278
Health and Social Security in July of that year. This meeting was attended by the government’s Chief Medical Officers and representatives of the GMC and the Joint Committee on Higher Medical Training (JCHMT). Prof John Crofton, then chairman of the JCHMT, expressed a worry that a doctor returning from "the continent" with an EC specialist certificate might, through the courts, achieve the right to be acknowledged as a specialist and therefore to be appointed as a National Health Service consultant. However, the GMC representatives assured him that the Council had legal advice that it could issue a "certificate of specialist training" and not a "certificate of completion of specialist training", and indeed claimed that the apparent need to have the word "complete" in the text arose only because of "a mistake in the English translation of the directives". If the issues had been debated in a more open forum the problems of specialist registration might well have been resolved in a different way. Instead, they were discussed in private and largely by those who were not eager for change. And in many of the meetings there was such disparity between the content of the discussion and the decisions eventually reached that an observer could be forgiven for concluding that some of the participants were working to a different agenda from everybody else. The latest crisis means that Britain’s postgraduate medical education and hospital career structure could face a radical shake-up. This should be achieved by open debate that involves those who will perforce be regulated. There seem to be only two courses of action the UK can take to comply with European law. The GMC could award EC certificates to UK doctors only on completion of their specialist training, which at present is either on accreditation or when they are appointed as consultants; that would disadvantage those wanting to work in other EC countries because they would have to train for more years than their European counterparts to get the certificate. The alternative is a radical revision of the existing hospital career structure, with the aim of providing posts to which holders of an EC Specialist Certificate might aspire but which would not undermine the present status or quality of consultants in the National Health Service. But who is going to be the first to define the difference between a consultant and a specialist? The government is to form a working group to study these issues, which will report within 6 months.
Pyridinium crosslinks as markers of bone resorption There has been considerable interest lately in non-invasive metabolism. 1,2
methods
of
monitoring bone Radioisotopic techniques and quantitative histomorphometry give very precise
information on rates of bone turnover but are unsuitable for repeated monitoring of therapy or for
screening studies. Measurement of urinary pyridinium crosslinks provides an index of bone resorption rates; this approach offers substantial advantages over urinary hydroxyproline estimations, which are non-specific and insensitive. Pyridinium crosslinks are products of a unique series of reactions during the maturation of collagen fibrils that lead to the formation of pyridinoline (also known as hydroxylysyl pyridinoline) and deoxypyridinoline (or lysyl pyridinoline). Bone collagen contains both pyridinoline (Pyd) and deoxypyridinoline (Dpd) and release of these components from bone undergoing resorption constitutes the main source of both crosslinks in urine. The Pyd:Dpd ratio in urine is usually similar to that found in bone, and the values for the two crosslinks in urine are highly correlated. Pyridinoline has the wider
distribution, being prevalent in cartilage and tendon,3but, because of their slow turnover, these tissues make a negligible contribution to urinary Unlike output. hydroxyproline, pyridinium crosslinks are not metabolised in the body; this feature enables quantitation of bone resorption rates. Development of methods for measuring the crosslinks in urine4 led to their application in clinical studies. Excretion of crosslinks is greatly increased in patients with Paget’s disease, primary hyperparathyroidism, osteomalacia, and osteoporosis, and these assays are especially useful for monitoring therapy.9 The good correlations between pyridinium crosslink excretion and bone turnover rates measured by radioisotope methods10 or histomorphometryll provide direct validation of the urinary markers. The variable relations between urinary crosslinks and hydroxyproline may be explained by fluctuations in dietary control for hydroxyproline; pyridinium crosslinks are not susceptible to dietary influences. 12 Crosslink tissue
have been used to show increased bone associated with rheumatoid arthritis and resorption and to document the efficacy of diseaseosetoarthritis, The increased resorption modifying drugs.l3 associated with hyperthyroidism has likewise been confirmed, and this method may be useful for monitoring thyroxine treatment.14 Other promising areas include identification of bone metastases in breast cancer, 15 and monitoring of in tumour-associated antiosteolytic therapy hypercalcaemia.16 Excretion of the crosslinks in children is much higher than in adults,17 and these markers have considerable potential in assessing treatment of growth deficiencies. Some questions remain to be resolved concerning standardisation between laboratories and we need to know more about normal physiological variation. Crosslink excretion changes with age in adults,13,18 but the extent of variation over 24 h is uncertain.19,20 Excretion rate is usually higher at night. It seems best to measure them relative to creatinine on an early morning spot urine sample. measurements
279
In most studies total crosslinks have been determined after acid hydrolysis of urine. More recently, simplified methods have been developed based on the consistent proportion of free crosslinks present in urine21,22 or on the assay of specific peptides derived from bone.23 Such simple, direct urinary immunoassays for measurement of bone resorption will have many clinical applications not only in the diagnosis and monitoring of therapy in metabolic bone diseases but also as part of screening programmes to assess the risks of osteoporotic fracture. 1. Delmas PD. Clinical use of biochemical markers of bone remodeling in osteoporosis. Bone 1992; 13: S17-S21. 2. Eyre DR. New markers of bone resorption. J Clin Endocrinol Metab 1992; 74: 470A-C. 3. Eyre DR, Koob TJ, Van Ness KP. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal Biochem 1984; 137: 380-88. 4. Black D, Duncan A, Robins SP. Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high-performance liquid chromatography. Anal Biochem 1988; 169: 197-203. 5. Uebelhart D, Gineyts E, Chapuy M-C, Delmas PD. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Min 1990; 8: 87-96. 6. Robins SP, Black D, Paterson CR, Reid DM, Duncan A, Seibel MJ. Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur J Clin Invest 1991; 21: 310-15. 7. McLaren AM, Hordon LD, Bird HA, Robins SP. Urinary excretion of
pyridinium crosslinks of collagen in patients with osteoporosis and the effects of bone fracture. Ann Rheum Dis 1992; 51: 648-51. 8. Seibel MJ, Gartenberg F, Silverberg SJ, Ratcliffe A, Robins SP, Bilezikian JP. Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption in primary hyperparathyroidism. J Clin Endocrinol Metab 1992; 74: 481-86. 9. Uebelhart D, Schlemmer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 1991; 72: 367-73. 10. Eastell R, Hampton L, Colwell A, et al. Urinary collagen crosslinks are highly correlated with radioisotopic measurements of bone resorption. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 469-70. 11. Delmas PD, Schlemmer A, Gineyts E, Riis B, Christiansen C. Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J Bone Min Res 1991; 6: 639-44. 12. Colwell A, Eastall R, Assiri AM A, Russell RGG. Effect of diet on deoxypyridinoline excretion. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 590-91. 13. Seibel MJ, Duncan A, Robins SP. Urinary hydroxy-pyridinium crosslinks provide indices of cartilage and bone involvement in arthritic diseases. J Rheumatol 1989; 16: 964-70. 14. Harvey RD, McHardy KC, Paterson F, Bewsher PD, Duncan A, Robins SP. Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium crosslinks as specific urinary markers. J Clin Endocrinol Metab 1991; 72: 1188-94. 15. Paterson CR, Robins SP, Horobin JM, Preece PE, Cuschieri A. Pyridinium crosslinks as markers of bone resorption in patients with breast cancer. Br J Cancer 1991; 64: 884-86. 16. Body JJ, Delmas PD. Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hyperglycemia. J Clin Endocrinol Metab 1992; 74: 471-75. 17. Fujimoto D, Suzuki M, Uchiyama A, Miyamoto S, Inoue T. Analysis of pyridinoline, a crosslinking compound of collagen fibers, in human urine. J Biochem 1983; 94: 1133-36. 18. Beardsworth LJ, Eyre DR, Dickson IR. Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Min Res 1990; 5: 671-76. 19. Schlemmer A, Hassager C, Jensen SB, Christiansen C. Marked diurnal variation in urinary excretion of pyridinium cross-links m premenopausal women. J Clin Endocrinol Metab 1992; 74: 476-80. 20. 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 1992; 74: 487-94.
SP, Duncan A, Riggs BL. Direct measurement of free hydroxy-pyridinium crosslinks of collagen in urine as new markers of bone resorption in osteoporosis. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 465-68. 22. Robins SP, Duncan A, McLaren AM. Structural specificity of an ELISA for the collagen crosslink, pyridinoline: implications for the measurement of free pyridinium crosslinks as indices of bone resorption in metabolic bone diseases. J Bone Min Res 1991; 6 (suppl): 642a. 23. Hanson DA, Eyre DR. A specific immunoassay for bone resorption based on cross-linked collagen peptides in urine. J Bone Min Res 1991; 6 (suppl): 669a. 21. Robins
Cricket under stress Cricket, that summer anchor of the very identity of many a nation, is threatened by a new disease-spinal stress fractures in fast bowlers. Or so one might think from headlines in the lay press. What is the truth behind such stories? Although renewed interest in spinal stress fractures in fast bowlers gives the impression that a "new" condition has arrived and is about to cull the brightest bowling prospects, the vulnerability of sportsmen and sportswomen to stress fractures is well recognised. Such fractures characteristically occur in a normal bone that is subject to repeated cyclical loading, the load being less than that which causes acute fracture. Bowlers typically get a bilateral fracture of the pars interarticularis of one of their lower lumbar vertebrae (spondylolysis), which is believed to be related to the hyperextension that precedes delivery. A contributory factor is the force of the delivery (to which today’s armour-clad batsmen bear witness), since fast bowlers are most afflicted. Several fast bowlers have had their
interrupted by a spondylolysis. Anxiety about the impact of stress fractures will not have been lessened by a report by Hardcastle and colleagues,1 who conducted a detailed study, including computed tomography (CT) and magnetic resonance imaging (MRI), of 24 fast bowlers aged 16-18 years who had been selected for special training careers
in Western Australia. Pars interarticularis defects diagnosed in 54%, and 63% had disc degeneration. These alarming figures warrant further were
analysis. The reported frequency of isthmic spondylolysis in European populations is about 5-7%,zand this figure is higher in sportsmen and sportswomen. However, such figures are based on standard radiographic examinations and predate the use of MRI and CT. Moreover, in the Australian series 50% of the defects were unilateral; such defects are rarely identified by conventional
radiography
and
are
not
always
symptomatic. This condition has previously been described in detail in a fast bowler.3Whereas the bilateral lesion is thought to be the result of extension, the main cause for the unilateral lesion may well be rotation. Symptomless lesions on the opposite side at the same level can be a predisposing factor. The high figure for defects in the lumbar spine in the Australian series therefore of detection.
largely reflects sensitive new methods
Health and Social Security in July of that year. This meeting was attended by the government’s Chief Medical Officers and representatives of the GMC and the Joint Committee on Higher Medical Training (JCHMT). Prof John Crofton, then chairman of the JCHMT, expressed a worry that a doctor returning from "the continent" with an EC specialist certificate might, through the courts, achieve the right to be acknowledged as a specialist and therefore to be appointed as a National Health Service consultant. However, the GMC representatives assured him that the Council had legal advice that it could issue a "certificate of specialist training" and not a "certificate of completion of specialist training", and indeed claimed that the apparent need to have the word "complete" in the text arose only because of "a mistake in the English translation of the directives". If the issues had been debated in a more open forum the problems of specialist registration might well have been resolved in a different way. Instead, they were discussed in private and largely by those who were not eager for change. And in many of the meetings there was such disparity between the content of the discussion and the decisions eventually reached that an observer could be forgiven for concluding that some of the participants were working to a different agenda from everybody else. The latest crisis means that Britain’s postgraduate medical education and hospital career structure could face a radical shake-up. This should be achieved by open debate that involves those who will perforce be regulated. There seem to be only two courses of action the UK can take to comply with European law. The GMC could award EC certificates to UK doctors only on completion of their specialist training, which at present is either on accreditation or when they are appointed as consultants; that would disadvantage those wanting to work in other EC countries because they would have to train for more years than their European counterparts to get the certificate. The alternative is a radical revision of the existing hospital career structure, with the aim of providing posts to which holders of an EC Specialist Certificate might aspire but which would not undermine the present status or quality of consultants in the National Health Service. But who is going to be the first to define the difference between a consultant and a specialist? The government is to form a working group to study these issues, which will report within 6 months.
Pyridinium crosslinks as markers of bone resorption There has been considerable interest lately in non-invasive metabolism. 1,2
methods
of
monitoring bone Radioisotopic techniques and quantitative histomorphometry give very precise
information on rates of bone turnover but are unsuitable for repeated monitoring of therapy or for
screening studies. Measurement of urinary pyridinium crosslinks provides an index of bone resorption rates; this approach offers substantial advantages over urinary hydroxyproline estimations, which are non-specific and insensitive. Pyridinium crosslinks are products of a unique series of reactions during the maturation of collagen fibrils that lead to the formation of pyridinoline (also known as hydroxylysyl pyridinoline) and deoxypyridinoline (or lysyl pyridinoline). Bone collagen contains both pyridinoline (Pyd) and deoxypyridinoline (Dpd) and release of these components from bone undergoing resorption constitutes the main source of both crosslinks in urine. The Pyd:Dpd ratio in urine is usually similar to that found in bone, and the values for the two crosslinks in urine are highly correlated. Pyridinoline has the wider
distribution, being prevalent in cartilage and tendon,3but, because of their slow turnover, these tissues make a negligible contribution to urinary Unlike output. hydroxyproline, pyridinium crosslinks are not metabolised in the body; this feature enables quantitation of bone resorption rates. Development of methods for measuring the crosslinks in urine4 led to their application in clinical studies. Excretion of crosslinks is greatly increased in patients with Paget’s disease, primary hyperparathyroidism, osteomalacia, and osteoporosis, and these assays are especially useful for monitoring therapy.9 The good correlations between pyridinium crosslink excretion and bone turnover rates measured by radioisotope methods10 or histomorphometryll provide direct validation of the urinary markers. The variable relations between urinary crosslinks and hydroxyproline may be explained by fluctuations in dietary control for hydroxyproline; pyridinium crosslinks are not susceptible to dietary influences. 12 Crosslink tissue
have been used to show increased bone associated with rheumatoid arthritis and resorption and to document the efficacy of diseaseosetoarthritis, The increased resorption modifying drugs.l3 associated with hyperthyroidism has likewise been confirmed, and this method may be useful for monitoring thyroxine treatment.14 Other promising areas include identification of bone metastases in breast cancer, 15 and monitoring of in tumour-associated antiosteolytic therapy hypercalcaemia.16 Excretion of the crosslinks in children is much higher than in adults,17 and these markers have considerable potential in assessing treatment of growth deficiencies. Some questions remain to be resolved concerning standardisation between laboratories and we need to know more about normal physiological variation. Crosslink excretion changes with age in adults,13,18 but the extent of variation over 24 h is uncertain.19,20 Excretion rate is usually higher at night. It seems best to measure them relative to creatinine on an early morning spot urine sample. measurements
279
In most studies total crosslinks have been determined after acid hydrolysis of urine. More recently, simplified methods have been developed based on the consistent proportion of free crosslinks present in urine21,22 or on the assay of specific peptides derived from bone.23 Such simple, direct urinary immunoassays for measurement of bone resorption will have many clinical applications not only in the diagnosis and monitoring of therapy in metabolic bone diseases but also as part of screening programmes to assess the risks of osteoporotic fracture. 1. Delmas PD. Clinical use of biochemical markers of bone remodeling in osteoporosis. Bone 1992; 13: S17-S21. 2. Eyre DR. New markers of bone resorption. J Clin Endocrinol Metab 1992; 74: 470A-C. 3. Eyre DR, Koob TJ, Van Ness KP. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal Biochem 1984; 137: 380-88. 4. Black D, Duncan A, Robins SP. Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high-performance liquid chromatography. Anal Biochem 1988; 169: 197-203. 5. Uebelhart D, Gineyts E, Chapuy M-C, Delmas PD. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Min 1990; 8: 87-96. 6. Robins SP, Black D, Paterson CR, Reid DM, Duncan A, Seibel MJ. Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur J Clin Invest 1991; 21: 310-15. 7. McLaren AM, Hordon LD, Bird HA, Robins SP. Urinary excretion of
pyridinium crosslinks of collagen in patients with osteoporosis and the effects of bone fracture. Ann Rheum Dis 1992; 51: 648-51. 8. Seibel MJ, Gartenberg F, Silverberg SJ, Ratcliffe A, Robins SP, Bilezikian JP. Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption in primary hyperparathyroidism. J Clin Endocrinol Metab 1992; 74: 481-86. 9. Uebelhart D, Schlemmer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 1991; 72: 367-73. 10. Eastell R, Hampton L, Colwell A, et al. Urinary collagen crosslinks are highly correlated with radioisotopic measurements of bone resorption. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 469-70. 11. Delmas PD, Schlemmer A, Gineyts E, Riis B, Christiansen C. Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J Bone Min Res 1991; 6: 639-44. 12. Colwell A, Eastall R, Assiri AM A, Russell RGG. Effect of diet on deoxypyridinoline excretion. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 590-91. 13. Seibel MJ, Duncan A, Robins SP. Urinary hydroxy-pyridinium crosslinks provide indices of cartilage and bone involvement in arthritic diseases. J Rheumatol 1989; 16: 964-70. 14. Harvey RD, McHardy KC, Paterson F, Bewsher PD, Duncan A, Robins SP. Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium crosslinks as specific urinary markers. J Clin Endocrinol Metab 1991; 72: 1188-94. 15. Paterson CR, Robins SP, Horobin JM, Preece PE, Cuschieri A. Pyridinium crosslinks as markers of bone resorption in patients with breast cancer. Br J Cancer 1991; 64: 884-86. 16. Body JJ, Delmas PD. Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hyperglycemia. J Clin Endocrinol Metab 1992; 74: 471-75. 17. Fujimoto D, Suzuki M, Uchiyama A, Miyamoto S, Inoue T. Analysis of pyridinoline, a crosslinking compound of collagen fibers, in human urine. J Biochem 1983; 94: 1133-36. 18. Beardsworth LJ, Eyre DR, Dickson IR. Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Min Res 1990; 5: 671-76. 19. Schlemmer A, Hassager C, Jensen SB, Christiansen C. Marked diurnal variation in urinary excretion of pyridinium cross-links m premenopausal women. J Clin Endocrinol Metab 1992; 74: 476-80. 20. 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 1992; 74: 487-94.
SP, Duncan A, Riggs BL. Direct measurement of free hydroxy-pyridinium crosslinks of collagen in urine as new markers of bone resorption in osteoporosis. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: 465-68. 22. Robins SP, Duncan A, McLaren AM. Structural specificity of an ELISA for the collagen crosslink, pyridinoline: implications for the measurement of free pyridinium crosslinks as indices of bone resorption in metabolic bone diseases. J Bone Min Res 1991; 6 (suppl): 642a. 23. Hanson DA, Eyre DR. A specific immunoassay for bone resorption based on cross-linked collagen peptides in urine. J Bone Min Res 1991; 6 (suppl): 669a. 21. Robins
Cricket under stress Cricket, that summer anchor of the very identity of many a nation, is threatened by a new disease-spinal stress fractures in fast bowlers. Or so one might think from headlines in the lay press. What is the truth behind such stories? Although renewed interest in spinal stress fractures in fast bowlers gives the impression that a "new" condition has arrived and is about to cull the brightest bowling prospects, the vulnerability of sportsmen and sportswomen to stress fractures is well recognised. Such fractures characteristically occur in a normal bone that is subject to repeated cyclical loading, the load being less than that which causes acute fracture. Bowlers typically get a bilateral fracture of the pars interarticularis of one of their lower lumbar vertebrae (spondylolysis), which is believed to be related to the hyperextension that precedes delivery. A contributory factor is the force of the delivery (to which today’s armour-clad batsmen bear witness), since fast bowlers are most afflicted. Several fast bowlers have had their
interrupted by a spondylolysis. Anxiety about the impact of stress fractures will not have been lessened by a report by Hardcastle and colleagues,1 who conducted a detailed study, including computed tomography (CT) and magnetic resonance imaging (MRI), of 24 fast bowlers aged 16-18 years who had been selected for special training careers
in Western Australia. Pars interarticularis defects diagnosed in 54%, and 63% had disc degeneration. These alarming figures warrant further were
analysis. The reported frequency of isthmic spondylolysis in European populations is about 5-7%,zand this figure is higher in sportsmen and sportswomen. However, such figures are based on standard radiographic examinations and predate the use of MRI and CT. Moreover, in the Australian series 50% of the defects were unilateral; such defects are rarely identified by conventional
radiography
and
are
not
always
symptomatic. This condition has previously been described in detail in a fast bowler.3Whereas the bilateral lesion is thought to be the result of extension, the main cause for the unilateral lesion may well be rotation. Symptomless lesions on the opposite side at the same level can be a predisposing factor. The high figure for defects in the lumbar spine in the Australian series therefore of detection.
largely reflects sensitive new methods
