Efficacy and tolerability of a new formulation of oral tiludronate (tablet) in the treatment of Paget's disease of bone.

We sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open-label uncontrolled trial. Patients received a daily dose of 400 mg oral tiludronate (two tablets). Treatment was for 6 months. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatine (OH/Cr) were measured every 3 months, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale (VAS). Statistical analysis revealed a significant reduction from baseline in SAP and OH/Cr levels, as well as VAS scores. In the whole population with evaluation under treatment, there was a reduction in initial SAP activity after 3 months (47.2 +/- 2.2%, mean +/- SEM) and 6 months (58.3 +/- 2.3%). In the population with SAP levels above twice the upper limit at inclusion and with evaluation at month 3 and month 6 (n = 96), the reduction in SAP levels was 49.3 +/- 2.4% after 3 months and of 59.5 +/- 2.6% after 6 months (ANOVA time effect, p = 0.0001). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance was good. Exhaustive biochemical investigation failed to reveal significant toxicity of tiludronate tablets at the dose of 400 mg/day. The dose of 400 mg daily of this new formulation appears to be a satisfactory tiludronate regimen for the treatment of Paget's disease of bone.

Sarcomatous degeneration in Paget's bone disease.

The authors report 12 cases (8 men and 4 women) of sarcomatous degeneration in Paget's bone disease, with an average age of 72.3 years. Sarcomatous degeneration occurred often in polyostotic Paget's disease, and osteitis deformans was seen in 4 cases. Femur and pelvis were the most affected bones. Pain was a constant feature, whereas tumefaction and fracture were less common. Osteolytic lesions were more frequent than condensed or mixed lesions and radiological signs of malignancy were usually found. Seven cases were histologically classified as osteogenic sarcoma and 3 cases as fibrosarcoma. Electron microscopy was performed on 2 osteogenic sarcomas and in 1 case revealed microcylindrical inclusions in Pagetic osteoclasts and in multinucleated giant tumor cells, but none in mononucleated tumor cells. The average survival time for the patients in this study was only 4.5 months.

Treatment of Paget's disease of bone with (4-chloro-phenyl) thiomethylene bisphosphonate.

Introduction of antiosteoclastic drugs, calcitonin and etidronate, has profoundly changed the treatment of active Paget's disease of bone. Nevertheless, the use of these drugs is limited in some patients by the occurrence of side-effects or by a resistance to therapy. We report the results of an open, nonrandomized study with a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate (Cl-TMBP), given orally to 35 patients with active Paget's disease of bone. At two different dosages this new bisphosphonate induced a significant decrease in disease activity. Patients receiving a mean dosage of 5 mg/kg/d (n = 14) showed a significant reduction of serum alkaline phosphatase levels to 43% of pretherapeutic values (from 499 +/- 91 to 214 +/- 41 IU/l) while hydroxyproline/creatinine ratio decreased to 43% of baseline (from 93 +/- 21 to 40 +/- 11). A second group of patients (n = 21) receiving a mean dosage of 11 mg/kg/d exhibited a similar response: serum alkaline phosphatase activity was reduced to 42% of initial values (from 1384 +/- 209 to 584 +/- 111 IU/l) while hydroxyproline/creatinine ratio fell to 48% of baseline (from 144 +/- 27 to 69 +/- 15). This was accompanied by a reduction in radionuclide uptake in pagetic areas. A prolonged beneficial effect was observed in most patients. In patients receiving the highest dosage significant reduction in serum calcium and rise in parathyroid hormone were observed. Otherwise no clinical or biological side-effect occurred throughout the study.

[Anti-centromere antibodies. Study of 67 positive sera]. / Anticorps anti-centromères. Etude de 67 sérums positifs.

From a series of 67 sera containing anticentromere antibodies we endeavoured to determine the principal clinical or biological peculiarities of these antibodies. The titers of anticentromere antibodies were usually high, with few differences between patients. Humoral immunity was frequently perturbed, with antinuclear autoantibodies (without anti-Scl 70), anti-mitochondria antibodies, rheumatoid factors, circulating immune complexes, etc. The disease predominated in women (97%) whose age and duration of symptoms varied considerably. The most frequent clinical manifestation noted in the 47 reports analyzed was Raynaud's phenomenon (93%) which in most cases (90%) was part of a complete or incomplete CREST syndrome. Telangiectasias, calcinosis and acrosclerosis were the main witnesses to the duration of these sclerodermas. Our findings were concordant with those of previous studies. However, the frequency of sicca syndrome (76%) was unexpected, and must be related to 2 laboratory results: the quasi-absence of anti-SSA and anti-SSB antibodies in our patients and the presence of two monoclonal immunoglobulins (IgM kappa and IgG lambda). There may be some degree of independence between the sicca syndrome and the sclerodermal manifestations.

[Seasonal variations of vitamin D metabolites in man]. / Variations saisonnières des métabolites de la vitamine D chez l'homme.

Studies concerning the influence of seasons and ultraviolet radiations on the metabolism of 1,25-dihydrocholecalciferol (1,25 (OH)2D), the active form of vitamin D, have given conflicting results. In the present study serum concentrations of the 3 main vitamin D metabolites--25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D--were measured by radiocompetitive assay (a) monthly during one year in 7 normal subjects, and (b) before, during and after 4 weeks of "whole body" exposure to ultraviolet radiations in 11 other subjects. In study (a) parallel changes in 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations were observed during the year, with a rise in the summer; there were no significant monthly or quarterly changes in 1,25-dihydroxyvitamin D concentrations. In study (b), 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations rose by 150% and 200% respectively after 4 weeks' exposure to ultraviolet radiations and again, there were no significant changes in 1,25-dihydroxyvitamin D concentrations. These results confirm that when synthesis of the substrate (25-hydroxyvitamin D) increases, synthesis of 1,25-dihydroxyvitamin D is inhibited by a regulatory process which does not apply to 24,25-dihydroxyvitamin D synthesis.

Different patterns of extension and recurrence in algodystrophy.

A true recurrence at exactly the same site is quite unusual in algodystrophy. Local or regional extension is possible. The bone scan is an easy way to demonstrate that the areas successively affected are not the same. An apparent local recurrence could in fact be a microscopic compression fracture of trabecular bone or cortical fractures or part of a factitious disorder.

Further vascular, bone and autonomic investigations in algodystrophy.

Direct clinical observation is the most common means of diagnosing algodystrophy. Further investigations may be helpful to rule out other pathological conditions, such as occult or stress fractures or avascular osteonecrosis and to obtain a better understanding of algodystrophy. Transient vascular hyperpermeability in the affected part is well demonstrated by the clinical findings, the MRI signs, and the three-bone scan features. 99m Technectium EHDP bone scan provides an evaluation of the vascular abnormalities and of the osteoblastic activity. Dermal microcirculation and its reactions to sympathetic stimuli are investigated by laser doppler fluximetry and videophotometric capillaroscopy. Perhaps the sweat test does unveil what might be specific about algodystrophy. The amount of bone loss in algodystrophy in a few weeks or months is what might be expected over 10 years during the natural history of uncomplicated osteoporosis. An initial fracture is undoubtedly an initiating event in the appearance of algodystrophy, but patients suffering from algodystrophy may still have significant osteoporosis for a long period and hence be at risk for fracture. Densitometry could be an aid to the diagnosis and probably to monitoring treatment as well. The local colonization of fibroblasts following the transient stage of hyperpermeability must be kept in mind to explain the results of joint, bone, muscles or neurological investigations in late algodystrophy.

[What is Paget's disease?]. / Qu'est-ce que la maladie de Paget?

Paget's disease of bone is characterized by the progressive and extensive replacement, in one or several bones, of normal bone tissue by a bone tissue of rough and irregular structure, the excessive and disorderly renewal of which gradually produces hyperdensity and hypertrophy of the bones involved. The condition results from the action of abnormal and overactive osteoclasts containing virus-like intranuclear and intracytoplasmic inclusions. The disease profoundly alters the physiology of bones in the region affected. The viral-looking inclusions that enter the osteoclasts seem to induce a loss of control of bone renewal and remodelling, as shown by histology and radiology. The resorption-formation mechanism persists but it is unbalanced, facilitating bone resorption during two to five years, then bone formation. In that way, subjects with Paget's disease, who have reached the age of physiological osteopenia, show an often important increase in bone density and mass. Paget's disease of bone is a disease grafted on the skeleton: it is partly dependent on the skeletal status of the host. The activity of Paget's disease is evaluated by measuring the ratio of plasma alkaline phosphatase levels to the volumes of normal and pagetic bones; the author suggests a mathematical formula for calculating this ratio.

[Paget's bone disease. Epidemiology and etiology]. / Maladie osseuse de Paget. Epidémiologie et étiologie.

Paget's bone disease is a chronic and usually benign bone disorder mainly found in people over fifty. The condition is characterized by excessive bone remodelling related to bone cell overactivity leading to abnormal bone structure. The viral origin of the disease, first proposed on the basis of ultrastructural observations, is now supported by immunocytological and molecular hybridization studies. Genetic and environmental elements may be involved, favouring and modulating the expressivity of this slow virus infection.

[Transient painful lumbar blocks]. / Les à-coups douloureux bloquants lombaires.

Recurrent painful locking of the lower back is suggested as an appropriate term for designating sudden episodes of jabbing low back pain with locking of the spine occurring in the absence of unusual exertion, resolving within one or two minutes, and recurring many times over several weeks or months. This retrospective study included 20 outpatients classified as having recurrent painful locking of the lower back between 1978 and 1992. Inclusion criteria were availability of roentgenograms taken at the time of the acute symptoms and a follow-up of at least two years. Two typical cases are reported with diagrams to show the timing of recurrent painful locking of the lower back with respects to other low back symptoms. Mean age at onset was 56 years. Seventy per cent of patients were females. A 10-year to 30 year history of lumbago was found in every case. Recurrent painful locking of the lower back occurred substantially later than lumbago suggesting that it denoted more advanced damage to the lumbar spine. Pathophysiologic hypotheses are discussed: the causative lesion may be a mobile flap at the posterior aspect of the anulus. In most patients, the symptoms resolved within six months.

[Migratory algodystrophy of the lower limbs involving the foot and complicated by two fatigue fractures. An histological bone study]. / Algodystrophies itératives des membres inférieurs, migratrices sur les pieds, compliquées de deux fractures de fatigue. Etude histologique osseuse.

A 62 year old male developed transient osteoporosis algodystrophy successively in several sites of the lower limbs (8 episodes of involvement of one or two sites over an 8-year period) three years after surgery for a chromophobic pituitary adenoma. Two stress fractures developed, during the sixth and seventh years, respectively, in bones previously affected by osteoporosis. A biopsy specimen from the distal tibia showed thin bone trabeculae and reduced cellular activity. The only etiologic factor was the patient's psychological profile characterized by anxiety and introversion.

[Osteomyelitis in the pagetic tibia]. / Ostéomyélite sur tibia pagétique.

Osteomyelitis developing in pagetic bone is a very rare event, of which only one instance has been reported to date, in a patient with mandibular disease. We have managed three patients with osteomyelitis of a pagetic tibia. The portal of entry was a skin lesion in all three cases. A Gram-negative organism was found in all three cases and was associated with the anaerobe Bacteroides melaninogenicus in one case. One of the patients was lost to follow up before eradication of the infection. Amputation was required in the other two after unsuccessful antimicrobial therapy for 23 and four years, respectively.