Dual x-ray absorptiometry is still considered the gold standard for diagnosing osteoporosis and monitoring therapy, but considerable scientific evidence supports the use of peripheral quantitative ultrasound in bone assessment.
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Dual x-ray absorptiometry is still considered the gold standard for diagnosing osteoporosis and monitoring therapy, but considerable scientific evidence supports the use of peripheral quantitative ultrasound in bone assessment.
With women now living more than one third of their lives after menopause, the clinical and metabolic consequences of estrogen deprivation have become a major concern. One of the most important problems clinicians must deal with, of course, is osteoporosis, which is perhaps the most wide-ranging social, physical, and economic consequence of an estrogen deficiency.
The statistics on the disease don't look very good: Women are far more likely to be affected by osteoporosis than men, and postmenopausal osteoporosis is by far the most frequent form of the disease.1-8 There's a nearly 40% lifetime fracture risk among women who are age 50. About one third of postmenopausal women are osteoporotic and a further 25% to 40% have skeletal demineralization below normal values.1 The incidence of osteoporotic fracture in western societies is constantly rising due to increasing life expectancy.
Diagnosing and managing osteoporosis have been based on the measurement of bone mineral density (BMD) using dual x-ray absorptiometry (DXA). In fact, the disease has been defined as a BMD that is more than 2.5 standard deviations (SD) below the young adult reference range (T-score). If a patient also has a history of a fragility fracture, her condition is labeled severe osteoporosis. A T-score between -1 and -2 SD is categorized as low bone mass, or osteopenia.1
One might compare bone densitometry to the measurement of blood pressure to assess the risk of stroke, or the measurement of blood glucose to assess the risk of diabetic complications. There is some logic to this, in as much as there are no symptoms of osteoporosis before fracture, which occurs late in the disease; most hip fractures, for example, occur in people older than 80 with associated high morbidity and mortality. It therefore makes sense to identify individuals at greatest risk because that risk can be roughly halved with effective treatment.
The relationship between BMD and fracture risk has been calculated in a large number of studies. But it is important to realize that defininition of osteoporosis as a BMD below 2 SD was originally made for epidemiologic reasons to compare female populationsand not as a threshold for intervention. The WHO criteria for the clinical diagnosis of osteoporosis is based on the measurement of BMD at the hip and spine using DXA.
The techniques for measuring bone may be divided into those that measure the central skeleton, including the spine, proximal femur, and whole skeleton, and those that measure peripheral sites. Measurement of the central skeleton is most widely carried out using DXA. It has been established that DXA bone measurement (with consideration of age) is the most effective way to estimate fracture risk in postmenopausal Caucasian women.9,10 For each SD of BMD below a baseline level (either mean peak bone mass or mean for the reference population of the person's age and sex), the fracture risk approximately doubles.
Although DXA has been considered the gold standard, concerns have been recently raised about its validity and clinical usefulness. With most clinicians focusing on DXA assessment of BMD, many have the false impression that osteoporosis is synonymous with a pathological BMD. But osteoporosis is a clinical diagnosis and low BMD is not a disease, but rather a risk factor for fractures. The DXA cannot identify the entire population at risk for future fractures, and some 30% to 40% of fractures occur in women with a normal DXA measurement.11
In addition, the results of fracture prevention trials clearly show that various antiresorptive agents can reduce the fracture incidence by 35% to 55%; but these clinical benefits are accompanied by only small increases of 3% to 8% in BMD.12,13 Clearly then, the prevention of fractures that follows treatment cannot be explained merely on the basis of increases in BMD.14 Antiresorptive treatments may be modifying not just bone density, but other characteristics of bone that cannot be detected by x-rays.
With that in mind, it's necessary to take into consideration other properties of bone tissue that cannot be measured by DXA, but which may be detectable by other techniques. Central DXA cannot discriminate the normal bone of a teenager from a porotic bone of an older woman.15 In fact, the mineral density measured by central DXA can be identical in these two populations, although the structural characteristics of bone in young and elderly subjects are completely different. Similarly, DXA cannot discriminate subjects with osteomalacia from those with osteoporosis.16 This observation underlines the intrinsic limitation of central and peripheral DXA BMD.
While the standard definition of osteoporosis has been "a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture," a more up-to-date definition views the disease as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.17 Bone strength primarily reflects both bone density and bone quality.18
The ideal technique for the measurement of bone should be reliable, fast, inexpensive, and it should not expose patients to radiation. It should also be very accurate so that it provides optimal evaluation of fracture risk in a given population. High precision is essential in the individual patient to monitor the effects of treatment. Furthermore, the technique should give a validated prediction of risk of subsequent fracture.
Recently, newer peripheral devices have been developed that are less expensive and portable. The commoner forms of these devices in Europe and North America include heel and forearm DXA and quantitative ultrasound of the heel (Figure 1, 2, 4, and 5) and phalanx (Figure 3). The various devices have similar overall predictive value for estimating fracture risk regardless of the skeletal site measured or technique used, although measurement at any particular site best predicts fracture at that location.19
In the last few years, low-cost, radiation-free quantitative ultrasound (QUS) has actually emerged as an alternative to DXA in the assessment of bone structure, bone quality, and fracture risk.18-47 As I mentioned previously, bone U/S can give information on bone strength and quality rather than on density. It's easy to use, technologically very sophisticated, versatile, suitable for outpatient use, and offers an excellent cost-benefit ratio.15,16,21-49
By definition, QUS cannot diagnose osteoporosis because it does not measure BMD (on which the official definition of osteoporosis is based). Nevertheless, peripheral QUS has been shown in large longitudinal studies to predict future fractures as accurately as DXA-derived BMD.20,21 QUS is more effective than patient-history questionnaires in screening programs and low readings represent a risk factor for osteoporosis, independent from DXA measurements.27,45 QUS can also be used for monitoring the effects of HRT and other osteoprotective therapies.46-50
The technique has recently been used in large-scale, prospective studies, and a meta-analysis of these studies shows a relative risk per standard deviation (RR/SD) of 1.6 (95% CI 1.41.8) for hip fracture.51-53 Although direct DXA hip measurement yielded a stronger prediction (RR/ SD of 2.4), the prediction of fracture risk by DXA BMD at other sites (wrist and spine) was lower than that observed with peripheral QUS.53 Of course, clinicians have to understand that peripheral QUS has limitations as well. Each of these instruments has its characteristics and device-specific equivalents of T-scores.
QUS measures structural characteristics that allow a clinician to differentiate between young and elderly bone, as well as between porotic bone and osteomalacic bone. Additionally, QUS correlates with the density and the elasticity of bone tissue.54-57 It uses different parameters to characterize bone tissue and identify patients at higher risk of fracture. Those parameters include speed of sound (SoS), broadband ultrasound attenuation (BUA), amplitude dependent speed of sound (AD-SoS), stiffness index (SI), and quantitative ultrasound index (QUI).57,58 SoS is closely related to bone mineralization and there is a close correlation between SoS and BMD at the same site (r = 0.780.91).46,47 BUA, on the other hand, is more influenced by the structural and elastic characteristics of trabecular bone, including porosity.59
The shape of the QUS wave can give information on the characteristics, structure, and geometry of the bone being analyzed.60,61 A series of parameters describes the mechanical properties of the bone, independent of mineral density.27,45
Just concentrating on one site for the moment, studies have shown that the bone architecture of the phalanx has an effect on QUS parameters.61-63 In a large European study on over 10,000 women, the application of signal processing techniques to the measurements recorded in phalangeal QUS led to the determination of a new parameter, the UBPI (Ultrasound Bone Profile Index), which is closely related to fracture risk.15
Several lines of evidence indicate that peripheral QUS and central DXA have a similar ability to predict osteoporosis-related fractures. The EPIDOS and the SOF trials, two large scale prospective studies that investigated the role of heel QUS and central DXA for fracture risk prediction, revealed that the odds ratios obtained for BUA and SoS were respectively 2.0 and 1.7.23,24 The odds ratio for phalanx AD-SoS in evaluating low-energy peripheral fractures was 1.5 [95% CI 1.11.7].64
The validity of peripheral bone assessment has been recently investigated in the NORA (National Osteoporosis Risk Assessment) study.11 More than 200,000 women have been investigated, showing the high degree of ability to predict the risk for future fracture for QUS at the phalanx, forearm and calcaneus. This study confirms that QUS can discriminate normal and pathologic bone and predict fracture risk, as previously reported in cross sectional and prospective, longitudinal studies.15,22-24,38,39,55,57,64
Thus, large studies have demonstrated no significant differences between peripheral QUS and central DXA in discriminating subjects with vertebral and hip fractures.15,65-68
The QUS technology available today is reliable and reproducible. The long-term coefficient of variation of QUS at the phalanx, for example, is less than 1%.15 In the early 1990s, a number of clinical research centers were involved in the study of QUS at the phalanx. This site is characterized by a high turnover and therefore is particularly affected by the metabolic modifications induced by menopause-related hormonal changes, and by hormone replacement.15,31,32,35,49,69,70 Similar studies with heel QUS have shown the effects of therapy with calcitonin, bisphosphonates, and HRT.47,48,50,71
There are also large studies on QUS applied to the calcaneus that show a coefficient of variation of 1% for SoS, less than 4% for BUA, and 1% for combination parameters like SI.23,24,55,58
Peripheral QUS has now been well validated and is supported by scientific documentation sufficient to warrant the following statement by the British National Osteoporosis Society (NOS)27:
Today portable and low-cost peripheral QUS devices can be used in primary-care screening to reduce fracture rates in older people. Peripheral QUS, when used in a systematic and wise manner and in conjunction with other risk factors, seems to be a reasonable approach for the prevention of osteoporosis in postmenopausal women.
1. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. WHO Technical Report Series, No. 843, WHO Study Group. 1994.
2. Slemenda C, Hui SL, Longcope C, et al. Sex steroids and bone mass. A study of changes about the time of menopause. J Clin Invest. 1987;80:1261-1269.
3. Riggs BL, Wahner HW, Dunn WL, et al. Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis. J Clin Invest. 1981;67:328-335.
4. Notelovitz M. Osteoporosis: screening, prevention, and management. Fertil Steril. 1993;59:707-725.
5. Nilas L, Christiansen C. The pathophysiology of peri- and postmenopausal bone loss. Br J Obstet Gynaecol. 1989;96:580-587.
6. Gambacciani M, Spinetti A, de Simone L, et al. The relative contributions of menopause and aging to postmenopausal vertebral osteopenia. J Clin Endocrinol Metab. 1993;77:1148-1151.
7. Gambacciani M, Spinetti A, De Simone L, et al. Postmenopausal bone loss of the proximal femur: estimated contributions of menopause and aging. Menopause. 1995;2:169-174.
8. Consensus development conference: diagnosing prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650.
9. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312:1254-1259.
10. Torgerson DJ, Campbell MK, Thomas RE, et al. Prediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res. 1996;11:293-297.
11. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 2001;286:2815-2821.
12. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet.1996;348:1535-1541.
13. Ettinger B, Black DM, Mitlak B, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645.
14. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. 2002;17:1-10.
15. Wüster C, Albanese C, De Aloysio D, et al. Phalangeal osteosonogrammetry study: age-related changes, diagnostic sensitivity, and discrimination power. The Phalangeal Osteosonogrammetry Study Group. J Bone Miner Res. 2000;15:1603-1614.
16. Luisetto G, Camozzi V, De Terlizzi F. Use of quantitative ultrasonography in differentiating osteomalacia from osteoporosis: preliminary study. J Ultrasound Med. 2000;19:251-256.
17. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650.
18. NIH Consensus Development Panel on Osteoporosis, Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2002;285:785-795. 19. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fracture. The Study of Osteoporotic Fractures Research Group. Lancet. 1993;341:72-75.
20. Hadji P, Bock K, Gotschalk M, et al. The influence of serum leptin concentration on bone mass assessed by quantitative ultrasonometry in pre- and postmenopausal women. Maturitas. 2003;44:141-148.
21. Langton CM, Palmer SB, Porter RW. The measurement of broadband ultrasonic attenuation in cancellous bone. Eng Med. 1984;13:89-91.
22. Glüer CC. Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. The International Quantitative Ultrasound Consensus Group. J Bone Miner Res. 1997;12:1280-1288.
23. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 1996;348:511-514.
24. Bauer DC, Glüer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. A prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med. 1997;157:629-634.
25. Hans D, Fuerst T, Lang T, et al. How can we measure bone quality? Baillieres Clin Rheumatol. 1997;11:495-515.
26. Sili Scavalli A, Marini M, Spadaro A, et al. Ultrasound transmission velocity of the proximal phalanxes of the non-dominant hand in the study of osteoporosis. Clin Rheumatol. 1997;16:396-403.
27. Reid DM, Stewart A. Position statement on the use of quantitative ultrasound in the management of osteoporosis. Bath: National Osteoporosis Society. 2001.
28. Gambacciani M, Spinetti A, Gallo R, et al. Ultrasonographic bone characteristics during normal pregnancy: longitudinal and cross-sectional evaluation. Am J Obstet Gynecol. 1995;173:890-893.
29. Rubin CT, Pratt GW, Porter AL, et al. The use of ultrasound in vivo to determine acute change in the mechanical properties of bone following intense physical activity. J Biomech. 1987;20:723-727.
30. Cepollaro C, Agnusdei D, Gonnelli S, et al. Ultrasonographic assessment of bone in normal Italian males and females. Brit J Radiol. 1995;68:910-914.
31. Gambacciani M, Benussi C, Cappagli B, et al. Quantitative bone ultrasonometry in climacteric women. J Clin Densitom. 1998;1:303-308.
32. Ventura V, Mauloni M, Mura M, et al. Ultrasound velocity changes at the proximal phalanxes of the hand in pre-, peri- and postmenopausal women. Osteoporos Int. 1996;6:368-375.
33. Murgia C, Cagnacci A, Paoletti AM, et al. Comparison between a new ultrasound densitometer and single-photon absorptiometry. Menopause. 1996;3:149-153.
34. Baran DT. Quantitative ultrasound: a technique to target women with low bone mass for preventive therapy. Am J Med. 1995;98:48S-51S.
35. de Aloysio D, Rovati LC, Cadossi R, et al. Bone effects of transdermal hormone replacement therapy in postmenopausal women as evaluated by means of ultrasound: an open one year prospective study. Maturitas. 1997;27:61-68.
36. Mautalen C, Vega E, Gonzalez D, et al. Ultrasound and dual x-ray absorptiometry densitometry in women with hip fracture. Calcif Tissue Int. 1995;57:165-168.
37. Faulkner KG, McClung MR, Coleman LJ, et al. Quantitative ultrasound of the heel: correlation with densitometric measurements at different skeletal sites. Osteoporosis Int. 1994;4:42-47.
38. Gonnelli S, Cepollaro C, Agnusdei D, et al. Diagnostic value of ultrasound analysis and bone densitometry as predictors of vertebral deformity in postmenopausal women. Osteoporosis Int. 1995;5:413-418.
39. Baran DT, Kelly AM, Karellas A, et al. Ultrasound attenuation of the os calcis in women with osteoporosis and hip fractures. Calcif Tissue Int. 1988;43:138-142.
40. Gregg EW, Kriska AM, Salamone LM, et al. The epidemiology of quantitative ultrasound: a review of the relationships with bone mass, osteoporosis and fracture risk. Osteoporos Int. 1997;7:89-99.
41. Hadji P, Hars O, Bock K, et al. Age changes of calcaneal ultrasonometry in healthy German women. Calcif Tissue Int. 1999;65:117-120.
42. Hadji P, Hars O, Sturm G, et al. The effect of long-term, non-suppressive levothyroxine treatment on quantitative ultrasonometry of bone in women. Eur J Endocrinol. 2000;142:445-450.
43. Hadji P, Kalder M, Backhus J, et al. Age-associated changes in bone ultrasonometry of the os calcis. J Clin Densitom. 2002;5:297-303.
44. Hadji P, Jäckel C, Hars O, et al. Bone mass in women with breast cancer. J Bone Miner Res. 1999;14(suppl 1):202.
45. Benitez CL, Schneider DL, Barrett-Connor E, et al. Hand ultrasound for osteoporosis screening in postmenopausal women. Osteoporos Int. 2000;11:203-210.
46. Machado AB, Ingle BM, Eastell R. Monitoring alendronate therapy with quantitative ultrasound (QUS) and dual x-ray absorptiometry (DXA). J Bone Miner Res. 1999;14(suppl 1):SU377.
47. Hadji P, Hars O, Schuler M, et al. Assessment by quantitative ultrasonometry of the effects of hormone replacement therapy on bone mass. Am J Obstet Gynecol. 2000;182:529-534.
48. Gonnelli S, Cepollaro C, Montagnani A, et al. Heel ultrasonography in monitoring alendronate therapy: a four-year longitudinal study. Osteoporos Int. 2002;13:415-421.
49. Mauloni M, Rovati LC, Cadossi R, et al. Monitoring bone effect of transdermal hormone replacement therapy by ultrasound investigation at the phalanx: a four-year follow-up study. Menopause. 2000;7:402-412.
50. Giorgino R, Lorusso D, Paparella P. Ultrasound bone densitometry and 2-year hormonal replacement therapy efficacy in the prevention of early postmenopausal bone loss. Osteoporos Int. 1996; 6(supp l1):S341.
51. Faulkner K, Abbott TA, Furman WD, et al. Fracture risk assessment in NORA is comparable across peripheral sites. J Bone Miner Res. 2001;16(suppl 1):S144.
52. Njeh CF, Hans D, Li J, et al. Comparison of six calcaneal quantitative ultrasound devices: precision and hip fracture discrimination. Osteoporos Int. 2000;11:1051-1062.
53. Woodhouse A, Black DM. BMD at various sites for the prediction of hip fractures: a meta analysis. J Bone Miner Res. 2000;15(suppl 1):S145.
54. De Terlizzi F, Battista S, Cavani F, et al. Influence of bone tissue density and elasticity on ultrasound propagation: an in vitro study. J Bone Miner Res. 2000;15:2458-2466.
55. Hans D, Njeh CF, Genant HK, et al. Quantitative ultrasound in bone status assessment. Rev Rhum Engl Ed. 1998;65:489-498.
56. Hans D, Wu C, Njeh CF, et al. Ultrasound velocity of trabecular bones reflects mainly bone density and elasticity. Calcif Tissue Int. 1999;64:18-23.
57. Njeh CF, Hans D, Fuerst T, et all. Quantitative Ultrasound: Assessment of Osteoporosis and Bone Status. London: Martin Dunitz Ltd; 1999:47-73.
58. Hadji P, Hars O, Wüster C, et al. Stiffness index identifies patients with osteoporotic fracture better than ultrasound velocity or attenuation alone. Maturitas. 1999;31:221-226.
59. Glüer CC, Wu CY, Jergas M, et al. Three quantitative ultrasound parameters reflect bone structure. Calcif Tissue Int. 1994;55:46-52.
60. Battista S, de Terlizzi F, Müller R, et al. Bone density and architecture: how do they affect ultrasound parameters? Presented at the 14th International Bone Densitometry Workshop, Warnemünde, Germany, Sept 3-8 2000.
61. Cadossi R, Canè V. Pathways of transmission of ultrasound energy through the distal metaphysics of the second phalanx of pigs: an in vitro study. Osteoporos Int. 1996;6:196-206.
62. Barkmann R, Lüsse S, Stampa B, et al. Assessment of the geometry of human finger phalanges using quantitative ultrasound in vivo. Osteoporos Int. 2000;11:745-755.
63. Chaffai S, Peyrin F, Nuzzo S, et al. Ultrasonic characterization of human cancellous bone using transmission and backscatter measurements: relationships to density and microstructure. Bone. 2002;30:229-237.
64. Mele R, Masci G, Ventura V, et al. Three-year longitudinal study with quantitative ultrasound at the hand phalanx in a female population. Osteoporos Int. 1997;7:550-557.
65. Reginster JY, Dethor M, Pirenne H, et al. Reproducibility and diagnostic sensitivity of ultrasonometry of the phalanges to assess osteoporosis. Int J Gynaecol Obstet. 1998;63:21-28.
66. Hartl F, Tyndall A, Kraenzlin M, et al. Discriminatory ability of quantitative ultrasound parameters and bone mineral density in a population-based sample of postmenopausal women with vertebral fractures: results of the Basel Osteoporosis Study. J Bone Miner Res. 2002;17:321-330.
67. Glüer CC, R Eastell, DM Reid, et al. Association of quantitative ultrasound parameters and bone density with osteoporotic vertebral deformities in a population based sample: the OPUS study. J Bone Miner Res. 2001;16(suppl 1):F103.
68. Krieg M, J Cornuz, P Burckardt and the SEMOF Study group. Comparison of three bone ultrasounds for determining hip fracture odds ratios. Results of the SEMOF study. J Bone Miner Res. 2001;16(suppl 1):F101.
69. Mauloni M, Ventura V, de Aloysio D, et al. Multicenter Italian Study on the Bone Mass Ultrasonographic Evaluation at the Phalanges in the Climacteric (VUMOF-CLIFE). Ital J Mineral Electrol Metab. 2000;14:23-26.
70. Gambacciani M, Donati Sarti C. Phalangeal quantitative ultrasonography at climacteric in the Italian menopause project. F-25-04 10th World Congress on the Menopause, Berlin, Germany, 2002.
71. Gonnelli S, Cepollaro C, Pondrelli C, et al. Ultrasound parameters in osteoporotic patients treated with salmon calcitonin: a longitudinal study. Osteoporos Int. 1996;6:303-307.
Marco Gambacciani. Advances in bone assessment.
Sep. 1, 2003;48:73-83.