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The effect of vitamin D deficiency was studied in 3 patients with Paget's disease of bone. The biochemical parameters of bone turnover strikingly increased, while the pagetic bone became radiolucent. This occurred whether the nonpagetic bones were osteomalacic or not. AU the observed changes were reversed upon correction of the deficiency. The effects of mithramycin and calcitonin on the biochemical parameters of bone turnover were compared sequentially in three cases. No treatment proved definitely superior in this regard. The effectiveness of calcitonin to induce a positive focal bone balance in osteolytic Paget's disease was studied radiologically and compared to the effects of the diphosphonate EHDP, and to the combined therapy of EHDP and calcitonin. Calcitonin showed a constructive action in 1 W o of the cases. EHDP, administered at low dosages (7.0 mg/kg/24 hr during a period of 7.4 months) did not demonstrate a uniformly constructive action in any patient. Radiolucent lesions appeared in 56% "dissociated'' effects (both a constructive and a destructive action) were seen in 3396, and no effect in 11% of the cases. Combined therapy was intermediate in its action between calcitonin and EHDP. After discontinuation of combined therapy, an EHDP-like effect was often a p parent . and Henneman ( I ) had demonstrated the action of corticosteroids on Paget's disease, and Maurice et al (2) the action of aspirin, which we have confirmed (3), the interest changed to sodium fluoride with variable success (3-6). Yet the overall results of therapy were disappointing when we reviewed the condition (5).The introduction of calcitonin (CT) in this field (7), soon to be followed by mithramycin (8), and the diphosphonate EHDP (9) provided the clinician in a short time with potent drugs. Each approached the disease in a different fashion, though all showed some disadvantages and particular side effects. These are still at present the three main therapeutic agents. Others, like actinomycin D and glucagon, have never gained wide acceptance.When evaluating these drugs, the biochemical parameters of bone turnover in the serum (alkaline phosphatase or AP) and the urine (total hydroxyproline) have been widely used. Indeed, a decrease of both parameters is a prerequisite for activity of any given drug. However, these changes in the right direction do not bring sufficient proof that the activity of a given drug is beneficial. The lesions could be adversely affected, even with a decreased bone turnover. If a negative focal bone balance were achieved, the pagetic process could be impaired rather than improved. It is therefore necessary to monitor the focal bone balance. This has usually been performed by means of repeated bone scans, an inadequate approach. Bone scans will eventually show that the focal bone turnover has decreased, as one is likely to expect. The disappearance of "hot spots" is therefore another prerequisite for activity of a given drug, but once more does not prove its beneficial action.The only approach to the possibi...
The effect of vitamin D deficiency was studied in 3 patients with Paget's disease of bone. The biochemical parameters of bone turnover strikingly increased, while the pagetic bone became radiolucent. This occurred whether the nonpagetic bones were osteomalacic or not. AU the observed changes were reversed upon correction of the deficiency. The effects of mithramycin and calcitonin on the biochemical parameters of bone turnover were compared sequentially in three cases. No treatment proved definitely superior in this regard. The effectiveness of calcitonin to induce a positive focal bone balance in osteolytic Paget's disease was studied radiologically and compared to the effects of the diphosphonate EHDP, and to the combined therapy of EHDP and calcitonin. Calcitonin showed a constructive action in 1 W o of the cases. EHDP, administered at low dosages (7.0 mg/kg/24 hr during a period of 7.4 months) did not demonstrate a uniformly constructive action in any patient. Radiolucent lesions appeared in 56% "dissociated'' effects (both a constructive and a destructive action) were seen in 3396, and no effect in 11% of the cases. Combined therapy was intermediate in its action between calcitonin and EHDP. After discontinuation of combined therapy, an EHDP-like effect was often a p parent . and Henneman ( I ) had demonstrated the action of corticosteroids on Paget's disease, and Maurice et al (2) the action of aspirin, which we have confirmed (3), the interest changed to sodium fluoride with variable success (3-6). Yet the overall results of therapy were disappointing when we reviewed the condition (5).The introduction of calcitonin (CT) in this field (7), soon to be followed by mithramycin (8), and the diphosphonate EHDP (9) provided the clinician in a short time with potent drugs. Each approached the disease in a different fashion, though all showed some disadvantages and particular side effects. These are still at present the three main therapeutic agents. Others, like actinomycin D and glucagon, have never gained wide acceptance.When evaluating these drugs, the biochemical parameters of bone turnover in the serum (alkaline phosphatase or AP) and the urine (total hydroxyproline) have been widely used. Indeed, a decrease of both parameters is a prerequisite for activity of any given drug. However, these changes in the right direction do not bring sufficient proof that the activity of a given drug is beneficial. The lesions could be adversely affected, even with a decreased bone turnover. If a negative focal bone balance were achieved, the pagetic process could be impaired rather than improved. It is therefore necessary to monitor the focal bone balance. This has usually been performed by means of repeated bone scans, an inadequate approach. Bone scans will eventually show that the focal bone turnover has decreased, as one is likely to expect. The disappearance of "hot spots" is therefore another prerequisite for activity of a given drug, but once more does not prove its beneficial action.The only approach to the possibi...
We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34), and recombinant human interleukin-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42'H446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42'446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.
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