Search

Few reports have investigated medication-related osteonecrosis of the jaws (MRONJ) in the pediatric population. The study purpose was to measure the frequency of MRONJ in pediatric patients receiving antiresorptive medications at our institution.This retrospective case series was granted an exemption by the University of Texas Southwestern Medical Center Institutional Review Board. The primary outcome variable was the presence or absence of MRONJ. Other variables of interest included 1) age at first dose of antiresorptive; 2) sex; 3) antiresorptive medication received; 4) reason for antiresorptive; 5) dental records available; 6) dental extractions that occurred after the start of antiresorptive; 7) exposure to immunosuppressants/chemotherapy; 8) time interval from the last dose of antiresorptive to dental extractions; and 9) longest follow-up after starting antiresorptive. Frequencies and proportions were calculated for categorical data. Medians, means, and standard deviations were calculated for continuous data.The study sample was composed of 122 subjects. We observed 0 cases of MRONJ during the study interval. At the start of antiresorptive treatment, the average age was 8.18 years (range 0.02-17; standard deviation (SD) 5.15). There were 67 males (55%) and 55 females (45%). The reason for antiresorptive treatment was osteogenesis imperfecta in 36 patients, malignancy in 6 patients, and other in 80 patients. Thirty patients received pamidronate, 72 received zoledronate, 17 received a combination, and 3 received only denosumab. A total of 16 patients had exposure to immunosuppressants and/or chemotherapy. The average follow-up time was 4.89 years (median 4 years). Twenty-six patients underwent dental extractions of 74 teeth following antiresorptive treatment.While there were no reported cases of MRONJ in the present study, it is advisable to monitor pediatric patients who have received antiresorptive treatment closely. When possible, appropriate dental treatment should be completed prior to starting antiresorptive therapy. In the absence of reported MRONJ cases, dental extractions should not be withheld because of previous antiresorptive exposure and antiresorptive medication dosing need not be altered in the pediatric population.

Patients with Osteogenesis Imperfecta (OI) present extra-skeletal manifestations, including important orodental and craniofacial features as dentinogenesis imperfecta, dental agenesis, failure of maxilla growth and hypotonia of masticatory muscles. These features may compromise vital functions speech and mastication. Studies have demonstrated that cyclic pamidronate infusion, the standard therapy for patients with moderate to severe OI, influences the histomorphometric pattern of different body bones. The present study aimed to investigate the condyle trabecular bone pattern in OI patients. We used fractal dimension (FD) analysis on dental panoramic radiographic images to characterize the mandibular condyle trabecular bone in adolescents diagnosed with OI and treated with pamidronate. Imaging exam of 33 adolescents of both sexes, aged between 12 and 17 years, were analyzed and compared with 99 age- and sex-matched healthy adolescents. FD in patients was significantly lower (1.23 ± 0.15) than in healthy controls (1.29 ± 0.11; p < 0.01). Type of OI, age at treatment onset, and the duration of therapy were variables that showed a statistically significant effect on the FD results. This study demonstrated that the bone architecture of mandibular condyles may be altered in pediatric patients with moderate and severe forms of OI. Also, pamidronate treatment seems to have a positive effect on condyle trabecular bone in these patients. This is supported by our finding that FD values were positively influenced by the length of cyclic pamidronate treatment at the time of imaging, as well as by the age of the individual at treatment onset.

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.

Objective Atrial fibrillation (AF) may be triggered by intravenous bisphosphonates (IVBPs) such as zoledronic acid or pamidronic acid. Our objective was to confirm the association between AF and IVBPs in a real-life large pharmacovigilance database. Design A systematic analysis of VigiBase, the World Health Organization's pharmacovigilance database. Methods Analysis of adverse events reported as ‘atrial fibrillation’ (according to the Medical Dictionary for Drug Regulatory Activities) associated with the use of zoledronic acid or pamidronic acid, in VigiBase, the World Health Organization's global Individual Case Safety Report (ICSR) database. All ICSRs reporting AF associated with zoledronic acid or pamidronic acid were included in a disproportionality analysis determining the lower end of the 95% credibility interval for the information component (IC025), showing a statistical association when >0. Results 530 ICSRs reporting on the association between AF and IVBPs were extracted. Bayesian disproportionality analysis detected a significant association between AF and use of zoledronic acid (IC025 = 1.83) and pamidronic acid (IC025 = 2.16). Further analysis of these ICSRs determined that AF was severe in 85.0% of cases and with a mortality of 17.7%. The risk of severe AF was increased (OR: 2.98 (95% CI: 1.17–7.57), P = 0.02) following zoledronic acid vs pamidronic acid, after adjustment for age and gender. Conclusions This is the first VigiBase pharmacoepidemiological study confirming the association between IVBPs and AF. Most AF were severe, with a high frequency of lethal outcome. The risk of severe AF was increased following zoledronic acid use compared to pamidronic acid, advocating for a cautious use of IVBPs.

Paget's disease of bone (PDB) is a focal disorder of accelerated skeletal remodelling that is uncommon in patients under the age of 40 years; it is more prevalent in older individuals. We report two cases of PDB diagnosed in early adulthood at the Mohamed Kassab Institute of Orthopedics, La Manouba, Tunisia. The first case was a 35-year-old male patient who presented in 2011 with a seven-month history of hip pain. The second case was a 39-year-old female patient who presented 2014 with chronic lower back pain. The PDB diagnosis was confirmed with clinical, biological and radiological investigations. Both patients were doing well on follow-up. Some previous cases have been reported in the literature, differing from the presented cases in some aspects; data of PDB features at differing ages is still insufficient. Early recognition of this clinical entity in young patients is important as early treatment can affect the progression of the disease.

Background: Osteogenesis imperfecta (OI), is a heritable, heterogeneous connective tissue disorder, characterized by fragile bones. There are conflicting results about genotype-phenotype correlations and efficiency of bisphosphonate treatment in this disorder. Aim: We aimed to evaluate the clinical, genetic characteristics, and long-term follow-up results of children and adolescents with OI. Materials and methods: A two-center retrospective study was conducted using demographic, clinical, and genetic data obtained from the medical records of the patients. Results: Twenty-nine patients (62% male, median age; 3.6 years) with OI diagnosis from 26 families were included in the study. Thirteen different variants (nine were novel) were described in 16 patients in COL1A1, COL1A2, and P3H1 genes. Our siblings with homozygous P3H1 variants had a severe phenotype with intrauterine and neonatal fractures. Twenty-two patients were treated with bisphosphonates (17 of them with pamidronate, five with alendronate) with a median duration of 3.0 (1.6-4.8) years. Eleven patients (50%) suffered from fractures after the treatment. Haploinsufficiency variants in COL1A1 caused a milder skeletal phenotype with less fracture count and better treatment outcomes than structural variants. When compared with the anthropometric measurements at the initial diagnosis time, height Z-scores were lower on the last clinical follow-up (p = 0.009). Conclusions: We could not find an obvious genotype-phenotype correlation in Turkish OI patients with COL1A1 or COL1A2 variants. Treatment with pamidronate was effective in reducing fracture counts, without any long-term adverse effects.

Objectives Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by recurrent fractures due to congenital bone fragility. The only bisphosphonate approved for OI in Japan is pamidronate (PAM). To investigate whether monthly intravenous alendronate (ALN) infusions can maintain bone strength in OI children following cyclical PAM treatment. Methods A prospective and non-inferiority study was conducted. Eight school-age OI patients aged 8.5±2.0 years who were treated with cyclical PAM for 6.0±2.3 years were enrolled and switched to monthly intravenous ALN (0.030 mg/kg/month). Changes in L1-4 bone mineral density (BMD) Z-scores, fracture rates, and bone turnover markers for 12 months were analyzed. Results Average BMD Z-scores were −3.0±1.9, −2.9±2.0, and −2.2±2.0 in 12 months before enrollment, at enrollment, and after 12 months of ALN treatment, respectively. BMD Z-scores increased significantly during treatment with both PAM and ALN (p=0.012), and the effect of ALN was not inferior to that of PAM (p=0.67). There was no change in fracture rates (p=0.86) and bone turnover markers during the 12 months before and after enrollment. Additionally, ALN showed no remarkable side effects. Conclusions Our results suggest that monthly intravenous ALN can maintain bone strength after primary usage of cyclical PAM. We concluded that monthly intravenous ALN as a maintenance treatment following cyclical PAM administration can be an option for OI children.

Bone-modifying agents (BMAs) are frequently used for the treatment of bone metastases. Both BMA and radiation therapy (RT) are effective; however, there are few studies that have evaluated the efficacy of the combination treatment. We evaluated the effectiveness of RT + BMA in breast cancer-induced osteolytic bone metastasis as compared to BMA alone. A total of 43 lesions in 25 patients were evaluated. The median follow-up period was 18 (range, 2–90) months. None of the lesions was treated with chemotherapy or molecular targeted drugs during the follow-up period for evaluating the local response. Patients with complete or partial response were considered as responders, while those with stable or progressive disease were considered as non-responders. The rate of response with RT + BMA was significantly higher than that with BMA alone (P = 0.001). The cumulative incidence rate of response at 6 months was 54.4% in the RT + BMA group and 27.5% in the BMA alone group. The median time to response was 4 (range, 2–11) months in the RT + BMA group and 6 (range, 4–16) months in the BMA alone group. The overall survival rate in the responder group (83.1% at 1 year) was significantly higher than that in the non-responder group (37.5% at 1 year) (P = 0.029). In conclusion, RT combined with BMA was found to be more effective than BMA alone for the treatment of osteolytic bone metastasis, which thereby improves the prognosis.

Background: Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. Methods and Results: A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. Conclusion: This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.

Background Studies evaluating treatment responses for chronic nonbacterial osteomyelitis (CNO) are lacking. We aimed to measure and compare response rates of medical treatments, time to response of medical treatments among patients with CNO of the mandible, and describe bacterial contamination rates from biopsy. Methods We conducted a retrospective chart review of all patients diagnosed with CNO of mandible between 2003 and 2017 and extracted demographic, clinical, laboratory, imaging and surgical data. Detailed medication use and response to medications were recorded. The primary outcome was response to medical treatments defined as improvement of presenting symptoms, inflammatory markers, and imaging if available. Medical treatments included nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti rheumatic drugs (DMARDs), anti-tumor necrosis factor (TNF) therapy, and pamidronate. Descriptive analysis was performed when appropriate. Multivariable logistic regression and Kaplan-Meier curves were applied to compare the responses to medical treatments and time to full response. Results We identified 22 patients with a median age of 11 and 36% were female. Four patients (18%) had multifocal bone lesions. CT findings (n = 21) showed lytic lesions (62%) and sclerosis (90%). MRI (n = 14) revealed hyperintensity within bone marrow (100%), soft tissue (71%) and bony expansion (71%). Non-antibiotic treatments including NSAIDs (n = 18), glucocorticoids (n = 10), DMARDs (n = 9), anti-TNF therapy (n = 5) and pamidronate (n = 6) were applied. Rates of full responses to anti-TNF therapy (60%) and pamidronate (67%) were higher than that to NSAIDs (11%) (p p = 0.01) when there was a full response. All had bone biopsies. Intraoral biopsy was performed in 12 of 13 operated in our center and the most common contaminants were Neisseria spp and Streptococcus viridians. Conclusion Both anti-TNF and pamidronate appeared superior to NSAIDs alone in treating mandibular CNO. Patients receiving pamidronate responded faster than those receiving anti-TNF therapy.

Background We investigated the efficacy of hyperbaric oxygen (HBO), low-intensity laser (LIL), and platelet-rich plasma (PRP) in the management of medication-related osteonecrosis of the jaws (MRONJ). Methods A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two examiners independently assessed eligibility and risk of bias and extracted data. Results There was improvement in 75.6% of the 41 patients submitted to HBO, with positive effects on pain relief and decreased size and number of lesions at a faster rate, with better effects when the drug was discontinued. For LIL, 158 (64.2%) of the 246 patients/sites improved the symptoms and 98 (39.8%) healed completely. Fourteen (17.3%) of the 81 patients treated with PRP significantly improved the symptoms and 65 (80.2%) completely healed. Conclusions These therapies served as safe and effective adjuvant modalities for MRONJ treatment. The lack of randomized clinical trials evidences the need for more high-quality investigations on the subject.

Eren, Erdal/0000-0002-1684-1053; yilmaz, gulay can/0000-0003-0525-1231; Demir, Korcan/0000-0002-8334-2422; UCAKTURK, Seyit Ahmet/0000-0001-8666-4454; Kara, Cengiz/0000-0002-8989-560X WOS: 000469271100005 PubMed: 30396880 Objective: No large study has been conducted to date to compare the effectiveness of prednisolone, alendronate and pamidronate as first-line treatment in children with hypercalcemia due to vitamin D intoxication. The aim was to perform a multicenter, retrospective study assessing clinical characteristics and treatment results. Methods: A standard questionnaire was uploaded to an online national database system to collect data on children with hypercalcemia (serum calcium level > 10.5 mg/dL) due to vitamin D intoxication [serum 25-hydroxyvitamin D (25(OH)D) level > 150 ng/mL] who were treated in pediatric endocrinology clinics. Results: Seventy-four children [median (range) age 1.06 (0.65-1.60) years, 45 males (61 %) from II centers] were included. High-dose vitamin D intake was evident in 77% of the cases. At diagnosis, serum calcium, phosphorus, alkaline phosphatase, 25(OH)D and parathyroid hormone concentrations were 15 +/- 3.2 mg/dl., 5.2 +/- 1.2 mg/dL, 268 +/- 132 IU/L, 322 (236-454) ng/ml, and 5.5 (3-10.5) pg/mL, respectively. Calcium levels showed moderate correlation with 25(OH)D levels (r(s) = 0.402, p

Objectives.Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder with an unpredictable disease course. The objective was to assess clinical and radiological disease activity in children with CNO including response to early-onset pamidronate treatment.Methods.A single-center retrospective study was conducted of children fulfilling the Bristol Criteria for CNO. At the time of diagnosis, whole-body magnetic resonance imaging (WB-MRI) or local MRI was performed to assess radiological disease activity. Children with multifocal or spinal bone inflammation and clinical disease activity not responding to nonsteroidal antiinflammatory drugs were categorized as having extended CNO. Clinical disease activity was assessed annually.Results.Fifty-one children were included. Median followup time was 4 years (interquartile range 3–7). Children categorized with extended CNO (n = 32) were treated in an early-onset 2-year pamidronate regimen. In extended CNO, WB-MRI was performed at time of diagnosis, and at years 1 and 2 in 88%, 84%, and 91% of cases, respectively. During the first year, the total number of radiologically active lesions and number of spinal lesions per patient declined (p = 0.01). Clinically inactive disease was recorded in 12/32 children (38%). However, 8/12 children (67%) experienced clinical relapse. In limited CNO (n = 19), 10/19 children (53%) presented with clinically inactive disease after 1 year and did not experience clinical relapse.Conclusion.Pamidronate might contribute to improvement in clinical and radiological disease activity in extended CNO, especially after 1 year of treatment. However, children with continuously active disease after 2 years of pamidronate treatment were seen.

Denosumab is an anti-RANKL antibody that is commonly used for the treatment of osteoporosis; in oncology, bisphosphonates and denosumab have become the standard therapies for the treatment and prevention of skeletal complications in patients with myeloma and solid tumors. In recent years, excessive bone remodeling following the discontinuation of denosumab has raised concerns. Several cases of hypercalcemia have been reported after the discontinuation of high-dose denosumab (120 mg every 4 weeks), mainly in children. In this study, we report a new case of severe refractory hypercalcemia in a 54-year-old woman who received high-dose denosumab for 5 years as an adjuvant therapy for breast cancer. She is currently in remission and undergoing treatment with anastrazole, an aromatase inhibitor. The peculiarities of this case are the presence of associated bone pain with subperiosteal bone resorption on hand X-rays, and diffuse, long bone diaphyseal uptake on a bone scan. Hyperparathyroidism has been ruled out, and existing evidence suggests that this high-level of bone remodeling could be due to a rebound hyperactivation of the RANKL pathway. In addition to rehydration, repeated use of i.v. bisphosphonates was required to control recurrent hypercalcemia. As hypercalcemia is a serious metabolic complication, a gradual dose reduction should be considered when interruption of high dose denosumab therapy is planned.

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.

Subcutaneous fat necrosis (SFN) in the newborn is a form of panniculitis which presents with erythematous nodules and indurated plaques. Severe life-threatening hypercalcaemia can occur as a late complication. A 2-month-old girl presented with severe hypercalcaemia and acute renal injury as a complication of SFN. She was admitted to hospital with the chief complaint of failure to thrive. She had a history of therapeutic hypothermia. After successful treatment of the hypercalcaemia with bisphosphonates, the acute renal injury recovered spontaneously. In neonates with SFN, acute renal injury is a rare complication of hypercalcaemia. Timely prevention of the complications of hypercalcaemia in SFN is essential.

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.

Aims: To evaluate whether 2 years of treatment with bisphosphonates in combination with calcium/vitamin D supplements has an effect on lumbar spine and hip bone mineral density (BMD) in ankylosing spondylitis (AS) patients starting tumour necrosis factor-α inhibitors or receiving conventional treatment. Secondly, to explore the development of radiographic vertebral fractures. Methods: Patients from the Groningen Leeuwarden AS cohort receiving bisphosphonates based on clinical indication and available 2-year follow-up BMD measurements were included. BMD of lumbar spine (L1–L4) and hip (total proximal femur) were measured using dual-energy X-ray absorptiometry. Spinal radiographs (Th4–L4) were scored for vertebral fractures according to the Genant method. Results: In the 20 included patients (median 52 years, 14 males), lumbar spine and hip BMD Z-scores increased significantly; median from −1.5 (interquartile range [IQR] −2.2 to 0.4) to 0.1 (IQR −1.5 to 1.0); P

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.

Context Bisphosphonates are effective for hypercalcemia of malignancy (HOM). Efficacy and safety data for bisphosphonates in parathyroid hormone–related hypercalcemia (PTHRH) are rare, including pamidronate (Pam), which is not indicated for this condition. Objective This work aims to evaluate the efficacy and safety of Pam for moderate-to-severe PTHRH. Methods This retrospective case-control study was conducted at a tertiary care medical center. Patients included adults hospitalized with serum calcium levels greater than 12 mg/dL, from October 29, 2013 to December 17, 2019. Etiology was categorized as PTHRH or PTH-independent. Clinical and laboratory data of PTHRH patients treated with Pam (PTHRH-Pam+) were compared to Pam-untreated counterparts (PTHRH-Pam–). Results Thirty-four patients with 37 hospitalizations for PTHRH (Pam-treated and -untreated) met the inclusion criteria. Pam was given in 24 of 37 cases (64.8%). Admission serum calcium levels for the PTHRH-Pam+ group were higher than for PTHRH-Pam– group (14.4 mg/dL vs 13.0 mg/dL, P = .005). Median total Pam dose was 60 mg (range, 30-180 mg) in the treated group. Serum calcium decreased 3.5 mg/dL for PTHRH-Pam+ vs 1.6 mg/dL for PTHRH-Pam– (P = .003). No PTHRH-Pam+ patients developed hypocalcemia or acute kidney injury. Nadir serum phosphorus levels were lower in the PTHRH-Pam+ vs PTHRH-Pam– group (1.7 mg/dL vs 2.4 mg/dL, respectively, P = .004). Three PTHRH-Pam+ patients developed severe hypophosphatemia; all resolved with intravenous and oral supplementation. Seventeen patients underwent parathyroidectomy, of whom 10 received Pam within 28 days preoperatively. Postoperatively, 4 developed hypocalcemia and 3 hypophosphatemia. Conclusion This study demonstrates that Pam is effective and safe for treating PTHRH, while ensuring close laboratory monitoring of calcium and phosphorus metabolism. Larger, prospective studies are needed to establish the role of Pam and other potent bisphosphonates in moderate-to-severe PTHRH.

Osteogenesis imperfecta is characterised by low bone mineral density, bone fragility, fractures and deformity. We present five such children treated with intravenous pamidronate, which resulted in a decrease of fracture rate and increase in spinal bone mineral density.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome shows a wide variability in musculoskeletal and cutaneous manifestations, and it is therefore underrecognized and misdiagnosed in the clinic due to a lack of specific markers. In this study, we aimed to identify specific biomarkers by screening serum autoantibodies in SAPHO patients with a 17K human whole-proteome microarray. The serum anti-Sp17 autoantibody was identified and verified to be a specific biomarker in patients with SAPHO syndrome. Indeed, the level of the anti-Sp17 autoantibody was significantly increased in patients with active SAPHO compared to patients with an inactive disease and healthy controls (P

The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ), a morbid condition associated with bisphosphonate administration, has not been fully elucidated. Recent research utilizing a murine model has revealed that the neutrophil becomes dysfunctional following exposure to bisphosphonates. Accordingly, the impairment of neutrophil function could play an important role in the pathogenesis of MRONJ via an infectious mechanism mediated by the suppression of the innate immune system. Currently, the existing human data are insufficient to substantiate this theory. To investigate, we isolated neutrophils from blood and oral rinse samples from bisphosphonate-naïve patients who were recently diagnosed with multiple myeloma both prior to and one month following their initial infusion of pamidronate, an intravenous bisphosphonate agent. Stimulated blood and oral neutrophil superoxide production and chemotactic capabilities were found to be impaired relative to baseline values. These results suggest that impaired neutrophil function may partially contribute to the aetiology underlying the pathophysiological processes linked to the development of MRONJ. Further, as the functional status of circulating neutrophils was reflected in the oral cavity where sampling can be accomplished in a non-invasive fashion, it is conceivable that neutrophil function could serve as a potential biomarker for MRONJ prognostication.

Objective: This is the first randomized double-blinded, placebo-controlled pilot trial to investigate the efficacy of pamidronate in reducing radiological and clinical disease activity in chronic non-bacterial osteomyelitis (CNO). Method: Patients received pamidronate or placebo at baseline and weeks 12 and 24. Whole-body magnetic resonance imaging was performed at baseline and weeks 12 and 36, and computed tomography of the anterior chest wall (ACW) at baseline and week 36. Radiological disease activity was systematically scored in the ACW and spine. Patient-reported outcomes [visual analogue scale (VAS) pain, VAS global health, Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions (EQ-5D), and 36-item Short-Form Health Survey (SF-36)] and biomarkers of bone turnover and inflammation were assessed at baseline and weeks 1, 4, 12, 24, and 36. Data are expressed as median [interquartile range]. Results: Fourteen patients were randomized and 12 were analysed. From baseline to week 36, the radiological disease activity score in the ACW decreased from 5 [4–7] to 2.5 [1–3] in the pamidronate group, but did not change in the placebo group (p = 0.04). From baseline to week 36, VAS pain and VAS global health tended to decrease more in the pamidronate than in the placebo group (p = 0.11, p = 0.08). Physical functioning (HAQ) and health-related quality of life (EQ-5D, SF-36) did not change. Biomarkers of bone turnover decreased only in the pamidronate group (p ≤ 0.02). Conclusion: Pamidronate may improve radiological and clinical disease activity in CNO. Methods to score radiological disease activity in adult CNO were suggested. Clinical Trials: NCT02594878.

Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by repeated fractures and skeletal disorders. At present, bisphosphonate (BP) therapy is the gold standard for OI treatment. The present retrospective study evaluated the effect of BP therapy on tooth development and eruption of permanent teeth in a cohort of children receiving pamidronate. Three groups were studied: patients with OI who were treated with BPs (n = 45), patients with OI who were not treated with BPs (n = 117), and age- and gender-matched healthy controls (n = 121). Dental age, dental maturity, and tooth eruption were assessed on panoramic radiographs using the methods of Demirjian et al. (Hum Biol 45(2):211–227, 1973) and Haavikko (Suom Hammaslaak Toim 66(3):103–170, 1970) and were evaluated using the t-test, Chi-square test, and the Mann–Whitney U test. Dental age in the study group was significantly (p p p

Summary We report the case of a 65-year-old female who presented with symptomatic hypercalcaemia (corrected calcium of 4.57 mmol/L) with confusion, myalgias and abdominal discomfort. She had a concomitant metabolic alkalosis (pH 7.46, HCO3- 40 mmol/L, pCO2 54.6 mmHg). A history of significant Quick-Eze use (a calcium carbonate based antacid) for abdominal discomfort, for 2 weeks prior to presentation, suggested a diagnosis of milk-alkali syndrome (MAS). Further investigations did not demonstrate malignancy or primary hyperparathyroidism. Following management with i.v. fluid rehydration and a single dose of i.v. bisphosphonate, she developed symptomatic hypocalcaemia requiring oral and parenteral calcium replacement. She was discharged from the hospital with stable biochemistry on follow-up. This case demonstrates the importance of a detailed history in the diagnosis of severe hypercalcaemia, with MAS representing the third most common cause of hypercalcaemia. We discuss its pathophysiology and clinical importance, which can often present with severe hypercalcaemia that can respond precipitously to calcium-lowering therapy. Learning points: Milk-alkali syndrome is an often unrecognised cause for hypercalcaemia, but is the third most common cause of admission for hypercalcaemia. Calcium ingestion leading to MAS can occur at intakes as low as 1.0–1.5 g per day in those with risk factors. Early recognition of this syndrome can avoid the use of calcium-lowering therapy such as bisphosphonates which can precipitate hypocalcaemia.

Background Optimal dosing of bone-targeted agents (BTAs), in patients with bone metastases remains an important clinical question. This trial compared 4-weekly versus 12-weekly therapy. Patients and methods Patients with bone metastases from breast or castration-resistant prostate cancer (CRPC), who were going to start or already on BTAs, were randomised 1:1 to 4-weekly or 12-weekly BTA treatment for one year. Primary end point was change in health-related quality of life (HRQoL)-physical function European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30). Secondary end points included pain (EORTC-QLQ-BM22), global health status (EORTC-QLQ-C30), symptomatic skeletal events (SSEs) rates and time to SSEs. Primary analysis was per protocol and a non-inferiority margin of 5 points was used. Results Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). Using repeated-measures analysis, across all time points, patients in the 4-weekly arm had a mean HRQL-physical subdomain score which was 1.2 (95% confidence interval: -1.6 to 4.0) higher than the 12-weekly arm. The study met the definition of non-inferiority for our primary outcome. Secondary outcomes showed no significant difference in scores for pain, global health status, SSE rates and SSE-free survival between arms. Subgroup analyses for cancer type, prior BTA use or BTA type showed no significant difference between arms. Conclusion These results in addition to those previously reported for de-escalating zoledronate and systematic reviews in both breast and prostate cancers, would support that de-escalation of commonly used BTAs is a reasonable treatment option., Highlights • Four- versus 12-weekly therapy of bone-targeting agents in patients with bone metastases from breast or prostate cancer. • BTAs used in the study are pamidronate, zoledronate and denosumab. • Twelve-weekly therapy was non-inferior to 4-weekly therapy for the primary outcome of health-related quality of life. • No significant difference was seen in symptomatic skeletal event (SSE) rates and SSE-free survival between arms. • Results consistent with previous studies, suggests that de-escalation of BTAs is a reasonable treatment option.

Context: Primary hyperparathyroidism (PHPT) in pregnancy has historically been associated with substantial maternofetal morbidity and mortality rates. The optimal treatment and timing of surgical intervention in pregnancy remain contested. Objective: To compare maternofetal outcomes of medically and surgically treated patients with PHPT in pregnancy. Design: Retrospective chart review. Setting: Quaternary referral hospital. Patients: Women with PHPT in pregnancy treated between 1 January 2000 and 31 December 2015. Interventions: Medical therapy or parathyroid surgery. Main Outcomes Measured: Timing of diagnosis; maternal corrected serum calcium concentrations; gestation, indication and mode of delivery; complications attributable to PHPT; birth weight; and admission to the neonatal intensive care unit (NICU). Results: Twenty-two pregnancies were managed medically, and six patients underwent parathyroidectomy in pregnancy (five in trimester 2, and one at 32 weeks gestation). Most patients treated medically either had a corrected serum calcium concentration

Summary Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment. Learning points: Metastases can develop many years after parathyroid cancer diagnosis. Surgery is the only curative treatment for parathyroid carcinoma. Chemotherapy and radiotherapy prove to be ineffective in parathyroid cancer treatment. Patient registering is required in order to delineate underlining pathology and offer specific treatment.

Objectives Fibrous dysplasia of bone is a rare sporadic benign congenital condition in which normal cancellous bone is replaced by fibro-osseous tissue with immature osteogenesis. Sarcomatous transformation is exceptional. Lesions may involve one bone (monostotic) or several (polyostotic). Fibrous dysplasia may be associated with cafe-au-lait skin macules and endocrinopathy in McCune-Albright syndrome, or with myxoma in Mazabraud's syndrome. Methods We report ten cases of patients followed up for craniofacial fibrous dysplasia in our center between 2010 and 2015. Results Mean age was 43 years (range, 10–72 years). Clinical symptoms comprised headache ( n = 3) and sensorineural disorder: recurrent anterior uveitis ( n = 1), visual acuity loss, epiphora and vestibular syndrome ( n = 1), and hearing loss ( n = 1). All cases were monostotic. The sphenoid bone was most commonly involved ( n = 5), followed by the ethmoid ( n = 1), frontal ( n = 1), fronto-ethmoid ( n = 1), temporal ( n = 1) and fronto-ethmoido-sphenoid ( n = 1) bones. Five patients were treated with intravenous pamidronate, a bisphosphonate: evolution was favorable for 3 of them at 1–6 months after treatment initiation, with resolution of headache or vestibular syndrome; the other 2 patients were stable. Two patients were operated on. Conclusion Diagnosis of craniofacial fibrous dysplasia should be considered in case of headache, neuralgia, sensory disorder, functional disorder or infectious ENT complications. A medico-surgical approach is useful for these patients.

Sternocostoclavicular hyperostosis (SCCH) is an infrequent chronic inflammatory disorder of the axial skeleton of unknown origin. SCCH goes often unrecognized due to a low level of awareness for the disorder. It typically presents with relapsing and remitting pain in the shoulder, neck, and anterior chest wall area with occasional swelling and tenderness of the sternoclavicular area. The diagnosis is confirmed radiologically by sclerosis and hyperostosis of the sternoclavicular joints. There have been several reports in which intravenous bisphosphonates and tumor necrosis factor-inhibitors have shown reasonable efficacy in the treatment of this disorder. We report a patient with a long history of SCCH in whom pamidronate 60 mg intravenously every 3 months for 3 years failed to reduce symptom severity and improve radiologic findings.

BACKGROUND Hypercalcemia is a common complication in the intensive care unit (ICU). It can be a result of diverse etiologies, such as malignancy. In this case, bisphosphonates can serve as an effective therapeutic option. However, bisphosphonates are not safe to use in patients with end stage renal disease. CASE REPORT We report a case of severe hypercalcemia possibly secondary to bone metastasis. The patient is known to have end-stage renal disease (ESRD) and undergoing dialysis 3 times a week. She had severe persistent hypercalcemia which did not resolve with regular measures or calcitonin. The literature was searched for the possibility of administering bisphosphonate as a treatment option. It was found that pamidronate pharmacokinetics can be safe and effective in end-stage renal disease patients. Therefore, Pamidronate was administered, showing effective results with regards to the level of calcium and no observed adverse effects. Re-dosing was required at an 8-week interval, with no adverse effects. CONCLUSIONS Pamidronate is a safe option to use in treating hypercalcemia in end-stage renal disease patients on dialysis. This can be especially beneficial in patients with sustained hypercalcemia secondary to malignancy.

Summary Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del). Learning points: Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management. In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered. Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis. In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months. Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.

During pregnancy and lactation, the maternal skeleton undergoes significant bone loss through increased resorption to provide the necessary calcium supply to the developing fetus and suckling neonate. This period of skeletal vulnerability has not been clearly associated with increased maternal fracture risk, but these physiological conditions can exacerbate an underlying metabolic bone condition like osteogenesis imperfecta. While bisphosphonates are commonly used in post-menopausal women, there are cases where pre-menopausal women taking bisphosphonates become pregnant. Given bisphosphonates’ long half-life, there is a need to establish how bisphosphonates affect the maternal skeleton during periods of demanding metabolic bone changes that are critical for the skeletal development of their offspring. In the present study, pamidronate amplified pregnancy-induced bone mass gains and lactation-induced bone loss was prevented. This preservation of bone mass was less robust when pamidronate was administered at late stages of lactation compared to early pregnancy and first day of lactation. Pregnancy-induced osteocyte osteolysis was also observed and was unaffected with pamidronate treatment. No negative skeletal effects were observed in offspring from pamidronate-treated dams in spite of lactation-induced bone loss prevention. These findings provide important insight into a treatment window for when pamidronate is most effective in preserving maternal bone mass and provides significant insight to the maternal changes in bone metabolism that maintain calcium homeostasis crucial for fetal and neonatal bone development.

Calcific uremic arteriolopathy (CUA) is a highly morbid condition usually found in ESRD patients that has rarely been reported after renal transplantation and renal function restoration. Furthermore, little is known about the optimal management of CUA in this setting. Herein, we report on the clinical case of AB, a 70-year-old woman who developed CUA after renal transplantation and renal function restoration. However, other risk factors for CUA such as diabetes and warfarin treatment, due to mechanical aortic valve implantation, were present. Thirty-eight months after renal transplantation she developed erythema and livedo reticularis in both legs and a gradually enlarging skin ulcer in the right leg. A skin biopsy of the ulcer showed features compatible with the CUA, such as sub-intimal calcification and luminal obstruction of the small dermal arterioles, tissue ischemia and signs of adipocytes degeneration. A multidisciplinary approach was adopted, including medical and non-medical treatments such as surgical debridement and vacuum-assisted closure therapy. Medical treatments included a five weeks course of once a week intravenous infusion of pamidronate and intravenous sodium thiosulfate (STS) at increasing doses. Four months after beginning the therapy with STS, a complete healing of the ulcer on the right leg and the disappearance of the livedo reticularis on the left leg was noted. In conclusion, although rare CUA may develop also in renal transplanted patients, a timely and combined therapeutic approach is essential for its resolutive treatment. Sodium thiosulfate therapy has proven to be effective and tolerated.

IntroductionChronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion.MethodsTwelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting.ResultsResults showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments.ConclusionsThe rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.

Bisphosphonates are regarded as standard of care for severe forms of osteogenesis imperfecta (OI).1 Intravenous administration is well tolerated and short-term adverse effects are mild; however, more severe reactions were occasionally reported.2 Although anaemia is a known side effect of intravenous bisphosphonates in adults,3 it has not been reported in children with OI. Here, we investigated blood parameters changes in patients with OI treated with intravenous pamidronate. In this retrospective study, we included children with OI treated in our site over April 2014–May 2018 period. Eligible patients had at least one treatment cycle with complete blood morphology data from before the first dose and >12 hours after last infusion. Pamidronate was administered according to the ‘standard protocol’2; it was diluted in 50 or 100 mL of 0.9% sodium chloride and administrated …

Background: To study the response to pamidronate using whole body magnetic resonance imaging (WB-MRI) in children with chronic non-bacterial osteitis (CNO) in a tertiary health centre. Methods: The medical records of children under the age of sixteen with a diagnosis of chronic non-bacterial osteitis between 2005 and 2018 were reviewed. All those who were treated with pamidronate were included and relevant data was collected. Response to therapy was determined based on the status of lesions on WB- MRI. Results: Forty six patients were included in the study. Pre- and post-treatment WB-MRI was available in forty patients. Cumulative lesions pre-treatment were 150 and reduced to 45 (30%) post-treatment. Seventeen patients (42.5%) had a good response with complete resolution of all lesions and nine patients (22.5%) worsened during or following treatment with pamidronate. Vertebral disease had a good response and 82.3% of the lesions resolved completely. Conclusion: Our study describes the experience with pamidronate in a tertiary health centre using WB-MRI as a marker of disease activity. Pamidronate was well tolerated in our cohort and treatment response was fairly good. Significance and innovation: 1. Bisphosphonates can be used in the treatment of CNO when response to NSAIDs is suboptimal. 2. In the presence of spinal or mandibular lesions bisphosphonates were used as first line. 3. Treatment was escalated to a TNF blocker when response to bisphosphonates was suboptimal.

Osteogenesis imperfecta (OI) consists of a group of genetically and phenotypically heterogeneous diseases characterised by bone fragility. Recent improvement in gene sequencing methods has helped us identify rare forms of OI that are inherited in an autosomal recessive manner. Paediatric endocrinology was consulted on a newborn girl with multiple fractures and wavy thin ribs noted on X-rays. In addition to the bone phenotype, she also has short stature and recurrent acute liver failure (ALF) episodes triggered by intercurrent illness. Whole exome sequencing revealed two novel compound heterozygous variants in neuroblastoma amplified sequence (NBAS) gene. NBAS gene codes for a protein that is involved in nonsense-mediated decay pathway and retrograde transport of proteins from Golgi to endoplasmic reticulum. Recognition of pathogenic variants in this gene as a rare cause of autosomal recessive OI and recurrent ALF has important therapeutic implications.

Atypical subtrochanteric and diaphyseal femoral fractures (AFFs) have emerged as a potential complication of bisphosphonate treatment in adults. Despite increasing off-label use of bisphosphonates in children and adolescents for a variety of skeletal disorders, there have been no reports of AFFs in children or adolescents outside of the osteogenesis imperfecta population. We present the case of a 16-year-old girl who developed a subtrochanteric femoral stress fracture following pamidronate treatment for idiopathic juvenile osteoporosis.

Pamidronate is a bisphosphonate drug widely utilized in veterinary oncologic practice for the palliation of malignant osteolysis. Pamidronate has not been previously reported to cause tissue injury upon extravasation in dogs. The medical records of 11 client-owned dogs undergoing palliative treatment for primary bone tumors with known or suspected pamidronate extravasation reactions were reviewed. The majority of adverse events were low grade in nature, however in some cases, the reactions were severe and led to euthanasia in one instance. Time to complete resolution of lesions ranged from within several days to greater than one and a half months. Aside from the dog that was euthanized, no long-term sequelae of extravasation were identified. Treatments employed to address the reactions varied widely. Pamidronate extravasation reaction appears to be an uncommon, but potentially serious complication of intravenous administration.

BACKGROUND Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. METHODS The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. RESULTS Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. CONCLUSION In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. IMPLICATIONS FOR PRACTICE Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.

Some children with cerebral palsy (CP) have frequent fractures due to low bone mineral density and receive treatment with pamidronate, an intravenous bisphosphonate. Our review evaluates the outcome of pamidronate treatment in these children.A retrospective chart review was performed, and 32 patients (14 girls and 18 boys) with CP Gross Motor Function Classification System level III (2 patients), IV (3 patients), and V (27 patients) treated with 5 courses of pamidronate for low mineral density were identified. Patients with a minimum of 2 years of follow-up were included in the study. Data collection was a review of the demographics and pretreatment, peritreatment, and posttreatment fracture history.The mean age at treatment was 11.6 years (range, 2.9 to 19.6 y). There were 102 fractures (mean duration 2.5 y) pretreatment and 28 fractures posttreatment. With an average follow-up of 6.4 years, posttreatment rate of fracture decreased to 0.10 fractures per year from the pretreatment rate of 2.4 fractures per year (P0.001). The femur was the most common bone fractured both pretreatment (54%) and posttreatment (61%); the major site was the distal third of the femur. There were 11 fractures during the course of pamidronate treatment at a rate of 0.33 fractures per year. Only 11 patients (34%) sustained fracture posttreatment. No correlation with fracture pattern or occurrence was found with patient age, number of pretreatment fractures, or sex. Most fractures were caused by low-energy injuries, and most were managed nonoperatively.In patients with CP and disuse osteoporosis, the most common fracture sustained involved the distal femur via low-velocity injury, and most fractures were treated nonoperatively. Although the fracture pattern and the treatment remained unchanged, reoccurring fractures in these children can be effectively treated medically to interrupt the fracturing tendency.

Patients with medication-related osteonecrosis of the jaw (MRONJ) are at risk for developing infections and often require long-term antimicrobial therapy for management. It is unclear whether patients with multiple myeloma (MM) who develop MRONJ experience increased morbidity when they undergo hematopoietic cell transplantation (HCT). The aim of this study was to characterize the course of HCT in MM patients with MRONJ. A retrospective chart review was conducted for patients with MM and MRONJ who underwent HCT between December 2005 and December 2014. Data collected included bisphosphonate use, MRONJ stage, positive blood cultures, number of febrile days, and length of hospital stay. Eleven patients (median age, 61; range, 46 to 71) fulfilled the criteria. Patients received zoledronic acid (72.7%), pamidronate (18.1%), or a combination of both (9%). At the time of HCT, 10 patients were in stage 1 MRONJ with 1 in stage 0. All patients had only mandibular involvement. No patient developed pain/infection at the MRONJ site during hospitalization. Bacteremia with positive blood cultures for Staphylococcus aureus occurred in 3 patients (27.2%), and 4 patients (36.3%) developed fever lasting between 4 to 6 days (of who 1 had positive blood cultures). The median length of hospital stay was 17 days (range, 7 to 22 days). These data suggests that patients with MM and MRONJ who undergo HCT are not at increased risk of developing symptoms associated with the MRONJ site or HCT-related infectious complications, and their MRONJ is not worsened by HCT.

Objectives Assessment of bisphosphonates efficiency in the therapy of NSAIDs-refractory Chronic Recurrent Multifocal Osteomyelitis. Methods Retrospective analysis of records of patients treated for Chronic Recurrent Multifocal Osteomyelitis between 2012 and 2018. Results Between 2012 and 2018, 76 children and adolescents were diagnosed with Chronic Recurrent Multifocal Osteomyelitis in our department. All patients underwent an initial course of NSAIDs therapy that provided a remission in 46% of cases. Of 41 NSAIDs-resistant cases, 7 patients were male and 34 were female. Disease started meanly in the age of 10. Most frequently pain localised in foot, clavicle and hip. In presented group, pamidronate was administered intravenously in the dose of 1 mg/kg/day for 3 days. Patients received 6 series (1-17 series) on average with mean interval of 10 weeks (4-14 weeks). Our observations demonstrated rapid decrease of symptoms intensity after first dose of pamidronate with relapse of pain after 3-4 weeks. The frequency of pamidronate dosage was dependent of patient’s symptoms. No serious adverse effects were reported. We finished the therapy after complete remission of symptoms and complete bone remodelling in imaging. Of 41 patients, 32 achieved remission and 9 continue their therapy. In remission group patients received 7 series of pamidronate on average and their treatment lasted meanly 20 months. Conclusions Pamidronate is a safe and efficient method of CRMO therapy, particularly in cases refractory to NSAIDs treatment. Treatment with pamidronate provides both symptomatic relief as well as normalisation of bone morphology.

Calciphylaxis is a rare and potentially fatal disease that affects the subcutaneous layer of the skin. It is a calcific vasculopathy induced by a systemic process that causes occlusion of small blood vessels. The mortality rate for individuals diagnosed with calciphylaxis is estimated between 52% and 81% with sepsis being the leading cause of death. Uraemic calciphylaxis and its known effective treatments are well documented in the literature. Unfortunately, there is no known effective treatment for non-uraemic calciphylaxis. Most of the current treatments for non-uraemic calciphylaxis are derived from uraemic calciphylaxis treatment protocols. We report a case of a 75-year-old female with calciphylaxis on the right lower extremity who was successfully treated with four pamidronate infusions in addition to local wound care. This case represents a non-uraemic calciphylaxis wound successfully treated with pamidronate infusions and standard wound care, and suggests that IV pamidronate can be an effective treatment option.

Bastug F, Nalcacioglu H, Bas VN, Tekatli-Celik B, Cetinkaya H, Yel S. Acute renal failure due to severe hypercalcemia and nephrocalcinosis treated with two doses of pamidronate in an infant with Williams-Beuren syndrome. Turk J Pediatr 2018; 60: 210-215. Infantile hypercalcemia has been reported in 15% of infants and children with Williams-Beuren syndrome (WBS) and has generally mild clinical symptoms. However, the need for pamidronate treatment in a few infants with severe hypercalcemia associated with WBS has been reported in literature. Many disorders, such as primary hyperoxaluria, associated with nephrocalcinosis can lead to renal failure, but there are only a few reports in infants with WBS who have decreased renal function and nephrocalsinosis. We present a 23-month-old girl with WBS (confirmed with fluorescent in situ hybridization probes) who presented with acute renal failure with severe symptomatic hypercalcemia and nephrocalcinosis, which responded to two infusions of pamidronate.