Two patients with osteoporosis circumscripta of the skull are presented who have each been treated with a 3-month course of intravenous infusions of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) (total dose of 185 and 375 mg), which in both cases was associated with rapid and dramatic remineralization of the porotic bone and marked clinical and biochemical remission. However, osteolytic disease reappeared (after 9 and 18 months, respectively) in both cases as an osteolytic ring showing high uptake of radiolabelled bisphosphonate on bone scan, in formerly unaffected bone just distal to the original leading edge of osteolysis. Further treatment was associated with healing of these new lesions. These cases suggest that the diseased osteoclasts entering previously normal bone are protected against the drug probably because normal bone matrix takes up relatively little APD, and that APD taken up by diseased bone behind this front confers long-term resistance to further resorption. In assessing treatment strategies with bisphosphonates for Paget's disease, the response at the leading edge of osteoporosis circumscripta may be particularly informative.