Alendronate use and bone mineral density gains in women with moderate-severe (stages 3B-5) chronic kidney disease: an open cohort multivariable and propensity score analysis from Funen, Denmark.

Bisphosphonates are contraindicated in moderate-to-severe chronic kidney disease patients. However, they are used to prevent fragility fractures in patients with impaired kidney function, despite a lack of evidence on their effects on bone density in these patients. We demonstrated that Alendronate had a positive effect on bone in these patients. PURPOSE: This study aimed to assess the association between alendronate use and bone mineral density (BMD) change in subjects with moderate-severe chronic kidney disease (CKD). METHODS: We created a cohort of CKD stage 3B-5 patients by linking all DXA-based measurements in the Funen area, Denmark, to biochemistry, national health registries and filled prescriptions. Exposure was dispensation of alendronate and the outcome was annualized percentage change in BMD at the femoral neck, total hip and lumbar spine. Individuals were followed from first BMD to the latest of subsequent DXA measurements. Alendronate non-users were identified using incidence density sampling and matched groups were created using propensity scores. Linear regression was used to estimate average differences in the annualized BMD. RESULTS: Use of alendronate was rare in this group of patients: propensity score matching (PSM) resulted in 71 alendronate users and 142 non-users with stage 3B-5 CKD (as in the 1 year before DXA). Whilst alendronate users gained an average 1.07% femoral neck BMD per year, non-users lost an average of 1.59% per annum. The PSM mean differences in annualized BMD were + 2.65% (1.32%, 3.99%), + 3.01% (1.74%, 4.28%) and + 2.12% (0.98%, 3.25%) at the femoral neck, total hip and spine BMD, respectively, all in favour of alendronate users. CONCLUSION: In a real-world cohort of women with stage 3B-5 CKD, use of alendronate appears associated with a significant improvement of 2-3% per year in the femoral neck, total hip and spine BMD. More data are needed on the anti-fracture effectiveness and safety of bisphosphonate therapy in moderate-severe CKD.

Assessment of fracture risk in women with eating disorders: The utility of dual-energy x-ray absorptiometry (DXA)-Clinical cohort study.

OBJECTIVE: Eating disorders (EDs) are associated with decreased bone mineral density (BMD) and increased fracture risk. The association between BMD and fracture risk in EDs is not well elucidated. We aimed to assess BMD in an ED cohort of patients with active disease and patients in remission, and to assess the predictive value of BMD on incidence of fractures. METHOD: We included 344 female patients (median age 19, IQR 16; 24) referred to ED treatment. Later, patients were invited to follow-up including assessment of remission status and a dual-energy x-ray absorptiometry (DXA)-scan. Information on fractures was obtained through the Danish National Registry of Patients. RESULTS: Patients with current anorexia nervosa (AN) had significantly lower BMD compared to controls at lumbar spine (16% lower, p < .0001), femoral neck (18% lower, p < .0001), and total hip (23% lower, p < .0001). Recovered AN patients had higher BMD compared to those with current disease (p < .0001 for all measures), but lower BMD compared to controls at lumbar spine (p < .01) and hip (p < .001). BMD did not differ between BN patients and controls. In patients with active eating disorders not otherwise specified, BMD was lower only at the total hip (p < .005). We found no association between BMD and fracture risk. CONCLUSION: We confirm that AN is associated with low BMD, whereas BN is not. Remission is associated with higher BMD compared to patients with active AN, but a deficit remains. We found no significant association between BMD and fracture risk, challenging the benefit of the widespread use of DXA scans in young women with ED. CLINICAL TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov, number NCT00267228.

Fractures in women with eating disorders-Incidence, predictive factors, and the impact of disease remission: Cohort study with background population controls.

OBJECTIVE: Malnutrition and low weight in eating disorders (EDs) are associated with increased fracture risk compared to the general population. In a cohort study, we aimed to determine fracture rates compared to age and gender matched controls (ratio 5:1), assess the impact of disease remission on fracture risk, and establish predictive factors for fractures. METHOD: Of note, 803 ED patients referred to specialized ED treatment between 1994 and 2004 were included. In 2016, data on fractures were obtained through the Danish National Registry of Patients. RESULTS: Fracture risk was increased in anorexia nervosa (AN; IRR 2.2 [CI 99%: 1.6-3.0]) but not in bulimia nervosa (BN; IRR 1.3, ns) or other specified feeding or eating disorders (OSFED; IRR 1.8, ns). IRR in the AN group were increased for vertebral fractures (IRR 3.8 [CI 99%: 1.4-10.3]), upper arm (IRR 3.0 (CI 99% 1.6-5.5) and hip (IRR 6.6 [CI 99%: 2.6-18.0]). Disease remission in AN is associated to lower fracture risk compared to active disease, but higher fracture risk compared to controls (IRR 1.7 [CI 99%: 1.1-2.7]). In regression analysis, age at debut of disease, nadir BMI and duration of disease before referral to treatment, independently predicted fracture. DISCUSSION: We confirm increased fracture risk in AN, and show significant differences in fracture risk between patients in disease remission and patients with active disease. Furthermore, we show that age at debut of disease and duration of disease before referral to treatment is positively correlated to fracture risk, whereas nadir BMI is negatively correlated to fracture risk.

Bone disease in diabetes: another manifestation of microvascular disease?

Type 1 and type 2 diabetes are generally accepted to be associated with increased bone fracture risk. However, the pathophysiological mechanisms of diabetic bone disease are poorly understood, and whether the associated increased skeletal fragility is a comorbidity or a complication of diabetes remains under debate. Although there is some indication of a direct deleterious effect of microangiopathy on bone, the evidence is open to question, and whether diabetic osteopathy can be classified as a chronic, microvascular complication of diabetes remains uncertain. Here, we review the current knowledge of potential contributory factors to diabetic bone disease, particularly the association between diabetic microangiopathy and bone mineral density, bone structure, and bone turnover. Additionally, we discuss and propose a pathophysiological model of the effects of diabetic microvascular disease on bone, and examine the progression of bone disease alongside the evolution of diabetes.

Calcaneal quantitative ultrasound and phalangeal radiographic absorptiometry alone or in combination in a triage approach for assessment of osteoporosis: a study of older women with a high prevalence of falls.

BACKGROUND: The objective of this study was to investigate if application of United Kingdom National Osteoporosis Society (UK-NOS) triage approach, using calcaneal quantitative ultrasound (QUS), phalangeal radiographic absorptiometry (RA), or both methods in combination, for identification of women with osteoporosis, would reduce the percentage of women who need further assessment with Dual Energy X-ray Absorptiometry (DXA) among older women with a high prevalence of falls. METHODS: We assessed 286 women with DXA of hip and spine (Hologic Discovery) of whom 221 were assessed with calcaneal QUS (Achilles Lunar), 245 were assessed with phalangeal RA (Aleris Metriscan), and 202 were assessed with all three methods. Receiver operator characteristics (ROC) curve for QUS, RA, and both methods in combination predicting osteoporosis defined by central DXA were performed. We identified cutoffs at different sensitivity and specificity values and applied the triage approach recommended by UK-NOS. The percentage of women who would not need further examination with DXA was calculated. RESULTS: Median age was 80 years (interquartile range [IQR]) [75-85], range 65-98. 66.8% reported at least one fall within the last 12 months. Prevalence of osteoporosis was 44.4%. Area under the ROC-curve (AUC) (95% confidence interval (CI)) was 0.808 (0.748-0.867) for QUS, 0.800 (0.738-0.863) for RA, and 0.848 (0.796-0.900) for RA and QUS in combination. At 90% certainty levels, UK-NOS triage approach would reduce the percentage of women who need further assessment with DXA by 60% for QUS, and 43% for RA. The false negative and false positive rates ranged from 4% to 5% for QUS and RA respectively. For the combined approach using 90% certainty level the proportion of DXAs saved was 22%, the false negative rate was 0% and false positive rate was 0.5%. Using 85% certainty level for the combined approach the proportion of DXAs saved increased to 41%, but false negative and false positive values remained low (0.5%, and 0.5% respectively). CONCLUSIONS: In a two-step, triage approach calcaneal QUS and phalangeal RA perform well, reducing the number of women who would need assessment with central DXA. Combining RA and QUS reduces misclassifications whilst still reducing the need for DXAs.

Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and to effect of estrogen treatment.

OBJECTIVES: The purinergic P2RX7 receptor (P2RX7) has been shown to play a role in the regulation of osteoblast and osteoclast activity. The aim of this study was to determine the presence of polymorphisms in exon 13 of the P2X7 gene and the association with osteoclast apoptosis in vitro and bone status in vivo. METHODS: A total of 1764 postmenopausal women were genotyped for three single nucleotide polymorphisms detected after sequencing of exon 13 of P2X7. Bone markers, bone mineral density of the hip and lumbar spine were determined at baseline and after 10 years, and vertebral fracture incidence after 10 years. In-vitro ATP-induced caspase-1 determinations were performed on osteoclasts from the different genotypes. RESULTS: Three polymorphisms were detected (Gln460Arg, Glu496Ala, and Ile568Asn). None of the polymorphisms was related to bone mineral density or changes in bone mineral density over 10 years in hormone replacement therapy naïve women. The Ile568Asn polymorphism was however, associated with effect of hormone replacement therapy. Furthermore, the 10-year fracture incidence was significantly associated with both the Glu496Ala and the Ile568Asn. The Glu496Ala polymorphism was closely related to ATP-induced osteoclast apoptosis in vitro, as osteoclasts from individuals homozygous for the C allele had significantly decreased apoptotic activity. CONCLUSION: The P2X7 Glu496Ala and the Ile568Asn single nucleotide polymorphisms are associated with 10-year fracture risk in postmenopausal women and response to hormone replacement therapy treatment. Further, the Glu496Ala polymorphism is strongly influencing osteoclast apoptosis in vitro, which could contribute to increased fracture risk.