Charles H. Chesnut

A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study

PURPOSE We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. SUBJECTS AND METHODS A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group. RESULTS During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43- to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1. 5%, P<0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo. CONCLUSION Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.

Effects of Oral Ibandronate Administered Daily or Intermittently on Fracture Risk in Postmenopausal Osteoporosis

Oral daily (2.5 mg) and intermittent ibandronate (between‐dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate.

Intermittent cyclical etidronate treatment of postmenopausal osteoporosis

Abstract Background. To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia. Methods. The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs. Results. After two years, the patients receiving etidro...

Bone mineral content of amenorrheic and eumenorrheic athletes

This study was designed to determine whether the hypoestrogenic status of 14 amenorrheic athletes was associated with a decrease in regional bone mass relative to that of 14 of their eumenorrheic peers. The two groups of athletes were matched for age, height, weight, sport, and training regimens. Bone mass was measured by dual-photon and single-photon absorptiometry at the lumbar vertebrae (L1 to L4) and at two sites on the radius. Vertebral mineral density was significantly lower in the amenorrheic group (mean, 1.12 g per square centimeter) than in the eumenorrheic group (mean, 1.30 g per square centimeter). There was no significant difference at either radial site. Radioimmunoassay confirmed a lower mean estradiol concentration (amenorrheic group, 38.58 pg per milliliter; eumenorrheic group, 106.99 pg per milliliter) and progesterone peak (amenorrheic group, 1.25 ng per milliliter; eumenorrheic group, 12.75 ng per milliliter) in the amenorrheic women, in four venous samples drawn at seven-day intervals. A three-day dietary history showed no significant differences in nutritional intake, including calcium with and without supplements. The two groups were similar in percentage of body fat, age at menarche, years of athletic participation, and frequency and duration of training but differed in number of miles run per week (amenorrheic group, 41.8 miles [67.3 km]; eumenorrheic group, 24.9 miles [40.1 km]). We conclude that the amenorrhea that is observed in female athletes may be accompanied by a decrease in mineral density of the lumbar vertebrae.

Fractures Attributable to Osteoporosis: Report from the National Osteoporosis Foundation

To assess the cost‐effectiveness of interventions to prevent osteoporosis, it is necessary to estimate total health care expenditures for the treatment of osteoporotic fractures. Resources utilized for the treatment of many diseases can be estimated from secondary databases using relevant diagnosis codes, but such codes do not indicate which fractures are osteoporotic in nature. Therefore, a panel of experts was convened to make judgments about the probabilities that fractures of different types might be related to osteoporosis according to patient age, gender, and race. A three‐round Delphi process was applied to estimate the proportion of fractures related to osteoporosis (i.e., the osteoporosis attribution probabilities) in 72 categories comprised of four specific fracture types (hip, spine, forearm, all other sites combined) stratified by three age groups (45–64 years, 65–84 years, 85 years and older), three racial groups (white, black, all others), and both genders (female, male). It was estimated that at least 90% of all hip and spine fractures among elderly white women should be attributed to osteoporosis. Much smaller proportions of the other fractures were attributed to osteoporosis. Regardless of fracture type, attribution probabilities were less for men than women and generally less for non‐whites than whites. These probabilities will be used to estimate the total direct medical costs associated with osteoporosis‐related fractures in the United States.

Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling

BACKGROUND The effects of the aminobisphosphonate alendronate sodium on bone mass and markers of bone remodeling were investigated. PATIENTS AND METHODS In a multicenter, randomized, double-blind, placebo-controlled, 2-year study, 188 postmenopausal women, aged 42 to 75 years, with low bone mineral density (BMD) of the lumbar spine were randomly assigned to 1 of 6 daily treatment groups: placebo for 2 years, alendronate 5 or 10 mg for 2 years, alendronate 20 or 40 mg for 1 year followed by placebo for 1 year, or alendronate 40 mg for 3 months followed by 2.5 mg for 21 months. All subjects were given 500 mg/d of elemental calcium as calcium carbonate. RESULTS At each dose, alendronate produced significant reductions in markers of bone resorption and formation, and significantly increased bone mass at the lumbar spine, hip, and total body, as compared with decreases (significant at lumbar spine) in subjects receiving placebo. In the 10-mg group, mean urinary deoxypyridinoline/creatinine had declined by 47% at 3 months, and mean serum osteocalcin by 53% at 6 months. Mean changes in BMD over 24 months with 10 mg alendronate were +7.21% +/- 0.49% for the lumbar spine, +5.27% +/- 0.70% for total hip, and +2.53% +/- 0.68% for total body (each P < 0.01) compared to changes of -1.35% +/- 0.61%, -1.20% +/- 0.64% and -0.31% +/- 0.44% at these sites, respectively, with placebo treatment. Progressive increases in BMD of both lumbar spine and total hip were observed in the second year of treatment with 10 mg alendronate (both P < 0.05). CONCLUSION Alendronate, a potent inhibitor of bone resorption, reduces markers of bone remodeling and significantly increases BMD at the lumbar spine, hip, and total body, and is well tolerated at therapeutic doses (5 or 10 mg daily) in the treatment of osteoporosis in postmenopausal women.

Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy

Abstract purpose: To determine the effect of long-term intermittent cyclic etidronate treatment on spinal bone density and vertebral fracture rates. patients and methods: Postmenopausal osteoporotic women (n = 423) were randomized initially into a 2-year, double-blind, multicenter study; it was extended to a third year of blinded treatment followed by open-label treatment: 357 patients continued treatment in Year 3 (305 receiving blinded therapy and 52 receiving calcium supplementation) and 277 in Year 4. During Years 1 through 3, patients received doubleblind treatment with phosphate (1.0 g) or placebo twice daily for 3 days, etidronate (400 mg) or placebo daily for 14 days, and calcium (500 mg) daily for the remainder of each 91-day treatment cycle. During Year 4, open-label intermittent cyclic etidronate therapy (without preceding phosphate) was administered to all patients. Spinal bone density and vertebral fracture rates were the main outcome measures. results: During Year 3, etidronate therapy maintained the significant increases in spinal bone mineral density of the first 2 years. Over the 3-year period, proximal femur bone density increased in etidronate-treated patients. Etidronate therapy for 3 years significantly decreased the vertebral fracture rate in patients at higher risk for fracture (low spinal bone density and three or more vertebral fractures at study entry), as compared with nonetidronate treatment (228 versus 412 fractures per 1,000 patient-years, respectively; p conclusions: Three years of intermittent cyclic etidronate therapy produced significant increases in spinal and hip bone density, with a significant reduction in vertebral fracture rates in patients at higher fracture risk. Maintenance of bone mass and low fracture rate were observed when etidronate was continued for an additional year.

Hormone Replacement Therapy in Postmenopausal Women: Urinary N-Telopeptide of Type I Collagen Monitors Therapeutic Effect and Predicts Response of Bone Mineral Density

PURPOSE To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women. PATIENTS AND METHODS To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group). RESULTS In the treated group NTx significantly (P < 0.0001) decreased, and spine and hip BMD significantly (P < 0.00001 and P < 0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P < 0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (-66% to -87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P < 0.05 and P < 0.005). For every increase of 30 units in baseline NTx the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (> 67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT. CONCLUSION These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.

Long-term calcitonin therapy in postmenopausal osteoporosis

Results are presented from a 2-year controlled study evaluating the efficacy of 100 units synthetic salmon calcitonin/d in the treatment of postmenopausal osteoporosis. All patients received 400 units D2 po qd and 1200 mg CaCO3 po qd. The 21 control and 24 treated patients (mean age 65) were not statistically different at baseline. Although mean total body calcium (TBCa) was not significantly different between treated and control patients throughout the study, mean differences in the change in TBCa from baseline (treated minus control) were significant at 12, 18, and 26 months. The mean slope of TBCa for treated patients, but not for controls, was significantly positive through 18 months. Iliac crest bone biopsies showed (1) a significantly greater percent total bone area in treated compared to control patients at 2 years, and (2) a significantly decreased percent resorbing surface in treated patients when evaluated by paired difference from baseline. At 4 months, serum calcium values were significantly lower in treated patients than in controls (mean difference, treated minus controls), but were not statistically different from controls at study completion. Urine calcium increased significantly for the first 4 months in treated subjects and then declined to baseline levels. Since urinary calcium increased, the increase in TBCa was probably associated with an increase in net intestinal calcium absorption.

Relationships between mandibular and skeletal bone in an osteoporotic population

This study attempted to determine relationships between bone mass in the mandible and skeletal bone mass in a group of 85 postmenopausal women with osteoporosis. Mandibular bone mass was determined by microdensitometry, cortical thickness at the gonion, the height of the alveolar ridge in subjects who were edentulous, and periodontal probings. Skeletal measures were made up of total body calcium, bone mass at the radius, and the two newer bone mass measures of dual photon and computed tomography of the vertebrae. The height of the edentulous ridge correlated with total body calcium and mandibular mass. Most of the edentulous patients had ridges that were extremely resorbed. Mandibular mass correlated with all skeletal measures.