard ratios were determined using Cox proportional hazard regression and are reported here with 95 percent confidence intervals. The relative hazard ratio of hip fracture, other non-spinal fractures, and any non-spinal fractures for one standard deviation decrease in CUBAClinical BUA is summarized by subject sex and for all subjects in Table 6 below. An increased relative hazard ratio is indicated by values greater than 1.0. As shown in Table 6, the relative hazard ratio for CUBAClinical BUA is greater than 1.0 for hip fractures and any non-spinal fractures in female subjects. The lower 95% CI is less than 1.0 for other non-spinal fractures, and for all non-spinal fracture endpoints in the male population.
Table 6. Relative Hazard Ratio of Hip, Other Non-Spinal, and Any Non-Spinal Fracture for CUBAClinical BUA for Study B
| Gender | Hip Fracture | | Other Non-Spinal Fractures | | Any Non-Spinal Fracture | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | RR | 95% CI | RR | 95% CI | RR | 95% CI |
| Females | BUA | 2.27 | 1.41-3.66 | 1.29 | 0.96 - 1.73 | 1.52 | 1.17 - 1.97 |
| Males | BUA | 2.68 | 0.79 - 9.06 | 2.71 | 0.24 - 30.71 | 2.68 | 0.79 - 9.06 |
| Overall | BUA | 2.34 | 1.46 - 3.75 | 1.62 | 1.18 - 2.22 | 1.83 | 1.39 - 2.42 |
STUDY C: Centre for Metabolic Bone Disease, Hull Royal Infirmary, Hull, U.K.
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This study was conducted by Christian M. Langton, Ph.D. to assess the usefulness of the McCue CUBAClinical to pre-screen subjects for bone density measurements and to determine if assessment with the CUBAClinical was superior to presently used clinical referral criteria. Data collected in this study were analyzed to assess the diagnostic performance of the CUBAClinical and how its performance compares to DEXA BMD.
This was an open enrollment study of 106 Caucasian female subjects between the age of 60 and 69 (mean: 64 years) who were recruited from the general patient population of three local general practitioners. Subjects were excluded if they weighed more than 280 pounds, had bilateral foot deformity, and were participating in a research study for another medical device or drug. One subject was excluded from analysis, leaving a total of 105 subjects.
BMD measurements of the spine and femoral neck and CUBAClinical BUA measurements were performed on all subjects on the same day. BUA measurements were performed on both heels of all subjects. Analysis of the results found that differences in the mean BUA for the right and left heel was not significantly different. Therefore, the left heel results were used in the analysis for all subjects.
Subjects were also evaluated to determine if they met one or more of five clinical referral criteria used for referring subjects to BMD. Forty-seven of the 105 subjects (45 percent) met one or more of the five general clinical referral criteria for BMD. The age, height, weight, CUBAClinical BUA measurements, spinal BMD and femoral neck BMD values of the 47 subjects meeting at least one of the clinical referral criteria was compared to that of the other 58 subjects who did not meet any of the clinical referral criteria. Differences in these parameters between the two groups were not statistically significant.
The ability of CUBAClinical BUA to identify subjects that BMD classifies as normal, osteopenic, or osteoporotic was assessed. Each subject was classified as normal, osteopenic, or osteoporotic based on the values for BMD spine and BMD femoral neck given in the operating instructions for the Lunar DPX-1. Table 7 summarizes these classifications.
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Table 7. Classification of Study C Subjects Based on Femoral Neck BMD and Spine BMD
| Diagnostic Category | Femoral Neck BMD | Number of Subjects Classified by Spine BMD |
| --- | --- | --- |
| Normal | 34 (32%) | 49 (47%) |
| Osteopenic | 58 (55%) | 36 (34%) |
| Osteoporotic | 13 (12%) | 20 (19%) |
| Total | 105 (100%) | 105 (100%) |
Thirteen of the 105 subjects were classified as osteoporotic by femoral neck BMD, and 20 subjects were classified as osteoporotic by spine BMD. Clinical referral criteria was positive on 4 of the 13 (31%) osteoporotics identified by femoral neck BMD, and 9 of the 20 osteoporotics (45%) identified by spine BMD.
Table 8 summarizes the CUBA Clinical BUA T-Scores and Z-Scores for the three diagnostic classifications as assigned by femoral neck BMD, and Table 9 summarizes the CUBA Clinical BUA T-Scores and Z-Scores for the diagnostic classifications assigned by spine BMD. In both tables, mean T-Scores and Z-Scores get progressively lower from the normal group to the osteoporotic group. The osteoporotic groups had mean BUA T-Scores of -2.15 regardless of whether femoral neck or spine BMD was used to classify subjects. The mean Z-Scores of the osteoporotics were also virtually identical (-0.67 and -0.69) for either classification.
Table 8. Summary of Study C CUBA Clinical BUA T-Scores and BUA Z-Scores by Diagnostic Group as defined by Femoral Neck BMD [Means (SD)]
| Groups defined by Femoral Neck BMD | CUBA Clinical BUA T-Score | CUBA Clinical BUA Z-Score |
| --- | --- | --- |
| Normal (n=34; 33%) | -0.88 (0.91) | 0.56 (0.91) |
| Osteopenic (n=58; 55%) | -1.50 (0.75) | -0.03 (0.75) |
| Osteoporotic (n=13; 12%) | -2.15 (1.13) | -0.67 (1.09) |
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Table 9. Summary of Study C CUBAClinical BUA T-Scores and BUA Z-Scores by Diagnostic Group as defined by Spine BMD [Mean (SD)]
| Group (n=49; 47%) | Group 1 (n=49; 47%) | Group 2 (n=49; 47%) |
| --- | --- | --- |
| Normal (n=49; 47%) | -1.05 (0.83) | 0.40 (0.82) |
| Osteopenic (n=36; 34%) | -1.40 (0.91) | 0.07 (0.91) |
| Osteoporotic (n=20; 19%) | -2.15 (0.78) | -0.69 (0.75) |
ROC curves were generated for CUBAClinical BUA, femoral neck BMD, and spine BMD, and areas under the ROC curves were determined. The areas under the curves are summarized in Table 10.
Table 10. Areas under the ROC Curves for Discrimination of Osteoporotic from Non-Osteoporotic Subjects as defined by BMD (Femoral Neck and Spine) for Study C
| Measurement | Osteoporosis Defined by Femoral Neck BMD AUC (95% CI) | Osteoporosis Defined by Spine BMD AUC (95% CI) |
| --- | --- | --- |
| CUBAClinical BUA | 0.72 (0.56, 0.88) | 0.79 (0.67, 0.91) |
| BMDFemoral Neck | | 0.87 (0.77, 0.97) |
| BMD Spine | 0.89 (0.77, 1.01) | |
Sensitivity and specificity for CUBAClinical BUA discrimination of osteoporotic subjects from non-osteoporotic subjects were determined for T-Score thresholds of -2.5, -2.0, and -1.5. Classification of each subject as osteoporotic was based on the femoral neck or spine BMD values, as summarized in Tables 8 and 9 above. Table 11 summarizes the sensitivity and specificity of BUA based on femoral neck or spine BMD classifications. It also shows the number of subjects that were classified as osteoporotic by both BUA and BMD. At a T-Score of -2.0, CUBAClinical BUA has a sensitivity of about 60 percent, and a specificity of about 80 percent. For comparison, the sensitivity and specificity of clinical referral criteria was 31 percent and 53 percent, respectively, for osteoporosis as defined by femoral neck BMD, and 45 percent and 55 percent, respectively, for osteoporosis as defined by spine BMD.
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Table 11. Summary of CUBAClinical BUA Sensitivity and Specificity for Study C
| CUBAClinical BUA 1 Score Distribution | | Specificity (95% CI) | Corrected by Spine BMD (n=40) |
| --- | --- | --- | --- |
| -2.5 | Number (%) Identified by BUA as osteoporotic | 5 (38 %) | 6(30 %) |
| | Sensitivity | 38 % | 30 % |
| | Specificity | 91 % | 92 % |
| -2.0 | Number (%) Identified by BUA as osteoporotic | 8 (62 %) | 12(60 %) |
| | Sensitivity | 62 % | 60 % |
| | Specificity | 80 % | 82 % |
| -1.5 | Number (%) Identified by BUA as osteoporotic | 8 (62 %) | 15 (75 %) |
| | Sensitivity | 62 % | 75 % |
| | Specificity | 60 % | 65 % |
STUDY D: University of Aberdeen
This study was conducted at the Osteoporosis Research Unit at the University of Aberdeen, Foresterhill, U.K., by Doctors David M. Reid and Alison Stewart. A total of 250 Caucasian women who had no history of osteoporotic fracture and who were referred for bone mineral density scans were enrolled in the study. Four subjects were missing critical data, and were excluded from the analysis. The age of the subjects ranged from 23 to 79 (mean 54), and 184 (75 percent) were postmenopausal.
BMD of the hip and spine and CUBAClinical BUA were measured on each subject on the same day. T-Scores for the CUBAClinical BUA were calculated using the machine reference population. T-Scores for BMD were determined using a site-specific local reference population. Table 12 summarizes the mean T-Scores and Z-Scores for the CUBAClinical BUA and BMD measurements.
Table 12. Summary of T-Scores and Z-Scores for Study D
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| Battlement | T-Score Mean (SD) | Z-Score Mean (SD) |
| --- | --- | --- |
| CUBAClinical BUA | -1.36 (1.02) | 0.14 (0.95) |
| Femoral Neck BMD | -1.29 (1.15) | -0.23 (0.98) |
| Spine BMD | -1.69 (1.44) | -0.21 (1.03) |
Pearson’s product moment correlation coefficients were generated for the CUBAClinical BUA, BMD femoral neck, and BMD spine measurements. CUBAClinical and the BMD measurements exhibited moderate correlations. The highest correlation (0.774) was found for femoral neck BMD to spine BMD. Other correlations ranged from 0.450 to 0.662.
Subjects were categorized as osteoporotic, osteopenic, or normal according to the BMD T-Scores of the femoral neck and spine using established WHO criteria. Thirty-one subjects were classified as osteoporotic by femoral neck BMD, and 73 were classified as osteoporotic by spine BMD. The ability of CUBAClinical BUA to discriminate between osteoporotic and non-osteoporotic subjects was evaluated using BUA T-Score thresholds of -2.5, -2.0, and -1.5. Table 13 summarizes the CUBAClinical BUA T-Scores and Z-Scores for the diagnostic classifications assigned by femoral neck BMD. Also shown, for comparison, are the spine BMD T-Scores and Z-Scores for the femoral neck BMD classifications. Likewise, Table 14 summarizes the T-Scores and Z-Scores for the diagnostic classifications assigned by spine BMD. In both tables, mean T-Scores and Z-Scores get progressively lower from the normal group to the osteoporotic group.
Table 13. CUBAClinical BUA T-Scores and Z-Scores for Diagnostic Categories Defined by Femoral Neck BMD [Mean (SD)] for Study D
| Diagnostic Category
as Defined by
Femoral Neck
BMD T-Scores
(Number of Subjects, %) | CUBAClinical BUA | | BMD Spine | |
| --- | --- | --- | --- | --- |
| | T-Score | Z-Score | T-Score | Z-Score |
| Normal (n=98; 40%) | -0.85 (0.95) | 0.45 (0.93) | -0.67 (1.32) | 0.32 (1.07) |
| Osteopenic (n=117; 48%) | -1.53 (0.82) | 0.04 (0.87) | -2.12 (0.97) | -0.46 (0.82) |
| Osteoporotic (n=31; 12%) | -2.37 (0.94) | -0.46 (0.96) | -3.26 (0.97) | -1.05 (0.75) |
Table 14. CUBAClinical BUA T-Scores and Z-Scores for Diagnostic Categories
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Defined by Spine BMD [Mean (SD)] for Study D
| Diagnostic Category
As Defined by Spine BMD
T-Scores
(Number of Subjects, %) | CUBA Clinical BUA | | BMD Femoral Neck | |
| --- | --- | --- | --- | --- |
| | 1 Score | 2 Score | 1 Score | 2 Score |
| Normal (n=72; 29%) | -0.78 (0.92) | 0.54 (0.88) | 0.20 (0.94) | 0.56 (0.97) |
| Osteopenic (n=101; 41%) | -1.35 (0.87) | 0.10 (0.92) | -1.40 (0.77) | -0.36 (0.74) |
| Osteoporotic (n=73; 30%) | -1.96 (0.95) | -0.19 (0.91) | -2.20 (0.86) | -0.83 (0.74) |
ROC curves were generated to evaluate the ability of CUBA Clinical BUA to discriminate between osteoporotic and non-osteoporotic subjects as classified by femoral neck BMD and spine BMD T-Scores. The areas under the ROC curves with 95 percent confidence intervals are provided in Table 15.
Table 15. Areas under the ROC Curves for Discrimination of Osteoporotic from Non-Osteoporotic Subjects as defined by BMD (Femoral Neck and Spine) for Study D
| Measurement
Technique | Osteoporotic
Definitive
Femoral Neck
BMD
AUC (95% CI) | Osteoporotic
Defined by
Spine BMD
AUC (95% CI) |
| --- | --- | --- |
| CUBA Clinical BUA | 0.73 (0.63, 0.83) | 0.73 (0.67, 0.79) |
| BMD Femoral Neck | | 0.83 (0.77, 0.89) |
| BMD Spine | 0.85 (0.80, 0.94) | |
Sensitivity and specificity for CUBA Clinical BUA discrimination of osteoporotic subjects from non-osteoporotic subjects were determined for T-Score thresholds of -2.5, -2.0, and -1.5. Classification of each subject as osteoporotic was based on femoral neck or spine BMD T-Scores of -2.5 or less. Table 16 summarizes the sensitivity and specificity of BUA based on the resulting femoral neck or spine BMD classifications. It also shows the number of subjects that were classified as osteoporotic by both BUA and BMD. At a T-Score of -2.0, CUBA Clinical BUA has a sensitivity of 61 percent, and a specificity of 81 percent when osteoporosis is defined by femoral neck BMD. When osteoporosis is defined by spine BMD, BUA has a sensitivity of 49 percent and a specificity of 87 percent.
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Table 16. Summary of Sensitivity and Specificity for CUBAClinical BUA for Study D
| CUBAClinical BUA | | Osteoporosis by
Easier to meet BMD
(n=31) | Osteoporosis by
Spline BMD (n=63) |
| --- | --- | --- | --- |
| -2.5 | Number (%) Identified | 13 (42 %) | 18 (25 %) |
| | Sensitivity | 42 % | 25 % |
| | Specificity | 92 % | 93 % |
| -2.0 | Number (%) Identified | 19 (61 %) | 36 (49 %) |
| | Sensitivity | 61 % | 49 % |
| | Specificity | 81 % | 87 % |
| -1.5 | Number (%) Identified | 25 (81 %) | 49(68 %) |
| | Sensitivity | 81 % | 68 % |
| | Specificity | 59 % | 63 % |
STUDY E: University of Aberdeen
This study was also conducted at the Osteoporosis Research Unit, University of Aberdeen. The principle Investigator was Dr. Alison Stewart. This was an open enrollment study for Caucasian women who were referred to the Osteoporosis Research Unit for a DEXA scan of the spine and hip. Subjects were evaluated with two ultrasound devices, the CUBAClinical and the Lunar Achilles, and had BMD of the hip, spine, and heel measured. All measurements were performed on the same day.
A total of 138 Caucasian women subjects were enrolled. Twenty of the 138 subjects were missing a key measurement and were excluded from this analysis. The subjects ranged in age from 33 to 80 years (mean: 56 years), but 82 percent of the subjects were between the ages of 50 to 59. Ninety-six subjects (82 percent) were post-menopausal. Table 17 summarizes the T-Scores and Z-Scores for CUBAClinical BUA, Lunar Achilles Stiffness Index, and BMD of the femoral neck, spine, and heel.
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Table 17. Summary of T-Scores and Z-Scores [Mean (SD)] for Study E
| Recirculation | T-Score | Z-Score |
| --- | --- | --- |
| CUBAClinical BUA | -1.50 (0.90) | -0.32 (0.85) |
| Lunar Achilles Stiffness | -1.65 (1.18) | -0.17 (1.09) |
| Femoral Neck BMD | -0.98 (1.01) | -0.43 (0.89) |
| Spine BMD | -1.30 (1.47) | 0.10 (1.14) |
| Heel BMD | -0.12 (1.15) | not available |
Pearson’s product moment correlation coefficients were generated for CUBAClinical BUA, Lunar Achilles Stiffness Index, BMD femoral neck, BMD spine, and BMD heel measurements. CUBAClinical and the BMD measurements exhibited moderate correlations. The highest correlation was between CUBAClinical BUA and the Achilles Stiffness Index (0.801). Correlations between CUBAClinical and BMD measurements were moderate, ranging from 0.420 to 0.646 and were comparable to the correlations between the different BMD sites (.570 to .655), and the correlations between the Achilles Stiffness Index and BMD (0.575 to 0.762).
Subjects were categorized as osteoporotic, osteopenic, or normal according to the BMD T-Scores of the femoral neck and spine using established WHO criteria. Eleven subjects were classified as osteoporotic by femoral neck BMD, and 24 were classified as osteoporotic by spine BMD. The ability of CUBAClinical BUA to discriminate between the osteoporotic and non-osteoporotic subjects was evaluated using BUA T-Score thresholds of -2.5, -2.0, and -1.5. Table 18 summarizes the CUBAClinical BUA T-Scores and Z-Scores for the diagnostic classifications assigned by femoral neck BMD. Also shown, for comparison, are the spine BMD T-Scores and Z-Scores for the femoral neck BMD classifications. Likewise, Table 19 summarizes the CUBAClinical BUA T-Scores and Z-Scores for the diagnostic classifications assigned by spine BMD. In both tables, mean T-Scores and Z-Scores get progressively lower from the normal group to the osteoporotic group.
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Table 18. CUBAClinical BUA T-Scores and Z-Scores for Diagnostic Categories Defined by Femoral Neck BMD [Mean (SD)] for Study E
| Diagnostic Category
Defined by Femoral Neck BMD T-Scores
(# Subjects, %) | CUBAClinical BUA | | Spine BMD | |
| --- | --- | --- | --- | --- |
| | T-Score | Z-Score | T-Score | Z-Score |
| Normal (n=79; 67%) | -1.30 (0.79) | -0.16 (0.79) | -0.98 (1.27) | 0.23 (1.11) |
| Osteopenic (n=28; 24%) | -1.66(0.92) | -0.48 (0.91) | -1.55 (1.45) | -0.09 (1.16) |
| Osteoporotic (n=11; 9%) | -2.60 (0.78) | -1.08 (0.66) | -2.96 (1.73) | -0.54 (1.28) |
Table 19. CUBAClinical BUA T-Scores and Z-Scores for Diagnostic Categories Defined by Spine BMD [Mean (SD)] for Study E
| Diagnostic Category
Defined by Femoral Neck BMD T-Scores
(# Subjects, %) | CUBAClinical BUA | | Spine & Neck BMD | |
| --- | --- | --- | --- | --- |
| | T-Score | Z-Score | T-Score | Z-Score |
| Normal (n=54;46%) | -1.13 (0.85) | -0.01 (0.85) | -0.60,(0.82) | -0.10 (0.95) |
| Osteopenic (n=40;34%) | -1.60 (0.70) | -0.42 (0.67) | -1.00 (0.87) | -0.63 (0.57) |
| Osteoporotic (n=24; 20%) | -2.18 (0.90) | -0.87 (0.82) | -1.78 (1.14) | -0.87 (0.97) |
ROC curves were generated to evaluate the ability of the CUBAClinical to discriminate between osteoporotic and non-osteoporotic subjects as classified by femoral neck BMD and spine BMD T-Scores. The areas under the ROC curves with 95 percent confidence intervals are provided in Table 20. The highest AUC (0.85) was for CUBAClinical BUA.
Table 20. Areas under the ROC Curves for Discrimination of Osteoporotic from Non-Osteoporotic Subjects as defined by BMD (Femoral Neck and Spine) for Study E
| Measurement Technique | Osteoporotic defined by BMD Femoral Neck T-Score
AUC (95% CI) | Osteoporotic defined by BMD Spine T-Score
AUC (95% CI) |
| --- | --- | --- |
| CUBAClinical BUA | 0.85 (0.69, 1.01) | 0.74 (0.62, 0.86) |
| BMD Femoral Neck | | 0.72 (0.60, 0.84) |
| BMD Spine | 0.78 (0.62, 0.94) | |
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Sensitivity and specificity for CUBAClinical BUA discrimination of osteoporotic subjects from non-osteoporotic subjects were determined for T-Score thresholds of -2.5, -2.0, and -1.5. Classification of each subject as osteoporotic was based on femoral neck or spine BMD T-Scores of -2.5 or less. Table 21 summarizes the sensitivity and specificity of BUA based on the resulting femoral neck or spine BMD classifications. It also shows the number of subjects that were classified as osteoporotic by both BUA and BMD. At a T-Score of -2.0, CUBAClinical BUA has a sensitivity of 64 percent, and a specificity of 78 percent when osteoporosis is defined by femoral neck BMD. Likewise, for a T-Score threshold of -2.0, when osteoporosis is defined by spine BMD, BUA has a sensitivity of 58 percent and a specificity of 82 percent.
Table 21. Summary of Sensitivity and Specificity for CUBAClinical BUA for Study E
| CUBAClinical BUA
T-Score Threshold | | Femoral Neck BMD
(n=11) | Spine BMD
(n=24) |
| --- | --- | --- | --- |
| -2.5 | Number of Subject (%) | 6 (55%) | 9 (38%) |
| | Sensitivity | 55% | 38% |
| | Specificity | 92% | 94% |
| -2.0 | Number (%) Identified | 7 (64%) | 14 (58%) |
| | Sensitivity | 64% | 58% |
| | Specificity | 78% | 82% |
| -1.5 | Number (%) Identified | 10 (91%) | 16 (67%) |
| | Sensitivity | 91% | 67% |
| | Specificity | 60% | 61% |
C. Precision
The precision of the CUBAClinical BUA has been reported in published clinical studies to be typically in the range of 2 to 4 percent. In 1996 Arden, et al., performed duplicate CUBAClinical BUA measurements on 30 subjects. Percent CV in these BUA measurements was 2.5 percent. These results were confirmed by Bennell, et al (1998) who performed three sequential measurements with repositioning between each measurement in each subject. Twenty normal, healthy subjects ranging in age from 25 to 56 years were enrolled in this study. The mean CV% was 2.96 percent for BUA. In 1997, Greenspan, et al. reported CV%
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measurements of 4.3 to 4.4 percent in a study which measured instrument, positioning, short term and interobserver precision in four ultrasound devices. Interobserver precision was 7.58 percent in this study. The %CV for the other ultrasound devices in the study ranged from 2 percent to 9 percent. Njeh, et al., (1997) reported CV% of 4.3 percent for CUBAClinical BUA in thirty elderly patients. Each patient was measured twice during one visit. Five other bone sonometers were also included in the study and had CV% ranging from 1.9 percent to 6.4 percent for BUA. Pluijm, et al., (1999) recently reported results of a precision study in 20 healthy volunteers. CV% for the CUBAClinical BUA in these 20 subjects was 3.4 percent.
McCue, PLC also conducted an in vivo clinical precision study as part of the validation of the CUBAClinical 2.6. The purpose of the study was to compare the clinical precision of the CUBAClinical Mark 2.0 (the model used in the clinical studies) to the CUBAClinical Mark 2.6 (the model to be marketed in the U.S.). In this study precision of BUA and VOS, expressed as the percent coefficient of variation (CV%), was determined using two different operators who performed three separate measurements on fourteen subjects. The precision of the Mark 2.6 was found to be equal to, or better than, that of the Mark 2.0.
## D. Reference Population
Three clinical sites, two in the United Kingdom and one in Ireland, provided the reference population data for the CUBAClinical software. Age dependent reference ranges for Caucasian females were developed for the CUBAClinical using BUA results for 4358 females from ages 20 through 80 who were evaluated at those clinical sites. The large number of subjects and geographic diversity minimizes the possibility of statistical or regional bias. The CUBAClinical uses the regression line and the pooled population standard deviation of the BUA measurements for this reference population for determining T-Scores and Z-Scores.
## E. Comparability of Results Obtained in the Clinical Studies with those Obtained with the Proposed Product
To evaluate potential differences between the CUBAClinical Mark 2 used for the clinical studies presented in the PMA and the proposed CUBAClinical Mark 2.6, McCue PLC conducted a study of 55 subjects
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who were enrolled at three different clinical sites. Measurements were performed by three different operators (one at each site) using the same Mark 2 and Mark 2.6 at all three sites. Results were analyzed using a Deming Regression.
Two regressions were run, one with the Mark 2 CUBAClinical BUA measurement as the dependent variable, and the other with the Mark 2.6 BUA measurement as the dependent variable. Estimates of the regression parameters are summarized in Table 22 below.
Table 22. Estimates of the Deming Regression Parameters
| Dependent variable | Standard error | Standard error | Standard error (SE) | Observed difference (SE) |
| --- | --- | --- | --- | --- |
| BUA (Mark 2/V3.6) Old | 1.09 (0.011) | (1.071, 1.115) | -5.24 (0.798) | (-6.84, -3.64) |
| BUA (Mark 2.6/V4.1) New | 0.92 (0.009) | (0.896, 0.934) | 4.79 (0.682) | (3.43, 6.16) |
It is important to note that the threshold between osteopenia and osteoporosis and therefore the area of greatest importance, is at CUBAClinical T-Scores between -1.5 and -2. These T-Scores coincide with BUA values of approximately 48 to 59 dB. As shown in the Deming regression, the two regression lines show the point of intersection (56.5, 56.5) to be in that region of interest. Thus, in the range of interest, differences between devices were minimal.
The results of the Deming regression analysis comparing the Mark 2 and proposed Mark 2.6 for this study therefore show that despite minor differences between the BUA measurements of the two devices, the clinical impact of these differences is negligible.
## XI. CONCLUSIONS DRAWN FROM THE STUDIES
### A. Safety
There were no adverse effects from the McCue CUBAClinical measurements reported in any of the studies involving a total of 5775
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subjects. This clinical experience, combined with the total worldwide experience with earlier versions of the CUBAClinical, demonstrates the safety of the CUBAClinical.
## B. Effectiveness
The studies in the PMA show that the McCue CUBAClinical measures bone quality in subjects at risk for osteoporosis in a manner similar to bone mineral density (by ionizing radiation). CUBAClinical BUA measurements can be used in conjunction with other clinical risk factors as an aid to the physician in the diagnosis of osteoporosis and medical conditions leading to reduced bone density, and ultimately in the determination of fracture risk.
## C. Risk/Benefit Analysis
The McCue CUBAClinical is safe and effective as a clinical indicator of skeletal status with performance comparable to that of bone mineral density measurements. Skeletal status and relative risk of fracture can be evaluated without the need for exposure to the ionizing radiation produced by the BMD devices. The acoustic output of the device is lower than the levels used by medical ultrasound imaging systems, which are considered safe. Based on the clinical and non-clinical evidence provided, the benefits of the CUBAClinical outweigh the risks of illness or injury when used according to the CUBAClinical User Manual.
## XII. PANEL RECOMMENDATIONS N/A
## XIII. FDA DECISION
The applicant’s manufacturing facility was inspected on October 4-7, 1999 and was found to be in compliance with the device Good Manufacturing Practice regulations. FDA issued an approval order on January 7, 2000.
## XIV. APPROVAL SPECIFICATIONS
Directions for use: See attached labeling.
Conditions of Approval: CDRH approval of this PMA is subject to full compliance with the conditions described in the approval order.
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The sale, distribution, and use of this device are restricted to prescription use in accordance with 21 CFR 801.109 within the meaning of section 520 (e) of the Federal Food, Drug, and Cosmetic Act (the act) under the authority of section 515(d)(1)(B)(ii) of the act. FDA has also determined that to ensure the safe and effective use of the device that the device is further restricted within the meaning of section 520(e) under the authority of section 515(d)(1)(B)(ii) insofar as the sale, distribution, and use must not violate sections 502(q) and (r) of the act.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the attached labeling.
## XV. REFERENCES
1. Arden NK, Keen RW, Lanchbury JS, Spector TD. Polymorphism of the vitamin D receptor gene do not predict quantitative ultrasound of the calcaneus or hip axis length. *Osteoporosis International* 1996; 6:334-7.
2. Bennel KL, Hart P, Nattrass C, Wark JD. Acute and Subacute Changes in the Ultrasound Measurements of the Calcaneus following Intense Exercise. *Calcified Tissue International* 1998; 63: 505-509.
3. Greenspan SL, Bouxsein ML, Melton ME, Kolodny AH, Clair JH, Delucca PT, et al. Precision and discriminatory ability of calcaneal bone assessment technologies. *Journal of Bone and Mineral Research* 1997;12(8): 1303-13.
4. Njeh CF, Fan B, Hans D, Tsuda E, He Y, Fuerst T, Genant HK. Precision of Dry and Wet Quantitative Ultrasound Systems on Elderly Patients. [Abstract]. Presented at the Society of Clinical Densitometry, Orlando, Florida, January 1998.
5. Pluijm SMF, Graafmans WC, Bouter LM, Lips P. Ultrasound Measurements for the Prediction of Osteoporotic Fractures in Elderly People. *Osteoporosis International* 1999; 9: 550-556.
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