Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with norethindrone acetate in the prevention of bone loss in early postmenopausal women: dose-dependent effects.

OBJECTIVE: A 2-year multicenter, double-blind, randomized, placebo-controlled study examined the efficacy and safety of different doses of 17beta-estradiol (E(2)) alone and continuous-combined oral formulations of E(2) and norethindrone acetate (NETA) versus placebo in the prevention of bone loss in newly menopausal women. DESIGN: Patients were randomized to one of seven groups: placebo, E(2) 0.25 mg, E2 0.5 mg, E(2) 1 mg, E(2) 1 mg/NETA 0.25 mg, E(2) 1 mg/NETA 0.5 mg, or E(2) 2 mg/NETA 1 mg. Treatment was a once-daily tablet taken for 26 months. The primary efficacy endpoint was the change in bone mineral density (BMD) at the lumbar spine, measured by dual-energy x-ray absorptiometry, at screening and at 13, 19, and 26 months. BMD changes at the femoral neck and trochanter were also assessed. Biochemical markers of bone metabolism were measured at baseline, and at 3, 6, 13, 19, and 26 months. Histological diagnoses of endometrial samples were tabulated for each treatment group. RESULTS: A total of 327 women were randomized and 189 women completed the 2-year trial. BMD at the lumbar spine decreased 2.3% in the placebo group. The lowest dose of unopposed E(2) prevented bone loss at the spine and hip. Significant increases in spine BMD compared with placebo occurred in all groups of treatment with E(2) and were more pronounced in the combination groups. Compared with placebo, women receiving active treatment experienced greater reductions in bone resorption markers. The effects were evident by 6 months and generally remained stable thereafter. Adverse events, primarily associated with the endometrium, were the most common reasons for discontinuation. CONCLUSIONS: There is a dose-dependent effect of E(2) on BMD. The addition of NETA seems to enhance the response in BMD observed with E(2). Low doses of E(2) (1 mg and lower) can be considered for the prevention of osteoporosis, while titrating the hormone dose to individual patient's needs.

Clinical use of serum and urine bone markers in the management of osteoporosis.

Osteoporosis is a common disease characterized by decreased bone mass, increased bone turnover, and increased susceptibility to fracture. Almost 44 million Americans are estimated to have low bone mass, which puts them at increased risk of developing osteoporosis and fractures. Osteoporosis is diagnosed by a low bone density (BMD) measurement, because a low BMD is known to contribute to increased fracture risk, which is the main source of morbidity and mortality for osteoporosis. However, changes in bone mass and density in response to anti-resorptive therapy account for only a small portion of the predicted fracture risk reduction. Whereas dynamic changes in bone turnover, estimated by measurement of bone biochemical markers, such as breakdown products of type-I collagen and proteins secreted by osteoblasts and osteoclasts in blood and urine, can account for a major portion of anti-fracture efficacy of anti-resorptive agents. Most anti-resorptive agents act by rapidly reducing bone markers. This has led to advocacy for use of bone turnover markers, in complement to BMD measurement, in the management of osteoporosis. In general, higher bone turnover is associated with accelerated bone loss and potential deterioration in bone quality. Several clinical trials have established the potential utility of markers to identify patients with rapid bone loss, to aid in therapeutic decision-making, and to monitor therapeutic efficacy of various treatments. Elevated marker levels have been shown to be associated with increased risk of fracture in elderly women, but their utility in predicting fracture is not yet established. In this article, we provide a brief summary to primary practitioners about the role bone markers can play in the management of osteoporosis.

Effects of prasterone on bone mineral density in women with systemic lupus erythematosus receiving chronic glucocorticoid therapy.

OBJECTIVE: To assess the effects of treatment with prasterone (dehydroepiandrosterone) on bone mineral density (BMD) in female patients with mild to moderate systemic lupus erythematosus (SLE) receiving chronic treatment with glucocorticoids. METHODS: Fifty-five female patients with SLE who had received prednisone (or glucocorticoid equivalent) /= 6 months were treated for 1 year with either prasterone 200 mg/day (n = 24) or placebo (n = 31) in this randomized, double blind trial. Prasterone or placebo was added to each patient's one or more concomitant standard SLE medications, including glucocorticoids, nonsteroidal antiinflammatory drugs, antimalarials, methotrexate, azathioprine, and other immunosuppressives, which were to be maintained at fixed doses for the duration of the study. RESULTS: BMD was significantly improved in patients who received prasterone compared to placebo. At the lumbar spine, there was a mean (SEM) gain in BMD of 1.7 +/- 0.8% in the prasterone group compared to a mean loss in BMD of -1.1 +/- 0.5% in the placebo group (p = 0.003 between groups). For the total hip, mean gain was 2.0 +/- 0.9% in the prasterone group vs a mean loss of -0.3 +/- 0.4% in the placebo group (p = 0.013 between groups). In the prasterone treatment group, the mean gains from baseline at both lumbar spine and hip were statistically significant. CONCLUSION: Prasterone treatment prevented BMD loss and significantly increased BMD at both the lumbar spine and total hip in female patients with SLE receiving exogenous glucocorticoids.

A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of a selective inhibitor of secretory phospholipase (sPLA2), LY333013, in the treatment of rheumatoid arthritis (RA). METHODS: Two hundred and fifty-one patients with active RA despite treatment with one or more disease modifying antirheumatic drugs (DMARD) received oral doses of LY333013 (50, 250, and 1000 mg) or placebo once daily for 12 weeks. Concomitant low-dose glucocorticoids (< or = 10 mg/day prednisone equivalent) were allowed. Clinical improvement was assessed using the response criteria of the American College of Rheumatology (ACR20), and safety was evaluated with respect to adverse events and laboratory test abnormalities. RESULTS: The demographic characteristics of the treatment groups were similar. Dose-response relationships were found for ACR20 responses (p = 0.058) and reductions in C-reactive protein (p = 0.058) at week 1. The proportions of patients with an ACR20 response subsequently increased in all study groups including the placebo group at weeks 4 and 8, and the initial treatment benefit was lost. Adverse events were generally mild in severity and not associated with treatment. CONCLUSION: Treatment with LY333013 for 12 weeks was well tolerated but ineffective as an adjunct to DMARD treatment of active RA.

Densitometry in glucocorticoid-induced osteoporosis.

Bone density measurement is a critical tool in the management of glucocorticoid-induced osteoporosis (GIOP). This review addresses the utility of various measurement devices (dual-energy X-ray absorptiometry [DXA], quantitative ultrasound [QUS], quantitative CAT scanning [QCT]), their role in monitoring changes in bone mineral density (BMD), and the relationship of BMD and fracture risk in GIOP. A higher BMD threshold should be utilized for estimating fracture risk in patients on glucocorticoids.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

OBJECTIVE: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms. METHODS: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale). RESULTS: A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group. CONCLUSION: In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists.

OBJECTIVE: To describe a group of patients who were treated with tumor necrosis factor alpha (TNF alpha) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNF alpha antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis. METHODS: Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNF alpha antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center. RESULTS: Thirteen cases of documented coccidioidomycosis were associated with TNF alpha antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01). CONCLUSION: Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.

Recognizing and treating glucocorticoid-induced osteoporosis in patients with pulmonary diseases.

Glucocorticoids are frequently used to treat patients with pulmonary diseases, but continuous long-term use of glucocorticoids may lead to significant bone loss and an increased risk of fragility fractures. Patients with certain lung diseases, regardless of pharmacotherapy-particularly COPD and cystic fibrosis-and patients waiting for lung transplantation are also at increased risk of osteoporosis. Fragility fractures, especially of the hip, will have substantial effects on the health and well-being of older patients. Vertebral collapse and kyphosis secondary to glucocorticoid-induced osteoporosis (GIO) may affect lung function. Identification of patients with osteopenia, osteoporosis, or fragility fractures related to osteoporosis is strongly recommended and should lead to appropriate treatment. Prevention of GIO in patients receiving continuous oral glucocorticoids is also recommended. In patients receiving either high-dose inhaled glucocorticoids or low- to medium-dose inhaled glucocorticoids with frequent courses of oral glucocorticoids, bone mineral density measurements should be performed to screen for osteopenia and osteoporosis. A bisphosphonate (risedronate or alendronate), calcium and vitamin D supplementation, and lifestyle modifications are recommended for the prevention and treatment of GIO.

The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture.

OBJECTIVES: To evaluate the effects of MK-0677, an orally active growth hormone (GH) secretagogue, on functional recovery from hip fracture in previously mobile older individuals. DESIGN: Placebo-controlled, randomized, double-blind trial. SETTING: Thirteen medical centers in England, Sweden, Denmark, Belgium, Switzerland, Canada, and the United States. Patients were recruited between 3 and 14 days postoperatively, or no more than 18 days postfracture, at acute care hospitals and rehabilitation centers. PARTICIPANTS: One hundred sixty-one hip-fracture patients were enrolled. Entry criteria included consenting hip-fracture patients who were aged 65 and older and who were ambulatory before their fracture, medically stable postoperatively, and mentally competent. Patients were excluded if they had multiple fractures or severe trauma, diabetes mellitus, cancer, uncontrolled hypertension, congestive heart failure, or total hip replacement in the involved extremity. INTERVENTION: Random assignment to 6 months of daily treatment with MK-0677 or placebo. Patients were followed for an additional 6 months after completion of therapy. MEASUREMENTS: Change from Week 6 to Week 26 in a panel of functional performance measures. Additional outcome measures included change in the Sickness Impact Profile for Nursing Homes (SIP-NH), the ability to live independently, and insulin-like growth factor I (IGF-I) levels. RESULTS: MK-0677 treatment increased serum IGF-I levels by 84% (95% confidence interval (CI)=63-107), compared with an increase of 17% (95% CI=8-28) on placebo. There were no significant differences between MK-0677 and placebo in improvement in functional performance measures or in the overall SIP-NH score. Although MK-0677 patients showed greater improvement relative to placebo in three of four lower extremity functional performance measures, in the physical domain of the SIP, and in the ability to live independently, these differences were not statistically significant. CONCLUSION: Although MK-0677 treatment increased serum IGF-I, it is uncertain whether clinically significant effects on physical function were achieved. Measuring function in clinical trials in hip-fracture patients is difficult because of the lack of validated outcome measures, high variability, and the lack of a baseline assessment. Present functional performance measures may not be sufficiently responsive for use as the primary endpoint of small intervention studies; alternatively, stimulation of GH may not result in significant functional improvement.

Limb fractures in elderly men as indicators of subsequent fracture risk.

BACKGROUND: Whether limb fracture in elderly men predicts future fracture is unknown. METHODS: Electronic health records were examined to determine fracture incidence among men 60 years or older who were members of a large health maintenance organization, experienced no fracture in the past 2 years, and experienced an ankle, hip, humerus, or wrist fracture between July 1, 1997, and August 31, 2001. Proportional hazards models were used to compare risk of new fracture (ankle, hip, humerus, or wrist) between groups. Recurrent fractures of the same type were excluded from analysis. RESULTS: During the follow-up period (mean duration, 2.4 years), 0.5% of the control subjects without fractures experienced a subsequent ankle fracture; 0.6%, a hip fracture; 0.2%, a humerus fracture; and 0.4%, a wrist fracture. A limb fracture was about 4 times more likely to occur in persons who experienced a previous humerus fracture (relative risk, 3.9; 95% confidence interval, 2.5-6.0), about 3 times more likely to occur in persons who experienced a previous hip fracture (relative risk, 2.8; 95% confidence interval, 1.7-4.5), and about 2 times more likely to occur in persons who experienced a previous wrist fracture (relative risk, 2.2; 95% confidence interval, 1.4-3.5) than in controls. In contrast, persons who experienced a previous ankle fracture had no greater risk of subsequent fracture than nonfracture controls (relative risk, 1.0; 95% confidence interval, 0.5-1.9). CONCLUSIONS: Among men 60 years or older, a recent hip, humerus, or wrist fracture is a statistically and clinically significant predictor of future limb fracture risk. An increased risk of future fracture is greatest after a humerus fracture and is lowest after a wrist fracture; however, among elderly men, a previous ankle fracture is not an indicator of future fracture risk.

Opciones de tratamiento en osteoporosis / Treatment options to osteoporosis

Se presenta un caso ilustrativo de osteoporosis, se define cómo se diagnostica y cuál es la mejor estrategia terapéutica a seguir en pacientes con esta patología, haciendo enfasis en los ultimos avances que existen en este aspecto.

Skeletal and nonskeletal effects of raloxifene.

Raloxifene, a selective estrogen receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density and suppression of bone turnover markers in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation study was the pivotal treatment trial for raloxifene. It demonstrated significant reduction in the risk for vertebral fractures after 1 and 3 years. Significant reduction of nonvertebral fractures with raloxifene has not yet been demonstrated. In addition to the effects of raloxifene on bone, potentially beneficial effects on the cardiovascular system, breast, and uterus have been described. Most of these nonskeletal effects have been reported as secondary endpoints from large osteoporosis trials with raloxifene. Prospective, randomized, double-blind studies of raloxifene with breast cancer prevention and cardiovascular protection as primary endpoints are now underway.

Raloxifene: recent information on skeletal and non-skeletal effects.

Raloxifene, a selective estrogen receptor modulator, is currently used for both prevention and treatment of postmenopausal osteoporosis. Recent data from the MORE (Multiple Outcomes of Raloxifene Evaluation) trial have evaluated health-related quality of life, 1-year clinical vertebral fracture reduction, and the correlation of bone mineral density and biochemical markers of bone turnover with vertebral fracture reduction. In addition, new information on the effects of raloxifene in breast cancer prevention, cardiovascular disease in high-risk women, and uterine disorders is reviewed.

Review of raloxifene and its clinical applications in osteoporosis.

Raloxifene, a selective oestrogen receptor modulator, is currently utilised for both the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density, suppression of markers of bone turnover and maintenance of normal bone histology for up to 4 years in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial, the pivotal treatment trial of raloxifene, demonstrated significant reductions in the risk of vertebral fractures after 1 and 3 years, which is comparable to other currently available agents. Significant reductions in non-vertebral fractures with raloxifene have not been demonstrated yet. In addition to the effects of raloxifene on bone, a number of beneficial non-skeletal effects have been reported on the breast, uterus and cardiovascular system. These latter findings are mainly derived from secondary end points and analyses of the large osteoporosis studies with raloxifene. Two large, prospective, randomised, double-blind studies examining the effects of raloxifene on breast cancer prevention and cardiovascular protection are now underway. Recent information on the effects of raloxifene in postmenopausal osteoporosis, breast cancer prevention and cardiovascular disease in high-risk women and those with uterine disorders is reviewed in this article.

A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca.

OBJECTIVE: To evaluate the safety and efficacy of 2 dosages of cevimeline for the treatment of xerostomia and keratoconjunctivitis sicca in patients with Sjögren's syndrome. METHODS: A 12-week double-blind, randomized, placebo-controlled study was performed. Patients were randomly assigned to receive either placebo, 15 mg of cevimeline 3 times daily, or 30 mg of cevimeline 3 times daily. Patients were evaluated at baseline and throughout the study for their global assessment of dryness (mouth, eyes, overall) as well as their subjective assessment of the specific symptoms of dry mouth and dry eyes. Total saliva and tear flow also were measured. RESULTS: Patients taking 30 mg of cevimeline 3 times daily had statistically significant improvements in their subjective global assessment of dry eyes (P = 0.0453), dry mouth (P = 0.0004), and increased salivary flow (P = 0.007). Patients receiving the 30-mg dosage also showed greater objective improvement (increased salivary and lacrimal flow rates, as measured by Schirmer's test) than did patients receiving placebo. Frequently reported adverse events included headache, increased sweating, abdominal pain, and nausea. CONCLUSION: Treatment with cevimeline at a dosage of 30 mg 3 times daily resulted in substantive improvement by increasing the rate of saliva and tear flow in patients with Sjögren's syndrome, as well as improving subjective symptoms of dry mouth, dry eyes, and overall dryness. The 15-mg dosage relieved some symptoms, and both dosages were well tolerated.