A Curious Case of Two-Photon Absorption in n-Helicene and n-Phenylene, n=6-10: Why n=7 is Different?

n-Helicenes and n-Phenylenes are interesting examples of twisted molecules, where although the atoms are connected through conjugated π ${\pi }$ -bonds, the π ${\pi }$ -conjugation is largely hindered by the twisted nature of the bonds. Such structures provide a unique opportunity to study the effect of twisted π ${\pi }$ -system on non-linear optical properties. In this work, we studied the two-photon absorption in donor-acceptor substituted n-helicenes and n-phenylenes employing the state-of-the-art RI-CC2 method and reported a unique feature we observed in n=7 systems. We found that both 7-helicene and 7-phenylene systems exhibit largest two-photon absorption than other members in their respective classes. Furthermore, using generalized few-state model, we provided a detailed microscopic mechanism of this unique observation involving participation of different transition dipole moment vectors and their relative orientations.

Why does the orientation of azulene affect the two-photon activity of a porphyrinoid-azulene system?

Attaching a dipolar molecule in a symmetric system induces a major change in the electronic structure, which may be reflected as the enhancement of the optical and charge-transfer properties of the combined system as compared to the pristine ones. Furthermore, the orientation of the dipolar molecule may also affect the said properties. This idea is explored in this work by taking porphyrinoid molecules as the pristine systems. We attached azulene, a dipolar molecule, at various positions of five porphyrinoid cores and studied the effect on charge-transfer and one- and two-photon absorption properties using the state-of-the-art RICC2 method. The attachment of azulene produces two major effects - firstly it introduces asymmetry in the system and, secondly, being dipolar, it makes the resultant molecule dipolar/quadrupolar. Porphyrin, N-confused porphyrin, sub-porphyrin, sapphyrin, and hexaphyrin are used as core porphyrinoid systems. The change in charge-transfer has been studied using the orbital analysis and charge-transfer distance parameter for the first five singlet states of the systems. The effect of orientation of azulene on the said properties is also explored. The insights gained from our observations are explored further at the dipole and transition dipole moment levels using a three-state model.

Injectable Bone Cement Reinforced with Gold Nanodots Decorated rGO-Hydroxyapatite Nanocomposites, Augment Bone Regeneration.

Interest in the development of new generation injectable bone cements having appropriate mechanical properties, biodegradability, and bioactivity has been rekindled with the advent of nanoscience. Injectable bone cements made with calcium sulfate (CS) are of significant interest, owing to its compatibility and optimal self-setting property. Its rapid resorption rate, lack of bioactivity, and poor mechanical strength serve as a deterrent for its wide application. Herein, a significantly improved CS-based injectable bone cement (modified calcium sulfate termed as CSmod ), reinforced with various concentrations (0-15%) of a conductive nanocomposite containing gold nanodots and nanohydroxyapatite decorated reduced graphene oxide (rGO) sheets (AuHp@rGO), and functionalized with vancomycin, is presented. The piezo-responsive cement exhibits favorable injectability and setting times, along with improved mechanical properties. The antimicrobial, osteoinductive, and osteoconductive properties of the CSmod cement are confirmed using appropriate in vitro studies. There is an upregulation of the paracrine signaling mediated crosstalk between mesenchymal stem cells and human umbilical vein endothelial cells seeded on these cements. The ability of CSmod to induce endothelial cell recruitment and augment bone regeneration is evidenced in relevant rat models. The results imply that the multipronged activity exhibited by the novel-CSmod cement would be beneficial for bone repair.

Efficient Nitric Oxide Scavenging by Urea-Functionalized Push-Pull Chromophore Modulates NO-Mediated Diseases.

The excess nitric oxide (NO) produced in the body in response to bacterial/proinflammatory stimuli is responsible for several pathological conditions. The current approaches that target the production of excess NO, either through the inhibition of nitric oxide synthase enzyme or its downstream mediators have been clinically unsuccessful. With an aim to regulate the excess NO, urea-functionalized push-pull chromophores containing 1,1,4,4-tetracyanobuta-1,3-dienes (TCBD) or expanded TCBD (eTCBD) were developed as NO scavengers. The NMR mechanistic studies revealed that upon NO binding, these molecules are converted to uncommon stable NONOates. The unique emissive property of Urea-eTCBD enables its application in vitro, as a NO-sensor. Furthermore, the cytocompatible Urea-eTCBD, rapidly inactivated the NO released from LPS-activated cells. The therapeutic efficacy of the molecule in modulating NO-mediated pathological condition was confirmed using a carrageenan-induced inflammatory paw model and a corneal injury model. While the results confirm the advantages of scavenging the excess NO to address a multitude of NO-mediated diseases, the promising sensing and bioactivity of Urea-eTCBD can motivate further exploration of such molecules in allied areas of research.

Post-Implantation Stiffening by a Bioinspired, Double-Network, Self-Healing Hydrogel Facilitates Minimally Invasive Cell Delivery for Cartilage Regeneration.

Injectable hydrogels have demonstrated advantages in cartilage repair by enabling the delivery of cells through a minimally invasive approach. However, several injectable hydrogels suffer from rapid degradation and low mechanical strength. Moreover, higher mechanical stiffness in hydrogels can have a detrimental effect on post-implantation cell viability. To address these challenges, we developed an in situ forming bioinspired double network hydrogel (BDNH) that exhibits temperature-dependent stiffening after implantation. The BDNH mimics the microarchitecture of aggrecan, with hyaluronic acid-conjugated poly(N-isopropylacrylamide) providing rigidity and Schiff base crosslinked polymers serving as the ductile counterpart. BDNHs exhibited self-healing property and enhanced stiffness at physiological temperature. Excellent cell viability, long time cell proliferation, and cartilage specific matrix production were observed in the chondrocytes cultured in the BDNH hydrogel. Evidence of cartilage regeneration in a rabbit cartilage defect model using chondrocyte-laden BDNH has suggested it to be a potential candidate for cartilage tissue engineering.

Chromophore Planarity, -BH Bridge Effect, and Two-Photon Activity: Bi- and Ter-Phenyl Derivatives as a Case Study.

In this work, we have employed electronic structure theories to explore the effect of the planarity of the chromophore on the two-photon absorption properties of bi- and ter-phenyl systems. To that end, we have considered 11 bi- and 7 ter-phenyl-based chromophores presenting a donor-π-acceptor architecture. In some cases, the planarity has been enforced by bridging the rings at ortho-positions by -CH2 and/or -BH, -O, -S, and -NH moieties. The results presented herein demonstrate that in bi- and ter-phenyl systems, the planarity achieved via a -CH2 bridge increases the 2PA activity. However, the introduction of a bridge with the -BH moiety perturbs the electronic structure to a large extent, thus diminishing the two-photon transition strength to the lowest electronic excited state. As far as two-photon absorption activity is concerned, this work hints toward avoiding -BH bridge(s) to enforce planarity in bi- and ter-phenyl systems; however, one may use -CH2 bridge(s) to achieve the enhancement of the property in question. All of these conclusions have been supported by in-depth analyses based on generalized few-state models.

Designing a Propellane-based Nonlinear Optically Active System Absorbing in Three Different Wavelength Regions.

The aim of this work is to demonstrate the possibility of using propellane in designing a molecule that can absorb in three different wavelength regions and their nonlinear optical (NLO) activity can be fine-tuned by varying the three wings. We considered 22 tailor-made propellane derivatives consisting of phenyl, naphthyl, and biphenyl wings for this purpose. Using the state-of-the-art linear and quadratic response methods within TD-DFT and RI-CC2 theories and a suitable generalized few-state model that quantifies the effect of orientation of different transition moments on NLO properties, we discussed how and why the linear and nonlinear optical activity of propellane vary when the three wings are assembled successively to construct a full-propellane.

First-order hyperpolarizabilities of propellanes: elucidating structure-property relationships.

Following recent experimental work demonstrating strong nonlinear optical properties, namely second harmonic generation of light, in crystals composed of 16,20-dinitro-(3,4,8,9)-dibenzo-2,7-dioxa-5,10-diaza[4.4.4]propellane molecules [A. Miniewicz, S. Bartkiewicz, E. Wojaczynska, T. Galica, R. Zalesny and R. Jakubas, J. Mater. Chem. C, 2019, 7, 1255-1262] in this paper we aim to investigate "structure-property" relationships for a series of 16 propellanes presenting a wide palette of substituents with varying electron-accepting/donating capabilities. To that end, we use electronic- and vibrational-structure theories and a recently developed generalized few-state model combined with a range-separated CAM-B3LYP functional to analyze electronic and vibrational contributions to the first hyperpolarizability for the whole series of molecules. The variations in computed properties are large among the studied set of substituents and can reach an order of magnitude. It has been demonstrated that the maximum values of frequency-independent first hyperpolarizability are expected for strong electron-accepting NO2 substituents, but only at the preferred position with respect to the electronegative oxygen atom in the 1,4-oxazine moiety. This holds for electronic as well as vibrational counterparts.

Optical modulator based on a silicon-ITO grating embedded rib structure with a tunable group delay.

An optical modulator based on an engineered silicon-indium tin oxide (Si-ITO) structure is proposed with a tunable group delay. A large group delay is reported by slowing down the light in a Si-ITO grating embedded rib structure. Optical modulation and a tunable group delay are realized by utilizing the electrically tunable permittivity of ITO in the engineered waveguide. The extinction ratio over 8 dB for a 10 µm long device and the modulation efficiency around 12 V-µm are reported for a wide wavelength from 1530 to 1570 nm. The resulting modulation efficiency and the extinction ratio show a significant improvement as compared to conventional modulators based on rib waveguides. We also report around 82 psec electrical tuning in the group delay for a wide wavelength range. This concept is promising in view of realizing tunable delay lines, along with slow light modulators with a reduced device footprint and low energy dissipation.

Optical switch with ultra high extinction ratio using electrically controlled metal diffusion.

An optical switch with ultra high extinction ratio is proposed. Optical switching is realized using the resistive switching effect through the lateral coupling between the input nanophotonic waveguide and output waveguide at a wavelength of 1550 nm. The coupled waveguide system is engineered to increase the number of mode beats in a unit length of the device. An increase in the number of mode beats and controlled diffusion of metal ions through a thin dielectric layer with an applied electric field is responsible for a high optical extinction ratio of 27 dB for a 20 µm long device. Compared to electrical control by plasma dispersion in silicon, the resistive switching effect enables a reduction in the coupling length and an increase in the waveguide absorption, leading to an almost 100 times higher extinction ratio. The proposed compact on-chip silicon-based nanophotonic resistive device is a potential candidate for a large-scale integrated photonic circuit for applications in optical switching, modulation, memory, and computation.

Human Relevance of Preclinical Studies on the Skeletal Impact of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Inflammatory bowel disease (IBD) is a relapsing chronic idiopathic inflammatory condition. The increased risks of fractures in the spine and decreased BMD at all weight-bearing skeletal sites have been reported in IBD patients. The understanding of the mechanisms of IBD-induced bone loss is far from complete. Appropriate animal models are a prerequisite for studying IBD-induced bone loss, which prompted us to undertake quantitative meta-analyses by pooling data from the available IBD models that assessed various bone parameters. Sufficient data for meta-analysis are obtained from chemically- but not genetically induced models. Among the chemically induced models, only the effects of dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) on bone parameters have been reported. Meta-analysis showed that both DSS (Hedge's g = 2.124, p = 0.001) and TNBS (Hedge's g = 6.292, p = 0.000) increased inflammatory disease severity. In pooled analysis, bone volumes in femur (Hedge's g = - 3.42, p = 0.000) and tibia (Hedge's g = - 2.49, p = 0.000) showed significant losses upon DSS administration. Similarly, bone formation rate was significantly reduced upon IBD induction (Hedge's g = - 3.495, p = 0.006). Besides, cortical thickness was reduced and trabecular microstructure deteriorated by IBD induction. Insufficient data precluded us from determining the effect of IBD on bone strength and calciotropic hormones, as well as the impact of proinflammatory cytokines on bone turnover. This meta-analysis showed that IBD induction in rodents causes significant bone loss. Impaired osteoblast function appears to be the cause of this impact.

Engineered nanophotonic waveguide with ultra-low dispersion.

A silicon-based engineered hybrid plasmonic waveguide with ultra-low dispersion is proposed. The ridge-shaped structure of the nanophotonic waveguide enables nano-scale confinement with electrically tunable characteristics using the plasma dispersion effect in silicon. The waveguide exhibits ultra-low dispersion of $1.28\;{{\rm ps}^2}/{\rm m}$ at telecommunication wavelength (1550 nm) in C band together with dual flatband dispersion over a wavelength range of 370 nm. The hybrid plasmonic mode is made to be confined in 15 nm thick ${{\rm SiO}_2}$ with a propagation loss of 15.3 dB/mm utilizing the engineered ridge structure comprising Si, ${{\rm SiO}_2}$, and gold. In addition, the proposed waveguide shows six zero-dispersion wavelengths. The imaginary and real parts of the effective refractive index of the guided hybrid plasmonic mode are reported to be tunable with the applied voltage. The reported numerical results can pave the way for achieving intensity modulators and other electrically tunable devices at telecommunication wavelengths. The ultra-low dispersion and electrical tuning make this nanophotonic waveguide an absolute contender for applications including efficient nonlinear signal processing such as wide wavelength conversion based on four-wave mixing, supercontinuum generation, and other nanoscale integrated photonic devices.

COVID-19 and Gut Microbiota: A Potential Connection.

Currently, world is facing a global outbreak causing a pandemic threat known as COVID-19. This infectious disease is triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Gut microbiota harbours multi species community with a strong impact on host immune homeostasis. However, our knowledge about this gut microbiota and its symbiotic relationship with immune activation in association with SARS-CoV-2 is limited. Unbalanced bacterial flora with too many opportunistic infections can shift immune system towards a cascade of inflammatory responses leading to multi organ damage. This review will highlight immune-regulation via various mechanisms in SARS-CoV-2 infection. Diet has an unbelievable influence on gut microbiome that allows a new state of homeostasis to be reached through timing, frequency and duration of intake. This review article focuses on gut, lung microbiota and immunomodulation with specific attention on immune activation by gut microbiota.

mTORC2 modulates the amplitude and duration of GFAT1 Ser-243 phosphorylation to maintain flux through the hexosamine pathway during starvation.

The mechanistic target of rapamycin (mTOR) controls metabolic pathways in response to nutrients. Recently, we have shown that mTOR complex 2 (mTORC2) modulates the hexosamine biosynthetic pathway (HBP) by promoting the expression of the key enzyme of the HBP, glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1). Here, we found that GFAT1 Ser-243 phosphorylation is also modulated in an mTORC2-dependent manner. In response to glutamine limitation, active mTORC2 prolongs the duration of Ser-243 phosphorylation, albeit at lower amplitude. Blocking glycolysis using 2-deoxyglucose robustly enhances Ser-243 phosphorylation, correlating with heightened mTORC2 activation, increased AMPK activity, and O-GlcNAcylation. However, when 2-deoxyglucose is combined with glutamine deprivation, GFAT1 Ser-243 phosphorylation and mTORC2 activation remain elevated, whereas AMPK activation and O-GlcNAcylation diminish. Phosphorylation at Ser-243 promotes GFAT1 expression and production of GFAT1-generated metabolites including ample production of the HBP end-product, UDP-GlcNAc, despite nutrient starvation. Hence, we propose that the mTORC2-mediated increase in GFAT1 Ser-243 phosphorylation promotes flux through the HBP to maintain production of UDP-GlcNAc when nutrients are limiting. Our findings provide insights on how the HBP is reprogrammed via mTORC2 in nutrient-addicted cancer cells.

Polymorphisms in the Runx2 and osteocalcin genes affect BMD in postmenopausal women: a systematic review and meta-analysis.

PURPOSE: Runx2 and osteocalcin have pivotal roles in bone homeostasis. Polymorphism of these two genes could alter the function of osteoblasts and consequently bone mineral density (BMD). Attempts to understand the relationship between these polymorphisms and BMD in postmenopausal women across a variety of populations have yielded inconsistent results. This meta-analysis seeks to define the relationship between these polymorphisms with BMD in postmenopausal women. METHODS: Eligible studies were identified from three electronic databases. Data were extracted from the eligible studies (4 studies on Runx2 and 6 studies on osteocalcin), and associations of Runx2 T > C and osteocalcin HindIII polymorphisms with BMD in postmenopausal women were assessed using standard difference in means (SDM) and 95% confidence intervals (CI) as statistical measures. RESULTS: A significant difference in the lumbar spine (LS) BMD in postmenopausal women was observed between the TT and CC homozygotes for the Runx2 T > C (SDM = -0.445, p-value = 0.034). The mutant genotypes (CC) showed significantly lower LS BMD in comparison to wild type genotypes under recessive model of genetic analysis (TC + TT vs. CC: SDM = -0.451, p-value = 0.032). For osteocalcin, HindIII polymorphism, the mutant genotypes (HH) was associated with significantly higher BMD for both LS and femoral neck (FN) than the wild type (hh) homozygotes (SDM = 0.152, p-value = 0.008 and SDM = 0.139, p-value = 0.016 for LS and FN, respectively). There was no association between total hip (TH) BMD and the osteocalcin HindIII polymorphism. CONCLUSIONS: Runx2 T > C and osteocalcin HindIII polymorphisms influence the level of BMD in postmenopausal women and may be used as predictive markers of osteoporosis.

Multiscale effects of the calcimimetic drug, etelcalcetide on bone health of rats with secondary hyperparathyroidism induced by chronic kidney disease.

Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.

Nickel(II) Complexes of Tripodal Ligands as Catalysts for Fixation of Atmospheric CO2 as Organic Carbonates.

The fixation of atmospheric CO2 into value-added products is a promising methodology. A series of novel nickel(II) complexes of the type [Ni(L)(CH3 CN)2 ](BPh4 )2 1-5, where L=N,N-bis(2-pyridylmethyl)-N', N'-dimethylpropane-1,3-diamine (L1), N,N-dimethyl-N'-(2-(pyridin-2-yl)ethyl)-N'-(pyridin-2-ylmethyl) propane-1,3-diamine (L2), N,N-bis((4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-N',N'-dimethylpropane-1,3-diamine (L3), N-(2-(dimethylamino) benzyl)-N',N'-dimethyl-N-(pyridin-2-ylmethyl) propane-1,3-diamine (L4) and N,N-bis(2-(dimethylamino)benzyl)-N', N'-dimethylpropane-1,3-diamine (L5) have been synthesized and characterized as the catalysts for the conversion of atmospheric CO2 into organic cyclic carbonates. The single-crystal X-ray structure of 2 was determined and exhibited distorted octahedral coordination geometry with cis-α configuration. The complexes have been used as a catalyst for converting CO2 and epoxides into five-membered cyclic carbonates under 1 atmospheric (atm) pressure at room temperature in the presence of Bu4 NBr. The catalyst containing electron-releasing -Me and -OMe groups afforded the maximum yield of cyclic carbonates, 34% (TON, 680) under 1 atm air. It was drastically enhanced to 89% (TON, 1780) under pure CO2 gas at 1 atm. It is the highest catalytic efficiency known for CO2 fixation using nickel-based catalysts at room temperature and 1 atm pressure. The electronic and steric factors of the ligands strongly influence the catalytic efficiency. Furthermore, all the catalysts can convert a wide range of epoxides (ten examples) into corresponding cyclic carbonate with excellent selectivity (>99%) under this mild condition.

All optical modulation in vertically coupled indium tin oxide ring resonator employing epsilon near zero state.

We present an innovative approach to achieve all-optical modulation within an ITO-based vertically coupled ring resonator. This method leverages the material's enhanced nonlinear response in the near-infrared wavelengths, particularly within the epsilon-near-zero (ENZ) state. To enhance the interaction between light and the material while minimizing scattering losses, our approach employs an ITO-based vertically connected ring resonator. The vertical arrangement eliminates the need for etching fine gaps to separate the ring and bus waveguide. The novel waveguide design addresses the necessity of high sensitivity, non-linear effects and compact size opening the possibilities for all-optical signal processing. This unique resonator structure effectively facilitates the coupling of a high-intensity pump wavelength into the ITO-based micro-ring resonator. Consequently, this optical pumping induces electron heating within the ITO material, leading to a significant increase in its nonlinear optical properties. This, in turn, results in a noteworthy alteration of ITO's refractive index, specifically in the unity order, thereby modifying the complex effective index of the optical beam propagating at 1550 nm. Our experimental findings demonstrate an impressive extinction ratio of 18 dB for a 30 µm long device, which highlights the efficiency of our approach in achieving all-optical modulation through the optical pumping of an ITO-based vertically coupled ring resonator. The proposed all-optical modulator has outperformed as compared to conventional waveguide-based modulators in terms of extinction ratio and footprint. This novel technique holds immense potential for advancing high-speed data communication systems in the future. As the demand for advanced processing capabilities, such as artificial intelligence, continues to grow, all-optical modulation emerges as a groundbreaking technology poised to revolutionize the next generation of computing and communication systems.

Efficacy of antiresorptive agents bisphosphonates and denosumab in mitigating hypercalcemia and bone loss in primary hyperparathyroidism: A systematic review and meta-analysis.

Purpose: Primary hyperparathyroidism (PHPT) is characterized by increased bone remodeling and hypercalcemia. Parathyroidectomy (PTX), the current standard of care, is recommended in all symptomatic and some groups of asymptomatic patients. Anti-resorptive therapies (bisphosphonates and denosumab) have been used in patients where PTX is refused or contraindicated. In this meta-analysis, we investigated the effectiveness of anti-resorptives in preventing/treating PHPT-induced bone loss and mitigating hypercalcemia. Method: PubMed, Scopus, and Cochrane Library databases were searched for articles with keywords containing PHPT, bisphosphonates, and denosumab in various combinations. We extracted and tabulated areal BMD (aBMD), serum mineral, and bone turnover parameters from the qualified studies and used comprehensive meta-analysis software for analysis. Results: Of the 1,914 articles screened, 13 were eligible for meta-analysis. In the pooled analysis, 12 months of anti-resoptives (bisphosphonates and denosumab) therapy significantly increased aBMD at the lumbar spine (Standard difference in means (SDM)=0.447, 95% CI=0.230 to 0.664, p=0.0001), femoral neck (SDM=0.270, 95% CI=0.049 to 0.491, p=0.017) and increased serum PTH (SDM=0.489, 95% CI=0.139 to 0.839, p=0.006), and decreased serum calcium (SDM=-0.545, 95% CI=-0.937 to -0.154, p=0.006) compared with baseline. 12 months of bisphosphonate use significantly increased aBMD only at the lumbar spine (SDM=0.330, 95% CI=0.088 to 0.571, p=0.007) with a significant increased in serum PTH levels (SDM=0.546, 95% CI= 0.162 to 0.930, p=0.005), and a decreased in serum calcium (SDM=-0.608, 95% CI=-1.048 to -0.169, p=0.007) and bone-turnover markers (BTMs) compared with baseline. Denosumab use for 12 months significantly increased aBMD at both the lumbar spine (SDM=0.828, 95% CI=0.378 to 1.278, p=0.0001) and femur neck (SDM=0.575, 95% CI=0.135 to 1.015, p=0.010) compared with baseline. Mean lumbar spine aBMD (SDM=0.350, 95% CI=0.041 to 0.659, p=0.027) and serum PTH (SDM=0.602, 95% CI= 0.145 to 1.059, p=0.010) were significantly increased after 12 months of alendronate use compared with placebo. When compared with baseline, alendronate significantly decreased BTMs after 12 months and increased aBMD without altering the PTH and calcium levels after 24 months. Conclusion: Anti-resorptives are effective in mitigating bone loss and hypercalcemia in PHPT while maintaining or increasing aBMD. PTX reversed all changes in PHPT and normalized PTH levels.

Hormonal and non-hormonal oral contraceptives given long-term to pubertal rats differently affect bone mass, quality and metabolism.

Introduction: We investigated the effects of hormonal and non-hormonal oral contraceptives (OCs) on bone mass, mineralization, composition, mechanical properties, and metabolites in pubertal female SD rats. Methods: OCs were given for 3-, and 7 months at human equivalent doses. The combined hormonal contraceptive (CHC) was ethinyl estradiol and progestin, whereas the non-hormonal contraceptive (NHC) was ormeloxifene. MicroCT was used to assess bone microarchitecture and BMD. Bone formation and mineralization were assessed by static and dynamic histomorphometry. The 3-point bending test, nanoindentation, FTIR, and cyclic reference point indentation (cRPI) measured the changes in bone strength and material composition. Bone and serum metabolomes were studied to identify potential biomarkers of drug efficacy and safety and gain insight into the underlying mechanisms of action of the OCs. Results: NHC increased bone mass in the femur metaphysis after 3 months, but the gain was lost after 7 months. After 7 months, both OCs decreased bone mass and deteriorated trabecular microarchitecture in the femur metaphysis and lumbar spine. Also, both OCs decreased the mineral: matrix ratio and increased the unmineralized matrix after 7 months. After 3 months, the OCs increased carbonate: phosphate and carbonate: amide I ratios, indicating a disordered hydroxyapatite crystal structure susceptible to resorption, but these changes mostly reversed after 7 months, indicating that the early changes contributed to demineralization at the later time. In the femur 3-point bending test, CHC reduced energy storage, resilience, and ultimate stress, indicating increased susceptibility to micro-damage and fracture, while NHC only decreased energy storage. In the cyclic loading test, both OCs decreased creep indentation distance, but CHC increased the average unloading slope, implying decreased microdamage risk and improved deformation resistance by the OCs. Thus, reduced bone mineralization by the OCs appears to affect bone mechanical properties under static loading, but not its cyclic loading ability. When compared to an age-matched control, after 7 months, CHC affected 24 metabolic pathways in bone and 9 in serum, whereas NHC altered 17 in bone and none in serum. 6 metabolites were common between the serum and bone of CHC rats, suggesting their potential as biomarkers of bone health in women taking CHC. Conclusion: Both OCs have adverse effects on various skeletal parameters, with CHC having a greater negative impact on bone strength.