The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice.

Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. PURPOSE: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. METHODS: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). RESULTS: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01-0.27; 95%CI 0.06-0.10) and SERMs (average: 0.08; range 0.03-0.15; 95%CI 0.05-0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08-0.13 vs. average: 0.06; 95%CI 0.05-0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. CONCLUSION: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.

Efficacy of denosumab monotherapy among adults with Langerhans cell histiocytosis: A prospective clinical trial.

This phase IIb clinical trial evaluated the efficacy of a bimonthly treatment schedule (Q8W) with 4 subcutaneous doses of denosumab 120 mg among adults with Langerhans cell histiocytosis needing first-line systemic therapy for either multifocal single-system disease or multisystem disease without risk organ involvement. Two months after the last treatment administration, seven patients showed disease regression, one stable disease, one non-active disease, and one disease progression. One year after treatment, progression was evident in two patients, while the remaining exhibited either a regression (three patients) or non-active disease (five patients). No permanent sequalae developed during the study and no adverse events were adjudicated in treatment. In conclusion, four doses of denosumab 120 mg Q8W subcutaneously are an effective treatment option in Langerhans cell histiocytosis patients without risk organ involvement exhibiting a response rate of 80%. Further studies are needed to confirm its role as a disease modifying agent.

Structural Speciation of Ti(IV)-(α-Hydroxycarboxylic Acid) Complexes in Metabolism-Related (Patho)Physiology-In Vitro Approaches to (Pre)Adipocyte Differentiation and Mineralization.

The prospect of developing soluble and bioavailable Ti(IV) complex forms with physiological substrates, capable of influencing (patho)physiological aberrations, emerges as a challenge in the case of metabolism-related pathologies (e.g., diabetes mellitus 1 and 2). To that end, pH-specific synthetic efforts on binary Ti(IV)-(α-hydroxycarboxylic acid) systems, involving natural physiological chelator ligands (α-hydroxy isobutyric acid, D-quinic acid, 2-ethyl-2-hydroxybutyric acid) in aqueous media, led to the successful isolation of binary crystalline Ti(IV)-containing products. The new materials were physicochemically characterized by elemental analysis, FT-IR, TGA, and X-ray crystallography, revealing in all cases the presence of mononuclear Ti(IV) complexes bearing a TiO6 core, with three bound ligands of variable deprotonation state. Solution studies through electrospray ionization mass spectrometry (ESI-MS) revealed the nature of species arising upon dissolution of the title compounds in water, thereby formulating a solid-state-solution correlation profile necessary for further employment in biological experiments. The ensuing cytotoxicity profile (pre-adipocytes and osteoblasts) of the new materials supported their use in cell differentiation experiments, thereby unraveling their structure-specific favorable effect toward adipogenesis and mineralization through an arsenal of in vitro biological assays. Collectively, well-defined atoxic binary Ti(IV)-hydroxycaboxylato complexes, bearing bound physiological substrates, emerge as competent inducers of cell differentiation, intimately associated with cell maturation, thereby (a) associating the adipogenic (insulin mimetic properties) and osteogenic potential (mineralization) of titanium and (b) justifying further investigation into the development of a new class of multipotent titanodrugs.

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID.

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic-pituitary-adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic-pituitary-adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

Adrenocortical dysfunction in rheumatoid arthritis: Α narrative review and future directions.

BACKGROUND: Iatrogenic adrenal insufficiency (AI) secondary to long-term treatment with exogenous glucocorticoids (GC) is common in patients with systematic rheumatic diseases, including rheumatoid arthritis (RA). Moreover, a proportion of these patients is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs. METHODS: We conducted a literature review up to December 2020 on (a) the incidence of AI in both long-term GC-treated and GC-treatment naïve RA patients; (b) the potential effects of increased levels of circulating proinflammatory cytokines, as well as of chronic stress, in adrenocortical function in RA; (c) the circadian cortisol rhythm in RA; and (d) established and evolving methods of assessment of adrenocortical function. RESULTS: Up to 48% of RA patients develop glucocorticoid-induced AI; however, predictors are not established, while adrenocortical dysfunction may also occur in GC-treatment naïve RA patients. Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. A precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management. CONCLUSION: Apart from iatrogenic AI, an intrinsically compromised adrenal reserve in RA may have a pathogenetic role and interfere with effective management, thus deserving further research.

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism.

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients' characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose.

OBJECTIVES: To examine adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases (RMD) who relapse upon tapering of low glucocorticoid dose, despite concomitant treatment with disease-modifying anti-rheumatic drugs (DMARDs). METHODS: A morning standard dose of 250 mcg tetracosactide (Synacthen test) was given in 25 consecutive patients (13 rheumatoid arthritis, 2 psoriatic arthritis, 5 systemic lupus erythematosus, 2 dermatomyositis, 1 systemic sclerosis, 2 temporal arteritis) at the time of relapse upon small reductions (1-2 mg daily) of low prednisolone dose (<7.5 mg daily), while being on stable concomitant treatment with methotrexate, leflunomide, hydroxychloroquine, azathioprine, mycophenolate, tofacitinib, belimumab, anti-TNF, anti-IL-6 or anti-IL-1 regimens (n=14; 3; 9; 1; 2; 1; 1; 5; 2; 1, respectively). Sex-matched apparently healthy individuals (n=45) served as controls. RESULTS: Baseline cortisol levels and time-integrated cortisol response to tetracosactide were lower in patients than controls (12.01±4.47 vs. 15.63±4.16 mcg/dl, p=0.001, and 1050±286 vs. 1284±182, p<0.001, respectively). No significant associations were observed between the cortisol response to tetracosactide and age, duration of disease or glucocorticoid treatment. An abnormal Synacthen test, indicative of adrenal insufficiency, presumably secondary to chronic glucocorticoid administration, was noted in 5/25 patients. The remaining 20 patients (80%) had normal Synacthen test demonstrating, however, lower cortisol response than controls, independently of age (ß-coefficient=-0.373, p=0.033). CONCLUSIONS: Patients with RMD in remission under DMARDs who relapse upon concomitant low glucocorticoid dose tapering should be tested for iatrogenic adrenal insufficiency. Whether a marginally normal Synacthen test should discourage further attempts to withdraw glucocorticoid treatment in these patients warrants further investigation.

Prevalence of the BRAF V600E mutation in Greek adults with Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations. The activation of the MAP kinase pathway plays an integral role in its pathogenesis with genetic alterations found in the majority of cases that most frequently involve a somatic mutation of the oncogenic BRAFV600E variant. In this study we investigated the prevalence of the BRAFV600E mutation and its clinical relevance in adult Greek patients with LCH. Among 37 patients studied, the BRAFV600E mutation was identified in 12 out of 31 (38.7%), whereas in six patients (19.3%) the results were in conclusive. The presence of the mutation did not correlate with age at diagnosis, organ involvement, disease extent, response to initial treatment, development of diabetes insipidus and relapse risk. In our series the prevalence of the BRAFV600E mutation is at the lower range of the relative percentage found in children, but in line to that obtained in previous studies of adult patients with LCH that have found an up to 50% prevalence of the BRAFV600E mutation in these patients. Further studies with a larger number of adults are needed to identify the exact prevalence of mutations in the RAS-RAF-MEK-ERK pathway and their role on clinical parameters and disease outcomes.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2029988 .

Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Teriparatide Treatment in Patients with Pregnancy- and Lactation-Associated Osteoporosis.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disease, presenting in most cases with severe back pain due to low energy vertebral fractures (VFs). Our purpose was to assess the effect of teriparatide (TPTD) vs. conventional management on areal bone mineral density (aBMD) and trabecular bone score (TBS) in patients with PLO. A multicenter retrospective cohort study concerning premenopausal women with PLO. Nineteen women were treated with TPTD (20 µg/day) (group A) plus calcium and vitamin D and eight women with calcium and vitamin D only (group B) for up to 24 months. The primary end-point was between group differences in lumbar spine (LS) and total hip (TH) aBMD, and TBS at 12 and 24 months. Patients in group A had sustained a median of 4.0 VFs (3-9) vs. 2.5 VFs (1-10) in group B (p = 0.02). At 12 months, patients on TPTD vs. controls achieved a mean aBMD increase of 20.9  ±  11.9% vs. 6.2  ±  4.8% at the LS (p < 0.001), 10.0  ±  11.6% vs. 5.8  ±  2.8% at the TH (p = 0.43), and 6.7  ±  6.9% vs. 0.9  ±  3.7% in TBS (p = 0.09), respectively. At 24 months, seven patients on TPTD and six controls achieved a mean LS aBMD increase of 32.9  ±  13.4% vs. 12.2  ±  4.2% (p = 0.001). P1NP levels during the first month of TPTD treatment were positively correlated with the 1-year LS aBMD change (r = 0.68, p = 0.03). No new clinical fractures occurred while on-treatment. In patients with PLO, TPTD treatment resulted in significantly greater increases in LS aBMD compared with calcium and vitamin D supplementation at 12 and 24 months.

Efficacy of Antiosteoporotic Medications in Patients With Rebound-Associated Fractures After Denosumab Discontinuation.

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.

Evaluation of Insulin-Like Activity of Novel Zinc Metal-Organics toward Adipogenesis Signaling.

Diabetes mellitus is a debilitating disease, plaguing a significant number of people around the globe. Attempts to develop new drugs on well-defined atoxic metalloforms, which are capable of influencing fundamental cellular processes overcoming insulin resistance, has triggered an upsurge in molecular research linked to zinc metallodrugs. To that end, meticulous efforts were launched toward the design and synthesis of materials with insulin mimetic potential. Henceforth, trigonelline and N-(2-hydroxyethyl)-iminodiacetic acid (HEIDAH2) were selected as organic substrates seeking binding to zinc (Zn(II)), with new crystalline compounds characterized by elemental analysis, FT-IR, X-rays, thermogravimetry (TGA), luminescence, NMR, and ESI-MS spectrometry. Physicochemical characterization was followed by in vitro biochemical experiments, in which three out of the five zinc compounds emerged as atoxic, exhibiting bio-activity profiles reflecting enhanced adipogenic potential. Concurrently, well-defined qualitative-quantitative experiments provided links to genetic loci responsible for the observed effects, thereby unraveling their key involvement in signaling pathways in adipocyte tissue and insulin mimetic behavior. The collective results (a) signify the quintessential role of molecular studies in unearthing unknown facets of pathophysiological events in diabetes mellitus II, (b) reflect the close associations of properly configured molecular zincoforms to well-defined biological profiles, and (c) set the stage for further physicochemical-based development of efficient zinc antidiabetic metallodrugs.

Aggravated Dental and Periodontal Status in Patients with Sickle Cell Disease and Its Association with Serum Ferritin.

AIM: The present study aimed to evaluate the possible consequences of sickle cell disease (SCD) on dental and periodontal health in middle-aged patients and to examine the association of certain cardiovascular parameters and serum ferritin with the dental and periodontal status. MATERIALS AND METHODS: Thirty-seven patients (mean age 43.2 years old) with SCD and 30 non-SCD and otherwise healthy individuals (mean age 38.9 years old) were examined for caries experience and periodontal status in addition to cardiovascular characteristics and ferritin level in serum. RESULTS: Compared to controls, SCD patients exhibited higher plaque and gingival bleeding scores, higher prevalence of periodontal diseases, and higher caries experience. Multiple stepwise linear regression analysis showed that caries experience was predominantly determined by the presence of SCD and the age, while major determinants of periodontitis were the ferritin levels and the male gender. The results reveal an aggravation of oral health in SCD patients regarding both caries and periodontal diseases. CONCLUSION: A potential role of the increased central inflammatory response, reflected by the elevated ferritin level in serum, is suggested for the impaired periodontal health of SCD patients. CLINICAL SIGNIFICANCE: Compliance with precautionary dental checks and early management of dental complications is of great importance in order to improve oral health status and prevent general health complications in SCD patients.

Changes in peripheral monocyte populations 48-72 hours after subcutaneous denosumab administration in women with osteoporosis.

OBJECTIVES: To examine the effect of denosumab administration in the peripheral blood white cell population, to further elucidate a plausible pathophysiological link between denosumab and osteonecrosis of the jaw. METHODS: Thirty women with osteoporosis, after denosumab treatment were included. Peripheral blood samples were obtained prior to and 48-72 hours following denosumab administration. Flow cytometry gated at the monocyte population for CD14/CD23/CD123/CD16 stainings were performed. RESULTS: We were able to record a number of changes in the monocyte populations between baseline and after denosumab administration. Most importantly, in the monocyte populations we were able to detect statistically significant increased populations of CD14+/CD23+ (p=0.044), CD14-/CD23+ (p=0.044), CD14+/CD123+ (p=0.011), CD14+/CD123- (p=0.011) and CD14-/CD16+ (p=0.028). In contrast, statistically significant decreased populations of CD14-/CD123+ (p=0.034), CD14+/CD16+ (p=0.037) and CD14+/CD16- (p=0.014) were detected. CONCLUSIONS: Our results provide evidence supporting the hypothesis that denosumab administration modifies the monocyte mediated immune response in a manner similar to that of bisphosphonates. This may partly explain the trivial immunity changes recorded with denosumab.

Gender Predilection in Sporadic Parathyroid Adenomas.

Primary hyperparathyroidism is a common endocrinopathy that is mainly caused by benign parathyroid adenomas. The frequency, clinical presentation and complications of the disease show significant differences between genders, with the majority of cases being reported in postmenopausal women. Due to this gender predilection, several studies have investigated the role of sex hormones in the pathogenesis of the disease and their potential use as targets for optimal and gender-specific management. Epigenetic mechanisms that regulate gene transcription may also contribute to these differences between genders. In this review, we outline what is currently known regarding the role of sex hormones and the recent data on the role of non-coding RNAs in the differences between genders in primary hyperparathyroidism due to sporadic parathyroid adenomas.

Effects of systematic bisphosphonate use in patients under orthodontic treatment: a systematic review.

BACKGROUND: Bisphosphonates are a class of drugs prescribed for several osseous related disorders owing to their ability to regulate bone turnover, which could in turn affect orthodontic treatment outcomes. OBJECTIVE: To examine the effect of bisphosphonate (BP) use on orthodontic patients through clinical and radiographic measurements. SEARCH METHODS: Systematic and unrestricted search of 17 databases complemented with additional hand-searches were performed up to March 2019. SELECTION CRITERIA: Articles reporting on human patients with a history of BPs administration that received orthodontic treatment were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data regarding the medical profile of the patients, the specific type of malocclusion and the performed treatment plan, as well as the clinical and radiographic outcomes were extracted. Quality assessment was performed by the ROBINS-I tool for the cohort studies and by a slightly modified checklist from the original one proposed by Agbabiaka et al. for the case reports. RESULTS: 7 articles (1 retrospective cohort study and 6 case reports) were eventually included in the present review including 122 subjects (29 patients and 93 controls) reporting on the clinical and radiographic changes following orthodontic treatment of patients during or after BPs use. BPs seem to have a controversial effect on the clinical and patient-reported variables, even though the majority of the included patients presented with compromised treatment results and a rather slow rate of tooth movement. Most radiographic findings revealed mild root resorption, widened periodontal ligament spaces and sclerotic changes on the surrounding alveolar bone. However, these results should be interpreted with caution, due to the limited number of the eligible articles and their limitations. LIMITATIONS: The included studies were of rather low quality due to study design and incomplete reporting. CONCLUSIONS AND IMPLICATIONS: BP administration seems to be associated with compromised clinical outcomes, prolonged treatment time, and moderate changes on the roots and surrounding tissues of orthodontic patients. REGISTRATION: Non-registered. FUNDING: None.

Circulating noggin levels following treatment with denosumab or teriparatide in postmenopausal women with low bone mass.

OBJECTIVES: Noggin inactivates bone morphogenetic proteins (BMPs), possibly exerting negative effects on the skeleton.We aimed to compare the effect of agents with opposite impact on bone turnover on noggin circulating levels. METHODS: In this observational, open label, non-randomized clinical study postmenopausal women with low bone mass were treated with either denosumab (n=30) or teriparatide (n=30). Serum samples were obtained at baseline, three and twelve months after treatment initiation. Prevalent fractures were recorded at baseline and lumbar spine bone mineral density (LS BMD) was measured at baseline and twelve months. Measured parameters included noggin, BMP-2, BMP-4, procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTx). RESULTS: Noggin levels remained unchanged after either denosumab or teriparatide treatment. Baseline noggin levels were not different between women with vs. without previous anti-osteoporotic treatment, or between those with vs. without vertebral or non-vertebral fractures and were not correlated with age or LS BMD. At twelve months, noggin levels were positively correlated with P1NP within the denosumab (rs= 0.47; p=0.014), whereas negatively within the teriparatide group (rs= -0.43; p=0.019). CONCLUSIONS: In postmenopausal women with low bone mass noggin levels were not correlated with bone parameters at any time point, except with P1NP at 12 months, and remained stable with both denosumab and teriparatide treatment.

The "dark matter" of DNA and the regulation of bone metabolism: The role of non-coding RNAs.

Epigenetics, present a new discipline that attempts to explain significant differences in phenotypes among patients with the same disease. In contrast to the other epigenetic mechanisms that modulate gene transcription, non-coding RNAs act at the post-transcriptional level. They directly modulate the gene expression of mRNA genes leading to mRNA target cleavage and degradation and translation repression. Bioinformatic predictions indicate that non coding RNAs may be involved in the regulation of 60% of the coding genes and each non-coding RNA can have multiple target genes, and each gene may be regulated by more than one non-coding RNAs. In the last decade several studies have shown a significant role of non-coding RNAs in the regulation of bone metabolism and function of bone cells opening a new era in the understanding of bone biology in health and disease.