368 OSTEOGENESIS IMPERFECTA
SIR,-I read with interest the paper by Dickson
et
al.’ and
the
ensuing correspondence. Information about the abnormal non-collagenous proteins obtained at the Nuffield Orthopaedic
Centre, Oxford23 seems to have been overlooked. It was established in the 1960s that in osteogenesis imperfecta only partial osteogenic cell differentiation takes place before matrix production, while the abnormal and chemically unstable matrix is itself formed prematurely. In severe cases the abnormal matrix is formed not only by osteoblast precursor cells but also by cells of the sinusoid vessel walls from which they are derived, and may be observed within vessels. In less severe cases, the more normal the differentiation of cells, the more normal is the matrix they produce. Even in very severe cases the histological appearance of granulation tissue and woven bone is normal. This evidence, together with histochemical studies4 shows that cell membranes are abnormal. Also consistent with abnormal membrane properties is the observation that the increased production of steroid hormones at adolescence leads to almost normal bone formation. Reactivation in women after the menopause5 is a strong indication that it is the anticatabolic hormones that suppress the consequences of the primary defect. Such observations imply that the defect is in the growth-hormone/insulin/thyroxine group of hormones. These affect membrane transport systems.6-9 The presence of enlarged nucleoli, most commonly associated with a lack of vitamin C, is consistent with transport difficulties, and extra vitamin C has been found to result in clinical improvement. 10 Insulin and thyroxine interact with growth hormone at cell surfaces. An abnormal distribution of fat cells,3 together with histochemical observations4 suggest an increased insulin activity, while Cropp and Myers5 have not only established that osteogenesis imperfecta is a general metabolic disorder but also they have shown that symptoms are associated with high thyroxine levels. There has been no evidence to suggest that either insulin or thyroxine are in any way abnormal, but only that they are secreted in abnormal quantities. This could be an indication that the action of growth hormone at the cell surfaces is in some way inadequate. Growth hormone is responsible for the production of the more labile compounds of the intercellular matrices in the young, and steroids for the more stable compounds in adults;l’ and in osteogenesis imperfecta we find it is the more labile is also recompounds that are abnormal. Growth hormone sponsible for the activation of stem cells," 13 and cell division and differentiation are visibly abnormal in severe cases. Again, repair tissues proliferate normally, and proliferation of these, unlike the proliferation of stem cells, is not dependent upon the action of growth hormone. We thus have a pattern of observations consistent with a defective action of growth hormone. It is possible, therefore, that treatment with normal human growth hormone might have beneficial results. The use of synthetic polypeptides is another possibility, especially if any interaction were found between normal human growth hormone and the patient’s growth hormone. A preliminary screening test for these would be to culture fragments of bone from a young rabbit in a medium such as that used by Rigal. 12 13 In the absence of growth hormone or compounds with the required properties haemopoietic tissue cells rapidly Dickson, I. R., Millar, E. A., Veis A. Lancet, 1975, ii, 586. Little, K. J. Bone Jt. Surg. 1963, 45B, 221. 3. Little, K. Bone Behaviour; p. 186. London, 1973. 4. Doty, S. B., Mathews, R. S. J. Bone Jt. Surg. 1970, 52A, 601. 5. Cropp, G. J. A., Myers, D. N. Pediatrics, 1972, 49, 375. 6. Hechter, O. Mechanisms of Hormone Action (edited by P. Karlson). New York, 1955. 7. Prop, F. J. A. Path. Biol. Pams. 1961, 9, 640. 8. Prop, F. J. Expl. Cell Res. 1965, 40, 277. 9. Manchester, K. L., Young, F. G. Vitams Horm. 1961, 19, 95. 10. Kurz, D., Eyring, E. J. Pediatrics, 1974, 54, 56. 11. Davidson, E. A., Small, W. Biochim. Biophys. Acta 1963, 69, 445. 12. Rigal, W. M. D.PHIL. thesis, University of Oxford, 1961. 13. Rigal, W. M. Proc. Soc. exp. Biol. Med. 1964, 117, 794. 1. 2.
die, while in the presence of a potentially suitable compound they would survive. Again, abnormalities in leucocyte1411 and platelet 16 production have been observed in cases of osteogenesis imperfecta. Potentially suitable compounds would need to be further screened, using fragments of bone taken at oper. ation. It need hardly be said that in this condition thereis no justification for the use of biopsy. Ridgway Consultants, 19 Victoria Road,
Abingdon,
K. LITTLE
Oxfordshire OX14 1DN.
CLONIDINE WITHDRAWAL
SIR,-Clonidine is
an
increasingly prescribed hypotensive
agent. It has been associated with rebound hypertension" (blood-pressure above any previously recorded for that patient) when treatment is stopped. This rebound is said to be avoidable provided the drug is tailed off over 2-4 days." We have seen a patient in whom dangerous rebound hypertension occurred during gradual reduction of clonidine. A 52-year-old man, known to have essential hypertension for a year, was admitted because of poor blood-pressure control (200/120 mm Hg). His medication on admission was donidine 0 - 3 mg four times per day, propranolol 160 mg four times per day, and slow-release cyclopenthiazide with potassium chloride (’Navidrex K’) one tablet per day. He had taken donidine in increasing doses for 6 weeks without therapeutic effect, and it was decided to withdraw the drug gradually and at the same time start prazosin hydrochloride instead. Propranolol and navidrex K were continued. The dose of clonidine was reduced to 0.2mg four times per day for 24 h, then 01mg four times per day for 24 h, and finally 0- 1 mg twice daily for 24 h. After 72 h, while still taking clonidine 0.1 mg twice daily, the patient had a blood-pressure of 250/150 mm Hg and the following day, when clonidine had been stopped, the bloodpressure reached a peak of 290/170 mm Hg. The highest previously recorded blood-pressure, treated or untreated, had been 220/140 mm Hg. The rise in blood-pressure was associated with severe headache and vomiting. Urinary catechola. mine and vanillylmandelic acid (V.M.A.) levels had been mea. sured on three previous occasions and had always been normal. During the rebound period both were raised (catecholamines 75 .mol/mol creatinine, normal 40 or less; V.M.A. 4-4J .mol/mol creatinine, normal 3.5 or less) and subsequently returned to normal. The rebound period lasted for 4 days During this time an intramuscular injection of 10 mg guanettidine transiently reduced the patient’s blood-pressure by 90 mm Hg systolic and 40 mm Hg diastolic. The rebound hypertension happened despite carefully controlled reduction in the dose of clonidine and before complete withdrawal of the drug. The raised catecholamine excretion d seen suggests sympathetic overactivity as the mechanism rebound."The symptoms resemble the crisis of a phaeochromocytoma, but were modified in our patient by p-blockade. Guanethidine reduced the blood-pressure but a-blockade would clearly have been a more rational approach to lus rebound hypertension. Physicians should realise the poteatiii hazard of even gradual clonidine withdrawal and should make it clear to their patients that treatment should on no account be altered without medical advice. S. A. CAIRNS Bristol Royal Infirmary, A. J. MARSHALL Bristol BS2 8HW.
14. 15. 16. 17. 18.
Solomons, C. C., Millan, E. A., Hathaway, W. E., Ott, J. E. J. BoneJt. Surg. 1971, 53A, 2. Humbert, J. R., Solomons, C. C., Ott, J. E. J. Pediat. 1971, 78, 648. Hathaway., W. E., Solomons, C. C., Ott, J. E. Blood, 1972, 39, 500. Hunyor, S. N., Hansson, L., Harrison, T. S., Hoobler, S. W. Br med.J. 1973, ii, 209. Pettinger, W. A. New Engl. J. Med. 1975, 293, 1179.
SIR,-I read with interest the paper by Dickson
et
al.’ and
the
ensuing correspondence. Information about the abnormal non-collagenous proteins obtained at the Nuffield Orthopaedic
Centre, Oxford23 seems to have been overlooked. It was established in the 1960s that in osteogenesis imperfecta only partial osteogenic cell differentiation takes place before matrix production, while the abnormal and chemically unstable matrix is itself formed prematurely. In severe cases the abnormal matrix is formed not only by osteoblast precursor cells but also by cells of the sinusoid vessel walls from which they are derived, and may be observed within vessels. In less severe cases, the more normal the differentiation of cells, the more normal is the matrix they produce. Even in very severe cases the histological appearance of granulation tissue and woven bone is normal. This evidence, together with histochemical studies4 shows that cell membranes are abnormal. Also consistent with abnormal membrane properties is the observation that the increased production of steroid hormones at adolescence leads to almost normal bone formation. Reactivation in women after the menopause5 is a strong indication that it is the anticatabolic hormones that suppress the consequences of the primary defect. Such observations imply that the defect is in the growth-hormone/insulin/thyroxine group of hormones. These affect membrane transport systems.6-9 The presence of enlarged nucleoli, most commonly associated with a lack of vitamin C, is consistent with transport difficulties, and extra vitamin C has been found to result in clinical improvement. 10 Insulin and thyroxine interact with growth hormone at cell surfaces. An abnormal distribution of fat cells,3 together with histochemical observations4 suggest an increased insulin activity, while Cropp and Myers5 have not only established that osteogenesis imperfecta is a general metabolic disorder but also they have shown that symptoms are associated with high thyroxine levels. There has been no evidence to suggest that either insulin or thyroxine are in any way abnormal, but only that they are secreted in abnormal quantities. This could be an indication that the action of growth hormone at the cell surfaces is in some way inadequate. Growth hormone is responsible for the production of the more labile compounds of the intercellular matrices in the young, and steroids for the more stable compounds in adults;l’ and in osteogenesis imperfecta we find it is the more labile is also recompounds that are abnormal. Growth hormone sponsible for the activation of stem cells," 13 and cell division and differentiation are visibly abnormal in severe cases. Again, repair tissues proliferate normally, and proliferation of these, unlike the proliferation of stem cells, is not dependent upon the action of growth hormone. We thus have a pattern of observations consistent with a defective action of growth hormone. It is possible, therefore, that treatment with normal human growth hormone might have beneficial results. The use of synthetic polypeptides is another possibility, especially if any interaction were found between normal human growth hormone and the patient’s growth hormone. A preliminary screening test for these would be to culture fragments of bone from a young rabbit in a medium such as that used by Rigal. 12 13 In the absence of growth hormone or compounds with the required properties haemopoietic tissue cells rapidly Dickson, I. R., Millar, E. A., Veis A. Lancet, 1975, ii, 586. Little, K. J. Bone Jt. Surg. 1963, 45B, 221. 3. Little, K. Bone Behaviour; p. 186. London, 1973. 4. Doty, S. B., Mathews, R. S. J. Bone Jt. Surg. 1970, 52A, 601. 5. Cropp, G. J. A., Myers, D. N. Pediatrics, 1972, 49, 375. 6. Hechter, O. Mechanisms of Hormone Action (edited by P. Karlson). New York, 1955. 7. Prop, F. J. A. Path. Biol. Pams. 1961, 9, 640. 8. Prop, F. J. Expl. Cell Res. 1965, 40, 277. 9. Manchester, K. L., Young, F. G. Vitams Horm. 1961, 19, 95. 10. Kurz, D., Eyring, E. J. Pediatrics, 1974, 54, 56. 11. Davidson, E. A., Small, W. Biochim. Biophys. Acta 1963, 69, 445. 12. Rigal, W. M. D.PHIL. thesis, University of Oxford, 1961. 13. Rigal, W. M. Proc. Soc. exp. Biol. Med. 1964, 117, 794. 1. 2.
die, while in the presence of a potentially suitable compound they would survive. Again, abnormalities in leucocyte1411 and platelet 16 production have been observed in cases of osteogenesis imperfecta. Potentially suitable compounds would need to be further screened, using fragments of bone taken at oper. ation. It need hardly be said that in this condition thereis no justification for the use of biopsy. Ridgway Consultants, 19 Victoria Road,
Abingdon,
K. LITTLE
Oxfordshire OX14 1DN.
CLONIDINE WITHDRAWAL
SIR,-Clonidine is
an
increasingly prescribed hypotensive
agent. It has been associated with rebound hypertension" (blood-pressure above any previously recorded for that patient) when treatment is stopped. This rebound is said to be avoidable provided the drug is tailed off over 2-4 days." We have seen a patient in whom dangerous rebound hypertension occurred during gradual reduction of clonidine. A 52-year-old man, known to have essential hypertension for a year, was admitted because of poor blood-pressure control (200/120 mm Hg). His medication on admission was donidine 0 - 3 mg four times per day, propranolol 160 mg four times per day, and slow-release cyclopenthiazide with potassium chloride (’Navidrex K’) one tablet per day. He had taken donidine in increasing doses for 6 weeks without therapeutic effect, and it was decided to withdraw the drug gradually and at the same time start prazosin hydrochloride instead. Propranolol and navidrex K were continued. The dose of clonidine was reduced to 0.2mg four times per day for 24 h, then 01mg four times per day for 24 h, and finally 0- 1 mg twice daily for 24 h. After 72 h, while still taking clonidine 0.1 mg twice daily, the patient had a blood-pressure of 250/150 mm Hg and the following day, when clonidine had been stopped, the bloodpressure reached a peak of 290/170 mm Hg. The highest previously recorded blood-pressure, treated or untreated, had been 220/140 mm Hg. The rise in blood-pressure was associated with severe headache and vomiting. Urinary catechola. mine and vanillylmandelic acid (V.M.A.) levels had been mea. sured on three previous occasions and had always been normal. During the rebound period both were raised (catecholamines 75 .mol/mol creatinine, normal 40 or less; V.M.A. 4-4J .mol/mol creatinine, normal 3.5 or less) and subsequently returned to normal. The rebound period lasted for 4 days During this time an intramuscular injection of 10 mg guanettidine transiently reduced the patient’s blood-pressure by 90 mm Hg systolic and 40 mm Hg diastolic. The rebound hypertension happened despite carefully controlled reduction in the dose of clonidine and before complete withdrawal of the drug. The raised catecholamine excretion d seen suggests sympathetic overactivity as the mechanism rebound."The symptoms resemble the crisis of a phaeochromocytoma, but were modified in our patient by p-blockade. Guanethidine reduced the blood-pressure but a-blockade would clearly have been a more rational approach to lus rebound hypertension. Physicians should realise the poteatiii hazard of even gradual clonidine withdrawal and should make it clear to their patients that treatment should on no account be altered without medical advice. S. A. CAIRNS Bristol Royal Infirmary, A. J. MARSHALL Bristol BS2 8HW.
14. 15. 16. 17. 18.
Solomons, C. C., Millan, E. A., Hathaway, W. E., Ott, J. E. J. BoneJt. Surg. 1971, 53A, 2. Humbert, J. R., Solomons, C. C., Ott, J. E. J. Pediat. 1971, 78, 648. Hathaway., W. E., Solomons, C. C., Ott, J. E. Blood, 1972, 39, 500. Hunyor, S. N., Hansson, L., Harrison, T. S., Hoobler, S. W. Br med.J. 1973, ii, 209. Pettinger, W. A. New Engl. J. Med. 1975, 293, 1179.
