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Monitoring corticosteroid-induced damage to the structural integrity of the bone by dual-energy X-ray absorptiometry or quantitative ultrasound

  1. Top of page
  2. Monitoring corticosteroid-induced damage to the structural integrity of the bone by dual-energy X-ray absorptiometry or quantitative ultrasound
  3. Conflict of interest statement
  4. References

Dear Sir,

Glucocorticoids (GCs) have been in use for years in a large variety of debilitating conditions as various as chronic lung, rheumatic, inflammatory bowel and skin diseases. Their side effects are as numerous as their multiple therapeutic indications. Their most debilitating complication consists of osteoporotic fragility fractures. As Malerba et al. state, the pathophysiology of GC-induced osteoporosis (GC-OP) is not yet fully understood. Oral GCs have been by far the most studied. Both daily, alternate day, cumulative doses as well as GC treatment duration have been implicated in the development of GC-OP [1, 2]. As mentioned by Malerba et al., fractures in GC users may occur at a higher bone mineral density (BMD) than in postmenopausal OP [3], well in line with the rapid occurrence soon after the start of GC therapy. Age, gender, menopausal status, BMD before GC therapy, as well as the systemic condition necessitating GC might all have a role. Additionally, differences exist in individual susceptibility to GC-OP, some patients being paradoxically threatened by small doses and others proving to be resistant to elevated doses [4, 5].

Inhaled GCs have demonstrated their efficacy in the treatment of asthma [6]. However, they are certainly not devoid of after-effects on BMD [7], and may even be associated with fracture occurrence [8]. Whether bone fragility pertains directly to inhaled GC-induced bone loss or to the underlying condition and in which proportion these factors play a role remains definitely unanswered [9, 10].

Glucocorticoids induce both a modest increase in bone resorption and a proportionally more marked decrease in bone formation, leading to a decrease in BMD. Several mechanisms concur to act more or less synergistically in patients: secondary hyperparathyroidism induced by a decreased intestinal calcium absorption [11], increased urinary calcium excretion [12], increased sensitivity of osteoblasts to PTH [13], interference with growth hormone-insulin growth factor-1 axis at the hypothalamic, pituitary and target organ levels, and depression of osteoblast function [14], probably through inhibition of their recruitment and activity as well as increased apoptosis of osteoblasts and osteocytes [15]. Osteoclastic bone resorption might be promoted through an increase in receptor activator of NF-κB ligand (RANKL) and a decrease in osteoprotegerin [16]. The secretion of oestrogens and testosterone is also impaired [17]. GC-induced myopathy might further lead to decreased BMD.

As indicated, BMD measurement by dual-energy X-ray absorptiometry (DXA) might show a higher BMD in GC-OP patients with fractures than in postmenopausal patients with fractures [3]. These observations have led to the recommendation of an intervention threshold for therapy at higher T-scores than in non GC-exposed patients [18–20]. The finding that structural damage to the bone in GC-treated patients is not fully reflected in DXA measurements is in line with recent evidence that there is more to osteoporosis than low bone density alone. Over the past few years, concepts of what constitutes osteoporosis have evolved from the single criterion of low bone mass to a more inclusive consideration of bone strength, based on both quantity and quality and integrating those traditional measures of bone quantity (mass) with more recently examined components of bone quality like, for example, turnover and architecture [21]. Because of the increasing awareness that bone quantity is only one of the factors involved, assessment of the aetiology of osteoporotic fractures is still ongoing. Although a number of methods have been developed to measure aspects of bone quality, the resulting data have thus far been exploratory. Histomorphometric assessment of bone biopsy specimens have been the basis for indirect, two-dimensional assessments of trabecular structure, whilst development of micro-computed tomography (micro-CT) scanning has enabled three-dimensional evaluation of trabecular bone specimens to assess trabecular connectivity [22]. However, the invasive nature of these procedures limits wide use. New methods are needed to provide insight into the causes and effects of bone fragility.

In this regard, quantitative ultrasound (QUS) has recently been proposed as an adjunct or alternative to X-ray-based bone densitometry as it does not involve exposure to ionizing radiation and is relatively simple to implement and process. QUS at the calcaneus is an attractive screening tool because of the (relatively) low cost, the lack of ionizing radiation, and the fact that it has been shown to predict future fracture risk [23, 24]. However, calcaneal QUS thresholds for the diagnosis or treatment of osteoporosis have not as yet been defined. In view of these limitations, QUS is mainly used to prescreen for potentially osteoporotic individuals [25]. In most centres, patients with low ultrasound values are referred for additional density measurement by DXA.

As a mechanical wave, ultrasound interacts with bone in a fundamentally different way from ionizing electromagnetic radiation and may be sensitive to some aspect of bone structure other than bone density. In line with this concept, evidence from a number of in vitro studies suggests that QUS may be sensitive, in certain circumstances, to cancellous bone architecture in addition to density [26–30]. This has led to an implicit assumption that clinical QUS measurements at the calcaneus may provide useful information about trabecular architecture in addition to density.

However, there are several reasons for caution before drawing such a conclusion. Many in vitro studies have used high density animal cancellous bone which can display very different acoustic behaviour from human bone [26–28]. Other studies have drawn conclusions about the role of trabecular architecture from QUS measurements in three orthogonal axes, whereas clinical measurements are made in a single direction, thereby limiting the possible influence of architecture [27, 30]. Furthermore, some of these studies have used experimental conditions far removed from the clinical situation, such as crushing or demineralization of real bone. Finally, few studies have investigated the relationships between QUS, density and architecture directly in the human calcaneus, and none has reported evidence for significant associations between architecture and QUS independently of density [29, 31, 32]. In most of these studies sample sizes were small, architecture was assessed using two-dimensional histomorphometry, and/or QUS measurements were not made on excised cancellous bone samples.

In our own research programme, we utilized a large number of vertebral cancellous bone samples and micro-CT architecture measurements and observed significant density-independent relationships between QUS and architecture, albeit as part of a complex orientation-dependent pattern of associations [30]. However, because these results cannot necessarily be extrapolated to the heel where clinical measurements are most commonly made, we subsequently investigated the relationship of QUS to micro-CT-derived density and trabecular architecture measurements in a large number of human calcaneal samples [33]. Our data demonstrated a modest but significant density-independent relationship between QUS and trabecular architecture in the human calcaneus, but the causal relationship behind the variation in acoustic properties remained obscure. Given the relative weakness and complexity of the emerging associations between QUS and architecture, we concluded that it is prudent to regard current clinically available QUS measurements in calcaneal bone primarily as an indicator of calcaneal bone density rather than of trabecular architecture.

This conclusion fits with the available clinical evidence. Prospective studies have confirmed the value of ultrasound for predicting hip fracture risk, and provided evidence that calcaneal BUA or hip or calcaneal BMD have similar predictive accuracy [23, 24]. In these studies, BUA remained predictive of hip fracture after control for hip BMD, but there was little benefit from a combination of BUA and BMD, and the relationship between calcaneal BUA and hip fracture risk was no longer statistically significant after adjustment for calcaneal BMD [24]. Taken together, these clinical findings suggest that current ultrasound measurements at the heel do not provide clinically relevant information on fracture risk that is independent of calcaneal bone density. Overall, they emphasize the need for more research with non-DXA technologies before the latter could be routinely used in patients with GC-OP [20].

References

  1. Top of page
  2. Monitoring corticosteroid-induced damage to the structural integrity of the bone by dual-energy X-ray absorptiometry or quantitative ultrasound
  3. Conflict of interest statement
  4. References
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