Abnormal Bone Turnover Research Articles

Abnormal bone turnover in individuals with low serum alkaline phosphatase.

The clinical spectrum of hypophosphatasia (HPP) is broad and variable within families. Along severe infantile forms, adult forms with mild manifestations may be incidentally discovered by the presence of low alkaline phosphatase (ALP) activity in serum. However, it is still unclear whether individuals with persistently low levels of ALP, in the absence of overt manifestations of HPP, have subclinical abnormalities of bone remodeling or bone mass. The aim of this study was to obtain a better understanding of the skeletal phenotype of adults with low ALP by analyzing bone mineral density (BMD), bone microarchitecture (trabecular bone score, TBS), and bone turnover markers (P1NP and ß-crosslaps). We studied 42 individuals with persistently low serum ALP. They showed lower levels of P1NP (31.4 ± 13.7 versus 48.9 ± 24.4ng/ml; p = 0.0002) and ß-crosslaps (0.21 ± 0.17 versus 0.34 ± 0.22ng/ml, p = 0.0015) than individuals in the control group. There were no significant differences in BMD, bone mineral content, or TBS. These data suggest that individuals with hypophosphatasemia have an overall reduction of bone turnover, even in the absence of overt manifestations of HPP or low BMD. We evaluated bone mineral density (BMD), bone microarchitecture, and bone turnover markers in patients with low serum levels of alkaline phosphatase. Our results show that these patients have low bone remodeling even in the absence of BMD abnormalities, thus supporting the recommendation of avoiding antiresorptives such as bisphosphonates in these subjects.

Fracture probability assessed using FRAX® in elderly women with benign paroxysmal positional vertigo

ObjectivePatients with benign paroxysmal positional vertigo (BPPV) can have vitamin D deficiency, which is a cause of abnormal bone turnover. Several studies have established a relationship between osteoporosis and BPPV. The World Health Organization Fracture Risk Assessment Tool, widely known as FRAX® (http://www.shef.ac.uk/FRAX), is a computer-based algorithm for assessing fracture risk. No direct comparison has been made between the FRAX scores of patients with BPPV and controls. The purpose of this study was to determine whether women with BPPV are at high risk of fracture as assessed using FRAX. MethodsThe study involved 40 postmenopausal women diagnosed with BPPV between July 2015 and April 2016, and 40 postmenopausal women as controls. The 10-year major osteoporotic and hip fracture risks were calculated using FRAX and were compared between BPPV patients and controls using Welch’s t test and a general linear model. ResultsThe 10-year major osteoporotic fracture risk was 20.4%±12.1% for BPPV patients (aged 72.4±8.6years) and 14.3%±6.5% for controls (aged 71.2±6.3years). The 10-year hip fracture risk was 9.0%±9.8% for BPPV patients and 5.0%±3.9% for controls. The BPPV group had significantly higher 10-year major risks of osteoporotic fracture (p=0.0069) and hip fracture (p=0.0202) compared with controls. Similarly, after adjustment for age, the BPPV group had significantly higher 10-year risks of major osteoporotic fracture (p=0.0007) and hip fracture (p=0.0092) compared with controls. ConclusionFracture risk calculated using FRAX was significantly higher in the BPPV group than in controls. Women with BPPV may need early intervention to prevent future fractures.

Role of microRNAs in progenitor cell commitment and osteogenic differentiation in health and disease (Review).

MicroRNAs (miRNAs) are considered 'micro- managers of gene expression' and awareness of their fundamental role in the control of biological functions is constantly increasing. Bone formation and homeostasis are complex processes involving the differentiation and interaction of various cell types. Several miRNAs have been shown to be involved in different pathways and stages in the regulation of normal and abnormal bone formation and turnover. This present review focuses on the involvement of miRNAs in terms of their effect on the commitment of bone marrow mesenchymal stem cells towards osteogenesis, adipogenesis and chondrogenesis, respectively. The miRNAs involved in regulating osteoblast, chondroblast and osteoclast activity, are also taken into consideration, as are their interactions. miRNA expression levels, which may differ significantly in healthy versus pathological conditions, can be readily monitored and represent useful biomarkers. Several studies have suggested that miRNAs offer potential as useful biomarkers of bone pathologies, including osteoporosis and osteosarcoma. The development of efficient methods of delivering miRNA mimics or miRNA inhibitors into specific cells remains a challenge for novel therapeutic applications in the field of personalized medicine.

Nanoindentation time-dependent deformation/recovery suggestive of methylglyoxal induced glycation in calcified nodules

Although empirical findings have indicated increase in bone fracture risk in type 2 diabetes patients, that has yet to be proven by results obtained at the material level. Here, we report evidence showing nanoscale time-dependent deformation/recovery of in vitro calcified nodules mimicking bone turnover in type 2 diabetes in respect to methylglyoxal (MG)-induced glycation. Nanoindentation test results revealed that calcified nodules cultured with MG did not show adequate dimensional recovery, despite a large creep rate during constant load indentation testing. This lesser recovery is likely based on the linear matrix polymerization network formed by advanced glycation end products (AGEs) as a secondary product of MG. Since elevated serum MG and abnormal bone turnover related to the amount of AGEs are observed in cases of type 2 diabetes, this time-dependent behavior may be one of the factors of the bone fracture mechanism at the material level in affected patients.

Indoxyl sulfate, a uremic toxin in chronic kidney disease, suppresses both bone formation and bone resorption.

Abnormalities of bone turnover are commonly observed in patients with chronic kidney disease (CKD), and the low‐turnover bone disease is considered to be associated with low serum parathyroid hormone (PTH) levels and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood of patients with CKD. Recently, we have reported that IS exacerbates low bone turnover induced by parathyroidectomy (PTX) in adult rats, and suggested that IS directly induces low bone turnover through the inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH. To define the direct action of IS in bone turnover, we examined the effects of IS on bone formation and bone resorption in vitro. In cultures of mouse primary osteoblasts, IS suppressed the expression of osterix, osteocalcin, and bone morphogenetic protein 2 (BMP2) mRNA and clearly inhibited the formation of mineralized bone nodules. Therefore, IS directly acts on osteoblastic cells to suppress bone formation. On the other hand, IS suppressed interleukin (IL)‐1‐induced osteoclast formation in cocultures of bone marrow cells and osteoblasts, and IL‐1‐induced bone resorption in calvarial organ cultures. In cultures of osteoblasts, IS suppressed the mRNA expression of RANKL, the receptor activator of NF‐κB ligand, which is a pivotal factor for osteoclast differentiation. Moreover, IS acted on osteoclast precursor, bone marrow‐derived macrophages and RAW264.7 cells, and suppressed RANKL‐dependent differentiation into mature osteoclasts. IS may induce low‐turnover bone disease in patients with CKD by its direct action on both osteoblasts and osteoclast precursors to suppress bone formation and bone resorption.

Bone metabolism and inflammatory characteristics in 14 cases of chronic nonbacterial osteomyelitis

BackgroundChronic nonbacterial osteomyelitis (CNO) is a multifocal autoinflammatory disease that often impairs daily life in children. This study aimed to investigate the bone metabolic and inflammatory characteristics of patients with CNO, and to assess the differences between responders and nonresponders to conservative treatment.MethodsWe investigated the clinical symptoms; laboratory data including inflammatory and bone metabolic biomarkers; and imaging findings from plain radiography, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and dual-energy x-ray absorption (DEXA) in 14 patients with CNO. All patients underwent first-line treatment comprising systemic nonsteroidal anti-inflammatory drugs with or without bisphosphonate. According to the response to the first-line treatment, the patients were divided into the clinical remission/partial response group and the no response group. The differences in bone metabolic and inflammatory characteristics between the two groups were assessed.ResultsAll patients had low bone mineral density assessed with DEXA. The bone metabolic biomarkers (bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b) were increased in boys of all ages and in young girls. Multiple inflammatory regions were detected in all patients by using FDG-PET including asymptomatic regions. The no response group had higher immunoglobulin G (IgG) and a greater number of bone inflammatory lesions detected on MRI than the clinical remission/partial response group.ConclusionOur data indicate the involvement of abnormal bone turnover, necessity of whole-body scanning, and association of higher serum IgG levels and greater numbers of inflammatory lesions with prolonged disease activity in patients with CNO.

Anti-osteoclastic agent, denosumab, for a giant cell tumor of the bone with concurrent Paget's disease: A case report.

Paget's disease of the bone may predispose the development of malignant bone tumors such as osteosarcoma. Giant cell tumor (GCT) as a consequence of Paget's disease is rare. Bone GCT is characterized by rapid growth, the destruction of bone, extension to the surrounding soft tissue and abnormal bone turnover caused by an abnormality of the receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) pathway. Denosumab is a RANK-RANKL inhibitor, which is used to treat osteoporosis and bone GCT. In the current study, a 60-year-old male presented with severe pain located between the right thigh and the knee. The patient could not bear weight on the affected leg. The patient had suffered from Paget's disease for 15 years. The complications from Paget's disease included degenerative hip disease, for which the patient underwent a right total hip replacement. A right periacetabular lesion was identified and confirmed as Paget's disease-induced GCT by needle biopsy. A positron emission tomography (PET) scan revealed significant tumor metabolic activity. Subsequent to obtaining informed consent, the patient started treatment with denosumab. A total of 2.5 months after starting denosumab, a PET scan showed no residual pathological uptake at the site of the previously identified large PET avid tumor. After 1 year, the patient exhibited a satisfactory clinical improvement. In conclusion, treatment with denosumab markedly reduced the size of the hemi-pelvic GCT and led to a complete metabolic response.

A histomorphometric study of the cancellous spinal process bone in adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity with increased risk of osteopenia of unknown etiology. This study examined the dynamic histomorphometry of AIS patients to gain insight into the underlying pathogenesis of bone metabolism changes in AIS. Bone histomorphometry of the spinous process of the 12th thoracic vertebra was analyzed in 33 AIS patients and compared to age-matched normative data. Patients were classified into bone turnover subgroups, based on bone formation rate. Bone volume was subnormal in 67% of AIS patients, but normal in 33%. Bone turnover was high in 76% of the patients, normal in 9%, and low in 15%. Compared to those in the low-turnover group, the high-turnover group patients were taller and had higher TRAP5b values. Bone histomorphometry indicated that bone fragility and abnormal bone turnover were common in AIS patients. These abnormalities might contribute to the poor bone status and etiology in AIS.

Repeated oral administration of a cathepsin K inhibitor significantly suppresses bone resorption in exercising horses with evidence of increased bone formation and maintained bone turnover.

Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle. Baseline and poststudy nuclear scintigraphy, blood sampling and analysis of plasma bone biomarkers (CTX-1 and osteocalcin), poststudy bone fluorescent labeling, and bone biopsy were performed. Bone specimens were further processed for microcomputed tomography and bone histomorphometry. Each dose of this CatKI transiently inhibited plasma CTX-1 (reflecting inhibition of bone collagen resorption) and increased bone plasma osteocalcin concentrations, with no detectable adverse effect on normal bone turnover in the face of exercise. Bone morphology, density, and formation rate were not different between control and treated group. Further investigation of CatK inhibition in abnormal bone turnover is required in animals with bone diseases.

Paget Disease of Bone.

Paget disease (PD) is a common disease of bone associated with abnormal bone turnover that in turn is due to an imbalance between osteoclastic and osteoblastic activity. There is good evidence that PD is reducing in incidence, prevalence, and severity. The disease is most often asymptomatic and is usually detected incidentally on imaging examinations performed for other reasons. The features of PD are relatively specific on radiographs and computed tomography. However, the appearances on magnetic resonance imaging are subtle and nonspecific, although it has become the initial imaging choice for several clinical indications including back pain, neurologic dysfunction, and knee pain. It is therefore important to be familiar with the various imaging appearances of this relatively common disease in an increasingly aging population. In this article we discuss the various imaging appearances of PD and its complications.

Osteoporosis and Fracture Risk in Chronic Pancreatitis Patients

Introduction: Chronic pancreatitis is well-known to lead to fat malabsorption and ultimately malabsorption of the fat-soluble vitamins, namely A, D, E, and K. It is unclear, however, if this vitamin malabsorption increases the risk for osteoporosis and fractures. This study examined the risk of fractures and osteoporosis in chronic pancreatitis patients with known exocrine insufficiency. Methods: Patients with chronic pancreatitis and exocrine insufficiency (previously diagnosed with endoscopic ultrasound and pancreatic function testing) underwent Dual-energy X-ray absorptiometry (DEXA) scans to evaluate for osteoporosis and had a FRAX® score calculated to assess their fracture risk. Nutritional status was also measured using the Malnutrition Universal Screening Tool (MUST). Results: 12.5% (2/16) of the patients from our chronic pancreatitis clinic were found to have osteoporosis and 68.8% (11/16) were found to have osteopenia based on DEXA scans. Based on the FRAX® score, the average 10-year major osteoporotic fracture risk was 5.5 ± 2.8% and the average 10-year hip fracture risk was 1.4 ± 2.1%. There was no significant correlation with level of malnutrition based on the MUST screen with T scores (r=0.11, p < 0.74) or FRAX® scores (r=0.49, p < 0.13 for major osteoporotic fracture risk and r=0.29, p < 0.38 for hip fracture risk). See Figure 1.Figure 1Conclusion: There was no significant correlation with nutritional status and osteoporosis or fracture risk. This likely reflects the multi-faceted nature of osteoporosis and emphasizes that malabsorption remains a theoretical risk factor for decreased bone mineral density. A recent case-matched study demonstrated an association between abnormal bone turnover and decreased bone mineral density in chronic pancreatitis patients, but what remains unclear is if this process is secondary to malabsorption or inflammation. While larger studies will need to be conducted to establish the link between malabsorption and decreased bone mineral density, this study highlights the importance in screening for osteopenia and osteoporosis in this population.

Preoperative Bone Mineral Density and Bone Turnover in Women Before Primary Knee Arthroplasty.

Purpose:The preoperative prevalence of osteoporosis and/or osteopenia and overall bone quality in prospective total knee arthroplasty (TKA) patients may affect the postoperative outcome after prosthetic insertion into the bone. The purpose of this study is to determine the baseline bone mineral density (BMD) and bone turnover in preoperative, female, primary TKA patients.Methods:We prospectively measured the lumbar spine and hip BMDs using dual-energy X-ray absorptiometry (DEXA) scans in a cohort of 119 knees (107 patients) one day before surgery. We also assessed bone turnover using urinary levels of N-telopeptide (NTX), a type I collagen crosslinker, normalized to creatinine.Results:The prevalence of osteoporosis by DEXA scan (T-score ≤ −2.5) among the TKAs was 12% in the spine and 10% in the hip. Eighty-three knees (70%) had osteopenia or osteoporosis of either the spine or hip. The mean T-score of the spine was −0.7 (SD 1.6), which is within normal limits, and of the hip was −1.2 (SD 1.0), which is defined as osteopenia. The mean Z-scores of 0.9 (SD 1.4) in the spine and 0.6 (SD 0.9) in the hip were positive. The median urinary NTX/creatinine ratio was elevated at 58.1 (interquartile range: 13.7 to 188.4).Conclusion:Based on Z-scores, the TKA patients had higher spine and hip BMDs than the age-matched general population. Elevated NTX levels may suggest a systemic or local abnormal bone turnover. Further study is needed to determine whether such turnover, as a type of patient-related medical systemic disorder, affects postoperative clinical outcomes.

Adverse bone health and abnormal bone turnover among perinatally HIV‐infected Asian adolescents with virological suppression

This study aimed to determine the prevalence of low bone mass and assess its relationship with abnormal bone turnover among HIV-infected Asian adolescents. A multicentre, cross-sectional study was conducted at four paediatric HIV centres in Thailand and Indonesia. Perinatally HIV-infected adolescents aged 10-18 years receiving antiretroviral therapy (ART) with virological suppression (HIV RNA < 400 copies/mL) were enrolled. Study assessments included lumbar spine (L2-L4) dual-energy X-ray absorptiometry and measurement of bone turnover markers. Bone mineral density (BMD) and bone mineral apparent density (BMAD) Z-scores were calculated based on Thai normative age- and sex-matched references. Low bone mass was defined as BMD or BMAD Z-scores ≤ -2. Of 396 participants, 57% were female. The median age was 15.0 [interquartile range (IQR) 13.3-16.9] years, and 73% were in Tanner stage 3-5. At enrolment, the median CD4 T-cell count was 734 (IQR 581-907) cells/μL, and 37% were on protease inhibitor (PI)-based regimens. The overall prevalence of lumbar spine BMD and BMAD Z-scores ≤ -2 were 16.4% and 8.3%, respectively. Z-scores were lower with older age, female sex, body mass index (BMI) <5th percentile, boosted PI exposure and CD4 T-cell percentage < 15% before ART initiation. Increased bone turnover markers were inversely associated with BMD and BMAD Z-scores. Low bone mass was linked to older age, female sex, low BMI, boosted PI exposure, and poor immunological status before ART commencement in our cohort of perinatally HIV-infected Asian adolescents. Dysregulation of bone turnover was associated with bone demineralization. Screening for low bone mass should be implemented to identify individuals who might benefit from interventions to preserve bone health.

Oxidative stress in otosclerosis

Objectives: Otosclerosis is a disease involving abnormal bone turnover in the human otic capsule that results in hearing loss. Several hypotheses have been suggested for the etiopathogenesis of otosclerosis; however, its etiology remains unclear.Methods: This study evaluated the correlation between otosclerosis and levels of paraoxonase-1 (PON1), arylesterase, total antioxidant status, total oxidant status (TOS), oxidative stress index (OSI), total sulfhydryl (-SH) groups, lipid hydroperoxide, and ceruloplasmin in the serum of otosclerosis patients and healthy subjects with respect to oxidative stress.Results: In our study, TOS and OSI levels were higher in the otosclerosis patients than in the controls. The PON1 levels showed that oxidative stress was severe, and as a result, antioxidants were consumed and depleted.Discussion: When an imbalance between oxygen free radical production and antioxidative defense mechanisms occurs, reactive oxygen species levels may increase, which in turn may damage cells and tissues through the peroxidation of phospholipid membrane structures. The body initially responds with increased antioxidant production, but if the oxidative stress is severe, decreased antioxidant levels may result. This study reports expression levels of oxidative stress species in otosclerosis patients.

Abnormal bone mineral density and bone turnover marker expression profiles in patients with primary spontaneous pneumothorax.

To examine the bone mineral density (BMD) and the role of bone biomarkers, including bone formation marker procollagen type I aminoterminal propeptide (PINP) and N-terminal midmolecule fragment osteocalcin (N-MID), bone resorption marker b-C-telopeptides of type I collagen (b-CTX) and tartrate-resistant acid phosphatase 5b (TRACP5b) in the pathogenesis of PSP. Eighty-three consecutive primary spontaneous pneumothorax (PSP) patients (PSP group) and 87 healthy individuals (control group) were enrolled in this study. General data, including gender, age, height, weight, and body mass index (BMI), were recorded. Dual-energy X-ray absorptiometry, electrochemiluminescence immunoassay (ECLIA), and ELISA were used to evaluate bone mineral density and expression levels of bone metabolism markers, including PINP, b-CTX, TRACP5b, N-MID, and 25-hydroxyvitamin D (25-OH VD). Mean height was significantly greater in the PSP group compared with the control group, whereas weight and BMI were lower. Patients in the PSP group had significantly lower average bone mineral density, which mainly manifested as osteopenia (11/12, 91.7%); however, only one patient (8.3%) developed osteoporosis. Serum overexpression of PINP, b-CTX, TRACP5b, and N-MID were found in PSP patients. Expression of 25-OH VD was low in PSP patients. Bone resorption markers showed positive linear relationships with bone formation markers in all participants; whereas only TRACP5b expression negatively correlated with 25-OH VD. Expression levels of all bone turnover markers negatively correlated with BMI. Regression analysis identified risk factors of PSP as age, height, weight, and TRACP5b and 25-OH VD expression levels; whereas gender and PINP, b-CTX, and N-MID expression levels were not significantly associated with the onset of PSP. It had lower bone mineral density in PSP patients. Bone formation marker PINP, N-MID and bone resorption marker b-CTX, TRACP5b were upregulated in PSP patients. 25-OH VD expression was relatively low in this population of PSP patients. Age, height, weight, and expression levels of TRACP5b and 25-OH VD may be risk factors for PSP.

Modulation of Osteoblastic Cell Efferocytosis by Bone Marrow Macrophages.

Apoptosis occurs at an extraordinary rate in the human body and the effective clearance of dead cells (efferocytosis) is necessary to maintain homeostasis and promote healing, yet the contribution and impact of this process in bone is unclear. Bone formation requires that bone marrow stromal cells (BMSCs) differentiate into osteoblasts which direct matrix formation and either become osteocytes, bone lining cells, or undergo apoptosis. A series of experiments were performed to identify the regulators and consequences of macrophage efferocytosis of apoptotic BMSCs (apBMSCs). Bone marrow derived macrophages treated with the anti-inflammatory cytokine interleukin-10 (IL-10) exhibited increased efferocytosis of apBMSCs compared to vehicle treated macrophages. Additionally, IL-10 increased anti-inflammatory M2-like macrophages (CD206+ ), and further enhanced efferocytosis within the CD206+ population. Stattic, an inhibitor of STAT3 phosphorylation, reduced the IL-10-mediated shift in M2 macrophage polarization and diminished IL-10-directed efferocytosis of apBMSCs by macrophages implicating the STAT3 signaling pathway. Cell culture supernatants and RNA from macrophages co-cultured with apoptotic bone cells showed increased secretion of monocyte chemotactic protein 1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) and transforming growth factor beta 1 (TGF-β1) and increased ccl2 gene expression. In conclusion, IL-10 increases M2 macrophage polarization and enhances macrophage-mediated engulfment of apBMSCs in a STAT3 phosphorylation-dependent manner. After engulfment of apoptotic bone cells, macrophages secrete TGF-β1 and MCP-1/CCL2, factors which fuel the remodeling process. A better understanding of the role of macrophage efferocytosis as it relates to normal and abnormal bone turnover will provide vital information for future therapeutic approaches to treat bone related diseases. J. Cell. Biochem. 117: 2697-2706, 2016. © 2016 Wiley Periodicals, Inc.

Cholesteatoma affected incus bone surface shows unusual iron-rich crystals, microvesicles and altered bone turnover

Cholesteatoma is a noncancerous cystic lesion consisting in an abnormal growth of keratinizing squamous epithelium that invades the middle ear cavity. Due to its capacity of intracranial complications, cholesteatoma is cause of pediatric morbidity and death in countries with scarce hygiene and low possibility to access to advanced medical care (1). In order to understand cholesteatoma etiopathogenesis, we performed a SEM morphological analysis of 11 incus bones affected by cholesteatoma. Samples were fixed immediately upon recovery in 2.5% glutaraldehyde in PBS at 4°C for 48 h, then they were gently sonicated (to remove excess of keratinizing squamous epithelium, that would have prevented surface observation) and finally they were prepared with standard method for scanning electron microscopy observation. Five consecutive fields at 100X magnification aligned in 3 raws, the first one proximal and the last one distal to surgical removal point were analized. Images were obtained in secondary electron mode and in backscattering, bidimensional EDX analysis and mapping was also carried on. Incus bone surface analysis reveals the existence of an environment in which abnormal bone turnover takes place, in fact area of marked erosion were present together with areas of new bone formation. Resorbing bone surfaces with their characteristic lacunae were observed, resting surfaces (smooth and with collagen fibre bundles evident) were found and forming bone surface (collagen bundles in which calcium salts were just deposited) were also observed. Unusual flower-like apatite crystals rich in iron were uncovered in one sample. Iron presence may be due to cholesteatoma itself, being it made up of corneocytes that are iron-rich cells (2). Microvesicles of cellular origin, alone or clustered in groups or in about to fusing together, were found. Macrophages, lymphocytes osteoblast and osteoclast were observed in fully activated stage. The picture of these cell near to each other is the morphological representation of the complex cytochemical dialog existing among them. Taken all together our morphological results let us hypothesize that cholesteatoma creates an environment of chronic infection with peculiar biochemical characteristics that alters normal bone turnover on incus bone.This work was supported by grants from MIUR.

Long term clinical outcome of dental implants placed in a patient with Singleton–Merten syndrome

PatientsSingleton–Merten syndrome is an extremely rare autosomal dominant condition with less than 10 reported cases in the literature. It is characterized by abnormal aortic calcifications and dental abnormalities. The goal of this case report is to discuss the abnormal oral clinical features and the modified treatment protocol that was used in order to achieve osseointegration of dental implants in a patient having abnormal bone density and bone turnover associated with Singleton–Merten Syndrome. DiscussionFollowing extraction of the remaining teeth, titanium implants (Friadent GmbH, Mannheim, Germany and Straumann®, Basel, Switzerland) were placed in the upper and lower jaw of the patient. The upper jaw which was treated with dental implants, received a bar supported implant retained prosthesis and the lower jaw an implant retained telescopic prosthesis. The patient was regularly followed up for the past 13 years during which, clinical and radiological evaluation of osseointegration was undertaken. All the loaded implants showed clinical and radiographic evidence of osseointegration. With a follow up of 13 years after insertion of the first implant, the patient reported functioning well with no complications. ConclusionThe treatment with dental implants in the extremely rare Singleton–Merten syndrome patients is a reasonable treatment option to rehabilitate maxillofacial aesthetics and establish normal function of the jaws.

Mineral metabolism disturbances are associated with the presence and severity of calcific aortic valve disease.

We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease (CAVD) in patients with normal or mildly impaired renal function. We measured serum levels of calcium, phosphate, alkaline phosphatase (AKP), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-OHD), and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis (AVSc) (n=164) or stenosis (AVS) (n=96) and in 164 age- and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels (all P<0.001). Similarly, osteocalcin, procollagen I N-terminal peptide, and β-isomerized type I collagen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS (all P<0.001). In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding variables, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were independently associated with the presence and severity of CAVD. This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism.

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

Psoriatic arthritis (PsA) is a potentially crippling systemic inflammatory joint disease with a heterogeneous clinical presentation that may include articular inflammation, enthesitis, dactylitis, abnormal bone turnover, and plaque psoriasis. Until very recently, patients with PsA had very few treatment options available to them and suffered immense physical and social burden from this disease. The use of anti-TNF agents offered some hope to these patients as a percentage of them found improvement of their psoriasis and psoriatic arthritis. However, over time, the biggest issue with anti-TNF drugs for PsA has been the findings that up to 50 % of patients do not respond to or do not tolerate these agents. Ustekinumab (UST) was one of the first agents to offer an alternative mechanism for the treatment of psoriasis and PsA, by blocking the IL12 and IL23 cytokines. The use of this medication relates directly to our improved understanding of the pathophysiology of psoriasis and PsA as being driven by Th1 and Th17 cells. In the PSUMMIT II study, patients naive to anti-TNF agents responded better to UST than patients who were previously treated with those medications. These data indicate that a subset of PsA patients manifest persistently active disease refractory to agents that target alternative immune inflammatory pathways not directly related to TNF. These findings have also been observed in RA. Thus, targeting more than one molecule with an antibody that recognizes two different targets or combination biologics may be required to drive higher treatment responses or even remission. Of course, a major obstacle aside from safety is cost; on average UST, the 90-mg dose can be significantly more expensive compared to anti-TNF agent. However, as new safe and efficacious agents become available for the treatment of psoriasis and PsA, our treatment algorithm for the treatment of PsA will need to be re-evaluated.