The Effect of Effervescent and Buffered Alendronate Compared to Conventional Alendronate on Markers of Bone Turnover: A Randomized Non-inferiority Trial.

Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < -1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI - 38.42:- 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established.

Opportunities for biomineralization research using multiscale computed X-ray tomography as exemplified by bone imaging.

Biominerals typically have complex hierarchical structures traversing many length scales. This makes their structural characterization complicated, since it requires 3D techniques that can probe full specimens at down to nanometer-resolution, a combination that is difficult - if not impossible - to achieve simultaneously. One challenging example is bone, a mineralized tissue with a highly complex architecture that is replete with a network of cells. X-ray computed tomography techniques enable multiscale structural characterization through the combination of various equipment and emerge as promising tools for characterizing biominerals. Using bone as an example, we discuss how combining different X-ray imaging instruments allow characterizing bone structures from the nano- to the organ-scale. In particular, we compare and contrast human and rodent bone, emphasize the importance of the osteocyte lacuno-canalicular network in bone, and finally illustrate how combining synchrotron X-ray imaging with laboratory instrumentation for computed tomography is especially helpful for multiscale characterization of biominerals.

Long-Term High-Dose Resveratrol Supplementation Reduces Bone Mass and Fracture Strength in Rats.

Resveratrol (RSV) is a natural polyphenolic compound. A recent study suggests a positive effect on BMD in men; however, the underlying changes in microstructure and strength remain unknown. We aimed to investigate the effects of RSV on the skeleton in hindlimb-immobilized and non-immobilized rats. Seventy-two female Wistar rats were divided into six groups. Two baseline (BSL) groups underwent short-term diet intervention for 4 weeks before sacrifice [phytoestrogen-deficient diet (PD) (BSL + PD) or RSV diet (600 mg/kg body weight/day) (BSL + RSV)]. Four groups were injected in the right hindlimb with botulinum toxin (BTX) (immobilized) or saline (non-immobilized), and fed either PD diet or RSV diet 4 weeks pre-injection and 6 weeks post-injection before sacrifice (BTX + PD, BTX + RSV, PD, and RSV, respectively). DXA, µCT, dynamic histomorphometry, and mechanical tests were performed. Short-term RSV treatment did not affect bone parameters, whereas long-term RSV exposure had a consistent negative impact on non-immobilized rats (RSV vs. PD); whole femoral aBMD (p = 0.01) and distal femoral metaphyseal Tb.N (p = 0.01), Tb.Sp (p = 0.02), and BV/TV (p = 0.07). At the femoral mid-diaphysis, RSV increased periosteal resorption (p = 0.01) and increased endosteal formation (p = 0.02), while mineralization was unaffected. In addition, RSV reduced femoral mid-diaphyseal three-point bending strength (p = 0.03) and stiffness (p = 0.04). BTX-induced immobilization resulted in significant bone loss and reduced bone strength; however, RSV supplementation was unable to prevent this. In conclusion, long-term high-dose RSV reduced bone mass and fracture strength and did not prevent immobilization-induced bone loss in rats.

Bone Mineral Density Measurements Around Osseointegrated Implants: A Precision Study and Validation of Scan Protocol for Transfemoral Amputees.

Visual evaluation of bone changes around an osseointegration (OI) implant in femoral amputees examined on plain radiographs shows that periprosthetic bone resorption takes place during the first years after OI surgery, but the bone mineral density (BMD) change has not been previously quantified by dual-energy X-ray absorptiometry (DXA). Precision is vital when monitoring BMD changes around implants, and thus the aim of this study was to evaluate the precision and feasibility of a scan protocol for BMD measurements in proximity of OI implants. The proximal part of 2 human cadaveric femoral bones (specimens A and B) with OI implants were mounted in a positioning jig and DXA scans were repeated 5 times in increments of 5° from neutral (0°) to 20° flexion and rotation. BMD changes as a result of change in leg position were evaluated. Repeated patient examinations (n = 20) were conducted in a clinical setting and the precision error was calculated for each of 7 periprosthetic custom-made regions of interest (ROIs). The precision of cadaveric BMD measurements in neutral position was <3.3%. Even 5° flexion or rotation in femur position caused significant changes in average BMD (p <0.04). Depending on ROI, the percentage of coefficient of variation (%CV) and average BMD was <6% at 10° flexion and rotation. At 20° flexion, %CV increased up to 12.7% and average BMD increased up to 9.9%. The clinical short-term precision root mean square standard deviation ranged from 0.031 g/cm2 to 0.047 g/cm2 and %CV ranged from 3.12% to 6.57% depending on ROI. Simulated hip flexion or rotation of the femur affected periprosthetic BMD measurements around OI implants in cadaveric femoral bones, which stresses the importance of a reproducible set-up during DXA scans to reduce measurement errors caused by variation in leg position. Adherence to the scan protocol with a relaxed position of the residual limb resulted in an acceptable short-term precision below 6.6%.

Bone Mineral Density is Lower in Patients with Severe Knee Osteoarthritis and Attrition.

Bone quality is probably important for the survival of knee arthroplasty (KA), but little is known about systemic bone mineral density and bone turnover in patients prior to KA surgery. The aim of this study was to explore the prevalence of osteoporosis and bone turnover in relation to knee osteoarthritis (OA) grade in patients scheduled for KA surgery. Prospective preoperative evaluation of 450 patients (259 females) prior to KA between 2014 and 2016 with standing knee radiography, Dual-energy X-ray absorptiometry (DXA), biomarkers for bone turnover (CTX, P1NP), and vitamin D. Grading of knee OA was done with the Altman Atlas and Kellgren Lawrence (KL). Adjustments for age and BMI were made. The mean age was 67.9 years (range 39-94), and mean BMI was 28.8 (SD 4.8). The prevalence of osteoporosis was 9.6% (CI 95% 7.2; 12.7), while the proportion of patients with osteopenia was 36.0%. T score was similar between KL OA grade 3 and 4 (p = 0.06); however, T score was lower (p = 0.02) with the worst knee OA grade (attrition). The median serum Vitamin D level was 78.5 nmol/L (range 10-196), and there was no association between serum vitamin D and the grade of OA (p > 0.88). P1NP was significantly higher in KL grade 4 compared to KL grade 3 (p = 0.03), but there was no association between KL grade and CTX (p = 0.21). 10% had osteoporosis, which is similar to the age-matched background population. Bone mineral density was lower with severe knee osteoarthritis (attrition), and P1NP was higher with worse osteoarthritis grading.

Managing a Bone Healthy Lifestyle After Attending Multifaceted Group Education.

We examined patients with osteoporosis implementation of recommendations regarding a bone healthy lifestyle after the patients attended multifaceted osteoporosis group education (GE). Our findings suggest that GE can support and influence patients' transfer of preventive actions. Still patients are challenged by concerns related to social roles and physical ability. We investigated if and how patients implemented knowledge from attending multifaceted osteoporosis GE in their daily lives. An interpretive description design using ethnographic field work was applied. In all 14 women and three men diagnosed with osteoporosis who attended multifaceted GE at a Danish hospital participated. Data consisted of field work and individual interviews in the participants' everyday environment after completion of GE. After attending multifaceted GE, participants experienced increased attention to and reflected more on how to implement osteoporosis preventive actions or activities. Participants who felt confident on how to act and experienced a clear need and motivation, or who could make the preventive activity into a social event, demonstrated an increased implementation of the preventive activity. On the contrary, attending GE was in some cases not sufficient to overcome social and physical concerns, or to eliminate uncertainty about recommendations or to make participants identify with the osteoporosis diagnosis, which thus impeded implementation of a bone healthy lifestyle. Attending multifaceted GE can support and influence participants' transfer of preventive actions into daily life. Being aware of how concerns about valued social roles and physical ability interfere with the implementation of medical recommendations obviously needs attention during GE.

Resveratrol Increases Osteoblast Differentiation In Vitro Independently of Inflammation.

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

Hypercalcemia in metastatic GIST caused by systemic elevated calcitriol: a case report and review of the literature.

BACKGROUND: Hypercalcemia is the most common oncologic metabolic emergency but very rarely observed in patients with gastrointestinal stromal tumour, which is a rare mesenchymal malignancy of the gastrointestinal tract. We describe a case of hypercalcemia caused by elevated levels of activated vitamin D in a patient with gastrointestinal tumour. Prior to this case report, only one paper has reported an association between hypercalcemia, gastrointestinal stromal tumours and elevated levels of vitamin D. CASE PRESENTATION: An otherwise healthy 70-year-old Caucasian woman, previously treated for duodenal gastrointestinal stromal tumour, was diagnosed with liver metastasis, and relapse of gastrointestinal stromal tumour was confirmed by biopsy. At presentation, the patient suffered from severe symptoms of hypercalcemia. The most common causes of hypercalcemia, hyperparathyrodism, parathyroid hormone-related peptide secretion from tumour cells, and metastatic bone disease, were all dismissed as the etiology. Analysis of vitamin D subtypes revealed normal levels of both 25-OH Vitamin D2 and 25-OH Vitamin D3, whereas the level of activated vitamin D, 1,25 OH Vitamin D3, also referred to as calcitriol, was elevated. CONCLUSION: The fact that plasma calcitriol decreased after initiation of oncological treatment and the finding that hypercalcemia did not recur during treatment support the conclusion that elevated calcitriol was a consequence of the gastrointestinal stromal tumour. We suggest that gastrointestinal stromal tumours should be added to the list of causes of humoral hypercalcemia in malignancy, and propose that gastrointestinal stromal tumour tissue may have high activity of the specific enzyme 1α-hydroxylase, which can lead to increased levels of calcitriol and secondarily hypercalcemia.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Zoledronate Increases Bone Mineral Density in Nonambulant Children With Cerebral Palsy: A Randomized Controlled Trial.

CONTEXT: Zoledronate appears to reduce fracture rates in children with cerebral palsy (CP), but no previous randomized, controlled trial has been performed to compare the effect of zoledronate to placebo in children with CP. OBJECTIVE: To investigate the effect of zoledronate on bone mineral density (BMD) Z-scores in children with nonambulant CP in a randomized, controlled, double-blind trial. METHODS: Nonambulant children with CP (5 to 16 years of age) were randomized 1:1 to receive 2 doses of zoledronate or placebo at a 6-month interval. BMD Z-score changes at the lumbar spine and the lateral distal femur (LDF) were calculated from dual-energy x-ray absorptiometry scans. Monitoring included weight, bone age, pubertal staging, knee-heel length, adverse events, biochemical markers, and questionnaires. RESULTS: Twenty-four participants were randomized and all completed the study. Fourteen were assigned to zoledronate. The mean lumbar spine BMD Z-score increased 0.8 SD (95% CI: 0.4; 1.2) in the zoledronate group, which was significant when compared to 0.0 SD (95% CI: -0.3; 0.3) in the placebo group. Similarly, the LDF BMD Z-scores increased more in the zoledronate group. Severe acute phase symptoms affected 50% of the patients in the zoledronate group but were reported exclusively after the first dose. Growth parameters were similar in both groups. CONCLUSION: Zoledronate for 12 months increased BMD Z-scores significantly without affecting growth, but first-dose side effects were common and considerable. Studies into lower first doses and long-term outcomes are needed.

Osteoarthritis in osteogenesis imperfecta: A nationwide register-based cohort study.

BACKGROUND: Osteogenesis Imperfecta (OI) is a genetic disease characterized by skeletal fragility. Collagen type 1 is found in many tissues and collagen abnormalities may result in organ specific symptomatology. Musculoskeletal pain is a known issue for patients with OI, osteoarthritis (OA) can be a likely cause. Only few studies have investigated the relationship between OI and OA but demonstrated a greater propensity in OI patients to develop rapidly progressing OA. Therefore, we wanted to investigate if OA is more frequent in patients with OI compared to the general population. OBJECTIVE: To evaluate the risk of osteoarthritis in patients with OI. DESIGN: A Danish nationwide, population-based and register-based longitudinal open cohort study. PARTICIPANTS: From 1977 to 2019, all patients registered with an OI diagnosis and a reference population matched on age and sex 5:1. MEASUREMENTS: Sub-hazard ratios for any, hip, and knee osteoarthritis comparing the OI cohort to the reference population. RESULTS: We identified 907 patients with OI (493 women) and included 4535 patients in the reference population (2465 women). The Sub Hazard Ratio was 2.20 [95% CI 1.73-2.79] for any osteoarthritis with 11.4% of the OI population and 5.4% of the reference population being registered. We found lower incidences of upper extremity joint OA compared to lower joint OA, but upper extremity joint OA was significantly more frequent in the OI population 2.1% vs 0.6%, SHR 3.19 [95% CI 1.78-5.70]. CONCLUSION: Patients with OI have a higher risk of OA than the reference population. MINIABSTRACT: Osteogenesis Imperfecta (OI) is a hereditary connective tissue disorder with skeletal fragility and extraskeletal manifestations. Osteoarthritis is a frequent joint disease and the incidence increases with age. In a population-register-based study, the risk of osteoarthritis was higher in patients with OI at an earlier age compared to a reference population.

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.

Cardiovascular Safety and Sclerostin Inhibition.

Sclerostin, which is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials, romosozumab, an antibody against sclerostin, increases bone mineral density and reduces the risk of fractures compared with placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the 2 treatment groups. Compared with alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and post hoc analyses should therefore be interpreted with caution; however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.

Vitamin K2 (menaquinone-7) increases plasma adiponectin but does not affect insulin sensitivity in postmenopausal women: a randomized controlled trial.

BACKGROUND/OBJECTIVES: Vitamin K is a co-factor in the carboxylation of the bone matrix protein osteocalcin (OC), and thus decreases the concentration of undercarboxylated osteocalcin (ucOC). Animal and in vitro studies suggest that ucOC increases insulin sensitivity. However, epidemiological studies find positive associations between vitamin K intake and insulin sensitivity. We aimed to investigate the effect of vitamin K2 in the form of menaquinone-7 (MK-7) on serum ucOC, bone mass, and insulin sensitivity in postmenopausal women. SUBJECTS/METHODS: This was a randomized placebo-controlled trial. One hundred forty-eight postmenopausal women received MK-7 375 µg daily or placebo, as an add-on to calcium (800 mg) and vitamin D (38 µg) for 12 months. We measured serum ucOC, insulin sensitivity by HOMA-IR, and plasma adiponectin and leptin at baseline and after 12 months. RESULTS: S-ucOC decreased in the MK-7 group (-70.3 (-75.6; -63.8) %) compared to the placebo group (-7.2 (-15.9; 2.0) %) after 12 months (p < 0.01). P-adiponectin increased in the MK-7 group (6.1 ± 20.1%) (mean ± SD) compared to the placebo group (-0.7 ± 15.5%) after 12 months (p = 0.03). HOMA-IR and p-leptin did not change in the two groups. CONCLUSION: Treatment with MK-7 for 12 months decreased p-ucOC, increased p-adiponectin, but did not change insulin sensitivity suggesting that ucOC does not affect insulin sensitivity in healthy postmenopausal women.

The expression of IL-6 by osteoblasts is increased in healthy elderly individuals: stimulated proliferation and differentiation are unaffected by age.

Increasing age is associated with reduced bone mineral content and increased risk of fractures. This is caused by a relative insufficiency of osteoblasts compared with osteoclasts. We therefore wanted to examine the potential differences in proliferation, differentiation, and expression of cytokines between human osteoblasts (hOBs) obtained from young and elderly individuals. Cultures of hOBs were obtained from 11 elderly (73-85 years) and 15 young (21-27 years) healthy individuals. The cells were stimulated with hGH, IGF-I, hGH + IGF-I, and TGF-ß1. Proliferation was evaluated by thymidine incorporation, and differentiation was evaluated by alkaline phosphatase, OPG, and PINP production. Expression of IL-6, TGF-ß1, OPG, and RANKL was investigated using real-time PCR and three carefully selected housekeeping genes. Combined stimulation with hGH and IGF-I increased proliferation without differences between hOBs obtained from young and elderly individuals. hOBs from young individuals responded to stimulation with vitamin D with a more pronounced increase in alkaline phosphatase: 107 ± 17% vs. 43 ± 5%, P < 0.01. Stimulation with TGF-ß1 decreased OPG production by hOBs from elderly individuals but not from young individuals, P < 0.05. hOBs from elderly individuals expressed significantly higher amounts of IL-6 mRNA (P < 0.05) and less OPG and TGF-ß1 mRNA (P = 0.08 and P = 0.08, respectively) compared with hOBs from young individuals. In conclusion, hOBs from elderly individuals express more IL-6 mRNA and less OPG and TGF-ß1 mRNA than hOBs from young individuals. This could partly explain the reduced bone mass and increased fracture risk seen in the elderly. hOBs from young and elderly individuals responded similarly to short-term stimulation of proliferation and differentiation.

Changes in periprosthetic bone mineral density and bone turnover markers after osseointegrated implant surgery: A cohort study of 20 transfemoral amputees with 30-month follow-up.

BACKGROUND: The osseointegrated implant system is a treatment option for people with transfemoral amputation, but implant removal is not uncommon. The association between bone mineral density changes or bone turnover markers and the need for implant removal has not previously been investigated. OBJECTIVES: The aim was to evaluate changes in bone mineral density and bone turnover markers in people with transfemoral amputations treated with osseointegrated implants. STUDY DESIGN: This is a prospective cohort study. METHODS: Nineteen patients were followed up for 30 months or until implant removal. Bone mineral density was measured in the lumbar spine, proximal femur and seven periprosthetic regions. 25-hydroxyvitamin (D2 + D3), parathyroid hormone, N-terminal propeptide of type-I procollagen, C-telopeptide of type-I collagen, bone-specific alkaline phosphatase and osteocalcin were measured in blood samples. RESULTS: Four fixtures and three abutments were removed. Patients with removed implants had a decreased bone mineral density in the seven periprosthetic regions between 27% (95% confidence interval = 6; 43) and 38% (95% confidence interval = 19; 52) at 30-month follow-up compared to baseline (p < 0.02), whereas bone mineral density around non-removed implants normalized to baseline values (p > 0.08). C-telopeptide of type-I collagen was significantly different between the groups at 18- and 24-month follow-up (p < 0.05). None of the measured variables were significant predictors of implant removal (p > 0.07). CONCLUSION: Implant removal was associated with loss of periprosthetic bone mineral density and increase in C-telopeptide of type-I collagen in the years following osseointegrated surgery. CLINICAL RELEVANCE: This study offers new insight into changes in bone mineral density and bone turnover markers that precipitate aseptic or septic osseointegrated implant removal. Results of this study could contribute to clinical guidelines for monitoring rehabilitation progress and implant removal through dual-energy X-ray absorptiometry or surrogate markers like C-telopeptide of type-I collagen.

Does migration of osseointegrated implants for transfemoral amputees predict later revision? A prospective 2-year radiostereometric analysis with 5-years clinical follow-up.

BACKGROUND: The osseointegrated (OI) prosthesis is a treatment option for transfemoral amputees with a short residual femur and/or difficulties caused by using the prosthetic socket. Implant removal due to aseptic or septic loosening is not uncommon, but the association between implant migration patterns and the need for removal has not previously been studied. We conducted a prospective model-based radiostereometric analysis study to investigate: if the OI implant migration pattern 1) differs between later removed implants and non-removed implants, (2) predicts later implant removal, and (3) if the precision of the method is acceptable. HYPOTHESIS: Model-based radiostereometric analysis of the OI implant migration pattern can be used to predict later OI implant removal. MATERIAL AND METHODS: A prospective cohort of 17 consecutive transfemoral amputees suitable for surgery (11 males), mean age 50 (range 32-66) were treated with an OI implant (Integrum AB, Sweden). Postoperative stereoradiographs of the OI implant were obtained during 24-month follow-up. X, Y, and Z translations and total translations were evaluated using CAD-implant models. Implant survival was followed for up to 60 months. RESULTS: Six total implant removals (fixture and abutment) and four partial removals (abutment) were conducted (10/17 (59%)), and one patient did not use the OI implant. The removed implants group migrated a mean (±standard deviation) 0.55mm±0.75mm (p=0.009) and the non-removed implants group migrated 0.31mm±0.51mm (p=0.22) in total translations from 3 months to last follow-up. Odds ratio for implant removal was 22.5 (95% CI: 1.6 to 314 (p=0.021)) if the OI implants migrated distally. CONCLUSION: Later removed OI implants migrated from 3 months to last follow-up and more than the non-removed OI implants. Distal implant migration greatly increased the odds of implant removal. Ten out of 17 OI implants were removed within 5 years of follow-up. We advise to use OI implants with caution and close follow-up in consideration of the risk of complications. LEVEL OF EVIDENCE: IV, Prospective study.

Bone Health in Patients with Type 2 Diabetes Treated by Roux-En-Y Gastric Bypass and the Role of Diabetes Remission.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) has been associated with negative effects on bone. Whether this association is affected by pre-surgical type 2 diabetes (T2D) and surgically induced diabetes remission is unknown. METHODS: In this cross-sectional, matched cohort study 6 years after RYGB, we investigated bone health in 96 individuals with body mass index (BMI) > 35 kg/m2 and T2D (stratified on current diabetes status) treated by RYGB 6 years earlier compared with 49 non-operated individuals with T2D matched with respect to sex, age, and current BMI. Main outcome measures were areal and volumetric bone mineral density (aBMD and vBMD), bone turnover, and odds ratio of osteoporosis/osteopenia. RESULTS: The RYGB group had lower hip (0.916 vs 1.010 g/cm2, p < 0.001), forearm (0.497 g/cm2 vs 0.554 g/cm2, p < 0.001) aBMD, (269.63 mg/cm3 vs 306.07 mg/cm3, p < 0.001) tibial, and radial (238.57 mg/cm3 vs 278.14 mg/cm3, p < 0.0001) vBMD than the control group. Relative to the control group, c-terminal cross-linked telopeptide, procollagen type I amino-terminal propeptide, and osteocalcin were 75%, 41%, and 72% higher in the RYGB group, respectively (all p < 0.001). Odds ratio for osteopenia/osteoporosis in operated individuals was 2.21 (95% CI 1.06; 4.79, p = 0.05). Overall, stratified analysis on current diabetes status did not alter these outcomes. CONCLUSIONS: Individuals with T2D treated by RYGB, compared to individuals with T2D of similar age and body composition not treated by RYGB, have lower BMD, lower bone strength, and increased levels of several bone turnover markers. Bone health was not associated with current diabetes status in the RYGB group.

Treatment of Osteoporosis: Unmet Needs and Emerging Solutions.

Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%, only one anabolic option is available in most parts of the world-the effect of which levels off over time, and the evidence for combination therapy targeting both resorption and formation is limited. In addition, identification and treatment of patients with high and imminent fracture risk following a recent fracture and long-term adherence to treatment are 2 other very prominent challenges to the management of osteoporosis. The current review will focus on emerging osteoporosis treatments and optimized use of the existing treatments that may help overcome the currently unmet needs in the management of osteoporosis.

Skeletal Fragility in Type 2 Diabetes Mellitus.

Type 2 diabetes (T2D) is associated with an increased risk of fracture, which has been reported in several epidemiological studies. However, bone mineral density in T2D is increased and underestimates the fracture risk. Common risk factors for fracture do not fully explain the increased fracture risk observed in patients with T2D. We propose that the pathogenesis of increased fracture risk in T2D is due to low bone turnover caused by osteocyte dysfunction resulting in bone microcracks and fractures. Increased levels of sclerostin may mediate the low bone turnover and may be a novel marker of increased fracture risk, although further research is needed. An impaired incretin response in T2D may also affect bone turnover. Accumulation of advanced glycosylation endproducts may also impair bone strength. Concerning antidiabetic medication, the glitazones are detrimental to bone health and associated with increased fracture risk, and the sulphonylureas may increase fracture risk by causing hypoglycemia. So far, the results on the effect of other antidiabetics are ambiguous. No specific guideline for the management of bone disease in T2D is available and current evidence on the effects of antiosteoporotic medication in T2D is sparse. The aim of this review is to collate current evidence of the pathogenesis, detection and treatment of diabetic bone disease.