Anna Zambrano

Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: Casuality or causality?

Osteogenesis imperfecta (OI) is a rare inherited connective disorder causing increased bone fragility and low bone mass. OI includes severe bone fragility, impaired dentinogenesis, with less common alterations in the joints, blood vessels, heart valves, skin. Interestingly, description of left ventricular rupture, aortic dissection and heart valves incompetence has been previously described. Death may occur in OI patients for cardiac disease in asyntomatic subjects. Aim of our study has been to evaluate the presence of potential subclinical cardiac disorders and to characterize cardiac functional parameters by echocardiography in adults with OI in absence of cardiac symptoms. Forty patients (21 females and 19 males) affected by type I, III, IV OI and 40 control subjects (20 females and 20 males) were evaluated in the study. Patients and controls underwent clinical examination, screening for endocrine and metabolic disorders, 12-lead electrocardiogram and echocardiogram. In particular, all subjects were evaluated by two-dimensional echocardiography with continuous- and pulse-wave Doppler. Patients and controls belonged to NYHA class I and no significant electrocardiographic alteration was documented in both groups. Thirty-eight patients (95%) showed valvular regurgitation compared to one control subject (2.5%; P<0.001). As regards the diastolic function parameters, in OI patients E wave velocity was reduced by 23% (95% CI: 9% to 29%; P<0.001), E/A ratio was reduced by 17% (95% CI: 15% to 26%; P<0.001) while isovolumetric relaxation time (IRT) was increased by 47% (95% CI: 26% to 53%; P<0.001) and E wave deceleration time (DT) was increased by 18% (95% CI: 13% to 26%; P<0.001) compared to controls. In conclusion, our data indicate that adult patients affected by OI have an altered diastolic function in absence of other metabolic alterations. These diastolic echocardiographic parameters might worsen over time, especially if other cardiovascular risk factors (e.g., smoking, hypertension, metabolic and endocrine alterations) are not carefully checked, monitored and treated. In the context of a multidisciplinary evaluation of OI patients, our data suggest that a careful cardiological evaluation of these patients is indicated beside skeletal evaluation and therapeutical skeletal options.

Neutrophil Glutamine Deficiency in Relation to Genotype in Children with Cystic Fibrosis

Pulmonary disease in cystic fibrosis (CF) is characterized by a chronic neutrophil-dominated inflammation of lung tissue. Inasmuch as some amino acids (AA) play a pivotal role in various aspects of neutrophil metabolism, the aim of this study was to investigate a possible alteration of neutrophil AA metabolism and to evaluate its relation (if any) with the genotype. We performed plasma and neutrophil AA analysis in 26 CF patients with known genotype, 10 patients with non-CF bronchiectasis, and 20 normal subjects. The CF group showed a significant decrease of free intracellular neutrophil glutamine (Gln) content compared with controls and the non-CF bronchiectasis group. In the latter group, levels of neutrophil Gln were significantly lower compared with the controls. Amino acid plasma concentration in non-CF bronchiectasis showed a decrease of Gln and taurine compared with controls. Neutrophil Gln content showed values significantly lower in CF patients with severe mutations (class I, II, and III mutations) compared with mild mutations (class IV and V mutations). Results of our study add further evidence for intrinsic neutrophil alterations that could play an important role in the pathogenesis of chronic pulmonary disease in CF patients.

Taurine deficiency in thalassemia major-induced osteoporosis treated with neridronate

The aetiology of thalassemia major-induced osteoporosis is multifactorial. Up to now, bisphosphonates seem to be a promising therapy. Taurine is found in a high concentration in bone cells enhancing bone tissue formation and inhibiting bone loss. Recently we found a decrease taurine plasma level in children affected by osteogenesis imperfecta during neridronate (amino-bisphosphonate) therapy suggesting a possible interaction between pharmacological effect of this drug and taurine availability. On the basis of these results, we performed plasma and urine amino acid (AA) analysis in thalassemia major-induced osteoporosis before and after 12 months of neridronate treatment. Twelve patients, five males and seven females, aged from 20 to 29 years following a hypertransfusion treatment protocol were enrolled in the study. Patients were treated with neridronate infusion every one month (30 mg in 100ml of saline). Plasma and urine specimens for AA analysis, bone mineral density, bone mineral content and vertebral project area were examined at baseline (T0) and after 12 months of treatment (T12). A significant decrease was observed for plasma level and urinary excretion of taurine (T0 vs. T12=p<0.01) whereas bone mineral content and vertebral projection area showed a statistical significant increase (T0 vs. T12=p<0.05). These results and other experimental researches warrant further studies examining the long-term effect of taurine supplementation in association with neridronate treatment.

High levels of serum prostaglandin E2 in children with osteogenesis imperfecta are reduced by neridronate treatment.

Prostaglandin E2 (PGE2) is an activator of bone remodeling, and increase levels of PGE2 are found in several disorders characterized by chronic inflammation. Bisphosphonates are used in the treatment of osteogenesis imperfecta (OI), an inherited disorder characterized by bone fragility and low bone mass. We evaluated the serum PGE2 (ng/mL) level in 16 children affected by OI (11 with mild and 5 with severe forms) at basal time and during treatment with neridronate. The levels of PGE2 in mild and severe forms were increased at basal time compared with controls (13.14 ± 4.2 versus 0.72 ± 0.05, p < 0.01; 15.1 ± 1.5 versus 0.72 ± 0.05, p < 0.01, respectively) and showed a significant decrease after the second (T1) cycle of treatment (mild: 4.97 ± 5.0 versus 13.14 ± 4.2, p < 0.01; severe: 5.32 ± 4.5 versus 15.1 ± 1.5, p < 0.01) with a further significant decrease after the fourth (T2) cycle. The high basal PGE2 levels in OI, a noninflammatory disorder, could be explained by stress-induced release mediated by inducible cyclooxygenase-2-catalyzed pathway. The reduction obtained by treatment with bisphosphonates could be attributed to a direct pharmacological effect since these drugs has been reported to modulate the release of proinflammatory mediators.

Serum brain-type creatine kinase increases in children with osteogenesis imperfecta during neridronate treatment

Background:Creatine kinase (Ck) catalyzes the reversible transfer of high-energy phosphate groups between adenosine triphosphate and phosphocreatine. The brain isoform (Ckbb) is greatly induced in mature osteoclasts, playing an important role in bone-resorbing function during osteoclastogenesis. High Ckbb serum level has been found in patients with osteopetrosis and in patients with bisphosphonate (BP)-induced osteopetrosis. BPs are considered the treatment of choice for children with osteogenesis imperfecta (OI), acting as potent inhibitors of bone resorption by suppressing the activity of osteoclasts.Methods:We determined total serum Ck and isoform activity in 18 prepubertal children with type I OI, before and during treatment with the BP neridronate infusions.Results:Basal serum Ckbb levels were slightly elevated with respect to controls (mean ± SD = 3.0 ± 2.7 vs. 2.0 ± 2.2) and progressively increased after neridronate treatment (t0 vs. t4: mean ± SD = 3.0 ± 2.7 to 10.8 ± 8.1), with significant increment after first, second, and fourth infusions (P < 0.01). An inverse correlation was found between serum Ckbb and serum CTx at basal level.Conclusion:Our results support previous observations that increased serum Ckbb reflects failure of osteoclasts or, at least, suppression of osteoclasts. Upon considering that BPs are long acting, this information could be useful to prevent the risk of overtreatment after long-term BP exposure in pediatric patients with OI.

Osteogenesis imperfecta and rapid maxillary expansion: Report of 3 patients

INTRODUCTION The aim of this study was to analyze the effects of orthopedic therapy with rapid maxillary expansion (RME) in growing patients affected by osteogenesis imperfecta and treated with bisphosphonates. METHODS Three boys with osteogenesis imperfecta (mean age, 10.6 years) were treated with RME. They all had treatment with quarterly intravenous infusions of bisphosphonates. They were in either the early or the late mixed dentition and had indications for RME. The expansion screw was activated twice daily until correction of the transverse relationships was achieved. The retention period with the expander in place was 6 months. In 2 Class III patients, RME was associated with the use of a facemask. In all patients, occlusal radiographs were taken at the end of active RME therapy to assess the opening of the midpalatal suture and 1 year after the end of active expansion therapy to evaluate the reossification and reorganization of the midpalatal suture. RESULTS In all patients, the opening of the midpalatal suture and the healing with reorganization of the midpalatal suture were documented with the occlusal radiographs. No complications were found after a 1-year follow-up. CONCLUSIONS In growing patients affected by osteogenesis imperfecta and treated with bisphosphonates, it is possible to perform RME with a standard protocol with no complications after a 1-year follow-up.

Intraoperative bleeding in patients with osteogenesis imperfecta type III treated by Fassier-Duval femoral rodding: analysis of risk factors

The surgical treatment of osteogenesis imperfecta (OI) is negatively influenced by clinical features such as osteoporosis, limb deformities and bone changes caused by bisphosphonate therapy. Blood loss during femoral nailing surgeries in patients with OI is a serious problem. Platelet anomalies have been associated with an elevation of the serum pyrophosphate originating from the platelets during clotting, even if the causality with the platelet dysfunction has not yet been established. To identify predictive risk factors regarding intraoperative bleeding, a retrospective analysis was conducted on 23 patients aged between 6 and 13 years, affected by OI type III, who were treated to correct femoral deformities or to perform an osteosynthesis for femoral shaft fractures, using the Fassier–Duval telescopic nail. Osteotomies were performed in 14 cases of deformities and in two out of seven cases of fractures. A survey about the bleeding had been obtained by calculating the sum of the blood aspirated and that lost with the gauzes or present on the surgical drapes. To obtain an estimate of the intraoperative blood losses, one must resort to a calculation based on an algorithm that evaluates the ratio between the effective blood loss divided by the total blood volume expected as per age and weight (&ggr; distribution). The average blood loss was 237.4 ml (0.12 &ggr;). In seven cases, it was necessary to perform postoperative transfusions, owing to an average blood loss of 502.8 ml (0.27 &ggr;). Patients aged less than 10 years had a minor blood loss. A greater number of osteotomies was associated with a significant increase of average bleeding (P=0.046). Patients who were never treated with bisphosphonates showed a significantly greater bleeding rate (P=0.048). Patients affected by OI type III have a high risk of severe blood loss during surgery, even caused by the platelet disfunction, which characterizes this OI type. In addition to this predisposing factor, there are other risk factors to consider in preoperative surgical planning. In patients who were never treated with bisphosphonates, the bleeding was higher than in the ones treated with bisphosphonates since at least 1 year. The effects of bisphosphonates on bone tissue (such as the medullar canal narrowing and the bone cortex thickening) could reduce the spongious bone amount and the bleeding. Inhibiting the farnesyl pyrophosphate synthase enzyme and reducing the prenylation of many plasma proteins, including the methylene tetrahydrofolate reductase, the bisphosphonates could lead to an alteration of the coagulation cascade. The correlation found with the intake of bisphosphonates, capable of inhibiting the action of the farnesyl pyrophosphate synthase enzyme, thus influencing coagulation, requires further prospective studies with research of the methylene tetrahydrofolate reductase mutation in patients with OI type III undergoing surgical procedures. The number of osteotomies, the patient’s age and the intake of bisphosphonates for at least 1 year seem to be the best predictive factors for blood loss.

Clinical and biochemical response to neridronate treatment in a patient with osteoporosis-pseudoglioma syndrome (OPPG)

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive syndrome characterized by juvenile-onset osteoporosis and ocular abnormalities due to a low-density lipoprotein receptor-related protein 5 (LRP5) gene mutation. Treatment with bisphosphonates, particularly with pamidronate and risedronate, has been reported to be of some efficacy in this condition. We report on a patient with OPPG due to an LRP5 gene mutation, who showed an encouraging response after a 36-month period of neridronate therapy. We report a case of a patient treated with bisphosphonates. Bisphosphonates should be administered in OPPG patients as a first-line therapy during early childhood.

Isolated olecranon fractures in children affected by osteogenesis imperfecta type I treated with single screw or tension band wiring system: Outcomes and pitfalls in relation to bone mineral density

Abstract The purpose of this study is to compare the results of 2 techniques, tension band wiring (TBW) and fixation with screws, in olecranon fractures in children affected with osteogenesis imperfecta (OI) type I. Between 2010 and 2014, 21 olecranon fractures in 18 children with OI (average age: 12 years old) were treated surgically. Ten patients were treated with the screw fixation and 11 with TBW. A total of 65% of olecranon fractures occurred as a result of a spontaneous avulsion of the olecranon during the contraction of the triceps muscle. The average follow-up was 36 months. Among the children treated with 1 screw, 5 patients needed a surgical revision with TBW due to a mobilization of the screw. In this group, the satisfactory results were 50%. In patients treated with TBW, the satisfactory results were 100% of the cases. The average Z-score, the last one recorded in the patients before the trauma, was −2.53 in patients treated with screw fixation and −2.04 in those treated with TBW. TBW represents the safest surgical treatment for patients suffering from OI type I, as it helps to prevent the rigidity of the elbow through an earlier recovery of the range of motion, and there was no loosening of the implant. In analyzing the average Z-score before any fracture, the fixation with screws has an increased risk of failure in combination with low bone mineral density.

Osteogenesis imperfecta and clubfoot—a rare combination: Case report and review of the literature

Background: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-&agr; type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patients mother also suffers from OI type IV. Methods: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. Results: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. Conclusion: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes, especially by both the mothers bisphosphonate drug therapy and the amniocentesis performed during her pregnancy to drain polyhydramnios. In our analysis, those environmental factors could have interacted with an already altered genetic substratum, contributing to develop this rare combination of congenital disorders.