Sodium Etidronate in the Treatment of Paget's Disease of Bone

Khairi, M. R. A.; Altman, Roy D.; DeRosa, G. Paul; Zimmermann, J.; Schenk, Robert K.; Johnston, C. Conrad

doi:10.7326/0003-4819-87-6-656

Cited by 138 publications

(49 citation statements)

References 9 publications

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“…Serum alkaline phosphatase tended to lag for 1-2 months, but subsequently decreased to the same extent as hydroxyproline. Doses of 5-7.5 mg/kg/day may still produce a reduction of hydroxyproline and alkaline phosphatase to 50-60% at 6 months, but further reduction is rare, results becoming very variable (5,8,33). Biopsies show that higher doses cause the appearance of increased and sometimes huge unmineralized areas.…”

Section: Efficacy In Paget's Diseasementioning

confidence: 99%

“…Biopsies show that higher doses cause the appearance of increased and sometimes huge unmineralized areas. A predisposal to fracture, delayed fracture healing, and radiologic demineralization have been noted (5,(34)(35)(36)(37). Despite this, clinical and biochemical remissions have resulted, which in some patients have lasted as long as 2 years after discontinuation of treatment (5).…”

Section: Efficacy In Paget's Diseasementioning

confidence: 99%

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Apd in paget's disease of bone role of the mononuclear phagocyte system?

Bijvoet

Frijlink

Jie

et al. 1980

Arthritis & Rheumatism

125

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Section: Efficacy In Paget's Diseasementioning

confidence: 99%

Section: Efficacy In Paget's Diseasementioning

confidence: 99%

Apd in paget's disease of bone role of the mononuclear phagocyte system?

Bijvoet

Frijlink

Jie

et al. 1980

Arthritis & Rheumatism

125

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“…The drug was found to significantly lower serum alkaline phosphatase and urinary hydroxyproline in a dose-related fashion (3). There was also a significant reduction in pain found in a doubleblind placebo-controlled trial (1).…”

Section: Use Of Etidronate (Ehdp) Inmentioning

confidence: 88%

“…We have previously reported our experience with different doses of etidronate in the treatment of Paget's disease of bone (1)(2)(3)(4)(5). The drug was found to significantly lower serum alkaline phosphatase and urinary hydroxyproline in a dose-related fashion (3).…”

Section: Use Of Etidronate (Ehdp) Inmentioning

confidence: 99%

Use of etidronate (ehdp) in paget's disease of bone

Johnston

Khairi

Meunier

1980

Arthritis & Rheumatism

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Etidronate used in recommended doses (usually 5 mg/kg/day for 6 months) produces symptomatic improvement in approximately 60% of patients. The serum alkaline phosphatase and urinary hydroxyproline are reduced to about 50% of initial values. A sustained remission occurs in many patients and retreatment is usually effective upon relapse. The abnormally elevated osteoclast count and resorption surfaces are reduced, and at the low dose there is no accumulation of osteoid. The medication is generally well tolerated and at the recommended dosage there is no evidence of increased fracture rate.We have previously reported our experience with different doses of etidronate in the treatment of Paget's disease of bone (1-5). The drug was found to significantly lower serum alkaline phosphatase and urinary hydroxyproline in a dose-related fashion (3). There was also a significant reduction in pain found in a doubleblind placebo-controlled trial (1). Studies of bone biopsies showed a reduction in osteoclast number and in marrow fibrosis with appearance of lamellar bone; however, calcification rate was reduced and, at the higher doses, osteoid accumulated (33). It was also found that some patients experienced bone pain (6) and it was suggested that there was an increased incidence of fracture (7) at the higher doses. Thus, the recommended dose of etidronate is, for most patients, 5 mg/ kg/day for a 6-month period. If a dose of 20 mg/kg/day is used at all, it should be limited to 3 months' duration. It is our purpose here to provide further data on the long-term use of the drug at the recommended doses, especially 5 mg/kg/day for 6 months. MATERIALS AND METHODSAll patients who received therapy were judged to have symptomatic Paget's disease of bone by the investigators. Response in symptoms was evaluated by both the patient and the investigator, and no change, mild, moderate or marked improvement or deterioration was noted. Serum alkaline phosphatase and urinary hydroxyproline were measured as previously reported (3). Iliac crest biopsies were performed after double labeling with tetracycline and measurements were made in Dr. Meunier's laboratory (5,8). The majority of patients were followed in Indianapolis; however, some of the data to be presented are from patients followed by Drs. R. D. Altman, Robert Canfield, and Gerald Finerman, in order to give sufficient numbers for evaluation. RESULTSClinical improvement is difficult to evaluate unless a double-blind placebo-controlled study is performed. In our initial study of this type, a significant dose-response curve reflecting moderate or marked reduction of pain was found. Canfield et al (6) found better pain relief at the lower doses of etidronate than at the higher doses. Subsequent studies were historically controlled and are thus less reliable in evaluating the effect on pain. However, the percent of patients responding remains quite similar to that seen in the initial report. That study showed that of 24 patients receiving 5, 10, or 20 mg/kg/day, 16, or 67%, had symptomati...

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“…This can be seen when an agent such as EHDP is given, which inhibits mineralization of bone. Khairi et a1 (26) compared the effects of a dosage of 5 mg/kg/24 hr with those of 10 mg/kg/24 hr. The average width of osteoid seams (normal value given is 9.0 f 3.7 pm) increased from 8.3 to 18.3 pm in nonpagetic bone, and from 9.1 to 33.1 pm in pagetic bone.…”

Section: Discussionmentioning

confidence: 99%

The action of the main therapeutic regimes on paget's disease of bone, with a note on the effect of vitamin d deficiency

Malghem

Maldague

et al. 1980

Arthritis & Rheumatism

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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...

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Sodium Etidronate in the Treatment of Paget's Disease of Bone

Cited by 138 publications

References 9 publications

Apd in paget's disease of bone role of the mononuclear phagocyte system?

Apd in paget's disease of bone role of the mononuclear phagocyte system?

Use of etidronate (ehdp) in paget's disease of bone

The action of the main therapeutic regimes on paget's disease of bone, with a note on the effect of vitamin d deficiency

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