Influence of zoledronic acid and pamidronate on tooth eruption in children with osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children. METHODS: An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption. RESULTS: The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration. CONCLUSION: Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.

Transcriptomic profile of human iPSC-derived podocyte-like cells exposed to a panel of xenobiotics.

Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular barrier causing permanent damage leading to progressive chronic kidney disease. Matured podocytes have little proliferative potential, which makes them critical cells from a health perspective, but also challenging cells to maintain in vitro. Differentiating podocyte-like cells from induced pluripotent stem cells (iPSC) provides a novel and continuous source of cells. Here, we investigated the effect of a 24-h exposure to eight compounds, including the known glomerular toxins doxorubicin and pamidronate, on transcriptomic alterations in iPSC derived podocytes. Doxorubicin (50 nM), pamidronate (50 µM), sodium arsenite (10 µM), and cyclosporine A (15 µM) had a strong impact on the transcriptome, gentamicin (450 µg/ml), lead chloride (15 µM) and valproic acid (500 µM) had a mild impact and busulfan (50 µM) exhibited no impact. Gene alterations and pathways analysis provided mechanistic insight for example, doxorubicin exposure affected the p53 pathway and dedifferentiation, pamidronate activated several pathways including HIF1alpha and sodium arsenite up-regulated oxidative stress and metal responses. The results demonstrate the applicability of iPSC derived podocytes for toxicological and mechanistic investigations.

Combined chemotherapy of zoledronic acid and pamidronate in the treatment of bone metastases from nonsmall cell lung cancer and the effects on pain stress and bone metabolic indices.

OBJECTIVE: We conducted this paper to decipher the efficacy of the combined chemotherapy of zoledronic acid and pamidronate in treating bone metastases from nonsmall cell lung cancer (NSCLC) and the effects on pain stress and bone metabolic indices. METHODS: Patients with bone metastases from NSCLC were allocated into Group A and Group B. Patients in the Group A were administrated with pamidronate combined chemotherapy and patients in the Group B were administrated with zoledronic acid combined chemotherapy. The efficacy, pain symptom scores, quality of life scores, serum inflammatory factor, serum bone metabolic indices, serum pain stress indicators, and the occurrence of adverse effects were compared in patients of the two groups. RESULTS: The total effective rate of treatment was higher in the Group B than in the Group A. After treatment, reduced Numerical Rating Scale scores and elevated Karnofsky Performance Score score, reduced serum levels of N-terminal mid-fragment of osteocalcin, N-terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and type I collagen hydroxyl terminal peptide ß special sequence, reduced serum levels of C-reactive protein, procalcitonin, tumor necrosis factor-α, and interleukin-6, as well as decreased levels of bradykinin, substance P, neuropeptide Y, and ß-endorphin were found in the Group B versus the Group A. No notable difference was witnessed in the rate of adverse reactions between the Group A and the Group B. CONCLUSION: Zoledronic acid combined with chemotherapy can effectively treat bone metastases of NSCLC and improve pain stress and bone metabolic status, which has value that can be promoted and applied in clinical treatment.

Treatment Patterns of Bone-targeting Agents Among Solid Tumor Patients With Bone Metastases: An Analysis of Electronic Health Record Data in the United States From 2014 to 2018.

OBJECTIVES: This study evaluated real-world treatment patterns of approved bone-targeting agents (BTAs) with various mechanisms of action-pamidronate, zoledronic acid, and denosumab-for the prevention of skeletal-related events in patients with bone metastases (BM) from solid tumors. METHODS: Adult patients with BM secondary to solid tumors between January 1, 2014, and December 31, 2018, were identified from the Flatiron Health Oncology Services Comprehensive Electronic Records database and categorized by BTA use and therapy type. Time from diagnosis to initiation, persistence (mean time on treatment), and compliance (≥12 administrations/year) with BTA with up to 4 years of follow-up were examined. RESULTS: This study included 27,268 patients with BM (breast cancer, 32.7%; lung cancer, 16.5%; prostate cancer, 17.2%; and other solid tumors, 33.6%); of these, 41.4% initiated denosumab after BM diagnosis; 21.3%, zoledronic acid; 0.6%, pamidronate; and 36.7% had no treatment record. Mean (SD) time to initiation for denosumab or zoledronic acid was 68.6 (157.0) days (denosumab, 70.3 (160.4) days; zoledronic acid, 65.2 [150.2] days). Mean persistence and compliance (first year of treatment) were significantly higher for denosumab than for zoledronic acid (22.0 vs. 14.9 mo [ P <0.0001] and 42.3% vs. 34.8% [ P <0.0001], respectively). Treatment compliance was the highest in patients with breast cancer (denosumab, 48.2%; zoledronic acid, 39.1%). CONCLUSION: Real-world BTA treatment patterns in the United States suggest that over one-third of patients with BM secondary to solid tumors remain untreated and less than 50% of the patients received ≥12 administrations/year of BTA therapy.

Function of gamma delta (γδ) T cell in cancer with special emphasis on cervical cancer.

Cervical cancer is the second-most prevalent gynecologic cancer in India. It is typically detected in women between the ages of 35 and 44. Cervical cancer is mainly associated with the human papillomavirus (HPV). The report shows that 70 % of cervical cancer is caused by HPV 16 and 18. There are few therapeutic options and vaccines available for cervical cancer treatment and γδ T cell therapy is one of them. This therapy can kill various types of cancers, including cervical cancer. The major γδ T cell subset is the Vγ9Vδ2 T cell, mainly distributed in peripheral blood which recognize non-MHC peptide antigens and can eliminate MHC-downregulated cancer. Moreover, γδ T cells can express different types of receptors that bind to the molecules of stressed cells, often produced on cancerous cells but absent from healthy tissue. γδ T cells possess both direct and indirect cytotoxic capabilities against malignancies and show potential antitumoral responses. However, γδ T cells also encourage the progression of cancer. Cancer immunotherapy using γδ T cells will be a potential cancer treatment, as well as cervical cancer. This review focused on the γδ T cell and its function in cancer, with special emphasis on cervical cancer. It also focused on the ligand recognition site of γδ T cells, galectin-mediated therapy and pamidronate-treated therapy for cervical cancer. Instead of the great potential of γδ T cell for the eradication of cervical cancer, no comprehensive in-depth review is available to date, so there is a need to jot down the various roles and modes of action and different applications of γδ T cells for cancer research, which we believe will be a handy tool for the researchers and the readers.

Atypical femur fracture associated with common anti-osteoporosis drugs in FDA adverse event reporting system.

Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for osteoporosis currently. However, further evidence is needed to learn more regarding other common anti-osteoporosis drugs and the risk for AFF. In this study, reports of AFF were identified from Food and Drug Administration Adverse Event Reporting System database. Disproportionality analyses were performed to examine the reporting odds ratio (ROR), information component (IC) and adjusted ROR (adj. ROR) signals for AFF for common anti-osteoporosis drugs. A total of 1692 unique AFF reports were identified. The disproportionality signals (the lower bound of 95% confidence interval > 1 for ROR and adjusted ROR, and > 0 for IC) were detected for alendronate, denosumab, pamidronate, risedronate, zoledronate, ibandronate, and teriparatide while no signal was detected for raloxifene, abaloparatide, and romosozumab. When restricted in patients with osteoporosis, the disproportionality signals were still detected for alendronate, pamidronate, risedronate, denosumab, and ibandronate. Our results suggest that alendronate has the largest risk signal, while the risks varied among different bisphosphonates. In addition, denosumab was found statistically associated with AFF in both the entire database and patients with osteoporosis.

Diagnostic and therapeutic practices in adult chronic nonbacterial osteomyelitis (CNO).

BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans. METHODS: A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring. RESULTS: 36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments. CONCLUSIONS: Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.

Treatment for osteoporosis in people with beta-thalassaemia.

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.

Cyclic intravenous pamidronate for an infant with osteogenesis imperfecta type II.

A woman in her 30s underwent a 17-week ultrasound which revealed short bowed long bones. Fetal CT at 28 weeks' gestation showed decreased ossification of the skull, a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI) type II. The newborn was delivered via caesarean delivery, and tracheal intubation was performed due to the respiratory distress. A heterozygous variant in COL1A1 (c.1679G>T, p. Gly358Val) was ascertained, confirming the diagnosis of OI type II.Cyclic intravenous pamidronate was started at 41 days old with dose modification and was successfully administered every month. Currently, the infant is 8 months old without any new bone fracture. He was extubated successfully at 7 months of age and is now stable using high flow nasal cannula. The efficacy, safety, and optimal dose and timing of cyclic pamidronate for OI type II remain undefined. We report our experience of successful cyclic intravenous pamidronate treatment for an infant with OI type II.

Descriptive assessment of 54 cases with complex regional pain syndrome in lower limbs.

INTRODUCTION: Complex regional pain syndrome (CRPS), also known as Sudeck syndrome, is a chronic painful condition usually affecting the limbs after trauma or surgery. Its presentation is heterogeneous and its physiopathology, diagnosis and treatment remain controversial. The objective of this study was to analyze a group of patients with this rare syndrome, describing in detail the results of the dual energy X-ray absorptiometry (DXA) and the response to bisphosphonate treatment. METHOD: We retrospectively analyzed 54 patients with CRPS, taking into account their demographic features, inciting events and diagnostic tests. As regards treatment, we analyzed the results and adverse events of the use of bisphosphonates Results: We found a female predominance (74%), with 55 ± 13 years. The most common inciting event was trauma (59%), followed by surgery. The difference in bone mineral density between the affected limb and the healthy one was 12 to 15%. Forty-four patients were treated with bisphosphonates (pamidronate, ibandronate, zoledronic acid) and showed a clinical improvement, mainly in terms of pain intensity. Only six patients presented with adverse events, like pseudoflu syndrome and acute phase symptoms. CONCLUSION: In our cohort, lower limbs CRPS predominantly affects middle aged women. DXA scans are tests used to quantify bone loss and the response to treatment. The use of bisphosphonates is an interesting therapeutic option to improve clinical symptoms in most patients. Future prospective randomized studies will be needed to confirm our results.

Introducción: El síndrome doloroso regional complejo (SDRC), también conocido como síndrome de Sudeck, es una enfermedad dolorosa crónica que generalmente afecta a las extremidades luego de un trauma o cirugía. Su presentación es heterogénea y existen controversias sobre su fisiopatología, adecuado diagnóstico y tratamiento. El objetivo de este trabajo es describir un grupo de pacientes con SDRC en miembros inferiores, describiendo los resultados de la densitometría mineral ósea (DMO) y la respuesta al tratamiento con bifosfonatos. Método: Analizamos retrospectivamente 54 pacientes con SDRC, teniendo en cuenta características demográficas, factores desencadenantes y estudios diagnósticos. En relación al tratamiento, analizamos los resultados y efectos adversos del uso de bifosfonatos. Resultados: Encontramos un predominio femenino (74%), con una edad de 55 ± 13 años. Los factores desencadenantes más comunes fueron los traumatismos (59%) y la cirugía. La diferencia de densidad mineral ósea entre el miembro comprometido y el sano fue 12 a 15%. En los 44 pacientes fueron tratados con bifosfonatos (pamidronato, ibandronato y ácido zoledrónico), su uso se asoció a mejoría clínica, especialmente del dolor. Seis pacientes tuvieron efectos adversos como sindrome pseudogripal y síntomas de fase aguda. Conclusión: En nuestra población, el SDRC de miembros inferiores predomina en mujeres de edad media. La DMO es un método que permite cuantificar la pérdida ósea y la respuesta al tratamiento. Los bifosfonatos son una buena opción terapéutica para el control de síntomas. Son necesarios futuros estudios de naturaleza prospectiva y aleatorizada para confirmar nuestros resultados.

An unusual presentation of chronic recurrent multifocal osteomyelitis involving bones of the skull.

Chronic recurrent multifocal osteomyelitis is a rare, multisystemic inflammatory disease that affects children and adolescents. We present the case of an African-American adolescent male who presented with recurrent swelling of the temporal region with skull involvement on head imaging, which is atypical for chronic recurrent multifocal osteomyelitis. He had clinical and laboratory improvement after initiation of indomethacin and pamidronate.

Pulsed electromagnetic field attenuates bone fragility in estrogen-deficient osteoporosis in rats.

BACKGROUND: The pulsed electromagnetic fields (PEMFs) seem effective in increasing bone mineral density and promoting osteogenesis and bone healing. OBJECTIVE: To examine the effect of two different modalities of PEMFs therapy in comparison with the recommended pharmacological treatment on experimental osteoporosis in rats. METHODS: The experimental model of estrogen-deficient osteoporosis induced by ovariectomy was used in this study. The animals were exposed to PEMFs of various frequencies (40 Hz and 25 Hzk), intensities (10 mT and 36.4 µT), lengths of exposure, and the effects were compared with the standard treatment with pamidronate, vitamin D, and calcium supplementation. RESULTS: The application of PEMF40Hz, significantly reduced the osteoporotic bone loss in female rats that were confirmed with biochemical, biomechanical, and histological analyses. These effects were more pronounced than in osteoporotic animals treated with pamidronate, vitamin D, and calcium supplementation. On the contrary, the exposure to PEMF25Hz did not show restorative effects but led to further progression of osteoporosis. CONCLUSION: The exposure to PEMF40Hz, significantly restored osteoporosis and attenuated bone fragility in comparison to the rats exposed to PEMF25Hz or those treated with pamidronate, vitamin D, and calcium supplementation.

Chronic recurrent multifocal osteomyelitis with a comprehensive approach to differential diagnosis of paediatric skull pain.

A girl in middle childhood was referred to rheumatology with a 1-month history of progressive skull pain, preceded by fleeting musculoskeletal symptoms. Apart from a scaly rash on her scalp, she was well, with moderately elevated inflammatory markers. Skull imaging (radiographs, CT and MRI) revealed osteolytic lesions, soft tissue swelling and pachymeningeal enhancement at frontal and temporal convexities. Langerhans cell histiocytosis, bone infection/inflammation or malignancy was considered. Skin and bone biopsies eventually ruled out mimicking diseases and confirmed the diagnosis of chronic recurrent multifocal osteomyelitis (CRMO). She was treated with intravenous pamidronate (IVPAM) for 9 months, with rapid resolution of pain and gradual resolution of bony abnormalities. She remains in remission at 15-month follow-up. While CRMO can affect any bone, skull involvement is extremely rare, with a broad differential diagnosis. We recommend bone biopsy to confirm skull CRMO. The patient achieved excellent clinical and radiological response to IVPAM.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

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.

Precision engineering designed phospholipid-tagged pamidronate complex functionalized SNEDDS for the treatment of postmenopausal osteoporosis.

Disodium pamidronate, a second-generation bisphosphonate is a potent drug for the treatment of osteoporosis, which has been very well established by previous literature. It has very low oral permeability, leading to its low oral bioavailability, which restrict this drug to being administered orally. Therefore, the present research work includes the development of an orally effective nanoformulation of pamidronate. In this work, disodium pamidronate was complexed with phospholipon 90G for the enhancement of permeability and to investigate the phospholipon 90G-tagged pamidronate complex-loaded SNEDDS for oral delivery with promises of enhanced bioavailability and anti-osteoporotic activity. The rational design and optimization was employed using Central Composite Design (Design Expert® 12, software) to optimize nanoformulation parameters. In this work, a commercially potential self nano-emulsifying drug delivery system (SNEDDS) has been developed and evaluated for improved oral bioavailability and better clinical acceptance. The hot micro-emulsification and ultracentrifugation method with vortex mixing was utilized for effective tagging of phospholipon 90G with pamidronate and then loading into the SNEDDS nanocarrier. The optimized Pam-PLc SNEDDS formulation was characterized for particle size, PDI, and zeta potential and found to be 56.38 ± 1.37 nm, 0.218 ± 0.113, and 22.41 ± 1.14 respectively. Also, a 37.9% improved bioavailability of pamidronate compared to marketed tablet was observed. Similarly, in vivo pharmacokinetic studies suggest a 31.77% increased bone density and significant enhanced bone biomarkers compared to marketed tablets. The developed formulation is safe and effectively overcomes anti-osteoporosis promises with improved therapeutic potential. This work provides very significant achievements in postmenopausal osteoporosis treatment and may lead to possible use of nanotherapeutic-driven emerging biodegradable carriers-based drug delivery.

Ocular Side Effects of Bisphosphonates: A Review of Literature.

In rare cases, bisphosphonates are well established to cause ocular inflammation, presenting as uveitis, episcleritis, scleritis, orbital inflammation, and/or conjunctivitis. Some reports of bisphosphonate-associated neuro-ophthalmic complications also exist. We identified 101 reports in the literature relating to bisphosphonate-associated ocular complications. In a great majority of cases, symptoms resolve after discontinuation of the drug and anti-inflammatory treatment. Many cases recur if rechallenged with the same bisphosphonate. First-generation nonamino bisphosphonates, including clodronate and etidronate, are not associated with ocular inflammation. Only 2nd- and 3rd-generation amino bisphosphonates, including pamidronate, alendronate, risedronate, ibandronate, and zoledronate are associated with these complications. The mechanism of bisphosphonate-induced ocular inflammation may be related to activation of γ/δ T cells or M1 macrophages. Intravenous forms, such as pamidronate and zoledronate, tend to have higher rates and faster onset of ocular inflammation, generally presenting within days of infusion. In oral bisphosphonates, such as alendronate and risedronate, these complications present with more sporadic timing. Rates of complications are also higher when bisphosphonates are used for malignancy, as doses tend to be higher compared with doses for osteoporosis.

Novel Synergistic Combination of Pamidronate and Temozolomide for Breast Cancer Therapeutics.

OBJECTIVE: Human breast cancer is among one major health concerns with high prevalence and mortality among women worldwide. Various cellular signaling pathways are implicated in carcinogenesis. One of the major pathways that affect the downstream cellular growth cascades is Mevalonate pathway (MVA). The inhibition of MVA is therapeutically beneficial for various cancers. Pamidronate (PAM) (MVA inhibitor), a nitrogen-containing bisphosphosphonate, is an antiresorptive FDAapproved drug. The objective of our study was to explore adjuvant therapy using a combination of PAM and an alkylating agent, Temozolomide (TMZ) against breast cancer. METHODS: We have examined the differential gene and protein expression in response to the combination treatment strategy. For gene expression analysis RT-qPCR and for proteomic study, twodimensional gel electrophoresis and mass spectrometry techniques were utilized. RESULTS: Combination treatment (PAM+TMZ) showed more pronounced cytotoxic effect as compared to single agent treatment. Our results indicate that MVA pathway regulatory genes (FDFT1, FDPS, KRAS) are significantly (p<0.05) downregulated in combination-treated breast cancer cells. The differential proteomic analysis showed lower expression of GFAP, PPA1 and TRIM68 proteins after synergistic treatment whereas, these proteins are found to be up-regulated in multiple cancers. CONCLUSION: The present study reveals that a combination of PAM and TMZ produces an effective anti-cancerous effect on breast cancer cells. Therefore, this novel therapeutic regimen is likely to provide a better treatment strategy for breast cancer.

Preparation, Optimisation, and In Vitro Evaluation of [18F]AlF-NOTA-Pamidronic Acid for Bone Imaging PET.

[18F]sodium fluoride ([18F]NaF) is recognised to be superior to [99mTc]-methyl diphosphate ([99mTc]Tc-MDP) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in bone imaging. However, there is concern that [18F]NaF uptake is not cancer-specific, leading to a higher number of false-positive interpretations. Therefore, in this work, [18F]AlF-NOTA-pamidronic acid was prepared, optimised, and tested for its in vitro uptake. NOTA-pamidronic acid was prepared by an N-Hydroxysuccinimide (NHS) ester strategy and validated by liquid chromatography-mass spectrometry analysis (LC-MS/MS). Radiolabeling of [18F]AlF-NOTA-pamidronic acid was optimised, and it was ensured that all quality control analysis requirements for the radiopharmaceuticals were met prior to the in vitro cell uptake studies. NOTA-pamidronic acid was successfully prepared and radiolabeled with 18F. The radiolabel was prepared in a 1:1 molar ratio of aluminium chloride (AlCl3) to NOTA-pamidronic acid and heated at 100 °C for 15 min in the presence of 50% ethanol (v/v), which proved to be optimal. The preliminary in vitro results of the binding of the hydroxyapatite showed that [18F]AlF-NOTA-pamidronic acid was as sensitive as [18F]sodium fluoride ([18F]NaF). Normal human osteoblast cell lines (hFOB 1.19) and human osteosarcoma cell lines (Saos-2) were used for the in vitro cellular uptake studies. It was found that [18F]NaF was higher in both cell lines, but [18F]AlF-NOTA-pamidronic acid showed promising cellular uptake in Saos-2. The preliminary results suggest that further preclinical studies of [18F]AlF-NOTA-pamidronic acid are needed before it is transferred to clinical research.