Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling.

Osteoblast adherence to bone surfaces is important for remodeling bone tissue. This study demonstrates that deficiency of TG-interacting factor 1 (Tgif1) in osteoblasts results in altered cell morphology, reduced adherence to collagen type I-coated surfaces, and impaired migration capacity. Tgif1 is essential for osteoblasts to adapt a regular cell morphology and to efficiently adhere and migrate on collagen type I-rich matrices in vitro. Furthermore, Tgif1 acts as a transcriptional repressor of p21-activated kinase 3 (Pak3), an important regulator of focal adhesion formation and osteoblast spreading. Absence of Tgif1 leads to increased Pak3 expression, which impairs osteoblast spreading. Additionally, Tgif1 is implicated in osteoblast recruitment and activation of bone surfaces in the context of bone regeneration and in response to parathyroid hormone 1-34 (PTH 1-34) treatment in vivo in mice. These findings provide important novel insights in the regulation of the cytoskeletal architecture of osteoblasts.

Fibrous Dysplasia of the Jaw: Advances in Imaging and Treatment.

A total of 7% of all benign bone lesions are diagnosed as fibrous dysplasia (FD). The symptoms of FD of the jaw range from asymptomatic to dental anomalies, pain and facial asymmetry. Due to its resemblance to other fibro-osseous bone lesions, misdiagnosis often occurs and can lead to inadequate treatment. Particularly in the jaw, this lesion does not become quiescent during puberty, making fundamental knowledge about the diagnosis and treatment of FD crucial. Mutational analysis and nonsurgical approaches offer new diagnostic and therapeutic options. In this review, we examine the advances and the difficulties of the diagnosis and the various treatment modalities of FD of the jaw in order to capture the current scientific knowledge on this bone disease.

Regulation of bone homeostasis by MERTK and TYRO3.

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.

Antagonizing microRNA-19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice.

Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl-Ab). Here, we show that PTH and Scl-Ab reduce the expression of microRNA-19a and microRNA-19b (miR-19a/b) in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR-19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR-19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG-interacting factor 1 (Tgif1) as the target of miR-19a/b in osteoblasts and essential for the increase in bone mass following miR-19a/b inhibition. Furthermore, antagonizing miR-19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF-κB ligand (RANKL)-dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

Muscle and Bone Defects in Metastatic Disease.

PURPOSE OF REVIEW: The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. RECENT FINDINGS: Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism have been implicated in cancer-induced regeneration defect and muscle loss. Moreover, we review novel in vitro and animal models including promising new drug candidates for bone metastases and cancer cachexia. Preservation of bone health could be highly beneficial for maintaining muscle mass and function. Therefore, a better understanding of molecular pathways implicated in bone and muscle crosstalk in metastatic disease may provide new insights and identify new strategies to improve current anticancer therapeutics.

Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss.

Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast's activity and protecting osteocytes from oxidative stresses.

Romosozumab Followed by Antiresorptive Treatment Increases the Probability of Achieving Bone Mineral Density Treatment Goals.

Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to -3.0, the probability of achieving a T-score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to -2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to -3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition.

Collagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF; also known as VEGFA) in bone-forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we used murine osteocalcin-specific Vegf knockout (OcnVEGFKO) and performed ex vivo multiscale analysis at the tibiofibular junction of both sexes. Label-free and non-destructive polarisation-resolved second-harmonic generation (p-SHG) microscopy revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed that the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-strand stability, in addition to matrix carbonation and mineralisation. Vegf deletion in male and female murine OB cultures in vitro further highlighted divergence in genes regulating local ECM structure, including Adamts2, Spp1, Mmp9 and Lama1. Our results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders that clinically manifest in pathological nano- and macro-level disorganisation. This article has an associated First Person interview with the first author of the paper.

Non-coding RNAs in bone remodelling and bone metastasis: Mechanisms of action and translational relevance.

Bone metastases are frequent complications in patients with advanced cancer, which can be fatal or may rapidly impede the quality of life of patients. Current treatments for patients with bone metastases are palliative. Therefore, a better understanding of the molecular mechanisms that precede the overt development of skeletal lesions could lead to better therapeutic interventions. In this review, we present evidence that non-coding RNAs (ncRNAs) such as long ncRNAs, microRNAs, and circular RNAs are emerging as master regulators of bone metastasis formation. We highlight potential opportunities for the therapeutic targeting of ncRNAs. Furthermore, we discuss the possibility that ncRNAs may be used as biomarkers in the context of bone metastases, which might provide insight for improving the response to current bone-targeting therapies. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.

T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial.

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Breast cancer bone metastases are attenuated in a Tgif1-deficient bone microenvironment.

BACKGROUND: Osteoclast activation is a hallmark of breast cancer-induced bone disease while little is known about the role of osteoblasts in this process. Recently, we identified the homeodomain protein TG-interacting factor-1 (Tgif1) as a crucial regulator of osteoblast function. In this study, we demonstrate that lack of Tgif1 also restricts the progression of breast cancer bone metastases. METHODS: Transwell migration assays were used to investigate the osteoblast-breast cancer cell interaction in vitro. Molecular analyses included RNA sequencing, immunoblotting, and qRT-PCR. To determine the role of Tgif1 in metastatic bone disease, 4T1 breast cancer cells were injected intracardially into mice with a germ line deletion of Tgif1 (Tgif1-/-) or control littermates (Tgif1+/+). Progression of bone metastases and alterations in the bone microenvironment were assessed using bioluminescence imaging, immunofluorescence staining, confocal microscopy, and histomorphometry. RESULTS: Medium conditioned by osteoblasts stimulated breast cancer cell migration, indicating a potential role of osteoblasts during bone metastasis progression. Tgif1 expression was strongly increased in osteoblasts upon stimulation by breast cancer cells, demonstrating the implication of Tgif1 in the osteoblast-breast cancer cell interaction. Indeed, conditioned medium from osteoblasts of Tgif1-/- mice failed to induce breast cancer cell migration compared to control, suggesting that Tgif1 in osteoblasts augments cancer cell motility. Semaphorin 3E (Sema3E), which is abundantly secreted by Tgif1-/- osteoblasts, dose-dependently reduced breast cancer cell migration while silencing of Sema3E expression in Tgif1-/- osteoblasts partially restored the impaired migration. In vivo, we observed a decreased number of breast cancer bone metastases in Tgif1-/- mice compared to control littermates. Consistently, the presence of single breast cancer cells or micro-metastases in the tibiae was reduced in Tgif1-/- mice. Breast cancer cells localized in close proximity to Endomucin-positive vascular cells as well as to osteoblasts. Although Tgif1 deficiency did not affect the bone marrow vasculature, the number and activity of osteoblasts were reduced compared to control. This suggests that the protective effect on bone metastases might be mediated by osteoblasts rather than by the bone marrow vasculature. CONCLUSION: We propose that the lack of Tgif1 in osteoblasts increases Sema3E expression and attenuates breast cancer cell migration as well as metastases formation.

[Importance of osteoporosis-related fractures for patients]. / Bedeutung osteoporosebedingter Frakturen für den Patienten.

BACKGROUND: Osteoporosis is a common disease that affects both women and men. Due to a reduced bone mineral density and increasing age, the risk for atraumatic fractures increases. These fractures cause pain due to the fracture itself and also have far-reaching sequelae in nearly all areas of life of patients. OBJECTIVE: The aim of this article is to summarize the consequences of osteoporotic fractures from the patient's point of view and to highlight the consequences of osteoporosis for the patient. The necessity for timely diagnostics and treatment after a fracture event is explained. MATERIAL AND METHODS: For each term a literature search was performed using key topic-related terms and the results are presented as a narrative review. RESULTS: Various areas of importance for patients were identified. A direct assessment of the patient's point of view was not feasible using a literature search; however, studies with surveys of patients could be identified and therefore, the patient's point of view could be integrated. Areas of interest that could be identified in the literature were pain, psychological well-being, cognitive abilities, mortality and long-term need for nursing. CONCLUSION: The effects of osteoporosis and fractures are multifactorial and often severe for the patient. The measures for prevention of osteoporotic fractures should be consistently implemented in the daily clinical routine and the necessary diagnostics and treatment should be rapidly initiated.

[Establishment of fracture liaison services in Germany]. / Etablierung von Frakturnetzwerken in Deutschland.

BACKGROUND: Osteoporosis results in fragility fractures that are associated with a high morbidity and mortality as well as an increased risk for subsequent fragility fractures. Thus, the first fragility fracture should be the last. To achieve this goal patients need treatment of osteoporosis according to the prevailing clinical guidelines. OBJECTIVE: This article presents the current clinical care situation of patients with a manifest osteoporosis in Germany and the accompanying risks. As a possible solution the concept of a fracture liaison service (FLS) as a new intersectoral care concept is presented and options for the establishment of FLS in Germany are provided. MATERIAL AND METHODS: A literature search (PubMed) was conducted using key terms. The practical experiences of the authors in the context of establishing an FLS were also considered. RESULTS: Compared to other countries, in Germany only a minority of patients receive treatment for osteoporosis after fragility fractures. To improve the care situation an intersectoral FLS provides a coordinated referral of patients with fragility fractures from inpatient care in hospitals to specialists in private practice. This enables the strict identification and treatment of high-risk patients according to the prevailing clinical guidelines. In Germany, different options exist to structure an FLS under consideration of the local circumstances. CONCLUSION: In Germany, FLS should be established nationwide and according to uniform standards. This would significantly improve the quality of clinical care of patients with manifest osteoporosis.

Regulation of the Bone Vascular Network is Sexually Dimorphic.

Osteoblast (OB) lineage cells are an important source of vascular endothelial growth factor (VEGF), which is critical for bone growth and repair. During bone development, pubertal differences in males and females exist, but little is known about whether VEGF signaling contributes to skeletal sexual dimorphism. We have found that in mice, conditional disruption of VEGF in osteocalcin-expressing cells (OcnVEGFKO) exerts a divergent influence on morphological, cellular, and whole bone properties between sexes. Furthermore, we describe an underlying sexual divergence in VEGF signaling in OB cultures in vitro independent of circulating sex hormones. High-resolution synchrotron computed tomography and backscattered scanning electron microscopy revealed, in males, extensive unmineralized osteoid encasing enlarged blood vessel canals and osteocyte lacunae in cortical bone after VEGF deletion, which contributed to increased porosity. VEGF was deleted in male and female long bone-derived OBs (OBVEGKO) in vitro and Raman spectroscopic analyses of mineral and matrix repertoires highlighted differences between male and female OBVEGFKO cells, with increased immature phosphate species prevalent in male OBVEGFKO cultures versus wild type (WT). Further sexual dimorphism was observed in bone marrow endothelial cell gene expression in vitro after VEGF deletion and in sclerostin protein expression, which was increased in male OcnVEGFKO bones versus WT. The impact of altered OB matrix composition after VEGF deletion on whole bone geometry was assessed between sexes, although significant differences between OcnVEGFKO and WT were identified only in females. Our results suggest that bone-derived VEGF regulates matrix mineralization and vascularization distinctly in males and females, which results in divergent physical bone traits.

[Influence of specific osteoporosis drugs on fracture healing]. / Einfluss spezifischer Osteoporosemedikamente auf die Frakturheilung.

BACKGROUND: For the treatment of disturbed fracture healing, drugs could be given in addition to surgical procedures. Specific osteoporosis drugs affect the bone metabolism and are used to treat osteoporosis, particularly after a fragility fracture has occurred. Therefore, their use would be conceivable to improve a disturbed fracture healing. OBJECTIVE: This article presents the available and upcoming specific osteoporosis drugs and investigates whether these substances affect fracture healing in the context of osteoporosis. Furthermore, it is discussed whether disturbed fracture healing can be improved by the use of these substances. MATERIAL AND METHODS: A literature search (PubMed) was conducted using key terms. Preclinical studies, clinical studies, reviews and meta-analyses were considered in order to present the current knowledge in a clinically relevant context. RESULTS: Preclinical and clinical studies show that specific osteoporosis drugs have no relevant negative impact on the healing of fragility fractures. A tendency to improve a disturbed fracture healing was attributed to bone anabolic substances; however, studies are inconsistent and there is no approval for this application. CONCLUSION: Following a fragility fracture, osteoporosis should be diagnosed according to the guidelines and, if necessary, treated with specific osteoporosis drugs, since in principle they do not impair fracture healing but significantly reduce the risk of subsequent fractures. Approval to improve fracture healing requires further investigations.

Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness.

Breast cancer bone metastases often cause a debilitating non-curable condition with osteolytic lesions, muscle weakness and a high mortality. Current treatment comprises chemotherapy, irradiation, surgery and anti-resorptive drugs that restrict but do not revert bone destruction. In metastatic breast cancer cells, we determined the expression of sclerostin, a soluble Wnt inhibitor that represses osteoblast differentiation and bone formation. In mice with breast cancer bone metastases, pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases without tumor cell dissemination to other distant sites. Sclerostin inhibition prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. During advanced disease, NF-κB and p38 signaling was increased in muscles in a TGF-ß1-dependent manner, causing muscle fiber atrophy, muscle weakness and tissue regeneration with an increase in Pax7-positive satellite cells. Scl-Ab treatment restored NF-κB and p38 signaling, the abundance of Pax7-positive cells and ultimately muscle function. These effects improved the overall health condition and expanded the life span of cancer-bearing mice. Together, these results demonstrate that pharmacological inhibition of sclerostin reduces bone metastatic burden and muscle weakness with a prolongation of the survival time. This might provide novel options for treating musculoskeletal complications in breast cancer patients. .

TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone.

Osteoporosis is caused by increased bone resorption and decreased bone formation. Intermittent administration of a fragment of Parathyroid hormone (PTH) activates osteoblast-mediated bone formation and is used in patients with severe osteoporosis. However, the mechanisms by which PTH elicits its anabolic effect are not fully elucidated. Here we show that the absence of the homeodomain protein TG-interacting factor 1 (Tgif1) impairs osteoblast differentiation and activity, leading to a reduced bone formation. Deletion of Tgif1 in osteoblasts and osteocytes decreases bone resorption due to an increased secretion of Semaphorin 3E (Sema3E), an osteoclast-inhibiting factor. Tgif1 is a PTH target gene and PTH treatment failed to increase bone formation and bone mass in Tgif1-deficient mice. Thus, our study identifies Tgif1 as a novel regulator of bone remodeling and an essential component of the PTH anabolic action. These insights contribute to a better understanding of bone metabolism and the anabolic function of PTH.

MicroRNAs in Bone Metastasis.

PURPOSE OF REVIEW: This review provides an update on the recent literature describing the role of microRNAs (miRNAs) in cancer formation and bone metastasis. We confined our focus on osteosarcoma, breast cancer, prostate cancer, and epithelial-mesenchymal transition. RECENT FINDINGS: In all areas covered, major discoveries on the role of miRNAs in tumorigenesis and metastasis have been made. Novel signaling networks were identified with miRNAs having a central function. Potential improvements in the diagnosis of malignant diseases and the long-term follow-up might become possible by the use of miRNAs. Furthermore, miRNAs also have disease-modifying properties and might emerge as a new class of therapeutic molecules. MiRNAs are novel and important regulators of multiple cellular and molecular events. Due to their functions, miRNAs might become useful to improve the diagnosis, follow-up and treatment of cancer, and metastases. Thus, miRNAs are molecules of great interest in translational medicine.

Sarcopenia - Endocrinological and Neurological Aspects.

Sarcopenia in geriatric patients is often associated with or even caused by changes of the endocrine and nervous system. The multifactorial pathogenesis of sarcopenia and additional multimorbidity in geriatric patients makes it difficult to study distinct pathogenic pathways leading to sarcopenia. Patients suffering from diabetes, Cushing's syndrome, chronic kidney disease, Klinefelter's syndrome or motor neuron diseases, such as amyotrophic lateral sclerosis for example are known to have impaired muscle property and reduced physical performance. These patients are typically younger and suffer from conditions caused by a known molecular disease mechanism and a peculiar sarcopenic phenotype. Therefore, these sequelae can serve as prototypic disease models to study isolated endocrinological and neurodegenerative causes for sarcopenia. This review focuses on diseases whose etiopathogenesis of muscle impairment is known. The idea is to use these diseases as proof of principles to develop a classification algorithm of sarcopenia in the elderly to make a more mechanism-oriented therapy be possible.