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Effect of antiresorptive therapy on aromatase inhibitor induced bone loss in postmenopausal women with early-stage breast cancer: A systematic review and meta-analysis of randomized controlled trials.
Bassatne, A, Bou Khalil, A, Chakhtoura, M, Arabi, A, Van Poznak, C, El-Hajj Fuleihan, G
Metabolism: clinical and experimental. 2022;:154962
Abstract
BACKGROUND Aromatase inhibitors (AIs) are routinely used to treat postmenopausal women with early-stage breast cancer. Although AIs improve breast cancer outcomes, they increase the risk of osteoporosis and fractures. This systematic review and meta-analysis assesses the effect of antiresorptive drugs on AI induced bone loss in postmenopausal women with non-metastatic breast cancer. METHODS We searched four databases until November 4th 2020. We included Randomized controlled trials (RCTs) of antiresorptive drugs in postmenopausal women with breast cancer treated with AI. Two authors screened studies, extracted data and assessed the risk of bias independently and in duplicate. RESULTS We identified 14 RCTs: 7 on zoledronic acid, 6 on oral bisphosphonates and 1 on denosumab. The mean difference in bone mineral density (BMD) was 5% at the lumbar spine and 4% at the total hip, at 12 months, favoring zoledronic acid compared to control. The certainty of the evidence was low for lumbar spine and moderate for total hip BMD. Similarly, the mean difference was 3% at the lumbar spine and 2% at the total hip, favoring oral bisphosphonates with moderate certainty. The mean difference was 6% at the lumbar spine, and 4% at the total hip BMD favoring denosumab compared to placebo. In addition, zoledronic acid resulted in a mean difference in bone turnover marker levels of -35-41%, and the relarive risk for morphometric vertebral fractures was 0.7 [0.3-1.4], compared to control. Denosumab reduced fracture incidence by 50% compared to placebo. CONCLUSION Evidence suggests a protective effect of antiresorptive drugs on BMD and bone turnover markers in postmenopausal women with non-metastatic breast cancer on AI. However, data on fracture risk reduction remains unclear.
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Endocrinology of bone mineralization: An update.
Jannin, A, Kerlan, V, Desailloud, R
Annales d'endocrinologie. 2022;(1):46-53
Abstract
Throughout the world, millions of people suffer from fragilizing osteopathies such as osteomalacia and osteoporosis. Osteomalacia is a rare disorder, corresponding to mineralization abnormalities in adult bone, as opposed to rickets in children. Renal phosphate loss and hypophosphatasia are the main causes of vitamin-resistant osteomalacia. Diagnosis is based on clinical history, phosphocalcic metabolism assessment and, if necessary, molecular characterization, and must be rapid in order to initiate the most appropriate treatment and consider new treatments such as burosumab if necessary. Osteoporosis is characterized by reduced bone mass and strength, which increases the risk of fragility fracture. Fracture-related burden is expected to increase over the coming decades linked to the aging of population and a treatment gap. In order to reduce this treatment gap, it is important to develop two strategies: improvement of screening and of treatment. Systematic screening using the FRAX® fracture risk assessment tool could be useful to increase anti-osteoporosis medical treatment and reduce fracture rates. The question of treatment sequencing in osteoporosis is another challenge, notably after denosumab cessation, complicated by a decrease in bone mineral density and increased risk of fracture. New treatments are also available, including romosozumab, a humanized monoclonal antibody, which promotes bone formation and inhibits bone resorption by inhibiting sclerostin. Romosozumab is approved in several countries, including France, for treating severe osteoporosis in postmenopausal women at high risk of fracture and free of cardiovascular comorbidity. Endocrinologists need to be aware of these fragilizing osteopathies in order to improve both diagnosis and treatment.
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Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.
Pawade, TA, Doris, MK, Bing, R, White, AC, Forsyth, L, Evans, E, Graham, C, Williams, MC, van Beek, EJR, Fletcher, A, et al
Circulation. 2021;(25):2418-2427
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Abstract
BACKGROUND Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. METHODS In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. RESULTS A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93-3.82 m/s]; aortic valve calcium score, 1152 AU [655-2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18-0.33 µg/L] to 0.11 µg/L [0.08-0.17 µg/L]) and alendronic acid (0.20 [0.14-0.28 µg/L] to 0.09 µg/L [0.08-0.13 µg/L]) but was unchanged with placebo (0.23 [0.17-0.30 µg/L] to 0.26 µg/L [0.16-0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198-804 AU] versus 354 AU [76-675 AU]; P=0.41) or alendronic acid and placebo (326 [138-813 AU] versus 354 AU [76-675 AU]; P=0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18F-sodium fluoride aortic valve uptake. CONCLUSIONS Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.
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2019 EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older.
Adams, J, Wilson, N, Hurkmans, E, Bakkers, M, Balážová, P, Baxter, M, Blavnsfeldt, AB, Briot, K, Chiari, C, Cooper, C, et al
Annals of the rheumatic diseases. 2021;(1):57-64
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Abstract
OBJECTIVE To establish European League Against Rheumatism (EULAR) points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older. METHODS Points to consider were developed in accordance with EULAR standard operating procedures for EULAR-endorsed recommendations, led by an international multidisciplinary task force, including patient research partners and different health professionals from 10 European countries. Level of evidence and strength of recommendation were determined for each point to consider, and the mean level of agreement among the task force members was calculated. RESULTS Two overarching principles and seven points to consider were formulated based on scientific evidence and the expert opinion of the task force. The two overarching principles focus on shared decisions between patients and non-physician health professionals and involvement of different non-physician health professionals in prevention and management of fragility fractures. Four points to consider relate to prevention: identification of patients at risk of fracture, fall risk evaluation, multicomponent interventions to prevent primary fracture and discouragement of smoking and overuse of alcohol. The remaining three focus on management of fragility fractures: exercise and nutritional interventions, the organisation and coordination of multidisciplinary services for post-fracture models of care and adherence to anti-osteoporosis medicines. The mean level of agreement among the task force for the overarching principles and the points to consider ranged between 8.4 and 9.6. CONCLUSION These first EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older serve to guide healthcare practice and education.
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Bone-modifying Agents (BMAs) in Breast Cancer.
Shapiro, CL
Clinical breast cancer. 2021;(5):e618-e630
Abstract
Bone-modifying agents (BMAs) are mainstays in breast cancer and prevent and treat osteoporosis in early-stage disease and reduce skeletal metastases complications in advanced disease. There is some evidence to support that BMA also prevents skeletal metastases and improves overall survival. Bone loss occurs with chemotherapy-induced ovarian failure, gonadotrophin-releasing hormone (GnRH) agonists, and aromatase inhibitors. In some women, the bone loss will be of sufficient magnitude to increase the risks of osteoporosis or fractures. Recommended steps in osteoporosis prevention or treatment include risk factor assessment, taking adequate amounts of calcium and vitamin D3, and periodic evaluations with dual-energy x-ray absorptiometry scanning. If clinically indicated by the T-scores and fracture-risk prediction algorithms treat with oral, IV bisphosphonates or subcutaneous denosumab (DEN). Zoledronic acid (ZA) or DEN reduces skeletal metastases complications, including pathological fracture, spinal cord compression, or the necessity for radiation or surgery to bone. Also, both of these drugs have the side-effect of osteonecrosis at a similar incidence. Monthly administration of ZA or DEN is standard, but several recent randomized trials show noninferiority between ZA monthly and every 3-month ZA. Every 3-month ZA is a new standard of care. Similar trials of the schedule of DEN are ongoing. ZA anticancer effect is only in postmenopausal women or premenopausal women rendered postmenopausal by GnRH agonists or bilateral oopherectomy. High-risk women, either postmenopausal or premenopausal, receiving GnRH/oopherctomy should consider adjuvant ZA. There are insufficient data to support DEN in this setting. Herein, this narrative review covers the mechanism of action of BMA, randomized clinical trials, and adverse events, both common and rare.
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Pharmacological prevention of fractures in patients undergoing glucocorticoid therapies: a systematic review and network meta-analysis.
Deng, J, Silver, Z, Huang, E, Zheng, E, Kavanagh, K, Wen, A, Cheng, W, Dobransky, J, Sanger, S, Grammatopoulos, G
Rheumatology (Oxford, England). 2021;(2):649-657
Abstract
OBJECTIVE To perform a network meta-analysis (NMA) on the efficacy of antiosteoporotic interventions in the prevention of vertebral and non-vertebral fractures in adult patients taking glucocorticoids (GCs). METHODS We performed NMAs based on a prospectively developed protocol. A librarian-assisted database search of MEDLINE, EMBASE, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials (CENTRAL) and Chinese databases was conducted for randomized controlled trials (RCTs) comparing antiosteoporotic interventions in adult patients taking GCs. Outcomes were vertebral and non-vertebral fracture incidences. RESULTS We included 56 RCTs containing 6479 eligible patients in our analysis. We found that alendronate and teriparatide were associated with decreased odds of both vertebral and non-vertebral fractures. Denosumab and risedronate were associated with decreased odds of vertebral fractures, while etidronate, ibandronate and alfacalcidol were associated with decreased odds of non-vertebral fractures. We observed low network heterogeneity as indicated by the I2 statistic, and we did not detect evidence of publication bias. All outcomes were based on a moderate quality of evidence according to GRADE. CONCLUSION Bisphosphonates, teriparatide and denosumab are associated with decreased odds of fracture in patients undergoing GC therapy. Vitamin D metabolites and analogues (e.g. alfacalcidol) may have greater anti-fracture efficacy compared with plain vitamin D. SYSTEMATIC REVIEW REGISTRATION The International Prospective Register of Systematic Reviews (PROSPERO)-CRD42019127073.
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Therapies for Preventing Bone Loss with Glucocorticoid Treatment.
Agarwal, A, Adachi, JD
Current osteoporosis reports. 2021;(1):34-39
Abstract
PURPOSE OF REVIEW We aim to critically review recent recommendations regarding preventative strategies for glucocorticoid-induced osteoporosis and provide a summary of key evidence regarding available interventions. RECENT FINDINGS Lifestyle optimization remains the hallmark of bone health preservation. Early initiation of anti-osteoporotic agents in the setting of glucocorticoid exposure is essential, guided by appropriate risk stratification. Recommendations for calcium and vitamin D intake optimization are well-supported across all risk strata. Bisphosphonates are the mainstay of pharmacological therapy. Newer agents such as denosumab and teriparatide have demonstrated comparative benefit in terms of incident fracture risk reduction and bone mineral density preservation, with comparable adverse events. With due consideration to cost, resource availability, and patient values and preferences, these agents may warrant use as the first-line agents in this setting. Glucocorticoid-induced osteoporosis remains preventable and warrants early and targeted evidence-based therapy.
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The use of bone turnover markers for monitoring the treatment of osteoporosis in postmenopausal females undergoing total knee arthroplasty: a prospective randomized study.
Ma, R, Wu, M, Li, Y, Wang, J, Yang, P, Chen, Y, Wang, W, Song, J, Wang, K
Journal of orthopaedic surgery and research. 2021;(1):195
Abstract
BACKGROUND Osteoporosis (OP) and osteoarthritis (OA) commonly coexist in postmenopausal females. The decrease in bone density and increase in bone resorption in postmenopausal females with OP may consequently affect the surgical outcome of total knee arthroplasty (TKA). However, clinicians often ignore monitoring the treatment of OP in the perioperative management of TKA. Bone turnover marker (BTM) can timely and accurately reflect bone metabolism to monitor the treatment of OP. The purpose of this study was to investigate the effect of BTM monitoring to guide the treatment of OP in postmenopausal females undergoing TKA. METHODS Postmenopausal females with OP who underwent primary unilateral TKA were randomly divided into two groups (monitoring group and control group), given oral medication (alendronate, calcitriol, and calcium), and followed for 1 year. In the monitoring group, serum BTMs (C-telopeptide of type I collagen (CTX-I), N-terminal propeptide of type I procollagen (PINP), and 25(OH)D) were assessed preoperatively and repeated postoperatively; alendronate was withdrawn when CTX-I and PINP reached the reference interval; and calcitriol and calcium were withdrawn when 25(OH)D reached the reference interval. In the control group, oral medication was implemented for a uniform duration of 3 months. During the 1-year follow-up, the mean maximum total point motion (MTPM) of the tibial component, bone mineral density (BMD), visual analog scale (VAS) score, range of motion, and Oxford Knee Score (OKS) score were obtained. RESULTS In the monitoring group, BTM monitoring prolonged the medication duration, but did not cause more adverse reactions than in the control group. The mean MTPM values at 6 m and 12 m in the monitoring group were lower than those in the control group, and the BMD at 12 m in the monitoring group was significantly higher than that in the control group. Patients in the monitoring group had lower VAS scores at 6 m and higher OKS scores at 6 m and 12 m than those in the control group. CONCLUSION In postmenopausal females with osteoporosis undergoing primary TKA, the application of BTM monitoring to guide the treatment of osteoporosis can enhance bone density, maintain prosthesis stability, and improve surgical outcome. TRIAL REGISTRATION ChiCTR ChiCTR-INR-17010495 . Registered on 22 January 2017.
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Effect of Vitamin D Supplementation on Vitamin D Level and Bone Mineral Density in Patients With Cirrhosis: A Randomized Clinical Trial.
Grover, I, Gunjan, D, Singh, N, Benjamin, J, Ramakrishnan, L, Pandey, RM, Sati, HC, Saraya, A
The American journal of gastroenterology. 2021;(10):2098-2104
Abstract
INTRODUCTION In patients with cirrhosis, highly prevalent vitamin D deficiency and low bone mineral density (BMD) increase the burden of disease, and role of vitamin D supplementation is not clear. So, our aim was to determine the effect of vitamin D supplementation on vitamin D level and BMD in patients with cirrhosis. METHODS Patients with cirrhosis (18-60 years) of any etiology were enrolled. We measured serum 25(OH)D, parathyroid hormone, thyroid-stimulating hormone, free T4, bone-specific alkaline phosphatase, insulin-like growth factor (IGF)-1, and health-related quality of life at entry and at 1 year; however, serum calcium was measured at 3-month interval. BMD was measured by dual-energy x-ray absorptiometry at lumbar spine and left hip neck at entry and after 1 year. Statistical analysis was performed according to intention-to-treat analysis. RESULTS Of 390 screened patients with cirrhosis, 164 participants (82 in each group) were randomized. There was significant increase in 25(OH)D levels in intervention group after 1 year (33.7 [24.3-45.7] ng/mL vs 23.1 [17-28.2] ng/mL; P < 0.001) when compared with placebo. The mean difference in BMD at lumbar spine and left hip neck was not significantly changed after 1 year of intervention with vitamin D between both groups. There was no significant change in both the groups in levels of calcium, thyroid-stimulating hormone, parathyroid hormone, free T4, IGF-1, and bone-specific alkaline phosphatase and quality of life. DISCUSSION Supplementation with vitamin D for 1 year improves vitamin D levels but did not result in improvement in BMD at lumbar spine and left hip neck in patients with cirrhosis.
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Bisphosphonate Therapy for Treating Osteonecrosis in Pediatric Leukemia Patients: A Systematic Review.
Daneshdoost, SM, El Abiad, JM, Ruble, KJ, Jones, LC, Crane, JL, Morris, CD, Levin, AS
Journal of pediatric hematology/oncology. 2021;(3):e365-e370
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BACKGROUND Despite improved outcomes in children with leukemia, complications such as osteonecrosis are common. We conducted a systematic review to investigate the role of bisphosphonates in reducing pain, improving mobility, and stabilizing lesions in pediatric leukemia survivors. METHODS Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched the PubMed, Embase, Cochrane, Web of Science, Scopus, CINAHL, and ClinicalTrials.gov databases. Five of 221 articles retrieved met our inclusion criteria. RESULTS Bisphosphonates, especially when combined with dietary calcium and vitamin D supplements and physical therapy (supplements/PT) were associated with improved pain and mobility in 54% and 50% of patients, respectively. A significantly greater proportion of patients treated with bisphosphonates (83%) reported mild/moderate pain or no pain compared with those with supplements/PT alone (36%) (P<0.001). Sixty-six percent of patients treated with bisphosphonates achieved improved/full mobility compared with 27% of those treated with supplements/PT alone (P=0.02). However, 46% of patients showed progressive joint destruction despite bisphosphonate therapy. No adverse events were reported, except for acute phase reactions to intravenous therapies. CONCLUSIONS Bisphosphonates, when combined with supplements/PT, were associated with less pain and improved mobility, but not prevention of joint destruction in pediatric leukemia patients with osteonecrosis.