BONE ASSESSMENT

Advances in bone assessment

By Marco Gambacciani, MD

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 But it is important to realize that defininition of osteoporosis as a BMD below 2 SD was originally made for epidemiologic reasons to compare female populations—and not as a threshold for intervention.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.

Central DXA does have its limitations

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

A role for quantitative ultrasound

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 1.4–1.8) 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 = 0.78–0.91).^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

Using peripheral QUS to assess fracture risk

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 1.1–1.7].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

An official position on QUS

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:

• A low QUS value constitutes an independent risk factor for osteoporotic fracture in postmenopausal women.

• A low QUS value is a marker for low bone mass that is more important than clinical risk factors.

• Patients with low QUS values can be prescribed a further BMD test or a therapeutic regimen if other clinical risk factors are present.

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.

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Dr. Gambacciani is the Chief of the Menopause and Osteoporosis Unit, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, "Piero Fioretti" University of Pisa, Pisa, Italy.

Key points

• Although DXA has been considered the gold standard, many clinicians 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.

• Central DXA cannot distinguish the normal bone of a teenager from a porotic bone of an older woman, nor can it differentiate osteomalacia from osteoporosis.

• Bone ultrasound can give information on bone strength and quality rather than on density. In recent years, cost-effective, radiation-free quantitative ultrasound has emerged as an alternative to DXA in the assessment of bone structure, bone quality, and of fracture risk.

• Large-scale prospective studies of QUS show a relative risk of hip fracture per standard deviation (RR/SD) of 1.6. Although direct DXA hip measurement yielded a stronger prediction (RR/SD of 2.4), the prediction of fracture risk by DXA bone mineral density at the wrist and spine was lower than that observed with peripheral QUS.

Marco Gambacciani. Advances in bone assessment.

Contemporary Ob/Gyn

Sep. 1, 2003;48:73-83.