(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Osteoporosis

A 65-year-old man had surgery in June 1995 for femoral neuralgia. The plain films of the spine were normal at the time. In September of the same year, when he was beginning to walk gradually longer distances, he started experiencing back pain. Crush fractures of T8 and L2 were seen on plain films. His pain worsened, and he was admitted in December 1995. A third set of plain films disclosed fractures of all the vertebral bodies from T8 through L5, with increased density of the endplates of the same vertebras. Serum and urinary levels of calcium and phosphate were normal. Dual-energy X-ray absorptiometry demonstrated osteoporosis predominating in the trabecular bone. Evidence of increased bone resorption was seen on the histomorphometric study. Large amounts of dihydroxypyridinoline were found in the urine. Investigations for the classical causes of osteoporosis in males were unrewarding. Careful questioning revealed that the patient had been taking inhaled beclomethasone for seven years to treat chronic obstructive lung disease. Serum levels of cortisol and ACTH were low, consistent with a diagnosis of treatment-induced hypercorticism. To our knowledge, this is the first reported case of osteoporotic vertebral fractures in a male due to inhaled glucocorticoid therapy. Inhaled glucocorticoids are generally believed to induce only minimal systemic effects. However, decreased serum osteocalcin levels and increased urinary excretion of bone resorption markers have been reported in patients under inhaled beclomethasone therapy. Low spinal bone mineral density values correlated with the degree of pituitary-adrenal gland suppression as evaluated using the ACTH test have also been found in several groups of patients treated with inhaled glucocorticoids.

Topics: Administration, Inhalation; Administration, Topical; Aged; Anti-Inflammatory Agents; Beclomethasone; Glucocorticoids; Humans; Lumbar Vertebrae; Lung Diseases, Obstructive; Male; Osteoporosis; Radiography; Spinal Fractures; Thoracic Vertebrae

Topics: Administration, Inhalation; Administration, Topical; Adrenal Glands; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Dose-Response Relationship, Drug; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Growth; Humans; Osteoporosis; Pregnenediones; Triamcinolone Acetonide

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; Child; Glucocorticoids; Growth; Humans; Longitudinal Studies; Osteoporosis; Pregnenediones

From the experience above, it may be concluded that corticosteroid therapy in allergic disease has become more effective than ever before. The expected variations in usage of new important pharmacologic agents is seen with special clarity in the use of corticosteroids. The wide acclaim for the "miracle drug of the 1950's", which followed penicillin of the 1940's, soon gave away to anguish about side-effects that threatened to abolish its use entirely in the late 1950's. The 1960's brought alternate day therapy for chronic usage and recognition that short term usage was relatively safe. The 1970's saw proliferation of topically active steroids similar to those so important to the practice of Dermatology in the previous decade. Results in treating asthma and nasal diseases have been excellent and extensive research for adverse effects has been largely unrevealing.

Topics: Administration, Intranasal; Adrenal Cortex Hormones; Asthma; Beclomethasone; Cataract; Cushing Syndrome; Humans; Hypersensitivity; Hypersensitivity, Immediate; Long-Term Care; Nasal Polyps; Osteonecrosis; Osteoporosis; Prednisone; Rhinitis; Sleep Initiation and Maintenance Disorders; Stress, Physiological

Combination of inhaled corticosteroids (ICS) with long acting beta2 agonists has been used increasingly in the treatment of moderate-severe asthma, however there is indefinitive data about their effect on bone loss. The aim of this study was to compare the effects of treatment with single ICS and combination of ICS with long acting beta2 agonists (combination therapy) on BMD and biomarkers of bone metabolism in adult patients with asthma over 1 year period. Forty-three patients with asthma were enrolled. Patients were separated into two groups according to their use of asthma drugs: single ICS or combination therapy (ICS plus long-acting inhaled beta2-agonist). Change in bone mineral density (BMD) and biochemical markers of bone metabolism were measured at baseline and at the end of 1 year. Mean ages and basal BMD of patients did not differ between the two groups (P > 0.05). The decrease in BMD was higher in the single ICS group than the combination therapy group, however there was no significant difference between them (P > 0.05). One year change (%) in BMD and biochemical markers of bone metabolism were not different between two groups (P > 0.05). In conclusion, use of ICS-in the range of doses used- does not seem to have an effect on the change of BMD. However, our data indicate a nonsignificant trend towards reducing bone loss with the use of combination therapy. Future studies are needed to provide definitive evidence for this trend to allow us suggesting combination therapy for minimizing bone loss.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adult; Albuterol; Androstadienes; Asthma; Beclomethasone; Bone Density; Bone Resorption; Budesonide; Drug Therapy, Combination; Ethanolamines; Female; Fluticasone; Formoterol Fumarate; Humans; Male; Middle Aged; Osteoporosis; Salmeterol Xinafoate

Steroid therapy is the third most common cause of osteoporosis, after loss of gonad function and senescence. The aim of the present study was to evaluate the protective action of clodronate on bone mass loss induced by steroid therapy. Sixty patients with bronchial asthma receiving either fluticasone (250 mg x 4/day) or beclomethasone (250 mg x 4/day) inhaled corticosteroid treatment were enrolled. Half the patients received combination treatment with clodronate (100 mg i.m./14 days), for a total period of 12 months. All patients were evaluated at baseline and at the end of treatment for bone mineral density (BMD) and calcium/phosphor metabolism parameters (kalemia, kaluria, phosphoremia, phosphaturia, alkaline phosphatase and hydroxyprolinuria over a 24-h period). The results of this preliminary study confirm the protective influence of clodronate on bone mass loss, as documented by the increment in mean values in BMD reported at the end of treatment compared with baseline values.

Topics: Administration, Inhalation; Aged; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bone Density; Chronic Disease; Clodronic Acid; Fluticasone; Humans; Infusion Pumps; Male; Middle Aged; Osteoporosis

Clodronate is a novel drug used for inhibiting osteoclastic activity. The aim of the present double-blind study was to evaluate the efficacy and tolerability of clodronate (Leiras, Finland) in corticosteroid-induced bone loss among asthmatic patients. Seventy-four adult patients (41 women and 33 men, mean age 57.3 years) having a long history (mean 8.1 years) of oral and inhaled corticosteroid therapy were randomized to four parallel treatment groups: clodronate 800, 1600, or 2400 mg/day, or an identical placebo. The bone mineral density (BMD) of the lumbar spine (L2-4), femoral neck, and trochanter were assessed using dual-energy X-ray absortiometry at entry, 6 months, and 12 months. The baseline BMDs did not differ significantly between the study groups. In the lumbar spine, the mean BMD increased significantly between the baseline and 12-month visit in the clodronate groups of 1600 and 2400 mg/day, 2.6% (0.02 g/cm2, p < 0.02) and 3.0% (0.03 g/cm2, p < 0.01), respectively, but not in the placebo and clodronate 800 mg/day groups. The test for a linear trend (BMD percent change for L2-4) at 12 months was significant (p < 0.02), indicating a dose response to clodronate. The mean BMD values of the femoral neck increased significantly in the 2400 mg/day group, 4.3% (0.03 g/cm2, p < 0.0001), as well as in the trochanter region 2.8% (0.02 g/cm2, p < 0.02). Gastric irritation was the most common adverse effect noted on a clodronate dose of 2400 mg/day. We conclude that oral clodronate is effective in preventing bone loss or increasing bone mass in asthmatic patients having a long history of continuous peroral and inhaled corticosteroid administration.

Topics: Absorptiometry, Photon; Administration, Inhalation; Administration, Oral; Analgesics, Non-Narcotic; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bone Density; Clodronic Acid; Dose-Response Relationship, Drug; Double-Blind Method; Female; Femur; Femur Neck; Glucocorticoids; Humans; Lumbar Vertebrae; Male; Osteoporosis; Prednisolone

Inhaled glucocorticoids are pivotal in maintenance therapy of chronic bronchial asthma; however, conflict exists over their effects on bone and mineral metabolism. We measured bone mineral density (BMD), bone turnover markers, and adrenal steroid hormones in 53 patients (34 female, 19 male) with chronic bronchial asthma who had taken either inhaled beclomethasone or budesonide in doses of > or = 1500 microg/day for at least 12 months to determine pathogenetic mechanisms of bone loss. To account for the effect of prior oral glucocorticoid exposure we divided patients into two groups: one with (OG) and the other without (IG) a past history of maintenance (> 1 month) oral glucocorticoid therapy. Lumbar spine (LS) and proximal femur BMDs were approximately 1 SD lower in men and women taking OG or high-dose IG for chronic bronchial asthma, potentially equivalent to a doubling of the risk of fracture at these sites. Prior exposure to OG in women was also associated with lower LS and proximal femur BMDs, while men were more sensitive to the adverse effects of IG on LS and Ward's triangle BMDs. Bone formation markers were decreased; however, bone resorption marker concentrations were normal. All patients had evidence of suppression of both endogenous glucocorticoid and adrenal androgen production. Both total duration of OG and biochemical bone turnover marker concentrations were negatively related to proximal femur and rib BMDs and total body bone mineral content, but not to LS BMD. These were stronger for bone resorption markers. Uncoupling of ongoing normal bone resorption from suppressed bone formation may therefore contribute to glucocorticoid-associated bone loss in asthma. Adrenal androgen suppression may also increase the susceptibility of postmenopausal women in particular to bone loss with OG. Although the effects of high-dose IG on BMD are associated with lower LS BMD in men, this observation should now be investigated further in prospective studies.

Topics: Absorptiometry, Photon; Administration, Inhalation; Adolescent; Adult; Aged; Asthma; Beclomethasone; Biomarkers; Bone Density; Budesonide; Dehydroepiandrosterone Sulfate; Female; Femur; Glucocorticoids; Humans; Hydrocortisone; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Ribs

Bone mass and biochemical bone markers were prospectively studied in 33 patients with chronic obstructive pulmonary disease treated for 1 year with inhaled beclomethasone 200 micrograms/q.i.d. (group A, 8 men and 4 women), inhaled budesonide 200 micrograms/q.i.d. (group B, 6 men and 5 women), or not requiring steroids (group C, 6 men and 4 women). Both inhaled corticosteroids decreased serum concentrations of the osteoblastic markers, osteocalcin and carboxy-terminal propeptide of type I collagen (PICP). The osteoclastic marker cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) increased significantly more in patients on beclomethasone than in those on budesonide. The decrease in bone mineral density was more pronounced in patients treated with beclomethasone (1.1% in the spine 1.7% in the hip P < 0.05) compared to those treated with budesonide (0.6% in both spine and hip) or in the control group. Inhaled corticosteroids affect biochemical bone markers and bone mineral density, but there is a different effect for the two corticosteroids evaluated in the present study.

Topics: Administration, Inhalation; Adult; Aged; Alkaline Phosphatase; Beclomethasone; Biomarkers; Bone Density; Budesonide; Calcium; Collagen; Collagen Type I; Female; Glucocorticoids; Homeostasis; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Osteocalcin; Osteoporosis; Peptide Fragments; Peptides; Pregnenediones; Procollagen; Prospective Studies

Topics: Administration, Inhalation; Adult; Beclomethasone; Double-Blind Method; Humans; Osteocalcin; Osteoporosis

Osteoporosis is a serious side effect of systemic treatment with steroids. Cloprednol, a synthetic glucocorticoid with an anti-inflammatory potency twice that of prednisone, causes less calcium and nitrogen excretion than does prednisone in equipotent doses. Therefore a double-blind study was undertaken comparing the effects of alternate-day cloprednol and prednisone therapy on bone mineral density in 39 patients (cloprendol: 13 men and 8 women aged 48.5 +/- 2.8 years; prednisone: 9 men and 9 women aged 49.7 +/- 1.7 years) with lung diseases. Ten patients with asthma (9 men and 1 woman aged 37.8 +/- 3.7 years) inhaling daily beclomethasone served as control subjects. Trabecular and total bone density of the distal tibia and radius was determined quarterly during 1 year with a special-purpose computed tomographic system. Initial mean trabecular bone density of the patients receiving cloprednol and prednisone was 17% below normal. After a treatment period of 1 year, we found a loss of radial trabecular bone density (mean +/- SEM) of 1.33% +/- 0.49% in the cloprednol group and 2.38% +/- 0.69% in the prednisone group. In postmenopausal women, prednisone but not cloprednol therapy caused significant (p less than 0.01) trabecular bone loss (5.29% +/- 0.99% versus 0.70% +/- 0.65%). The control group lost 0.91% +/- 0.79%. Loss of cortical bone was insignificant in all three groups. In post-menopausal women, 1 year of alternate-day cloprednol therapy was associated with significantly less bone loss than was prednisone therapy in equipotent dosages.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Beclomethasone; Bone Density; Double-Blind Method; Drug Administration Schedule; Female; Humans; Longitudinal Studies; Lung Diseases; Male; Middle Aged; Osteoporosis; Prednisone; Pregnenediones; Prospective Studies

Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters and presence of vertebral fractures were investigated to further clarify the role of cortical bone quality in fractures in 86 postmenopausal (>5 years after menopause) asthmatic patients on high-dose oral steroid (>10 g cumulative oral prednisolone) (steroid group) and 194 age-matched controls (control group). Cortical and trabecular bone was subjected to measurement of various parameters using pQCT (Stratec XCT960). Relative Cortical Volume (RCV) was calculated by dividing the cortical area by the total bone area. Strength Strain Index (SSI) was determined in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. Patients treated with high doses of oral steroid (>10 g cumulative oral prednisolone) were found to have an increased risk of fracture compared with control women receiving no steroid medication (odds ratio, 8.85; 95% CI, 4.21-18.60) after adjustment was made for years since menopause, body mass index and RCV. In both groups, the diagnostic and predictive ability of the pQCT parameters for vertebral fracture was assessed by the areas under their receiver operating characteristic (ROC) curves. All parameters were found to be significant predictors ( p<0.0001) in the control group. In the steroid group, however, the cortical bone mineral density (BMD) ( p = 0.001), RCV ( p<0.0001) and SSI ( p = 0.001) were found to be significant predictors, but not trabecular BMD ( p = 0.176). For comparison between the two groups, thresholds of all parameters for vertebral fracture were also calculated by the point of coincidence of sensitivity with specificity in ROC testing and the 90th percentile value. Although a rise in fracture threshold in the steroid group was suggested, considerable difference in the values obtained by the two methods of calculation precluded any conclusion. High-dose oral steroid administration was associated with an increased risk of fracture. Cortical bone parameters obtained by pQCT could play a role as good predictors of future corticosteroid-induced vertebral fractures.

Topics: Administration, Oral; Aged; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bone and Bones; Bone Density; Epidemiologic Studies; Female; Humans; Osteoporosis; Prednisolone; Radius; Risk Factors; Spinal Fractures; Tomography, X-Ray Computed

It is not certain whether inhaled corticosteroid (ICS) therapy reduces bone mineral density (BMD) in asthmatic patients. In addition, the potential risk of osteoporosis associated with the rescue use of short courses of oral corticosteroids (SC-OCS) is unclear.. To evaluate the effect of inhaled beclomethasone dipropionate (BDP) and SC-OCS on BMD in asthmatic patients.. A 4-year longitudinal study.. Lumbar BMD was measured twice by dual-energy x-ray absorptiometry at a mean (+/- SD) interval of 4.2 +/- 0.1 years in 35 asthmatic adults (15 men and 20 postmenopausal women; mean age at the second evaluation, 60.6 +/- 11.5 years) who had been treated with BDP and SC-OCS.. The average period of BDP treatment was 7.7 +/- 2.2 years (range, 4.8 to 13.0 years) at the second evaluation. During the study period, the daily dose of BDP was 765 +/- 389 microg (range, 100 to 1,730 microg), and the frequency of SC-OCS was 1.9 +/- 2.7 courses per year (range, 0.0 to 8.9 courses per year). As a whole, lumbar BMD was unchanged during the course of the study, whereas the Z score (ie, the percentage of normal value predicted from age and sex) increased significantly. Changes in BMD and Z scores in patients receiving high doses of BDP (ie, > 1,000 microg/d; n = 9) were not significantly different from those of patients receiving lower doses (ie, 2.5 courses per year; n = 9) showed a significantly greater loss in BMD and Z score compared with those receiving sporadic courses (ie,

Topics: Absorptiometry, Photon; Administration, Inhalation; Administration, Oral; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bone Density; Bone Diseases, Metabolic; Dexamethasone; Drug Administration Schedule; Female; Glucocorticoids; Humans; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Prednisolone

Osteoporosis is a major complication of long-term corticosteroid administration, but the magnitude of the effect in patients with chronic obstructive pulmonary disease (COPD) is not well defined. In a cross-sectional study, we evaluated the association between steroid use and vertebral fractures in 312 men, 50 yr of age or older, with COPD. Subjects were evaluated according to their corticosteroid use: Never Steroid Users (NSU) (n = 117), Inhaled Steroid Users (ISU) (n = 70), and Systemic Steroid Users (SSU) (n = 125). The prevalence of one or more vertebral fractures was 48.7% in the NSU group, 57.1% in the ISU group, and 63.3% in the SSU group. Compared with NSU, SSU were two times as likely to have one or more vertebral fractures: age-adjusted odds ratio (OR) = 1.80; 95% CI, 1.08 to 3.07. This relationship was primarily due to a strong association between continuous systemic steroid use and vertebral fractures: age-adjusted OR = 2.36; 95% CI, 1.26 to 4.38. In addition, fractures in SSU were more likely to be multiple and more severe. A weaker relationship existed between inhaled steroid use and vertebral fractures: age-adjusted OR = 1.35; 95% CI, 0.77 to 2.56 compared with NSU. These data indicate that vertebral fractures are common in older men with COPD; the likelihood of these fractures is greatest in those men using continuous systemic steroids.

Topics: Administration, Inhalation; Administration, Oral; Adrenergic beta-Agonists; Age Factors; Aged; Anti-Inflammatory Agents; Beclomethasone; Confidence Intervals; Cross-Sectional Studies; Evaluation Studies as Topic; Forced Expiratory Volume; Glucocorticoids; Humans; Logistic Models; Lung Diseases, Obstructive; Male; Middle Aged; Odds Ratio; Osteoporosis; Prednisone; Prevalence; Smoking; Spinal Fractures; Triamcinolone Acetonide; Vital Capacity

Inhaled corticosteroids have become a key element in the maintenance treatment of bronchial asthma. It is well-known that long-term systemic steroid use causes osteoporosis, whereas its inhaled counterpart has been believed to be devoid of such a side-effect. However, recent studies showed that administration of inhaled corticosteroids was associated with biochemical evidence of derangement in bone turnover. We therefore studied bone mineral density (BMD) by dual energy x-ray absorptiometry in 30 patients (18 females, 12 males) with bronchial asthma treated with steroids, essentially by the inhaled route only (both nasal and tracheobronchial), and compared them with healthy subjects individually matched for age, sex, menopausal status, and body mass index (BMI). There was a significant decrease in BMD in the patient group at the hip (neck of femur, p = 0.007; trochanter of femur, p = 0.034; Ward's triangle, p = 0.016) and the lumbar area of the spine (L2-4, p = 0.041). Further analysis showed that this difference from control subjects was mainly seen in the female patients and not in the male patients (neck of femur, p = 0.049; Ward's triangle, p = 0.025; lumbar spine, p = 0.039). In the female patients, there was significant negative correlation of BMD of the lumbar area of the spine and the trochanter of femur with daily inhaled steroid dose and positive correlation of BMD of the trochanter with BMI.

Topics: Absorptiometry, Photon; Administration, Inhalation; Adult; Aerosols; Asthma; Beclomethasone; Bone Density; Bronchodilator Agents; Budesonide; Female; Humans; Male; Osteoporosis; Pregnenediones; Premenopause; Risk Factors; Time Factors

A secondary hyperparathyroidism resulting from decreased intestinal calcium (Ca) absorption has been proposed as a contributory factor to glucocorticoid-induced osteoporosis. Inhaled steroids do not usually suppress adrenal gland function unless daily doses above 1,500 microgram are used. A recent study, however, has shown a reduced total body calcium in patients on regular beclomethasone treatment. In theory, osteopenia in these patients could be due to a direct effect of inhaled steroids on bone or due to an impaired intestinal calcium absorption. In this study, Ca absorption and parathyroid hormone (PTH) secretion were evaluated in three groups: 1) asthmatics on continuous oral and inhaled steroid treatment (11.3 +/- 4.4, range 5-33.5 mg.day-1 prednisone and 660 +/- 265, range 400-1,600 microgram.day-1 beclomethasone, respectively); 2) asthmatics on regular beclomethasone therapy (585 +/- 210, range 400-1,200 microgram.day-1); and 3) healthy subjects. The prevalence of vertebral fractures was evaluated by a spinal X-ray. No differences were found in either Ca absorption or PTH serum levels between asthmatics and healthy subjects (analysis of variance-ANOVA). Vertebral fractures were significantly more frequent in patients from group 1 (14 of 25) than in those from group 2 (2 or 25). We conclude that both prolonged oral steroid treatment and inhaled steroids, at doses lower than 1,600 microgram.day-1 do not cause Ca malabsorption, and that hyperparathyroidism does not contribute to osteoporosis in these patients.

Topics: Administration, Inhalation; Administration, Oral; Asthma; Beclomethasone; Calcium; Female; Humans; Intestinal Absorption; Male; Middle Aged; Osteoporosis; Parathyroid Hormone; Prednisone; Time Factors