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1.
N Engl J Med ; 387(4): 299-309, 2022 07 28.
Article in English | MEDLINE | ID: mdl-35939577

ABSTRACT

BACKGROUND: Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. METHODS: In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. RESULTS: Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. CONCLUSIONS: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).


Subject(s)
Cholecalciferol , Dietary Supplements , Fatty Acids, Omega-3 , Fractures, Bone , Aged , Cholecalciferol/therapeutic use , Double-Blind Method , Fatty Acids, Omega-3/therapeutic use , Female , Fractures, Bone/epidemiology , Fractures, Bone/prevention & control , Hip Fractures/epidemiology , Hip Fractures/prevention & control , Humans , Male , Middle Aged , Osteoporosis , Vitamin D Deficiency
4.
Obstet Gynecol ; 132(1): 147-160, 2018 07.
Article in English | MEDLINE | ID: mdl-29889764

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain. METHODS: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate. RESULTS: Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%)."After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings. CONCLUSION: Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01760954 and NCT02143713.


Subject(s)
Dysmenorrhea/drug therapy , Dyspareunia/drug therapy , Endometriosis/drug therapy , Hydrocarbons, Fluorinated/administration & dosage , Pelvic Pain/drug therapy , Pyrimidines/administration & dosage , Adolescent , Adult , Double-Blind Method , Drug Administration Schedule , Dysmenorrhea/etiology , Dyspareunia/etiology , Endometriosis/complications , Female , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hot Flashes/chemically induced , Humans , Middle Aged , Pelvic Pain/etiology , Time Factors , Treatment Outcome , Young Adult
5.
N Engl J Med ; 377(1): 28-40, 2017 07 06.
Article in English | MEDLINE | ID: mdl-28525302

ABSTRACT

BACKGROUND: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. METHODS: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. RESULTS: A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. CONCLUSIONS: Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).


Subject(s)
Dysmenorrhea/drug therapy , Endometriosis/drug therapy , Estrogen Antagonists/administration & dosage , Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hydrocarbons, Fluorinated/administration & dosage , Pelvic Pain/drug therapy , Pyrimidines/administration & dosage , Adolescent , Adult , Bone Density/drug effects , Dose-Response Relationship, Drug , Double-Blind Method , Dysmenorrhea/etiology , Endometriosis/complications , Estrogen Antagonists/adverse effects , Female , Hot Flashes/chemically induced , Humans , Hydrocarbons, Fluorinated/adverse effects , Lipids/blood , Middle Aged , Pelvic Pain/etiology , Premenopause , Pyrimidines/adverse effects , Young Adult
6.
J Bone Miner Res ; 26(3): 538-45, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20890933

ABSTRACT

Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation. 2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D(3) (2MD) is a vitamin D analogue that potently stimulates bone formation activity in vitro and in the ovariectomized rat model. In this randomized, double-blind, placebo-controlled study of osteopenic women, the effect of daily oral treatment with 2MD on bone mineral density (BMD), serum markers of bone turnover, and safety were assessed over 1 year. Volunteers were randomly assigned to three treatment groups: placebo (n = 50), 220 ng of 2MD (n = 54), and 440 ng of 2MD (n = 53). In general, 2MD was well tolerated. Although 2MD caused a marked increase in markers of bone formation, it did not significantly increase BMD. Since 2MD also shows marked activity on bone resorption (as revealed by dose-dependent increases in serum C-telopeptide cross-links of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone remodeling.


Subject(s)
Bone Density/drug effects , Bone Diseases, Metabolic/drug therapy , Bone Diseases, Metabolic/physiopathology , Bone Remodeling/drug effects , Calcitriol/analogs & derivatives , Postmenopause/drug effects , Vitamin D/analogs & derivatives , Animals , Biomarkers/blood , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/pharmacology , Bone Density Conservation Agents/therapeutic use , Bone Diseases, Metabolic/blood , Calcitriol/adverse effects , Calcitriol/pharmacology , Calcitriol/therapeutic use , Calcium/blood , Demography , Double-Blind Method , Female , Humans , Middle Aged , Parathyroid Hormone/blood , Placebos , Postmenopause/blood , Rats
9.
Maturitas ; 65(4): 301-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20116187

ABSTRACT

Osteoporosis is a major public health problem for adults over age 55 years costing billions of euros/dollars. Over the last 20 years anti-resorptive drugs were the treatment of choice for osteoporosis and most were derived from the bisphosphonate molecule. In the last 7 years remarkable advances in molecular biology and genetics have led to a detailed understanding of the bone remodeling cycle and as a result new therapeutic targets for treatment emerged. These new compounds have different modes of action depending on their role in the bone remodeling cycle. A major discovery was the important role of RANKL (receptor activator of nuclear factor kappa B ligand) secreted by osteoblasts and responsible for stimulating osteoclastic bone resorption. This led to development of a potent monoclonal antibody that blocks its action. This drug should be available soon as a new treatment for osteoporosis. Other molecular targets in resorption have been identified and several specific antagonists are potential treatments. However, a significant limiting factor for a new anti-resorptive drug is the cost of bringing it to the market because of the huge costs of a fracture trial. Although anti-resorptive agents have been the backbone of osteoporosis treatment they do not rebuild bone architecture and development of anabolic agents is needed. These are likely to evolve from an understanding of the LRP/Wnt signaling pathway. Already an antibody against sclerostin has shown promise in animal studies, and not to forget parathyroid hormone which was the first clinically useful anabolic treatment for osteoporosis.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Remodeling , Osteoporosis/drug therapy , Bone Density Conservation Agents/pharmacology , Humans , Osteoporosis/prevention & control
11.
Maturitas ; 60(1): 65-9, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18555623

ABSTRACT

Recent advances in bone biology have led to a more detailed understanding of bone remodeling which is a process that leads to resorption of old bone and replacement by formation of new bone. The most important discoveries in this process of bone remodeling were those of the RANK Ligand/RANK/OPG system which is now recognized the dominant pathway regulating bone resorption. RANK Ligand (RANKL) is a cytokine belonging to the tumor necrosis factor family and is expressed by osteoblasts; it binds to membrane bound receptor RANK on osteoclasts and promotes differentiation of marrow cells through various stages to multinucleated osteoclasts which resorb bone. Several hormones such as parathyroid hormone, calcitriol and prostaglandins stimulate RANK Ligand expression by osteoblasts. Osteoblasts also secrete osteoprotegerin (OPG) which is a soluble receptor that is a potent antagonist of osteoclast formation by binding and inactivating RANKL and OPG is therefore an important regulator of bone resorption. OPG is stimulated by estrogen. OPG has been genetically engineered and in human subjects is a potent inhibitor of bone resorption. Another method for preventing bone resorption is to develope antibodies against RANKL and this has been shown to be a successful strategy. A single subcutaneous injection of this antibody (Denosumab) every 6 months proved to be a potent inhibitor of bone resorption and clinical fracture trials using this agent are now underway. These are novel developments that have risen from basic research in bone biology and other discoveries in the bone remodeling process can be expected to lead to further treatment options for various bone diseases.


Subject(s)
Osteogenesis/physiology , Osteoporosis/drug therapy , Osteoporosis/physiopathology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Denosumab , Humans , Osteoprotegerin/physiology , RANK Ligand/immunology , RANK Ligand/physiology , RANK Ligand/therapeutic use , Signal Transduction/physiology
12.
Fertil Steril ; 88(4): 866-78, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17548089

ABSTRACT

OBJECTIVE: To address the endometrial safety of tibolone. DESIGN: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). SETTING: Multi-country, multi-center ambulatory care setting. PATIENT(S): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women. INTERVENTION(S): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA. MAIN OUTCOME MEASURE(S): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA. RESULT(S): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized. CONCLUSION(S): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.


Subject(s)
Endometrium/anatomy & histology , Norpregnenes/administration & dosage , Postmenopause/physiology , Aged , Breast , Double-Blind Method , Endometrial Hyperplasia , Endometrium/pathology , Female , Humans , Middle Aged , Pain , Vacuum Curettage
13.
J Clin Endocrinol Metab ; 92(3): 911-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17192288

ABSTRACT

BACKGROUND AND OBJECTIVES: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d). METHODS: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA. RESULTS: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%). CONCLUSION: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.


Subject(s)
Endometrium/drug effects , Norpregnenes/pharmacology , Aged , Carcinoma/chemically induced , Carcinoma/epidemiology , Cohort Studies , Double-Blind Method , Drug Combinations , Endometrial Hyperplasia/chemically induced , Endometrial Hyperplasia/epidemiology , Endometrial Neoplasms/chemically induced , Endometrial Neoplasms/epidemiology , Estrogen Replacement Therapy/adverse effects , Estrogens, Conjugated (USP)/administration & dosage , Female , Humans , Medroxyprogesterone Acetate/administration & dosage , Middle Aged , Norpregnenes/adverse effects , Norpregnenes/therapeutic use , Pain/chemically induced , Uterine Hemorrhage/chemically induced , Uterine Hemorrhage/epidemiology
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