Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study.

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug. INTRODUCTION: The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1-34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis. METHODS: Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N = 65) or quarterly intravenous IBN (N = 122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared. RESULTS: Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9 ± 7.4 years, body mass index 23.8 ± 3.8 kg/m(2), BMD L1-L4 0.741 ± 0.100 g/cm(2), and TBS 1.208 ± 0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 % ± 6.3 vs. +2.9 % ± 3.3 and +4.3 % ± 6.6 vs. +0.3 % ± 4.1, respectively; P < 0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r (2) = 0.04) with no correlation between the changes in BMD and TBS over 24 months. CONCLUSIONS: In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.

Regulation of proliferation and differentiation of human fetal bone cells.

During the last decade, extensive research has been performed in the field of orthopedic medicine to develop cell-based therapies for the restoration of injured bone tissue. We previously demonstrated that human primary fetal bone cells (HFBCs) associated with porous scaffolds induced a bone formation in critical calvaria defect; however, the environmental factors regulating their behavior in culture have not been identified. HFBCs (human fetal femur,12 week development) were compared to marrow-derived human mesenchymal stem cells (HMSCs) for their capacity to proliferate and differentiate into osteoblasts under various culture conditions. When cultured in standard alphaMEM medium, PDGF and FGF-2 increased cell proliferation of both cell types. Investigation of the differentiating capacity of HFBCs and HMSCs in a normal culture medium indicated that HFBCs expressed higher expression levels of RUNX2, OSX, and osteogenic markers compared with HMSCs, while SOX9 was expressed at very low levels in both cells types. However, HMSCs, but not HFBCs enhanced osteoblastic markers in response to osteogenic factors. Surprisingly, BMP-2 with osteogenic factors increased cell numbers and reduced osteoblastic differentiation in HFBCs with the opposite effect seen in HMSCs. Associated with a higher expression of osteoblastic markers, HFBCs produced a higher calcified extra cellular matrix compared with HMSCs. Taken together, data presented in this study suggest that HFBCs have characteristics of osteoprecursor cells that are more advanced in their osteogenesis development compared with mesenchymal stem cells, making fetal cells an interesting biological tool for treatment of skeletal defects and diseases.

CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche.

Plasma cells represent the end stage of B-cell development and play a key role in providing an efficient antibody response, but they are also involved in numerous pathologies. Here we show that CD93, a receptor expressed during early B-cell development, is reinduced during plasma-cell differentiation. High CD93/CD138 expression was restricted to antibody-secreting cells both in T-dependent and T-independent responses as naive, memory, and germinal-center B cells remained CD93-negative. CD93 was expressed on (pre)plasmablasts/plasma cells, including long-lived plasma cells that showed decreased cell cycle activity, high levels of isotype-switched Ig secretion, and modification of the transcriptional network. T-independent and T-dependent stimuli led to re-expression of CD93 via 2 pathways, either before or after CD138 or Blimp-1 expression. Strikingly, while humoral immune responses initially proceeded normally, CD93-deficient mice were unable to maintain antibody secretion and bone-marrow plasma-cell numbers, demonstrating that CD93 is important for the maintenance of plasma cells in bone marrow niches.

Bone regeneration and stem cells.

?  Introduction ?  Bone fracture healing and healing problems ?  Biomaterial scaffolds and tissue engineering in bone formation -  Bone tissue engineering -  Biomaterial scaffolds -  Synthetic scaffolds -  Micro- and nanostructural properties of scaffolds -  Conclusion ?  Mesenchymal stem cells and osteogenesis -  Bone tissue -  Origin of osteoblasts -  Isolation and characterization of bone marrow derived MSC -  In vitro differentiation of MSC into osteoblast lineage cells -  In vivo differentiation of MSC into bone -  Factors and pathways controlling osteoblast differentiation of hMSC -  Defining the relationship between osteoblast and adipocyte differentiation from MSC -  MSC and sex hormones -  Effect of aging on osteoblastogenesis -  Conclusion ?  Embryonic, foetal and adult stem cells in osteogenesis -  Cell-based therapies for bone -  Specific features of bone cells needed to be advantageous for clinical use -  Development of therapeutic biological agents -  Clinical application concerns -  Conclusion ?  Platelet-rich plasma (PRP), growth factors and osteogenesis -  PRP effects in vitro on the cells involved in bone repair -  PRP effects on osteoblasts -  PRP effects on osteoclasts -  PRP effects on endothelial cells -  PRP effects in vivo on experimental animals -  The clinical use of PRP for bone repair -  Non-union -  Distraction osteogenesis -  Spinal fusion -  Foot and ankle surgery -  Total knee arthroplasty -  Odontostomatology and maxillofacial surgery -  Conclusion ?  Molecular control of osteogenesis -  TGF-β signalling -  FGF signalling -  IGF signalling -  PDGF signalling -  MAPK signalling pathway -  Wnt signalling pathway -  Hedgehog signalling -  Notch signalling -  Ephrin signalling -  Transcription factors regulating osteoblast differentiation -  Conclusion ?  Summary This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet-rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.

Postgraduate Symposium: Positive influence of nutritional alkalinity on bone health.

There is growing evidence that consumption of a Western diet is a risk factor for osteoporosis through excess acid supply, while fruits and vegetables balance the excess acidity, mostly by providing K-rich bicarbonate-rich foods. Western diets consumed by adults generate approximately 50-100 mEq acid/d; therefore, healthy adults consuming such a diet are at risk of chronic low-grade metabolic acidosis, which worsens with age as a result of declining kidney function. Bone buffers the excess acid by delivering cations and it is considered that with time an overstimulation of this process will lead to the dissolution of the bone mineral content and hence to reduced bone mass. Intakes of K, Mg and fruit and vegetables have been associated with a higher alkaline status and a subsequent beneficial effect on bone health. In healthy male volunteers an acid-forming diet increases urinary Ca excretion by 74% and urinary C-terminal telopeptide of type I collagen (C-telopeptide) excretion by 19% when compared with an alkali (base-forming) diet. Cross-sectional studies have shown that there is a correlation between the nutritional acid load and bone health measured by bone ultrasound or dual-energy X-ray absorptiometry. Few studies have been undertaken in very elderly women (>75 years), whose osteoporosis risk is very pertinent. The EVAluation of Nutrients Intakes and Bone Ultra Sound Study has developed and validated (n 51) an FFQ for use in a very elderly Swiss population (mean age 80.4 (sd 2.99) years), which has shown intakes of key nutrients (energy, fat, carbohydrate, Ca, Mg, vitamin C, D and E) to be low in 401 subjects. A subsequent study to assess net endogenous acid production (NEAP) and bone ultrasound results in 256 women aged > or = 75 years has shown that lower NEAP (P=0.023) and higher K intake (P=0.033) are correlated with higher bone ultrasound results. High acid load may be an important additional risk factor that may be particularly relevant in very elderly patients with an already-high fracture risk. The latter study adds to knowledge by confirming a positive link between dietary alkalinity and bone health indices in the very elderly. In a further study to complement these findings it has also been shown in a group of thirty young women that in Ca sufficiency an acid Ca-rich water has no effect on bone resorption, while an alkaline bicarbonate-rich water leads to a decrease in both serum parathyroid hormone and serum C-telopeptide. Further investigations need to be undertaken to study whether these positive effects on bone loss are maintained over long-term treatment. Mineral-water consumption could be an easy and inexpensive way of helping to prevent osteoporosis and could be of major interest for long-term prevention of bone loss.

PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers.

BACKGROUND: Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. METHODS: A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score <-0.5, n = 30; group 2: z-score -0.5-0.5, n = 36; group 3: z-score >0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. RESULTS: An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. CONCLUSION: Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium diet.

Weight-bearing bones are more sensitive to physical exercise in boys than in girls during pre- and early puberty: a cross-sectional study.

We carried out a cross-section study of the sex-specific relationship between bone mineral content and physical activity at sites with different loading in pre- and early pubertal girls and boys. There was significant sensitivity of bone mineral content of the hip to physical exercise in boys, but not in girls. BACKGROUND: Since little is known whether there are sex differences in sensitivity of bone to loading, we investigated sex differences in the cross-sectional association between measures of physical activity (PA) and bone mass and size in pre- and early pubertal children of both sexes. METHODS: We measured bone mineral content/density (BMC/BMD) and fat-free mass (FFM) in 269 6- to 13-year-old children from randomly selected schools by dual-energy X-ray absorptiometry. Physical activity (PA) was measured by accelerometers and lower extremity strength by a jump-and-reach test. RESULTS: Boys (n = 128) had higher hip and total body BMC and BMD, higher FFM, higher muscle strength and were more physically active than girls (n = 141). Total hip BMC was positively associated with time spent in total and vigorous PA in boys (r = 0.20-0.33, p < 0.01), but not in girls (r = 0.02-0.04, p = ns), even after adjusting for FFM and strength. While boys and girls in the lowest tertile of vigorous PA (22 min/day) did not differ in hip BMC (15.62 vs 15.52 g), boys in the highest tertile (72 min/day) had significantly higher values than the corresponding girls (16.84 vs 15.71 g, p < 0.05). CONCLUSIONS: Sex differences in BMC during pre- and early puberty may be related to a different sensitivity of bone to physical loading, irrespective of muscle mass.

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three-year study.

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m(2) ; TBS, 1.178 ± 0.1 but for LS T-score (ZOL-2.9 ± 1.5 versus PLB-2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus-0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once-yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.

Bone marrow dosimetry in rats using direct tissue counting after injection of radio-iodinated intact monoclonal antibodies or F(ab')2 fragments.

Normal rats were injected intravenously with 131I- and 125I-labeled intact murine and chimeric mouse-human monoclonal antibodies directed against carcinoembryonic antigen or with the corresponding F(ab')2 fragments. At different times after injection, individual animals were killed and radioactivity of blood and major organs, including bones and bone marrow, was determined. Ratios comparing radioactivity concentration in different tissues with that of bone marrow were calculated and found to remain stable during several effective half-lives of the antibodies. Mean bone marrow radioactivity was 35% (range, 29%-40%) of that of blood and 126% (range, 108%-147%) of that of liver after injection of intact Mabs or F(ab')2 fragments. In nude rats bearing human colon carcinoma xenografts producing carcinoembryonic antigen, relative bone marrow radioactivity was slightly lower than that in normal rats.

Early stage disc degeneration does not have an appreciable affect on stiffness and load transfer following vertebroplasty and kyphoplasty.

Vertebroplasty and kyphoplasty have been reported to alter the mechanical behavior of the treated and adjacent-level segments, and have been suggested to increase the risk for adjacent-level fractures. The intervertebral disc (IVD) plays an important role in the mechanical behavior of vertebral motion segments. Comparisons between normal and degenerative IVD motion segments following cement augmentation have yet to be reported. A microstructural finite element model of a degenerative IVD motion segment was constructed from micro-CT images. Microdamage within the vertebral body trabecular structure was used to simulate a slightly (I = 83.5% of intact stiffness), moderately (II = 57.8% of intact stiffness), and severely (III = 16.0% of intact stiffness) damaged motion segment. Six variable geometry single-segment cement repair strategies (models A-F) were studied at each damage level (I-III). IVD and bone stresses, and motion segment stiffness, were compared with the intact and baseline damage models (untreated), as well as, previous findings using normal IVD models with the same repair strategies. Overall, small differences were observed in motion segment stiffness and average stresses between the degenerative and normal disc repair models. We did however observe a reduction in endplate bulge and a redistribution in the microstructural tissue level stresses across both endplates and in the treated segment following early stage IVD degeneration. The cement augmentation strategy placing bone cement along the periphery of the vertebra (model E) proved to be the most advantageous in treating the degenerative IVD models by showing larger reductions in the average bone stresses (vertebral and endplate) as compared to the normal IVD models. Furthermore, only this repair strategy, and the complete cement fill strategy (model F), were able to restore the slightly damaged (I) motion segment stiffness above pre-damaged (intact) levels. Early stage IVD degeneration does not have an appreciable effect in motion segment stiffness and average stresses in the treated and adjacent-level segments following vertebroplasty and kyphoplasty. Placing bone cement in the periphery of the damaged vertebra in a degenerative IVD motion segment, minimizes load transfer, and may reduce the likelihood of adjacent-level fractures.