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Clinical Therapeutics Sep 2021To perform a systematic review and meta-analysis of randomized clinical trials (RCTs) to elucidate the effects of raloxifene on the lipid profile in elderly individuals. (Meta-Analysis)
Meta-Analysis
PURPOSE
To perform a systematic review and meta-analysis of randomized clinical trials (RCTs) to elucidate the effects of raloxifene on the lipid profile in elderly individuals.
METHODS
A systematic review and meta-analysis of RCTs was performed following the PRISMA statement. Data on triglycerides (TGs), total cholesterol (TC), HDL-C, and LDL-C were extracted. Relevant publications up to October 2020 were detected through searches in the PubMed/MEDLINE, Web of Science, Scopus, and Embase databases. Changes were reported as weighted mean differences (WMDs) and 95% CIs using random-effects models.
FINDINGS
Nine studies were selected, with a duration of intervention ranging from 2 and 12 months and a raloxifene dose of 60 to 120 mg/d. Studies were performed in healthy individuals and in those with disorders, such as osteoporosis, type 2 diabetes, and kidney disease required long-term hemodialysis. Overall, TG (WMD, -6.50 mg/dL; 95% CI, -34.18 to 21.20 mg/eL; P = 0.646), LDL-C (WMD, -17.86 mg/dL; 95% CI, -42.44 to 6.72 mg/dL; P = 0.154), and HDL-C (WMD, 2.35 mg/dL; 95% CI, -1.14 to 5.84 mg/dL; P = 0.187) levels did not change significantly after the administration of raloxifene. In contrast, TC levels decreased after raloxifene therapy (WMD, -6.59 mg/dL; 95% CI, -13.13 to -0.05 mg/dL; P = 0.048).
IMPLICATIONS
Raloxifene therapy decreased TC levels but did not alter TG, HDL-C, and LDL-C concentrations in elderly individuals. Regarding the LDL-C levels, although the finding lacked statistical significance, we believe that there was a mean reduction that deserves further clinical attention as much as TC.
Topics: Aged; Diabetes Mellitus, Type 2; Humans; Lipids; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Triglycerides
PubMed: 34462124
DOI: 10.1016/j.clinthera.2021.07.017 -
Hormone and Metabolic Research =... Nov 2021As a selective estrogen receptor modulator (SERM), raloxifene is used in healthy postmenopausal women to prevent bone loss and reduce fractures. However, the benefit of... (Meta-Analysis)
Meta-Analysis
As a selective estrogen receptor modulator (SERM), raloxifene is used in healthy postmenopausal women to prevent bone loss and reduce fractures. However, the benefit of raloxifene is uncertain in the treatment of osteoporosis among patients with end-stage renal disease (ESRD) or those who require maintenance dialysis. We assessed the safety and efficacy of raloxifene in this particular population. Studies were selected from PubMed, Springer, CNKI (Chinese National Knowledge Infrastructure) and Wanfang Database. Randomized controlled trials (RCTs) and prospective studies with control/placebo groups were included. Five studies were included with a total of 244 participants (121 patients in the raloxifene group and 123 patients in the placebo/control group). The median duration of treatment was 12 months. The incidence rate of side effects of raloxifene was 0/121 (0%). There was a significant improvement of lumbar spine bone mineral density (BMD) levels in the raloxifene group compared with the placebo group (MD: 33.88, 95% CI: 10.93, 56.84, p=0.004). There was no significant difference concerning the improvement of femoral neck BMD (MD: 8.42, 95% CI: -10.21, 27.04, p=0.38), intact parathyroid hormone (iPTH) (MD: -12.62, 95% CI: -35.36, 10.13, p=0.28), calcium (MD: -0.08, 95% CI: -0.61, 0.44, p=0.76), phosphorus (MD: 0.18, 95% CI: -0.12, 0.48, p=0.23) or bone alkaline phosphatase (BAP) (MD: -4.33, 95% CI: -14.44, 5.79, p=0.40). Raloxifene seems to be effective in improving the lumbar spine BMD in postmenopausal women with ESRD. More large RCTs are necessary to evaluate the long-term safety of raloxifene in uremic patients.
Topics: Aged; Female; Humans; Kidney Failure, Chronic; Middle Aged; Osteoporosis, Postmenopausal; Postmenopause; Raloxifene Hydrochloride
PubMed: 34740274
DOI: 10.1055/a-1655-4362 -
The Cochrane Database of Systematic... Jul 2021Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism.
OBJECTIVES
To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D).
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence).
AUTHORS' CONCLUSIONS
Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.
Topics: Antibodies, Monoclonal; Bias; Bone Density; Bone Density Conservation Agents; Denosumab; Female; Femur Neck; Fractures, Spontaneous; Hip; Humans; Indoles; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Parathyroid Hormone-Related Protein; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Spinal Fractures; Teriparatide; Thiophenes; Watchful Waiting
PubMed: 34231877
DOI: 10.1002/14651858.CD013424.pub2 -
Bone Jan 2020To determine the clinical effectiveness of denosumab (DEN), raloxifene (RLX), romosozumab (ROMO) and teriparatide (TPTD), within their licensed (or anticipated licensed)... (Meta-Analysis)
Meta-Analysis
Clinical effectiveness of denosumab, raloxifene, romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures: A systematic review and network meta-analysis.
OBJECTIVES
To determine the clinical effectiveness of denosumab (DEN), raloxifene (RLX), romosozumab (ROMO) and teriparatide (TPTD), within their licensed (or anticipated licensed) indications, for the treatment of osteoporosis.
METHODS
A systematic review was conducted. Nine electronic databases and trial registries were searched up to the end of July 2018. Studies were eligible for inclusion if they were randomised controlled trials (RCT) in a population at risk of osteoporotic fracture, comparing these four non-bisphosphonates DEN, RLX, ROMO, or TPTD with each other, a non-active treatment, or the bisphosphonates alendronate (ALN), risedronate (RIS), ibandronate (IBN) and zoledronic acid (ZOL). Quality of included studies was assessed using the Cochrane Risk of Bias tool. Network meta-analyses (NMA) were used to determine the relative effectiveness of treatments.
RESULTS
The systematic review identified 7898 citations. Forty-six RCTs of non-bisphosphonates met the inclusion criteria for the review and provided data for analyses. Additionally 49 RCTs of bisphosphonates were used in the NMAs. Forty-six RCTs were included in the NMA of vertebral fracture data, 23 RCTs for hip fractures and 73 RCTs in the NMA of femoral neck bone mineral density (FN BMD). For vertebral fractures, all four non-bisphosphonates showed statistically significant benefit relative to placebo: TPTD HR 0.23 (95% credible internal (CrI) 0.16, 0.32); ROMO followed by ALN 0.25 (95% CrI 0.15, 0.43); DEN HR 0.30 (95% CrI 0.21, 0.43); RLX HR 0.61 (95% CrI 0.44, 0.80). The four non-bisphosphonates interventions studied also showed statistically significant benefit relative to placebo for FN BMD, and for hip fractures TPTD, ROMO followed by ALN, and DEN showed statistically significant benefit relative to placebo.
CONCLUSIONS
The four non-bisphosphonate interventions studied were all statistically significantly clinically effective for reducing vertebral fractures when compared to placebo, and were beneficial for change in FN BMD compared to placebo. All reduced hip fractures, and this was statistically significant for TPTD, ROMO followed by ALN, and DEN.
Topics: Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Humans; Network Meta-Analysis; Osteoporotic Fractures; Raloxifene Hydrochloride; Teriparatide; Treatment Outcome
PubMed: 31626995
DOI: 10.1016/j.bone.2019.115081 -
The Cochrane Database of Systematic... May 2021Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. This chronic and recurring condition occurs in women of reproductive age. It...
BACKGROUND
Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. This chronic and recurring condition occurs in women of reproductive age. It is a common cause of pain or infertility and can cause non-specific symptoms such as lower back pain, dyspareunia (pain during or after intercourse), and dysmenorrhoea (menstrual pain). Endometriosis is an oestrogen-dependent disease. Medical treatment aims to relieve symptoms and shrink lesions by suppressing the normal menstrual cycle. In this review, we consider medication specifically aiming to modulate oestrogen receptors as an alternative method of treatment.
OBJECTIVES
To evaluate the effectiveness and safety of selective oestrogen receptor modulators (SERMs) in the management of endometriosis.
SEARCH METHODS
We searched for trials in the following databases (from their inception to 28 May 2020): Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies (CRS Online), MEDLINE, Embase, CINAHL, PsycINFO, and registers of ongoing trials. In addition, we searched all reference lists of included trials, and we contacted experts in the field, in an attempt to locate trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing selective oestrogen receptor modulators (SERMs) with placebo, no treatment, other medical treatment, or surgery for endometriosis.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. Two review authors independently selected trials for inclusion, assessed risk of bias, and extracted data using data extraction forms. We used risk ratios (RRs) with 95% confidence intervals (CIs) for reporting dichotomous data. Primary review outcomes were relief of pelvic pain and adverse events. Secondary outcomes included quality of life, recurrence rate, and economic and fertility outcomes.
MAIN RESULTS
We included only one RCT, which included 93 women, comparing the SERM raloxifene with placebo in biopsy-proven endometriosis. All women first underwent complete surgical excision of all lesions. Evidence was of very low quality: the main limitation was imprecision - with very sparse data from only one small study, which included only women after surgical treatment. Relief of pelvic pain The included study did not specifically measure the primary outcome of pain relief. Study authors reported that time to return of pelvic pain (defined as two months of pain equal to or more severe than pain at study entry) was more rapid in the raloxifene group (P = 0.03). Adverse events The included study reported adverse events such as pelvic pain, ovarian cyst, headache, migraine, and depression. We are uncertain whether raloxifene improves the incidence of pelvic pain (RR 1.25, 95% CI 0.63 to 2.45), ovarian cysts (RR 1.57, 95% CI 0.55 to 4.43), headache (RR 1.09, 95% CI 0.49 to 2.43), migraine (RR 0.73, 95% CI 0.28 to 1.95), depression (RR 1.96, 95% CI 0.63 to 6.06), or other adverse events (RR 0.08, 95% CI 0.00 to 1.30) (all: 1 study, n = 93; very low-quality evidence). Quality of life The study described a statistically significant difference in mental health quality of life (QoL) by 12 months, in favour of placebo treatment (mean difference 11.1, 95% CI 0.01 to 21.19). Other QoL data did not differ between groups but were not reported in detail. Recurrence rate, fertility, and economic outcomes We are uncertain whether raloxifene improves the recurrence rate of endometriosis, proven by biopsy, when compared to placebo (RR 1.20, 95% CI 0.66 to 2.21; 1 study, n = 93; very low-quality evidence). This suggests that if 28% of women taking placebo have biopsy-proven recurrence of endometriosis, between 19% and 62% of those taking raloxifene will do so. These outcomes are prone to bias, as not all women had an actual second laparoscopy. Recurrence based on symptoms (non-menstrual pain, dysmenorrhoea, or dyspareunia) was described; in these cases, symptoms improved after use of raloxifene as well as after use of placebo. The included study did not report data on economic outcomes. No comparative data were available on pregnancy, as the study included only women who agreed to postpone pregnancy until after the study endpoint; the few pregnancies that did occur were uneventful but were regarded as an adverse event. AUTHORS' CONCLUSIONS: Based on a single, small RCT and incomplete data, we are uncertain of the effects of SERMs on pain relief in surgically treated patients with endometriosis. The included study was stopped prematurely because of higher pain scores among women who took SERMs when compared to scores among those receiving placebo. Further research is needed to fully evaluate the role of SERMs in endometriosis.
Topics: Dysmenorrhea; Dyspareunia; Endometriosis; Female; Humans; Pelvic Pain; Placebos; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators
PubMed: 33973648
DOI: 10.1002/14651858.CD011169.pub2 -
Psychoneuroendocrinology Jul 2018Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause...
Targeting hypothalamic-pituitary-adrenal axis hormones and sex steroids for improving cognition in major mood disorders and schizophrenia: a systematic review and narrative synthesis.
Cognitive deficits are a core feature of serious mental illnesses such as schizophrenia, major depressive disorder (MDD) and bipolar disorder (BD) and are a common cause of functional disability. There is limited efficacy of pharmacological interventions for improving the cognitive deficits in these disorders. As pro-cognitive pharmacological treatments are lacking, hormones or drugs that target the endocrine system may become potential candidates for 'repurposing' trials aiming to improve cognition. We aimed to study whether treatment with drugs targeting the hypothalamic-pituitary-adrenal (HPA) axis and sex steroids can improve cognition in patients with schizophrenia, MDD or BD. A systematic search was performed using PubMed (Medline), PsychInfo and clinicaltrials.gov, and a narrative synthesis was included. The systematic review identified 12 studies dealing with HPA-related drugs (mifepristone [n = 3], cortisol synthesis inhibitors [ketoconazole, n = 2], dehydroepiandrosterone [n = 5], fludrocortisone [n = 2]) and 14 studies dealing with sex steroids (oestradiol [n = 2], selective oestrogen receptor modulators [raloxifene, n = 7], pregnenolone [n = 5]). Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone). A replication of positive findings by at least two clinical trials was found for mifepristone in BD and raloxifene and pregnenolone in schizophrenia. The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.
Topics: Affective Disorders, Psychotic; Bipolar Disorder; Cognition Disorders; Cognitive Dysfunction; Depressive Disorder, Major; Female; Gonadal Steroid Hormones; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Mifepristone; Mood Disorders; Pituitary-Adrenal System; Pregnenolone; Raloxifene Hydrochloride; Schizophrenia
PubMed: 29680774
DOI: 10.1016/j.psyneuen.2018.04.012 -
Pharmacological Research Apr 2021There is robust evidence that the appropriate treatment of dyslipidaemia substantially reduces cardiovascular disease-related morbidity and mortality. Raloxifene is a... (Meta-Analysis)
Meta-Analysis
There is robust evidence that the appropriate treatment of dyslipidaemia substantially reduces cardiovascular disease-related morbidity and mortality. Raloxifene is a selective oestrogen receptor modulator that also interferes with the lipid metabolism and may be of aid in the management of lipid abnormalities in females. Therefore, we conducted a systematic review and meta-analysis of the available randomized clinical trials (RCTs) exploring the effect of raloxifene on the lipid profile in women. The Scopus, Web of Science, PubMed/Medline and EMBASE databases were systematically and independently searched by two assessors from inception until 20 November 2020 without time and language restrictions. The overall findings were generated from 30 eligible RCTs. As compared to controls, raloxifene resulted in a significant elevation of the high-density lipoprotein-cholesterol (HDL-C) (WMD: 2.41 mg/dL, 95% CI: 0.84-3.97, P = 0.003) and a significant reduction of the total cholesterol (TC) (WMD:-14.84 mg/dL, 95% CI: -20.37 to -9.317, P = 0.000) and of the low-density lipoprotein-cholesterol (LDL-C) (WMD: -17 mg/dL, 95% CI: -25.77, -8.22, P = 0.000). In the stratified analysis, a significant decrease of serum triglycerides (TG) (WMD: -22.06 mg/dL) was achieved in the RCTs with a duration of ≤ 26 weeks (WMD -8.70 mg/dL) and with baseline TG concentrations of ≥ 130 mg/dL (WMD: -23.02 mg/dL). In conclusion, raloxifene treatment can increase HDL-C and lower LDL-C and TC. In terms of TG, a significant decrease can be observed if the administration of raloxifene lasts ≤ 26 weeks and if the baseline TG concentrations are ≥ 130 mg/dL.
Topics: Cardiovascular Diseases; Dyslipidemias; Estrogen Antagonists; Heart Disease Risk Factors; Humans; Lipid Metabolism; Lipids; Protective Factors; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic
PubMed: 33617974
DOI: 10.1016/j.phrs.2021.105512 -
European Journal of Cancer Prevention :... Nov 2015To evaluate all the in-vitro raloxifene (RAL) mechanisms of action on normal, Ishikawa, and different endometrium-derived cell lines to explain the in-vivo RAL... (Review)
Review
Could in-vitro studies on Ishikawa cell lines explain the endometrial safety of raloxifene? Systematic literature review and starting points for future oncological research.
To evaluate all the in-vitro raloxifene (RAL) mechanisms of action on normal, Ishikawa, and different endometrium-derived cell lines to explain the in-vivo RAL endometrial effects, a systematic literature search was performed in the electronic databases MEDLINE, EMBASE ScienceDirect, and the Cochrane Library for the time period between 2002 and 2012. Outcomes were considered in relation to in-vitro stimulatory, inhibitory, or neutral actions of RAL in Ishikawa cell lines compared with different endometrial-derived cell lines (both cancerous and normal endometrium). We also considered all the RAL molecular mechanisms responsible for the in-vitro effects observed. More than 150 articles were available in the scientific database literature, but only 21 fulfilled our selection criteria. Although in-vitro studies appear to yield conflicting results, most evidence has shown that RAL seems to induce endometrial cell mitochondria-mediated apoptosis, and to inhibit estrogen-related cell proliferation and endometrial carcinogenesis by inducing antiangiogenic factors, and reducing cytoskeletal reorganization. If the endometrial safety profile of RAL is confirmed, in the near future, selective estrogen receptor modulators could represent an efficient alternative adjuvant treatment to tamoxifen (TAM) in women with breast cancer considered to be at an increased risk of endometrial disease. The confirmation of the endometrial safety profile could enable the proposal of RAL by clinicians as the most appropriate treatment for BRCA1-2 patients after prophylactic salpingo-oophorectomy.
Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Endometrium; Female; Humans; In Vitro Techniques; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators
PubMed: 25536299
DOI: 10.1097/CEJ.0000000000000107 -
Growth Hormone & IGF Research :... 2021To ascertain the clinical magnitude of raloxifene administration on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3)... (Meta-Analysis)
Meta-Analysis
Effects of raloxifene administration on serum levels of insulin-like growth factor-1 and insulin-like growth factor-binding protein 3 levels: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
To ascertain the clinical magnitude of raloxifene administration on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.
METHODS
A systematic comprehensive search was performed without language limitation up to 14 December 2020. We included only trials that assessed the effect of raloxifene on IGF-1 and IGFBP-3 in adults. Meta-analysis was performed using the Stata software (Stata Corp. College Station, Texas, USA).
RESULTS
Seven arms were included, encompassing postmenopausal women with type 2 diabetes mellitus, postmenopausal women with breast cancer, healthy postmenopausal women, and healthy elderly men. Raloxifene therapy significantly reduced IGF-1 levels (WMD: -2.92 nmol/L, 95% CI: -3.49, -2.35, p < 0.001) compared to placebo. Raloxifene dosage ˃60 mg/day (WMD: -3.29 ng/mL, 95% CI: -3.50 to -3.08, I = 0.0%) decreased IGF-1 levels more than 60 mg/day (WMD: -2.29 ng/mL, 95% CI: -2.90 to -1.69, I = 16%). Moreover, intervention duration ˃26 weeks (WMD: -3.48 ng/mL, 95% CI: -5.26 to -1.69, I = 0.0%) reduced IGF-1 levels more than ˂26 weeks (WMD: -2.55 ng/mL, 95% CI: -3.31 to -1.79, I = 92%). In contrast, overall results from the random-effects model did not suggest a significant change in IGFBP-3 levels upon raloxifene therapy.
CONCLUSION
Raloxifene therapy significantly reduced serum levels of IGF-1 levels but without changes in IGFPB-3 levels.
Topics: Biomarkers; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Postmenopause; Prognosis; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators
PubMed: 34384975
DOI: 10.1016/j.ghir.2021.101421 -
The Cochrane Database of Systematic... Mar 2015Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects.
OBJECTIVES
To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms.
SEARCH METHODS
We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014.
SELECTION CRITERIA
Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria.
MAIN RESULTS
Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings.
AUTHORS' CONCLUSIONS
There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.
Topics: Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Drug Therapy, Combination; Estriol; Female; Gonadotropin-Releasing Hormone; Humans; Isoflavones; Leiomyoma; Medroxyprogesterone; Norpregnenes; Quality of Life; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 25793972
DOI: 10.1002/14651858.CD010854.pub2