Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice.

In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap-/- mice but not in growing male Col1a1Jrt/+ mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.

In vitro retention force changes during cyclic dislodging of three novel attachment systems for implant overdentures with different implant angulations.

OBJECTIVES: This in vitro study aimed to compare changes in retentive force due to cyclic dislodging of three novel un-splinted attachments. MATERIALS AND METHODS: Experimental models simulating a mandibular two-implant overdenture situation, with implants positioned with various interimplant discrepancies (0°, 20°, 40°, and 60°) were fabricated. Three attachment systems were tested, "N": a straight or 15°-angulated stud; "L": a sole straight stud; and "C": a straight or individually angulated stud. All models underwent wet testing and were subjected to 10,000 insertion-removal cycles in a universal testing machine. The mean retentive forces were calculated for cycles 10, 100, 1,000, 5,000, and 10,000. Multiple mixed-effects linear regression models were applied for statistical analyses (⍺ < 0.05). RESULTS: "N" demonstrated an increasing retention until 1,000 cycles, which subsequently diminished back to its initial retention at 10,000 cycles, showing no significant loss during the entire experiment. Statistical models demonstrated no effect of implant angulation on retention, except for 60° after 10,000 cycles (p < .05). "L" showed an early peak at 100 cycles and did not significantly lose retentive force before 5,000 cycles. Angulations of 40° or higher were shown to lead to lower retentive forces (0° vs. 40° cycle 5,000: p < .05; 0° vs. 60° cycle 100: p < .05, ≥cycle 1,000: p < .001). "C" showed stable retentive forces with no significant loss only at 10,000 cycles (all angles: p < .001) or 5,000 cycles (0° vs. 60°: p < .05). CONCLUSIONS: All systems showed retentive forces promising successful clinical use in implant overdentures, even in situations with extremely angulated implants. Specific abutments compensating interimplant angulation maintain retention longer in situations with high axe divergencies.

[Orthogeriatric care†: what specificities†?] / Prise en charge orthogériatrique†: quelles spécificités†?

Hip fracture in the elderly is associated with an increase in disability and mortality. Early intervention programs accelerate the recovery period and reduce mortality. The intervention of geriatricians, with direct responsibility during the acute phase, has demonstrated an optimal benefit, as well as joint management by a geriatrician and an orthopedist. Recruiting motivated patients, able to walk with or without help before the fracture and regardless of their cognitive level, ensures successful intervention and reduced costs. The most effective interventions are those aimed at recovery of activities of daily living, with occupational therapy and muscle training. Correction of protein and vitamin intake also has a significant effect on the patient's progress in rehabilitation.

La fracture de hanche chez la personne âgée est associée avec une augmentation du handicap et de la mortalité. Les programmes d'intervention précoce accélèrent la période de récupération et réduisent la mortalité. L'intervention des gériatres, avec une responsabilité directe durant la phase aiguë, a démontré un bénéfice optimal, de même que la prise en charge conjointe par un gériatre et un orthopédiste. Le recrutement de patients motivés, capables de marcher avec ou sans aide avant la fracture et indépendamment de leur niveau cognitif, assure le succès de l'intervention et une réduction des coûts. Les interventions les plus efficaces sont celles qui visent une récupération des activités de la vie quotidienne, avec une thérapie occupationnelle et un entraînement musculaire. La correction de l'apport protéique et vitaminique a aussi un effet significatif sur l'évolution du patient en réhabilitation.

Influence of Fatigue Loading and Bone Turnover on Bone Strength and Pattern of Experimental Fractures of the Tibia in Mice.

Bone fragility depends on bone mass, structure, and material properties, including damage. The relationship between bone turnover, fatigue damage, and the pattern and location of fractures, however, remains poorly understood. We examined these factors and their integrated effects on fracture strength and patterns in tibia. Adult male mice received RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2×/week), or vehicle (Veh) 2 days prior to fatigue loading of one tibia by in vivo axial compression, with treatments continuing up to 28 more days. One day post fatigue, crack density was similarly increased in fatigued tibiae from all treatment groups. After 28 days, the RANKL group exhibited reduced bone mass and increased crack density, resulting in reduced bone strength, while the OPG-Fc group had greater bone mass and bone strength. Injury repair altered the pattern and location of fractures created by ex vivo destructive testing, with fractures occurring more proximally and obliquely relative to non-fatigued tibia. A similar pattern was observed in both non-fatigued and fatigued tibia of RANKL. In contrast, OPG-Fc prevented this fatigue-related shift in fracture pattern by maintaining fractures more distal and transverse. Correlation analysis showed that bone strength was predominantly determined by aBMD with minor contributions from structure and intrinsic strength as measured by nanoindentation and cracks density. In contrast, fracture location was predicted equally by aBMD, crack density and intrinsic modulus. The data suggest that not only bone strength but also the fracture pattern depends on previous damage and the effects of bone turnover on bone mass and structure. These observations may be relevant to further understand the mechanisms contributing to fracture pattern in long bone with different levels of bone remodeling, including atypical femur fracture.

Peri-implant bone adaptations to overloading in rat tibiae: experimental investigations and numerical predictions.

OBJECTIVES: (i) To assess the effects of mechanical overloading on implant integration in rat tibiae, and (ii) to numerically predict peri-implant bone adaptation. MATERIALS AND METHODS: Transcutaneous titanium implants were simultaneously placed into both tibiae of rats (n = 40). After 2 weeks of integration, the implants of the right tibiae were stimulated daily for 4 weeks with loads up to 5N (corresponding to peak equivalent strains of 3300 ± 500 µÎµ). The effects of stimulation were assessed by ex vivo mechanical tests and quantification of bone mineral density (BMD) in selected regions of interests (ROIs). Specimen-specific finite element models were generated and processed through an iterative algorithm to mimic bone adaptation. RESULTS: Bilateral implantation provoked an unstable integration that worsened when mild (2-4N) external loads were applied. In contrast, a stimulation at 5N tended to "counterbalance" the harmful effects of daily activity and, if applied to well-integrated specimens, significantly augmented the implants' resistance to failure (force: +73% P < 0.01, displacement: +50% P < 0.01 and energy: +153% P < 0.01). Specimen-specific numerical predictions were in close agreement with the experimental findings. Both local and overall BMD variations, as well as the implants' lateral stability, were predicted with small errors (0.14 gHA/cm3 and 0.64%, respectively). CONCLUSIONS: The rats' daily activity detrimentally affects implant integration. Conversely, external stimulations of large magnitudes counterbalance this effect and definitively improve integration. These changes can be predicted using the proposed numerical approach.

Influence of implant angulation and cyclic dislodging on the retentive force of two different overdenture attachments - an in vitro study.

OBJECTIVE: This in vitro study evaluated the influence of implant angulations on the retentive behavior of two overdenture attachments during cyclic dislodging. METHODS: Models simulating a two-implant overdenture situation were fabricated. They were divided into five groups based on their simulated implant angulations (Groups: 1 = 0°; 2 = 20°; 3 = 30°; 4 = 40°; and 5 = 60°; n = 90). Each group was further divided into two subgroups based on its attachment system (control attachment: LOCATOR(®) ; test attachment: SFI-Anchor(®) ) except for group 5 which had no LOCATOR(®) group. All models underwent 10,000 insertion-removal cycles in a wet environment. Mean retentive forces were recorded. ANOVA and linear regression models were used for statistical analyses, and the level of significance was at P < 0.05. RESULTS: The ANOVA model revealed an effect of dislodging cycles for both attachments (P = 0.0070). The linear regression model with repeated measures revealed a significant effect of angulation within the LOCATOR(®) groups (0° vs. 20°: P < 0.0001; 0° vs. 30°: P < 0.0001; 0° vs. 40°: P < 0.0001), but was insignificant within the SFI-Anchor(®) groups (0° vs. 20°: P = 0.544; 0° vs. 30°: P = 0.134; 0° vs. 40°: P = 0.254; 0° vs. 60°: P = 0.979). It further revealed a significant increase in the retentive force between the LOCATOR(®) and the SFI-Anchor(®) (20°: P = 0.041; 30°: P < 0.0001; 40°: P < 0.0001), although there was no significant difference between the attachments at 0° (P = 0.623). CONCLUSIONS: This study confirms that the retentive behavior of SFI-Anchor(®) is not influenced by implant axial inclination even at angulations of up to 60°. The SFI-Anchor(®) may therefore be particularly indicated for clinical situations with marked implant axial discrepancies.

Influence of different lubricants on the retentive force of LOCATOR(®) attachments - an in vitro pilot study.

OBJECTIVE: The aim of this in vitro pilot study was to evaluate the influence of an artificial saliva (AS) lubricant on the retentive force of a stud-type attachment (LOCATOR(®) ) for implant overdentures (IODs). METHODS: Twenty custom-made models simulating a two-IOD with parallel implant situation were fabricated using LOCATOR(®) attachments. The in vitro testing was carried out with an Instron(®) universal testing machine for a total of 10,000 insertion-removal cycles, for each model, in two different aqueous test mediums (Group 1: 0.9% sodium chloride solution (NaCl), n = 10; Group 2: AS, n = 10). Changes in the mean retentive force (F) were plotted against the cycle numbers #10, #100, #1000, #5000, and #10,000. Mixed regression models were applied for statistical analyses. RESULTS: A mixed regression (not considering interactions) predicted, compared to cycle #10, higher retentive forces at cycles #100 (P < 0.0001), #1000 (P = 0.017), similar forces at #5000 (P = 0.277), and lower forces at #10,000 (P = 0.012); there was no overall effect of the medium (P = 0.159). A second statistical model, employing the interaction term "cycle##medium", confirmed similarly the effect. Although the interaction term was significant at cycle #100 (p = 0.045), there was no significant difference between the two groups (P = 0.140). CONCLUSION: In this in vitro pilot experiment, there was no difference in mean retentive forces of the LOCATOR(®) attachments when tested with either 0.9% NaCl or a Glandosane(®) -like artificial saliva lubricant. A larger scale study may still confirm the superiority of either lubricant for quasiclinical bench experiments.

Effects of in vitro cyclic dislodging on retentive force and removal torque of three overdenture attachment systems.

BACKGROUND: Mandibular two-implant-retained overdentures were suggested as first choice of treatment for edentulous mandibles. However, wear of the attachments may reduce their retention and compromise long-term clinical success. AIM: The aim of this in vitro study was to compare the change in the retentive force and removal torque of three attachment systems during simulation of insertion-removal cycles. MATERIALS AND METHODS: Thirty custom-manufactured polyvinyl chloride blocks mimicking an implant-retained overdenture using Locator(®) -, spherical Dalbo(®) -PLUS - and SFI(®) -Bar-attachments on Straumann(®) RN Implants were fabricated. The samples were distributed equally into three groups which were subdivided into two sets of five blocks, one set with implants parallel to one another and the other with angulated implants (12°). All attachments were tightened to 35Ncm, while the fixation screws of the SFI(®) -Bar were tightened to 15Ncm. Testing was carried out with an Instron(®) universal testing machine for a total of 14,600 insertion-removal cycles in 0.9% sodium chloride solution. Retentive forces from cycles 10, 100, 1000, 5000, 10,000 and 14,600 were used for the analysis. The removal torque of the attachments was measured before and at the end of the study. Statistical analysis comprised three-way ANOVA and multiple linear regression models. RESULTS: Initially, all three attachment systems demonstrated increasing retentive forces. From cycle 5000 on, Locator(®) -attachments showed lower mean retentive forces than the Dalbo(®) -PLUS and SFI(®) -Bar-groups. The Dalbo(®) -PLUS and SFI(®) -Bar-attachments showed a steady yet not significant increase during the whole observation period. Implant-angulation had no significant influence on the retention forces. The final mean removal torques were significantly reduced. No complete failure was observed. CONCLUSIONS AND CLINICAL IMPLICATIONS: Within the limits of this in vitro study, it can be concluded that the investigated overdenture attachment systems are sufficiently resistant to wear. However, the Dalbo(®) -Plus- and SFI(®) -Bar- exhibit higher retentive capacities than the Locator(®) -attachment over time. The fixation screw of the SFI(®) -Bar may loosen during long-term use, but these observations might be less important if 1-year recall intervals are respected. An angulation of up to 12° between implants does not seem to have a significant effect on attachment wear.

Clinical and histological evaluation of postextraction platelet-rich fibrin socket filling: a prospective randomized controlled study.

OBJECTIVES: The aims were to investigate whether the use of platelet-rich fibrin membranes (PRF) for socket filling could improve microarchitecture and intrinsic bone tissue quality of the alveolar bone after premolar extraction and to assess the influence of the surgical procedure before implant placement. MATERIAL AND METHODS: Twenty-three patients requiring premolar extraction followed by implant placement were randomized to three groups: (1) simple extraction and socket filling with PRF, (2) extraction with mucosal flap and socket filling with PRF, and (3) controls with simple extraction without socket filling. Implant placement was performed at week 8, and a bone biopsy was obtained for histomorphometric analysis. RESULTS: Analysis by microcomputed tomography showed better bone healing with improvement of the microarchitecture (P < 0.05) in group 1. This treatment had also a significant effect (P < 0.05) on intrinsic bone tissue quality and preservation of the alveolar width. An invasive surgical procedure with a mucosal flap appeared to completely neutralize the advantages of the PRF. CONCLUSIONS: These results support the use of a minimally traumatic procedure for tooth extraction and socket filling with PRF to achieve preservation of hard tissue.

Implementation of the "loaded implant" model in the rat using a miniaturized setup--description of the method and first results.

OBJECTIVE: To miniaturize the "loaded implant" model to permit its application to small rodents. In this model, two titanium implants are placed 8 mm apart with their heads protruding from the skin and are forced together by a dedicated actuator. To assess the effect of (i) the post-implantation healing period and the duration of stimulation and (ii) the intratissular strain level on the microtomographical bone parameters BV/TV, Tb.N., Tb.Th. and BIC. MATERIALS AND METHODS: Implants, 1 × 8 mm, were machined, inserted into the tibiae of rats and activated. A total of 123 animals were used. In series 1, the implants were left to heal for 2/4 weeks and then loaded to generate intratissular strains of 1125 ± 5% µÎµ for 4/8 weeks. Series 2 had their implants loaded to 750, 1500 and 2250 ± 5% µÎµ, respectively. RESULTS: Bone to implant contact increased upon loading. In series 1, no difference was observed regarding the duration of healing or the stimulation period. In series 2, at 750 µÎµ, the bone parameters did not differ from baseline. At 1500 µÎµ, all four parameters increased. At 2250 µÎµ, three of four parameters decreased relative to 1500 µÎµ. CONCLUSIONS: (i) The loaded implant model can be miniaturized to the millimeter range; (ii) in the present model, implant activation beyond 4 weeks did not affect the bone parameters; (iii) mechanical stimulation increased bone to implant contact by up to 20%; (iv) the results obtained are consistent with the concept of an anabolic effect from 750 to 1500 µÎµ and deleterious effects at strains in the 2250 µÎµ range; and (v) strains at 2250 µÎµ did not lead to implant dis-integration.

Impact of moderate dietary protein restriction on glucose homeostasis in a model of estrogen deficiency.

The need to consume adequate dietary protein to preserve physical function during ageing is well recognized. However, the effect of protein intakes on glucose metabolism is still intensively debated. During age-related estrogen withdrawal at the time of the menopause, it is known that glucose homeostasis may be impaired but the influence of dietary protein levels in this context is unknown. The aim of the present study is to elucidate the individual and interactive effects of estrogen deficiency and suboptimal protein intake on glucose homeostasis in a preclinical model involving ovariectomy (OVX) and a 13 week period of a moderately reduced protein intake in 7 month-old ageing rats. To investigate mechanisms of action acting via the pancreas-liver-muscle axis, fasting circulating levels of insulin, glucagon, IGF-1, FGF21 and glycemia were measured. The hepatic lipid infiltration and the protein expression of GLUT4 in the gastrocnemius were analyzed. The gene expression of some hepatokines, myokines and lipid storage/oxidation related transcription factors were quantified in the liver and the gastrocnemius. We show that, regardless of the estrogen status, moderate dietary protein restriction increases fasting glycemia without modifying insulinemia, body weight gain and composition. This fasting hyperglycemia is associated with estrogen status-specific metabolic alterations in the muscle and liver. In estrogen-replete (SHAM) rats, GLUT4 was down-regulated in skeletal muscle while in estrogen-deficient (OVX) rats, hepatic stress-associated hyperglucagonemia and high serum FGF21 were observed. These findings highlight the importance of meeting dietary protein needs to avoid disturbances in glucose homeostasis in ageing female rats with or without estrogen withdrawal.

Material and nanomechanical properties of bone structural units of cortical and trabecular iliac bone tissues from untreated postmenopausal osteoporotic women.

The differences in bone nanomechanical properties between cortical (Ct) and trabecular (Tb) bone remain uncertain, whereas knowing the respective contribution of each compartment is critical to understand the origin of bone strength. Our purpose was to compare bone mechanical and intrinsic properties of Ct and Tb compartments, at the bone structural unit (BSU) level, in iliac bone taken from a homogeneous untreated human population. Among 60 PMMA-embedded transiliac bone biopsies from untreated postmenopausal osteoporotic women (64 ± 7 year-old), >2000 BSUs were analysed by nanoindentation in physiological wet conditions [indentation modulus (elasticity), hardness, dissipated energy], by Fourier transform infrared (FTIRM) and Raman microspectroscopy (mineral and organic characteristics), and by X-ray microradiography (degree of mineralization of bone, DMB). BSUs were categorized based on tissue age, osteonal (Ost) and interstitial (Int) tissues location and bone compartments (Ct and Tb). Indentation modulus was higher in Ct than in Tb BSUs, both in Ost and Int. dissipated energy was higher in Ct than Tb, in Int BSUs. Hardness was not different between Ct and Tb BSUs. In Ost or Int BSUs, mineral maturity (conversion of non-apatitic into apatitic phosphates) was higher in Ct than in Tb, as well as for collagen maturity (Ost). Mineral content assessed as mineral/matrix (FTIRM and Raman) or as DMB, was lower in Ct than in Tb. Crystallinity (FTIRM) was similar in BSUs from Ct and Tb, and slightly lower in Ct than in Tb when measured by Raman, indicating that the crystal size/perfection was quite similar between Ct and Tb BSUs. The differences found between Ost and Int tissues were much higher than the difference found between Ct and Tb for all those bone material properties. Multiple regression analysis showed that Indentation modulus and dissipated energy were mainly explained by mineral maturity in Ct and by collagen maturity in Tb, and hardness by mineral content in both Ct and Tb. In conclusion, in untreated human iliac bone, Ct and Tb BSUs exhibit different characteristics. Ct BSUs have higher indentation modulus, dissipated energy (Int), mineral and organic maturities than Tb BSUs, without difference in hardness. Although those differences are relatively small compared to those found between Ost and Int BSUs, they may influence bone strength at macroscale.

Mechanically Driven Counter-Regulation of Cortical Bone Formation in Response to Sclerostin-Neutralizing Antibodies.

Sclerostin (Scl) antibodies (Scl-Ab) potently stimulate bone formation, but these effects are transient. Whether the rapid inhibition of Scl-Ab anabolic effects is due to a loss of bone cells' capacity to form new bone or to a mechanostatic downregulation of Wnt signaling once bone strength exceeds stress remains unclear. We hypothesized that bone formation under Scl-Ab could be reactivated by increasing the dose of Scl-Ab and/or by adding mechanical stimuli, and investigated the molecular mechanisms involved in this response, in particular the role of periostin (Postn), a co-activator of the Wnt pathway in bone. For this purpose, C57Bl/6, Postn-/- and Postn+/+ mice were treated with vehicle or Scl-Ab (50 to 100 mg/kg/wk) for various durations and subsequently subjected to tibia axial compressive loading. In wild-type (WT) mice, Scl-Ab anabolic effects peaked between 2 and 4 weeks and declined thereafter, with no further increase in bone volume and strength between 7 and 10 weeks. Doubling the dose of Scl-Ab did not rescue the decline in bone formation. In contrast, mechanical stimulation was able to restore cortical bone formation concomitantly to Scl-Ab treatment at both doses. Several Wnt inhibitors, including Dkk1, Sost, and Twist1, were upregulated, whereas Postn was markedly downregulated by 2 to 4 weeks of Scl-Ab. Mechanical loading specifically upregulated Postn gene expression. In turn, Scl-Ab effects on cortical bone were more rapidly downregulated in Postn-/- mice. These results indicate that bone formation is not exhausted by Scl-Ab but inhibited by a mechanically driven downregulation of Wnt signaling. Hence, increasing mechanical loads restores bone formation on cortical surfaces, in parallel with Postn upregulation. © 2020 American Society for Bone and Mineral Research (ASBMR).

Bone matrix quality in paired iliac bone biopsies from postmenopausal women treated for 12 months with strontium ranelate or alendronate.

Bone quality is altered mainly by osteoporosis, which is treated with modulators of bone quality. Knowledge of their mechanisms of action is crucial to understand their effects on bone quality. The goal of our study was to compare the action of alendronate (ALN) and strontium ranelate (SrRan) on the determinants of bone quality. The investigation was performed on over 60 paired human iliac biopsies. Paired samples correspond to biopsies obtained from the same patient, one before treatment (baseline) and one after 12 months of treatment, in postmenopausal women with osteoporosis. Vibrational spectroscopy (Raman and FTIRM) and nanoindentation were used to evaluate the effect of both drugs on bone quality at the ultrastructural level. Outcomes measured by vibrational spectroscopy and nanoindentation are sensitive to bone age. New bone packets are distinguished from old bone packets. Thus, the effect of bone age is distinguished from the treatment effect. Both drugs modify the mineral and organic composition in new and old bone in different fashions after 12 months of administration. The new bone formed during ALN administration is characterized by an increased mineral content, carbonation and apatite crystal size/perfection compared to baseline. Post-translational modifications of collagen are observed through an increase in the hydroxyproline/proline ratio in new bone. The proteoglycan content is also increased in new bone. SrRan directly modulates bone quality through its physicochemical actions, independent of an effect on bone remodeling. Strontium cations are captured by the hydrated layer of the mineral matrix. The mineral matrix formed during SrRan administration has a lower carbonate content and crystallinity after 12 months than at baseline. Strontium might create bonds (crosslinks) with collagen and noncollagenous proteins in new and old bone. The nanomechanical properties of bone were not modified with either ALN or SrRan, probably due to the short duration of administration. Our results show that ALN and SrRan have differential effects on bone quality in relation to their mechanism of action.

Effects of transgenic Pit-1 overexpression on calcium phosphate and bone metabolism.

The type III inorganic phosphate (Pi) transporter Pit-1 was previously found to be preferentially expressed in developing long bones. Several studies also described a regulation of its expression in cultured bone cells by osteotropic factors, suggesting a role of this transporter in bone metabolism. In the present study, we investigated the effects of the transgenic overexpression of Pit-1 in Wistar male rats on calcium phosphate and bone metabolism. A threefold increase and doubling of Pi transport activity were recorded in primary cultured osteoblastic cells derived from calvaria of two transgenic (Tg) lines compared with wild-type littermates (WT), respectively. Skeletal development was not affected by the transgene, and bone mass, analyzed by DXA, was slightly decreased in Tg compared with WT. Enhanced Pi uptake in calvaria-derived osteoblasts from Pit-1 Tg was associated with a significantly decreased expression of alkaline phosphatase activity and a normal deposition and calcification of the collagenous matrix. In 4-month-old adult Tg rats, serum Pi and renal Pi transport were increased compared with WT. The decrease of serum Ca concentration was associated with increased serum parathyroid hormone levels. Variations in serum Pi in Pit-1 Tg rats were negatively correlated with serum fibroblast growth factor-23, whereas 1,25-dihydroxyvitamin D(3) was not affected by Pit-1 overexpression. In conclusion, transgenic Pit-1 overexpression in rats affected bone and calcium phosphate metabolism. It also decreased alkaline phosphatase activity in osteoblasts without influencing bone matrix mineralization as well as skeletal development.

Sclerostin antibody reduces long bone fractures in the oim/oim model of osteogenesis imperfecta.

Osteogenesis imperfecta type III (OI) is a serious genetic condition with poor bone quality and a high fracture rate in children. In a previous study, it was shown that a monoclonal antibody neutralizing sclerostin (Scl-Ab) increases strength and vertebral bone mass while reducing the number of axial fractures in oim/oim, a mouse model of OI type III. Here, we analyze the impact of Scl-Ab on long bones in OI mice. After 9 weeks of treatment, Scl-Ab significantly reduced long bone fractures (3.6 ±â€¯0.3 versus 2.1 ±â€¯0.8 per mouse, p < 0.001). In addition, the cortical thickness of the tibial midshaft was increased (+42%, p < 0.001), as well as BMD (+28%, p < 0.001), ultimate load (+86%, p < 0.05), plastic energy (+184%; p < 0.05) and stiffness (+172%; p < 0.01) in OI Scl-Ab mice compared to OI vehicle controls. Similar effects of Scl-Ab were observed in Wild type (Wt) mice. The plastic energy, which reflects the fragility of the tissue, was lower in the OI than in the Wt and significantly improved with the Scl-Ab treatment. At the tissue level by nanoindentation, Scl-Ab slightly increased the elastic modulus in bones of both OI and Wt, while moderately increasing tissue hardness (+13% compared to the vehicle; p < 0.05) in Wt bones, but not in OI bones. Although it did not change the properties of the OI bone matrix material, Scl-Ab reduced the fracture rate of the long bones by improving its bone mass, density, geometry, and biomechanical strength. These results suggest that Scl-Ab can reduce long-bone fractures in patients with OI.

Bone reactions to controlled loading of endosseous implants: a pilot study.

OBJECTIVES: To validate an experimental setup designed to apply load onto bone tissue using osseointegrated implants in a rabbit model. Specifically, (1) to design an apparatus capable of generating controlled forces, (2) to assess implant placement, maintenance and loading and (3) to evaluate outcome variables using three radiological methods. MATERIAL AND METHODS: New Zealand White rabbits were used. Two dental implants were inserted 15-18 mm apart in the animals' tibiae. After 3 months of healing, the implants were loaded normal to their long axes using a pneumatically activated device. A 15 min load regimen at 1 Hz was applied 5 days per week. Every week the applied load was increased by 5 N up to week 8 and by 10 N up to 100 N by week 14. Groups of animals (n=3) were sacrificed at load levels 25, 50 and 100 N. One unloaded controlateral implant in each group provided the baseline data. The rabbits were computer tomography (CT) scanned and radiographed using conventional frames every 4-5 weeks. After sacrifice, a volume of interest (VOI) located in the inter-implant zones and a VOI set as a ring surrounding the distal implant were analyzed using micro computer tomography (microCT). RESULTS: A variety of osseous responses was observed, ranging from minor alterations to significant increases in porosity and lamelling of the cortical layer. microCT data of the inter-implant VOI demonstrated an initial increase in total volume (upto 50 N) followed by stabilization. Concomitantly, bone volumetric density first decreased and then augmented until the end of the experiment. This phenomenon was not observed in the peri-implant VOI, for which volumetric density augmented from the beginning to the end of the experiment. CONCLUSIONS: 1. In future trials the loading devices must be constructed so as to sustain heavy cyclic loads over prolonged periods. 2. When properly handled, rabbits are cooperative animals in this application. In a third of the sites, signs of inflammation were observed. 3. In the inter-implant VOI, the cortical bone tended to react in two phases: first, as an increase in porosity and lamelling and second, as an augmentation of bone volumetric density. The peri-implant VOI adapted only by augmenting volumetric density.

Different responsiveness of alveolar and tibial bone to bone loss stimuli.

UNLABELLED: Mandibular and systemic bone loss are poorly associated. We compared the effect of isocaloric protein undernutrition and/or ovariectomy on BMD and microstructure of mandibular alveolar and proximal tibia sites in adult rats. Mandibular bone was significantly less affected. INTRODUCTION: Whether mandibular bone and axial or peripheral skeleton respond similarly to systemic bone loss remains a subject of controversy. We have previously shown that mechanical loading during mastication influences bone mass and architecture of the mandibular alveolar bone. Isocaloric protein undernutrition and ovariectomy are known to cause bone loss and deterioration of bone microarchitecture at various axial and peripheral skeletal sites. We studied how the mandible, which is subjected to heavy, abrupt, and intermittent forces during mastication, responds to low-protein intake and/or ovariectomy and compared this response to that of the proximal tibia in adult rats. MATERIALS AND METHODS: Forty-four 6-month-old female Sprague-Dawley rats underwent transabdominal ovariectomy (OVX; n=22) or sham operation (n=22) and were pair-fed isocaloric diets containing either 15% or 2.5% casein (sham 15%, n=11; sham 2.5%, n=11; OVX 15%, n=11; and OVX 2.5%, n=11) for 16 weeks. BMD and bone microarchitecture parameters (e.g., bone volume fraction [BV/TV] and trabecular thickness and number) of the mandible and the proximal tibia were measured at the end of the experiment using DXA and microCT. RESULTS: Mandibular alveolar bone was negatively influenced by both protein undernutrition and OVX, but to a significantly lesser extent than the proximal tibia. In sham-operated animals, low-protein intake led to a 17.3% reduction of BV/TV in the mandible and 84.6% in the tibia (p<0.001). In normal protein diet-fed animals, OVX led to a reduction of BV/TV of 4.9% in the mandible but 82% in the tibia (p<0.001). In the mandible, protein undernutrition resulted in thinner trabeculae (p<0.05), whereas OVX led to a reduction of trabecular number (p<0.05). CONCLUSIONS: Mandibular alveolar bone was found to be less sensitive to either protein undernutrition or OVX than the proximal tibia spongiosa. We hypothesize that the mechanical loading of the alveolar process during mastication may protect the alveolar bone from the detrimental effects observed in other skeletal sites, such as the proximal tibia. Morphological and embryological differences between the two skeletal sites might also play a role.

Defective implant osseointegration under protein undernutrition: prevention by PTH or pamidronate.

UNLABELLED: Protein deficiency is associated with impaired titanium osseointegration. We studied whether systemic treatment with PTH or pamidronate could influence the resistance to pull-out of titanium rods implanted into rats proximal tibia under normal and isocaloric low protein intake. PTH or pamidronate prevented the deleterious effects of protein undernutrition on bone microarchitecture close to the implant and on mechanical fixation. PTH even significantly improved implant osseointegration. INTRODUCTION: Protein deficiency is highly prevalent among elderly patients hospitalized in orthopedic wards. Reduced protein intake impairs titanium osseointegration in rats. Whether stimulator of bone formation or inhibitor of bone resorption could improve implant osseointegration under protein deprivation is not known. We studied the effects of systemic treatment with PTH or pamidronate on the resistance to pull-out of titanium rods implanted into rats proximal tibia under normal and isocaloric low protein intake. MATERIALS AND METHODS: We measured the resistance to pull-out 1-mm-diameter titanium rods implanted into the proximal tibias of 49 adult female rats receiving a normal or an isocaloric low protein diet. After 2 wk on either diet, the implants were inserted, and the rats received PTH(1-34), pamidronate or saline vehicle for 8 wk. The tibias were removed for microCT morphometry, followed by the evaluation of pull-out strength. RESULTS: Pull-out strength was lower in rats fed an isocaloric low protein diet compared with rats fed a normal protein intake (-29%). PTH and pamidronate significantly increased pull-out strength in animals fed a normal or a low protein diet, the effect of PTH being of higher magnitude. The PTH- or pamidronate-mediated increase in pull-out strength was associated with significant increases of relative bone volume, bone-to-implant contact, and trabecular thickness, whereas trabecular spacing was reduced, in the vicinity of the implants. CONCLUSIONS: We confirmed that isocaloric low protein intake impairs titanium implant osseointegration. PTH or pamidronate prevented the deleterious effects of protein undernutrition and even significantly improved the implant osseointegration. These results indicate that systemic administration of PTH or pamidronate could be considered for preventing uncemented arthroplasty loosening in protein undernourished patients.

Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength.

UNLABELLED: Beside its influence on determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality as evaluated by nanoindentation, increasing elastic modulus, hardness, and dissipated energy in vertebrae of rats treated for 104 wk with daily dose from 0 to 900 mg/kg. INTRODUCTION: We previously showed that strontium ranelate treatment improves the mechanical properties of the vertebral body and long bone midshaft in intact rats. The increased energy to failure obtained with strontium ranelate is essentially caused by an increase in plastic energy, suggesting that bone formed during treatment can withstand greater deformation before fracture. In the bone mineral phase, strontium is mainly located in the hydrated shell and could thus potentially influence intrinsic bone tissue quality. MATERIALS AND METHODS: To study whether strontium ranelate treatment could positively influence intrinsic bone tissue quality (elastic modulus, hardness, and dissipated energy), nanoindentation tests were performed at the level of trabecular nodes and cortex under physiological or dry conditions in vertebrae of rats treated for 104 wk with strontium ranelate at a daily dose of 0, 225, 450, or 900 mg/kg (n = 12 per group). Ex vivo microCT measurements and axial compression tests of adjacent vertebral bodies were also performed. Significance of difference was evaluated using ANOVA. RESULTS: In agreement with previous results, strontium ranelate (900 mg/kg/d) [corrected] increased versus controls in maximal load (+23%), total energy (+71%), and plastic energy (+143%). At the level of trabecular bone, strontium ranelate treatment resulted in a significant increase in elastic modulus (+15.1%, p < 0.01), hardness (+11.5%, p < 0.05), and dissipated energy (+16.2%, p < 0.001) versus controls in physiological, but not in dry, conditions. The effect was less pronounced in cortex. CONCLUSIONS: These results show for the first time a direct action of strontium ranelate on bone tissue quality. Beside its shown influence on classical determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality. This could contribute to the increase in bone strength and thus be involved in the reduction of fracture risk in postmenopausal osteoporotic patients treated with strontium ranelate.