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Osteoporosis International : a Journal... Jun 2022To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an...
UNLABELLED
To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence.
INTRODUCTION
Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively).
METHODS
We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available).
RESULTS
With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab).
CONCLUSION
In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.
Topics: Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Denosumab; Female; Humans; Osteoporosis, Postmenopausal; Teriparatide
PubMed: 35165774
DOI: 10.1007/s00198-021-06174-0 -
Journal of Bone and Mineral Research :... Aug 2022Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (-28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function. © 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: Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Female; Femur Neck; Fractures, Bone; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause; Renal Insufficiency, Chronic
PubMed: 35466448
DOI: 10.1002/jbmr.4563 -
Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.Journal of Bone and Mineral Research :... Jan 2020Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines....
Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.
Topics: Alendronate; Bone Density Conservation Agents; Consensus; Diphosphonates; Humans; Osteoporosis; Osteoporotic Fractures; Risedronic Acid
PubMed: 31538675
DOI: 10.1002/jbmr.3877 -
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 -
Women's Health (London, England) 2022Increased understanding of the Wnt signaling pathway has led to the development of romosozumab, one of the most potent osteoanabolic agents to date for osteoporosis... (Review)
Review
Increased understanding of the Wnt signaling pathway has led to the development of romosozumab, one of the most potent osteoanabolic agents to date for osteoporosis treatment. Romosozumab is a monoclonal antibody that inhibits sclerostin, a natural inhibitor of the Wnt signaling pathway. Romosozumab, by inhibiting sclerostin activates the Wnt signaling pathway, leading to increased bone formation and decreased bone resorption. The pivotal ARCH and FRAME studies established romosozumab's fracture reduction efficacy. Romosozumab was superior to alendronate in fracture reduction and bone mineral density gain in the ARCH study. Romosozumab treatment should be followed sequentially with a potent antiresorptive agent. The antifracture efficacy gained from romosozumab is maintained or improved after transitioning to an antiresorptive agent. As one of the most potent osteoanabolic agents, the introduction of romosozumab has significantly increased our ability to treat osteoporosis. Studies have provided important information on using romosozumab with other osteoporosis medications to optimize osteoporosis treatment. Romosozumab used before antiresorptive medications is associated with more significant bone mineral density increases than when an antiresorptive agent is used before romosozumab. Romosozumab is recommended for osteoporosis treatment in patients at very high risk for fracture with low cardiovascular risk. Romosozumab is generally well tolerated, with 4%-5% of patients having injection site reactions. The ARCH trial showed a higher risk of cardiovascular events in patients receiving romosozumab. Romosozumab carries a black box warning that romosozumab should not be initiated in patients with myocardial infarction or stroke in the preceding year. However, the information on romosozumab and increased cardiovascular risk is conflicting. The risk of cardiovascular disease with romosozumab is unclear. While romosozumab has demonstrated significant osteoanabolic effect and antifracture efficacy and will benefit high fracture risk patients, further studies are needed to investigate the cardiovascular safety of romosozumab.
Topics: Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Cardiovascular Diseases; Female; Heart Disease Risk Factors; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Risk Factors
PubMed: 36154750
DOI: 10.1177/17455057221125577 -
Bone Aug 2020Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption...
Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption and obtained a patent covering its use in the treatment of osteoporosis and other disorders of excessive bone resorption in the 1980s. Merck licensed alendronate in 1988 and its pharmaceutical chemists reformulated it as a sodium salt with good solubility in a tablet that reduced its potential for esophageal irritation. Clinical trials proved that it reduced bone turnover, increased BMD and reduced the risk of vertebral fractures in postmenopausal osteoporotic women. Merck sponsored a large clinical trials that won FDA approval for treatment of osteoporosis in postmenopausal women and showed that it reduced the risk of spine and hip fractures. Its approval in the US in 1995 spurred sales of bone densitometers and BMD testing to screen for low bone mineral density and identify osteoporosis. Bone mass measurement was supported by medical society guidelines and reimbursement by Medicare and other insurers in the USA. A 70 mg weekly instead of 10 mg daily dose of alendronate produced the same effect on BMD and biochemical markers of bone remodelling with greater convenience and reduced potential for upper GI adverse events. Consequently, by 2006, about 30 million prescriptions for alendronate were written annually in the U.S. for about 15% of postmenopausal women in the U.S. Thereafter, publicity about rare but concerning atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) along with the expiry of Merck's patent (in 2008) and cessation of their promotion of alendronate, and a decline in use of densitometry led to a steady slide in its use even among patients for whom the benefits of alendronate far outweigh its potential risks. Nevertheless, in 25 years since its regulatory approval, alendronate has undoubtedly prevented millions of fractures world-wide.
Topics: Aged; Alendronate; Bone Density; Bone Remodeling; Female; Humans; Medicare; Osteoporosis, Postmenopausal; United States
PubMed: 32437874
DOI: 10.1016/j.bone.2020.115411 -
Journal of Bone and Mineral Research :... Nov 2021The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214)... (Clinical Trial)
Clinical Trial
Romosozumab improves lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women: results from the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial.
The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 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: Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Female; Humans; Lumbar Vertebrae; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause
PubMed: 34190361
DOI: 10.1002/jbmr.4409 -
Osteoporosis International : a Journal... Mar 2023A retrospective study of 121 patients who stopped denosumab (Dmab) then received no treatment (NT), risedronate (RIS), alendronate (ALN), or zoledronic acid (ZOL). Bone...
UNLABELLED
A retrospective study of 121 patients who stopped denosumab (Dmab) then received no treatment (NT), risedronate (RIS), alendronate (ALN), or zoledronic acid (ZOL). Bone density (spine and hip) during and after Dmab discontinuation was measured. Treatment with ALN or ZOL, not NT and RIS, mitigated BMD loss after Dmab discontinuation.
INTRODUCTION
Denosumab (Dmab) discontinuation is associated with bone loss and multiple vertebral fractures. The purpose was to compare bone mineral density (BMD) change in patients following Dmab discontinuation with no subsequent treatment (NT) and three bisphosphonate (BP) treatments: risedronate (RIS), alendronate (ALN), and zoledronic acid (ZOL).
METHODS
In a review of 121 patients aged 71.2 ± 8.1 years, discontinuing Dmab (mean 5.4 doses), 33 received NT and 88 received BP (22 RIS; 34 ALN; 32 ZOL). BMD change after 1 year was compared between groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Risk factors for bone loss after Dmab discontinuation were compared between groups and incidence of vertebral fractures was determined.
RESULTS
Following Dmab discontinuation, LS mean change (g/cm; 95% CI) was for NT: - 0.041 (- 0.062 to - 0.021); RIS: - 0.035 (- 0.052 to - 0.017); ALN: - 0.005 (- 0.020 to 0.009); and ZOL: - 0.009 (- 0.025 to 0.008). Differences in LS were found between NT and ALN (p = 0.015), and NT and ZOL (p=0.037), but not between NT and RIS. The only significant difference in TH was found between NT and ZOL (p 0.034) with no group differences in FN. BMD gains during Dmab treatment were associated with BMD loss after Dmab discontinuation. In a subset, discontinuation after Dmab treatment (> 5 doses) followed by ALN (n = 22) and ZOL (n = 11) showed no difference in BMD. Five of 7 vertebral fractures occurred after Dmab discontinuation in NT.
CONCLUSION
Subsequent treatment with ALN or ZOL but not NT and RIS mitigates BMD loss after Dmab discontinuation.
Topics: Female; Humans; Alendronate; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Denosumab; Diphosphonates; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Retrospective Studies; Risedronic Acid; Spinal Fractures; Zoledronic Acid
PubMed: 36602607
DOI: 10.1007/s00198-022-06648-9 -
The Journal of Allergy and Clinical... Sep 2019
Topics: Adrenergic beta-Antagonists; Alendronate; Bronchodilator Agents; Lung
PubMed: 31300279
DOI: 10.1016/j.jaci.2019.05.029