Incident peptic ulcers and concomitant treatment of direct oral anticoagulants and oral bisphosphonates-a real-world cohort study.

Oral bisphosphonates and direct oral anticoagulants are related to upper gastrointestinal ulcers. The present study investigated whether concomitant use of these drugs increase the risk of upper gastrointestinal ulcers and report no increased risk of upper gastrointestinal ulcers compared to the use of either drug alone, when individuals with previous upper gastrointestinal ulcers are excluded. INTRODUCTION: This study examines whether concomitant use of oral bisphosphonates (oBP) and direct oral anticoagulants (DOAC) increases the risk of peptic ulcers more than any drug alone. METHODS: A population-based cohort study was performed. We sampled a cohort of oBP and DOAC users from a sample of 2,622,742 individuals, consisting of diabetes patients and age- and gender-matched controls, obtained from the Danish National Patient Register. The exposures were concomitant use of oBP and DOAC and single use of DOAC and single use of oBP. The primary endpoint was the first incident peptic ulcer. Information on exposure and outcome were collected from national registries. The period of observation was from 01.01.2008 until 31.12.2018. Unadjusted and adjusted Cox regressions were performed. RESULTS: 8077 individuals received concomitant treatment with DOAC and oBP; 96,451 individuals used DOAC and no oBP; and 118,675 used oBP and no DOAC. The mean duration of follow-up was 1.9 years for concomitant users, 2.5 years for DOAC users, and 4.5 years for oBP users. A total of 4742 individuals with incident peptic ulcers were collected. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to single DOAC treatment in the adjusted analysis (HR = 1.23, 95% CI: 1.03; 1.48). However, the effects were abolished when excluding individuals with a previous ulcer. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to users of oBP in the adjusted model (HR = 1.34, 95% CI: 1.11; 1.63). CONCLUSION: Based on our results, concomitant use of oBP and DOAC is associated with a slight increase in the risk of peptic ulcers compared to either drug alone. The prescribing physician should weigh the slight increased risk of ulcer in concomitant users of oBP and DOAC with beneficial reductions in stroke and fractures.

Risk of fractures in primary hyperparathyroidism: a systematic review and meta-analysis.

An increased risk of fractures in primary hyperparathyroidism (PHPT) has been reported in a number of relatively small studies. Performing a systematic literature search, we identified available studies and calculated common estimates by pooling results from the individual studies in a meta-analysis. Searching EMBASE and PubMed, we identified published studies reporting the risk of fractures in PHPT compared to a control group. We calculated odds ratio (OR) with 95% confidence interval (CI). A total of 804 studies were identified of which 12 studies were included. Risk of any fracture was increased compared to controls (OR 2.01; 95% CI, 1.61-2.50; I2 46%, 5 studies). Analysis of fracture risk at specific sites showed an increased risk of fracture at the forearm (OR 2.36; 95% CI, 1.64-3.38; I2 0%, 4 studies) and spine (OR 3.00; 95% CI, 1.41, 6.37, I2 88%, 9 studies). Risk estimate for hip fractures was non-significantly increased (OR 1.27; 95% CI, 0.97-1.66; I2 0%, 3 studies). Risk of vertebral fractures (VFx) was also increased if analyses were restricted to only studies with a healthy control group (OR 5.76; 95% CI, 3.86-8.60; I2 29%, 6 studies), studies including patients with mild PHPT (OR 4.22; 95% CI, 2.20-8.12; I2 57%, 4 studies) or studies including postmenopausal women (OR 8.07; 95% CI, 4.79-13.59; I2 0%, 3 studies). PHPT is associated with an increased risk of fractures. Although a number of studies are limited-it seems that the risk is increased across different skeletal sites including patients with mild PHPT and postmenopausal women.

Fracture rates in patients discontinuing alendronate treatment in real life: a population-based cohort study.

In this nationwide register-based cohort study, we found no difference in the risk of fractures in patients discontinuing versus continuing alendronate (ALN) treatment after 5 years. INTRODUCTION: Information on fracture risk in patients discontinuing ALN in a real-life setting is sparse. We aimed to examine ALN discontinuation patterns, compare fracture rates in patients discontinuing versus continuing ALN after 5 years of treatment, and define determinants of fractures in ALN discontinuers. METHODS: A nationwide population-based cohort study using Danish health registry data. Our source population was individuals who had redeemed ≥ 2 ALN prescriptions between January 1, 1995, and September 1, 2017. RESULTS: We found that 25% of all ALN initiators used ALN for less than 1 year and 43% continued treatment for at least 5 years. We classified n = 1865 as ALN discontinuers and n = 29,619 as ALN continuers. Using Cox proportional hazards regression analysis and an "as-treated" approach, we observed no increased risk of any fracture (incidence rate ratio (IRR) 1.06, 95% CI 0.92-1.23), vertebral fracture (IRR 0.59, 95% CI 0.33-1.05), hip fracture (IRR 1.04, 95% CI 0.75-1.45), or major osteoporotic fracture (IRR 1.05, 95% CI 0.88-1.25) in the ALN discontinuers compared to continuers during a follow-up time of 1.84 ± 1.56 years (mean ± SD) and 2.51 ± 1.60 years, respectively. ALN re-initiation was a major determinant of follow-up among the discontinuers. Old age (> 80 vs. 50-60 years, unadjusted IRR 2.92, 95% CI 1.18-7.24) was the strongest determinant for fractures following ALN discontinuation. CONCLUSION: In a real-world setting, less than 50% continued ALN treatment for 5 years. We found no difference in the risk of fractures in patients discontinuing versus continuing ALN after 5 years.

The predictive value of bone turnover markers during discontinuation of alendronate: the PROSA study.

In patients discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years), BMD decreased, and bone turnover markers increased within the premenopausal reference range over 2 years. Increased p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD is dependent on continued suppression of bone turnover. INTRODUCTION: It is unknown how to monitor patients discontinuing alendronate (ALN) after more than 5 years. We investigated if BTM measured before or during treatment discontinuation with ALN predict bone loss after 1 or 2 years. METHODS: PROSA was a cohort study conducted at Aarhus University Hospital including postmenopausal women and men above 50 years treated with ALN ≥ 5 years who had osteopenia at the hip and BMD T-score at the lumbar spine > - 4. ALN was discontinued and BTMs were measured at baseline, months (M) 1, 3, 6, and 12, and DXA was performed at baseline, M6, and M12. We extended the study and measured BTMs and performed DXA at M24. The primary endpoint was if changes in p-CTX at M3 or M6 predict changes in THBMD after 1 year ( Clinicaltrials.gov : NCT03051620). RESULTS: We enrolled 136 participants discontinuing ALN after a median of 7.0 years (range 5.0-20.0 years) in PROSA and 124 participants in PROSA Extension. There was a significant decrease in LSBMD - 0.74% ± 0.27, THBMD - 2.65% ± 0.39, FNBMD - 2.35% ± 0.33, and trabecular bone score - 0.97% ± 0.35 and an increase in p-CTX by 61.1% ± 4.7 (p < 0.05 for all) after 24 months. Increase in p-CTX at M3 was associated with bone loss at the hip sites at M12 and M24. CONCLUSION: In patients discontinuing ALN, BMD decreased significantly and BTMs increased within the reference range over 2 years. An increase in p-CTX after 3 months was associated with greater bone loss at the hip confirming that maintenance of BMD during treatment discontinuation is dependent on continued suppression of bone turnover.

The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial.

We conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups. INTRODUCTION: Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. METHODS: We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 µg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 µg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. RESULTS: Undercarboxylated osteocalcin decreased in the MK-7-group (- 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (- 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. CONCLUSION: Treatment with MK-7 375 µg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov : NCT01922804 .

Glucose-Lowering Drugs and Fracture Risk-a Systematic Review.

PURPOSE OF REVIEW: Diabetes mellitus (DM) is associated with increased fracture risk. The aim of this systematic review was to examine the effects of different classes of glucose-lowering drugs on fracture risk in patients with type 2 DM. The heterogeneity of the included studies did not allow formal statistical analyses. RECENT FINDINGS: Sixty studies were included in the review. Metformin, dipeptidylpeptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2-inhibitors do not appear to increase fracture risk. Results for insulin and sulphonylureas were more disparate, although there may be an increased fracture risk related to hypoglycemia and falls with these treatments. Glitazones were consistently associated with increased fracture risk in women, although the evidence was sparser in men. New glucose-lowering drugs are continuously being developed and better understanding of these is leading to changes in prescription patterns. Our findings warrant continued research on the effects of glucose-lowering drugs on fracture risk, elucidating the class-specific effects of these drugs.

Treatment with zoledronic acid subsequent to odanacatib prevents bone loss in postmenopausal women with osteoporosis.

Treatment with zoledronic acid 5 mg maintained bone turnover markers in the premenopausal range, increased lumbar spine bone mineral density, and maintained hip bone mineral density in women previously treated with odanacatib 50 mg weekly. INTRODUCTION: The development of odanacatib (ODN), a cathepsin K inhibitor, for treatment of osteoporosis was discontinued due to an increased risk of cardiovascular events. As the treatment is considered reversible, participants from the LOFT trial in Aarhus, Denmark, were offered treatment with zoledronic acid (ZOL). METHODS: Sixty-seven postmenopausal women were treated with ZOL 5 mg and followed for 12 months. Of these, 39 had received ODN for 7 years and 28 had received placebo for 5 years and ODN for 2 years. Bone turnover markers (BTM) were measured 3, 6, and 12 months after ZOL, and DXA of spine and hip were performed at time of ZOL treatment and after 12 months. RESULTS: Within the entire study population, BMD at the lumbar spine increased by 2.8 ± 0.9% (mean ± SEM) (p < 0.01) from baseline to month 12. There was no significant change in BMD at the total hip (p = 0.17) or femoral neck (p = 0.39). There was no difference in the changes in BMD from baseline to 12 months between the two groups at any site (p ≥ 0.20 for all). CTX increased by 107 ± 9% (p < 0.001), PINP by 102 ± 16% (p < 0.001), osteocalcin by 32 ± 6% (p = 0.001) and BSAP by 79 ± 37% (p = 0.001) between 3 and 12 months after ZOL. At month 12, BTM were still within the premenopausal reference range. S-25-hydroxyvitamin D increased (p = 0.059), while PTH (p = 0.007) and eGFR (p = 0.014) decreased during the year following ZOL administration. CONCLUSION: Treatment with ZOL 5 mg maintained BTMs in the premenopausal range and prevented bone loss in women previously treated with ODN.

Do femoral fractures in adult patients with osteogenesis imperfecta imitate atypical femoral fractures? A case series.

Atypical femoral fractures (AFFs) are low-energy femoral fractures with characteristic radiological features and a suspected relation to treatment with bisphosphonate (BP) or denosumab. In osteogenesis imperfecta (OI), BP is currently the drug of choice when medical treatment is indicated. Due to bone deformities, the radiologic appearance of femoral fractures may be different in patients with OI and patients with osteoporosis. We investigated the prevalence and appearance of femoral fractures in a cohort of adult patients with confirmed OI (55 patients, age range 19-69 years, 26 women (47%) and 35 patients (64%) had received BP treatment), who attended the outpatient clinic at Aarhus University Hospital. The fractures were evaluated according to major and minor AFF criteria. In our OI cohort, we found that eight out of 55 patients had suffered a femoral fracture in adult year: five women and three men, aged 25 to 54 years. One patient had OI type I, two had OI type III, four had OI type IV, and one had OI type V. All fractures were associated with no or minimal trauma. Four patients had fractures that fulfilled the criteria of AFFs. Two of the four patients had received long-term BP treatment prior to the fracture and three patients had severe deformities of the femur. Femoral fractures in OI imitate AFFs. This suggests that bone deformity, collagen deficiencies, and alterations in mineralization of bone may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. Bone deformities should be monitored as part of the management of adult patients with OI. Continuous dull or aching pain in the groin or thigh should lead to radiographic examination. The radiologic appearance of femoral fractures may be different in patients with osteogenesis imperfecta (OI) and patients with osteoporosis, thus imitate atypical femoral fractures (AFF). We found that bone deformity, collagen deficiencies, and alterations in bone mineralization may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment.

Comparison of bone turnover markers in peripheral blood and bone marrow aspirate.

BACKGROUND: Bone remodeling takes place in the bone marrow environment. We investigated if levels of bone turnover markers (BTMs) differ between bone marrow and peripheral blood, if the bone marrow is an independent compartment, and how well the measurements in bone marrow correlate with bone mineral density. METHODS: Sixty-six men participated in a placebo controlled study designed to evaluate the effect of 16 weeks supplementation with resveratrol on bone mineral density and BTM. Bone marrow aspirates and blood samples were drawn at baseline and at week 16. Procollagen I N-terminal propeptide (PINP), C-terminal telopeptide of type I collagen (CTx), osteocalcin, bone specific alkaline phosphatase (BAP), and osteoprogeterin (OPG) were analyzed. Bland-Altman analysis was used to compare measurements across compartment to detect possible systematic or proportional differences. Paired t-test was performed if no proportional difference was revealed at the difference vs concentration plot. RESULTS: Measurements of PINP, CTx, and BAP differed proportionally between compartments depending on concentration; at low concentrations absolute values were only slightly different, while at higher average concentrations the levels were much higher in bone marrow than blood. Osteocalcin measures in bone marrow were systematically and significantly lower than in blood (mean ±â€¯SD; 14.4 µg/L ±â€¯5.3 µg/L versus 21.7 µg/L ±â€¯6.0 µg/L respectively, p < 0.001). OPG measures were comparable between compartments (p = 0.69). CTx and OPG measured in blood were negatively associated with lumbar spine BMD (ß = -0.22, p = 0.05 and ß = -0.02, p = 0.02, respectively), whereas both markers measured in bone marrow were not (p = 0.60 and p = 0.50 respectively). None of the BTMs, bone marrow or blood, were associated with total hip BMD. DISCUSSION: The levels of most BTMs differed significantly between bone marrow and peripheral blood, while OPG was comparable. Levels of PINP, CTx, and BAP differed between compartments depending on concentration, suggesting bone marrow to represent a compartment separate from the general circulation. Unexpectedly, osteocalcin was lower in the marrow, a gradient that was independent of concentration. BTMs measured in bone marrow did not show any association with bone mineral density. Although further studies are needed to investigate potential explanatory causes of the differences, BTMs in bone marrow do not seem to contribute further to fracture risk assessment.

Osteogenesis imperfecta and the teeth, eyes, and ears-a study of non-skeletal phenotypes in adults.

Osteogenesis imperfecta (OI) is a disease causing bone fragility; however, it potentially affects all organs with a high content of collagen, including ears, teeth, and eyes. The study is cross-sectional and compares non-skeletal characteristics in adults with OI that clinicians should be aware of when caring for patients with OI. INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder. The skeletal fragility is pronounced; however, OI leads to a number of extra-skeletal symptoms related to the ubiquity of collagen type 1 throughout the human body. The vast majority of knowledge is derived from studies performed in the pediatric population. Thus, we aimed to investigate the nature and prevalence of ophthalmologic, odontologic, and otologic phenotypes in an adult population with OI. METHODS: The study population comprises 85 Danish OI patients (age 44.9 ± 15.9 years). Fifty-eight patients had OI type I, 12 OI type III, and 15 OI type IV according to the classification by Sillence. Audiometric evaluations and dental examinations were performed in 62 and 73 patients, respectively. Ophthalmologic investigations were performed in 64 patients, including measurements of the central corneal thickness. RESULTS: All patients, except two, had corneal thickness below the normal reference value. Patients with OI type I and patients with a quantitative collagen defect had thinner corneas compared to patients with OI type III and other patients with a qualitative collagen defect. One patient in this cohort was diagnosed with and treated for acute glaucoma. Dentinogenesis imperfecta was diagnosed in one fourth of the patients, based on clinical and radiographic findings. This condition was predominately seen in patients with moderate to severe OI. Hearing loss requiring treatment was found in 15 of 62 patients, of whom three were untreated. The most prevalent type of hearing loss (HL) was sensorineural hearing loss, whereas conductive HL was solely seen in patients with OI type III. The patients with the most severe degrees of HL were patients with mild forms of OI. Age was associated with increased HL. CONCLUSION: Although significant health problems outside the skeleton are frequent in adult patients with OI, the patients are not consistently monitored and treated for their symptoms. Clinicians treating adult patients with OI should be aware of non-skeletal health issues and consider including regular interdisciplinary check-ups in the management plan for adult OI patients.

Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study.

BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by a number of deviations in the orofacial region. The aims of the present study were to investigate the occurrence of temporomandibular disorders, to evaluate the psychosocial status, and to assess the dental occlusion in a population of adult OI patients. METHODS: Participants (n = 75) were classified with mild OI, type I (n = 56), or moderate-severe OI, type III and IV (n = 19). OI patients were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders (axis I and II). RESULTS: Temporomandibular disorders and functional limitations in the orofacial region were rare and did not differ between patients with mild and moderate-severe OI (P > 0.050). No significant differences between Graded Chronic Pain Scale grades 0, 1, and 2 were found in mild OI vs. moderate-severe OI (P > 0.160). Few patients (16%) had signs of depression, but close to half (48%) had signs of somatization. Patients with moderate-severe OI had a lower mean number of teeth compared to patients with mild OI (P <  0.050). In general, malocclusions were prevalent, and mandibular overjet and posterior cross-bite were found more often in moderate-severe OI compared with mild (P <  0.050). CONCLUSIONS: Patients with moderate-severe OI had more malocclusions than patients with mild OI. The psychosocial status of OI patients was remarkably healthy considering the severity of this disabling systemic disorder. The bodily pain complaints frequently reported in OI patients were not largely reflected in the orofacial area as painful temporomandibular disorders.

Polypropelene-mesh properties and type of anchoring do not influence strength of parietal ingrowth.

PURPOSE: In laparoscopic ventral hernia repair, parietal ingrowth of the mesh is of crucial importance. Until significant ingrowth occurs integrity of the repair depends solely on mesh overlap and anchoring device. Relatively few studies have addressed the effect of mesh properties and anchoring device on long-term parietal ingrowth. METHODS: In 20 sheep, using laparoscopy, we inserted two different polypropylene-based meshes, Physiomesh™ and Ventralight™ ST, anchored with Protack™, SecureStrap™, or Glubran™. After 6 and 12 months, 10 sheep at each time point were euthanized, and we harvested the meshes with corresponding fascia. Mesh with fascia was attached on an Alwetron™ materials testing machine and pulled apart obtaining the peel-off energy (kilojoule (kJ)). RESULTS: The strength of parietal ingrowth at 6 months was 5.99 ± 0.54 kJ (mean ± SEM), 4.94 ± 0.54 kJ and 7.35 ± 0.55 kJ when anchored with Protack™, Glubran™, or SecureStrap™, respectively. At 6 months, the strength of parietal ingrowth of SecureStrap™ was significantly higher than Glubran™ (p = 0.04). No significant difference was seen between any other combinations. Parietal ingrowth at 12 months was 7.05 ± 0.56 kJ, 7.55 ± 0.54 kJ, and 5.73 ± 0.54 kJ when anchored with Protack™, Glubran™, and SecureStrap™, respectively. No significant difference in strength of parietal ingrowth was seen between the three types of anchoring, (p = 1.00, p = 1.00, and p = 0.29). CONCLUSIONS: At 12 months, the strength of parietal ingrowth was the same for all comparisons. The two polypropylene meshes showed equal strength of parietal ingrowth independent of mesh properties and anchoring devices used.

Mesh shrinkage depends on mesh properties and anchoring device: an experimental long-term study in sheep.

PURPOSE: The choice of mesh and anchoring device in laparoscopic ventral hernia repair is controversial. Clinically important long-term properties of mesh and anchoring device such as mesh shrinkage have been sparsely investigated. Furthermore, the effect of various anchoring devices on mesh properties has never been examined. METHODS: In 20 sheep, using laparoscopy, we inserted three PhysiomeshTM (large pore, lightweight) and three VentralightTMST (small pore, mediumweight), anchored with ProTackTM, SecurestrapTM or GlubranTM, respectively. After 6 and 12 months, 10 sheep at each time-point, we euthanized the animals, harvested the meshes with fascia, and measured the exact size and area of the mesh, expressing mesh shrinkage as a percentage of the initial area. RESULTS: The shrinkage of PhysiomeshTM was 35.7 %, 23.8 % and 17.7 % when anchored with ProtackTM, GlubranTM or SecurestrapTM, respectively. Shrinkage with ProtackTM was significantly higher than with either GlubranTM or SecurestrapTM, respectively (p<0.01 and p<0.01). The shrinkage of VentralightTMST was 19.3 %, 22.2 % and 19.6 % when anchored with ProtackTM, GlubranTM and SecurestrapTM, respectively (p>0.05 for all pairwise comparisons). Overall shrinkage of PhysiomeshTM anchored with ProtackTM was significantly higher for all comparisons (p<0.01). CONCLUSION: Our results suggest that mesh shrinkage in sheep takes place within 6 months after implantation. A significant interaction between mesh and type of anchoring indicates that shrinkage may depend on both mesh properties and anchoring device. The results of the current study imply that the combined effect of mesh and anchoring device should be evaluated in future studies.

Skeletal phenotypes in adult patients with osteogenesis imperfecta-correlations with COL1A1/COL1A2 genotype and collagen structure.

Osteogenesis imperfecta (OI) is characterized by a high fracture rate and great heterogeneity. This cross-sectional study presents skeletal investigations and protein analyses in 85 adult OI patients. We find significant differences in bone mass, architecture, and fracture rate that correlate well with the underlying biochemical and molecular abnormalities. INTRODUCTION: OI is a hereditary disease characterized by compromised connective tissue predominantly caused by mutations in collagen type 1 (COL-1) encoding genes. Widespread symptoms reflect the ubiquity of COL-1 throughout the body. The purpose of this study was to improve our understanding of clinical manifestations by investigating anthropometry and skeletal phenotypes (DXA, HRpQCT) in an adult OI population and compare the findings to underlying COL-1 genotype and structure. METHODS: The study comprised 85 OI patients aged 45 (19-78) years, Sillence type I (n = 58), III (n = 12), and IV (n = 15). All patients underwent DXA, HRpQCT, spine X-ray, biochemical testing, and anthropometry. COL1A1 and COL1A2 were sequenced and 68 OI causing mutations identified (46 in COL1A1, 22 in COL1A2). Analysis of COL-1 structure (quantitative/qualitative defect) by SDS-PAGE was performed in a subset (n = 67). RESULTS: A qualitative collagen defect predisposed to a more severe phenotype with reduced aBMD, more fractures, and affected anthropometry compared to patients with a quantitative COL-1 defect (p < 0.05). HRpQCT revealed significant differences between patients with OI type I and IV. Patients with type I had lower vBMD (p < 0.005), thinner cortexes (p < 0.001), and reduced trabecular number (p < 0.005) compared to patients with type IV indicating that HRpQCT may distinguish type I from type IV better than DXA. CONCLUSION: The defective collagen in patients with OI has pronounced effects on the skeleton. The classical OI types based on the clinical classification show profound differences in bone mass and architecture and the differences correlate well with the underlying biochemical and molecular collagen abnormalities.

Hypercalcemia after discontinuation of long-term denosumab treatment.

UNLABELLED: Denosumab is used for treatment of osteoporosis. We present a case report of hypoparathyroid hypercalcemia and increased bone turnover associated with discontinuation of treatment for 10 years with denosumab. There is a need for evidence-based guidelines on discontinuation of long-term denosumab treatment to avoid side effects and preserving anti-fracture efficacy. PURPOSE: Denosumab is commonly used as an anti-resorptive agent for the treatment of osteoporosis. After discontinuation of denosumab, however, bone resorption increases again, and the bone mass gained during therapy is rapidly declining. Thus, treatment with denosumab is considered to be reversible. METHODS: We present a case report of asymptomatic hypoparathyroid hypercalcemia in a patient who discontinued long-term treatment with denosumab. RESULTS: A 67-year-old woman with osteoporosis was treated with denosumab 60 mg subcutaneously every 6 months from 2004 to 2014. She received the last injection in May 2014. Routine biochemistry in November 2014 showed increased s-ionized calcium (I-Ca) 1.64 mmol/L (1.18-1.32 mmol/L) and suppressed p-parathyroid hormone (PTH) 1.6 pmol/L (1.6-6.9 pmol/L). The patient was extensively examined, but no underlying disease was found. In January 2015, the patient began treatment with alendronat 70 mg weekly. In April 2015, serum levels of type 1 collagen C-terminal cross-linked telopeptide, procollagen type 1 N-terminal propeptide and bone-specific alkaline phosphatase were still markedly elevated. From then on, I-Ca and PTH normalized and the bone turnover markers (BTM) decreased. CONCLUSION: In this case report, we describe increased BTMs and hypercalcemia associated with discontinuation of 10 years treatment with denosumab. The increase in BTMs is assumed to be temporary and normalization is expected. Since denosumab is commonly used, there is an urgent need for evidence-based guidelines on discontinuation of long-term treatment, avoiding side effects and preserving anti-fracture efficacy.

Flow cytometry detection of vitamin D receptor changes during vitamin D treatment in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disease associated with a dysregulated T cell response towards intestinal microflora. Vitamin D has immune modulatory effects on T cells through the nuclear vitamin D receptor (VDR) in vitro. It is unclear how oral vitamin D treatment affects VDR expression. The aim of this study was to establish a flow cytometry protocol, including nuclear and cytoplasmic VDR expression, and to investigate the effects of vitamin D treatment on T cell VDR expression in CD patients. The flow cytometry protocol for VDR staining was developed using the human acute monocytic leukaemia cell line (THP-1). The protocol was evaluated in anti-CD3/CD28-stimulated peripheral blood mononuclear cells (PBMCs) from vitamin D3- (n = 9) and placebo-treated (n = 9) CD patients. Anti-VDR-stained PBMCs were examined by flow cytometry, and their cytokine production was determined by cytokine bead array. VDR, CYP27B1 and RXRα mRNA expression levels in CD4(+) T cells were measured by quantitative reverse transcriptase polymerase chain reaction. The flow cytometry protocol enabled detection of cytoplasmic and nuclear VDR expression. The results were confirmed by confocal microscopy and supported by correlation with VDR mRNA expression. VDR expression in CD4(+) T cells increased following stimulation. This VDR up-regulation was inhibited with 30% by vitamin D treatment compared to placebo in CD patients (P = 0027). VDR expression was correlated with in-vitro interferon-γ production in stimulated PBMCs (P = 0.01). Flow cytometry is a useful method with which to measure intracellular VDR expression. Vitamin D treatment in CD patients reduces T cell receptor-mediated VDR up-regulation.

Subsequent fracture rates in a nationwide population-based cohort study with a 10-year perspective.

SUMMARY: Fractures after the age of 50 are frequently observed in Denmark, and many of these may be osteoporotic. This study examined the incidence of all and subsequent fractures in a 10-year period from 2001 to 2011. The incidence of subsequent fractures was high, especially following hip fracture. INTRODUCTION: The purpose of this study is to examine patterns of subsequent fractures and mortality rates over a 10-year period in patients already suffering from fracture. METHODS: The study was designed as a nationwide, register-based follow-up study. Patients were included if diagnosed with an index fracture (ICD-10 codes: S22.x, S32.x, S42.x, S52.x, S62.x, S72.x, S82.x, S92.x, T02.x, T08.x, T10.x and T12.x) between January 1st, 2001 and December 31st, 2001 and if older than 50 years at time of fracture. The patients were investigated for future subsequent fractures from January 1st, 2002 to December 31st, 2011. RESULTS: In this study, we demonstrated that patients with fractures (especially hip fractures) have a high risk of subsequent fractures, especially hip fracture. Other fractures, which are not commonly considered as osteoporotic fractures, such as lower leg, were frequently observed in the 10 years following index fracture. The cumulative incidence proportion (CIP) of subsequent fractures during the 10-year follow-up period was high for all recurrent fractures (9-46 %). Subsequent hip fracture, regardless of index fracture, had the highest CIP across the study period, ranging from 9 to 40 %. Appendicular fractures were often followed by a recurrent fracture, or subsequent fractures at a more proximal location in the same limb, i.e. forearm fractures were followed by humerus fractures. These results have not been previously demonstrated to this extent, and according to our knowledge, no previous studies have estimated cumulative 10-year subsequent fracture incidences for any non-hip fractures. CONCLUSION: Patients suffering a fracture (and especially a hip fracture) have a high incidence of subsequent fracture. Fractures after the age of 50 may be considered an early warning of increased risk for future fractures in many patients.

A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk.

CONTEXT: Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. OBJECTIVE: The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. DESIGN: This was a prospective, comprehensive, cohort study (number NCT00252408). PARTICIPANTS: A total of 1686 perimenopausal women were included. MAIN OUTCOME MEASURES: Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. RESULTS: After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures. CONCLUSION: This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

Polymorphisms of muscle genes are associated with bone mass and incident osteoporotic fractures in Caucasians.

The interaction between muscle and bone is complex. The aim of this study was to investigate if variations in the muscle genes myostatin (MSTN), its receptor (ACVR2B), myogenin (MYOG), and myoD1 (MYOD1) were associated with fracture risk, bone mineral density (BMD), bone mineral content (BMC), and lean body mass. We analyzed two independent cohorts: the Danish Osteoporosis Prevention Study (DOPS), comprising 2,016 perimenopausal women treated with hormone therapy or not and followed for 10 years, and the Odense Androgen Study (OAS), a cross-sectional, population-based study on 783 men aged 20-29 years. Nine tag SNPs in the four genes were investigated. In the DOPS, individuals homozygous for the variant allele of the MSTN SNP rs7570532 had an increased risk of any osteoporotic fracture, with an HR of 1.82 (95 % CI 1.15-2.90, p = 0.01), and of nonvertebral osteoporotic fracture, with an HR of 2.02 (95 % CI 1.20-3.41, p = 0.01). The same allele was associated with increased bone loss (BMC) at the total hip of 4.1 versus 0.5 % in individuals either heterozygous or homozygous for the common allele (p = 0.006), a reduced 10-year growth in bone area at the total hip of 0.4 versus 2.2 and 2.3 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.01), and a nonsignificantly increased 10-year loss of total-hip BMD of 4.4 versus 2.7 and 2.9 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.08). This study is the first to demonstrate an association between a variant in MSTN and fracture risk and bone loss. Further studies are needed to confirm the findings.