How to manage mineral metabolism disorders in renal failure

Mineral metabolism abnormalities are frequently observed in patients with chronic kidney disease (CKD). The bone and cardiovascular consequences should lead to the implementation of some adapted strategies for the prevention and treatment on the basis of the physiopathology of the disease and international recommendations. Biological bone markers such as serum parathyroid hormone (PTH) and alkaline phosphatase (ALP) are necessary to classify bone diseases without the need for bone biopsy. Elevated levels of bone markers are detected in cases of secondary hyperparathyroidism (SHPT), whereas decreased levels are observed in cases of adynamic bone disease (ABD). Bone mineral density, however, is not useful for the diagnosis. Vitamin D supplementation and reducing hyperphosphataemia by dietary phosphate-intake restriction, phosphate binders, and dialysis, are the main steps for the prevention of SHPT. Calcitriol analogs and calcimimetics should be used in second line in cases of SHPT. For the treatment of ABD, excess use of calcium salts and calcitriol analogs need to be avoided. Managing these therapies adequately can help maintain the main biological values (i.e. serum PTH, calcium, phosphorus, and ALP) within their recommended ranges.     

Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease.

The aim of this study was to investigate the usefulness of biochemical markers of bone turnover for monitoring treatment efficacy of Paget's disease of bone, and also to evaluate the utility of biological variation data in choosing the best markers for assessment of biochemical response to therapy. Thirty-eight patients with Paget's disease were included in a prospective study. All received 400 mg/day of oral tiludronate for 3 months. In 31 patients that completed treatment, biochemical markers were measured at baseline and at 1 and 6 months after treatment ended. In serum we determined the levels of total alkaline phosphatase (tAP), bone alkaline phosphatase (bAP), procollagen type I N-terminal propeptide (PINP), and C-terminal telopeptide of type I collagen (sCTx). Urine samples were analyzed for hydroxyproline (Hyp) and for C- and N-terminal telopeptides of type I collagen (CTx and NTx, respectively). Quantitative bone scintigraphy was performed at baseline and at 6 months after discontinuation of therapy. A ratio for monitoring response to treatment was obtained for each marker. This ratio reflected the size of treatment response of the marker in relation to the value of its critical difference. Thus, ratio values of >1 indicated a significant decrease of the marker after therapy. In addition, response to therapy was evaluated according to disease activity. Mean values of all markers of bone turnover decreased significantly after therapy. Serum bAP and PINP and urinary NTx showed the highest percentage reduction (between 58% and 68%). Furthermore, serum bAP and PINP showed the highest ratios for monitoring changes induced by treatment, followed by serum tAP and urinary NTx. sCTx and urinary CTx as well as Hyp showed mean ratios for monitoring changes of <1, indicating a low sensitivity for monitoring treatment. Patients with polyostotic disease showed a continuous decrease in mean values for all markers at 6 months from the end of therapy, whereas, in monostotic patients, there was a trend toward increased levels at this timepoint. In conclusion, serum bAP and PINP were the most sensitive markers for monitoring treatment efficacy in Paget's disease, although serum tAP and urinary NTx were also sensitive markers for monitoring changes. Data on biological variation are useful for assessing actual changes induced by treatment.     

Components of biological variation of biochemical markers of bone turnover in Paget's bone disease

The aims of this study were to evaluate the components of biological variation of the new markers of bone turnover in patients with Paget’s bone disease and to compare the results with data obtained in healthy subjects. Fifteen patients with Paget’s disease in a stable period of the disease and 12 healthy premenopausal women were included for a 1 year follow-up study. Within- and between-subject biological variation, indices of individuality, and critical differences were evaluated for the following biochemical markers: in serum, total (tAP), and bone (bAP) alkaline phosphatases, procollagen type I N-terminal propeptide (PINP) and β-carboxyterminal telopeptide of type I collagen (sCTx); in urine, hydroxyproline (Hyp), and amino (NTx) and β-carboxyterminal (CTx) telopeptides of collagen type I. Serum markers of bone turnover showed lower biological variability than urinary markers. Within-subject biological variation was higher in pagetic patients than in healthy subjects for all serum markers. In both groups, bAP presented the lowest within-subject biological variation. In pagetic patients, all markers presented indices of individuality of <0.6, indicating their usefulness for patient monitoring. Critical differences were lower for serum markers than for urinary markers. Among pagetic patients, serum bAP and PINP showed the lowest critical differences with values close to 30%, whereas urinary CTx presented the highest critical differences (near 70%). Conversely, in healthy subjects, tAP was the marker with the lowest critical differences, being two-fold higher in pagetic patients. This study confirms the lower sensitivity of urinary markers to detect significant changes and indicates that data obtained on biological variations from healthy populations cannot always be extrapolated to pathological conditions. In addition, serum bAP and PINP seem to be the markers that best reflect a significant change in activity of Paget’s disease.     

Clinical and Biochemical Response of TNFRSF11A-Mediated Early-Onset Familial Paget Disease to Bisphosphonate Therapy

Early-onset familial Paget disease of bone (EoPDB) is a rare condition caused by a 27-bp insertion mutation affecting the signal peptide of TNFRSF11A, which encodes RANK. EoPDB shows phenotypic overlap to both familial expansile osteolysis and expansile skeletal hyperphosphatasia, which are caused by similar mutations in TNFRSF11A. Although EoPDB is characterized by elevated bone turnover, there is no published information on the response of this condition to antiresorptive therapy. Here, we describe the clinical and biochemical response to bisphosphonate therapy in three patients with EoPDB. In all cases, treatment with the first-generation bisphosphonate etidronate at high doses reduced biochemical markers of bone turnover but the response was incomplete and short-lived. In contrast, treatment with aminobisphosphonates resulted in greater suppression of biochemical markers of bone turnover with an extended duration of response. From a clinical perspective, the results were less impressive and there was no clear benefit from antiresorptive treatment in terms of bone deformity, deafness, and tooth loss, although bone pain improved in one patient. We conclude that intravenous aminobisphosphonate therapy may be the preferred mode of treatment for EoPDB to provide long-term suppression of bone turnover. The long-term clinical effects of treatment on the natural history of the bone disease remain uncertain however, and this will require further study.     

Measurements and clinical usefulness of carboxyterminal propeptide of type I collagen and cross-linked carboxyterminal telopeptide of type I collagen in patients with prostate cancer]

Carboxyterminal propeptide of type I collagen (P1CP) and cross-linked carboxyterminal telopeptide of type I collagen (1CTP) are known as parameters of bone metastasis in patients with prostate cancer (PCa). We measured the serum P1CP and 1CTP levels in 52 PCa patients and evaluated the clinical usefulness of these serum markers. Both serum levels of P1CP and 1CTP were significantly higher in patients with extent of disease (EOD) grade 2 or 3 bone metastases than in patients without bone metastasis. Thus, P1CP and 1CTP are not as useful at first detection of bone metastases as bone scintigram. On the other hand, in the patients who indicated high serum levels of P1CP or 1CTP before initial treatment, the changes in the concentrations of these markers may be helpful in evaluating the response to treatment or the progression of disease. Our results suggest that P1CP and 1CTP are useful markers for monitoring the metastatic burden in the bone of PCa patients, but the efficacy is limited in high EOD grade cases.     

Bone markers in osteoporosis

Current biological markers of bone turnover have proven useful in improving fracture risk assessment and monitoring treatment efficacy in postmenopausal osteoporosis. Recent developments in the field of bone markers include 1) identification of new biochemical markers providing additional information on the complex pathways leading to bone fragility; 2) application of novel technologies such as proteomics for the discovery of novel markers; 3) automation and multiplexing for improving analytical performance and convenience; and 4) refinement of the clinical interpretation of markers. Currently, however, for the management of individual patients, their most established application is to monitor treatment efficacy and possibly to improve fracture risk assessment. The role of bone markers for improving adherence to therapy will need to be investigated in further studies. This brief review discusses these novel technological developments and the recent clinical data on the use of established and new markers in postmenopausal osteoporosis.     

Bone sialoprotein, bone morphogenetic protein 6 and thymidine phosphorylase expression in localized human prostatic adenocarcinoma as predictors of clinical outcome: a clinicopathological and immunohistochemical study of 43 cases

PURPOSE: Skeletal metastases are the hallmark of advanced prostate cancer and recurrence after local surgery is common. Currently to our knowledge no biological markers predict the risk of disease progression in individuals with localized prostate cancer. In a search for predictive markers we evaluated the expression of bone sialoprotein and bone morphogenetic protein 6, 2 bone related proteins, and the angiogenic factor thymidine phosphorylase. MATERIALS AND METHODS: The study population included 43 men who presented with localized prostate cancer treated with radical prostatectomy. Bone sialoprotein, bone morphogenetic protein 6 and thymidine phosphorylase expression was assessed by immunohistochemical testing. Results were analyzed in relation to pathological disease stage, Gleason score and clinical outcome. Clinical followup was 4.3 to 11.4 years after surgery (median 7.9). RESULTS: Disease did not progress in 17 of the 43 cases, while recurrence and/or metastasis developed in the other 26 at a median of 6.5 and 6.9 years, respectively. Bone sialoprotein and bone morphogenetic protein 6 expression detected in 28 (65%) and 29 (67%) of the 43 samples, respectively, was significantly associated (p = 0.0001). Thymidine phosphorylase detected in 26 samples (60%) was not related to bone sialoprotein and/or bone morphogenetic protein 6 positivity. Bone sialoprotein and/or bone morphogenetic protein 6 expression correlated with bone metastasis, while thymidine phosphorylase expression was related to local recurrence (p = 0.002 and/or 0.007, and 0.00007, respectively). On multivariate analysis only the correlation of thymidine phosphorylase expression with recurrence remained statistically significant (p = 0.002). Co-expression of the 3 markers was observed in the samples of 10 of the 11 patients (90%) with bone metastases and only in 5 of the 17 (29%) who were disease-free. CONCLUSIONS: This study indicates that the expression of bone sialoprotein, bone morphogenetic protein 6 and thymidine phosphorylase determined at a clinically early stage of disease by a simple immunohistochemical technique would enable subgroups of patients to be identified that are at different risks of bone metastasis or recurrence. Detection of such markers would provide additional prognostic information that would be useful for patients with intermediate or low Gleason score or stage disease. These patients would benefit from a more adapted clinical follow-up.     

骨质疏松治疗培训对脆性髋部骨折患者骨质疏松诊疗率的影响

目的观察骨质疏松的治疗培训对髋部骨折患者骨质疏松诊疗率的影响。方法回顾性分析福建医科大学附属第二医院2013年1月至2015年12月收治的651例老年脆性髋部骨折住院患者,根据是否对治疗的医师进行骨质疏松治疗培训,将651例患者分为培训组和未培训组,比较两组医师对脆性髋部骨折患者骨质疏松诊疗的情况。结果培训组220例,其中接受骨密度检查者109例(49. 5%),接受骨转换标志物检测者130例(59%),骨质疏松治疗率为80. 5%;未培训组431例,其中接受骨密度检查者142例(32. 9%),接受骨转换标志物检测者124例(28. 8%),骨质疏松治疗率为72. 6%(χ~2=16. 940、56. 277、4. 800,P均0. 05)。结论通过对骨科医师进行骨质疏松相关知识的培训,有助于改善骨质疏松患者骨转换标志物及骨密度的检测率,提高骨质疏松的治疗率。     

Comparative responses of bone turnover markers to bisphosphonate therapy in Paget's disease of bone

The measurement of biochemical markers of bone turnover is integral to the diagnosis and management of Paget's disease. Recently, there has been a proliferation of new markers and a move to carry out existing assays on automated platforms. We have assessed the performance of seven currently available markers in 20 patients with Paget's disease undergoing ibandronate therapy (6 or 12 mg) and in nine placebo-treated controls. Samples were collected at baseline and 6 months following intervention. The mean reductions in serum markers following treatment with either dose of ibandronate were: total alkaline phosphatase (AP; Roche Modular) 70%, bone AP (Beckman Access, Ostase) 80%, osteocalcin (Roche Elecsys 2010) 33%, beta-C-terminal telopeptide of type I collagen (betaCTX; Roche Elecsys 2010) 50%, and procollagen-N-terminal peptide (P1NP; Roche Elecsys 2010) 80%. For urine markers the reductions were: free deoxypyridinoline/creatinine (fDPD/creat) (DPC Immulite 2000) 36%, and N-telopeptide/creatinine (NTX/creat) (Osteomark) 81%. Total AP, bone AP, P1NP, and NTX all showed >95% of subjects to have abnormal values at baseline, reducing to 15-30% following treatment, and these treatment effects were highly significant (P < or = 0.0005), except for NTX (P = 0.02). The poorer precision of NTX reduced its utility. Baseline sensitivity was lower for the other markers (osteocalcin 68% of subjects abnormal, fDPD 22%, betaCTX 50%). Total AP, bone AP, and P1NP are suitable osteoblast markers for monitoring bisphosphonate therapy in Paget's disease, with performance approaching that of bone scintigraphy. NTX is less sensitive in detecting the effects of therapy, but is the best performing bone resorption marker. There is no clear evidence from this study that any of these newer markers are superior to total AP in assessing patients with this severity of Paget's disease.     

Bone turnover markers: tools for prognosis and monitoring response to bisphosphonates?

Skeletal homeostasis is maintained by spatially coupled and balanced processes of osteolysis and osteogenesis. Several factors across the breast cancer continuum (e.g., adjuvant therapies, bone metastases in advanced disease) can disrupt this balance. Circulating levels of specific biochemical markers released during bone turnover provide relatively non-invasive means to assess ongoing rates of skeletal metabolism. Such markers may provide insight into the risk of bone loss and fractures in women with osteoporosis and during adjuvant therapy for breast cancer. In addition, bone marker levels and alterations might reflect tumor-bone interactions and response to bisphosphonate treatment in patients with bone metastases. Thus far, the largest body of evidence supports a potential role for urinary N-terminal cross-linked telopeptide of type I collagen (NTX) in predicting risks of skeletal morbidity and death, and monitoring response during zoledronic acid treatment, in patients with bone metastases. Other possible applications for bone markers include diagnosis of bone metastases and monitoring bone disease progression. Ongoing clinical trials evaluating the potential for bone marker changes to provide insights into the disease course and response to various classes of antiresorptive therapies are expected to expand the role of bone markers in the management of patients with breast cancer.     

Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone.

A new resorption assay measuring non-isomerized collagen type I C-telopeptide fragments (alpha-alpha CTX) was evaluated in a cohort comprising 32 Pagetic patients and 48 healthy controls. alpha-alpha CTX was found to be a sensitive marker for assessing disease activity and monitoring treatment efficacy in Paget's disease of bone compared with isomerized CTX (beta-beta CTX) and a number of other established bone turnover markers. INTRODUCTION: Collagen type I fragments are generated by resorbing osteoclasts, and some of them can be measured using a C-telopeptide (CTX) immunoassay. The C-telopeptide of collagen type I comprises a DG-motif susceptible to isomerization. In newly synthesized collagen, this motif is in the native form denoted alpha, but spontaneously converts to an isomerized form (beta) during aging of bone. CTX fragments composed of at least two alpha CTX chains (alpha-alpha CTX) originating from degradation of newly formed bone can be determined in the urine using a newly developed sandwich ELISA. The aim of this study was to assess the ability of this marker to monitor disease activity and treatment efficacy in patients with Paget's disease compared with established bone turnover markers. MATERIALS AND METHODS: A total of 32 patients diagnosed with Paget's disease of bone was included in the study. All received 400 mg/day of oral tiludronate for 3 months. Urinary alpha-alpha CTX (U alpha-alpha CTX) was measured at baseline and at 1 and 6 months after discontinuation of therapy and in 48 untreated age-matched and healthy controls. Other markers of bone turnover, including urinary beta-beta CTX, N-terminal cross-linking telopeptide of type I collagen, and deoxypyridinoline, were also measured for comparison. RESULTS AND CONCLUSIONS: The U alpha-alpha CTX marker showed a marked reduction (-82% and -77% at 1 and 6 months of treatment, respectively) in response to antiresorptive therapy in patients with Paget's disease. The response to treatment in this marker exceeded that of the other markers (p < 0.01). The alpha-alpha CTX marker also provided a high correlation (r = 0.89) to disease activity as assessed by scintigraphic activity index. In conclusion, alpha-alpha CTX seems to be a sensitive marker for assessing disease activity and monitoring treatment efficacy in Paget's disease.     

Increased Bone Resorption Is Associated With Increased Risk of Cardiovascular Events in Men: The MINOS Study

Better assessment of the association between cardiovascular disease and osteoporosis in older men may help identify shared etiologies for bone and heart health in this population. We assessed the association of BMD and bone turnover markers (BTMs) with risk of cardiovascular events (myocardial infarction or stroke) in 744 men ≥50 yr of age. During the 7.5‐yr prospective follow‐up, 43 strokes and 40 myocardial infarctions occurred in 79 men. After adjustment for confounders (age, weight, height, smoking, education, physical activity, self‐reported history of diabetes, hypertension, and prevalent ischemic heart disease), men in the lowest quartile of BMD at the spine, whole body, and forearm had a 2‐fold increased risk of cardiovascular events. Men in the highest quartile of bone resorption markers (deoxypyridinoline [DPD], C‐telopeptide of type I collagen) had a 2‐fold increased risk of cardiovascular events (e.g., multivariable‐adjusted hazard ratio [including additional adjustment for BMD] was 2.11 [95% CI: 1.26–3.56], for the highest quartile of free DPD relative to the lowest three quartiles). The results were similar for men without prevalent ischemic heart disease and for myocardial infarction and stroke analyzed separately. Our data suggest that men with low BMD or high bone resorption may be at increased risk of myocardial infarction and stroke in addition to fracture. Thus, men with osteoporosis may benefit from screening for cardiovascular disease. Further study to elucidate the biological mechanism shared by bone and vascular disease may help efforts to identify men at risk or develop treatment.     

Cystic Bone Angiomatosis: A Case Report Treated with Aminobisphosphonates and Review of the Literature

Cystic angiomatosis (CA) is a rare disease characterized by multifocal hemangiomatous and/or lymphangiomatous lesions of the skeleton with possible visceral organ involvement. The exact pathogenetic mechanism of the disease is still unknown. We describe a patient affected by CA of bone treated with surgical procedures and subsequently with intravenous aminobisphosphonates for 7 years. During the follow-up progression of lesions, the painful symptoms, markers of bone turnover, computed tomographic examination, and bone mineral density were evaluated. Aminobisphosphonate therapy showed an immediate effectiveness in reducing bone pain, with a significant decrease in circulating bone alkaline phosphatase and stable radiological findings during clinical follow-up. In addition, at baseline, high levels of bone biomarkers and cytokines (osteoprotegerin, osteopontin, and interleukin-6) capable of controlling bone metabolism and angiomatosis were identified. Aminobisphosphonate treatment produced a decrease of all these increased markers. Local cell therapy with bone marrow osteoblast precursors did not produce any measurable clinical improvement. Aminobisphosphonate therapy represents an elective treatment for bone angiomatosis syndromes, but further studies are necessary to understand the molecular basis of these disorders and of their pharmacological treatment.     

Epithelioid angiosarcoma of the bone: a series of 10 cases

The clinical and pathologic features of 10 epithelioid angiosarcomas of bone were analyzed. There were eight males and two females who ranged in age from 26 to 83 years (mean 62 years). Four tumors were solitary and six were multifocal. In two consultation cases, the submitted diagnosis was metastatic carcinoma. Microscopically, the tumor cells were arranged in solid and infiltrative sheets, and in most cases vascular channels or cystically dilated spaces were present. The neoplastic cells had abundant eosinophilic cytoplasm and large nuclei with open chromatin and prominent eosinophilic nucleoli. Intratumoral hemorrhage, neutrophilic infiltrates, and intracytoplasmic lumina were frequently present. All 10 tumors stained positive for one or more endothelial markers, with CD31 being the most sensitive marker. Seven cases stained positive for cytokeratin. Ultrastructural examination in three tumors confirmed their endothelial differentiation. In the absence of obvious vascular differentiation, abundant intratumoral hemorrhage and intratumoral neutrophils are useful ancillary morphologic features that may suggest a vascular origin. Six patients are dead of disease, one is alive with metastasis, and two patients are currently disease free. Epithelioid angiosarcoma of bone should be included in the differential diagnosis of epithelioid neoplasms of bone, and endothelial markers should be a part of their immunohistochemical analysis to avoid the misdiagnosis of a metastatic carcinoma because of the significant differences in the treatment and clinical outcomes of these entities.     

An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone.

An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. INTRODUCTION: Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. MATERIALS AND METHODS: Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). RESULTS: The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and -0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, -0.42 to -0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. CONCLUSIONS: This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome.     

Variable efficacy of bone remodeling biochemical markers in the management of patients with Paget’s disease of bone treated with tiludronate

The aim of this work was to evaluate the response of different biochemical bone markers to tiludronate administration in Paget’s disease of bone. Ten patients (five men and five women), 56–77 years old (67 ± 6.5), were treated for 3 months with tiludronate tablets (400 mg/day). Bone formation markers: alkaline phosphatase (AP), bone alkaline phosphatase (bAP), osteocalcin (BGP), and procollagen I carboxyterminal propeptide (PICP) in serum; and bone resorption markers: serum cross-linked carboxyterminal telopeptides of type I collagen (ICTP), urinary hydroxyproline/creatinine (Hyp/Cr), pyridinoline/Cr (Pyr/Cr), and alpha-1 collagen chain products degradation (CrossLaps) were assessed. Samples were taken before and at monthly intervals for 3 months after treatment began. The results of the present work show that serum AP and bAP are sensitive and reliable biochemical markers of bone formation in the follow-up of tiludronate in this disease. Serum PICP shows less sensitivity than serum AP, and serum BGP is not indicated as biochemical marker in these types of studies. Urinary hydroxyproline seems to be the most reliable biochemical marker of bone resorption. More studies should be performed with urinary Pyr and CrossLaps determinations. Serum ICTP is not adequate for the follow-up of tiludronate treatment in Paget’s disease of bone.     

The use of zoledronic acid for paget’s disease of bone

Paget’s disease of bone is a common skeletal disorder of the elderly that often results in significant morbidity and disability. Although there are a number of oral bisphosphonates currently available for treatment, normalization of biochemical markers of bone turnover with these agents is rarely accomplished due to difficulty with administration, adherence, and possibly resistance to individual bisphosphonates. This paper will focus on zoledronic acid, a potent and easily administered intravenous bisphosphonate that appears to result in a higher percentage of patients with normalization of markers of bone turnover and results in improvements in quality of life in patients with Paget’s disease of bone.     

Prognostic Factors Including Proliferation Markers Ki-67, bax, and bcl-2 in Temporal Bone Paraganglioma

Valuable criteria with which to predict the clinical behavior of the temporal bone paraganglioma or the response to treatment are lacking. The analysis of markers of cell proliferation is a possibility to estimate the prognosis. Extensive patient data on 40 temporal bone paragangliomas were gathered over the years and correlated with the data obtained by staining histologic sections with bcl-2, bax, and MIB I markers of cellular proliferation. The immunohistochemistry was in all cases negative for bcl-2, positive for bax, and for Ki-67 positive in 20% of tumors. The scores for Ki-67 did not correlate with the majority of clinical parameters, except for treatment modality, preoperative hearing loss, and cranial nerve involvement. The tendency toward poorer hearing and a higher incidence of preoperative lower cranial nerve palsies was demonstrated in patients with higher Ki-67 scores. Furthermore, the higher rate of subtotal tumor removals in these patients reveals technical difficulties in accomplishing a radical removal, although the incidence of residual tumors was thus not affected. In view of the present information obtained with proliferation markers, the site of tumor origin still remains the most predictive variable for the course of the disease.     

Short-Term Risedronate Treatment in Postmenopausal Women: Effects on Biochemical Markers of Bone Turnover

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4–10 weeks after therapy – an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget”s disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers. Received: 18 August 1999 / Accepted: 18 January 2000     

Prognostic Factors Including Proliferation Markers Ki-67, bax, and bcl-2 in Temporal Bone Paraganglioma

Valuable criteria with which to predict the clinical behavior of the temporal bone paraganglioma or the response to treatment are lacking. The analysis of markers of cell proliferation is a possibility to estimate the prognosis. Extensive patient data on 40 temporal bone paragangliomas were gathered over the years and correlated with the data obtained by staining histologic sections with bcl-2, bax, and MIB I markers of cellular proliferation. The immunohistochemistry was in all cases negative for bcl-2, positive for bax, and for Ki-67 positive in 20% of tumors. The scores for Ki-67 did not correlate with the majority of clinical parameters, except for treatment modality, preoperative hearing loss, and cranial nerve involvement. The tendency toward poorer hearing and a higher incidence of preoperative lower cranial nerve palsies was demonstrated in patients with higher Ki-67 scores. Furthermore, the higher rate of subtotal tumor removals in these patients reveals technical difficulties in accomplishing a radical removal, although the incidence of residual tumors was thus not affected. In view of the present information obtained with proliferation markers, the site of tumor origin still remains the most predictive variable for the course of the disease.