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Biochemical measurements in Paget's disease of bone

Biochemical measurements in Paget's disease of bone
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   iochemical Measurements in Paget’s Disease of one By R.G.G. Russell, A. Colwell, R.A. Hannon, A. Blumsohn, Abdul Wahed Al-Dehaimi, A.M.A. Assiri, N.F.A. Peel, and R. Eastell zyxwvutsrqponmlkjihgfedcbaZYXW M ANY PRODUCTS derived from the in- creased metabolism of bone appear in serum or urine, where they can be measured as indicators of bone turnover and disease activ- ity.‘,’ In Paget’s disease, thcrc arc three major uses for such measurements: (1) to monitor disease activity in individual patients; (2) to evaluate dose-response relationships to new drugs in therapeutic trials; and (3) to evaluate the value of novel biochemical markers of bone metabolism, compared with established mark- ers. The requirements for each application are somewhat different. In general, the criteria that determine the value of any biochemical marker of tissue metabolism are its tissue specificity. the factors that control its synthesis and metabo- lism, its entry into and removal from the circula- tion, and its ease and reproducibility of measurc- ment. Alkaline phosphatase in serum is the most frequently used marker of bone metabolism, is of proven value in monitoring disease activity in individuals with Paget’s disease. is the standard measurement used in clinical trials, and is used for comparison with new markers. Alkaline phosphatase is an ectoenzyme anchored to cell surfaces. The bone isoenzyme is coded by the same gene as for the liver and kidney enzyme but differs as a result of posttranslational modi- fications with sialic acid residues. Based on studies of hypophosphatasia. the natural sub- strates for alkaline phosphatasc appear to in- clude pyridoxal phosphate, phosphoethanol- amine and inorganic pyrophosphate. The bone isoenzyme is used as a marker of bone forma- tion and can be measured selcctivcly by mcth- zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHG From the Department o Ifumrn Mettrbolrsrn rrtld C‘litlrc~nl Biochemistry, Univer.siq of‘Sh@eld Mrdktrl School, Sheffirld. England. Address repritlt requests to R. G. G. Rtr~wll, Depurtmwt of Human Metabolism and Clinicul Blocherrzrst~. Utlilvr.sit\~ f Shefield Medical School, Beech Hill Road, Shrfirlti. SI 0 2Rx, England. Copyright 0 1994 by W. B. Saur~den C’ornprrr~~ 0049-0172/9412304-0013 5.00/0 ods based on ditfcrentlal heat dcnaturatlon. ctcctrophorcsih. precipitation with wheat germ lcctin. and immunoassay with monoclonal OI- polyclonal antibodies. As bpccilic method5 t’or the bone isoenzymc arc becoming more rcadil available. thcsc arc likelv to hc used more frcqucntly. although the &grcc ot’ chany ob- served in Paget’s disease makes this lex\ nccc\- harv than in milder disorders ol’ bone turnoicr. However. measurement 01‘ the hone ibocnryme also should bc useful in monitoring patients whose alkaline phosphatasc levels arc initlailq within the normal reference range. in ibhom changes in the bone isocnzyme should hc ~LI;~II- titatively much greater in response to ment. The analytical precision of routine assms for alkaline phosphatasc is high. in the or&l ;)1 I ‘; to 2“;. and the day-to-day and month-to- month biological variation is small. Thcrctorc. changes of IO’; or more usually rcprc\cnt significant changes. Howcvcr. for clinical pur-- poses and in trials of therapies ;I dcc~-caxc (>I 7.5”; or more usually is rcquircd to indicate ;I signiticant clinical rcsponsc. The best-established marker of bone I-c\clr-p- tion is the measurement of hydroxyprolinc 111 urine. Hydroxyprolinc is dcrivcd from pcptidc breakdown products of ccjllagen. but hecausc hydroxyprolinc is not specific to hone collagen and is derived from collagen products in the diet and is metabolized. thcsc assays arc likclk to bc replaced bb measurcmcnts ot pcridinolinc\\. crosslinks derived from collagen. which do not suffer from these Jisadvantagcs. Ncvcrthelcsx. measurements of hydroxyproline. particularI in early morning fasting urines. have pr~>Lccl usef’uI in evaluating responses in trials clt‘ nc’\\ therapies. Their LIX in individual paticntk i\ handicapped by the low ~~rccision;re~~rociucihil- ity of assays, with coefficients of variation ((‘VI) typically ranging from IO’G to 3S? A change ot WY or so may therefore bc required in two consecutive measurements hcforc ii signiticant rcsponsc can be claimed. There is much hope that measurements of pyridinotincs, cspccialt 240 %m/narS ,nArthr/tfs amf/?heunJat~ll ol 23, NO (February). 1994, pp 240 243  BIOCHEMICAL MEASUREMENTS 241 deoxypyridinoline, which appears to be specific to bone, will provide more robust indicators of bone resorption rates.3-5 These assays currently depend mainly on high-performance liquid chro- matography techniques, which are labor-inten- sive. The CVs are approximately lo%, and there appear to be significant circadian6 and other sources of biological variation so that further validation is needed. In Paget’s disease the changes that occur are large, and there may be little advantage to using pyridinolines in- stead of hydroxyproline for practical purposes.5 However, in the future, fast and reproducible immunoassays, either of free pyridinolines or of degradation peptides containing them, are likely to make measurements of pyridinolines as readily available as alkaline phosphatase. Be- cause of their theoretical advantages, they are therefore likely to become established as the measurements of choice for evaluating changes in bone resorption. bone metabolism (eg, osteocalcin) and other collagen-derived peptides and bone matrix pro- teins often show unexpected deviations from the predicted increases compared with alkaline phosphatase and hydroxyproline, which may reflect aberrant production and metabolism of these products in untreated Paget’s disease. This is an important reminder that different biochemical markers reflect different biological processes. Levels of serum proteins (eg 1x-2 HS glycoprotein) that have a high affinity for bone may be reduced in the serum of patients with active Paget’s disease. Many other products of bone have been shown to have increased levels in serum and/or urine in Paget’s disease and reduced levels on treatment. These include products associ- ated with bone formation (eg, osteocalcin (also known as BGP, bone Gla protein), osteonectin, N- and C-terminal [ = PICP] propeptides of type I collagen), or with bone resorption (eg, acid phosphatase [ie, TRAP, tartrate-resistant acid phosphatase], free y-carboxy-glutamate, and hy- droxylysine glycosides, of which galactosyl-hy- droxylysine appears to be relatively specific for bone). Measurement of these other products of The currently used potent treatments for Paget’s disease, especially the bisphosphonates, can induce complete biochemical remissions. Because these drugs are inhibitors of bone resorption, the earliest biochemical changes that occur are in the resorption markers, which can show full responses within only a few days of starting treatment. In the routine treatment of patients, alkaline phosphatase levels change more slowly in response to treatment than those of markers of bone resorption, and the full response may not be seen for several weeks or even months.’ Judging responses on alkaline phosphatase level alone may therefore give a misleading picture of how effective treatment has been. For this reason, measurements of both alkaline phosphatase and appropriate bone resorption markers should become routine in the therapeutic management of Paget’s disease to ensure adequate responses to treatment. zyxwvutsrqponmlkji REFERENCES 1. Azria M, Russell RGG: Biochemical approaches to the measurement of bone metabolism in vivo. Curr Opin Orthop 3:103-109,199Z 2. Russell RGG, Beard DJ, Cameron EC, et al: Biochemi- cat markers of bone turnover in Paget’s disease. Metab Bone Dis Rel Res 3:255-262,198l 3. Editorial: Pyridinium crosslinks as markers of bone resorption. Lancet 2:278-279,1992 4. Uebelhart D, Gineyts E, Chapuy M-C, et al: Urinary excretion of pyridinium crosslinks: a new markers of bone disease. Bone Miner 8:87-96,1989 5. Hamdy NAT, Papapoulos SE, Colwell A, et al: Uri- nary collagen crosslink excretion: a better index of bone resorption than hydroxyproline in Paget’s disease of bone? Bone Miner 22:1-8,1993 6. Eastell R, Calvo MS, Burritt MF, et al: Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab 74:487-494, 1992 7. Yates AJP, Gray RES, Urwin GH, et al: Intravenous clodronate in the treatment and retreatment of Paget’s disease of bone. Lancet 1:1474-1477,1985
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