melphalan and Fractures--Bone

Fibrogenesis imperfecta ossium (FIO) is an extremely uncommon fatal bone disorder of poorly understood etiology. The pathogenesis of FIO is not well known. The fundamental skeletal defect appears to be an abnormality in organic matrix of bone characterized by defective mineralization of the abnormal collagen. FIO clinically manifests in middle-aged adults presenting with fracture and bone pain. Elevated serum alkaline phosphatase is the only and the most consistent biochemical abnormality. Although paraproteinemia is observed in one-third of cases, the pathogenic link to the disease process is unclear. Limited information on FIO and its close resemblance to many metabolic bone disorders leads to delayed or missed diagnoses and management. Prednisolone, bisphosphonates, melphalan and steroids have been tried previously with variable success. Recently, a trial of recombinant growth hormone therapy was found to be effective. Further research focused on the pathogenetic mechanisms of FIO is needed to identify and develop targeted therapeutic options.

Topics: Alkaline Phosphatase; Biopsy; Bone and Bones; Bone Diseases, Metabolic; Collagen; Diphosphonates; Disease Progression; Fractures, Bone; Humans; Melphalan; Mutation; Osteogenesis Imperfecta; Paraproteinemias; Prednisolone; Prognosis; Radionuclide Imaging; Steroids

The clinical features, investigation, treatment and outcome of two adults with fibrogenesis imperfecta ossium are described. In this rare acquired disorder of bone, normal lamellar collagen is replaced by structurally unsound collagen-deficient tissue, which leads to extreme bone fragility and ununited fractures. Transmission microscopy and SEM showed striking ultrastructural changes in bone structure and mineralisation. Both patients had monoclonal IgG paraproteins in the plasma and one excreted monoclonal lambda light chains in the urine. No abnormal plasma cells were found in the bone marrow and there was no evidence of amyloid deposition in the tissues. In both patients initial treatment with 1 alpha-hydroxycholecalciferol appeared to be ineffective, but in one, repeated courses of melphalan and corticosteroids over three years together with 1 alpha-hydroxycholecalciferol produced striking clinical and histological improvement. The findings in these and other patients strongly suggest that paraproteinaemia is an integral feature of fibrogenesis imperfecta ossium, and this needs further investigation.

Topics: Adrenal Cortex Hormones; Adult; Aged; Bone and Bones; Bone Diseases; Child; Collagen; Collagen Diseases; Female; Fractures, Bone; Humans; Hydroxycholecalciferols; Male; Melphalan; Microscopy, Electron; Middle Aged; Paraproteinemias; Tendons

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal-related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi-centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha-interferon) treatment. With a median treatment duration of about 550d, no statistically significant reduction in skeletal-related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P=0.02) and a decreased reduction of body height of 1.5 cm (P= 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Body Height; Bone Diseases; Diphosphonates; Double-Blind Method; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Multiple Myeloma; Pain; Pamidronate; Prednisolone; Treatment Failure

In 1989, a prospective randomized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients. The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications: pain, pathologic fractures, and hypercalcemia. We now report first results as an interim analysis, including data obtained from 26 patients (total number of Tübingen patients n = 36) who entered the study at the Medizinische Universitätsklinik Tübingen. Patients were randomized to receive either chemotherapy alone (melphalan 15 mg/m2 i.v. on day 1 and prednisolone 60 mg/m2 orally on days 1-4 every 4 weeks (control group) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year. Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine. Clodronate treatment resulted in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption. No clodronate-related toxicity or hypocalcemia was observed. In patients treated with chemotherapy alone, this effect was less marked and discontinuous. Clodronate-treated patients developed fewer progressive bone lesions (significant for lytic, not for osteoporotic lesions). No hypercalcemic episodes occurred in the clodronate-treated patients, but there were six episodes in the control group. Whereas the number of vertebral fractures was evidently less is clodronate-treated patients, three of those patients suffered from multiple fractures of long bones and ribs. All together, 12 pathologic fractures occurred in five clodronate-treated patients, whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period. The final analysis of all multicenter included patients should clarify these findings. There was a significant finding that clodronate proved to have an analgesic effect.

Topics: Adult; Aged; Analgesia; Bone Diseases; Bone Resorption; Calcium; Clodronic Acid; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteoporosis; Prednisolone; Prospective Studies

Patients with asymptomatic or smoldering multiple myeloma should not be treated but should be observed closely for progression. For symptomatic myeloma, chemotherapy is indicated. Melphalan, the agent of choice, should be given with prednisone for 1 week of every 6 weeks, If melphalan brings no response, or response and then relapse, cyclophosphamide (Cytoxan) should be give intravenously every 4 weeks or orally every day. BCNU, CCNU, and doxorubicin (Adriamycin) have also shown activity in myeloma. Hypercalcemia occurs in one-third of patients and should be countered with hydration, corticosteroids, Neutra-Phos, or mithramycin. Long-term hemodialysis has achieved some success. The combination of sodium flouride and calcium carbonate produces new bone formation; it seems a useful adjunct in treatment for myelomatous bone disease. Radiation should be utilized only for severe, localized pain or for solitary lesions. Survival with multiple myeloma varies, mean durations being 2 to 3 years. Multivariate analysis indicates that serum creatinine and calcium levels are the most significant indicators regarding 2-year survival. We have found monoclonal proteinuria not significantly more frequent with renal insufficiency than with normal renal function, renal insufficiency not significantly more frequent with lambda than with kappa chains, and survival not significantly greater with IgG myeloma than with IgA.

Topics: Anemia; Bacterial Infections; BCG Vaccine; Carmustine; Cyclophosphamide; Fractures, Bone; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Mycobacterium bovis; Prognosis

Topics: Adult; Aged; Fractures, Bone; Hip; Humans; Lymph Nodes; Male; Maxillary Sinus; Melphalan; Middle Aged; Osteoporosis; Plasmacytoma; Prednisolone; Radiotherapy