Familial expansile osteolysis: a morphological, histomorphometric and serological study.

Biopsies from the diseased bones of patients with familial expansile osteolysis (FEO) were examined by light and electron microscopy. Focal concentrations of multinuclear osteoclasts were present, and these contained viral-like microcylindrical inclusions which appeared exclusive to their nuclei. No consistent relationship was found between osteoclast size and the number of osteoclast nuclei containing microcylindrical inclusions. Quantitative histomorphometry showed evidence of increased bone remodelling with high bone cell densities and a decrease of the reversal period in bone remodelling. The lesions contained prominent woven bone and fibrovascular tissue, together with mononuclear cells and adipocytes. Little bone was found in the most radiolucent lesions, which were almost totally occupied by adipocytes and fibrovascular tissue. Serology did not reveal any significant differences between the viral antibody titres of patients and their age- and sex-matched controls. The present study suggests that intranuclear viral-like microcylindrical inclusions of osteoclasts are not a specific feature of Paget's disease, and are found in other disorders of osteoclast function, including pycnodysostosis, osteopetrosis, giant cell tumours, and familial expansile osteolysis.     

Paramyxovirus-like inclusions in two cases of pycnodysostosis

We describe the biochemical and histological features of two related patients with pycnodysostosis. Examination of bone biopsies taken from both patients showed the presence of large nonfunctional osteoclasts which contained paramyxovirus-like inclusions similar in size and arrangement to those found in Paget's disease of bone. No radiographic, histologic or biochemical evidence for Paget's disease was found in either patient. The presence of osteoclast inclusions may not be specific for Paget's disease, therefore, and could be the result rather than the cause of abnormal osteoclast metabolism.     

Acute effects of deflazacort and prednisone on rates of mineralization and bone formation

The aims of this study were to determine (1) whether acute suppression of bone formation could be evaluated after the administration of corticosteroids in man by quantitative bone histomorphometry; and (2) whether there were significant differences between the effects of prednisone and its analog deflazacort. Thirteen patients who needed high-dose corticosteroid therapy were randomly allocated to two groups of treatment (prednisone or deflazacort). Quantitative bone histomorphometry, using the technique of triple labeling, and biochemical measurements of bone turnover were studied. There were no differences in biochemical indices of bone turnover between prednisone and deflazacort at the beginning and end of the 15 days of treatment course. During corticosteroid treatment, there were no significant changes in biochemical indices of bone turnover but a significant decline in total alkaline phosphatase (P<0.01). Histomorphometric indices, as revealed by measurements of tetracycline interval and extent of labeling, showed no significant differences in either mineral apposition rate or bone formation rate in the two groups. We conclude that the acute glucocorticoid suppression of bone turnover by glucocorticoids is not detectable within the first 2 weeks of treatment by histomorphometric techniques. No differences in bone effects of prednisone and deflazacort were detected in this short-term study.     

Biochemical and histological evidence that carcinoma of the prostate is associated with increased bone resorption

We have investigated the hypothesis that carcinoma of the prostate with skeletal metastases is associated with increased bone resorption. In 54 affected patients a close correlation was observed between serum activity of alkaline phosphatase and urinary excretion of hydroxyproline (r = +0.818; P less than 0.001), comparable to that seen in Paget's disease of bone. The administration of synthetic salmon calcitonin (100 U subcutaneously) induced a significant fall in serum calcium and urinary excretion of hydroxyproline, proportional to the prevailing rate of bone turnover, as assessed by serum alkaline phosphatase or hydroxyprolinuria. Administration of the diphosphonate, etidronate, also decreased hydroxyprolinuria, suggesting that urinary hydroxyproline reflected increased rates of bone resorption in this disorder. Histology of bone in sites adjacent to and distant from skeletal metastases showed increased histological indices of bone resorption. These results suggest that the skeletal disease associated with prostatic carcinoma is characterized by generalized increases in bone resorption as well as focal increases in bone formation.     

Relationship between 5-fluorouracil exposure and outcome in patients receiving continuous venous infusion with or without concomitant radiotherapy

AIMS: Toxicity and response are correlated with plasma 5-fluorouracil (5-FU) concentration in patients treated with 5-FU at a dose of 1000 mg m(-2) day(-1). Head and neck cancer patients are treated with various therapeutic regimens, including chemotherapy with 5-FU at a dose of 600 mg m(-2) day(-1) with radiotherapy. We investigated the plasma concentration-effect relationship for this regimen, with the aim of developing recommendations for dose adjustment. METHODS: Patients received 5-FU at doses of 600 or 1000 mg m(-2) day(-1), as a continuous infusion over 4 or 5 days, with or without radiotherapy for the 600 mg m(-2) day(-1) regimen. The area under the curve (AUC) for 5-FU concentration was estimated, based on a single morning blood sample taken each day during treatment. AUC values were compared between patients with and without toxicity. This simplified method for AUC estimation was compared with the standard two-samples-per-day method in an independent group of 50 patients. RESULTS: Forty-six patients, corresponding to 115 courses, were included in this prospective study. Considerable interindividual variability in estimated AUC was observed for both doses. Grade 3-4 toxicity occurred in 10 and 21% of patients given doses of 600 and 1000 mg m(-2) day(-1), respectively. Ths study confirmed the relationship between plasma 5-FU concentration and toxicity previously reported for 1000 mg m(-2) day(-1), but found no such relationship for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. CONCLUSIONS: Our results do not support the use of therapeutic drug monitoring to improve tolerance for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. A simplified method is proposed for 5-FU monitoring for the 1000 mg m(-2) day(-1) regimen.