Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients.

The aim of the study was to assess risedronate's effect on bone mineral density in postmenopausal women with rheumatoid arthritis receiving glucocorticoids. We carried out a two center, 2 year, double-masked, placebo-controlled trial with a third year of nontreatment follow-up. We studied 120 women requiring long-term glucocorticoid therapy at > 2.5 mg/day prednisolone randomized to treatment with daily placebo; daily 2.5 mg risedronate; or cyclical 15 mg risedronate (2 out of 12 weeks). At 97 weeks, bone mineral density was maintained at the lumbar spine (+1.4%) and trochanter (+0.4%) in the daily 2.5 mg risedronate group, while significant bone loss occurred in the placebo group (-1.6%, p = 0.03; and 4.0%, p < 0.005, respectively). At the femoral neck, there was a nonsignificant bone loss in the daily 2.5 mg risedronate group (-1.0%) while in the placebo group bone mass decreased significantly (-3.6%, p < 0.001). The difference between placebo and daily 2.5 mg risedronate groups was significant at the lumbar spine (p = 0.009) and trochanter (p = 0.02) but did not reach statistical significance at the femoral neck. Although not significantly different from placebo at the lumbar spine, the overall effect of the cyclical regimen was similar to that of the daily 2.5 mg risedronate regimen. Treatment withdrawal led to bone loss in the risedronate groups that was significant at the lumbar spine. A similar number of patients experienced adverse events (including upper gastrointestinal events) across treatment groups and risedronate was generally well tolerated. Thus risedronate preserves bone mass in postmenopausal women with rheumatoid arthritis receiving glucocorticoids while patients receiving a placebo have significant bone loss.

Long-term effects of percutaneous estradiol on bone loss and bone metabolism in postmenopausal hysterectomized women.

OBJECTIVE: To determine whether percutaneous estradiol (pE2) (1.5 mg/day) is able to counteract the postmenopausal bone loss in postmenopausal hysterectomized women, in a double-blind study versus oral estriol (E3) (2 mg/day). METHODS: The bone mineral density of the lumbar spine (LS) and of the proximal femur (PF) was measured every 3 months by dual energy X-ray absorptiometry for 2 years in 43 hysterectomized postmenopausal women (21 in the E2 group and 22 in the E3 control group), and in a subset of patients for a 3rd year. The statistical analyses were performed on Macintosh using Stat View II. RESULTS: A significant bone loss of 1.2 (0.4%)% and of 1.3 (0.3)% per year was observed in the control group, respectively at LS and at PF, versus a significant gain of 1.2 (0.5)% per year in the treated group at the LS. No significant change at PF occurred in the treated group. In the 20 patients followed up for a 3rd year on pE2, an increase of 1.2 (0.9) and 2.5 (1.4)% at LS in the 12 former active group patients and the eight formerly control patients, respectively was seen. The same trend was observed at the proximal femur. CONCLUSION: pE2 (1.5 mg E2) is able to counteract the postmenopausal bone loss in hysterectomized women, whereas E3 (2 mg/day administered orally) is unable to maintain bone mass.

Effect of a stemless femoral implant for total hip arthroplasty on the bone mineral density of the proximal femur. A prospective longitudinal study.

After total hip arthroplasty with a medullary stem, significant loss of bone mineral density (BMD) has been demonstrated in the proximal-medial femoral cortex. In an attempt to prevent bone loss, a stemless femoral component was designed. Owing to promising experimental results, a prospective clinical trial was undertaken in a limited group of patients, all below the age of 50. Yearly BMD measurements were carried out in the vicinity of the implant and compared with the BMD values obtained in the immediate perioperative period and with the values on the unaffected side. The follow-up period in this study was 4 to 6 years, involving 32 hips in 31 patients. Maintenance of BMD in the operated femur was demonstrated. A statistically significant increase in the BMD of the proximal medial femoral cortex was observed in those patients who had low initial values. In active patients with a life expectancy greater than 30 years, preservation of the proximal bone stock after total hip arthroplasty appears beneficial, as these patients are most likely to need revision surgery, which is more difficult if significant bone loss has occurred. The data further reinforce the crucial role of mechanical stress in BMD maintenance.

Hematological changes in anorexia nervosa are correlated with total body fat mass depletion.

OBJECTIVE: To assess the relationships between total body fat mass (FM) and hematological abnormalities in anorexia nervosa (AN). METHOD: Peripheral blood parameters and body composition were determined in 10 anorectic patients and 19 age- and sex-matched healthy subjects. In patients with AN, magnetic resonance imaging (MRI) studies of bone marrow were also performed. RESULTS: Compared with controls, patients with AN had -41% body weight, -81% FM, -18.8% lean tissue mass (LTM), and -22.6% bone mineral content; they also had lower mean total leukocyte (4.52 +/- 0.47 vs. 6.28 +/- 0.33 x 10(3)/microliter, p < .005), neutrophil (2.45 +/- 0.34 vs. 3.46 +/- 0.20 x 10(3)/microliter, p < .005), monocyte (0.24 +/- 0.03 vs. 0.37 +/- 0.03 x 10(3)/microliter, p < .05), and platelet counts (184 +/- 17 vs. 238 +/- 9 x 10(3)/microliter, p < .005). Hemoglobin level was normal and comparable in both groups. In patients with AN, but not in controls, total leukocyte, neutrophil, eosinophil, and monocyte counts as well as hemoglobin level were highly correlated with FM expressed in absolute values or in percentage of body weight, but not with LTM. Moreover, AN patients with signal intensity patterns suggestive of serous atrophy of bone marrow at MRI had not only lower erythrocyte, leukocyte, neutrophil, and platelet counts, but they also had lower FM than AN patients with normal MRI patterns. DISCUSSION: Hematological changes in AN, as assessed by peripheral blood parameters and MRI patterns of bone marrow, are correlated with total body FM depletion, suggesting that the reduction of adipose tissue adversely affects hematopoiesis.

Biological and radiological responses to oral etidronate and tiludronate in Paget's disease of bone.

Paget's disease of bone is characterized by a high bone turnover. Therefore, antiresorbing agents such as bisphosphonates are clearly indicated. However, as they accumulate in the pagetic lesions, they could produce some focal defects of bone mineralization. In a double-blind study, we have had the opportunity to compare the effects of tiludronate and of etidronate (both at a fixed dose of 400 mg/day orally) on the radiological changes of 12 patients suffering from Paget's disease of bone. After breaking the code, good agreement was observed between the radiological evaluations and the applied therapy: All positive bone balances were observed in the tiludronate group, except for three questionable densifications in the etidronate group, and the negative bone balances in the etidronate group. This confirms our previous experience with etidronate in Paget's disease when X-ray films of the lesions are followed sequentially during therapy.

Use of pamidronate in chronic and acute bone loss conditions.

Involutional osteoporosis (OP), Osteogenesis imperfecta (OI) and Reflex sympathetic dystrophy syndrome (RSDS) are conditions in which an increase in bone resorption has been described. It therefore seems logical to prescribe a potent inhibitor of bone resorption like pamidronate (APD) in a patient suffering from any of these conditions. In our experience, oral as well as intravenous APD therapy was able to increase significantly bone mineral density (BMD) in patients with OP. This increase was more marked at the lumbar spine than at the proximal femur. With cyclical intermittent APD therapy, a plateauing effect in the BMD results during the third year appeared. After weaning from APD therapy, a remanent effect was observed: no loss of bone apparently occurred for at least two years, but the biological remodeling parameters re-increased earlier. The protective action on OP fractures has still to be clearly demonstrated, however. In children with OI, oral APD therapy has produced a dramatic increase in bone mass, without adversely interfering with the growth spur. The effect on fracture rate is still debatable in such a protean condition. Intravenous APD administered daily for twelve days has provoked a dramatic improvement in patients with long lasting RSDS which had resisted to various well-accepted therapies. However, this was an open trial, and these favorable preliminary results should be confirmed in a double-blind study.

Trabecular and cortical bone loss in systemic lupus erythematosus.

We measured lumbar spine, hip (total and sub-regions) and total body bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) in 47 premenopausal female patients suffering from systemic lupus erythematosus (SLE). As compared to health controls, SLE patients had lower BMDs at all trabecular and cortical sites. Comparison of BMDs between patients ever and never treated with glucocorticoids indicated that patients who had ever received glucocorticoids had a significantly lower lumbar spine BMD compared to those who never did. Moreover, bone loss in patients ever treated with glucocorticoids was commensurate with their cumulated oral glucocorticoid intake. Interestingly, patients never treated with glucocorticoids had a lower hip BMD compared to controls, thereby suggesting that the disease per se might induce some bone loss. Taken together, SLE patients suffer from a significant trabecular and cortical bone loss indicative of an increased risk of future fracture.

Antacid-induced osteomalacia.

The case of a 49-year-old woman suffering from generalized skeletal pain and multiple fractures accompanied by severe hypophosphataemia and low urinary phosphorus excretion is reported. She had been taking large amounts of antacids containing aluminum hydroxide for many years. A diagnosis of antacid-induced osteomalacia was made. It was confirmed by biological work-up, radiographs and bone biopsy. A dramatic biological, osteodensitometric, and clinical improvement was achieved by withdrawal of antacids and phosphorus administration. The literature concerning this unusual condition has been reviewed.

Fluoride therapy of type I osteoporosis.

Sodium Fluoride (NaF) is the only medication so far clinically available with a bone formation stimulating property, through its peculiar mitogenic dose-dependent action on the osteoblast cell line. Bone strength is commensurate to bone mass, and in a condition with fragility fractures, like osteoporosis, it seems logical to restore bone mass without weakening bone strength. However, as with any active drug. NaF therapy requires adhesion to elementary rules if drawbacks are to be prevented. A first mandatory rule is not to prescribe NaF without calcium supplementation, if bone loss at the appendicular skeleton is to be avoided; to prevent this, the availability of monofluorophosphate (MFP), containing the fluoride and calcium salts in the same preparation has enhanced the compliance to calcium supplementation. A second rule is not to give supraphysiological doses of vitamin D, for the same reason. Third, if one wants to avoid a calcium shift from cortical to trabecular bone and osteomalacia, one should use small doses of NaF, of the order of 50 mg/day. With this in mind, the bioavailability of the drug has to be taken into account, particularly its gastrointestinal absorption which is dramatically enhanced if a plain non entericoated (EC) capsule is used, as compared to that of an EC tablet with the same face value. Too much NaF is deleterious to bone, a fact known for years. Already in 1972, it was noted that in all patients receiving 60 mg or more of NEC NaF, daily, morphologically abnormal bone developed and which appeared irregular and contained areas of incompletely mineralized bone. The bone was histologically and microradiographically normal in patients receiving 45 mg or less of NEC NaF/day. Fourth, NaF therapy is contraindicated in renal insufficiency owing to an enhanced retention in the skeleton. NaF is, however, by no means the ideal medication, because its therapeutic window is narrow. It has many bothersome drawbacks, and notably it is irritating for the gastric mucosa, a hazard which may be partly circumvented by the use of an Ec or slow release tablet. Furthermore, peripheral stress fractures may occur, and, in our experience, they were seen in 17% of patients, almost exclusively in females with a low lumbar BMD. Their occurrence should be curtailed by not allowing an increase in alkaline phosphatase activity of more than 50%. This is a relatively benign complication, because no stress fracture degenerated into a complete fracture. In all cases, the stress fractures healed after a transitory drug discontinuation. If there is some concern about cortical bone, NaF therapy may be associated with an antiresorber like estrogens which will prevent any further bone loss, and does not impair the response to NaF. NaF therapy should be reserved for patients suffering chiefly from trabecular osteoporosis and should be avoided in senile osteoporosis, because of a frequently impaired renal function. Currently, we would recommend in clinical practice a daily dose of 50 mg EC-NaF or 150 mg Ca-MFP as the therapy of involutional osteoporosis in women, reserving the dose of 75 mg EC-NAF or 200 mg MFP for males or female patients resistant to lower dose. The therapy should be maintained for 2 to 3 years, or more, according to the bone response, taking into account that patients with the vertebral crush fracture syndrome have lost on average 30%, as compard to the young adult mean.

A rare case of primary skeletal muscle lymphoma: the value of octreotide scintigraphy.

We report a case of non-Hodgkin lymphoma presenting as a painless mass of the quadriceps femoris muscle that was detected by a somatostatin analogue (octreotide) scintigraphy. We review the few reported cases of primary muscular lymphoma and discuss the potential value of octreotide imaging as a new diagnostic tool.

Effects of tenoxicam and aspirin on the metabolism of proteoglycans and hyaluronan in normal and osteoarthritic human articular cartilage.

1. As nonsteroidal anti-inflammatory drugs may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in the metabolism of newly synthesized proteoglycan (PG) and hyaluronan (HA) molecules produced by tenoxicam and aspirin in human normal cartilage explants and in osteoarthritic (OA) cartilage from age-matched donors. 2. Explants were sampled from the medial femoral condyle and were classified by use of Mankin's histological-histochemical grading system. Cartilage specimens were normal in 10 subjects, exhibited moderate OA (MOA) in 10 and had severe OA (SOA) in 10. 3. Cartilage explants were pulsed with [3H]-glucosamine and chased in the absence and in the presence of either aspirin (190 micrograms ml-1) or tenoxicam (4-16 micrograms ml-1). After papain digestion, the labelled chondroitin sulphate ([3H]-PGs) and HA([3H]-HA) molecules present in the tissue and media were purified by anion-exchange chromatography. 4. In normal cartilage as well as in explants with MOA and SOA aspirin reduced more strongly PG and HA synthesis than the loss of [3H]-HA and [3H]-PGs. 5. In normal cartilage, tenoxicam did not affect PG metabolism whereas it reduced HA synthesis in a dose-dependent manner and did not change or even increased the net loss of [3H]-HA. In contrast, in OA cartilage, tenoxicam produced a stronger reduction in the loss of [3H]-PGs than in PG synthesis and this decrease occurred at lower concentrations in cartilage with SOA (4-8 micrograms ml-1) than in cartilage with MOA (8-16 micrograms ml-1). In cartilage with MOA, the metabolic balance of HA was unaffected by tenoxicam whereas in cartilage with SOA, the drug decreased the loss of [3H]-HA and concomitantly did not change or even increased HA synthesis.6. The data obtained in short-term in vitro cultures indicate that aspirin may produce OA-like changes in normal cartilage and is likely to worsen the disease process in OA tissue. On the other hand, although tenoxicam may reduce the HA content of normal cartilage, and, in so doing, may produce OA-like lesions, this drug should not per se accelerate joint failure in OA.

Comparison of the acute biological action of injectable salmon calcitonin and an injectable and oral calcitonin analogue.

In most countries, calcitonin is available in the form of injections, and less frequently as an intranasal spray. An oral route of administration should improve compliance. In a preliminary feasibility study, we have compared the acute biological action of injectable salmon calcitonin (50 IU), with the injectable calcitonin analogue ASC 710 (0.2 mg) and oral ASC 710 (20 mg) in 6 patients suffering from active Paget's disease of bone. The intensity and duration of the biological response were not significantly different in the 3 modes of therapy. In conclusion, the oral calcitonin analogue ASC 710 possesses an antiresorbing activity in Paget's disease comparable to that of an injection of salmon calcitonin which demonstrates that it can cross the intestinal barrier.

Automated computerized radiogrammetry of the second metacarpal and its correlation with absorptiometry of the forearm and spine.

The value of a new computerized radiogrammetric method of assessment of the second metacarpal has been evaluated, and its results have been compared with those of single (SPA) and dual photon absorptiometry measurements (forearm and spine) in 74 and 79 postmenopausal women, respectively. Standard hand X-rays were digitized by a video-camera connected to a microcomputer. The combined cortical thickness (CCT) was automatically calculated in a zone of 10 mm around the midpart of the second metacarpal. The intra- and interobserver coefficients of variation were close to 1%. The correlation between CCT and SPA of the proximal and midforearm (with a significant amount of cortical bone) was satisfactory (r = 0.62 and 0.50, respectively; P < 0.001). The correlation between CCT and osteodensitometry of sites comprising more trabecular bone were not so good (0.50 for lumbar and 0.44 for distal forearm bone mineral density, respectively), but still significant (P < 0.001). Radiogrammetry proved unaffected by a change of X-ray apparatus, as measurements of 48 metacarpals radiographed by two different kinds of X-ray apparatus were not significantly different. Radiogrammetry is by no means the best method to evaluate bone mass. Its automation did not improve the correlation with osteodensitometric values. Radiogrammetry is still of interest in mass screening, particularly when other more expensive techniques such as osteodensitometric methods of bone mass measurement are not readily available. Its automation makes it simpler, faster, and more precise, rendering its use easier on a larger scale.

[Semi-quantitative analysis of 3-phase bone scintigraphy data in algodystrophy of the limbs]. / Analyse semi-quantitative des données de la scintigraphie osseuse en trois temps dans l'algodystrophie des extrémités.

Three-phase bone scanning of the extremities (foot or hand) was performed in 40 normal subjects and in 56 patients with an unequivocal clinical diagnosis of reflex sympathetic dystrophy. Ten patients were in the "cold" or atrophic stage of the disease process, whereas 46 were in the "hot" or acute phase. The scintigraphic parameters studied were the ratios of tracer activity in the affected side over the healthy side established for blood flow (BF), blood pool (BP), early vasculo-tissular fixation (EF), and late bone fixation (LF). In the controls, blood flow, blood pool, and early fixation showed considerable interindividual variation and only the variation of late fixation remained within narrow limits. Among the patients, those at the hot stage of the disease had significantly higher values for all four parameters than those at the cold stage. The group at the cold stage did not differ from the controls except for a significantly higher late fixation value. Furthermore, among hot stage patients, 15% to 25% had normal or diminished blood flow, blood pool and early fixation values. At the cold stage of the disease, radionuclide parameters were similar in affected feet and hands, whereas at the hot stage values at the feet were double those at the hands. Finally, statistical analysis revealed that late fixation was most closely correlated with early fixation, which in turn was most close correlated with blood pool. The clinical and pathophysiological significance of these data is discussed.

Osteoporosis.

Osteoporosis constitutes a major financial burden for society, which will increase in the near future owing to the ageing of the population. Women are the most common victims of involutional osteoporosis because of post-menopausal bone loss induced by oestrogenic deficit. Men are nevertheless not completely untouched by osteoporosis, however, compared to women, they are under less threat. Every effort should be made to curtail the financial burden on society and to improve the quality of life of sufferers. The first steps should be to increase the calcium intake, the level of exercise and to decrease the risk of falls. A preventive therapy with oestroprogestogens should be instituted at the time of the menopause, provided there is no contraindication. In the absence of fracture data, the modalities of alternative therapies like calcitonin and bisphosphonates are still debated. For people already suffering from fractures, restorative therapy should be considered. Sodium fluoride therapy is able to provoke a decrease in vertebral fracture frequency without compromising cortical bone strength provided elementary rules for its use are respected. Whether bisphosphonates can protect against fractures is still unsettled. Vitamin D has a physiological role, particularly in institutionalized elderly patients deprived of any exposure to the sun. Anabolic steroids are not devoid of side effects, and furthermore, no fracture data are so far available.

Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate.

OBJECTIVE: To measure serum levels of tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) in patients with rheumatoid arthritis (RA) and age-matched control subjects and to study how these correlate with serum levels of hyaluronan (HA) and antigenic keratan sulfate (KS) and other biochemical as well as clinical indicators of disease activity. METHODS: Immunoassays were used to measure levels of TNF alpha, IL-6, HA, and antigenic KS in the serum of 35 patients with RA and a group of age- and sex-matched control subjects. Clinical disease activity in the RA group was assessed using the Lansbury index. Drug intake was recorded and the erythrocyte sedimentation rate, and levels of fibrinogen, creatinine, bilirubin, alkaline phosphatase, lactate dehydrogenase, and aminotransferase were measured. RESULTS: Serum levels of TNF alpha, IL-6, and HA were significantly higher in the RA population than in the control group. In patients with RA, serum levels of HA correlated positively with serum levels of TNF alpha and with clinical joint scores, but only weakly with other laboratory parameters of inflammation. Serum levels of antigenic KS correlated negatively with levels of circulating TNF alpha, but much more weakly with other clinical and biochemical parameters of disease activity. CONCLUSION: These in vivo data support in vitro studies which have shown that TNF alpha is a potent stimulator of HA synthesis by synovial lining cells. The results strengthen the contention that serum HA may be a unique marker of synovial involvement and inflammation, rather than of only inflammation, in RA.

Appendicular and vertebral bone mass in ankylosing spondylitis. A comparison of plain radiographs with single- and dual-photon absorptiometry and with quantitative computed tomography.

OBJECTIVE: We assessed the prevalence, severity, and anatomic distribution of ankylosing spondylitis (AS)-related osteopenia (OP). METHODS: We studied 70 patients (60 males, 10 premenopausal females) with AS (according to the New York criteria) to determine the frequency of OP. Bone mass was measured by plain radiographs of the spine, by single-photon absorptiometry (SPA) of the distal and midshaft of the radius on the nondominant side, by dual-photon absorptiometry (DPA) of the lumbar spine (L2-L4), and by quantitative computed tomography (QCT) of the lumbar spine. RESULTS: SPA values for the radius mass were normal in males and in females, both at the distal and midshaft sites. In contrast, spine radiographs showed diminished density of the vertebral bodies in 69% of the males and 50% of the premenopausal females. Two male patients had had a vertebral compression fracture, and one female patient had had two. DPA values for the spine mass were significantly diminished in the male patients compared with the controls, but not in the female patients. Males with less severe AS also had the largest reduction in lumbar bone mineral content. In patients with more severe disease, lumbar bone mineral content was not statistically different from that in controls. QCT of the lumbar spine performed in 10 patients disclosed low density of the trabecular bone of the vertebral bodies, more so in those with more severe AS and syndesmophyte formation and/or apophyseal joint fusion, which contrasts with the normal values on DPA in these patients. CONCLUSION: Male patients with AS have axial osteopenia. In those who have very severe AS with new bone formation, DPA demonstrates normal values as a result of two opposite trends: central osteopenia (as assessed from QCT) and peripheral new-bone formation, which transforms vertebral bodies into long bones. This could modify the mechanical resistance of the spine and account for the propensity for anteroposterior transvertebral and transdiscal fractures after trauma in AS.

Low bone mass in hypogonadal males. Effect of testosterone substitution therapy, a densitometric study.

Sixteen (16) male patients who were suffering from hypogonadism but who were free from bone symptoms were recruited from the Andrology Clinic. Their bone mineral density (BMD) was assessed by single photon absorptiometry in the non-dominant radius, at both the distal radius (DR) (27% trabecular bone) and the midshaft radius (MR) (90% cortical bone). Measurements were carried out before and during testosterone substitution therapy. BMD was found to be lower in the subjects than in the controls, to a similar extent at both the DR (0.47 +/- 0.02 g/cm2, i.e. 83.1 +/- 4.3% of the value in the controls, or Z score -1.42 +/- 0.39; P less than 0.01) and the MR (0.68 +/- 0.02 g/cm2, i.e. 87.8 +/- 2.4% of the value in the controls, or Z score -1.49 +/- 0.33; P less than 0.01). There was no correlation between testosterone levels and BMD at either the DR or the MR at the beginning of the study. Following testosterone substitution therapy, bone mineral content (BMC) increased significantly at the DR (+5.9 +/- 1.4% per year; P less than 0.01) and at the MR (+1.1 +/- 0.9% per year; P less than 0.01). If the study is limited to the subjects who had achieved full bone age maturity before the start of therapy, the bone gain remains significant only at the DR, a site with a sizeable proportion of trabecular bone.