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Annals of Internal Medicine Feb 2023The prevalence of osteoporosis is increasing in the United States. (Meta-Analysis)
Meta-Analysis Review
Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.
BACKGROUND
The prevalence of osteoporosis is increasing in the United States.
PURPOSE
To evaluate low bone mass and osteoporosis treatments to prevent fractures.
DATA SOURCES
Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022.
STUDY SELECTION
Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies ( ≥1000) for harms.
DATA EXTRACTION
Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE).
DATA SYNTHESIS
We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE).
LIMITATION
Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years.
CONCLUSION
Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare.
PRIMARY FUNDING SOURCE
American College of Physicians. (PROSPERO: CRD42021236220).
Topics: Male; Adult; Female; Humans; Aged; Bone Density Conservation Agents; Teriparatide; Alendronate; Osteoporosis, Postmenopausal; Denosumab; Network Meta-Analysis; Fractures, Bone; Osteoporosis; Diphosphonates; Spinal Fractures; Physicians
PubMed: 36592455
DOI: 10.7326/M22-0684 -
Annals of Internal Medicine Jul 2019Optimal long-term osteoporosis drug treatment (ODT) is uncertain.
BACKGROUND
Optimal long-term osteoporosis drug treatment (ODT) is uncertain.
PURPOSE
To summarize the effects of long-term ODT and ODT discontinuation and holidays.
DATA SOURCES
Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies.
STUDY SELECTION
48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB).
DATA EXTRACTION
Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy.
DATA SYNTHESIS
Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).
LIMITATION
No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays.
CONCLUSION
Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms.
PRIMARY FUNDING SOURCE
National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).
Topics: Alendronate; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Diphosphonates; Drug Administration Schedule; Duration of Therapy; Female; Hip Fractures; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Spinal Fractures; Zoledronic Acid
PubMed: 31009947
DOI: 10.7326/M19-0533 -
Sao Paulo Medical Journal = Revista... 2023Osteoporosis compromises bone strength and increases the risk of fractures. Zoledronate prevents loss of bone mass and reduces the risk of fractures. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Osteoporosis compromises bone strength and increases the risk of fractures. Zoledronate prevents loss of bone mass and reduces the risk of fractures.
OBJECTIVES
To determine the efficacy and safety of zoledronate in postmenopausal women with osteopenia and osteoporosis.
DESIGN AND SETTINGS
A systematic review and meta-analysis was conducted within the evidence-based health program at the Universidade Federal de São Paulo.
METHODS
An electronic search of the CENTRAL, MEDLINE, Embase, and LILACS databases was performed until February 2022. Randomized controlled trials comparing zoledronate with placebo or other bisphosphonates were included. Standard methodological procedures were performed according to the Cochrane Handbook and the certainty of evidence for the Grading of Recommendations Assessment, Development, and Evaluation Working Group. Two authors assessed the risk of bias and extracted data on fractures, adverse events, bone turnover markers (BTM), and bone mineral density (BMD).
RESULTS
Twelve trials from 6,652 records were included: nine compared zoledronate with placebo, two trials compared zoledronate with alendronate, and one trial compared zoledronate with ibandronate. Zoledronate reduced the incidence of fractures in osteoporotic [three years: morphometric vertebral fractures (relative risk, RR = 0.30 (95% confidence interval, CI: 0.24-0.38))] and osteopenic women [six years: morphometric vertebral fractures (RR = 0.39 (95%CI: 0.25-0.61))], increased incidence of post-dose symptoms [RR = 2.56 (95%CI: 1.80-3.65)], but not serious adverse events [RR = 0.97 (95%CI: 0.91-1.04)]. Zoledronate reduced BTM and increased BMD in osteoporotic and osteopenic women.
CONCLUSION
This review supports the efficacy and safety of zoledronate in postmenopausal women with osteopenia for six years and osteoporosis for three years.
PROSPERO REGISTRATION NUMBER
CRD42022309708, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=309708.
Topics: Female; Humans; Zoledronic Acid; Bone Density Conservation Agents; Postmenopause; Brazil; Osteoporosis; Fractures, Bone; Bone Density; Osteoporosis, Postmenopausal
PubMed: 37255065
DOI: 10.1590/1516-3180.2022.0480.R1.27032023 -
The Cochrane Database of Systematic... May 2023Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with... (Review)
Review
BACKGROUND
Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility. In people with beta-thalassaemia, osteoporosis represents an important cause of morbidity and is due to a number of factors. First, ineffective erythropoiesis causes bone marrow expansion, leading to reduced trabecular bone tissue with cortical thinning. Second, excessive iron loading causes endocrine dysfunction, leading to increased bone turnover. Lastly, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization. Treatments for osteoporosis in people with beta-thalassaemia include bisphosphonates (e.g. clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism). Denosumab, a fully human monoclonal antibody, inhibits bone resorption and increases bone mineral density (BMD). Finally, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption, thus contributing to a net gain in BMD, increased bone strength, and reduced fracture risk. This is an update of a previously published Cochrane Review.
OBJECTIVES
To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of most recent search: 4 August 2022.
SELECTION CRITERIA
Randomized controlled trials (RCTs) in people with beta-thalassaemia with: a BMD Z score below -2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and premenopausal females aged over 15 years; or a BMD T score below -2.5 SDs for postmenopausal females and males aged over 50 years.
DATA COLLECTION AND ANALYSIS
Two review authors assessed the eligibility and risk of bias of the included RCTs, and extracted and analysed data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included six RCTs (298 participants). Active interventions included bisphosphonates (3 trials, 169 participants), zinc supplementation (1 trial, 42 participants), denosumab (1 trial, 63 participants), and strontium ranelate (1 trial, 24 participants). The certainty of the evidence ranged from moderate to very low and was downgraded mainly due to concerns surrounding imprecision (low participant numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding. Bisphosphonates versus placebo or no treatment Two RCTs compared bisphosphonates to placebo or no treatment. After two years, one trial (25 participants) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95% confidence interval (CI) 0.22 to 0.58) and the lumbar spine (MD 0.14, 95% CI 0.05 to 0.23). One trial (118 participants) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at six and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only. All results were of very low-certainty. There were no major adverse effects of treatment. Participants in the neridronate group reported less back pain; we considered this representative of improved quality of life (QoL), though the certainty of the evidence was very low. One participant in the neridronate trial (116 participants) sustained multiple fractures as a result of a traffic accident. No trials reported BMD at the wrist or mobility. Different doses of bisphosphonate compared One 12-month trial (26 participants) assessed different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favouring the 60 mg dose at the lumbar spine (MD 0.43, 95% CI 0.10 to 0.76) and forearm (MD 0.87, 95% CI 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment. Zinc versus placebo One trial (42 participants) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95% CI 0.10 to 0.20; 37 participants) and 18 months (MD 0.34, 95% CI 0.28 to 0.40; 32 participants); the same was true for BMD at the hip after 12 months (MD 0.15, 95% CI 0.11 to 0.19; 37 participants) and 18 months (MD 0.26, 95% CI 0.21 to 0.31; 32 participants). The evidence for these results was of moderate certainty. The trial did not report BMD at the wrist, fracture incidence, mobility, QoL, or adverse effects of treatment. Denosumab versus placebo Based on one trial (63 participants), we are unsure about the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence). This trial did not report fracture incidence, mobility, QoL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analogue scale in the denosumab group after 12 months of treatment compared to placebo (MD -2.40 cm, 95% CI -3.80 to -1.00). Strontium ranelate One trial (24 participants) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence). This trial also found a reduction in back pain measured on a visual analogue scale after 24 months in the strontium ranelate group compared to the placebo group (MD -0.70 cm (95% CI -1.30 to -0.10); we considered this measure representative of improved quality of life.
AUTHORS' CONCLUSIONS
Bisphosphonates may increase BMD at the femoral neck, lumbar spine, and forearm compared to placebo after two years' therapy. Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months. Denosumab may make little or no difference to BMD, and we are uncertain about the effect of strontium on BMD. We recommend further long-term RCTs on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia-associated osteoporosis.
Topics: Adult; Child; Female; Male; Humans; Middle Aged; beta-Thalassemia; Alendronate; Pamidronate; Clodronic Acid; Denosumab; Osteoporosis; Diphosphonates; Fractures, Bone
PubMed: 37159055
DOI: 10.1002/14651858.CD010429.pub3 -
Frontiers in Pharmacology 2024Several medications have been used for glucocorticoids-induced osteoporosis (GIO). However, the best therapeutic option for GIO is still controversial. A Bayesian...
Several medications have been used for glucocorticoids-induced osteoporosis (GIO). However, the best therapeutic option for GIO is still controversial. A Bayesian network meta-analysis was conducted to compare the efficacy and safety of denosumab, teriparatide and bisphosphonates for patients with GIO. Relevant randomized controlled trials published in PubMed, Embase, Cochrane Library and ClinicalTrials.gov up to August 2023 were searched. The following efficiency and safety outcomes were extracted for comparison: bone mineral density (BMD) percentage changes in lumbar spine, femur neck and total hip, and incidences of adverse events (AEs), serious adverse events (SAEs), vertebrae and non-vertebrae fracture. Bayesian random effects models were used for multiple treatment comparisons. 11 eligible RCTs involving 2,877 patients were identified. All the six medications including alendronate, risedronate, etidronate, zoledronate, teriparatide, and denosumab and were effective in increasing BMD. Teriparatide and denosumab were more effective in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. Alendronate and denosumab were more effective in improving total hip BMD. Alendronate and teriparatide had the lowest incidences of AEs and SAEs. Teriparatide denosumab and the bisphosphonates are all effective in improving BMD for GIO patients. Based on this network meta-analysis, teriparatide and denosumab have higher efficiency in improving lumbar spine and femur neck BMD, and reducing vertebrae fracture. 10.17605/OSF.IO/2G8YA, identifier CRD42023456305.
PubMed: 38313307
DOI: 10.3389/fphar.2024.1336075 -
Journal of Bone and Mineral Research :... Nov 2022Both medical and surgical therapy represent potential management options for patients with asymptomatic primary hyperparathyroidism (PHPT). Because uncertainty remains... (Meta-Analysis)
Meta-Analysis
The Efficacy and Safety of Medical and Surgical Therapy in Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Both medical and surgical therapy represent potential management options for patients with asymptomatic primary hyperparathyroidism (PHPT). Because uncertainty remains regarding both medical and surgical therapy, this systematic review addresses the efficacy and safety of medical therapy in asymptomatic patients or symptomatic patients who decline surgery and surgery in asymptomatic patients. We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed from inception to December 2020, and included randomized controlled trials in patients with PHPT that compared nonsurgical management with medical therapy versus without medical therapy and surgery versus no surgery in patients with asymptomatic PHPT. For surgical complications we included observational studies. Paired reviewers addressed eligibility, assessed risk of bias, and abstracted data for patient-important outcomes. We conducted random-effects meta-analyses to pool relative risks and mean differences with 95% confidence intervals and used Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to assess quality of evidence for each outcome. For medical therapy, 11 trials reported in 12 publications including 438 patients proved eligible: three addressed alendronate, one denosumab, three cinacalcet, two vitamin D, and two estrogen therapy. Alendronate, denosumab, vitamin D, and estrogen therapy all increased bone density. Cinacalcet probably reduced serum calcium and parathyroid hormone (PTH) levels. Cinacalcet and vitamin D may have a small or no increase in overall adverse events. Very-low-quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab. The trials also provided low-quality evidence for increased bleeding and mastalgia with estrogen therapy. For surgery, six trials presented in 12 reports including 441 patients proved eligible. Surgery achieved biochemical cure in 96.1% (high quality). We found no convincing evidence supporting an impact of surgery on fracture, quality of life, occurrence of kidney stones, and renal function, but the evidence proved low or very low quality. Surgery was associated with an increase in bone mineral density. For patients with symptomatic and asymptomatic PHPT, who are not candidates for parathyroid surgery, cinacalcet probably reduced serum calcium and PTH levels; anti-resorptives increased bone density. For patients with asymptomatic PHPT, surgery usually achieves biochemical cure. These results can help to inform patients and clinicians regarding use of medical therapy and surgery in PHPT. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Cinacalcet; Hyperparathyroidism, Primary; Alendronate; Calcium; Quality of Life; Denosumab; Randomized Controlled Trials as Topic; Parathyroid Hormone; Vitamin D; Estrogens
PubMed: 36053960
DOI: 10.1002/jbmr.4685 -
Systematic Reviews Mar 2023To inform recommendations by the Canadian Task Force on Preventive Health Care, we reviewed evidence on the benefits, harms, and acceptability of screening and... (Meta-Analysis)
Meta-Analysis
Screening for the primary prevention of fragility fractures among adults aged 40 years and older in primary care: systematic reviews of the effects and acceptability of screening and treatment, and the accuracy of risk prediction tools.
BACKGROUND
To inform recommendations by the Canadian Task Force on Preventive Health Care, we reviewed evidence on the benefits, harms, and acceptability of screening and treatment, and on the accuracy of risk prediction tools for the primary prevention of fragility fractures among adults aged 40 years and older in primary care.
METHODS
For screening effectiveness, accuracy of risk prediction tools, and treatment benefits, our search methods involved integrating studies published up to 2016 from an existing systematic review. Then, to locate more recent studies and any evidence relating to acceptability and treatment harms, we searched online databases (2016 to April 4, 2022 [screening] or to June 1, 2021 [predictive accuracy]; 1995 to June 1, 2021, for acceptability; 2016 to March 2, 2020, for treatment benefits; 2015 to June 24, 2020, for treatment harms), trial registries and gray literature, and hand-searched reviews, guidelines, and the included studies. Two reviewers selected studies, extracted results, and appraised risk of bias, with disagreements resolved by consensus or a third reviewer. The overview of reviews on treatment harms relied on one reviewer, with verification of data by another reviewer to correct errors and omissions. When appropriate, study results were pooled using random effects meta-analysis; otherwise, findings were described narratively. Evidence certainty was rated according to the GRADE approach.
RESULTS
We included 4 randomized controlled trials (RCTs) and 1 controlled clinical trial (CCT) for the benefits and harms of screening, 1 RCT for comparative benefits and harms of different screening strategies, 32 validation cohort studies for the calibration of risk prediction tools (26 of these reporting on the Fracture Risk Assessment Tool without [i.e., clinical FRAX], or with the inclusion of bone mineral density (BMD) results [i.e., FRAX + BMD]), 27 RCTs for the benefits of treatment, 10 systematic reviews for the harms of treatment, and 12 studies for the acceptability of screening or initiating treatment. In females aged 65 years and older who are willing to independently complete a mailed fracture risk questionnaire (referred to as "selected population"), 2-step screening using a risk assessment tool with or without measurement of BMD probably (moderate certainty) reduces the risk of hip fractures (3 RCTs and 1 CCT, n = 43,736, absolute risk reduction [ARD] = 6.2 fewer in 1000, 95% CI 9.0-2.8 fewer, number needed to screen [NNS] = 161) and clinical fragility fractures (3 RCTs, n = 42,009, ARD = 5.9 fewer in 1000, 95% CI 10.9-0.8 fewer, NNS = 169). It probably does not reduce all-cause mortality (2 RCTs and 1 CCT, n = 26,511, ARD = no difference in 1000, 95% CI 7.1 fewer to 5.3 more) and may (low certainty) not affect health-related quality of life. Benefits for fracture outcomes were not replicated in an offer-to-screen population where the rate of response to mailed screening questionnaires was low. For females aged 68-80 years, population screening may not reduce the risk of hip fractures (1 RCT, n = 34,229, ARD = 0.3 fewer in 1000, 95% CI 4.2 fewer to 3.9 more) or clinical fragility fractures (1 RCT, n = 34,229, ARD = 1.0 fewer in 1000, 95% CI 8.0 fewer to 6.0 more) over 5 years of follow-up. The evidence for serious adverse events among all patients and for all outcomes among males and younger females (<65 years) is very uncertain. We defined overdiagnosis as the identification of high risk in individuals who, if not screened, would never have known that they were at risk and would never have experienced a fragility fracture. This was not directly reported in any of the trials. Estimates using data available in the trials suggest that among "selected" females offered screening, 12% of those meeting age-specific treatment thresholds based on clinical FRAX 10-year hip fracture risk, and 19% of those meeting thresholds based on clinical FRAX 10-year major osteoporotic fracture risk, may be overdiagnosed as being at high risk of fracture. Of those identified as being at high clinical FRAX 10-year hip fracture risk and who were referred for BMD assessment, 24% may be overdiagnosed. One RCT (n = 9268) provided evidence comparing 1-step to 2-step screening among postmenopausal females, but the evidence from this trial was very uncertain. For the calibration of risk prediction tools, evidence from three Canadian studies (n = 67,611) without serious risk of bias concerns indicates that clinical FRAX-Canada may be well calibrated for the 10-year prediction of hip fractures (observed-to-expected fracture ratio [O:E] = 1.13, 95% CI 0.74-1.72, I = 89.2%), and is probably well calibrated for the 10-year prediction of clinical fragility fractures (O:E = 1.10, 95% CI 1.01-1.20, I = 50.4%), both leading to some underestimation of the observed risk. Data from these same studies (n = 61,156) showed that FRAX-Canada with BMD may perform poorly to estimate 10-year hip fracture risk (O:E = 1.31, 95% CI 0.91-2.13, I = 92.7%), but is probably well calibrated for the 10-year prediction of clinical fragility fractures, with some underestimation of the observed risk (O:E 1.16, 95% CI 1.12-1.20, I = 0%). The Canadian Association of Radiologists and Osteoporosis Canada Risk Assessment (CAROC) tool may be well calibrated to predict a category of risk for 10-year clinical fractures (low, moderate, or high risk; 1 study, n = 34,060). The evidence for most other tools was limited, or in the case of FRAX tools calibrated for countries other than Canada, very uncertain due to serious risk of bias concerns and large inconsistency in findings across studies. Postmenopausal females in a primary prevention population defined as <50% prevalence of prior fragility fracture (median 16.9%, range 0 to 48% when reported in the trials) and at risk of fragility fracture, treatment with bisphosphonates as a class (median 2 years, range 1-6 years) probably reduces the risk of clinical fragility fractures (19 RCTs, n = 22,482, ARD = 11.1 fewer in 1000, 95% CI 15.0-6.6 fewer, [number needed to treat for an additional beneficial outcome] NNT = 90), and may reduce the risk of hip fractures (14 RCTs, n = 21,038, ARD = 2.9 fewer in 1000, 95% CI 4.6-0.9 fewer, NNT = 345) and clinical vertebral fractures (11 RCTs, n = 8921, ARD = 10.0 fewer in 1000, 95% CI 14.0-3.9 fewer, NNT = 100); it may not reduce all-cause mortality. There is low certainty evidence of little-to-no reduction in hip fractures with any individual bisphosphonate, but all provided evidence of decreased risk of clinical fragility fractures (moderate certainty for alendronate [NNT=68] and zoledronic acid [NNT=50], low certainty for risedronate [NNT=128]) among postmenopausal females. Evidence for an impact on risk of clinical vertebral fractures is very uncertain for alendronate and risedronate; zoledronic acid may reduce the risk of this outcome (4 RCTs, n = 2367, ARD = 18.7 fewer in 1000, 95% CI 25.6-6.6 fewer, NNT = 54) for postmenopausal females. Denosumab probably reduces the risk of clinical fragility fractures (6 RCTs, n = 9473, ARD = 9.1 fewer in 1000, 95% CI 12.1-5.6 fewer, NNT = 110) and clinical vertebral fractures (4 RCTs, n = 8639, ARD = 16.0 fewer in 1000, 95% CI 18.6-12.1 fewer, NNT=62), but may make little-to-no difference in the risk of hip fractures among postmenopausal females. Denosumab probably makes little-to-no difference in the risk of all-cause mortality or health-related quality of life among postmenopausal females. Evidence in males is limited to two trials (1 zoledronic acid, 1 denosumab); in this population, zoledronic acid may make little-to-no difference in the risk of hip or clinical fragility fractures, and evidence for all-cause mortality is very uncertain. The evidence for treatment with denosumab in males is very uncertain for all fracture outcomes (hip, clinical fragility, clinical vertebral) and all-cause mortality. There is moderate certainty evidence that treatment causes a small number of patients to experience a non-serious adverse event, notably non-serious gastrointestinal events (e.g., abdominal pain, reflux) with alendronate (50 RCTs, n = 22,549, ARD = 16.3 more in 1000, 95% CI 2.4-31.3 more, [number needed to treat for an additional harmful outcome] NNH = 61) but not with risedronate; influenza-like symptoms with zoledronic acid (5 RCTs, n = 10,695, ARD = 142.5 more in 1000, 95% CI 105.5-188.5 more, NNH = 7); and non-serious gastrointestinal adverse events (3 RCTs, n = 8454, ARD = 64.5 more in 1000, 95% CI 26.4-13.3 more, NNH = 16), dermatologic adverse events (3 RCTs, n = 8454, ARD = 15.6 more in 1000, 95% CI 7.6-27.0 more, NNH = 64), and infections (any severity; 4 RCTs, n = 8691, ARD = 1.8 more in 1000, 95% CI 0.1-4.0 more, NNH = 556) with denosumab. For serious adverse events overall and specific to stroke and myocardial infarction, treatment with bisphosphonates probably makes little-to-no difference; evidence for other specific serious harms was less certain or not available. There was low certainty evidence for an increased risk for the rare occurrence of atypical femoral fractures (0.06 to 0.08 more in 1000) and osteonecrosis of the jaw (0.22 more in 1000) with bisphosphonates (most evidence for alendronate). The evidence for these rare outcomes and for rebound fractures with denosumab was very uncertain. Younger (lower risk) females have high willingness to be screened. A minority of postmenopausal females at increased risk for fracture may accept treatment. Further, there is large heterogeneity in the level of risk at which patients may be accepting of initiating treatment, and treatment effects appear to be overestimated.
CONCLUSION
An offer of 2-step screening with risk assessment and BMD measurement to selected postmenopausal females with low prevalence of prior fracture probably results in a small reduction in the risk of clinical fragility fracture and hip fracture compared to no screening. These findings were most applicable to the use of clinical FRAX for risk assessment and were not replicated in the offer-to-screen population where the rate of response to mailed screening questionnaires was low. Limited direct evidence on harms of screening were available; using study data to provide estimates, there may be a moderate degree of overdiagnosis of high risk for fracture to consider. The evidence for younger females and males is very limited. The benefits of screening and treatment need to be weighed against the potential for harm; patient views on the acceptability of treatment are highly variable.
SYSTEMATIC REVIEW REGISTRATION
International Prospective Register of Systematic Reviews (PROSPERO): CRD42019123767.
Topics: Adult; Female; Humans; Male; Middle Aged; Alendronate; Canada; Denosumab; Diphosphonates; Hip Fractures; Osteoporotic Fractures; Primary Health Care; Primary Prevention; Risedronic Acid; Systematic Reviews as Topic; Zoledronic Acid
PubMed: 36945065
DOI: 10.1186/s13643-023-02181-w -
JBMR Plus Jun 2023Most women do not qualify for pharmacologic osteoporosis treatment until more than a decade after menopause, by which time they will have lost up to 30% of their bone...
Most women do not qualify for pharmacologic osteoporosis treatment until more than a decade after menopause, by which time they will have lost up to 30% of their bone mass and may have already sustained fractures. Short or intermittent courses of bisphosphonate therapy, initiated around the time of menopause, might prevent excessive bone loss and lower long-term fracture risk. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effects of nitrogen-containing bisphosphonates on fracture incidence, bone mineral density (BMD), and bone turnover markers in early menopausal women (ie, perimenopausal or <5 years postmenopausal) over ≥12 months. Medline, Embase, CENTRAL, and CINAHL were searched in July 2022. Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool. Random effect meta-analysis was undertaken using RevMan v5.3. In total, 12 trials were included ( = 1722 women); five evaluated alendronate, three risedronate, three ibandronate, and one zoledronate. Four were at low risk of bias; eight raised some concerns. Fractures were infrequent in the three studies that reported them. Compared with placebo, bisphosphonates improved BMD over 12 months (mean percentage difference, 95% confidence interval [CI]) at the spine (4.32%, 95% CI, 3.10%-5.54%, < 0.0001, = 8 studies), the femoral neck (2.56%, 95% CI, 1.85%-3.27%, = 0.001, = 6 studies), and the total hip (1.22%, 95% CI 0.16%-2.28%, = 0.002, = 4 studies). Over treatment durations of 24 to 72 months, bisphosphonates improved BMD at the spine (5.81%, 95% CI 4.71%-6.91%, < 0.0001, = 8 studies), femoral neck (3.89%, 95% CI 2.73%-5.05%, = 0.0001, = 5 studies) and total hip (4.09%, 95% CI 2.81%-5.37%, < 0.0001, = 4 studies). Bisphosphonates reduced urinary N-telopeptide (-52.2%, 95% CI -60.3% to -44.2%, < 0.00001, = 3 studies) and bone-specific alkaline phosphatase (-34.2%, 95% CI -42.6% to -25.8%, < 0.00001, = 4 studies) more than placebo at 12 months. This systematic review and meta-analysis shows that bisphosphonates improve BMD and lower bone turnover markers in early menopause, warranting further investigation of these agents for osteoporosis prevention. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37283657
DOI: 10.1002/jbm4.10748 -
Frontiers in Endocrinology 2023Primary hyperparathyroidism (PHPT) is characterized by increased bone remodeling and hypercalcemia. Parathyroidectomy (PTX), the current standard of care, is recommended... (Meta-Analysis)
Meta-Analysis
Efficacy of antiresorptive agents bisphosphonates and denosumab in mitigating hypercalcemia and bone loss in primary hyperparathyroidism: A systematic review and meta-analysis.
PURPOSE
Primary hyperparathyroidism (PHPT) is characterized by increased bone remodeling and hypercalcemia. Parathyroidectomy (PTX), the current standard of care, is recommended in all symptomatic and some groups of asymptomatic patients. Anti-resorptive therapies (bisphosphonates and denosumab) have been used in patients where PTX is refused or contraindicated. In this meta-analysis, we investigated the effectiveness of anti-resorptives in preventing/treating PHPT-induced bone loss and mitigating hypercalcemia.
METHOD
PubMed, Scopus, and Cochrane Library databases were searched for articles with keywords containing PHPT, bisphosphonates, and denosumab in various combinations. We extracted and tabulated areal BMD (aBMD), serum mineral, and bone turnover parameters from the qualified studies and used comprehensive meta-analysis software for analysis.
RESULTS
Of the 1,914 articles screened, 13 were eligible for meta-analysis. In the pooled analysis, 12 months of anti-resoptives (bisphosphonates and denosumab) therapy significantly increased aBMD at the lumbar spine (Standard difference in means (SDM)=0.447, 95% CI=0.230 to 0.664, p=0.0001), femoral neck (SDM=0.270, 95% CI=0.049 to 0.491, p=0.017) and increased serum PTH (SDM=0.489, 95% CI=0.139 to 0.839, p=0.006), and decreased serum calcium (SDM=-0.545, 95% CI=-0.937 to -0.154, p=0.006) compared with baseline. 12 months of bisphosphonate use significantly increased aBMD only at the lumbar spine (SDM=0.330, 95% CI=0.088 to 0.571, p=0.007) with a significant increased in serum PTH levels (SDM=0.546, 95% CI= 0.162 to 0.930, p=0.005), and a decreased in serum calcium (SDM=-0.608, 95% CI=-1.048 to -0.169, p=0.007) and bone-turnover markers (BTMs) compared with baseline. Denosumab use for 12 months significantly increased aBMD at both the lumbar spine (SDM=0.828, 95% CI=0.378 to 1.278, p=0.0001) and femur neck (SDM=0.575, 95% CI=0.135 to 1.015, p=0.010) compared with baseline. Mean lumbar spine aBMD (SDM=0.350, 95% CI=0.041 to 0.659, p=0.027) and serum PTH (SDM=0.602, 95% CI= 0.145 to 1.059, p=0.010) were significantly increased after 12 months of alendronate use compared with placebo. When compared with baseline, alendronate significantly decreased BTMs after 12 months and increased aBMD without altering the PTH and calcium levels after 24 months.
CONCLUSION
Anti-resorptives are effective in mitigating bone loss and hypercalcemia in PHPT while maintaining or increasing aBMD. PTX reversed all changes in PHPT and normalized PTH levels.
Topics: Humans; Bone Density Conservation Agents; Diphosphonates; Alendronate; Denosumab; Hypercalcemia; Calcium; Hyperparathyroidism, Primary; Bone Density; Parathyroid Hormone; Bone Diseases, Metabolic; Lumbar Vertebrae
PubMed: 36817591
DOI: 10.3389/fendo.2023.1098841 -
Journal of Orthopaedic Surgery and... Aug 2021Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density.
METHODS
The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis.
RESULTS
Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD -0.220; SE 3.379), followed by pamidronate (SMD -5.662; SE 2.635) and zoledronate (SMD -10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD -0.256; SE 3.184), followed by alendronate (SMD -17.032; SE 3.191) and ibandronate (SMD -17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD -16.030; SE 1.702) and ibandronate (SMD -17.000; SE 1.679).
CONCLUSION
Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD.
LEVEL OF EVIDENCE
Level I, Bayesian network meta-analysis of RCTs.
Topics: Alendronate; Bayes Theorem; Bone Density; Bone Density Conservation Agents; Denosumab; Female; Humans; Ibandronic Acid; Network Meta-Analysis; Osteoporosis; Osteoporosis, Postmenopausal; Pharmaceutical Preparations
PubMed: 34452621
DOI: 10.1186/s13018-021-02678-x