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.

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.

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.

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.

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.

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.

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.

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.

Updates on Paget's Disease of Bone.

Paget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case.

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

Standardized reporting and quantification of whole-body MRI findings in children with chronic non-bacterial osteomyelitis treated with pamidronate.

OBJECTIVES: The objectives were to assess changes in radiological disease activity in children with chronic non-bacterial osteomyelitis (CNO) receiving pamidronate therapy and to test a modified radiological index for non-bacterial osteitis (mRINBO) in CNO. mRINBO was used for standardized reporting and quantification of whole-body MRI (WBMRI) findings resulting in an individual summary patient score. METHODS: WBMRI was retrospectively assessed in 18 children with CNO at baseline and after receiving pamidronate therapy for one year. Parameters of interest were: number and anatomic site of radiologically active bone lesions (RAL), size of RAL, extramedullary affection, spinal involvement and changes in mRINBO, which includes both the number and maximal size of RAL (RALmax) in addition to extramedullary and chronic changes. RESULTS: At the time of diagnosis, the mean age of the children was 9.8 (sd, 8.7-10.9) years and 11/18 were females. The number of RALs per patient decreased from median [interquartile range] 4.5 [3-8] to 3 [2-5] RALs per patient (p = 0.02) and extramedullary inflammatory changes regressed. Sixty-one percent of all RALs occurring at baseline resolved and three children became without active inflammatory lesions by WBMRI. The median size of RALs did not change when taking new lesions occurring in 7/18 children into account, but RALmax decreased significantly from 39 [29-45] mm at baseline to 28 [20-40] mm (p < 0.01) at year-one with a concomitant decrease of mRINBO from a median of 5 [4-7] to 4 [3-5] (p = 0.05). CONCLUSIONS: Pamidronate therapy resulted in a decrease of mRINBO from baseline to year one. mRINBO may be a potential scoring method to quantify changes in radiological disease activity in children with CNO. However, further studies are needed to test feasibility and validity of mRINBO.

Bisphosphonate type-dependent cell viability suppressive effects of carbon nanohorn-calcium phosphate-bisphosphonate nanocomposites.

In the process of bone metastasis, tumor cells spread to the bones to activate osteoclasts, which cause pathological bone resorption and destruction. Bisphosphonates (BPs) inhibit osteoclast activation to resorb bone, reducing bone pain and fracture. We previously developed a nanocomposite for potential localized treatment of bone metastasis by loading a BP compound, ibandronate, onto oxidized carbon nanohorns (OxCNHs), a next-generation drug carrier, using calcium phosphates (CaPs) as mediators to generate OxCNH-CaP-BP nanocomposites. The objective of the present study was to determine nanocomposite formation and biological properties of nanocomposites constructed from two BPs, zoledronate and pamidronate. In vitro tests using murine macrophages (RAW264.7 cells) and osteoclasts differentiated from RAW264.7 cells revealed that the resulting OxCNH-CaP-BP nanocomposites suppressed cell viability in a BP type-dependent manner and more effectively than OxCNHs or BPs alone. The mechanism for the potent and BP type-dependent suppression of cell viability by OxCNH-CaP-BP nanocomposites, based on their relative cellular uptake and reactive oxygen species generation, is also discussed. The present study supports the conclusions that BPs can be loaded onto OxCNHs using CaPs as mediators, and that OxCNH-CaP-BP nanocomposites are putative medicines for localized treatment of metastatic bone destruction.

Effects of Pamidronate Disodium Combined with Calcium on BMD Values and Severity of Pain in Elderly Patients with Osteoporosis Based on Mobile Terminal Platform for Internet of Things.

Objective: To explore the effects of pamidronate disodium combined with calcium on BMD values and the severity of pain in elderly patients with osteoporosis based on the mobile terminal platform for the Internet of Things. Methods: The data of 120 patients admitted to our hospital from January 2019 to December 2020 were retrospectively analyzed. According to the patients' condition and medication wills, they were divided into the experimental group (n = 68) and the control group (n = 52). All patients were given chronic disease management based on the mobile terminals for the Internet of Things, and they received the treatment of bisphosphonates and calcium, with the supplement of calcium at a daily dose of 1000 mg. The control group was given alendronate sodium once a week, and the experimental group was given pamidronate disodium by intravenous infusion three times a month, with the treatment cycle as 1 year. The patients' bone mineral density (BMD) values and the pain indexes were compared after treatment. Results: There was no statistical difference in general information between the two groups (p > 0.05). The BMD values of the lumbar vertebrae L2-4, total hip, and femur neck at 6 months and 1 year after treatment in the experimental group were significantly higher than those in the control group (p < 0.001). The pain scores at 6 months and 1 year after treatment in the experimental group were significantly lower than those in the control group (p < 0.001). Conclusion: The treatment of pamidronate disodium combined with calcium based on the mobile terminal platform for the Internet of Things can reduce the severity of pain in elderly patients with osteoporosis and improve the BMD, which has a generalization value.

Genotype-Phenotype Relationship and Follow-up Analysis of a Chinese Cohort With Osteogenesis Imperfecta.

OBJECTIVE: To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI). METHODS: We established a Chinese hospitalized cohort with OI and followed them up for an average of 6 years. All patients were confirmed as having OI using whole-exome sequencing. We analyzed the genotype-phenotype relationship based on different types, pathogenic mechanisms, and gene inheritance patterns of OI. Additionally, we assessed whether there was a difference in treatment efficacy based on genotype. RESULTS: One hundred sixteen mutations in 6 pathogenic genes (COL1A1, COL1A2, IFITM5, SERPINF1, FKBP10, and WNT1) were identified in 116 patients with type I, III, IV, V, VI, XI, or XV OI. Compared with patients with COL1A1 mutations, patients with COL1A2 mutations were younger at the time of the first fracture, whereas other phenotypes were similar. When 3 groups (helical, haploinsufficiency, and non-collagen I gene mutations) were compared, patients with helical mutations were the shortest and most prone to dentinogenesis imperfecta. Patients with haploinsufficiency mutations were the oldest at the time of the first fracture. Moreover, patients with non-collagen I gene mutations were least susceptible to blue sclerae and had the highest fracture frequency. Furthermore, there were some minor phenotypic differences among non-collagen I gene mutations. Interestingly, pamidronate achieved excellent results in the treatment of patients with OI, and the treatment effect appeared to be unrelated to their genotypes. CONCLUSION: Our findings indicated a genotype-phenotype relationship and a similar effect of pamidronate treatment in patients with OI, which could provide a basis for guiding clinical treatment and predicting OI prognosis.

TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study.

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence.

One changing and challenging scenario: the treatment of cancer patients with bone metastases by bisphosphonates and denosumab, the cost-benefit evaluation of different options, and the risk of medication-related osteonecrosis of the jaw (MRONJ).

Antiresorptive drugs (bisphosphonates and denosumab) have become the cornerstone of medical supportive treatment of bone metastases in solid cancer patients. In the beginning, the choice of available antiresorptive agents was limited to bisphosphonates and the treatment options restricted principally to monthly pamidronate and monthly zoledronic acid. Introduction of new antiresorptive therapies (monthly denosumab) and schedules (zoledronic acid every 3 months, upfront or after initial period of monthly infusion) in the last decade increased the range of available options, thus challenging treatment decision making. Direct and indirect costs of very different treatment options are difficult to interpret in a global cost-benefit analysis. In addition, awareness of the increased risk of medication-related osteonecrosis of the jaw (MRONJ) in bone metastatic cancer patients receiving long-term antiresorptive medications is likely to influence therapy choice in the real-life scenario. We discuss the possible threat of MRONJ risk underestimation and the need for long-term risk stratification of patients based on actuarial data, the role of bisphosphonates and denosumab in that scenario, and the emerging role of surgical therapy to successfully cure MRONJ, in the light of the improved quality of life and survival of patients with bone metastases from solid cancers.

Pseudomyogenic hemangioendothelioma with bone and soft tissue involvement with favorable response to pamidronate: a case report and systematic review of the literature.

Pseudomyogenic hemangioendothelioma (PMH) can be a challenge for diagnosis and might be confused with other tumors, such as epithelioid sarcoma. Here we present a case and a systematic review of the literature to identify and discuss PMH treatment in primary bone involvement. A 25-year-old woman was referred for bone pain (10/10) in the left lower limb. Magnetic resonance imaging (MRI) showed multiple bone lesions (left femur, tibia, patella, ankle, and foot) with well-defined borders without signs of local aggressiveness. Positron Emission Tomography-Computed Tomography (PET-CT) showed multiple metabolic musculoskeletal lesions in the left lower limb. A CT scan-guided biopsy was performed. Histological and immunohistochemical findings confirmed the diagnosis of PMH. After treatment with intravenous pamidronate (90 mg/monthly), the patient had clinical improvement, mild pain 2/10 without the use of non-steroidal anti-inflammatory drugs or opiates. Follow-up was assessed by MRI and PET-CT. PET-CT showed metabolic resolution of most of the bone and muscular lesions and a significant improvement of the femoral lesion. MRI showed that the lesions in the left femur, tibia, and foot had a marked decrease in size without intravenous post-contrast enhancement and smaller lesions had disappeared. After a 3-year follow-up, PET-CT showed no metabolically active images. Literature review identified 31 records including 58 clinical cases of PMH with primary bone involvement and treatment description for qualitative analysis. Most lesions (69%) were treated by local excision or curettage. In addition, amputations were performed in a significant percentage of cases (20.7%). In the last years, mTOR inhibitors (n = 7) and anti-resorptive treatments (n = 4) were considered as alternative treatment options, especially in multifocal lesions.

Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma: A case report and management of neonatal hypercalcemia: Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma.

Congenital mesoblastic nephroma is a rare pediatric renal tumor and has been reported in patients presenting with palpable abdominal mass, arterial hypertension, hematuria, polyuria, or hypercalcemia. Here we present the case of a 1-month-old neonate with suspected parathyroid hormone (PTH)-related peptide (PTH-rp)-mediated severe hypercalcemia revealing congenital mesoblastic nephroma. Preoperatively, hypercalcemia was corrected with hydration, furosemide, pamidronate, and low-calcium infant formula. Unilateral nephrectomy led to the resolution of hypercalcemia, transient hyperparathyroidism, and transient vitamin D and mineral supplementation. We conclude that congenital mesoblastic nephroma can secrete PTH-rp that can cause severe hypercalcemia.

Patient-reported effectiveness and safety of Pamidronate in NSAIDs-refractory chronic recurrent multifocal osteomyelitis in children.

To evaluate patient-reported effectiveness, safety and social influence of Pamidronate in the therapy of NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis in children. Authors reviewed self-created questionnaires, which asked patients for symptoms alleviation, adverse drug reactions frequency and degree of severity and daily activities self-reliance. Only surveys with complete answers, which were returned to authors by an e-mail from juvenile patients treated for NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis at the University Children's Hospital of Cracow were analyzed. Between 2010 and 2019, 61 children were diagnosed with NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis at our department. Out of 61 requests sent, 42 complete replies (33 females, 9 males) were gathered and analyzed. All patients included in this research were administered with at least one set of Pamidronate intravenously in the dose of 1 mg/kg/day for 3 consecutive days. Our analysis shows remarkable in terms of patient's impressions decrease of pain intensity after 2.5 series of Pamidronate on average, and total pain resolution after 5.9 series on average. Overall number of adverse drug reaction events reported by responders was 105. One patient developed drug-dependent renal insufficiency in the course of therapy. Outcome assessment indicates that nearly 50% of the studied population was more eager to participate in social life just after the first infusion of the drug. 95% of the surveyed unanimously agreed to recommend Pamidronate therapy to cure NSAIDs-refractory CRMO. 39 out of 42 (93%) patients considered Pamidronate effective at the end of the treatment. Onset of Pamidronate's action is gradual and differs in terms of symptoms alleviation between sexes. The therapy can induce considerable number of adverse drug reactions (2.5 per patient). Only 3 out of 42 (7%) patients were free from any ADRs. To demonstrate the impact of the use of Pamidronate on daily activities more precisely, further research with quantification of the quality of life is warranted.