Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study.

BACKGROUND: Reducing bisphosphonate dosing frequency may improve suboptimal adherence to treatment and therefore therapeutic outcomes in postmenopausal osteoporosis. Once-monthly oral ibandronate has been developed to overcome this problem. OBJECTIVE: To confirm the 1 year results and provide more extensive safety and tolerability information for once-monthly dosing by a 2 year analysis. METHODS: MOBILE, a randomised, phase III, non-inferiority study, compared the efficacy and safety of once-monthly ibandronate with daily ibandronate, which has previously been shown to reduce vertebral fracture risk in comparison with placebo. RESULTS: 1609 postmenopausal women were randomised. Substantial increases in lumbar spine bone mineral density (BMD) were seen in all treatment arms: 5.0%, 5.3%, 5.6%, and 6.6% in the daily and once-monthly groups (50 + 50 mg, 100 mg, and 150 mg), respectively. It was confirmed that all once-monthly regimens were at least as effective as daily treatment, and in addition, 150 mg was found to be better (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were seen; 150 mg produced the most pronounced effect (p<0.05 versus daily treatment). Independent of the regimen, most participants (70.5-93.5%) achieved increases above baseline in lumbar spine or total hip BMD, or both. Pronounced decreases in the biochemical marker of bone resorption, sCTX, observed in all arms after 3 months, were maintained throughout. The 150 mg regimen consistently produced greater increases in BMD and sCTX suppression than the 100 mg and daily regimens. Ibandronate was well tolerated, with a similar incidence of adverse events across groups. CONCLUSIONS: Once-monthly oral ibandronate is at least as effective and well tolerated as daily treatment. Once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes.

Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study.

The bisphosphonate ibandronate, administered either daily or intermittently with an extended between-dose interval of >2 months, has been shown to reduce significantly the incidence of vertebral fractures, to increase bone mineral density and to reduce levels of biochemical markers of bone turnover in a phase III randomized study in women with postmenopausal osteoporosis (PMO). Bone histomorphometry was performed on a subgroup of women participating in this study in order to assess bone quality and architecture. The patients were randomized to receive one of the following: placebo, continuous oral daily ibandronate (2.5 mg/day) or intermittent oral ibandronate (20 mg every other day for 12 doses every 3 months). Out of the overall study population of 2,946 patients, 110 were randomly assigned to undergo transiliac bone biopsy at either month 22 or month 34 of treatment. The primary safety endpoint was osteoid thickness in trabecular bone, which was measured to exclude treatment-induced bone mineralization defects. Secondary safety endpoints assessed bone volume, bone turnover and micro-architecture. The primary efficacy endpoint was bone mineralizing surface. In all bone biopsy cores, newly formed trabecular bone retained its structure without any signs of woven bone. Marrow fibrosis and signs of cellular toxicity were not observed. Quantitative assessment demonstrated no impairment in mineralization of bone matrix: osteoid thickness tended to be similar or slightly lower in the ibandronate groups versus the placebo group. All secondary safety variables and the bone efficacy parameter were consistent with the production of normal-quality, newly formed bone and a modest reduction in bone turnover with both ibandronate regimens relative to placebo. Long-term treatment with oral ibandronate, even when administered with an extended between-dose interval of >2 months, produces normal-quality, newly formed bone in women with PMO.

Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study.

The prevention and treatment of glucocorticoid-induced osteoporosis is a major concern for rheumatologists since inflammatory joint disease is among the most common reasons for long-term glucocorticoid therapy. We used a randomized placebo-controlled design to evaluate the efficacy of one-year cyclical etidronate therapy in preventing bone loss in 83 glucocorticoid-treated patients with rheumatoid arthritis, polymyalgia rheumatica, or giant cell arteritis. Glucocorticoid treatment duration was shorter than three months, and the starting dose was greater than 7.5 mg of prednisone-equivalent per day. Etidronate was given according to the standard cyclical schedule, i.e. 400 mg/d for periods of 14 days separated by 76-day intervals during which patients took 500 mg of supplemental calcium per day. The primary evaluation criterion was the change in lumbar spine bone mineral density after one year of etidronate therapy. Bone mineral density decreased by 1.94 +/- 0.61% in the placebo group and increased by 0.86 +/- 0.6% in the etidronate group, yielding a between-group difference of 2.8 +/- 0.86% (P = 0.002). The difference was largest in postmenopausal women (3.38 +/- 1.11%; P = 0.004). At the femoral neck, there was a smaller bone mineral density decrease in the etidronate than in the placebo group, but the difference (1.11 +/- 1.13%) was not statistically significant. The most common side effects were gastrointestinal symptoms and showed no difference between the two groups. Four fractures (including one vertebral fracture) occurred in the placebo group versus two (including one vertebral) in the etidronate group. Etidronate prevents glucocorticoid-induced lumbar spine bone loss in patients with rheumatoid arthritis, polymyalgia rheumatica, or giant cell arteritis.

Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allergens in asthmatic patients. A preliminary study.

Platelet Activating Factor, PAF-acether, elicits acute and more prolonged inflammatory responses in both experimental animals and man, and is recognised as a possible mediator of asthma. The effect of a specific PAF-acether antagonist, BN 52063, on the early asthmatic response to inhaled allergen was assessed in a randomised, double-blind, crossover study in eight atopic asthmatics, who received three days treatment with BN 52063 or placebo, separated by a one week washout. On the third day of treatment, subjects were challenged with nebulised house dust mite or pollen allergen. BN 52063 significantly antagonised early bronchoconstriction and showed a tendency to inhibit residual bronchial hyperreactivity, assessed six hours after allergen challenge by a provocation test to acetylcholine. No side effects were reported during active treatment. This is the first study in man demonstrating the efficacy of a specific PAF-acether antagonist on the immediate response to inhaled allergen challenge in asthmatics. The findings support the possible role of specific PAF-acether antagonists in the treatment of asthma.

[Distribution of HLA-DR antigens in unrelated giant cell arteritis]. / Groupage HLA DR dans les artérites à cellules géantes non apparentées.

HLA-DR antigen distribution was determined by lymphotoxicity on total lymphocytes for locus A.B.C. antigens numbering 14,28 and 7 respectively, and by a search on B lymphocytes for the 12 antigens of locus DR. The normal population included 124 subjects typed for HLA-A.B.C. and 200 subjects typed for HLA-DR. The frequency of alleles was compared to that of the different groups of patients. Significant variations were evaluated by the X2 test, using Woolf's method; the P value obtained was multiplied by the number of antigens looked for (P corrected, or pc). No deviation in frequency was found with the HLA-A.B.C. antigens. Only the DR 4 antigen, present in 23% of the normal population, was increased in proportions that depended on clinical classification: 39.4% (Pc = 0.05) in all patients with giant cell arteritis: 27% (NS) in the 37 polymyalgia rheumatica patients with negative biopsy of the temporal artery; 46.8% (P 0.05) in the 62 patients with Horton's disease presenting either as clinical and histological temporal arteritis (26 cases; DR 4 = 38.5%; NS), or as clinical and/or histological temporal arteritis associated with polymyalgia rheumatica (36 cases; DR 4 = 52.8%; Pc less than 0.005). The frequency of DR 4 antigen in Horton's disease with typical temporal artery biopsy (37 cases) was 46% (Pc = 0.05).

Flattening of the rheumatoid foot in tarsal arthritis on X-ray.

222 consecutive and unselected patients suffering form classical or definite rheumatoid arthritis wee studied. 397 of their feet were examined. Talonavicular arthritis was the commonest finding (31.5% of all patients), followed by sub-talar (23.3%), cuneo-navicular (20.4%) cuneo-metatarsal (14.9%) and tibio-tarsal arthritis (12.6%). Rheumatoid disease of the tarsus becomes commoner as the disease progresses. The incidences of involvement of the talo-navicular and sub-talar joints show a similar pattern, with a leap of 25% between 5 years of duration of the disease and 10 years. The same is seen with involvement of the cuneo-navicular and cuneo-metatarsal joints, between a duration of 10 years of the disease and 15 years. The percentage of flat foot is greater in feet with tarsal arthritis (p less than 0.001). The authors observed a relationship between tarsal arthritis, the length of history of rheumatoid arthritis, and flat foot. The method of investigation is discussed, and theories about evolution of the rheumatoid foot are considered.

Bacterial endocarditis presenting as acute vertebral osteomyelitis: 14 cases.

Association between bacterial endocarditis (BE) and vertebral osteomyelitis (VO) has infrequently been noted. In a retrospective analysis of BE (280 cases) and VO (150 cases) 14 cases were found to have this association. There were 12 males and 2 females, ages ranging from 39 to 72 years, mean age 56.6. Blood cultures were positive for Streptococcus viridans (6 cases). Str. faecalis (4 cases), staphylococcus (2 cases), Gram negative bacteria (1 case). Organism was not isolated in one case. Fever and severe back pain antedate the diagnosis of VO 3.5 and 2.5 months. X rays films of the spine and bone scans (4 cases) revealed lumbar (6 cases) or cervical (4 cases), or dorsal (3 cases) or combined cervical and dorsal (1 case) locations. History of murmur (4 cases) and development of mitral (8 cases) or aortic (4 cases) or combined mitral and aortic (2 cases) insufficiencies were consistent with concomitant BE. Echocardiogram revealed vegetations in 6 out of 9 cases. Patients received antibiotic therapy for 3.5 months. Ten patients were cured with antibiotics only, 4 required valve replacement. One died. Thus age, sex, history of heart disease, valvular involvement, duration of symptoms prior to admission and bacteriological pictures are the same in BE with VO as in BE without VO. Survival rates are also the same if early recognition of BE and VO with prompt and prolonged antibiotic therapy may prevent severe haemodynamic or vertebral problems.

[Cytofluorometric study of the cell cycle and various lymphocyte differentiation membrane antigens in the synovial fluid in rheumatoid polyarthritis]. / Etude cytofluorométrique du cycle cellulaire et de certains antigènes membranaires de différenciation des lymphocytes du liquide synovial au cours de la polyarthrite rhumatoïde.

Synovial fluid lymphocytes were studied by cytofluorometry in 11 patients with classical or definite rheumatoid arthritis. This method allowed the study of the cellular cycle after acridine orange staining and of membrane antigens, expressed by normal and/or activated lymphocytes, which were demonstrated by using various monoclonal antibodies (OKT3, OKT4, OKT8, OKIa1, OKT10). The OKT4/OKT8 ratio was decreased in 4 out of 5 cases and the percentage of HLA DR + cells was clearly increased. In 6 out of the 11 patients, the percentage of dividing cells varied from 2.2 to 7.2 and was less than 1 in the others as in normal blood lymphocytes. Increase in cellular RNA content characterized the non dividing cells. The most elevated values of the cellular RNA content were observed in patients who had the smallest percentage of dividing cells, suggesting that the cellular cycle was stopped between the G1 and S phases. Study of the cellular cycle may reveal a lymphocyte activation parameter which could be unrelated to the expression of differentiation membrane antigens.

[Immunologic diagnosis of rheumatoid arthritis]. / Diagnostic immunologique de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA) is an autoimmune disease whose diagnosis was long based solely upon the demonstration of rheumatoid factors (RF) which are IgM antibodies with anti-IgG specificity. The development of modern techniques which are more sensitive and/or detect non-IgM rheumatoid factors has reduced the percentage of presumptive seronegative RA. Immunological studies of the disease also reveal other evidences of polyclonal B-lymphocyte activation: hypergammaglobulinemia, high levels of beta-2-microglobulin and circulating immune complexes, presence of various autoantibodies (anti-collagen, antilymphocyte and, in some instances, anti-nuclear antibodies). These anomalies are found, not only in the blood, but above all in the synovial fluid, which explains the low synovial complement level. The disturbances of cellular immunity cannot yet be used for diagnostic purposes, but suggest that the physiopathologic mechanism of RA involves a decreased T-suppressor lymphocyte activity and/or B-cell unresponsiveness to suppressor influences.

Increased DNA and/or RNA content of synovial fluid cells in rheumatoid arthritis: a flow-cytometry study.

Flow-cytometry studies of DNA and RNA content were carried out in acridine orange-stained synovial fluid lymphocytes from 11 patients presenting with classical or definite rheumatoid arthritis. Monoclonal antibodies were used to detect specific T cell surface antigens (OKT3, OKT4, OKT8) and antigens associated with lymphocyte activation (OKIa 1, OKT10). T3 positive cell percentages were comparable to those of normal blood, although T4/T8 ratios were decreased in 4 out of 5 cases, and HLA-DR positive cells increased. Six out of 11 patients showed percentages of dividing cells varying from 2.2 to 7.2% as compared with less than 1% in the other patients and in normal blood. Nondividing cells were characterised by an increase in their RNA content compared with normal blood. A greater increase of RNA content was observed in patients with lower percentages of dividing cells, suggesting a G1/S block. Changes in cellular DNA and/or RNA contents provide a valuable parameter of lymphocyte activation, not necessarily linked to the expression of differentiation antigens by activated cells.

[Ankylosing spondylarthritis. Pathogenesis of the destructive disco-vertebral lesions. 15 cases]. / Spondylarthrite ankylosante. Pathogénie des lésions destructrices disco-vertébrales. Quinze observations.

Fifteen cases of destructive disco-vertebral lesions discovered in patients with ankylosing spondylitis are reported. The incidence of these lesions was 5.5% and they were unrelated to underlying conditions. Radiologically, they fell into five categories: pseudodystrophic, pseudotuberculous, extensive erosions, bone condensation and isolated narrowing of the intervertebral spaces. From an analysis of these 15 cases and of published data, it would appear that these forms result from different pathogenetic processes: an inflammatory process for the pseudodystrophic and pseudotuberculous forms and for early extensive erosions; a mechanical process for bone condensation and perhaps also (though this is more controversial) for late extensive erosions and isolated intervertebral narrowing.

[Treatment of rheumatoid arthritis with isoprinosine. Personal experience]. / Traitement de la polyarthrite rhumatoïde par l'isoprinosine. Expérience personnelle.

Twenty patients with classical or proved rheumatoid arthritis were treated with Isoprinosine. 13 patients received a dose of 25 mg/kg/day and 7 received a dose of 50 mg/kg/day, continuously for 2 months and then discontinuously, 5 days every fortnight. The series being treated with 25 mg/kg/day (7 patients) have received treatment for 12 months. No side effects have been observed; the only reason for ceasing treatment was its ineffectiveness (after at least 3 months of administration). The dosage of the associated anti-inflammatory drugs did not need to be increased, but neither was it decreased. The authors conclude that Isoprinosine is largely ineffective clinically, on laboratory tests and in terms of immunology, at least with the therapeutic protocols tested here.