Osteoporotic Environment Research Articles

Therapeutic Potential of Stearoyl-CoA Desaturase1 (SCD1) in Modulating the Effects of Fatty Acids on Osteoporosis.

Osteoporosis is a common skeletal disease, primarily associated with aging, that results from decreased bone density and bone volume. This reduction significantly increases the risk of fractures in osteoporosis patients compared to individuals with normal bone density. Additionally, the bone regeneration process in these patients is slow, making complete healing difficult. Along with the decline in bone volume and density, osteoporosis is characterized by an increase in marrow adipose tissue (MAT), which is fat within the bone. In this altered bone microenvironment, osteoblasts are influenced by various factors secreted by adipocytes. Notably, saturated fatty acids promote osteoclast activity, inhibit osteoblast differentiation, and induce apoptosis, further reducing osteoblast formation. In contrast, monounsaturated fatty acids inhibit osteoclast formation and mitigate the apoptosis caused by saturated fatty acids. Leveraging these properties, we aimed to investigate the effects of overexpressing stearoyl-CoA desaturase 1 (SCD1), an enzyme that converts saturated fatty acids into monounsaturated fatty acids, on osteogenic differentiation and bone regeneration in both in vivo and in vitro models. Through this novel approach, we seek to develop a stem cell-based therapeutic strategy that harnesses SCD1 to improve bone regeneration in the adipocyte-rich osteoporotic environment.

Carbonate Apatite Honeycomb Scaffold-Based Drug Delivery System for Repairing Osteoporotic Bone Defects.

Osteoporotic bone defects are difficult to repair in elderly patients. This study aimed to repair osteoporotic bone defects using a combination of bone tissue engineering (BTE) and drug delivery systems (DDS). Herein, honeycomb granules (HCGs) composed of carbonate apatite microspheres were fabricated as BTE scaffolds. Each HCG possesses hexagonal macropores and abundant interconnected micropores between the microspheres. Owing to these multiscale interconnected pores, HCGs can readily contain antibodies against sclerostin (Scl), which causes imbalances in bone homeostasis. Anti-Scl antibody-loaded HCGs (Scl-Ab-HCGs) regulate the release of Scl-Abs in response to the pH of the osteoporotic environment. In ovariectomized rabbit osteoporotic femurs, HCG monotherapy forms new bone with less osteocyte damage (fewer empty bone lacunae) and fewer osteoclasts than osteoporotic bone; however, it is insufficient to prevent receptor activator of nuclear factor-kappa B ligand (RANKL) overexpression. Consequently, HCG monotherapy restores bone quantity better than no treatment but not to normal levels. In contrast, new bone tissue formed by Scl-Ab-HCG-based DDS predominantly expresses osteocalcin rather than RANKL, similar to normal bone, and shows a similar osteocyte apoptosis level, bone quantity, and osteoclast number as normal bone. Thus, Scl-Ab-HCG-based DDS is a promising approach for osteoporotic bone defect repair.

Electrospunned nanofiber membranes of PTH-related peptide loaded biopolymers for osteoporotic bone defect repair

Despite the rapid development of the application of tissue engineering techniques in regenerative bone repair, the repair of severe pathologic bone defects, represented by osteoporotic bone defects, is still a huge challenge. Recent studies have identified local delivery of parathyroid hormone relative peptides (PTHrPs) as a novel pathway for bone repair as well, but how to load and locally release PTHrPs for good bone repair is a major obstacle. Here, a biopolymer of PLGA-PLL loaded with PTHrP1 is electrospunned into nanofiber membranes for guided bone regeneration. In vitro experiments show that PLGA-PLL synergized with PTHrP1 significantly promote osteogenic differentiation and angiogenesis, providing a favorable bone regeneration microenvironment. In vivo experiments show that the membrane recruits endogenous stem cells and promotes their ectopic osteogenic differentiation in an osteoporotic environment. Furthermore, the membrane can promote osteogenic differentiation and angiogenesis in situ and improve the local osteoporotic microenvironment, ultimately promoting the repair of bone defects. Therefore, present study provides a promising strategy for local delivery of PTH, which opens a new pathway for the treatment of osteoporotic bone defects.

Tobacco heating system has less impact on bone metabolism than cigarette smoke.

Cigarette smoking promotes osteoclast activity, thus increasing the risk of secondary osteoporosis, leading to osteoporosis-associated fracture and impaired fracture healing. Heated tobacco products (HTP) are considered potential reduced-risk alternatives to cigarettes. However, their impact on bone metabolism remains to be elucidated. We developed an in vitro model that mimics in vivo bone cell interactions to comparatively evaluate the effects of HTPs and cigarette smoke on bone cell functionality and viability. We generated an in vitro coculture system with SCP-1 and THP-1 cells (1:8 ratio) cultured on a decellularized Saos-2 matrix with an optimized coculture medium. We found that, following acute or chronic exposure, particulate matter extract from the aerosol of an HTP, the Tobacco Heating System (THS), was less harmful to the bone coculture system than reference cigarette (1R6F) smoke extract. In the fracture healing model, cultures exposed to the THS extract maintained similar osteoclast activity and calcium deposits as control cultures. Conversely, smoke extract exposure promoted osteoclast activity, resulting in an osteoporotic environment, whose formation could be prevented by bisphosphonate coadministration. Thus, THS is potentially less harmful than cigarette smoke to bone cell differentiation and bone mineralization - both being crucial aspects during the reparative phase of fracture healing.

Strontium-doping promotes bone bonding of titanium implants in osteoporotic microenvironment

Osteoporosis is a major challenge to oral implants, and this study focused on improving the osseointegration ability of titanium (Ti) implants in osteoporosis environment via surface modification, including doping of strontium ion and preparation of nanoscale surface feature. Our previous studies have shown that strontium (Sr) ions can enhance osteogenic activity. Therefore, we aimed to comprehensively evaluate the effect of hydrothermal treatment of Sr-doped titanium implant coating on bone-binding properties in the microenvironment of osteoporosis in this study. We fabricated Sr-doped nanocoating (AHT-Sr) onto the surface of titanium implants via hydrothermal reaction. The rough Sr-doping had good biological functions and could apparently promote osteogenic differentiation of osteoporotic bone marrow mesenchymal stem cells (OVX-BMSCs). Most importantly, AHT-Sr significantly promoted bone integration in the osteoporosis environment. This study provides an effective approach to implant surface modification for better osseointegration in an osteoporotic environment.

Ultrasound-mediated rapamycin delivery for promoting osseointegration of 3D printed prosthetic interfaces via autophagy regulation in osteoporosis

Osteoporosis-derived bone marrow mesenchymal stem cells (OP-BMSCs) have impaired cell function, low osteogenic activity, and potential osteoclast inducibility, resulting in insufficient osseointegration and increased risk of catastrophic postoperative complications after arthroplasty. The low autophagy activity of OP-BMSCs contributed to poor osseointegration, which could be regulated by the classical autophagic activator, rapamycin. Hence, it is of great significance to regulate autophagy by rapamycin to promote osseointegration at the three-dimensional (3D) printed prosthetic interfaces under osteoporotic environment. In this study, 3D printed porous titanium alloy prosthetic interfaces with bionic pore size and porosity were prepared and implanted into the distal femur of osteoporosis rabbits. Subsequently, a transdermal drug delivery device was used to deliver rapamycin to the interfaces implantation sites. Ultrasound-mediated rapamycin delivery could restore the declined cellular activities (including cell viability, proliferation, migration, and osteogenesis), as well as inhibit potential osteoclast-inducing capacity and adipogenic differentiation by upregulating the autophagy level of OP-BMSCs. Moreover, percutaneous ultrasound-mediated rapamycin delivery significantly improved bone ingrowth and osseointegration of prosthetic interfaces in osteoporotic environment. To conclude, this novel therapy combining 3D printed bionic prosthesis and percutaneous ultrasound-mediated rapamycin delivery can effectively promote prosthetic interfaces osseointegration by regulating autophagy after arthroplasty for patients with osteoporosis.

Engineering Multifunctional Hydrogel-Integrated 3D Printed Bioactive Prosthetic Interfaces for Osteoporotic Osseointegration.

3D printed porous titanium alloy implants is an advanced orthopedic material for joint replacement. However, the high risk of aseptic loosening and periprosthetic infection is difficult to avoid, and the declined autophagy of osteoporosis-derived bone marrow mesenchymal stem cells (OP-BMSCs) further severely impairs the osseointegration under the osteoporotic circumstance. It is thus becoming urgently significant to develop orthopedic materials with autophagy regulation and antibacterial bioactivity. In this regard, a novel class of multifunctional hydrogel-integrated 3D printed bioactive prosthetic interfaces is engineered for in situ osseointegration in osteoporosis. The hydrogel is fabricated from the dynamic crosslinking of synthetic polymers, natural polymers, and silver nanowires to deliver autophagy-regulated rapamycin. Therefore, the resultant soft material exhibits antibacterial ability, biocompatibility, degradability, conductive, self-healing, and stimuli-responsive abilities. In vitro experiments demonstrate that the hydrogel-integrated 3D printed bioactive prosthetic interfaces can restore the declined cellular activities of OP-BMSCs by upregulating the autophagy level and show excellent antibacterial activity against S. aureus and MRSA. More remarkably, the multifunctional 3D printed bioactive prosthetic interfaces significantly improve osseointegration and inhibit infection in osteoporotic environment in vivo. This study provides an efficient strategy to develop novel prosthetic interfaces to reduce complications after arthroplasty for patients with osteoporosis.

Conjunction of gallium doping and calcium silicate mediates osteoblastic and osteoclastic performances of tricalcium phosphate bioceramics

Gallium-containing biomaterials are considered promising for reconstructing osteoporotic bone defects, owing to the potent effect of gallium on restraining osteoclast activities. Nevertheless, the gallium-containing biomaterials were demonstrated to disturb the osteoblast activities. In this study, tricalcium phosphate (TCP) bioceramics were modified by gallium doping in conjunction with incorporation of calcium silicate (CS). The results indicated that the incorporation of CS promoted transition of β-TCP to α-TCP, and accelerated densification process, but did not improve the mechanical strength of bioceramics. The silicon released from the composite bioceramics diminished the inhibition effect of released gallium on osteoblast activities, and maintained its effect on restraining osteoclast activities. The TCP-based bioceramics doped with 2.5 mol% gallium and incorporated with 10 mol% CS are considered suitable for treating the bone defects in the osteoporotic environment.

Physiological testosterone replacement effects on male aged rats with orchiectomy-induced osteoporosis in advanced stage: a tomographic and biomechanical pilot study

Aim: This study aimed to evaluate the effect of physiological testosterone replacement on male aged rats with orchiectomy-induced osteoporosis in advanced stage. Methods: Thirty male rats (Rattus norvegicus albinus, Holtzman lineage) were randomly distributed into 3 groups (n = 10): 1-sham, 2-orchiectomy (OCX), 3-OCX + testosterone replacement (OCX + T). On day 0, a sham or orchiectomy surgery was performed according to the groups. Thirty and sixty days after surgeries, the animals from OCX + T group received testosterone intramuscularly, and the rats in all groups were euthanized on day 77. The femurs were removed for micro-CT scanning and biomechanical test. Results: Orchiectomy resulted in a marked trabecular bone damage (p < 0.05), which was not reversed with testosterone treatment (OCX + T group). The femoral strength was lower in orchiectomized animals (p < 0.05), while the bone strength in OCX + T group was similar to that observed in the sham animals (p > 0.05) and correlated to this parameter the deformation of rupture was smaller in OCX + T group. Conclusion: In conclusion, testosterone depletion induced by orchiectomy established an osteoporotic environment, mainly affecting the trabecular bone. Moreover, even though testosterone treatment did not enhance these variables, the hormonal replacement improved the femoral fracture strength and promoted beneficial effects on the biomechanical parameters compromised by castration in femoral bone.

Osteoporotic Conditions Influence the Activity of Adipose-Derived Stem Cells.

Estrogen deficiency decreases bone density and increases the risk of osteoporosis and fracture, thereby necessitating reconstruction of bone regeneration. As bone marrow mesenchymal stem cell (BMSCs) lose viability and differentiation potential under osteoporotic conditions, it is impossible to use autologous BMSCs for osteoporosis treatment. As an alternative, adipose-derived stem cells (ADSCs) may serve as the source of therapeutic cells. We evaluated the effects of osteoporosis on the functional characteristics of ADSCs. Osteoporosis was induced in ovariectomy (OVX) rat model, and the ADSCs from Sham and OVX groups were cultured and analyzed comparatively. As a result, the viability was higher for the ADSCs from Sham group than those from OVX group. The analysis of the paracrine potential of ADSCs revealed the elevated levels of inflammatory and cellular senescence factors in the ADSCs from OVX group. The ADSCs from OVX group had much higher differentiation potential into adipocytes than those from the Sham group. Osteoporotic environment had no effect on the osteogenic potential of ADSCs. Osteoporosis may reduce the activity and influence immune response of ADSCs by modulating paracrine action and adipogenic potential. These characteristics of ADSCs should be given consideration for therapeutic purpose.

Aged Osteoporotic Bone Marrow Stromal Cells Demonstrate Defective Recruitment, Mechanosensitivity, and Matrix Deposition

Bone formation requires the replenishment of the osteoblast from a progenitor or stem cell population, which must be recruited, expanded, and differentiated to ensure continued anabolism. How this occurs and whether it is altered in the osteoporotic environment is poorly understood. Furthermore, given that emerging treatments for osteoporosis are targeting this progenitor population, it is critical to determine the regenerative capacity of this cell type in the setting of osteoporosis. Human bone marrow stromal cells (hMSCs) from a cohort of aged osteoporotic patients were compared to MSCs isolated from healthy donors in terms of the ability to undergo recruitment and proliferation, and also respond to both the biophysical and biochemical cues that drive osteogenic matrix deposition. hMSCs isolated from healthy donors demonstrate good recruitment, mechanosensitivity, proliferation, and differentiation capacity. Contrastingly, hMSCs isolated from aged osteoporotic patients had significantly diminished regenerative potential. Interestingly, we demonstrated that osteoporotic hMSCs no longer responded to chemokine-directing recruitment and became desensitised to mechanical stimulation. The osteoporotic MSCs had a reduced proliferative potential and, importantly, they demonstrated an attenuated differentiation capability with reduced mineral and lipid formation. Moreover, during osteogenesis, despite minimal differences in the quantity of deposited collagen, the distribution of collagen was dramatically altered in osteoporosis, suggesting a potential defect in matrix quality. Taken together, this study has demonstrated that hMSCs isolated from aged osteoporotic patients demonstrate defective cell behaviour on multiple fronts, resulting in a significantly reduced regenerative potential, which must be considered during the development of new anabolic therapies that target this cell population.

In vitro and in vivo assessment of nanostructured porous biphasic calcium phosphate ceramics for promoting osteogenesis in an osteoporotic environment.

Treatment of bone defects in osteoporotic patients with bone substitutes is difficult, due to insufficient osseointegration. The development of appropriate biomaterials to solve the problem requires the assessment of the material performance in an osteoporotic environment, which is rarely investigated. Herein, nanostructured biphasic calcium phosphate (nBCP) ceramics were prepared via the incorporation of hydroxyapatite nanoparticles (HANPs) into porous biphasic CaP (BCP) substrates, leading to an increase of over 500% in the specific surface area. Primary osteoblasts harvested from osteoporotic rats were cultured on the nBCP ceramics, and it was found that the osteoblast functions, including proliferation, alkaline phosphatase activity, osteocalcin secretion and expression of osteogenic genes, were significantly enhanced compared with osteoblasts grown on non-nanostructured BCP ceramics. To further assess the osteoinduction ability, the ceramics were implanted in the femur of osteoporotic rats. Compared to the rats implanted with non-nanostructured BCP ceramics, a higher amount of mechanically matured bone was newly formed in the rats with nBCP ceramics after 6 weeks of implantation. Such enhanced osteoinduction ability of the nBCP ceramics may be due to the incorporated HANPs, as well as the nanostructured topography induced by the HANPs. These results indicate good in vitro and in vivo osteoinductivity of the nBCP ceramics in an osteoporotic environment and offer potential benefits for treating bone defects in osteoporotic patients.

Do osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration? Investigating the efficacy of BMP-7 and zoledronate treatment of diaphyseal fractures in an open fracture osteoporotic rat model

SummaryOsteoporotic fractures may pose a challenge for skeletal regeneration. This study investigates if pharmaceutical interventions such as bone morphogenetic protein 7 (BMP-7) alone or in combination with Zoledronate have equivalent efficacy in osteoporotic bone? Our findings suggest they do and that an osteoporotic bone environment may increase sensitivity to BMP-7.IntroductionOsteoporosis is thought to contribute to delayed or impaired bone healing. Bone morphogenetic protein 7 (BMP-7) alone or synergistically combined with zoledronate (ZA) has proven effective in augmenting the regenerative response in healthy young male rats. Yet their comparative efficacy in an osteoporotic bone environment is unknown. Our study aimed to answer the following questions using the ovariectomized (OVX) rat model of osteoporosis: Do osteoporotic fractures pose a greater challenge for skeletal regeneration? Are interventions with BMP-7-alone or combined with ZA of equivalent efficacy in osteoporotic bone?MethodsSham operations (n = 33) or ovariectomies (n = 34) were performed in 12-week-old female Sprague-Dawley rats. Mid-diaphyseal open femoral osteotomies were created at 24 weeks of age and the rats allocated to either (i) untreated, (ii) BMP-7-only or (iii) BMP-7 + ZA treatment groups. At 6 weeks post-osteotomy, fracture healing was evaluated by radiography, μCT and 3-point bending mechanical tests.ResultsCumulatively, radiological, micro-structural and mechanical measures were equivalent in both healthy and osteoporotic environments. A reduced response to BMP-7-alone was observed in healthy rats that may be age/gender- or protocol/fracture-model dependent. Conversely, the BMP-7-only treated OVX group attained 100 % union in addition to significantly increased measures of mineralized bone volume, total callus volume, peak force and absorbed energy relative to untreated OVX fractures.ConclusionsOur findings refute the hypothesis that osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration. Furthermore, our results suggest that an oestrogen-deficient environment may in fact cause an increased sensitivity to BMP-7.

Vertebroplasty using bisphosphonate-loaded calcium phosphate cement in a standardized vertebral body bone defect in an osteoporotic sheep model

In the context of bone regeneration in an osteoporotic environment, the present study describes the development of an approach based on the use of calcium phosphate (CaP) bone substitutes that can promote new bone formation and locally deliver in situ bisphosphonate (BP) directly at the implantation site. The formulation of a CaP material has been optimized by designing an injectable apatitic cement that (i) hardens in situ despite the presence of BP and (ii) provides immediate mechanical properties adapted to clinical applications in an osteoporotic environment. We developed a large animal model for simulating lumbar vertebroplasty through a two-level lateral corpectomy on L3 and L4 vertebrae presenting a standardized osteopenic bone defect that was filled with cements. Both 2-D and 3-D analysis of microarchitectural parameters demonstrated that implantation of BP-loaded cement in such vertebral defects positively influenced the microarchitecture of the adjacent trabecular bone. This biological effect was dependent on the distance from the implant, emphasizing the in situ effect of the BP and its release from the cement. As a drug device combination, this BP-containing apatitic cement shows good promise as a local approach for the prevention of osteoporotic vertebral fractures through percutaneous vertebroplasty procedures.

The Effect of Pilot Hole Size on the Insertion Torque and Pullout Strength of Self-Tapping Cortical Bone Screws in Osteoporotic Bone

All surgical screws can experience failure if the torsional, tensile, and flexion loads exerted on the screws are excessively high. The use of self-tapping screws (STS) results in higher insertion torques (IT) as these screws cut their own threads in the pilot hole drilled in the bone. In this study, the torque for inserting the STS into an osteoporotic bone block for different pilot hole sizes (PHS) was measured and the pullout strength (PS) for extraction of the screws was determined for different depths of insertion, 0 mm, 1 mm, and 2 mm beyond the far cortex. Seventy-two Synthes stainless steel STS (40 mm length and 3.5 mm diameter) were inserted into pilot holes of sizes 2.55 (A: 73% OD), 2.50 (B: 71.5%), 2.45 (C: 70%), and 2.8 mm (D: 80%). Using a digital torque screwdriver, screws were inserted to 0 mm, 1 mm or 2 mm past the far cortex. Pullout tests were conducted with an Instron materials testing system. Analysis of variance and Student-Neuman-Keuls tests were performed to determine the effect of DOI and PHS on the loading energy, PS, and IT. Results demonstrated that IT of the screws inserted into pilot holes A, B, and C were higher than those in D. It was also observed that PS and loading energy for 1 mm and 2 mm penetration past the far cortex were higher than those for 0 mm regardless of PHS. This study also found that an increase in PHS to 2.8 mm will reduce IT but will also reduce the PS relative to a PHS of 2.5 mm, the current standard for 3.5 mm screws. The results of previously published studies regarding the effect of pilot hole size on PS in healthy cortical bone cannot be applied to the osteoporotic environment. The findings presented in this research support using PHS no larger than 71.5% of the screw outer diameter (i.e., pilot hole size of 2.5 mm for 3.5 mm screws) and inserting screws at least 2 mm beyond the far cortex to maximize PS and minimize iatrogenic damage in osteoporotic bone.