Pamidronate-induced irreversible symptomatic hypocalcemia in a dog with hypercalcemia after glucocorticoid withdrawal: a case report.

BACKGROUND: Pamidronate is used for the treatment of hypercalcemia. However, a rare but potential adverse event of pamidronate treatment is hypocalcemia. This report describes an unusual case of severe, irreversible hypocalcemia after a single injection of pamidronate for the treatment of hypercalcemia due to glucocorticoid withdrawal in a dog. CASE PRESENTATION: An 11-year-old castrated male Maltese dog presented with anorexia, vomiting, and diarrhea (day 0). The patient had calcinosis cutis throughout the body, calcification of intraabdominal organs, mild azotemia, and severe hypercalcemia. The severe calcification was attributed to long-term glucocorticoid administration, which was discontinued 1 month before presentation. Fluid therapy, diuretics, calcitonin, and a single intravenous injection of pamidronate were used for the treatment of hypercalcemia. On day 14, normocalcemia was achieved, but renal failure occurred. On day 20, severe and irreversible hypocalcemia occurred, and on day 42, the patient was euthanized at the owner's request because of worsened hypocalcemia and renal failure. CONCLUSIONS: Although hypocalcemia is an extremely rare adverse event of bisphosphonate treatment, bisphosphonates like pamidronate can result in potentially life-threatening conditions according to the patient's underlying conditions. Therefore, the patient's condition should be closely monitored and any underlying conditions should be carefully evaluated before initiating the treatment for hypercalcemia using pamidronate.

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.

Long-standing and poorly controlled disease in juvenile dermatomyositis is associated with calcinosis: a real-world experience from a low-middle income country.

To study the prevalence and predictors of calcinosis in Juvenile Dermatomyositis (JDM). Medical records over 20 years at a tertiary care rheumatology center in Northern India were reviewed to identify patients with JDM and clinical details were recorded. The frequency of calcinosis, predictors, specific treatment, and its outcomes were studied. Data are expressed as median and interquartile range. In eighty-six patients (median age 10) of JDM, the frequency of calcinosis was 18.2% (8.5% at presentation). Younger age at presentation, longer follow-up, heliotrope rash [Odds Ratio (95% confidence interval), 11.4 (1.4-92.12)], chronic or polycyclic course [4.4 (1.2-15.5)] and cyclophosphamide use [8.2 (1.6-41.9)] were associated with calcinosis. Dysphagia [0.14 (0.02-1.2)] and elevated muscle enzymes [0.14 (0.04-0.5)] were negatively associated with calcinosis. Treatment with pamidronate had a good to moderate response to calcinosis in five of seven children. Calcinosis in JDM is associated with long-standing, poorly controlled disease, and the use of bisphosphonates like pamidronate offer promise in the future for its treatment.

[How I treat vitamin D intoxication in a child with cystic fibrosis]. / Comment je traite une intoxication à la vitamine D chez un enfant atteint de mucoviscidose.

At least 80 % of persons with cystic fibrosis are pancreatic insufficient and benefit from daily supplementation with fat-soluble vitamins (ADEK). Magistral formulations offer ideal flexibility for prescriptions tailored to vitamin A, D and E blood levels. However, they expose to human errors, mainly leading to vitamin D intoxication whose clinical features are related to hypercalcaemia. Symptoms are mostly digestive (vomiting, constipation, abdominal pain …) and, less frequently, renal (nycturia …) complaints. When symptoms and/or serum calcium levels ≥ 14 mg/100 ml are present, prompt management is required. Besides interruption of supplementation, rapid intravenous hyperhydration (saline) is essential. Once hydration has been restored, and still under close biological supervision, a loop diuretic (furosemide) may be used but the drug of choice to achieve rapid normalization of blood calcium levels will often be intravenous pamidronate. Normalization of serum vitamin 25(OH)-D levels may take several months but the prognosis is very good. In Belgium, the very late reimbursement of a fixed combination of fat-soluble vitamins (Dekas®) meeting the standards of the pharmaceutical industry is expected to reduce the incidence of these intoxications, at the price, however, of less flexible prescription.

Au moins 80 % des patients atteints de mucoviscidose présentent une insuffisance pancréatique exocrine et bénéficient quotidiennement d'une supplémentation en vitamines liposolubles (ADEK). Une préparation magistrale offre alors une souplesse idéale de prescription. Elle expose cependant à des erreurs humaines, qui mènent surtout à des intoxications à la vitamine D. Les symptômes, souvent surtout digestifs (vomissements, constipation, douleurs abdominales …), voire rénaux (nycturie …), sont liés à l'hypercalcémie. En cas de symptômes et/ou de calcémie ≥ 14 mg/100 ml, une prise en charge immédiate est nécessaire. Outre l'interruption de la supplémentation, elle inclut d'abord une hyperhydratation rapide, par voie intraveineuse (sérum physiologique). Une fois l'hydratation restaurée, et toujours sous contrôles biologiques rapprochés, un diurétique de l'anse (furosémide) peut être utilisé, mais c'est souvent une administration intraveineuse de pamidronate qui permettra la normalisation rapide de la calcémie. Le taux sérique de vitamine 25(OH)-D peut mettre plusieurs mois à se normaliser, mais le pronostic est très bon. Remboursée tardivement en Belgique, une combinaison fixe de vitamines liposolubles (Dekas®), répondant aux normes de l'industrie pharmaceutique, devrait limiter le nombre de ces intoxications au prix, toutefois, d'une moindre souplesse de prescription.

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.

Novel 99mTc labeled complexes with bisphosphonate isocyanide: Radiosynthesis and evaluation as potential bone-seeking agents.

In order to develop 99mTc-labeled complexes with bisphosphonate isocyanide as novel bone imaging agents, two bisphosphonate isocyanide derivatives (CNALN and CNPAM) were synthesized and radiolabeling was performed for preparing the corresponding [99mTc]Tc(I) complexes. [99mTc]Tc-CNALN and [99mTc]Tc-CNPAM were obtained with high radiochemical purity and showed good in vitro stability. Both of them were hydrophilic and had high affinity to hydroxyapatite. The biodistribution studies in mice revealed [99mTc]Tc-CNALN showed higher bone/background ratios at 60 min post-injection. In single photon emission computed tomography (SPECT) imaging study, [99mTc]Tc-CNALN had an obvious accumulation in bone, suggesting it would be a promising bone-seeking agent.

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.

The Effects of Polyphenol, Tannic Acid, or Tannic Acid in Combination with Pamidronate on Human Osteoblast Cell Line Metabolism.

BACKGROUND: This study investigates the effect of tannic acid (TA) combined with pamidronate (PAM) on a human osteoblast cell line. METHODS: EC50 for TA, PAM, and different combination ratios of TA and PAM (25:75, 50:50, 75:25) were measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The combination index value was utilized to analyze the degree of drug interaction, while trypan blue assay was applied to analyze the cells proliferation effect. The mineralization and detection of bone BSP and Osx genes were determined via histochemical staining and PCR test, respectively. RESULTS: The EC50 of osteoblasts treated with TA and a 75:25 ratio of TA and PAM were more potent with lower EC50 at 0.56 µg/mL and 0.48 µg/mL, respectively. The combination of TA and PAM (75:25) was shown to have synergistic interaction. On Day 7, both TA and PAM groups showed significantly increased proliferation compared with control and combination groups. On Day 7, both the TA and combination-treated groups demonstrated a higher production of calcium deposits than the control and PAM-treated groups. Moreover, on Day 7, the combination-treated group showed a significantly higher expression of BSP and Osx genes than both the TA and PAM groups. CONCLUSION: Combination treatment of TA and PAM at 75:25 ameliorated the highest enhancement of osteoblast proliferation and mineralization as well as caused a high expression of BSP and Osx genes.

Bisphosphonate nephropathy: A case series and review of the literature.

From rat studies, human case reports and cohort studies, bisphosphonates seem to impair renal function. However, when critically reviewing the literature, zoledronate and pamidronate are more frequently involved in renal deterioration than other bisphosphonates. When bisphosphonate nephropathy occurs, zoledronate more frequently induces tubular toxicity whereas pamidronate typically induces focal segmental glomerulosclerosis. Thus, although bisphosphonates are highly effective in preventing complications for patients with osseous metastases and are highly effective in preventing fractures for patients with osteoporosis, renal function should be monitored closely after initiation of these drugs.

Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction.

BACKGROUND: Although intravenous (IV) bisphosphonates are first-line medications for the management of hypercalcemia, studies examining their use in patients with preexisting renal dysfunction are limited. OBJECTIVE: The objective of this study is to describe the safety and efficacy of pamidronate and zoledronic acid in the treatment of hypercalcemia in patients with baseline renal dysfunction. METHODS: A retrospective analysis was conducted of IV pamidronate and zoledronic acid in adult patients with hypercalcemia and creatinine clearance (CrCl) <60 mL/min. The primary endpoint was incidence of all-grade serum creatinine (SCr) elevations. Secondary endpoints included refractory hypercalcemia, hypocalcemia, osteonecrosis of the jaw (ONJ), corrected serum calcium (CSC) decrease ≥1.0 mg/dL by day 7 of bisphosphonate administration, and normalization of CSC ≤10.5 mg/dL by days 10 and 30. RESULTS: A total of 113 patients were included (n = 55 pamidronate, n = 58 zoledronic acid). The primary endpoint of all-grade SCr elevation occurred in 28 (24.8%) patients. Grades 3/4 SCr elevations occurred in 10.9% of patients treated with pamidronate and 1.7% of patients receiving zoledronic acid. Approximately 16% and 14% of patients developed grades 1 and 2 hypocalcemia, respectively, and there were no cases of ONJ. Overall, 64.6% of patients achieved normalization of CSC by day 10, and there were no statistical differences between bisphosphonate type and renal function. CONCLUSIONS AND RELEVANCE: The analysis suggests an association between IV bisphosphonates and increased rates of SCr elevations among patients with preexisting renal dysfunction. Future prospective studies are necessary to elucidate these findings.

Bisphosphonate Versus Bisphosphonate and Calcitonin for the Treatment of Moderate to Severe Hypercalcemia of Malignancy.

BACKGROUND: Historically, intravenous (IV) bisphosphonates with calcitonin are the treatment of choice for hypercalcemia of malignancy. However, evidence is lacking. OBJECTIVE: The objective of this study was to compare the use of bisphosphonate versus bisphosphonate with calcitonin for moderate to severe hypercalcemia of malignancy. METHODS: This was a retrospective study evaluating patients who received bisphosphonate and/or calcitonin for treatment of moderate to severe hypercalcemia of malignancy. Patients received usual care plus either (1) bisphosphonate or (2) bisphosphonate with calcitonin. The primary outcome was change in corrected serum calcium concentrations 48 hours after treatment. Secondary outcomes included corrected calcium levels, incidence of normocalcemia and hypocalcemia, time to normocalcemia, hospital length of stay, and cost avoidance. RESULTS: The 48-hour decrease in corrected calcium was less in the bisphosphonate group than in the combination group (2.4 [1.6-3.4] vs 3.9 [3.5-5.3]; P < 0.001). However, initial calcium levels in the combination group were higher than in the bisphosphonate group, and calcium levels at 24, 48, and 72 hours were similar. Secondary outcomes did not differ. Average cost avoidance with bisphosphonate monotherapy was $11 248 per patient and $291 448 per year. CONCLUSIONS AND RELEVANCE: In the treatment of moderate to severe hypercalcemia of malignancy, IV bisphosphonate in combination with calcitonin resulted in a higher difference in corrected calcium levels at 48 hours compared with bisphosphonate therapy alone. However, corrected calcium levels in the first 72 hours, time to normocalcemia, and clinical outcomes were similar. The addition of calcitonin increases cost without substantial clinical benefit, and providers may consider avoiding calcitonin.

Pamidronate as first-line treatment of hypercalcemia in neonatal subcutaneous fat necrosis: A case series.

BACKGROUND: Subcutaneous fat necrosis (SCFN) can be complicated by severe hypercalcemia, which is frequently asymptomatic. Nephrocalcinosis is associated with hypercalcemia and, in other clinical settings, has been linked to furosemide and glucocorticoid use. First-line bisphosphonate therapy treating hypercalcemia in neonatal SCFN is not well described. OBJECTIVES: To describe the biochemical changes and risk of nephrocalcinosis in infants with hypercalcemia, secondary to neonatal SCFN, treated with initial pamidronate. METHODS: A retrospective chart review of five infants treated with initial pamidronate and without furosemide or glucocorticoids. Data were collected on the following: timing of presentation, therapeutic response, and presence of nephrocalcinosis. RESULTS: Hypercalcemia resolved after 2.8±1.7 days; this is compared to 7.6±2.8 days from previously reported cases utilising alternative therapies (P=0.012). There were no episodes of rebound hypercalcemia or hypocalcemia. Nephrocalcinosis was present in four of five cases. When including published cases, age at diagnosis was associated with presenting serum calcium (P=0.003) and nephrocalcinosis was associated with higher serum calcium (P=0.014) and time from SCFN to hypercalcemia diagnosis (P=0.002). CONCLUSIONS: This retrospective case series demonstrates that first-line pamidronate treatment was effective and safe in the resolution of hypercalcemia. Nephrocalcinosis was observed, despite the avoidance of furosemide and glucocorticoid therapy, and associated with greater disease severity and duration of hypercalcemia.

Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia.

Skeletal fragility is a common complication of childhood acute lymphoblastic leukaemia (ALL) but the impact of bisphosphonate therapy on bone mass and fracture is unclear. We aim to conduct a systematic review to evaluate the effects of bisphosphonates on bone mineral density (BMD) and fracture incidence in children with ALL. METHODS: EMBASE, Medline and the Cochrane Library were thoroughly searched by two researchers. Inclusion criteria was any child under the age of 18 years with a diagnosis of ALL, who had received any bisphosphonate treatment and had serial measurements of bone density performed thereafter. All primary research studies of any study design, excluding case reports, were included. RESULTS: Ten full text papers were identified with two exclusively meeting the inclusion criteria. Both studies administered bisphosphonates to children receiving maintenance chemotherapy for varying durations. Bone density was assessed at regular intervals by dual x-ray absorptiometry (DXA). The majority of participants had an improvement in bone density at the end of each study. However, no size adjustment of DXA data was performed. Limited information on fracture occurrence was provided by one study but did not include routine screening for vertebral fractures. CONCLUSIONS: This systematic review identified that there is insufficient evidence to support routine use of prophylactic bisphosphonate therapy in childhood ALL for prevention of fracture and improvement of bone mass. Future well-designed clinical trials in those at highest risk of fractures in ALL are now needed.

Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model.

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.

Do Bisphosphonates Alleviate Pain in Children? A Systematic Review.

PURPOSE OF REVIEW: The goal of this systematic review is to analyze the effectiveness of bisphosphonates (BPs) to treat bone pain in children and adolescents who have diseases with skeletal involvement. RECENT FINDINGS: We included 24 studies (2 randomized controlled trials, 3 non-randomized controlled trials, 10 non-randomized open-label uncontrolled studies, 8 retrospective studies, and 1 study with design not specified). The majority of included studies assessed pain from a unidimensional approach, with pain intensity the most frequently evaluated dimension. Only 38% of studies used validated tools; visual analogue scale was the most frequently employed. BPs were used to alleviate bone pain in a wide variety of pediatrics conditions such as osteogenesis imperfecta, secondary osteoporosis, osteonecrosis related to chemotherapy, chronic non-bacterial osteitis, idiopathic juvenile osteoporosis, unresectable benign bone tumor, and cancer-related pain. Twenty of the 24 studies reported a positive effect of BPs for alleviating pain in different pathologies, but 58% of the studies were categorized as having high risk of bias. Intravenous BPs are helpful in alleviating bone pain in children and adolescents. It is advised that our results be interpreted with caution due to the heterogeneity of the doses used, duration of treatments, and types of pathologies included. In addition, this review shows the paucity of high-quality evidence in the available literature and further research is needed. TRIAL REGISTRATION: Before the completion of this review, the protocol was registered to PROSPERO (International prospective register of systematic reviews), PROSPERO 2020 ID # CRD42020158316. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020158316.

The Influence of Local Pamidronate Application on Alveolar Dimensional Preservation after Tooth Extraction-An Animal Experimental Study.

The aim of this randomized, controlled animal exploratory trial was to investigate the influence of local application of aminobisphosphonate pamidronate during the socket preservation procedure. Mandibular premolars were extracted in five Göttingen minipigs. Two animals underwent socket preservation using BEGO OSS (n = 8 sockets) and three animals using BEGO OSS + Pamifos (15 mg) (n = 12 sockets). After jaw impression, cast models (baseline, eight weeks postoperative) were digitized using an inLab X5 scanner (Dentsply Sirona) and the generated STL data were superimposed and analyzed with GOM Inspect 2018 (GOM, Braunschweig). After 16 weeks, the lower jaws were prepared and examined using standard histological methods. In the test group (BEGO OSS + pamidronate), buccooral dimensional loss was significantly lower, both vestibulary (0.80 ± 0.57 mm vs. 1.92 ± 0.63 mm; p = 0.00298) and lingually (1.36 ± 0.58 mm vs. 2.56 ± 0.65 mm; p = 0.00104) compared with the control group (BEGO OSS). The test group showed a significant difference between vestibular and lingual dimensional loss (p = 0.04036). Histology showed cortical and cancellous bone in the alveolar sockets without signs of local inflammation. Adjuvant application of pamidronate during socket preservation reduces alveolar dimensional loss significantly. Further investigations with regard to dose-response relationships, volume effects, side effects, and a verification of the suitability in combination with other bone substitute materials (BSMs) are necessary.

Prenylation-dependent Ras inhibition by pamidronate inhibits pediatric acute myeloid leukemia stem and differentiated cell growth and survival.

The clinical management of pediatric acute myeloid leukemia (AML) is still challenging and identification of drugs that can enhance the efficacy of standard of care is a potential therapeutic strategy. We show that pamidronate, a FDA-approved drug used for bone disorders, is an attractive candidate for AML treatment. Pamidronate inhibits proliferation and induces apoptosis of AML cells regardless of cellular and genetic heterogeneity. Pamidronate displays selective anti-AML activity by preferentially inhibiting survival and colony formation of AML CD34+ cells while normal bone marrow CD34+ cells are largely unaffected. Importantly, pamidronate remarkably enhances the inhibitory effects of all tested AML standard of care at subtoxic concentration. Mechanism studies show that pamidronate inhibits protein prenylation via dual action on geranylgeranylation and farnesylation, and subsequently decreases Ras activity. The rescue studies using overexpression of constitutively active Ras further confirm that pamidronate augments the efficacy of AML standard of care through inhibiting Ras. Since pamidronate is already used in clinic, our preclinical findings suggest that it may be an effective addition to treatment armamentarium for AML.

Development of scoliosis in young children with osteogenesis imperfecta undergoing intravenous bisphosphonate therapy.

The purpose of this study was to clarify the prevalence of scoliosis and determine risk factors for the development of scoliosis in young children with osteogenesis imperfecta (OI) who underwent intravenous pamidronate (PAM) therapy. Thirty-four young children with OI who had no scoliosis at the first PAM administration underwent cyclic PAM therapy alone. The medical records and radiographs of these patients were retrospectively reviewed. We examined the relationship between scoliosis (Cobb angle ≥ 10) and type of OI (Sillence classification: types I, III, and IV), physical mobility, Z-scores of bone mineral density in L2-4 of the lumbar spine (L2-4 BMD Z-scores), age of patients at first treatment with PAM, pelvic frontal tilt and leg-length discrepancy. The prevalence of scoliosis was 23.5% in 34 young children with OI who underwent PAM therapy for a mean of 4.2 years. Lower L2-4 BMD Z-scores, the presence of coronal and sagittal vertebral deformities and higher percentage of corrective osteotomy in the lower extremities were significant risk factors for the development of scoliosis. In patients with type III or IV OI, L2-4 BMD Z-scores were significantly lower (p = 0.02) and the percentage of patients who started PAM therapy in early childhood was significantly lower in scoliosis group than in the non-scoliosis group (p = 0.01). Development of scoliosis depends on the severity of OI and has a strong relationship with bone fragility even under PAM therapy. Starting intravenous PAM therapy in infancy or early childhood has a potential to prevent the occurrence and progression of scoliosis associated with bone fragility in young children with severe type III or IV OI.

Comparison of different treatment approaches of pediatric chronic non-bacterial osteomyelitis.

Chronic non-bacterial osteomyelitis (CNO) is a chronic inflammatory bone disease which usually manifests in children and adolescents. There are a few data about pathogenesis and treatment. The aim of the study to compare the efficacy of different treatment approaches in pediatric CNO cohort patient. Fifty two children (25 boys and 27 girls) with CNO with average age at the onset of the disease 8.4 years (5.4; 11.0), number of foci - 3.0 (2.0; 6.0, incl. multifocal cases in 80.8%). Non-steroid anti-inflammatory drugs (NSAID) was the first-line treatment for non-vertebral cases, as well as pamidronate (PAM) for vertebral involvement. Second-line treatment includes sulfasalazine (SSZ), methotrexate (MTX), PAM and tumor necrosis factor-α inhibitors (TNFα-inh). We evaluated the dynamics of pain, patient's and physician's (MDVAS) assessment with visual-analog scale (VAS) and ability to each medication to achieve remission of CNO activity. According to the NSAID, MTX, SSZ, PAM and TNFα-inh groups the following data were registered: patient's VAS: - 14.2% (p = 0.05), - 50.0% (p = 0.04), - 23.1 (p = 0.89), - 83.3% (p = 0.0001), - 73.6% (p = 0.0007); painVAS: - 21.9% (p = 0.01), - 18.6% (p = 0.13), + 36.4 (p = 0.89), - 79.7% (p = 0.00016), - 74.1%, (p = 0.0015); MDVAS: - 13.8% (p = 0.13); - 56.4% (p = 0.09), + 30.8% (p = 0.89), - 74.7%, (p = 0.0001), - 82.1 (p = 0.0015) respectively. The ability of each treatment strategy to achieve the CNO remission was 52.6%, 44.4%, 57,1%, 88.8% and 73.3%, respectively (log-rank test, p = 0.001). The efficacy of treatment approaches for CNO depended on the severity of the disease. NSAID, methotrexate, and sulfasalazine were effective in forms without spine involvement, but pamidronate and TNF-a inhibitors were useful in vertebral forms of CNO. Pamidronate and TNF-a inhibitors more extensively suppressed CNO activity. The randomized controlled trials for assessment of the efficacy and safety of these medications is mandatory to confirm these results.

Immediate implant placement following 1-year treatment with oral versus intravenous bisphosphonates: a histomorphometric canine study on peri-implant bone.

OBJECTIVES: Bisphosphonates (BPs) are anti-resorptive medications with inhibitory effects on osteoclasts which decrease bone turnover. The present study aimed to assess the early effects of BPs on peri-implant bone. MATERIALS AND METHODS: Twelve female mongrel dogs were assigned to one control and two experimental groups as follows: 12 months of oral alendronate (ALN, 3.5 mg/kg/week) or intravenous (IV) pamidronate (PAM, 1 mg/kg/week) for experimental groups. Following 8 weeks after implant insertion, the specimens were sacrificed, histological evaluation was performed, and C-terminal telopeptide of collagen I (CTx) analysis was performed on serums. RESULTS: PAM demonstrated the greatest marginal bone level (MBL), 2.64 ± 0.48, followed by ALN and control, 2.5 ± 0.4 and 0.66 ± 0.5 respectively. The least bone-implant contact was observed in PAM group (%39 ± 0.03) while it was significantly greater in the control group (p < 0.05). PAM and ALN demonstrated < 10 CTx levels versus > 300 in controls. CONCLUSION: It is assumed that long-term oral or IV BP therapy decreases marginal bone resorption and osseointegration. These changes were more accentuated in IV BP administration. CTx does not seem to be a precise predictor for bisphosphonate-related osteonecrosis of the jaw. CLINICAL RELEVANCE: BPs impair peri-implant bone remodeling and this phenomena may be effective for reducing resorption at esthetic zone implants; however, decrease in osseointegration may be a concern for implant treatment in patients receiving BPs.