Research progress of targeted therapy regulating Th17/Treg balance in bone immune diseases.

Rheumatoid arthritis (RA) and postmenopausal osteoporosis (PMOP) are common bone-immune diseases. The imbalance between helper (Th17) and regulatory T cells (Tregs) produced during differentiation of CD4+ T cells plays a key regulatory role in bone remodelling disorders in RA and PMOP. However, the specific regulatory mechanism of this imbalance in bone remodelling in RA and PMOP has not been clarified. Identifying the regulatory mechanism underlying the Th17/Treg imbalance in RA and PMOP during bone remodelling represents a key factor in the research and development of new drugs for bone immune diseases. In this review, the potential roles of Th17, Treg, and Th17/Treg imbalance in regulating bone remodelling in RA and PMOP have been summarised, and the potential mechanisms by which probiotics, traditional Chinese medicine compounds, and monomers maintain bone remodelling by regulating the Th17/Treg balance are expounded. The maintenance of Th17/Treg balance could be considered as an therapeutic alternative for the treatment of RA and PMOP. This study also summarizes the advantages and disadvantages of conventional treatments and the quality of life and rehabilitation of patients with RA and PMOP. The findings presented her will provide a better understanding of the close relationship between bone immunity and bone remodelling in chronic bone diseases and new ideas for future research, prevention, and treatment of bone immune diseases.

Maresin1: A multifunctional regulator in inflammatory bone diseases.

Inflammation plays a crucial role in the physical response to danger signals, the elimination of toxic stimuli, and the restoration of homeostasis. However, dysregulated inflammatory responses lead to tissue damage, and chronic inflammation can disrupt osteogenic-osteoclastic homeostasis, ultimately leading to bone loss. Maresin1 (MaR1), a member of the specialized pro-resolving mediators (SPMs) family, has been found to possess significant anti-inflammatory, anti-allergic, pro-hemolytic, pro-healing, and pain-relieving properties. MaR1 is synthesized by macrophages (Mφs) and omega-3 fatty acids, and it may have the potential to promote bone homeostasis and treat inflammatory bone diseases. MaR1 has been found to stimulate osteoblast proliferation through leucine-rich repeat G protein-coupled receptor 6 (LGR6). It also activates Mφ phagocytosis and M2-type polarization, which helps to control the immune system. MaR1 can regulate T cells to exert anti-inflammatory effects and inhibit neutrophil infiltration and recruitment. In addition, MaR1 is involved in antioxidant signaling, including nuclear factor erythroid 2-related factor 2 (NRF2). It has also been found to promote the autophagic behavior of periodontal ligament stem cells, stimulate Mφs against pathogenic bacteria, and regulate tissue regeneration and repair. In summary, this review provides new information and a comprehensive overview of the critical roles of MaR1 in inflammatory bone diseases, indicating its potential as a therapeutic approach for managing skeletal metabolism and inflammatory bone diseases.

Cannabis. Usos y aplicaciones en la práctica odontológica diaria: revisión de la literatura / Cannabis. Uses and applications in daily dental practice: a review of the literature

La evidencia científica presente en la literatura indica que el cannabis puede ser utilizado con fines terapéuticos para tratar distintas afecciones odontológicas. Dado el acceso sencillo a la cavidad bucal, las distintas formulaciones de cannabis pueden aplicarse de forma tópica. La aplicación local de dosis bajas de cannabis ha demostrado alta efectividad para tratar distintas afecciones bucales, constituyendo un tratamiento seguro con baja probabilidad de generar repercusiones sistémicas indeseadas. En la actualidad, está siendo incorporado a materiales convencionales de uso e higiene odontológica con la finalidad de aprovechar sus efectos terapéuticos. El cannabis tiene múltiples usos en odontología: como componen-te de enjuagues bucales y soluciones para la desinfección de conductos radiculares, en tratamientos de trastornos de ansiedad bucal, como complemento en terapias oncológicas, como analgésico para atenuar el dolor inflamatorio y el neuropático, como miorrelajante y condroprotector para tratar trastornos de articulación témporomandibular (ATM) y bruxismo, como osteomodulador para el tratamiento de patologías que comprometen la integridad ósea, como la enfermedad periodontal y la osteoporosis, y para la cicatrización ósea asociada a fracturas, extracciones dentarias e implantes, y como inmunomodulador con potencial terapéutico para tratar patologías autoinmunes como las enfermedades reumáticas. El trata-miento local con cannabis es efectivo, bien tolerado por el paciente y con pocos efectos adversos. Por lo tanto, se puede concluir que el cannabis aporta un enorme abanico de posibilidades terapéuticas para tratar distintas afecciones odontológicas, aunque aún se requiere mayor cantidad de estudios científicos que avalen su utilización en cada situación fisiopatológica particular (AU)

The scientific evidence present in the literature indicates that cannabis can be used for therapeutic purposes to treat different dental conditions. Given the easy access to the oral cavity, the different cannabis formulations can be applied topically. The local application of low doses of cannabis has shown high effectiveness in treating different oral conditions, constituting a safe treatment with a low probability of generating unwanted systemic repercussions. It is currently being incorporated into conventional materials for dental use and hygiene in order to take advantage of its therapeutic effects. Cannabis has multiple uses in dentistry: as a component of mouthwashes and solutions for disinfecting root canals, in the treatment of oral anxiety disorders, as a complement in oncological therapies, as an analgesic to reduce inflammatory and neuropathic pain, as a muscle relaxant and chondroprotective to treat temporomandibular joint disorders and bruxism, as an osteomodulator for the treatment of pathologies that compromise bone integrity, such as periodontal disease and osteoporosis, and or bone healing associated with fractures, dental extractions and implants, and as immunomodulator with therapeutic potential to treat autoimmune pathologies such as rheumatic diseases. Local treatment with cannabis is effective, well tolerated by the patient and with few adverse effects. Local treatment with cannabis is effective, well tolerated by the patient and with few adverse effects. Therefore, it can be concluded that cannabis provides an enormous range of therapeutic possibilities to treat different dental conditions, although more scientific studies are still required to support its use in each particular pathophysiological situation (AU)

Regenerating Critical Size Rat Segmental Bone Defects with a Self-Healing Hybrid Nanocomposite Hydrogel: Effect of Bone Condition and BMP-2 Incorporation.

The aim of the current study is to assess the biological performance of self-healing hydrogels based on calcium phosphate (CaP) nanoparticles and bisphosphonate (BP) conjugated hyaluronan (HA) in a critical size segmental femoral bone defect model in rats. Additionally, these hydrogels are loaded with bone morphogenetic protein 2 (BMP-2) and their performance is compared in healthy and osteoporotic bone conditions. Treatment groups comprise internal plate fixation and placement of a PTFE tube containing hydrogel (HABP -CaP) or hydrogel loaded with BMP-2 in two dosages (HABP -CaP-lowBMP2 or HABP -CaP-highBMP2). Twelve weeks after bone defect surgery, bone formation is analyzed by X-ray examination, micro-CT analysis, and histomorphometry. The data show that critical size, segmental femoral bone defects cannot be healed with HABP -CaP gel alone. Loading of the HABP -CaP gel with low dose BMP-2 significantly improve bone formation and resulted in defect bridging in 100% of the defects. Alternatively, high dose BMP-2 loading of the HABP -CaP gel does not improve bone formation within the defect area, but leads to excessive bone formation outside the defect area. Bone defect healing is not affected by osteoporotic bone conditions.

Network Pharmacological Study of Achyranthis bidentatae Radix Effect on Bone Trauma.

PURPOSE: Bone trauma is a clinical condition that afflicts the majority of the world's population. For the management of bone trauma, the underlying mechanisms of the drugs effective for bone healing are deemed necessary. Achyranthis bidentatae Radix (ABR) is a popular alternative medicine recommended in the treatment of bone trauma and injury, yet its mechanism of action persists to be vague. This study was conducted for the evaluation of the mode of action of ABR through network pharmacology in treating bone trauma. METHODS: An extensive survey of published works led to the development of a drug-target database, after which multiple protein targets for bone trauma were discerned. The protein-protein interaction network was developed by utilizing the STITCH database and gene ontology (GO) enrichment analysis using Cytoscape and ClueGO. Moreover, docking studies were performed for revealing the affinity of various ingredients with IL6. RESULTS: The extensive literature survey yielded the presence of 176 components in ABR, and 151 potential targets were acquired. Scrutinization of these targets revealed that 21 potential targets were found to be associated with bone trauma. Out of which, some remarkable targets such as IL6, MAPK14, MAPK8, SRC, PTGS2, and MMP2 were observed to be associated in the functional interaction of ABR. According to docking results, several ingredients of ABR such as Baicalien, Copistine, Epiberberine, Kaempferol, and Palmatine have the lowest docking scores (range between -6 and -7). CONCLUSIONS: The results of the study elucidated that ABR can positively be utilized for the management of bone trauma, which can be mediated by multiple molecular mechanisms such as ERBB2 signaling pathway, positive regulation of oxidoreductase activity, JNK cascade pathway, multicellular organism metabolic process, T cell costimulation, and the positive regulation of MAPK activity. The findings also suggest that several ingredients of ABR such as Baicalien, Copistine, Epiberberine, Kaempferol, and Palmatine have good affinity with IL6, suggesting the promising potential of ABR in treating bone trauma, likely through IL6.

Anacardic acid-mediated regulation of osteoblast differentiation involves mitigation of inflammasome activation pathways.

Disruption of the finely tuned osteoblast-osteoclast balance is the underlying basis of several inflammatory bone diseases, such as osteomyelitis, osteoporosis, and septic arthritis. Prolonged and unrestrained exposure to inflammatory environment results in reduction of bone mineral density by downregulating osteoblast differentiation. Earlier studies from our laboratory have identified that Anacardic acid (AA), a constituent of Cashew nut shell liquid that is used widely in traditional medicine, has potential inhibitory effect on gelatinases (MMP2 and MMP9) which are over-expressed in numerous inflammatory conditions (Omanakuttan et al. in Mol Pharmacol, 2012 and Nambiar et al. in Exp Cell Res, 2016). The study demonstrated for the first time that AA promotes osteoblast differentiation in lipopolysaccharide-treated osteosarcoma cells (MG63) by upregulating specific markers, like osteocalcin, receptor activator of NF-κB ligand, and alkaline phosphatase. Furthermore, expression of the negative regulators, such as nuclear factor-κB, matrix metalloproteinases (MMPs), namely MMP13, and MMP1, along with several inflammatory markers, such as Interleukin-1ß and Nod-like receptor protein 3 were downregulated by AA. Taken together, AA expounds as a novel template for development of potential pharmacological therapeutics for inflammatory bone diseases.

Layered Antimicrobial Selenium Nanoparticle-Calcium Phosphate Coating on 3D Printed Scaffolds Enhanced Bone Formation in Critical Size Defects.

Preventing bacterial colonization on scaffolds while supporting tissue formation is highly desirable in tissue engineering as bacterial infection remains a clinically significant risk to any implanted biomaterials. Elemental selenium (Se0) nanoparticles have emerged as a promising antimicrobial biomaterial without tissue cell toxicity, yet it remains unknown if their biological properties are from soluble Se ions or from direct cell-nanoparticle interactions. To answer this question, in this study, we developed a layered coating consisting of a Se nanoparticle layer underneath a micrometer-thick, biomimetic calcium phosphate (CaP) layer. We showed, for the first time, that the release of soluble HSe- ions from the Se nanoparticles strongly inhibited planktonic growth and biofilm formation of key bacteria, Staphylococcus aureus. The Se-CaP coating was found to support higher bone formation than the CaP-only coating in critical-size calvarial defects in rats; this finding could be directly attributed to the released soluble Se ions as the CaP layers in both groups had no detectable differences in the porous morphology, chemistry, and release of Ca or P. The Se-CaP coating was highly versatile and applicable to various surface chemistries as it formed through simple precipitation from aqueous solutions at room temperature and therefore could be promising in bone regeneration scaffolds or orthopedic implant applications.

A potential role for astaxanthin in the treatment of bone diseases (Review).

Alterations in molecular signaling impair cellular functions and induce degenerative diseases. Among the factors affecting intracellular signaling pathways, oxidative stress serves an important role. Astaxanthin (3,3'­dihydroxy­ß, ß­carotene-4,4'­dione), a pigment found in aquatic organisms, belongs to the xanthophylls family. Astaxanthin exerts a strong antioxidant activity and is widely used in food, cosmetic and pharmaceutical industries. Oxidative stress damages bone homeostasis by producing reactive oxygen species and increasing the production of pro­resorption cytokines, such as interleukin (IL)­1, tumor necrosis factor­α and IL­6. Therefore, antioxidant molecules can counteract the negative effects of oxidative stress on bone. Accordingly, previous studies have demonstrated that supplementation of astaxanthin in bone contributes to the restoration of bone homeostasis. The present review summarizes the negative effects of oxidative stress in bone and explores the role of astaxanthin in counteracting skeletal injuries consequent to oxidative stress.

A review on osteoclast diseases and osteoclastogenesis inhibitors recently developed from natural resources.

Natural products have been investigated as potential candidates of novel therapeutics and play a crucial role in advanced medicinal drugs. Natural resources, including local medicinal plants (especially folk medicinal plants), animals, bacteria, and fungi have been used for more than a century, and are precious gifts from nature, providing potential medicines with high safety. Osteoclast-related diseases, such as osteoporosis, rheumatoid arthritis, Paget's disease, osteoclastoma, and periprosthetic osteolysis, are currently the most common reasons for bone inflammation, pain and fractures, resulting in low quality of life. However, the curative effects of current therapeutic drugs for these osteoclast-related diseases are limited, and long-term treatment is needed. Further, in severe cases, surgical treatments are necessary, which may cause unaffordable expenses and subsequent influences such as neuralgia, mental stress, and even development of cancer. Thus, safer inhibitors and potential drugs with enhanced curative effects and quick relief are needed to treat patients with osteoclast diseases. This review aims to introduce the main osteoclast-related diseases and some of the recently developed naturally sourced inhibitors against osteoclastogenesis, also it is desired to attract people's attention on using widely available natural resources for the evolution of new types of osteoclast inhibitors with minimal or no side-effects upon long-term treatments.

Comorbidity and polypharmacy in patients with breast cancer.

BACKGROUND: Cancer sufferers are aged ≥ 65 years, but research has focused infrequently on elderly patients with the majority of cancer. We aimed not only to determine the frequency of comorbidity and polypharmacy, but also to present the discrepiancies in elderly versus non-elderly patients with breast cancer. METHODS: A total of 352 female patients aged over 18 years, 252 non-elderly and 100 elderly, followed-up in the oncology department of a tertiary hospital between January 2016 and September 2019 were retrospectively screened. Demographic data, comorbidity and medications of the patients were recorded hospital data processing system. Polypharmacy was defined as the use of ≥ 5 different medications. RESULTS: The most common four chronic diseases in both non-elderly and elderly groups were muscle-joint-bone disease, gastrointestinal diseases, diabetes mellitus and hypertension. The most common four prescribed drugs were NSAID, adjuvant endocrine therapy, PPI, and vitamin D or/and calcium in non-elderly group while those were ACEI-ARB, PPI, NSAID, and diuretics in elderly one. The frequency of polypharmacy was 50% (n = 126) in the non-elderly patients and 74% (n = 74) in the elderly ones. These were considered statistically significant (p < 0.001). The mean number of prescription medication categories reported was 5.02 (SD = 2.90; range 0-14) in non-elderly group whereas those was 6.83 (SD = 3.18; range 0-15) in elderly one (p < 0.001). The mean of ages were 47.9 years (without polypharmacy) and 51.3 years (with polypharmacy) in non-elderly patients while those are, respectively, 70.9 years and 74.7 years in elderly ones. These were considered statistically significant (respectively; p = 0.006, p = 0.009). CONCLUSIONS: We first gained to raise awareness in the literature of comorbidity and polypharmacy in patients with breast cancer and to compare between the elderly and non-elderly participants. For the effectiveness of cancer treatment, importance in geriatric population, attention to drug-drug interaction, such studies should be considered during clinical practice.

Nutritional vitamin D in CKD: Should we measure? Should we treat?

Vitamin Ddeficiency is frequently present in patients affected by chronic kidney disease (CKD). Experimental studies demonstrated that Vitamin D may play a role in the pathophysiology of diseases beyond mineral bone disorders in CKD (CKD-MBD). Unfortunately, the lack of large and interventional studies focused on the so called "non-classic" effects of 25(OH) Vitamin D supplementation in CKD patients, doesn't permit to conclude definitely about the beneficial effects of this supplementation in clinical practice. In conclusion, treatment of nutritional vitamin D deficiency in CKD may play a central role in both bone homeostasis and cardiovascular outcomes, but there is not clear evidence to support one formulation of nutritional vitamin D over another in CKD.

Treatment with Vancomycin Loaded Calcium Sulphate and Autogenous Bone in an Improved Rabbit Model of Bone Infection.

Bone infection results from bacterial invasion, which is extremely difficult to treat in clinical, orthopedic, and traumatic surgery. The bone infection may result in sustained inflammation, osteomyelitis, and eventual bone non-union. Establishment of a feasible, reproducible animal model is important to bone infection research and antibiotic treatment. As an in vivo model, the rabbit model is widely used in bone infection research. However, previous studies on rabbit bone infection models showed that the infection status was inconsistent, as the amount of bacteria was variable. This study presents an improved surgical method for inducing bone infection on a rabbit, by blocking the bacteria in the bone marrow. Then, multi-level evaluations can be carried out to verify the modelling method. In general, debriding necrotic tissue and implantation of vancomycin-loaded calcium sulphate (VCS) are predominant in antibiotic treatment. Although calcium sulphate in VCS benefits osteocyte crawling and new bone growth, massive bone defects occur after debriding. Autogenous bone (AB) is an appealing strategy to overcome bone defects for the treatment of massive bone defects after debriding necrotic bone. In this study, we used the tail bone as an autogenous bone implanted in the bone defect. Bone repair was measured using micro-computed-tomography (micro-CT) and histological analysis after animal sacrifice. As a result, in the VCS group, bone non-union was consistently obtained. In contrast, the bone defect areas in the VCS-AB group were decreased significantly. The present modeling method described a reproducible, feasible, stable method to prepare a bone infection model. The VCS-AB treatment resulted in lower bone non-union rates after antibiotic treatment. The improved bone infection model and the combination treatment of VCS and autogenous bone could be helpful in studying the underlying mechanisms in bone infection and bone regeneration pertinent to traumatology orthopedic applications.

Effect of Ascorbic Acid on Mineral and Bone Disorders in Hemodialysis Patients: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Hemodialysis (HD) patients often have inadequate nutrition, especially with respect to ascorbic acid (AA). It is reported that every HD session may cause a 50%- 75% decrease in plasma AA levels. Some studies have shown that supplementation of AA can change the outcome of chronic kidney disease-mineral bone disorders (CKD-MBD), but the effect of AA on HD patients with CKD-MBD remains controversial. Consequently, we decided to perform a meta-analysis to evaluate the efficacy of AA supplementation in CKD-MBD patients requiring dialysis. METHODS: A search was conducted using Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), Wanfang database and VIP information database up to April 2018 for all English and Chinese language publications. The main indicators of our study were changes in serum phosphate (P), calcium (Ca) and parathyroid hormone (PTH) levels after AA treatment. The efficacy of AA was evaluated by weighted mean difference (WMD) and confidence intervals (CI). Cardiovascular events, mortality and adverse events reported during the experiment were also noted. RESULTS: In total, 371 patients in six studies were involved in this meta-analysis. Compared to placebo, AA treatment had no positive effect on serum P (353 patients; WMD = -0.05; 95% CI, -0.3 to 0.2; I2 = 28%) or PTH levels (275 patients; WMD = -17.04; 95%CI, -63.79 to 29.72; I2 = 75%). The pooled mean difference of the change of Ca levels from baseline was higher in the AA therapy group versus placebo (353 patients; WMD = 0.15; 95% CI, 0.01 to 0.3; I2 = 0%). No side effects were observed. CONCLUSION: Our systematic review and meta-analysis does not support prescription of AA to HD patients with CKD-MBD. AA had no positive effect on CKD-MBD patients as it couldn't influence the serum P or PTH levels but did raise serum Ca levels in the short-term.

Magnesium in Hemodialysis Patients: A New Understanding of the Old Problem.

BACKGROUND: Despite the prognostic significance of mineral and bone disorders in patients undergoing hemodialysis, very few studies have focused on magnesium metabolism in this population. Nephrologists have paid much attention to hypermagnesemia, which is sometimes caused by magnesium administration, but the clinical implication of low magnesium has been largely overlooked. Recently, several cohort studies have reported that lower serum magnesium levels are associated with an increased risk of all-cause and cardiovascular mortality among hemodialysis patients. In addition to its beneficial effect on endothelium, magnesium has been shown to inhibit the progression of vascular calcification both in vitro and in vivo. Although the exact underlying mechanism is still uncertain, magnesium can suppress the maturation of calciprotein particles, a candidate culprit for vascular calcification, which is promoted by high phosphate. Thus, magnesium seems to be useful to alleviate the phosphate-induced calcification stress. Consistently, the risk of cardiovascular death associated with hyperphosphatemia is attenuated among hemodialysis patients with high serum magnesium levels, whereas this risk is exacerbated among those with low serum magnesium levels. In the context of the bone-vascular axis, magnesium may also be involved in the risk of fracture. It should be noted that, although total serum magnesium levels of hemodialysis patients are often above the reference range, the concentration of ionized magnesium, a biologically active form of magnesium, is largely normal or even low. SUMMARY: A growing number of observational studies have uncovered the relationship between lower serum magnesium levels and poorer survival of hemodialysis patients. Magnesium modulates the pathogenesis of mineral and bone disorders and might provide a novel therapeutic approach for vascular calcification. Key Messages: Future intervention studies should clarify whether magnesium supplementation and/or increasing dialysate magnesium concentration improves the prognosis of hemodialysis patients.

Response to Long-term Vitamin D Therapy for Bone Disease in Children With Sickle Cell Disease.

Patients with sickle cell disease (SCD) are at risk for bone fragility from multiple factors including vitamin D deficiency. To date, no studies have evaluated the efficacy and safety of long-term vitamin D therapy for bone disease in children with SCD. We report a cohort of 4 children with SCD found to have severe vitamin D deficiency, secondary hyperparathyroidism, and abnormal bone mineral density treated with monthly high-dose oral cholecalciferol over 2 years. All patients exhibited a positive response to therapy without hypervitaminosis D or hypercalcemia. Further studies are needed to standardize guidelines for optimal vitamin D dosing and prevention of toxicity.

A preliminary in vitro evaluation of the bioactive potential of cryogel scaffolds incorporated with Manuka honey for the treatment of chronic bone infections.

Previous studies have identified honey as an agent in bacterial inhibition and a mediator in lowering the pH at the wound site. Manuka honey (MH), indigenous to New Zealand, contains a Unique Manuka Factor that provides an additional antibacterial agent. While there are many potential benefits to incorporating MH into wounds, there is currently no ideal way to deliver the material to the site of injury. Cryogels are a type of scaffold that possess high porosity, mechanical stability, and a sponge-like consistency. This study uniquely incorporates varying amounts of MH into cryogel scaffolds, utilizing its properties in a sustained release fashion to assist in the overall healing process, while using the cryogel structure as a tissue template. All cryogels were evaluated to determine the effects of MH on porosity, swelling potential, mechanical durability, and cell compatibility. The release of MH was also quantified to evaluate bacterial clearance potential, and the scaffolds were mineralized to replicate native bone. It was determined that a 5% MH silk fibroin cryogel has the potential to inhibit bacterial growth while still maintaining adequate porosity, mechanical properties, and cell infiltration. Such a scaffold would have use in a number of applications, including bone regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1918-1933, 2018.

Response of serum 25(OH)D to Vitamin D and calcium supplementation in school-children from a semi-rural setting in India.

The objectives of this study were to: 1) Determine the impact of varying baseline serum 25OHD on increase in vitamin D concentrations after daily supplementation with vitamin D and calcium (1000 IU + 500 mg respectively) for six months in school-children from a semi-rural setting 2) Test the efficacy of daily vitamin D-calcium supplementation on improvement in serum vitamin D concentrations to ≥75 nmol/L. Data collected from 106 subjects (58 boys, 48 girls), aged 6-12 years, included anthropometric measures like height and weight, body composition analysis, three one-day dietary recalls and sunlight exposure (by questionnaire). Blood was collected at baseline and endline and estimated for serum vitamin D by ELISA technique using standard kits. Classification of Vitamin D status was performed according to the 2011 Endocrine Society Practice Guidelines: vitamin D deficiency - <50 nmol/L; insufficiency - 50.0-74.9 nmol/L; sufficiency - ≥75 nmol/L. Statistical analysis was performed using SPSS software. Mean baseline serum vitamin D concentration was 59.7 ±â€¯11.2 nmol/L; this rose to 79.8 ±â€¯23.3 nmol/L with no significant differences between genders at the two time-points. Inverse relationship was obtained between baseline serum 25(OH)D concentrations and change in serum concentrations after supplementation, implying that with increasing baseline serum concentrations of 25(OH)D, increase in vitamin D levels post supplementation were significantly lower (r = - 0.96, p < 0.0001). Greatest benefit of change in serum vitamin D concentrations after supplementation was experienced by children with basal concentrations of <45 nmol/L. Daily vitamin D supplementation was effective in improving serum 25(OH)D to ≥75 nmol/L in 44% of children. Significantly higher percentage of children who were deficient at baseline (64%) were able to attain serum concentrations of ≥75 nmol/L as compared to children who were vitamin D insufficient (43%) (p < 0.001). Thus, daily supplementation with 1000 IU of vitamin D along with 500 mg of calcium helped in improving serum vitamin D concentrations to ≥75 nmol/L. Children who were vitamin D deficient particularly experienced these benefits.

Bone Therapeutics: Safety Considerations, Session Summary.

This session was a series of presentations focused on safety considerations for late stage or currently marketed bone therapeutic agents. The first presentation was an overview of a major regulatory requirement in the nonclinical filing package for bone therapeutics, studies designed to assess the impact of an agent on bone quality. Two presentations focused on safety issues associated with drugs whose primary mechanism of action is inhibition of bone resorption. Typical findings associated with this class of agents in general and reproductive toxicology studies were reviewed, highlighting INHAND (International Harmonization of Nomenclature and Diagnostic Criteria) nomenclature. This was followed by an overview of safety issues that have been identified largely through clinical experience. Similar presentations followed emphasizing safety and regulatory issues associated with classes of drugs whose primary mechanism of action is stimulation of bone formation known broadly as bone anabolic agents. The major focus of these discussions was carcinogenicity risk assessment. The final presentation was an introduction to a rapidly evolving area in bone therapeutics, treatment of rare genetic bone diseases, and the developmental challenges associated with these indications and novel therapeutic modalities.

Baja masa ósea, osteoporosis primaria y secundaria en mujeres premenopáusicas / Low bone mass, primary and secondary osteoporosis in premenopausal women / Baixa massa óssea e osteoporose primária e secundária em mulheres na premenopáusicas

Existe escasa información sobre baja masa ósea y osteoporosis en mujeres premenopáusicas. Solo el 2% de las mujeres jóvenes consulta para evaluar la presencia de osteoporosis. En el 50% de las mujeres premenopáusicas que presentan una disminución de su masa ósea se diagnostican enfermedades o medicaciones que la provocan. Las causas deben ser cuidadosamente investigadas para no emitir un diagnóstico apresurado de osteoporosis premenopáusica. Al diagnóstico de baja masa ósea se arriba luego de descartar las causas que ocasionan osteoporosis secundaria y su etiología se relaciona genéticamente con un bajo pico de masa ósea. El cuadro de osteoporosis primaria presenta una densidad mineral ósea (DMO) muy disminuida y fracturas óseas por fragilidad. La etiología no es clara aún, la genética marca el 50-80% de lo que sucede con la masa ósea. Se ha encontrado en diferentes poblaciones, una disminución de la función osteoblástica, resistencia a IGF1, disminución de la hormona de crecimiento, bajos niveles de estradiol, alteración de la expresión del receptor a-estrogénico de los osteoblastos, alteración de la dinámica de secreción de la PTH y aumento de la excresión de interleuquina 1. El diagnóstico se realiza por densitometría, marcadores bioquímicos óseos y radiografías de columna dorsal y lumbar que permiten visualizar fracturas vertebrales asintomáticas. La International Society for Clinical Densitometry (ISCD) y las guías argentinas para osteoporosis sugieren definir la DMO premenopáusica por Z-score y se considera normal hasta -2.0. El tratamiento se basa fundamentalmente en generar hábitos saludables para el hueso: ingesta de calcio y vitamina D o suplementos de calcio y vitamina D, actividad física, evitar sustancias perjudiciales como alcohol y tabaco en exceso. Cuando la DMO es muy baja o existe una pérdida acelerada de DMO o fracturas por fragilidad, el tratamiento con teriparatide ha demostrado ser efectivo. Los bifosfonatos solo deben indicarse en situaciones especiales de osteoporosis. Cuando se diagnostica una osteoporosis secundaria, el tratamiento es el de la enfermedad que la provoca. Cada paciente debe ser analizada con mucha prudencia para arribar al diagnóstico correcto y al mejor tratamiento.

There is little information about low bone mass and osteoporosis in premenopausal women. Only 2% of young women consult to evaluate the presence of osteoporosis. A total of 50% of premenopausal women have a disease or take a medication that lessens their bone mass. The causes must be carefully investigated to arrive at a correct diagnosis. Diagnosing low bone mass up after ruling out secondary osteoporosis and its etiology is genetically related to low peak bone mass. Primary osteoporosis presents a very reduced bone mineral density (BMD) with bone fragility fractures. The etiology is not clear yet: genetics marks 50-80% of what happens with bone mass. Decreased osteoblast function, IGF1 resistance, decreased growth hormone, low estradiol levels, altered expression receptor a-estrogenic of osteoblasts, altered dynamics of PTH secretion, and increased excretion of interleukin-1 have been found in different populations. The diagnosis is not only performed by densitometry but also through bone biochemical markers and radiographs of thoracic and lumbar spine radiographs that can diagnose asymptomatic vertebral fractures. The International Society for Clinical Densitometry (ISCD) and Argentine guidelines suggest definition premenopausal osteoporosis by BMD Z -score, in which a value up to -2.0 is considered normal. The treatment is based primarily on healthy habits for the bone: intake of calcium and vitamin D or calcium and vitamin D supplements, physical activity, and avoiding damaging substances to the bone, like alcohol and tobacco in excess. When BMD is very low or there is a rapid loss of BMD or fragility fractures, teriparatide treatment has proven effective. The bisphosphonates should be indicated only in special patients with osteoporosis. When a secondary osteoporosis is diagnosed, the treatment given is for the disease that has caused it. Each patient must be analyzed with great care to arrive at the correct diagnosis and the best treatment.

Há pouca informação sobre baixa massa óssea e osteoporose em mulheres na pré-menopausa. Apenas 2% das mulheres jovens consulta para avaliar a presença de osteoporose. 50% das mulheres premenopáusicas que apresentam diminuição da massa óssea são diagnosticadas como causas doenças ou medicamentos. As causas devem ser cuidadosamente investigadas para emitir um diagnóstico rápido de osteoporose premenopáusica. Chega-se ao diagnóstico de baixa massa óssea após descartar as causas que provocam osteoporose secundária e sua etiologia é geneticamente relacionada com baixo pico de massa óssea. O quadro de osteoporose primária apresenta densidade mineral óssea (DMO) muito diminuída e fraturas ósseas por fragilidade. A etiologia ainda não está clara, a genética marca 50-80% do que acontece com a massa óssea. Foi encontrada em diferentes populações diminuição da função osteoblástica, resistência a IGF1, diminuição do hormônio de crescimento, baixos níveis de estradiol, alteração da expressão do receptor a-estrogênico dos osteoblastos, alteração da dinâmica de secreção de PTH, aumento da excreção de interleucina 1. O diagnóstco é realizado por densitometria, marcadores bioquímicos ósseos e radiografias de coluna dorsal e lombar que permitem visualizar fraturas vertebrais assintomáticas. A International Society for Clinical Densitometry (ISCD) e os Guias argentinos para osteoporose sugerem definir a DMO por Z-score e se considera normal até -2,0. O tratamento baseia-se principalmente em gerar hábitos saudáveis para o osso: ingestão de cálcio e vitamina D ou suplementos de cálcio e vitamina D, atividade física, evitar substâncias prejudiciais como álcool e tabaco em excesso. Quando a DMO é muito baixa ou há uma rápida perda de DMO ou fraturas por fragilidade, o tratamento com teriparatide demonstrou ser eficaz. Os bifosfonatos só devem ser indicados em situações especiais osteoporose. Quando uma osteoporose secundária é diagnosticada, o tratamento é o da doença que a provoca. Cada paciente deve ser analisado com muito cuidado para chegar ao diagnóstico correto e o melhor tratamento.