Effect of incretins on skeletal health.

PURPOSE OF REVIEW: The incretin hormones, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have been shown to decrease bone resorption in humans. The aim of this review is to collate evidence and current advances in the research within the last year on the effect of incretins on skeletal health. RECENT FINDINGS: Preclinical studies show potential direct beneficial effects on bone by GLP-1 and GIP, however real world epidemiological data show no effects of GLP-1 receptor analogues on fracture risk. This may be due to the weight loss accompanied by GLP-1 treatment which may have detrimental effects on bone. GIP is shown to reduce bone resorption and increase bone formation. Further evidence suggests an additive effect of GIP and glucagon like peptide-2, which could affect bone by different mechanisms. SUMMARY: GIP and GLP-1 based therapies are more widespread used and may have potential beneficial effects on bone, possibly counterbalanced by weight loss. Long-term effects and side-effects of GIP or GIP/ GLP-2 co-administration remain to be elucidated, and longer term treatment trials are needed.

Bone Density and Structure in Overweight Men With and Without Diabetes.

Objective: Metabolic syndrome (MetS), type 1 diabetes (T1D), and type 2 diabetes, are associated with an increased risk of fractures; however, the impact of obesity on bone deficits in diabetes is unknown. We aimed to compare markers of bone structure, bone density, and bone turnover in non-diabetic overweight men with MetS and overweight men with T1D or T2D. Methods and Research Design: In this cross-sectional study we included participants from two previously described study cohorts consisting of participants with diabetes and participants with MetS. Participants underwent dual-energy X-ray absorptiometry measuring areal bone mineral density (aBMD) at the hip and lumbar spine, High Resolution peripheral Quantitative (HRpQCT) scan of the tibia and radius and measurement of circulating bone turnover markers. We compared groups with unpaired t test and performed multiple linear regression with adjustment for age, body mass index, and smoking. Results: We included 33 participants with T1D, 25 participants with T2D, and 34 participants with MetS. Bone turnover markers levels were comparable between T1D and MetS. aBMD at the hip was lower in T1D compared to MetS, also after adjustment. P1NP and Osteocalcin levels were lower among individuals with T2D compared to MetS, whereas aBMD were similar between the groups after multiple adjustments. We observed no difference in volumetric BMD at the tibia or radius between MetS and T1D and T2D, respectively. Participants with T2D had a higher trabecular number and lower trabecular separation compared to individuals with MetS at the tibia, which remained signficant after multiple adjustments. Conclusion: In conclusion, we observed no clinically important differences in bone density or structure between men with T2D, T1D, or MetS. However, men with T2D displayed lower bone turnover compared to MetS highlighting that T2D per se and not obesity, is associated with low bone turnover.

Associations of Circulating Osteoglycin With Bone Parameters and Metabolic Markers in Patients With Diabetes.

Objective: Circulating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D). Design and methods: A cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics. Results: S-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all). Conclusion: Osteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01870557.

Consumption of nutrients and insulin resistance suppress markers of bone turnover in subjects with abdominal obesity.

OBJECTIVE: Abdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified. Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses. METHODS: We enrolled 64 subjects with abdominal obesity. Following 10 h of fasting, subjects initially underwent a standard OGTT (300 kcal) and approximately one week later a mixed meal tolerance test (1130 kcal). Circulating CTX, P1NP and PTH were assessed on both days at time = 0, after 30 min and after 90 min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response. RESULTS: CTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90 min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90 min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance. CONCLUSION: The acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover - which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.

Diabetes and Abdominal Aortic Calcification-a Systematic Review.

PURPOSE OF REVIEW: A systematic literature review was performed to evaluate diabetes mellitus (DM) as a risk factor of abdominal aortic calcification (AAC), and address factors that might contribute to the development of AAC in DM patients. RECENT FINDINGS: DM is an independent risk factor of AAC development. Bone metabolism along with lifestyle factors among DM patients makes them more prone to AAC. Hip and vertebral fractures, high phosphate, smoking, hypertension, and low osteocalcin could make DM patients prone to AAC. Low levels of high-density lipoprotein (HDL), high low-density lipoprotein (LDL), high total cholesterol/HDL ratio, low bone mineral density (BMD) may be risk factors, but the literature is more ambiguous. Body mass index (BMI) does not appear to increase risk of AAC. High phosphate levels and low osteocalcin levels seem to be biomarkers of AAC in patients with diabetes. However, the association between DM and AAC is complicated.

Differential Impact of Glucose Administered Intravenously and Orally on Circulating miR-375 Levels in Human Subjects.

Background: To date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however, their functional role in this compartment remains unclear. Objective: The aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge. Design: Twelve healthy males were recruited for an acute crossover study that consisted of two tests each following an 8-hour fasting period. An oral glucose tolerance test (OGTT) was performed, and blood samples were collected over a 3-hour period. Following a period of at least 1 week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood-collection protocol. Results: The glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected, systemic insulin levels were lower during the IIGI compared with the OGTT (P < 0.05). miR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide (GLP)-1, GLP-2, and glucose-dependent insulinotropic polypeptide. Conclusions: The present findings show levels of miR-375 increase following administration of an OGTT and, in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play an important role in the abundance and function of this miRNA in the blood.

Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study.

AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (≤0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. RESULTS: A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for ≤0.5 years of treatment and for malignant melanoma for 2-3 years (RR 1.92, 95% CI 1.02, 3.61) and 4-5 years (RR 3.55, 95% CI 1.68, 7.47]); among men, a lower risk was observed for pancreatic cancer for 2-3 years (RR 0.34, 95% CI 0.17, 0.66) and for liver cancer for 3-4 years (RR 0.36, 95% CI 0.14, 0.94) and >6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. CONCLUSIONS/INTERPRETATION: The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.

MECHANISMS IN ENDOCRINOLOGY: Diabetes mellitus, a state of low bone turnover - a systematic review and meta-analysis.

OBJECTIVE: To investigate the differences in bone turnover between diabetic patients and controls. DESIGN: A systematic review and meta-analysis. METHODS: A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers. RESULTS: A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (-0.10 ng/mL (-0.12, -0.08)) and the bone formation markers osteocalcin (-2.51 ng/mL (-3.01, -2.01)) and procollagen type 1 amino terminal propeptide (-10.80 ng/mL (-12.83, -8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (-0.31 U/L (-0.56, -0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)). CONCLUSIONS: Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this.

Differential impact of glucose administered intravenously or orally on bone turnover markers in healthy male subjects.

BACKGROUND: Patients with type-1 (T1D) and type-2 diabetes mellitus (T2D) have an increased risk of hip fracture. The underlying mechanisms may involve disturbances in the incretin hormones. Our aim was to clarify if glucose administration i.e. orally or intravenously differentially affects bone turnover markers in healthy males. METHODS: 12 healthy males were included in a cross-over study consisting of three tests following an 8hour fast. First, an oral glucose tolerance test (OGTT) was performed. Subsequently, we carried out an isoglycemic intravenous glucose infusion (IIGI) that closely mimicked the glucose response curve to the oral glucose load. We analyzed blood samples for the bone turnover markers serum C-terminal telopeptide of type I collagen (s-CTX) and serum procollagen type I N propeptide (s-P1NP), as well as insulin, glucose, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). Finally, eight of the twelve participants underwent a control experiment where they fasted for 3h (Control). RESULTS: While OGTT induced a 50% reduction in s-CTX, only a ~30% reduction was seen during the IIGI and the Control. Neither intervention influenced s-P1NP. The concentration of insulin was highest during the OGTT. However, insulin was also increased significantly during the IIGI compared to the Control. Plasma concentrations of GIP, GLP-1 and GLP-2 were higher under the OGTT than during the IIGI and Control. A linear regression indicated that peak p-GIP significantly predicts nadir s-CTX (p=0.03), and that peak p-GIP could explain 34% of the variability in nadir s-CTX (adjusted R2=0.34). CONCLUSION: This study indicates that glucose per se does not acutely affect bone turnover markers. However, gastrointestinal hormones, especially GIP, possibly in combination with hyperglycemia, may have an acute, uncoupling effect on bone turnover leading to a decrease in bone resorption but no change in bone formation.

Epidemiology of Fractures in Diabetes.

Diabetes mellitus is associated with an increased risk of fracture. The risk of a hip fracture is up to sevenfold increased in patients with type 1 diabetes and about 1.3-fold increased in patients with type 2 diabetes. However, these relative risk estimates may depend on the age and gender distribution of the population in question. Bone mineral density and the fracture risk assessment tool do not explain the increased fracture risk in patients with diabetes. Shared risk factors as pancreatitis, alcohol use, smoking and oral glucocorticoids may influence the observed fracture risk in patients with diabetes. This review examines the association between diabetes and fracture and attempts to disentangle the tight connection between diabetes per se, diabetes-related complications, comorbidities and shared risk factors. This is of great importance as the number of diabetes patients' increases with growing and aging populations and putting even more at risk of fracture.

Differences in biochemical bone markers by diabetes type and the impact of glucose.

BACKGROUND: Diabetes mellitus is associated with an increased fracture risk, however the fracture risk is 7 fold increased in patients with type 1 diabetes (T1D) and 1.4 fold increased in patients with type 2 diabetes (T2D) with decreased and increased bone mineral density, respectively. Oral ingestion of glucose causes an acute decrease in bone turnover markers, and thus glucose levels may affect bone turnover in diabetes. OBJECTIVE: The aim was to examine disparities in bone turnover markers between patients with T1D and T2D and evaluate the effect of glucose on bone turnover. METHODS: A cross-sectional study was conducted. Patients diagnosed with T1D (n=98) or T2D (n=96) were included from the outpatient clinics at two University Hospitals. All individuals had normal renal function. Glucose and bone turnover markers were measured in non-fasting blood samples. RESULTS: P-procollagen type 1 amino terminal propeptide (P1NP), p-osteocalcin (OC), and s-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL) were lower in patients with T2D compared to T1D, and s-osteoprotegerin (OPG) was higher in T2D. P-C-terminal cross-linked telopeptide of type-I collagen (CTX), p-fibroblast growth factor-23 (FGF-23), p-sclerostin, and p-undercarboxylated osteocalcin (ucOC) were similar in between the two groups of patients. Increasing non-fasting glucose levels were inversely related to p-CTX, p-P1NP, p-OC, and p-ucOC and directly related to s-OPG in simple linear and multiple linear regressions adjusted for factors influencing bone turnover markers including HbA1c. CONCLUSION: Bone turnover markers were lower in patients with T2D compared to T1D. Acute blood glucose alterations may change bone turnover mediated by OPG and have detrimental effects on bone health in diabetes. TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT01870557.

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence.

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.

Diabetes, cancer and treatment - a mini-review.

AIM: To conduct a systematic review of the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues. MATERIAL AND METHODS: The review was developed according to the PRISMA guidelines. A systematic search of Pubmed was performed using the key words: "insulin analogue", "insulin derative", "insulin homologue", "glargine", "Lantus", "degludec", "tresiba", "NPH", "lispro", "humalog", "detemir", "levemir", "glulisine", "apidra", "aspart", "novolog", "insulin treatment", "diabetes treatment", "insulin therapy" or "diabetes therapy" combined with "neoplasia", "tumor", "cancer", "carcinoma", "malignan*", "carcinog*" or " mitoge*". Eligible studies were those reporting on potential biological mechanisms, studies reporting on statistical or epidemiological associations were excluded. RESULTS: Per October 8, 2013, the search produced 28,276 hits in Pubmed. All studies were either mechanistic speculations based on epidemiological association studies, a few randomized controlled trials (several unpublished), or non-human studies (cell cultures or animal studies). The evidence level in human terms was low. CONCLUSION: In general many studies on pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues exist. However, the level of evidence of a causal association between diabetes and the treatment of diabetes and cancer is low.

Use of biguanides and the risk of colorectal cancer: a register-based cohort study.

Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies.

CARING (CAncer Risk and INsulin analoGues): the association of diabetes mellitus and cancer risk with focus on possible determinants - a systematic review and a meta-analysis.

BACKGROUND: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se. OBJECTIVE: To examine the association between DM and cancers by a systematic review and meta-analysis according to the PRISMA guidelines. DATA SOURCES: The systematic literature search includes Medline at PubMed, Embase, Cinahl, Bibliotek.dk, Cochrane library, Web of Science and SveMed+ with the search terms: "Diabetes mellitus", "Neoplasms", and "Risk of cancer". STUDY ELIGIBILITY CRITERIA: The included studies compared the risk of cancer in diabetic patients versus non-diabetic patients. All types of observational study designs were included. RESULTS: Diabetes patients were at a substantially increased risk of liver (RR=2.1), and pancreas (RR=2.2) cancer. Modestly elevated significant risks were also found for ovary (RR=1.2), breast (RR=1.1), cervix (RR=1.3), endometrial (RR=1.4), several digestive tract (RR=1.1-1.5), kidney (RR=1.4), and bladder cancer (RR=1.1). The findings were similar for men and women, and unrelated to study design. Meta-regression analyses showed limited effect modification of body mass index, and possible effect modification of age, gender, with some influence of study characteristics (population source, cancer- and diabetes ascertainment). LIMITATIONS: Publication bias seemed to be present. Only published data were used in the analyses. CONCLUSIONS: The systematic review and meta-analysis confirm the previous results of increased cancer risk in diabetes and extend this to additional cancer sites. Physicians in contact with patients with diabetes should be aware that diabetes patients are at an increased risk of cancer.

Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables.

OBJECTIVE: To study the prevalence of renal stones and nephrocalcinosis in patients with primary hyperparathyroidism (PHPT) and to appraise biochemical variables as risk factors for developing renal calcifications. DESIGN: Cross-sectional. MATERIALS AND METHODS: All patients (n=177) undergoing diagnostic evaluation and surgery for PHPT at Aarhus University Hospital between 2007 and 2009. All patients underwent routine spiral CT scans of the abdomen to determine the presence or absence of renal calcifications. RESULTS: A total of 45 patients (25.4%, 95% confidence intervals: 19.0-31.4%) had renal stones (15.3%) and/or renal calcifications (10.2%) on the CT scans. Compared with those without calcification (n=132), the group with calcification had a significantly lower plasma creatinine level (67.0±25.1 vs 74.6±17.5 µmol/l, 2P=0.03). Moreover, CaE was higher in PHPT patients with renal calcification than in PHPT patients without (0.91±0.28 vs 0.74±0.40 mmol/mmol, 2P=0.02). The other measured or derived biochemical variables were similar in the two groups. No biochemical variable was predictive for renal calcifications in a multiple regression analysis. CONCLUSION: We found a high prevalence of renal calcifications among PHPT patients but no deterioration of renal function. The occurrence of calcifications was related to low plasma creatinine and a high urine calcium/creatinine ratio. However, biochemical markers in general were poor predictors for the risk of renal stones or nephrocalcinosis indicating that routine image diagnostics may be needed for the identification of these complications in order to establish indication for surgery and ensure proper treatment.