Quantitative ultrasound of the calcaneus (QUS): A valuable tool in the identification of patients with non-metastatic prostate cancer requiring screening for osteoporosis.

Non-metastatic prostate cancer (PCa) patients are at increased risk for osteoporosis and fractures mainly due to androgen deprivation therapy (ADT)-associated hypogonadism, but this remains largely underdiagnosed and untreated. In this study, we examine the value of pre-screening calcaneal QUS in identifying patients who should be referred for screening for osteoporosis using dual-energy X-Ray absorptiometry (DXA). In a single-center retrospective cross-sectional cohort study, we analysed data on DXA and calcaneal QUS measurements systematically collected between 2011 and 2013 in all non-metastatic PCa patients attending our Uro-Oncological Clinic at the Leiden University Medical Center. Receiver operating characteristic curves were used to assess the positive (PPV) and negative (NPV) predictive values of QUS T-scores of 0, -1.0, and - 1.8 in identifying DXA-diagnosed osteoporosis (T-scores ≤ - 2.5 and ≤ -2) at lumbar spine and/or femoral neck. Complete sets of data were available in 256 patients, median age 70.9 (53.6-89.5) years; 93.0 % had received local treatment, 84.4 % with additional ADT. Prevalence of osteoporosis and osteopenia was respectively 10.5 % and 53 %. Mean QUS T-score was -0.54 ± 1.58. Whereas PPV at any QUS T-score was <25 %, precluding the use of QUS as surrogate for DXA in screening for osteoporosis, QUS T-scores of -1.0 to 0.0 had a NPV of ≥94.5 % for DXA T-scores ≤ 2.5 and ≤ -2 at any site, confidently identifying patients least likely to have osteoporosis, thereby significantly reducing the number of patients requiring DXA screening for diagnosing osteoporosis by up to two-third. Osteoporosis screening is a significant unmet need in non-metastatic prostate cancer patients treated with ADT, and QUS may represent a valuable alternative pre-screening strategy to overcome logistics, time demands, and economic barriers encountered with current strategies for osteoporosis screening in these patients. Summary: Osteoporosis and associated increased fracture risk are common in non-metastatic prostate carcinoma, mainly due to androgen deprivation therapy, but these often remain underdiagnosed and untreated. We demonstrate that QUS is a safe, less costly pre-screen tool that reduces by up to two-third the number of patients requiring referral for DXA for osteoporosis screening.

Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA).

Malignant transformation of fibrous dysplasia lesions has been reported in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). Recently, we have observed an increased risk for breast cancer. In this study, the prevalence of skeletal and extraskeletal malignancies in patients with FD/MAS in the Netherlands was assessed by analyzing data from our cohort of FD/MAS patients, the Dutch Pathology Registry (PALGA), and the Netherlands Cancer Registry (NCR). We extracted data on sex, age at diagnosis of FD/MAS, type of FD/MAS, type of malignancy, and age at diagnosis of malignancy and histology of bone and malignant tissue when available, including GNAS-mutation analysis from patients' medical records. Standardized Morbidity Ratios (SMRs) with 95% confidence intervals were calculated. Twelve malignancies were identified in the LUMC FD/MAS cohort and 100 in the PALGA cohort. In this cohort, SMR was increased for osteosarcoma (19.7, 95% CI 3.5-48.9), cervical cancer (4.93, 95%CI 1.7-8.2), thyroid cancer (3.71, 95% CI 1.1-7.8), prostate cancer (3.08, 95% CI 1.8-4.6), and melanoma (2.01, 95%CI 1.2-3.1). SMRs for pancreatic cancer or hepatocellular carcinoma could not be calculated due to low numbers. The small number of malignancies identified in our FD/MAS cohort precluded the calculation of SMRs for our cohort specifically. Our findings show that patients with FD/MAS appear to have an increased risk for osteosarcoma, cervical, thyroid, and prostate cancer and melanoma. However, these data should be interpreted with caution, as true incidence rates of the identified malignancies may be influenced by the inclusion of only patients with histologically confirmed FD/MAS. The etiology of this increased risk for malignancies still needs to be elucidated.

Burden of illness in patients with chronic hypoparathyroidism not adequately controlled with conventional therapy: a Belgium and the Netherlands survey.

PURPOSE: To determine the burden of illness in patients with not adequately controlled chronic hypoparathyroidism receiving conventional therapy in Belgium and the Netherlands. METHODS: Data were generated from a cross-sectional, two-part online survey where endocrinologists from both countries and nephrologists from Belgium were invited by phone to participate. Part 1 included collecting data on general management of patients with hypoparathyroidism. In Part 2, physicians were requested to provide data on one or two current cases of patients with chronic hypoparathyroidism not adequately controlled on conventional therapy. Data collected included aetiology of hypoparathyroidism, clinical manifestations, comorbidities, results of laboratory and other investigations used for diagnosis and screening for complications, therapy received, and physician's perception of impaired quality of life (QoL). RESULTS: Thirty-six endocrinologists and 29 nephrologists from Belgium and 28 endocrinologists from the Netherlands participated in the survey. Data included clinical symptoms, biochemical parameters, and QoL for 97 current patients with not adequately controlled chronic hypoparathyroidism on conventional therapy. Median duration of not adequately controlled hypoparathyroidism was 2.2 years, range 0.17-20.0. Most patients had neuromuscular (85%) and/or neurological (67%) symptoms, 71% had abnormal biochemical parameters, 10% were overweight, and physicians perceived that 71% had impaired QoL. Most frequently reported comorbidities included hypertension (25%), renal comorbidity (20%), diabetes mellitus (12%), and dyslipidaemia (11%). CONCLUSION: Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy experience a substantial burden of illness, mainly due to persistence of symptoms and presence of multiple comorbidities.

Passive Coping Strategies Are Associated With More Impairment In Quality Of Life In Patients With Fibrous Dysplasia.

Impairments in quality of life (QoL) have been reported in patients with fibrous dysplasia (FD). Here, we examine coping strategies in FD and assess whether these coping strategies are associated with QoL and disease severity. Ninety-two patients (66% females) filled out the Utrecht Coping List (UCL), Short Form-36, and the Brief Pain Inventory (BPI). Coping strategies of patients with FD were compared with reference data from a random sample of Dutch women and patients with chronic pain. Compared to healthy adults, patients expressed more emotions (p < 0.01). Compared to patients with chronic pain, patients with FD used more active coping strategies (p < 0.001), and sought more distraction (p = 0.01) and more social support (p < 0.001). Using more passive coping strategies was associated with more impairment in social function, physical role, mental health, vitality (all p < 0.001), and general health (p < 0.01). Using more avoidant coping strategies was associated with worse mental health and less vitality (both p < 0.01). More expression of emotions was associated with worse mental health (p < 0.01). Type and clinical severity of FD were not associated with coping behavior. Patients with FD have different coping strategies compared to random Dutch reference populations with or without pain. In FD, using more passive coping strategies was associated with more impairment in several aspects of QoL. There was no relationship between coping behavior and clinical characteristics, pointing to biomedical variables not determining the way patients cope with their illness. Recognition of less effective coping strategies can be helpful in the understanding and adaptation of these coping strategies, improving personalized clinical care, with the ultimate goal to improve QoL in patients with FD.

Illness Perceptions are Associated with Quality of Life in Patients with Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder in which normal bone is replaced by fibrous tissue resulting in pain, deformities, pathological fractures or asymptomatic disease. Illness perceptions are patients' cognitions and emotions about their illness and its treatment, which may impact on Quality of Life (QoL). Here, we explore illness perceptions in patients with FD compared to other disorders, identify factors associated with illness perceptions and evaluate their relationship with QoL. Ninety-seven out of 138 eligible patients from the LUMC FD cohort completed the Illness Perception Questionnaire-Revised (IPQ-R) and the Short Form-36 (SF-36). Age, Gender, Skeletal Burden Score (SBS), FGF-23 levels, type of FD and SF-36 scores were analysed for an association with illness perceptions. We observed significant (p < 0.01) differences in patients' illness perceptions between FD subtypes in the domains: identity, timeline acute/chronic and consequences. Patients with craniofacial FD reported to perceive more consequences (p = 0.022). High SBS was associated with perceiving more negative consequences and attributing the cause of FD to psychological factors (p < 0.01), and high FGF-23 levels with attributing more symptoms to the disease and perceiving more consequences (p < 0.01). The IPQ-R domain identity, timeline acute/chronic, timeline cyclical, consequences, emotional representations and treatment control were significantly associated with impairments in QoL. Illness perceptions in patients with FD relate to QoL, differ from those in patients with other disorders, and are associated with disease severity. Identifying and addressing maladaptive illness perceptions may improve quality of life in patients with FD.

Value and potential limitations of vertebral fracture assessment (VFA) compared to conventional spine radiography: experience from a fracture liaison service (FLS) and a meta-analysis.

We evaluated the value of VFA in the identification of vertebral fractures using a retrospective study and a meta-analysis. Performance of VFA was adequate in the meta-analysis although this was not demonstrated in our centre. We recommend checking the performance of VFA tools before exclusively relying on this tool. INTRODUCTION: Vertebral fractures are traditionally diagnosed using conventional radiographs of the spine. Vertebral fracture assessment (VFA) has been advocated as an alternative tool in the diagnosis of these fractures. METHODS: We conducted a retrospective study as well as a systematic review and a meta-analysis to evaluate the performance of VFA compared to conventional spinal radiography in patients who had sustained a fracture and thus at risk for osteoporosis. A risk of bias analysis was also performed. RESULTS: The diagnostic study included 542 patients (25% male) with fractures. The sensitivity of low-radiation VFA to detect a patient with a vertebral fracture ≥ Genant grade 2 was 0.77 and its specificity 0.80. Two hundred ninety-seven (55%) patients had ≥1 and 135(25%) ≥3 unevaluable vertebrae. The systematic review identified 16 studies including a total of 3238 subjects (19% male) with a mean age range of 45 to 74 years. Seven studies had a low risk of bias and 9 had an intermediate risk, mainly due to not consecutively including patients. The pooled sensitivity of VFA to detect a patient with a vertebral fracture ≥Genant grade 2 was 0.84 (95% CI, 0.72-0.92) and specificity 0.90 (95% CI, 0.84-0.94). CONCLUSIONS: Our findings from the meta-analysis suggest an adequate performance of VFA for the detection of vertebral fractures. However, we could not demonstrate these findings in our center, especially the specificity. Our data advocate caution with exclusively relying on VFA in the assessment of vertebral fractures without identifying performance and potential limitations of the technique.

Bone material strength index as measured by impact microindentation is low in patients with fractures irrespective of fracture site.

We evaluated the relationship between bone material strength index (BMSi) and fragility fractures, including vertebral fractures. Our data showed that BMSi is low in all fracture patients with low bone mass, independently of whether patients sustained a vertebral or a non-vertebral fracture. INTRODUCTION: Impact microindentation (IMI) is a new technique for the measurement of tissue level properties of cortical bone in vivo. Previous studies showed an association between BMSi and non-vertebral fractures, but an association with vertebral fractures is still being debated. The objective of this paper was to evaluate the relationship between BMSi and different types of fragility fractures, including vertebral fractures. METHODS: In this cross-sectional study, we measured BMSi in patients of both sexes with different types of fragility fractures and low bone mass with the IMI method using the Osteoprobe®. Vertebral fractures were diagnosed and graded on lateral spine radiographs. RESULTS: A total of 132 patients were included in the study, of whom 101 patients (65 women) had sustained a low energy fracture and 31 (mean age 57.7 ± 9.9 years) had no history or radiological evidence for a fracture. Of the fracture patients, 53 (mean age 62.8 ± 8.3 years) had only non-vertebral fractures (VF-/Fx+), 34 (mean age 62.8 ± 9.9 years) had vertebral and non-vertebral fractures (VF+/Fx+), and 14 (mean age 64.7 ± 9.3 years) had only vertebral fractures (VF+/Fx-). BMSi values, adjusted for age and BMD, were similar for all three groups of fracture patients (78.9 ± 0.7, 78.3 ± 0.9, and 78.4 ± 1.4, respectively; p = 0.866). BMSi values were not associated with number or severity of vertebral fractures. CONCLUSION: Our data demonstrate that BMSi is low in fracture patients with low bone mass, irrespective of whether they sustained a vertebral fracture or a non-vertebral fracture.

Bone material strength index as measured by impact microindentation is altered in patients with acromegaly.

OBJECTIVE: Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged ≥18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality. DESIGN AND METHODS: In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe. RESULTS: Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9-76.5), and 60.5 years (range 39.8-78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m2 ± 4.7 vs 26.6 kg/m2 ± 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm2 ± 0.21 vs 1.03 g/cm2 ± 0.13, P = 0.850) and at the femoral neck (0.84 g/cm2 ± 0.16 vs 0.80 g/cm2 ± 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 ± 0.7 vs 83.2 ± 0.7; P < 0.001). CONCLUSION: Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly.

[Fibrous dysplasia: a heterogeneous disease]. / Fibreuze dysplasie: een heterogeen ziektebeeld.

Fibrous dysplasia is a rare genetic bone disorder with a wide variation in clinical expression, ranging from asymptomatic patients to severely affected patients with extensive bone disease, pain, repetitive fractures and deformities and serious endocrinological symptoms (McCune-Albright syndrome). Here, we report on three different cases of fibrous dysplasia. First, a 46-year-old woman with a small solitary lesion in the proximal femur. Second, a 25-year-old man with polyostotic disease of the left leg who received both surgical and medical treatment. Third, a 7-year-old girl with McCune-Albright syndrome who was diagnosed with precocious puberty as a baby and who had extensive disease throughout the skeleton, including multiple lesions in the craniofacial region. The aetiology, clinical expression, diagnostic work-up and therapeutic options for fibrous dysplasia are discussed in a short résumé of the disease.

[Paget's disease of bone: diagnosis and treatment]. / De botziekte van Paget: diagnose en behandeling.

Paget's disease of bone is a focal disorder of bone remodelling that leads to changes in the shape and size of affected bones, and is associated with articular and vascular complications. The disorder is characterised by a localised increase in osteoclast number and activity in one or more affected sites while the rest of the skeleton remains unaffected. The excessive bone resorption leads to recruitment of osteoblasts to the remodelling sites, resulting in increased bone formation. This accelerated bone turnover causes deposition of bone with disorganised architecture and structural weakness. The precise aetiology is unknown. It is thought that the disease is caused by interactions between environmental and genetic factors; the nature of this interaction still has to be determined. The disease is progressive, but can be treated with a single infusion of zoledronic acid. In this manuscript three cases are described, along with a review of the current diagnostic tools and treatment.

High prevalence of secondary factors for bone fragility in patients with a recent fracture independently of BMD.

UNLABELLED: In this study, we demonstrate a high prevalence of secondary factors in patients with a recent fracture independently of bone mineral density (BMD). Our results suggest that patients with a recent fracture should be screened for secondary factors for bone fragility regardless of BMD values. INTRODUCTION: Secondary factors for bone fragility are common in patients with osteoporosis who have sustained a fracture. The majority of fragility fractures occurs, however, in patients with osteopenia, and it is not known whether secondary factors may contribute to fracture risk in these patients or in those with normal BMD. METHODS: Prospective cohort study evaluating the prevalence of secondary factors for bone fragility in consecutive patients referred to our fracture liaison service from June 2012 to June 2014 after a recent fracture. RESULTS: Seven hundred nine patients were included, 201 (28 %) with osteoporosis, 391 (55 %) with osteopenia and 117 (17 %) with normal BMD. Mean age was 66.0 ± 9.8 years, 504 (73 %) were women and 390 (57 %) had one or more underlying secondary factor. Evaluation of clinical risk factors using fracture risk assessment tool (FRAX) identified 38 % of patients with ≥1 secondary factor including smoking (18 %), excessive alcohol use (12 %), glucocorticoid use (12 %) and rheumatoid arthritis (3 %). Laboratory investigations revealed chronic kidney disease in 13 %, monoclonal gammopathy also in 13 % and primary or secondary hyperparathyroidism in 1 and 6 %, respectively. Secondary factors for bone fragility were equally prevalent in patients with osteoporosis, osteopenia or normal BMD. CONCLUSIONS: Our findings demonstrate a high prevalence of secondary factors for bone fragility in patients who have sustained a recent fracture, independently of BMD. The significant number of documented factors, which were treatable, suggest that patients who sustained a fracture should be screened for secondary factors for bone fragility regardless of BMD values to optimise secondary fracture prevention.

Vitamin D (25-0H D3) status and pathological response to neoadjuvant chemotherapy in stage II/III breast cancer: Data from the NEOZOTAC trial (BOOG 10-01).

BACKGROUND: Serum levels of 25-OH vitamin D3 (vitamin D) have been shown to be prognostic for disease-free survival in patients with breast cancer. We investigated the predictive value of these levels for pathological response after neoadjuvant chemotherapy in patients with breast cancer taking part in the NEOZOTAC phase-III trial. Additionally, the effect of chemotherapy on vitamin D levels was studied. MATERIALS AND METHODS: Serum vitamin D was measured at baseline and before the last cycle of chemotherapy. The relationship between these measurements and clinical outcome, as defined by pathological complete response in breast and lymph nodes (pCR) was examined. RESULTS: Baseline and end of treatment vitamin D data were available in 169 and 91 patients, respectively. Median baseline vitamin D values were 58.0 nmol/L. In patients treated with chemotherapy only, serum vitamin D levels decreased during neoadjuvant chemotherapy (median decrease of 16 nmol/L, P = 0.003). The prevalence of vitamin D levels < 50 nmol/L increased from 38.3% at baseline to 55.9% after chemotherapy. In the total population, baseline and end of therapy vitamin D levels were not related to pathological response. No associations were found between pCR and vitamin D level changes. CONCLUSION: The significant decrease in vitamin D post-neoadjuvant chemotherapy suggests that vitamin D levels should be monitored and in case of decrease of vitamin D levels, correction may be beneficial for skeletal health and possibly breast cancer outcome.

Effect of active infection on cytochrome P450-mediated metabolism of cyclosporine in renal transplant patients.

BACKGROUND: Infections downregulate cytochrome-P activities and thus may alter drug disposition, especially for drugs with a narrow therapeutic index. Cyclosporine (CyA), still used for the prevention of allograft rejection in renal transplant recipients in Egypt, seems to be affected by these infectious changes, based on random clinical observations. In the present study, the effects of bacterial and fungal infection on CyA metabolism were studied in renal transplant patients and subsequent nephrotoxicity was monitored. METHODS: Twenty renal transplant patients, diagnosed with fungal or bacterial infection, were recruited from the renal transplantation outpatient clinic in Alexandria University Hospitals. No dose adjustment in CyA was performed at least 1 week before the onset of infection. Exclusion criteria were patients with acute or chronic unstable liver disease, elderly patients, and patients on concomitant drugs affecting CyA metabolism. CyA trough levels and serum creatinine (SCR) concentrations were measured by fluorescence polarization immunoassay and enzymatic assay, respectively, pre-infection, during infection and in many cases, post infection. RESULTS: CyA trough levels and SCR concentrations increased significantly during the infection (P < 0.001, P = 0.002) respectively. Of the patients, 87% experienced a concomitant rise in CyA trough level and SCR concentrations. No significant difference between pre-infection and post-infection levels of CyA trough and SCR was found. CONCLUSIONS: CyA trough and SCR levels increased during bacterial and fungal infections and returned to pre-infection levels once the infection was resolved. The data generated stress the importance of monitoring CyA levels during episodes of infection. Our recommendations concerning CyA dose adjustment differ according to severity and duration of infection.

Changes in bone mineral density in newly diagnosed testicular cancer patients after anticancer treatment.

CONTEXT: Patients with germ cell tumors (GCTs) have an excellent prognosis but are at risk for silent fractures. Data on bone mineral density (BMD) after anticancer treatment are scarce. OBJECTIVE: The objective of the study was BMD monitoring in GCT patients treated with or without chemotherapy. DESIGN: We prospectively studied 63 newly diagnosed GCT patients with a median age of 33 years (range 16-70 y) within 3 months of unilateral orchidectomy. Twenty-seven patients (42.9%) had no metastases. Thirty-six patients (57.1%) with metastatic disease received combination chemotherapy. SETTING: This study was conducted at the outpatient clinic of a single academic institution. INTERVENTIONS: We performed dual-energy X-ray absorptiometry scans and collected blood samples on a yearly basis, before and up to 5 years after anticancer treatment. MAIN OUTCOME MEASURES: Changes in total hip and lumbar spine BMD, serum concentrations of gonadal hormones, and bone turnover markers were measured. RESULTS: BMD remained normal in stage I patients. In patients with metastatic disease, a significant decrease in lumbar spine BMD (-1.52%; P = .004) and total hip BMD (-2.05%; P < .0001) was observed 1 year after chemotherapy and remained stable thereafter for up to 5 years. There was no significant relationship between the observed decrease in BMD and gonadal status, vitamin D status, or cumulative dose of cisplatin or (antiemetic) corticosteroids. CONCLUSIONS: Metastatic GCT survivors demonstrate significant bone loss within the first year after curative combination chemotherapy, with no recovery up to 5 years after anticancer treatment. Whether this bone loss is associated with increased fracture risk and whether this could be prevented by bone modifying treatment remains to be established.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. PATIENTS AND METHODS: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. RESULTS: Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. CONCLUSIONS: Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Serum Dickkopf 1 levels in sclerostin deficiency.

CONTEXT: Sclerostin and Dickkopf 1 (DKK1) are antagonists of the canonical Wnt signaling pathway, both binding to the same low-density lipoprotein receptor-related protein 5/6 on osteoblasts, thereby inhibiting bone formation. It is not known whether there is an interaction between sclerostin and DKK1. OBJECTIVE: We examined whether a lack of sclerostin is compensated by increased DKK1 levels. DESIGN, SETTING, AND PATIENTS: We measured DKK1 levels in serum samples of patients and carriers of sclerosteosis (19 patients, 24 carriers) and van Buchem disease (VBD) (13 patients, 22 carriers) and 25 healthy controls. Sclerosteosis and VBD are caused by deficient sclerostin synthesis and are characterized by increased bone formation and hyperostotic phenotypes. MAIN OUTCOME MEASURES: DKK1 levels were compared between patients and carriers, and between patients and healthy controls. We also examined associations between levels of DKK1 and the bone turnover markers procollagen type 1 amino-terminal propeptide and carboxy-terminal cross-linking telopeptide. RESULTS: We found that DKK1 levels were significantly higher in patients with both sclerosteosis (4.28 ng/mL [95% confidence interval (CI), 3.46-5.11 ng/mL]) and VBD (5.28 ng/mL [95% CI, 3.84-6.71 ng/mL]), compared to levels in carriers of the two diseases (sclerosteosis, 2.03 ng/mL [95% CI, 1.78-2.29 ng/mL], P < .001; VBD, 3.47 ng/mL [95% CI, 2.97-3.97 ng/mL], P = 0.017) and to levels in healthy controls (2.77 ng/mL [95% CI, 2.45-3.08 ng/mL]; P = 0.004 and P < .001, respectively). Serum DKK1 levels were positively associated with levels of procollagen type 1 amino-terminal propeptide and carboxy-terminal cross-linking telopeptide in both disorders. CONCLUSIONS: These results suggest that increased DKK1 levels observed in patients with sclerosteosis and VBD represent an adaptive response to the increased bone formation characterizing these diseases, although these increased levels do not compensate for the lack of sclerostin on bone formation.

Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study.

BACKGROUND: In active acromegaly, pathologically elevated GH and IGF-1 levels are associated with increased bone turnover and a high bone mass, the latter being sustained after normalization of GH values. In a cross-sectional study design, we have previously reported a high prevalence of vertebral fractures (VFs) of about 60% in patients with controlled acromegaly, despite normal mean bone mineral density (BMD) values. Whether these fractures occur during the active acromegaly phase or after remission is achieved is not known. OBJECTIVE: Our objective was to study the natural progression of VFs and contributing risk factors in patients with controlled acromegaly over a 2.5-year follow-up period. METHODS: Forty-nine patients (mean age 61.3 ± 11.1 years, 37% female) with controlled acromegaly for ≥ 2 years after surgery, irradiation, and/or medical therapy and not using bisphosphonates were included in the study. Conventional spine radiographs including vertebrae Th4-L4 were assessed for VFs according to the Genant method. VF progression was defined as development of new/incident fractures and/or a minimum 1-point increase in the Genant scoring of preexisting VFs. BMD was assessed by dual-energy x-ray absorptiometry (Hologic 4500). RESULTS: Prevalence of baseline VFs was 63%, being highest in men, and fractures were unrelated to baseline BMD. VF progression was documented in 20% of patients, especially in men and in case of ≥ 2 VFs at baseline. VF progression was not related to BMD values or BMD changes over time. CONCLUSION: Findings from this longitudinal study show that VFs progress in the long term in 20% of patients with biochemically controlled acromegaly in the absence of osteoporosis or osteopenia. These data suggest that an abnormal bone quality persists in these patients after remission, possibly related to pretreatment long-term exposure to high circulating levels of GH.

Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors.

BACKGROUND: Testicular cancer patients have an increased risk for cardiovascular disease (CVD), which might be related to the increased prevalence of the metabolic syndrome (MetS) in this group of patients. METHODS: We assessed the prevalence of MetS and calculated the 10-year CVD risk in a cohort of 255 testicular germ cell tumour survivors (median age, 38.7 years; interquartile range, 31-48) at a mean of 7.8 years after anti-cancer treatment, and compared these with data obtained from 360 healthy men. RESULTS: Survivors had an age-adjusted increased risk for MetS of 1.9 compared with that of healthy controls. The risk for MetS was highest in survivors treated with combination chemotherapy (CT) 2.3 (Adult Treatment Panel of the National Cholesterol Education Program classification) and 2.2 (International Diabetes Federation classification). The risk of MetS was especially increased in survivors with testosterone levels in the lowest quartile (OR, 2.5). Ten-year cardiovascular risk as assessed by the Framingham Risk Score (3.0%) and Systemic Coronary Risk Evaluation (1.7%) algorithms was low, independent of treatment, and was comparable to controls. CONCLUSION: Testicular germ cell tumour survivors have an increased prevalence of MetS, with hypogonadism and CT treatment being clear risk factors for the development of the syndrome. The increased prevalence of MetS was not associated with an increased 10-year cardiovascular risk.

A large prospective European cohort study of patients treated with strontium ranelate and followed up over 3 years.

Strontium ranelate has been available as an osteoporosis treatment in Europe since 2004. This article describes a large European observational survey of the use of strontium ranelate in clinical daily practice. A retrospective observational registry included 32,446 women consulting for postmenopausal osteoporosis in seven countries. Within the registry, 12,046 women were receiving strontium ranelate and were followed up over 3 years. The baseline characteristics of the follow-up cohort were similar to those of the whole registry cohort (age, 68.9 ± 10.3 years; body mass index, 25.6 ± 4.3 kg/m(2); lumbar spine T-score, -2.57 ± 0.85 SD; femoral neck T-score, -2.11 ± 0.86 SD). At baseline, 77 % of patients had at least one risk factor for osteoporosis, and 46 % had a previous history of osteoporotic fracture. Mean duration of follow-up was 32.0 ± 9.7 months, and treatment duration was 25.2 ± 13.7 months (24,956 patient-years of treatment). Persistence with strontium ranelate was 80 % at 1 year, 68 % at 2 years, and 64 % at 32 months; most patients (about 80 %) reported rarely omitting a dose. At least one emergent adverse event was reported in 2,674 (22 %) patients, most frequently gastrointestinal side effects. The crude incidence of venous thromboembolic events was 2.1/1,000 patient-years. No cases of hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), Steven-Johnson syndrome, or toxic epidermal necrolysis, were reported. During follow-up, a fracture occurred in 890 patients (7 %); 429 of the fractures were nonvertebral fractures. Our observational survey over 32 months indicated good rates of adherence with strontium ranelate and confirmed its good safety profile in the management of postmenopausal osteoporosis.