Treatment of postmenopausal osteoporosis patients with teriparatide for 24 months reverts forming bone quality indices to premenopausal healthy control values.

Postmenopausal osteoporosis (PMOP) therapies are frequently evaluated by bone mineral density (BMD) gains against patients receiving placebo (calcium and vitamin D supplementation, a mild bone turnover-suppressing intervention), which is not equivalent to either healthy or treatment-naive PMOP. The aim of the present observational study was to assess the effects of TPTD treatment in PMOP (20 µg, once daily) at 6 (TPTD 6m; n = 28, age 65 ± 7.3 years), and 24 (TPTD 24m; n = 32, age 67.4 ± 6.15 years) months on bone quality indices at actively forming trabecular surfaces (with fluorescent double labels). Data from the TPTD-treated PMOP patients were compared with those in healthy adult premenopausal women (HC; n = 62, age 40.5 ± 10.6 years), and PMOP receiving placebo (PMOP-PLC; n = 94, age 70.6 ± 4.5 years). Iliac crest biopsies were analyzed by Raman microspectroscopy at three distinct tissue ages: mid-distance between the second label and the bone surface, mid-distance between the two labels, and 1 µm behind the first label. Mineral to matrix ratio (MM), mineral maturity/crystallinity (MMC), tissue water (TW), glycosaminoglycan (GAGs), and pyridinoline (Pyd) content were determined. Outcomes were compared by ANCOVA with subject age and tissue age as covariates, and health status as a fixed factor, followed by Sidak's post-hoc testing (significance assigned to p < 0.05). Both TPTD groups increased MM compared to PMOP-PLC. While TPTD 6m had values similar to HC, TPTD 24m had higher values compared to either HC or TPTD 6m. Both TPTD groups had lower MMC values compared to PMOP-PLC and similar to HC. TPTD 6m patients had higher TW content compared to HC, while TPTD 24m had values similar to HC and lower than either PMOP-PLC or TPTD 6m. Both TPTD groups had lower GAG content compared to HC group, while TPTD 6m had higher values compared to PMOP-PLC. Finally, TPTD 6m patients had higher Pyd content compared to HC and lower compared to PMOP-PLC, while TPTD 24m had lower values compared to PMOP-PLC and TPTD 6m, and similar to HC group. The results of the present study indicate that effects of TPTD on forming trabecular bone quality indices depend on treatment duration. At the recommended length of 24 m, TPTD restores bone mineral and organic matrix quality indices (MMC, TW, Pyd content) to premenopausal healthy (HC) levels.

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.

The doubled burden of diabetic bone disease: hip fracture and post-hip fracture mortality.

OBJECTIVE: Patients with diabetes have an increased risk of osteoporosis and shorter life expectancy. Hip fracture (HF) is the most serious consequence of osteoporosis and is associated with increased mortality risk. We aimed to assess the association of antidiabetic medications with HF and the post-hip fracture mortality risk among diabetic patients ≥50 years. DESIGN: In this nationwide case-control study 53 992 HF cases and 112 144 age-, sex- and region-matched non-hip fracture controls were analyzed. A cohort of hip-fractured diabetic patients were followed-up for an all-cause mortality. METHODS: We defined three groups of diabetic patients based on a prescription of antidiabetic medications: group 1 treated with insulin monotherapy (G1DM), group 2 (G2DM) treated with blood glucose-lowering drugs (BGLD) only, group 3 on a combined BGLD and insulin therapy (G3DM). We applied logistic regression and Cox regression. RESULTS: We identified 2757 G1DM patients, 15 310 G2DM patients, 3775 G3DM patients and 144 294 patients without any antidiabetic treatment. All three groups of diabetic patients had increased odds of HF compared to controls. G1DM patients aged 50-64 years (aOR: 4.80, 95% CI: 3.22-7.17) and G3DM patients (aOR: 1.39, 95% CI: 1.02-1.88) showed the highest HF odds, whereas G2DM patients had 18% decrease in HF odds than their non-diabetic controls (aOR: 0.82, 95% CI: 0.69-0.99). All diabetic patients had increased post-hip fracture mortality risk compared to non-diabetic controls. The highest mortality hazard was observed in G1DM patients, being greater for women than men (HR: 1.71, 95% CI: 1.55-1.89 and HR: 1.44, 95% CI: 1.27-1.64, respectively). CONCLUSIONS: Antidiabetic medications increase the probability of HF. Diabetic patients, who sustained HF have a higher mortality risk than non-diabetic patients.

Mineral and organic matrix composition at bone forming surfaces in postmenopausal women with osteoporosis treated with either teriparatide or zoledronic acid.

The ability of bone to resist fracture is dependent on the composite nature of its mineral and organic matrix content. Teriparatide (TPTD) and zoledronic acid (ZOL) are approved anabolic and antiresorptive therapies, respectively, to reduce fracture risk in women with postmenopausal osteoporosis. In the SHOTZ study, postmenopausal women with osteoporosis were treated with TPTD (20 µg daily, subcutaneous) or ZOL (5 mg/year, intravenous infusion) for 24 months. Iliac crest biopsies were obtained at 6 months and again at 24 months from approximately one third of the original study cohort. To investigate the early effects of these two drugs on the quality of newly formed bone, we used vibrational spectroscopic techniques to analyze tetracycline-labelled transiliac biopsies obtained from participants at the 6-month time point. Raman spectra were acquired at forming trabecular and intra-cortical surfaces (identified by fluorescent double labels), to determine mineral, organic matrix, glycosaminoglycan, and tissue water content, as well as mineral maturity/crystallinity at three specific tissue ages (1-5, 15, and ≥25 days). Fourier transformed infrared microspectroscopy was used to determine pyridinoline/divalent collagen cross-link ratios. At 6 months, treatment with TPTD versus ZOL resulted in lower mineral and higher organic matrix content, increased tissue water content, and lower mineral/matrix, mineral maturity/crystallinity, glycosaminoglycan content, and pyridinoline/divalent enzymatic collagen cross-link ratio. Our results suggest that TPTD and ZOL have differential effects on material properties of newly formed bone at individual remodeling sites, highlighting their different mechanisms of action.

Osteoporosis Therapeutics 2020.

Numerous safe and efficient drug therapies are currently available to decrease risk of low trauma fractures in patients with osteoporosis including postmenopausal, male, and secondary osteoporosis. In this chapter, we give first an overview of the most important outcomes regarding fracture risk reduction, change in bone mineral density (BMD by DXA) and/or bone markers of the phase III clinical studies of well-established therapies (such as Bisphosphonates, Denosumab or Teriparatide) and also novel therapies (such as Romosozumab or Abaloparatide) and highlight their mechanisms of action at bone tissue/material level. The latter understanding is not only essential for the choice of drug, duration and discontinuation of treatment but also for the interpretation of the clinical outcomes (in particular of eventual changes in BMD) after drug administration. In the second part of this chapter, we focus on the management of different forms of osteoporosis and give a review of the respective current guidelines for treatment. Adverse effects of treatment such as atypical femoral fractures, osteonecrosis of the jaw or influence of fracture healing are considered also in this context.

Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.

Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-ß/SMAD pathway.

Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical "dripping candle wax" melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-ß pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation-positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-ß pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-ß/SMAD3 activation by BMP signaling in SMAD3 mutation-positive endosteal melorheostosis, which may guide future therapies.

No evidence for alteration in early secondary mineralization by either alendronate, teriparatide or combination of both in transiliac bone biopsy samples from postmenopausal osteoporotic patients.

The influence of treatment with alendronate (ALN), teriparatide (TPTD) or concurrent treatment with both on the human bone matrix mineralization has not yet been fully elucidated. For this purpose we analyzed quadruple fluorochrome labelled transiliac bone biopsy samples (n = 66) from postmenopausal osteoporotic women with prior and ongoing ALN (ALN-Rx arm) or without ALN (Rx-Naïve arm) after 7 months treatment with cyclic or daily TPTD or without TPTD using quantitative backscattered electron imaging and confocal scanning laser microscopy. Additionally to the bone mineralization density distribution (BMDD) of entire cancellous and cortical compartments, we measured the mineralization kinetics, i.e. the calcium concentration between the younger (Ca_DL2) and older double labels (Ca_DL1), and in interstitial bone (Ca_int) in a subset of the biopsy cohort. We found the BMDD from the patients with prior and ongoing ALN generally shifted to higher calcium concentrations compared to those without ALN (average degree of mineralization in cancellous bone Cn.CaMean + 3.1%, p<0.001). The typical BMDD changes expected by cyclic or daily TPTD treatment due to the increased bone turnover/formation, e.g. an increase in low mineralized bone area were not observed. Additionally, we found no influence of treatment with ALN or TPTD or combination thereof on Ca_DL2, Ca_DL1, or Ca_int. Pooling the information from all groups, Ca_DL1 was +5.9% (p<0.001) higher compared to Ca_DL2, corresponding to a mineralization rate of 0.18 wt% Ca per week during the early secondary mineralization process. Our data suggest that the patients in the ALN-Rx arm had more highly mineralized bone matrix than those without ALN due to their lower bone turnover. The reason for the unexpected BMDD findings in the TPTD treated remain unknown and cannot be attributed to altered mineralization kinetics as no differences in the time course of early secondary mineralization were observed between the treatment groups.

Substitution of murine type I collagen A1 3-hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia.

Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.

Inflammatory Bowel Disease: A Nationwide Study of Hip Fracture and Mortality Risk After Hip Fracture.

BACKGROUND AND AIMS: With rising rates of inflammatory bowel diseases [IBD] in older adults, management of comorbidities such as osteoporosis is becoming increasingly important. Hip fracture [HF] is the most serious consequence of low bone mineral quality and is associated with excess risk of mortality. For older IBD patients, there are only limited data available. Therefore, we aimed to assess the association of IBD with HF, and all-cause mortality risk after HF, among IBD patients older than 50 years. METHODS: In a national database-registered case-control study, 56 821 HF cases aged ≥50 years, and 113 718 age-, sex- and region-matched non-hip-fracture controls, were analysed between 2012 and 2016. A history of IBD was assessed from data from Austrian social health insurance funds. Logistic regression and Cox proportional multivariate models were used to test the association of IBD with HF and post-hip fracture mortality risk. RESULTS: A total of 531 patients were identified with IBD (25.0% men, mean age 81.2 years, standard deviation [SD] 9.7). Analysis, adjusted for anti-osteoporotic treatment, use of glucocorticoids, and selected medications, showed that IBD patients had an increased odds of HF (odds ratio [[OR] 2.22, 95% confidence interval [CI] 1.86-2.64). Patients with Crohn's disease [CD] revealed a higher HF odds in contrast to patients with ulcerative colitis [OR 2.91, 95% CI 2.17-3.89 and OR 1.89, 95% CI 1.52-2.35, respectively]. Overall mortality risk after HF was higher among female CD patients [HR 1.75, 95% CI 1.28-2.41] than in the general population. CONCLUSIONS: IBD was strongly associated with HF in older patients. Post-hip fracture mortality risk was elevated particularly in women with CD.

Newly formed and remodeled human bone exhibits differences in the mineralization process.

During human skeletal growth, bone is formed via different processes. Two of them are: new bone formation by depositing bone at the periosteal (outer) surface and bone remodeling corresponding to a local renewal of tissue. Since in remodeling formation is preceded by resorption, we hypothesize that modeling and remodeling could require radically different transport paths for ionic precursors of mineralization. While remodeling may recycle locally resorbed mineral, modeling implies the transport over large distances to the site of bone apposition. Therefore, we searched for potential differences of size, arrangement and chemical composition of mineral particles just below surfaces of modeling and remodeling sites in femur midshaft cross-sections from healthy children. These bone sites were mapped using scanning synchrotron X-ray scattering, Raman microspectroscopy, energy dispersive X-ray analysis and quantitative backscattered electron microscopy. The results show clear differences in mineral particle size and composition between the sites, which cannot be explained by a change in the rate of mineral apposition or accumulation. At periosteal modeling sites, mineral crystals are distinctly larger, display higher crystallinity and exhibit a lower calcium to phosphorus ratio and elevated Na and Mg content. The latter may originate from Mg used for phase stabilization of mineral precursors and therefore indicate different time periods for mineral transport. We conclude that the mineralization process is distinctively different between modeling and remodeling sites due to varying requirements for the transport distance and, therefore, the stability of non-crystalline ionic precursors, resulting in distinct compositions of the deposited mineral phase. STATEMENT OF SIGNIFICANCE: In growing children new bone is formed either due to apposition of bone tissue e.g. at the outer ridge of long bones to allow growth in thickness (bone modeling), or in cavities inside the mineralized matrix when replacing tissue (bone remodeling). We demonstrate that mineral crystal shape and composition are not the same between these two sites, which is indicative of differences in mineralization precursors. We suggest that this may be due to a longer mineral transport distance to sites of new bone formation as compared to remodeling where mineral can be locally recycled.

Impact microindentation assesses subperiosteal bone material properties in humans.

Impact microindentation (IMI) is a Reference Point Indentation technique measuring tissue-level properties of cortical bone in humans in vivo. The nature, however, of the properties that can affect bone strength is incompletely understood. In the present study we examined bone material properties in transiliac bone biopsies obtained concurrently with measurements of Bone Material Strength index (BMSi) by IMI in 12 patients with different skeletal disorders and a wide range of BMD, with or without fractures (8 males, 4 females, mean age 48±12.2 (SD) years, range 15-60 years). IMI was performed in the mid-shaft of the right tibia with a hand-held microindenter (OsteoProbe). Cancellous and cortical bone mineralization density distributions (BMDD) were measured in the entire biopsy bone area by quantitative backscattered electron imaging. Raman measurements were obtained right at the outer edge of the cortex, and 5, 50, 100, 500µm inwards. The calculated parameters were: i) Mineral and organic matrix content as well as the mineral / matrix ratio. ii) Nanoporosity. iii) Glycosaminoglycan content. iv) Pyridinoline content. v) Maturity/crystallinity of the apatite crystallites. There was no relationship between BMSi values with any measurement of mineral content of whole bone tissue (BMD, BMDD) or maturity/crystallinity of bone mineral. On the other hand, a positive correlation between BMSi and local mineral content, and an inverse correlation between BMSi and nanoporosity at the mineralized subperiosteal edge of the sample and at 5µm inwards was found. A positive correlation was also observed between BMSi and pyridinoline content at the same locations. These results indicate that local mineral content, nanoporosity and pyridinoline content at the subperiosteal site in the transiliac bone biopsy are linked to the BMSi values measured in the tibia. As both high porosity at the nano level and low pyridinoline content of the bone matrix can negatively impact bone strength, our findings suggest that BMSi most likely assesses subperiosteal bone material properties.

Biomechanical and Bone Material Properties of Schnurri-3 Null Mice.

Schnurri-3 (Shn3) is an essential regulator of postnatal skeletal remodeling. Shn3-deficient mice (Shn3-/-) have high bone mass; however, their bone mechanical and material properties have not been investigated to date. We performed three-point bending of femora, compression tests of L3 vertebrae. We also measured intrinsic material properties, including bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics by quantitative backscatter electron imaging, as well as collagen cross-linking by Fourier transform infrared microspectroscopy of femora from Shn3-/- and WT mice at different ages (6 weeks, 4 months, and 18 months). Moreover, computer modeling was performed for the interpretation of the BMDD outcomes. Femora and L3 vertebrae from Shn3-/- aged 6 weeks revealed increased ultimate force (2.2- and 3.2-fold, p < .01, respectively). Mineralized bone volume at the distal femoral metaphysis was about twofold (at 6 weeks) to eightfold (at 4 and 18 months of age) in Shn3-/- (p < .001). Compared with WT, the average degree of trabecular bone mineralization was similar at 6 weeks, but increased at 4 and 18 months of age (+12.6% and +7.7%, p < .01, respectively) in Shn3-/-. The analysis of OLS characteristics revealed a higher OLS area for Shn3-/- versus WT at all ages (+16%, +23%, +21%, respectively, p < .01). The collagen cross-link ratio was similar between groups. We conclude that femora and vertebrae from Shn3-/- had higher ultimate force in mechanical testing. Computer modeling demonstrated that in cases of highly increased bone volume, the average degree of bone matrix mineralization can be higher than in WT bone, which was actually measured in the older Shn3-/- groups. The area of 2D osteocyte lacunae sections was also increased in Shn3-deficiency, which could only partly be explained by larger remnant areas of primary cortical bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Treatment Effects of Bisphosphonates and Denosumab on Survival and Refracture from Real-World Data of Hip-Fractured Patients.

We examined differences in patients' survival after hip fracture (HF) and risk for subsequent HF among patients treated with oral and intravenous bisphosphonates (oBPs, iBPs), denosumab (DMAB), and patients without therapy. We used data from all patients in Austria aged ≥ 50 who sustained a HF between 2012 and 2017 and were followed for a subsequent HF and all-cause mortality until 2017. Antiosteoporotic treatment-naïve patients, who were incident users of BPs and DMAB, were eligible for propensity score matching 1:1 to obtain comparable user groups. We applied competing risk approach and calculated cumulative incidence functions and subdistribution-hazards for refracture. Cox regression models were applied for mortality risk. A total of 54,145 hip-fractured patients were observed (1919 oBPs; 1870 iBPs; 555 DMAB users; and 42,795 untreated patients were included in the matched sets) and followed up for a median (interquartile range) of 22.6 months (26.2). Patients treated with antiresorptive medications had significantly longer survival time than patients without treatment. Receiving treatment significantly decreased a hazard of dying only for women by 17% for iBPs (HR 0.83, 95% CI 0.71-0.98, p = 0.023). For DMAB and oBPs, the results were not statistically significant. Higher risk of a subsequent HF was observed in women on DMAB (SHR 1.77, 95% CI 1.08-2.91) and on iBP (SHR 1.81, 95% CI 1.35-2.41), and in men on oBPs (SHR 2.89, 95% CI 1.58-5.30). Patients who were treated with antiresorptive medications after HF had longer survival than patients without treatment, highlighting the importance of initiation of antiresorptive treatment after HF.

Material properties and osteoporosis.

The main clinical tool for the diagnosis and treatment of skeletal diseases such as osteoporosis is the determination of bone mineral density by dual x-ray absorptiometry. Although this outcome contributes to the determination of bone strength, the clinical evidence to date suggests that it does not correlate strongly with fracture incidence. The main reason for this discrepancy is the fact that several other bone properties, such as material properties, are not taken into account. This short review summarizes the reasons why material properties are important in the determination of bone strength and briefly discusses some of them as well as their influence on bone's mechanical performance.

Melorheostosis: A Clinical, Pathologic, and Radiologic Case Series.

Melorheostosis is a rare sclerosing bone disease characterized by excessive cortical bone deposition that is frequently on the differential diagnosis for bone biopsies. Although the radiologic pattern of "dripping candle wax" is well known, the pathologic findings have been poorly defined. Here, we comprehensively describe the histology of melorheostosis in 15 patients who underwent bone biopsies. Common histologic findings included: dense cortical bone (73.3%), woven bone (60%), and hypervascular features and increased porosity (66.7%). One third of the patients (5/15) also had prominent cement lines. Multiple patients had >1 histologic pattern (ie, dense cortical bone and hypervascularity). Overall, this study suggests that melorheostosis exists with several histologically distinct patterns. When confronted with a case of suspected melorheostosis, the clinical pathologist should use the histologic features common to melorheostotic lesions presented here in conjunction with the patient's clinical presentation and radiographic findings to arrive at a diagnosis. An illustrative case is presented.

Bone matrix mineralization and osteocyte lacunae characteristics in patients with chronic kidney disease - mineral bone disorder (CKD-MBD).

OBJECTIVES: Little is known about bone mineralization and osteocyte lacunae properties in chronic kidney disease mineral bone disorder (CKD-MBD). METHODS: In this retrospective study, we measured the bone mineralization density distribution (BMDD) and osteocyte lacunar section (OLS) 2D-characteristics by quantitative backscatter electron imaging in Straumann drill biopsy samples from n=58 patients with CKD-MBD. Outcomes were studied in relation to serum parathyroid hormone (PTH), alkaline phosphatase (APH), histomorphometric bone turnover and treatment with cinacalcet or phosphate binders. RESULTS: Lower calcium concentrations in bone from high turnover (average degree of bone mineralization -6.2%, p<0.001) versus low turnover patients were observed. OLS-characteristics were distinctly different (p<0.01 to p<0.05) in patients with highest compared to those with lowest turnover. Patients with cinacalcet had different OLS-characteristics (p<0.05) compared to those without cinacalcet. Furthermore, patients with phosphate binders had differences in BMDD and OLS-characteristics (p<0.05) compared to patients without phosphate binders. CONCLUSIONS: Our findings suggest that in patients with CKD-MBD secondary hyperparathyroidism and increased bone turnover decrease the average degree of bone matrix mineralization. Conversely, density and lacunar size of the osteocytes are increased compared to adynamic bone disease pointing at distinct patterns of bone mineralization and osteocyte lacunar properties in these two disease entities.

Vascular cell adhesion molecule 1 in patients with severe osteoarthritis of the hip : A prospective cross-sectional study.

BACKGROUND: Osteoarthritis (OA) of the hip is a frequent and debilitating joint disease. Only few clinical risk factors for hip OA are established and clinically applicable biomarkers to identify patients at risk are still lacking. The glycoprotein vascular cell adhesion molecule 1 (VCAM-1) is expressed by chondrocytes and synovial tissue and was a predictive marker for development of severe large joint OA in a previous study. OBJECTIVE: It was tested whether increased serum levels of VCAM-1 are prevalent in patients with severe OA of the hips. METHODS: In this prospective, multicenter, cross-sectional study, risk factors of severe hip OA were investigated in patients scheduled for hip joint arthroplasty and 100 patients were randomly selected for validation of VCAM-1 as a potential biomarker for hip OA. Serum samples were analyzed by an enzyme-linked immunosorbent assay and compared with a sex and age-matched control cohort. RESULTS: The groups were similar in age, gender ratio and prevalence of diabetes. Serum concentrations of VCAM-1 were 8% higher in OA patients compared to controls, without reaching statistical significance (818 ng ml-1, 95% confidence interval, CI 746-891 ng ml-1 versus 759 ng m-1, 95% CI 711-807 ng ml-1; P = 0.4839). CONCLUSION: The results of this study show that serum concentrations of VCAM-1 cannot distinguish patients with severe hip OA from age and sex-matched controls.

Higher dose but not low dose proton pump inhibitors are associated with increased risk of subsequent hip fractures after first hip fracture: A nationwide observational cohort study.

AIM: To examine the association of proton pump inhibitor (PPI) use with subsequent hip fracture incidence in hip fracture patients, accounting for gender, age, PPI doses, PPI initiation before or after first fracture, and year from first fracture in which the first subsequent fracture occurred. METHODS: Data from 31,668 Austrian patients ≥50 years with the first hip fracture between July 2008 and December 2010 were analyzed retrospectively. After exclusion of patients on anti-osteoporotic medication, incidence of subsequent hip fractures was compared between users and non-users of PPIs using regression models. RESULTS: In general, use of PPIs among hip fracture patients was associated with increased risk for subsequent hip fracture (OR 1.58, 95%-CI 1.25-2.00), in particular in men, in the age group of 70-84 years, and when PPIs were initiated before the first fracture. Low PPI doses of ≤90 cumulative DDDs and ≤0.25 DDDs/day, however, were not linked to elevated subsequent fracture risk, especially among female patients. Subsequent hip fracture incidence was elevated within the first year after first fracture in female and male PPI users (OR 1.75, 95%-CI 1.28-2.38) and dropped in women but not in men in the second year. CONCLUSIONS: Low-dose PPI use is not associated with increased risk of subsequent hip fractures, especially in women. Patients thus get most benefit of short-term PPI use after a hip fracture that has previously been linked to lowered mortality if low doses are not exceeded. Varying risk profiles for the time of subsequent hip fracture could have implications for risk group-specific follow-up care.

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2.

Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated 6 families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant, c.148C>T (p.Arg50*), whereas the other families had a missense variant, c.185T>G (p.Ile62Ser) or c.191T>G (p.Met64Arg). Subjects with p.Arg50* presented with childhood-onset osteoporosis with or without cranial sclerosis. Patients with p.Ile62Ser or p.Met64Arg had a more severe presentation, with neonatal fractures, severe short stature, and spondylometaphyseal dysplasia. Several subjects had experienced peripheral facial nerve palsy or other neurological manifestations. Bone biopsies showed markedly altered bone material characteristics, including defective bone mineralization. Osteoclast formation and function in vitro was normal. While the p.Arg50* mutation yielded a catalytically inactive enzyme, p.Ile62Ser and p.Met64Arg each enhanced the rate of de novo sphingomyelin production by blocking export of a functional enzyme from the endoplasmic reticulum. SGMS2 pathogenic variants underlie a spectrum of skeletal conditions, ranging from isolated osteoporosis to complex skeletal dysplasia, suggesting a critical role for plasma membrane-bound sphingomyelin metabolism in skeletal homeostasis.