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Title: Effects of diphosphonates in disorders of bone turnover
Author: Yates, Ashley John Paul
ISNI:       0000 0004 2721 7779
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 1987
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This thesis describes several interrelated studies concerning the effects of diphosphonates in the treatment of disorders of bone turnover. Diphosphonates have previously been shown to suppress bone turnover in Paget's disease when given orally for at least three months. However, five daily intravenous infusions of the diphosphonates, clodronate, etidronate and a newer agent, aminohexane diphosphonate (AHDP), induced marked and sustained biochemical and clinical changes similar to those achieved with long-term oral treatment. These new regimens may be useful in the management of Paget's disease. The assessment of biochemical response in Paget's disease, particularly in re-treated patients, is more complex than hitherto described. The pre-treatment serum alkaline phosphatase and, in re-treated patients, the extent of biochemical relapse are important determinants of response. Little was previously known of the effects of high doses of diphosphonates on mineral metabolism. Inhibition of mineralisation occurred following all 3 intravenous diphosphonates. However, this effect was partial and short-lived following clodronate or AHDP, but was complete and much more sustained following etidronate. All three diphosphonates induced hyperphosphataemia by increasing renal tubular reabsorption of phosphate. This latter effect was related, both temporally and quantitatively, to the effects of these agents on skeletal mineralisation suggesting a possible causal relationship. Hypocalcaemic responses were consistently observed in pagetic patients following intravenous clodronate or AHDP, but not following etidronate. Similarly, infusions of either clodronate or AHDP, but not etidronate, induced normalisation of mean serum calcium in patients with hypercalcaemia of malignancy. Furthermore, oral clodronate, but neither high-dose nor low-dose oral etidronate, induced significant hypocalcaemic responses in patients with primary hyperparathyroidism. The degree of inhibition of bone resorption was similar for each of the diphosphonates in all of the disorders studied, suggesting that the attenuated hypocalcaemic effects of etidronate resulted from the greater impairment of mineralisation that occurred following treatment with this agent.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available