AbstractA double‐blind randomized study of 29 patients with symptomatic Paget's disease was conducted comparing the clinical, biochemical, and histomorphometric responses to 3‐month treatment with placebo (10 patients), low‐dose disodium etidronate (EHDP) (5–7 mg/kg/day) (10 patients), and low‐dose EHDP plus 1α‐hydroxy‐vitamin D3(1αD3) 0.5 mcg daily (9 patients). In placebo‐treated patients no significant changes were observed in symptoms, biochemistry, or bone histomorphometry. Histologically apparent mineralization defects developed after 3 months of therapy in 90% of patients in the EHDP group, compared with 45% of patients in the EHDP/1αD3group. In 19% of the patients treated with active medication, the mineralization defects in pagetic bone were accompanied by histological evidence of continued osteoclastic resorption. The development of mineralization defects was not related to serum levels of vitamin D metabolites, alkaline phosphatase, or intestinal calcium absorption but did correlate with the occurrence of hyperphosphatemia during treatment, which was most marked in patients treated with EHDP alone. Although mineralization defects were less frequent in the EHDP/1αD3group, these patients also responded less well symptomatically, thus limiting the potential usefulness of this drug combination in Paget's disease. It is suggested that the diminished response in the EHDP/1αD3group and the lower frequency of mineralization defects may have been related to an alteration in the intestinal absorption of EHDP by the vitamin D metabolite.Of patients treated with EHDP alone, 90% had symptomatic and biochemical improvement, suggesting that this agent is generally an effective and safe treatment in Paget's disease. However, in view of the high incidence of mineralization defects, we would continue to advise caution in the use of EHDP where there is significant deformity of, or lytic lesions, in