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The Cochrane Database of Systematic... Jan 2023Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and... (Review)
Review
BACKGROUND
Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review.
OBJECTIVES
To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis.
SEARCH METHODS
We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022.
SELECTION CRITERIA
Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS
Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE.
MAIN RESULTS
We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains. Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life. Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life.
AUTHORS' CONCLUSIONS
Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates.
Topics: Adult; Child; Female; Humans; Alendronate; Bone Density Conservation Agents; Cystic Fibrosis; Diphosphonates; Fractures, Bone; Musculoskeletal Pain; Osteoporosis; Pamidronate; Quality of Life; Spinal Fractures; Zoledronic Acid; Randomized Controlled Trials as Topic
PubMed: 36625789
DOI: 10.1002/14651858.CD002010.pub5 -
Clinical and Experimental Pediatrics Aug 2022Osteopenia and osteoporosis represent a prominent cause of morbidity in children with thalassemia. Multiple factors are responsible for the pathogenesis of bone loss in...
BACKGROUND
Osteopenia and osteoporosis represent a prominent cause of morbidity in children with thalassemia. Multiple factors are responsible for the pathogenesis of bone loss in thalassemia, including diabetes, hypothyroidism, parathyroid gland dysfunction, accelerated hemopoiesis, direct iron toxicity of osteoblasts, iron chelators, and deficiencies of growth hormone or insulin growth factors.
PURPOSE
To assess the effect of pamidronate administration on β-thalassemia major-induced osteoporosis in children.
METHODS
This study assessed the effects of different treatments (calcium and vitamin D versus calcium, vitamin D, and pamidronate) on patients with β-thalassemia major and osteoporosis. Bone mineral density (BMD) and z scores were measured at baseline and after 1 year of treatment using dual-energy x-ray absorptiometry.
RESULTS
The mean baseline BMD values of the lumbar spine were 0.71±0.07 (g/cm²) and 0.74±0.07 (g/cm²), respectively, while those at the end of the study were 0.81±0.07 (g/cm²) (P<0.001) and 0.78±0.07 (g/cm²) (P>0.05), respectively. The mean baseline z scores of the lumbar spine were -3.53±0.55 and -3.17±0.61, while those after treatment were -2.1±0.32 (P=0.001) and -3.11±0.67 (P>0.05), respectively. The baseline alkaline phosphatase levels were 351.5±86.07 μg/dL and 357.6±89.7 μg/dL, while those after treatment were 220.4± 59.26.07 μg/dL (P<0.001) and 320.3±83.99 μg/dL (P>0.05), respectively.
CONCLUSION
Pamidronate administration effectively increased the BMD and z scores of children with β-thalassemia major. Pamidronate had a favorable safety profile with no related serious adverse events during the study period.
PubMed: 35681246
DOI: 10.3345/cep.2019.00535 -
The Pan African Medical Journal 2015
Topics: Bone Density Conservation Agents; Chromogranins; Diphosphonates; Fibrous Dysplasia of Bone; GTP-Binding Protein alpha Subunits, Gs; Humans; Mutation; Pamidronate
PubMed: 26401215
DOI: 10.11604/pamj.2015.21.21.3487 -
Antiviral Research Feb 2018A severe inflammatory immune response with hypercytokinemia occurs in patients hospitalized with severe influenza, such as avian influenza A(H5N1), A(H7N9), and seasonal... (Review)
Review
A severe inflammatory immune response with hypercytokinemia occurs in patients hospitalized with severe influenza, such as avian influenza A(H5N1), A(H7N9), and seasonal A(H1N1)pdm09 virus infections. The role of immunomodulatory therapy is unclear as there have been limited published data based on randomized controlled trials (RCTs). Passive immunotherapy such as convalescent plasma and hyperimmune globulin have some studies demonstrating benefit when administered as an adjunctive therapy for severe influenza. Triple combination of oseltamivir, clarithromycin, and naproxen for severe influenza has one study supporting its use, and confirmatory studies would be of great interest. Likewise, confirmatory studies of sirolimus without concomitant corticosteroid therapy should be explored as a research priority. Other agents with potential immunomodulating effects, including non-immune intravenous immunoglobulin, N-acetylcysteine, acute use of statins, macrolides, pamidronate, nitazoxanide, chloroquine, antiC5a antibody, interferons, human mesenchymal stromal cells, mycophenolic acid, peroxisome proliferator-activated receptors agonists, non-steroidal anti-inflammatory agents, mesalazine, herbal medicine, and the role of plasmapheresis and hemoperfusion as rescue therapy have supportive preclinical or observational clinical data, and deserve more investigation preferably by RCTs. Systemic corticosteroids administered in high dose may increase the risk of mortality and morbidity in patients with severe influenza and should not be used, while the clinical utility of low dose systemic corticosteroids requires further investigation.
Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Drug Therapy, Combination; Humans; Immunologic Factors; Immunomodulation; Immunotherapy; Influenza, Human; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 29325970
DOI: 10.1016/j.antiviral.2018.01.002 -
The Cochrane Database of Systematic... Dec 2017Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012.
OBJECTIVES
To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia.
SEARCH METHODS
We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms.
SELECTION CRITERIA
Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted.
MAIN RESULTS
In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.
AUTHORS' CONCLUSIONS
Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.
Topics: Antineoplastic Agents; Bone Density Conservation Agents; Bone Diseases; Clodronic Acid; Diphosphonates; Disease-Free Survival; Etidronic Acid; Fractures, Bone; Humans; Imidazoles; Multiple Myeloma; Pamidronate; Randomized Controlled Trials as Topic; Spinal Fractures; Zoledronic Acid
PubMed: 29253322
DOI: 10.1002/14651858.CD003188.pub4 -
JPMA. the Journal of the Pakistan... Dec 2022Neonatal severe hyperparathyroidism (NSHPT) is a rare genetic disorder that presents within the first six months of life. We present the case report of a male child who...
Neonatal severe hyperparathyroidism (NSHPT) is a rare genetic disorder that presents within the first six months of life. We present the case report of a male child who presented to us in the first month of his life with symptoms of lethargy, constipation, and reluctance to feed. One sibling of the child had died earlier with similar symptoms in the first six months of life. Upon physical examination, the child was lethargic, dehydrated, had bradycardia with hyperreflexia. Serum electrolyte analysis showed hypercalcaemia and hypophosphataemia. Further workup revealed elevated serum parathyroid hormone levels and Calcium sensing receptor (CaSR) gene mutation in autosomal recessive patterns. The father was discovered to be heterozygous for the same mutation but is asymptomatic. Diagnosis of neonatal severe hyperparathyroidism was made and the child was managed medically with intravenous fluids, Furosemide, Pamidronate, and Cinacalcet. On inconsistent response to medical therapy, he underwent total parathyroidectomy with auto transplantation of half of the left lower parathyroid gland. Postoperatively, the child is being managed on oral calcium and Alpha Calcidiol supplementation and is doing well.
Topics: Infant, Newborn; Child; Humans; Male; Hyperparathyroidism, Primary; Cinacalcet; Mutation; Heterozygote; Hypercalcemia; Calcium
PubMed: 37246686
DOI: 10.47391/JPMA.4195 -
Frontiers in Immunology 2023Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure...
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Topics: Humans; HIV Infections; HIV-1; Virus Activation; Virus Latency; Alendronate; HIV Seropositivity
PubMed: 37744358
DOI: 10.3389/fimmu.2023.1219250 -
ACS Omega Mar 2021Organophosphorous compounds are still widely used as potential scale inhibitors in the upstream oil and gas industry, particularly in squeeze treatments as they have...
Organophosphorous compounds are still widely used as potential scale inhibitors in the upstream oil and gas industry, particularly in squeeze treatments as they have good adsorption properties on rock and are easily detectable. However, most phosphonate-based scale inhibitors have some drawbacks, such as poor biodegradability and various incompatibilities with the production system. The low toxicity of bisphosphonates motivated us to test a series of aliphatic and aromatic hydroxybisphosphonates as new oilfield scale inhibitors for calcium carbonate (calcite) and barium sulfate (barite) scales. Thus, the well-known bone-targeting drugs 3-amino-1-hydroxypropane-1,1-bisphosphonic acid (pamidronic acid, ), 4-amino-1-hydroxybutane-1,1-bisphosphonic acid (alendronic acid, ), 5-amino-1-hydroxypentane-1,1-bisphosphonic acid (), and hydroxyphenylmethylene-1,1-bisphosphonic acid (fenidronic acid, ) are studied along with novel, specially designed bisphosphonates (1,4-dihydroxybutane-1,1,4,4-tetrayl)tetrakisphosphonic acid (), (1,6-dihydroxyhexane-1,1,6,6-tetrayl)tetrakisphosphonic acid (), and ((4- aminophenyl)(hydroxy)methylene)bisphosphonic acid () in a dynamic tube-blocking scale rig at 100 °C and 80 bar according to typical North Sea conditions. The scale inhibition performance of the new SIs was compared to that of the commercial 1-hydroxyethylidene bisphosphonic acid () and aminotrismethylenephosphonic acid (). The results indicate that all synthesized hydroxybisphosphonates provide reasonable inhibition performance against calcite scaling and show good thermal stability at 130 °C for 7 days under anaerobic conditions.
PubMed: 33718740
DOI: 10.1021/acsomega.1c00379 -
BMJ Case Reports Sep 2017Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. Idiopathic juvenile osteoporosis is a primary osteoporosis of unknown...
Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. Idiopathic juvenile osteoporosis is a primary osteoporosis of unknown aetiology present in previously well children and is a diagnosis of exclusion. We describe a 10-year-old prepubertal boy who presented with back pain of 1-week duration. His spinal X-ray showed generalised loss of vertebral body heights in keeping with osteoporosis. Endocrine and haematological work-up were normal. He was treated with vitamin D supplement and intravenous pamidronate. This case illustrates the general work-up and causes for paediatric osteoporosis, and the management for idiopathic juvenile osteoporosis.
Topics: Administration, Intravenous; Back Pain; Bone Density Conservation Agents; Child; Diagnosis, Differential; Diphosphonates; Humans; Male; Osteoporosis; Pamidronate; Radiography; Spine; Treatment Outcome; Vitamin D
PubMed: 28866630
DOI: 10.1136/bcr-2017-220700 -
Quantitative Imaging in Medicine and... Feb 2021Osteoporosis is a highly prevalent multifactorial osteometabolic disease, classically diagnosed, , by dual energy X-ray absorptiometry (DXA). This study evaluated...
BACKGROUND
Osteoporosis is a highly prevalent multifactorial osteometabolic disease, classically diagnosed, , by dual energy X-ray absorptiometry (DXA). This study evaluated osteoporosis, , using vibro-acoustography (VA), an elastographic technique based on ultrasound radiation force.
METHODS
Three groups of mice femurs were used: (I) control group (CG), (II) osteoporosis group (OG) and (III) treated osteoporosis group (TOG), in which the animals received pamidronate, an antiresorptive drug. Evaluation was performed in an acoustic tank, using two high frequency focused beams produced by a confocal ultrasonic transducer. A hydrophone registered the low frequency acoustic response (AR) of bone samples. We used micro-computed tomography (microCT) as the reference standard and evaluated the correlation between VA and microCT parameters.
RESULTS
The spectral analyses of the ARs with estimated area under the curve (AUC) values (mean; st. dev.) were, respectively, 1.29e and 9.32e for the CG, 3.25e and 2.16e for the OG, and 1.50e and 8.37e for the TOG. VA differentiated the experimental groups (P<0.01) and the results were reproducible [interclass correlation coefficient (ICC): 0.43 (95% CI: 0.15-0.71)]. There was also a statistically significant association between VA and microCT connectivity (Conn.) (r=0.80; P<0.01) and connectivity density (Conn. D) (r=0.76; P<0.01).
CONCLUSIONS
These results encourage further studies aimed at evaluating the potential use of VA for the diagnosis of osteoporosis as a relatively low-cost and radiation-free alternative to DXA.
PubMed: 33532259
DOI: 10.21037/qims-20-610