Pediatr Nephrol (2000) 14:654–657
© IPNA 2000
R E V I E W A RT I C L E
Janusz Feber · Pierre Cochat · Pierre Braillon
Bone mineral density in children after renal transplantation
Received: 3 May 1999 / Revised: 16 January 2000 / Accepted: 23 January 2000
Abstract A successful kidney transplantation (Tx) offers good quality of life for children suffering from chronic renal failure. However, some metabolic abnormalities may not be corrected and may persist after Tx despite good graft function. Post-Tx bone disease seems to be a universal finding in adult Tx recipients, and is most probably related to steroids. Reports on bone mineral density (BMD) in children after renal Tx are not uniform. Recent studies suggest that BMD is normal when corrected for height. However, longitudinal studies show a transient decrease in BMD in the early post-Tx period. These controversial results raise the issue of the correct interpretation of dual-energy X-ray absorptiometry in children with stunted growth. Etiopathogenetic factors of the decreased BMD, preventive and therapeutic measures are discussed. In conclusion, the results of dual energy X-ray absorptiometry should be interpreted with caution, especially in children with disturbed growth. Key words Bone mineral density · Kidney transplantation · Dual energy X-ray absorptiometry
Introduction Kidney transplantation (Tx) has been regarded as the treatment of choice for patients suffering from chronic renal failure (CRF). Despite improved patient and graft survival, patients after Tx may not achieve full rehabilitation and good quality of life, due to persistence of metabolic abnormalities associated with CRF preceding Tx [1, 2]. Metabolic bone disease is a particularly intriguing J. Feber (✉) 1st Department of Pediatrics, University Hospital Motol, V uvalu 84, 150 06 Praha, Czech Republic e-mail:
[email protected] Tel.: +420-2-24432000, Fax: +420-2-24432020 P. Cochat · P. Braillon Department de Pédiatrie, Hôpital Edouard Herriot, Lyon, France
problem that may persist even after successful Tx. Immunosuppression regimens, especially administration of steroids, may also compromise normalization of bone mineral metabolism. An increased risk of fracture has been reported in adult transplant recipients [3]. Decreased bone mineral density (BMD), osteopenia, and aseptic necrosis were also observed in children after Tx [4, 5]. The aim of this article is to review available data on BMD after Tx. Advantages and drawbacks of densitometry measurement are given, especially with regard to growth retardation of children with CRF. The mechanism of post-Tx bone loss and possible preventive and therapeutic measures are also discussed.
Methods for bone analysis and their interpretation Classical X-ray has been traditionally used for bone imaging. However, it is not sensitive enough to detect early changes in bone structure, because pathology becomes evident when 30%–40% of bone mineral is already lost [6]. Dual-energy X-ray absorptiometry (DEXA) offers a rapid, accurate, and highly reproducible assessment of bone mineral content with a very low radiation exposure [7]. It has been widely used in adult patients for screening and monitoring of osteoporosis [8]. Its use in pediatrics is rather limited to children suffering from chronic disease associated with bone metabolic problems. The interpretation of DEXA results in the pediatric population is more complicated than in adults because of developmental changes, which must be taken into account. In addition, children with CRF are frequently growth retarded, so that their statural height does not correspond to their chronological age. Therefore, the interpretation of DEXA results may be incorrect if adjusted for age only. One solution would be to use height-adjusted BMD values [9]. But even when such adjustment is made, this technique measures only the amount of mineral in the
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scanned area (area density), usually vertebrae, and does not describe the true density measured per bone volume (volume density) [10]. This can be done by calculating the vertebral volume [11] or by the use of quantitative computed tomography (QCT). QCT is able to differentiate cortical and trabecular bone, but has a substantially higher radiation load and cannot be repeated as frequently as DEXA for monitoring changes in BMD. Another solution might be to use bone mineral content (BMC), which depends on both the size and density of skeletal bone. A low BMC adjusted for sex and age may be a reflection of a small skeleton (small bone area) or a low bone density. This has led to the concept of BMC adjusted for bone area [12]. In this method bone mineralization is assessed in three steps: height for age, bone area for height, and BMC for bone area. These three steps correspond to three different causes of reduced bone mass: short bones, narrow bones, and light bones. This technique may be especially important in children with chronic diseases because of the considerable variation in bone and body size for a given age, and because chronic disease affecting bone mineralization often affects body and bone size as well. It is also possible to use BMC values adjusted simultaneously for age, weight, and height [13]. Despite correction for height and volume, DEXA does not allow the assessment of bone quality, where the gold standard for bone quality assessment is represented by bone biopsy. However, bone biopsy is an invasive procedure, which cannot be used for screening and monitoring purposes. Therefore, attempts have been made to use ultrasound densitometry [14] for assessment of both bone quantity and bone quality. It is based on the assumption that ultrasound propagation and attenuation is dependent on bone density. Two parameters are measured: broadband ultrasound attenuation (BUA) and speed of ultrasound (SOS). BUA is related to bone density, whereas SOS reflects both bone density and elasticity [15]. Ultrasound densitometry was able to predict fracture risk as well as or even better than DEXA [16]. It seems therefore that this technique might be more widely used in the future, especially in children, since it is radiation free.
Bone density after renal Tx in adults BMD has been extensively studied over the past several years in this population. It is usually described as postTx bone disease [17]. Julian et al. [18] reported decreased BMD following Tx; the loss of BMD amounted to 6.8% at 6 months and 8.8% at 18 months compared with initial values. This loss corresponded to the decreased bone formation rate found in bone biopsy and was attributed to the side effects of steroids. The decrease in BMD following Tx was also observed by other authors [19, 20, 21, 22]. In most studies bone mineral loss was related to cumulative dose of steroids [23, 24, 25]. However, in some no correlation between BMD loss
and steroids was found [19, 20]. In addition, differences in BMD loss between males and females were noted [20, 23], which would indicate a possible influence of sex steroids. The loss of BMD is usually greater at the lumbar spine level compared with total body BMD [20] or distal skeleton (cortical bones) represented by radius [26]. Spinal bone loss is probably accelerated because of the relatively high metabolic activity of the vertebral trabecular bone, which is also more prone to the side effects of steroids. However, a recent study in long-term renal Tx patients showed a reduced BMD in both trabecular and cortical bone, but the reduction was not as severe as that reported earlier [27]. In summary, post-Tx bone disease seems to be a universal finding in adult renal Tx recipients and is probably related to steroids.
BMD in children following kidney Tx In pediatric renal Tx recipients the findings are not uniform, which may be due to interpretation problems outlined above. Chesney et al. [28] first described bone loss in children after kidney Tx. A significant demineralization was found in 62% of children and 61% of measurements. In addition, children receiving daily steroid treatment had a significantly greater loss of BMC than children on alternate-day steroid treatment. Moderate-tosevere osteopenia in children following Tx was also reported by other authors [29, 30]. In our longitudinal study, the greatest decrease in BMD was observed during the first 6 months following Tx and was correlated with cumulative dose of steroids [4]. Subsequent stabilization or normalization was noted as late as 12 and 24 months after Tx. However, in the above-mentioned studies BMD was related to chronological age only. Two recent crosssectional studies did not show a decreased BMD if adjusted for height and raised the issue of the correct interpretation of BMD results [9, 31]. Both studies emphasized the importance of height adjustment of DEXA results in children with growth retardation. But even after simultaneous age, weight, and height correction [13], we observed a transient decrease in BMC following kidney Tx. The lowest minimum median value was observed 6 and 12 month after Tx, with subsequent improvement during the 2nd and 3rd year after Tx [32]. In conclusion, bone mineral status may be normal in children after Tx as observed in cross-sectional studies, but a temporary decrease in BMC in the early post-Tx period has been observed in longitudinal studies.
Prophylactic and therapeutic strategies for prevention of bone loss The etiology of the post-Tx bone loss is probably multifactorial [33, 34]. Persistent hyperparathyroidism is noted in a substantial number of Tx patients and is often unresponsive to calcitriol therapy. Steroids are probably
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one of the major pathogenetic factors as they reduce the osteoblast activity and accelerate bone resorption. Other drugs, such as loop diuretics, heparin, and aluminumcontaining medicaments, may also negatively influence bone metabolism. Therefore, preventive measures are aimed at avoiding the use of these drugs and minimizing the dose of steroids. An oxazoline analogue of prednisone (deflazacort) has been shown to have fewer side effects on bone loss and fat accumulation in patients after Tx [35]. Administration of calcium and calcitriol may prevent corticosteroid-induced bone loss [36, 37]. A recent study has shown that calcitonin or biphosphonates (clodronate) may prevent bone loss in the early period after Tx [38]. Experience with biphosphonates in children is rather limited, but pamidronate was reported to be effective for the management of osteopenia in children with renal failure and/or renal Tx [39]. Unfortunately, no controlled trials on the use of calcitonin or biphosphonates in children after Tx are available to date. In conclusion, DEXA should be used with caution for the assessment of bone structure in children with CRF and after renal Tx. Statural height should be taken into account for the correct interpretation of DEXA results. Several preventive measures and drugs can be applied, even in children, in order to prevent and treat post-Tx bone disease.
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