A study of bone turnover markers in prepubertal children with phenylketonuria
A study of bone turnover markers in prepubertal children with phenylketonuria
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青春期前苯丙酮尿症儿童骨转换标志物的研究
DOI：
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发表时间：
2004
影响因子：
3.6
通讯作者：
T. Laskowska
中科院分区：
文献类型：
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作者：
J. Ambroszkiewicz;J. Gajewska;T. Laskowska
为了研究低苯丙氨酸饮食对骨骼矿化状况的影响，我们比较了患有苯丙酮尿症的青春期前儿童和年龄匹配的健康对照组的生化骨形成和骨吸收标记物。饮食苯丙氨酸(Phe)限制是唯一已知的预防苯丙酮尿症患者神经损害和智力低下的策略。总体而言，大多数苯丙酮尿症患者在低Phe饮食的情况下，可以达到正常生长发育和智力发育。然而，有人认为，这种形式的饮食可能会影响骨代谢，特别是在生长和骨质疏松症最密集的儿童和青春期。一些作者已经描述了PKU患者的骨密度降低和骨质疏松症[1，2，3，5]。骨密度的测量只反映骨的矿物质状态，而不是骨代谢的动力学。[1，2，3，5]。显示整体骨骼活动的非侵入性生化标记物最近已被开发和验证，用于骨形成和骨吸收过程的评估。其中，骨钙素(OC)、骨碱性磷酸酶(BALP)和胶原1型交联型C-端肽(CTX)被认为具有临床应用价值。最近，属于肿瘤坏死因子受体家族的新型细胞分裂素骨保护素(OPG)被确定为破骨细胞生成和吸收过程的内源性抑制因子。我们的研究人群包括37名在华沙母婴研究所儿科接受监测的PKU儿童。将患者分为两组。A组(n=12，中位年龄4.5岁，3~10岁)严格遵循治疗饮食，血清Phe浓度接近参考值(189.4±64.2lmol/L)；B组(n=25，中位年龄6.0岁，3~10岁)不坚持饮食，Phe浓度升高(649.2±140.6 lmol/L)。计算每个患者最近3年的平均血磷浓度。PKU患儿给予氨基酸混合物PAM、Milupa-PKU2或不含苯基的饲料喂养。这些患者的钙和磷的值都是正常的。27例健康儿童(n=27，中位年龄5.9岁，4~9岁)为对照组。所有接受调查的儿童在种族上都是同性的。空腹后取静脉血，离心后测定血清Phe、钙、磷水平。其余血清标本冰冻采集，测定BALP、OC、CTX和OPG。根据McCaman和Robbins对Phe进行计量分析；使用Cobas Integra分析仪按标准程序测定钙和磷酸盐(瑞士罗氏)。血清OcX和CTX用免疫酶ELISA法测定(丹麦Osteeter)。对于BALP的测定，使用来自美国Metra BiosSystems的碱性B试剂盒，对于OPG，使用来自Biomedica(奥地利)的试剂盒。采用带Bonferroni校正的单因素方差分析进行ff检验。A组的骨形成和骨吸收指标低于B组，但差异无统计学意义(fiff)(表1)。然而，两组北大儿童的骨钙素、环磷酰胺和骨钙素浓度均显著低于年龄匹配的健康对照组，只有少数文献报道了北大受试者的骨代谢标志物fi。Perez-Duenas等人[6]在一组年轻患者中观察到了相同水平的OC和BALP，并显著降低了血清BALP
To investigate the effect of low-phenylalanine diets onbone mineralisation status, we compared biochemicalbone formation and resorption markers in prepubertalchildren with phenylketonuria with those of age-mat-ched healthy controls.Dietary phenylalanine (Phe) restriction is the onlyknown strategy of preventing neurological impairmentand mental retardation in patients with phenylketonuria(PKU). In general, most phenylketonuric patients on alow-Phe diet can achieve normal growth and intellectualdevelopment. It is suggested, however, that this form ofdiet may influence bone metabolism, especially inchildhood and adolescence when growth and boneturnover are at their most intensive. Some authors havedescribed decreased bone mineral density and osteope-nia in patients suffering from PKU [1, 2, 3,5].Measurements of bone mineral density (BMD) reflectonly bone mineral status but not the dynamics of boneturnover. Non-invasive biochemical markers whichshow global skeletal activity have lately been developedand validated for the assessment of bone formation andbone resorption processes. Among them, osteocalcin(OC), bone alkaline phosphatase (BALP) and collagentype 1 cross-linked C-telopeptide (CTX) are consideredto be clinically useful. Recently, the novel cytokineosteoprotegerin (OPG), belonging to the tumournecrosis factor receptor family has been established asan endogenous inhibitor of osteoclastogenesis andresorption processes.Our study population consisted of 37 childrenwith PKU under surveillance at the Department ofPaediatrics at the Institute of Mother and Child inWarsaw. Patients were divided into two groups. Thosein group A (n =12; median age 4.5 years; range 3–10years) followed their therapeutic diet strictly and hadmean serum Phe concentrations close to the referencerange (189.4±64.2 lmol/l) and those in group B(n =25; median age 6.0 years; range 3–10 years) did notadhere to their diet and had increased Phe concentra-tions (649.2±140.6 lmol/l). The mean serum Pheconcentration was calculated for the last 3 years of thelife of each patient. Children with PKU were fed with anaminoacid mixture PAM, Milupa-PKU 2 or Phenyl-free. These patients have normal values for calcium andphosphate. Healthy children sent to our laboratory forroutine analytical control (n =27; median age 5.9 years;range 4–9 years) were the reference group. The wholegroup of investigated children was ethnically homoge-nous. Venous blood samples were collected after anovernight fast, centrifuged and serum levels of Phe,calcium and phosphate were determined. Remainingserum samples were frozen and collected for measure-ment of BALP, OC, CTX and OPG. Phe was assayedfluorometrically according to McCaman and Robbins;calcium and phosphate by standard procedures with aCobas Integra analyser (Roche, Switzerland). Serum OCand CTX were measured by immuno-enzymatic ELISAassays (Osteometer, Denmark). For determination ofBALP, the Alkphase-B kit from Metra Biosystems(USA) and for OPG, the kit from Biomedica (Austria)were used. The differences were evaluated by ANOVAwith Bonferroni correction. The significance was set atP <0.05.We observed lower levels of bone formation andbone resorption markers in group A than in group B,but these differences are not statistically significant(Table 1). However, OC, CTX and OPG concentrationswere significantly lower in both groups of PKU childrenin comparison to the healthy age-matched controls.There are only a few papers presenting values of boneturnover markers in PKU subjects. Perez-Duenas et al.[6] observed the same levels of OC and BALP in a groupof younger patients and significantly lower serum BALP