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ZusammenfassungDie Schilddrüsenhormone L-Thyroxin und 3,3',5-Triiod-L-thyronin spielen eine zentrale Rolle im Skelettwachstum und beim Erhalt eines gesunden Knochens im Erwachsenenalter. Auf zellulärer Ebene sind die Wirkungen von Schilddrüsenhormonen in Osteoblasten gut erforscht, während ihre Effekte auf Osteoklasten und Osteozyten nur unzureichend verstanden sind. Die Behandlung von Osteoblasten mit Schilddrüsenhormonen in vitro führt zu deren Leistungssteigerung, wobei drei wesentliche Faktoren ihre zelluläre Wirksamkeit bestimmen können: der Import in die Zelle, ihre Aktivierung oder Inaktivierung durch Dejodasen und die Verfügbarkeit der Schilddrüsenhormonrezeptoren. Präklinische Studien unter Verwendung transgener Mausmodelle zeigen, dass jeder dieser Faktoren eine wesentliche Rolle im Skelettwachstum und dem Erhalt der Knochenqualität, -struktur und -mineraldichte spielen. Schilddrüsenerkrankungen führen zu unterschiedlichen skelettalen Veränderungen im Kindes- und Erwachsenenalter und können in der Regel durch eine Therapie gut behandelt werden. Sowohl eine Hypo- als auch Hyperthyreose kann, wenn unbehandelt, im Kindesalter zu Kleinwuchs führen. In erwachsenen Betroffenen verursacht eine manifeste Hyperthyreose eine sekundäre Osteoporose mit erhöhten Frakturrisiko infolge eines gesteigerten Knochenaufbaus und -abbaus. Eine Hypothyreose hingegen verlangsamt den Knochenumbauzyklus und steigert die sekundäre Mineralisierung. Da Schilddrüsenhormone den Knochenumbau direkt regulieren können, nehmen sie ebenfalls Einfluss auf die Kalzium- und Phosphathomöostase im Körper. Zusammengefasst sind Schilddrüsenhormone wichtige Regulatoren des Knochen- und Mineralstoffwechsels.

The use of standard procedures for the diagnosis of osteoporosis and assessment of fracture risk significantly decreased during the COVID-19 pandemic, while the incidence of fragility fractures was mostly unaltered. Both COVID-19 per se and its treatments are associated with a negative impact on bone health. Preclinical models show that mice infected with SARS-CoV2 even without symptoms display loss of trabecular bone mass two weeks post infection, due to increased numbers of osteoclasts. Osteoporosis medications do not aggravate the clinical course of COVID-19, while preclinical data suggests possible beneficial effects of some therapies. While vitamin D deficiency is clearly associated with a worse clinical course of COVID-19, evidence of improved patient outcome with vitamin D supplementation is lacking. Osteoporosis treatment should not be generally discontinued, and recommendations for substituting therapies are available. Osteoporosis therapies do not interfere with the efficacy or side-effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination.

Context Many different inherited and acquired conditions can result in premature bone fragility/low bone mass disorders (LBMDs). Objective We aimed to elucidate the impact of genetic testing on differential diagnosis of adult LBMDs and at defining clinical criteria for predicting monogenic forms. Methods Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score Results In total, 20.8% of the participants carried rare disease-causing variants (DCVs) in genes known to cause osteogenesis imperfecta (COL1A1, COL1A2), hypophosphatasia (ALPL), and early-onset osteoporosis (LRP5, PLS3, and WNT1). In addition, we identified rare DCVs in ENPP1, LMNA, NOTCH2, and ZNF469. Three individuals had autosomal recessive, 75 autosomal dominant, and 4 X-linked disorders. A total of 9.7% of the participants harbored variants of unknown significance. A regression analysis revealed that the likelihood of detecting a DCV correlated with a positive family history of osteoporosis, peripheral fractures (> 2), and a high normal body mass index (BMI). In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD (eg, in LRP5) were overrepresented. Conclusion The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield.

Aim The COVID-19 pandemic has influenced the management of many chronic conditions including osteoporosis as resources are re-allocated to urgent care. Methods This mini-review summarizes the effects of COVID-19 on diagnosis and management of osteoporosis. Evidence regarding possible effects of osteoporosis medications on COVID-19 outcomes and the relationship of COVID-19 vaccination to osteoporosis care is reviewed. Finally, initiation and maintenance of osteoporosis treatment during the pandemic are highlighted. Results The use of standard procedures for the diagnosis of osteoporosis and assessment of fracture risk significantly decreased during the COVID-19 pandemic, while the incidence of fragility fractures was mostly unaltered. Both COVID-19 per se and its treatments are associated with a negative impact on bone health. Osteoporosis medications do not aggravate the clinical course of COVID-19, while preclinical data suggests possible beneficial effects of some therapies. While vitamin D deficiency is clearly associated with a worse clinical course of COVID-19, evidence of outcome improvement through vitamin D supplementation is lacking. Osteoporosis treatment should not be generally discontinued, and recommendations for substituting therapies are available. Osteoporosis therapies do not interfere with the efficacy or side-effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Conclusion The diagnosis and management of osteoporosis are challenging during the COVID-19 pandemic. Osteoporosis medications are safe and effective and should be continued. Further studies will elucidate the impact of the COVID-19 pandemic on long-term bone health.

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone–derived cells as healthy experimental controls.

Purpose of Review: To review the pathophysiology, the clinical consequences as well as way of mitigating the effects of denosumab discontinuation. Recent Findings: Treatment with denosumab (DMAB) is reversible and upon discontinuation there is a rapid increase in bone turnover and a subsequent bone loss. During this phase of high bone turnover, an increased risk of fractures has been reported. Therefore, treatment with DMAB could be considered life-long. However, side-effects may prompt the need for discontinuation and moreover, treatment with DMAB may have increased BMD to levels where continuing treatment does not provide further fracture risk reduction. Patients stopping DMAB should be offered subsequent antiresorptive treatment with an intense monitoring regimen during the initial year as most of the bone loss occurs within these initial 12 months. Summary: In this review, we evaluated the literature published over the past 1 to 3 years investigating DMAB withdrawal with focus on bone turnover markers, bone mineral density, and fracture risk and the transition to other anti-osteoporosis therapies. Furthermore, we summarized the current recommendations of international guidelines. Mini Abstract: In this review, we evaluated the literature published over the past 1 to 3 years investigating denosumab (DMAB) discontinuation and the transition to other anti-osteoporosis therapies. Additionally, we summarized the current recommendations of international guidelines.

Hyperthyroidism causes secondary osteoporosis through favoring bone resorption over bone formation, leading to bone loss with elevated bone fragility. Osteocytes that reside within lacunae inside the mineralized bone matrix orchestrate the process of bone remodeling and can themselves actively resorb bone upon certain stimuli. Nevertheless, the interaction between thyroid hormones and osteocytes and the impact of hyperthyroidism on osteocyte cell function are still unknown. In a preliminary study, we analyzed bones from male C57BL/6 mice with drug-induced hyperthyroidism, which led to mild osteocytic osteolysis with 1.14-fold larger osteocyte lacunae and by 108.33% higher tartrate-resistant acid phosphatase (TRAP) activity in osteocytes of hyperthyroid mice compared to euthyroid mice. To test whether hyperthyroidism-induced bone changes are reversible, we rendered male mice hyperthyroid by adding levothyroxine into their drinking water for 4 weeks, followed by a weaning period of 4 weeks with access to normal drinking water. Hyperthyroid mice displayed cortical and trabecular bone loss due to high bone turnover, which recovered with weaning. Although canalicular number and osteocyte lacunar area were similar in euthyroid, hyperthyroid and weaned mice, the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive osteocytes was 100% lower in the weaning group compared to euthyroid mice and the osteocytic TRAP activity was eightfold higher in hyperthyroid animals. The latter, along with a 3.75% lower average mineralization around the osteocyte lacunae in trabecular bone, suggests osteocytic osteolysis activity that, however, did not result in significantly enlarged osteocyte lacunae. In conclusion, we show a recovery of bone microarchitecture and turnover after reversal of hyperthyroidism to a euthyroid state. In contrast, osteocytic osteolysis was initiated in hyperthyroidism, but its effects were not reversed after 4 weeks of weaning. Due to the vast number of osteocytes in bone, we speculate that even minor individual cell functions might contribute to altered bone quality and mineral homeostasis in the setting of hyperthyroidism-induced bone disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

ZUSAMMENFASSUNGAufgrund ihrer hohen und mit zunehmendem Alter steigenden Prävalenz in der Allgemeinbevölkerung sind Osteoporose und Diabetes mellitus globale Gesundheitsprobleme. Osteoporose kann sowohl mit antiresorptiven, als auch osteoanabolen Medikamenten erfolgreich behandelt werden. Während diese Medikamente bei Patientinnen mit postmenopausaler und Patienten mit männlicher Osteo porose eindeutig das Frakturrisiko senken, ist noch unklar, ob sie bei Menschen mit diabetischer Knochenerkrankung die gleiche Wirksamkeit haben. Darüber hinaus sind aus dem Knochen stammende Zytokine (Osteokine) in der Lage, den Glukosestoffwechsel zu beeinflussen. Es ist denkbar, dass Medikamente gegen Osteoporose durch ihre Modulation des Knochen umsatzes und insbesondere der Osteokine den Blutzuckermetabolismus beeinflussen können. Die Modulation des Knochenumsatzes durch Osteoporosemedikamente scheint für den Glukosestoff- wechsel des Menschen jedoch keine klinisch bedeutsame Rolle zu spielen. Substanzen aus der Gruppe der Bisphosphonate sind Medikamente der 1. Wahl für die Behandlung der Osteoporose bei diabetischen Patient/-innen, während Denosumab für ältere Pa tient/-innen, insbesondere bei eingeschränkter Nierenfunktion, geeignet ist. Osteoanabole Substanzen wiederum kommen vorrangig bei Menschen mit schweren Formen von Osteoporose zum Einsatz.

ZUSAMMENFASSUNGDiabetes mellitus (Typ 1 und 2) kommt bei > 1,2 % aller Graviditäten vor und weist eine steigende Prävalenz auf. Schwangere Frauen mit manifestem Diabetes und ihre Kinder haben ein höheres Risiko für Komplikationen während der Schwangerschaft und perinatal. Im Rahmen der präkonzeptionellen Beratung sollte die glykämische Stoffwechsellage optimiert werden, eine Schulung bezüglich Monitorings und zu erwartenden Notfällen angeboten werden und ggf. orale Antidiabetika auf Insulin umgestellt werden. Weitere erkennbare Risiken wie Adipositas, Hypertonie, Retinopathie, Schilddrüsen- und Nierenerkrankungen sollten interdisziplinär evaluiert und behandelt werden. Folsäure und Jodid sollten verordnet werden und über die potenziellen Folgen für das Kind muss aufgeklärt werden. Wenn Frauen mit Kinderwunsch eine Normoglykämie erreichen und wenn die mütterlichen Begleitrisiken bereits präkonzeptionell optimiert werden, ist in der Regel mit einer weitgehend normalen Schwangerschaft zu rechnen.

The development of coronavirus disease 2019 (COVID‐19) vaccines has proceeded at an unprecedented pace, with numerous trials conducted simultaneously across the world as a result of massive technological and financial resource expenditures. With multiple vaccines having now received regulatory approval, public health efforts to promote widespread vaccine dissemination are currently underway. There has been particular emphasis placed on vaccination of older populations, the age group in which COVID‐19 infection has been most lethal. However, such widespread vaccination approaches have necessarily raised important questions related to potential interactions with underlying diseases and concomitant treatments among persons to be vaccinated. Osteoporosis is a chronic condition marked by reduced bone strength and an associated increased risk for fracture that generally requires sustained medical intervention(s). Osteoporosis is neither associated with a higher risk of COVID‐19 infection nor by more pronounced disease severity following infection, such that individuals with osteoporosis need not be more highly prioritized for COVID‐19 vaccination. Osteoporosis therapies do not interfere with the efficacy or side effect profiles of COVID‐19 vaccines and should not be stopped or indefinitely delayed because of vaccination. Depending on the specific drug profile within an anti‐osteoporosis medication category, minor adjustments to the timing of drug administration may be considered with respect to the patient's COVID‐19 vaccination schedule. Herein we provide practical recommendations for the care of patients requiring treatment for osteoporosis in the setting of COVID‐19 vaccination. © 2021 American Society for Bone and Mineral Research (ASBMR).

Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH.

This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic.The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking.The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.

Context Numerous studies have demonstrated detrimental skeletal consequences following bariatric surgery. Methods A working group of the European Calcified Tissue Society (ECTS) performed an updated review of existing literature on changes of bone turnover markers (BTMs), bone mineral density (BMD), and fracture risk following bariatric surgery and provided advice on management based on expert opinion. Literature review Based on observational studies, bariatric surgery is associated with a 21–44% higher risk of all fractures. Fracture risk is time-dependent and increases approximately 3 years after bariatric surgery. The bariatric procedures that have a malabsorptive component (including Roux-en-Y Gastric bypass (RYGB) and biliopancreatic diversion (BPD)) have clearly been associated with the highest risk of fracture. The extent of high-turnover bone loss suggests a severe skeletal insult. This is associated with diminished bone strength and compromised microarchitecture. RYGB was the most performed bariatric procedure worldwide until very recently, when sleeve gastrectomy (SG) became more prominent. There is growing evidence that RYGB is associated with greater reduction in BMD, greater increase in BTMs, and higher risk of fractures compared with SG but RCTs on optimal management are still lacking. Expert opinion In all patients, it is mandatory to treat vitamin D deficiency, to achieve adequate daily calcium and protein intake and to promote physical activity before and following bariatric surgery. In post-menopausal women and men older than 50 years, osteoporosis treatment would be reasonable in the presence of any of the following criteria: i) history of recent fragility fracture after 40 years of age, ii) BMD T-score ≤ −2 at hip or spine, iii) FRAX score with femoral neck BMD exceeding 20% for the 10-year major osteoporotic fracture probability or exceeding 3% for hip fracture. Zoledronate as first choice should be preferred due to intolerance of oral formulations and malabsorption. Zoledronate should be used with caution due to hypocemia risk. It is recommended to ensure adequate 25-OH vitamin D level and calcium supplementation before administering zoledronate. Conclusions The bariatric procedures that have a malabsorptive component have been associated with the highest turnover bone loss and risk of fracture. There is a knowledge gap on osteoporosis treatment in patients undergoing bariatric surgery. More research is necessary to direct and support guidelines.

Context Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment. Objective To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis. Design Observational, open label, nonrandomized clinical trial. Setting A single-center outpatient clinic. Patients and Interventions Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6). Main Outcome Measures Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment. Results Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P Conclusions TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.

Was ist neu? Epidemiologie Aufgrund der demografischen Entwicklung wird eine steigende Prävalenz osteoporotischer Frakturen und demzufolge ein höherer Versorgungsbedarf erwartet. Trotz der Häufigkeit osteoporotischer Frakturen (ca. 765 000 Fragilitätsfrakturen pro Jahr in Deutschland) und zahlreicher Therapieoptionen erhalten in den meisten Ländern, einschließlich Deutschland, nur etwa 10 % aller Patienten eine leitliniengerechte Behandlung. Diagnostik der Osteoporose Zur Einschätzung des Frakturrisikos ist neben der Messung der Knochendichte die Beurteilung des Sturzrisikos von entscheidender Bedeutung. Ein problemorientiertes geriatrisches Assessment zur Abschätzung des Sturzrisikos sollte neben Muskelkraft, Gehgeschwindigkeit und Ernährungszustand auch die psychische und kognitive Situation umfassen. Bei Frauen über 70 Jahren und Männern über 80 Jahren ist das Alter per se der dominierende Risikofaktor für eine Fraktur. Insbesondere nach osteoporotischen hüftnahen Femurfrakturen kann hier von einer Messung der Knochendichte abgesehen werden. Therapie Bewegung kombiniert mit gezieltem Training von Kraft, Ausdauer, Koordination und Balance sind neben einem allgemein gesunden und aktiven Lebensstil Grundpfeiler einer effektiven Sturz- und Frakturprävention. Eine ausreichende Versorgung mit Kalzium und Vitamin D sollte vor dem Einsatz spezifischer Osteoporose-Medikamente garantiert sein. Die zugelassenen Osteoporose-Medikamente sind gut verträglich und reduzieren auch bei geriatrischen Patienten das Frakturrisiko. Die Therapie der Osteoporose beim geriatrischen Patienten ist immer eine individualisierte Therapie. Konsequenz für den klinischen Alltag Eine effektive Osteoporose-Therapie in der Geriatrie erfordert einen ganzheitlichen, interdisziplinären Ansatz.

Osteoporosis is a chronic condition that reflects reduced bone strength and an associated increased risk for fracture. As a chronic condition, osteoporosis generally requires sustained medical intervention(s) to limit the risks for additional bone loss, compromise of skeletal integrity, and fracture occurrence. Further complicating this issue is the fact that the abrupt cessation of some therapies can be associated with an increased risk for harm. It is in this context that the COVID-19 pandemic has brought unprecedented disruption to the provision of health care globally, including near universal requirements for social distancing. In this Perspective, we provide evidence, where available, regarding the general care of patients with osteoporosis in the COVID-19 era and provide clinical recommendations based primarily on expert opinion when data are absent. Particular emphasis is placed on the transition from parenteral osteoporosis therapies. It is hoped that these recommendations can be used to safely guide care for patients with osteoporosis until a return to routine clinical care standards is available. © 2020 American Society for Bone and Mineral Research.

Thyroid hormones are indispensable for bone development and growth. Also in adults, bone mass maintenance is under the control of thyroid hormones. Preclinical and clinical studies established untreated hyperthyroidism as a cause for secondary osteoporosis with increased fracture risk. Thus, normal thyroid function is essential for bone health. Mechanistically, thyroid hormone excess accelerates bone turnover with predominant bone resorption. How thyroid hormones affect osteoblast and osteoclast functions, however, still remains ill-defined. The Wnt signaling pathway is a major determinant of bone mass and strength as it promotes osteoblastogenesis and bone formation, while inhibiting bone resorption. So far, only few studies investigated a possible link between thyroid hormones, bone metabolism and the Wnt pathway. In this review, we summarize the literature linking thyroid hormones to bone homeostasis through Wnt signaling and discuss its potential as a therapeutic approach to treat hyperthyroidism-induced bone loss.

INTRODUCTION. Tumor- and bone-derived soluble factors have been proposed to participate in the alterations of skeletal muscle size and function in cachexia. We previously showed that mice bearing ovarian cancer (OvCa) exhibit cachexia associated with marked bone loss, whereas bone-targeting agents, such as bisphosphonates, are able to preserve muscle mass in animals exposed to anticancer drugs. MATERIAL AND METHODS. De-identified CT images and plasma samples from female patients affected with OvCa were used for body composition assessment and quantification of circulating CTX-I and NFkB ligand RANKL, respectively. Female mice bearing ES-2 tumors were used to characterize cancer- and RANKL-associated effects on muscle and bone. Murine C2C12 and human HSMM myotube cultures were used to determine the OvCa- and RANKL-dependent effects on myofiber size. RESULTS. To the extent of isolating new regulators of bone and muscle in cachexia, here we demonstrate that subjects affected with OvCa display evidence of cachexia and increased bone turnover. Similarly, mice carrying OvCa present high RANKL levels. By using in vitro and in vivo experimental models, we found that elevated circulating RANKL is sufficient to cause skeletal muscle atrophy and bone resorption, whereas bone preservation by means of antiresorptive and anti-RANKL treatments concurrently benefits muscle mass and function in cancer cachexia. CONCLUSIONS. Altogether, our data contribute to identify RANKL as a novel therapeutic target for the treatment of musculoskeletal complications associated with RANKL-expressing non-metastatic cancers.

Bone-forming approaches to treat patients with severe osteoporosis are effective, but treatment options are limited, and there is an unmet clinical need for additional drugs. This review discusses two novel and advanced anabolic therapeutic concepts that have successfully completed phase 3 trials. Romosozumab is a monoclonal antibody that targets the Wnt inhibitor sclerostin. Two phase 3 trials (FRAME and ARCH) of romosozumab for the treatment of postmenopausal osteoporosis have been completed. Both trials successfully reached their primary endpoint by reducing vertebral fractures by 75% compared to placebo (FRAME trial) and 48% compared to alendronate (ARCH trial), respectively. Abaloparatide is a PTH-related protein (PTHrP) analog that has displayed bone anabolic activity. In the phase 3 ACTIVE trial, abaloparatide was compared to placebo and teriparatide for 18 months in postmenopausal women who had already experienced an osteoporotic fracture. Abaloparatide successfully reduced the rate of new vertebral fractures by 86% compared to placebo. Furthermore, abaloparatide achieved greater BMD increases at all measured sites compared to both placebo and teriparatide. Based on these results, abaloparatide was FDA approved in April 2017. This review discusses available data of both agents with regard to efficacy and safety as well as their possible future application.

Introduction Solid organ transplantation is an established therapy for end-stage organ failure. Both pre-transplantation bone disease and immunosuppressive regimens result in rapid bone loss and increased fracture rates. Methods The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the consequences of end-stage kidney, liver, heart, and lung disease on bone health. Moreover, we assessed the characteristics of post-transplant bone disease and the skeletal effects of immunosuppressive agents and aimed to provide recommendations for the prevention and treatment of transplantation-related osteoporosis. Results Characteristics of bone disease may differ depending on the organ that fails, but patients awaiting solid organ transplantation frequently depict a wide spectrum of bone and mineral abnormalities. Common features are a decreased bone mass and impaired bone strength with consequent high fracture risk, all of which are aggravated in the early post-transplantation period. Conclusion Both the underlying disease leading to end-stage organ failure and the immunosuppression regimens implemented after successful organ transplantation have detrimental effects on bone mass, quality and strength. Given existing ample data confirming the high frequency of bone disease in patients awaiting solid organ transplantation, we recommend that all transplant candidates should be assessed for osteoporosis and fracture risk and, if indicated, treated before and after transplantation. Since bone loss in the early post-transplantation period occurs in virtually all solid organ recipients and is associated with glucocorticoid administration, the goal should be to use the lowest possible dose and to taper and withdraw glucocorticoids as early as possible.

Thyroid hormones are critical regulators of bone metabolism. Their cellular import is guided through transporter proteins, including the monocarboxylate transporter 8 (MCT8). Conditional Mct8 knockout in osteoblast and osteoclast precursors leads to trabecular bone gain in 12-week-old male mice. Given that thyroid hormones regulate both skeletal development and bone maintenance, we investigated the effect of bone cell-specific Mct8 deletion in 6-week-old (young) and 24-week-old (adult) male mice. Mct8 ablation in osteoclast precursors led to trabecular bone gain at the spine in 6-week-old animals compared to age-matched controls, whereas adult animals displayed a shift towards trabecular bone loss in both femur and vertebra. Mct8 deficiency in osteoprogenitors increased osteoblast numbers and trabecular bone mass at the spine of young mice, without skeletal differences between adult knockout mice and littermate controls. In contrast, young mice lacking Mct8 in late osteoblasts/osteocytes exhibited lower trabecular bone volume at the spine and femur compared to respective controls, but no differences were detected at 24 weeks of age. In vitro studies of osteoblasts with Dmp1-Cre promotor driven Mct8 deletion showed no significant alterations of osteogenic marker gene expression and mineralization capacity suggesting that MCT8 is not crucial for osteoblast maturation. Overall, we observed mild effects with conditional Mct8 knockout on bone microarchitecture and bone turnover especially during growth implying a secondary role for MCT8 as a thyroid hormone transporter in bone.

Introduction: Adjuvant endocrine therapy induces bone loss and increases fracture risk in women with hormone-receptor positive, early-stage breast cancer (EBC). We aimed to update a previous position statement on the management of aromatase inhibitors (AIs) induced bone loss and now included premenopausal women. Methods: We conducted a systematic literature search of the medical databases from January 2017 to May 2020 and assessed 144 new studies. Results: Extended use of AIs beyond 5 years leads to persistent bone loss in breast cancer extended adjuvant trials and meta-analyses. In addition to bone mineral density (BMD), vertebral fracture assessment (VFA) and trabecular bone score (TBS) were shown to independently predict fracture risk in real life prospective studies. FRAX® tool does not seem to be reliable for assessing fracture risk in CTIBL. In premenopausal women, there is strong evidence that intravenous zoledronate prevents bone loss but weak conflicting evidence on reducing disease recurrence from independent randomised controlled trials (RCTs). In postmenopausal women, the strongest evidence for fracture prevention is for denosumab based on a well-powered RCT while there is strong evidence for bisphosphonates (BPs) to prevent and reduce CTIBL but no convincing data on fractures. Adjuvant denosumab has failed to show anticancer benefits in a large, well-designed RCT. Discussion and conclusions: Extended use of AIs and persistent bone loss from recent data reinforce the need to evaluate fracture risk in EBC women initiated on AIs. Fracture risk should be assessed with clinical risk factors and BMD along with VFA, but FRAX is not adapted to CTIBL. Anti-resorptive therapy should be considered in those with a BMD T-score < −2.0 SD or with ≥ 2 clinical risk factors including a BMD T-score < −1.0 SD. In premenopausal women, intravenous zoledronate is the only drug reported to prevent bone loss and may have additional anticancer benefits. In postmenopausal women, either denosumab or BPs can be prescribed for fracture prevention with pertinent attention to the rebound phenomenon after stopping denosumab. Adjuvant BPs, in contrast to denosumab, have shown high level evidence for reducing breast cancer recurrence in high-risk post-MP women which should be taken into account when choosing between these two., SCOPUS: re.j, info:eu-repo/semantics/published

Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures and significant long-term disability. Although both anti-resorptive treatments and osteoanabolic drugs, such as parathyroid hormone analogues, are effective in fracture prevention, limitations exist due to lack of compliance or contraindications to these drugs. Thus, there is a need for novel potent therapies, especially for patients at high fracture risk. Romosozumab is a monoclonal antibody against sclerostin with a dual mode of action. It enhances bone formation and simultaneously suppresses bone resorption, resulting in a large anabolic window. In this opinion-based narrative review, we highlight the role of sclerostin as a critical regulator of bone mass and present human diseases of sclerostin deficiency as well as preclinical models of genetically modified sclerostin expression, which led to the development of anti-sclerostin antibodies. We review clinical studies of romosozumab in terms of bone mass accrual and anti-fracture activity in the setting of postmenopausal and male osteoporosis, present sequential treatment regimens, and discuss its safety profile and possible limitations in its use. Moreover, an outlook comprising future translational applications of anti-sclerostin antibodies in diseases other than osteoporosis is given, highlighting the clinical significance and future scopes of Wnt signaling in these settings.

Context Denosumab discontinuation is characterized by an increase in bone turnover overriding pretreatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients. Methods A working group of the European Calcified Tissue Society performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion. Results Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment. Conclusions A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing randomized controlled trials. Patients who have sustained VFx should be offered prompt treatment to reduce high bone turnover.