Tumor-induced hypophosphatemic osteomalacia is a rare disease and its diagnosis presents certain difficulties. This is primarily due to small tumor size and to the absence of local clinical symptoms. Adult-onset newly diagnosed hypophosphatemia concurrent with hyperphosphaturia is a sign of tumor-induced hypophosphatemic osteomalacia. The paper describes a female patient with fibroblast growth factor 23-secreting tumor of the upper third of the femur. After tumor removal, pharmacological treatment involves prescribing calcium supplements and active vitamin D metabolite until normal bone mineral density is restored.

Background: Endogenous hypercortisolism due to Cushing’s disease (CD) is complicated by low-traumatic fractures in 50% of cases. Modern technologies allow to study pathogenetic changes in the regulation of bone remodeling in hypercortisolism and to offer new serum biomarkers.Aims: To evaluate levels of Wnt proteins related to bone remodeling regulation in serum samples from patients with CD.Materials and methods: Fasting serum samples were taken and stored in aliquot at ≤-80 °C from 42 consecutive subjects with clinically evident and biochemically confirmed active CD and 42 healthy volunteers matched by age, sex and body mass index (BMI). Evaluation of the levels of Wnt proteins (Wnt3a, Wnt10b) was measured by immunochemiluminescence assay using the WNT3a SEL818Hu (USCN) and the WNT10b SEP553Hu (USCN). Twenty-four hours urine free cortisol (24hUFC) (60−413 nmol/24h) and bone turnover markers was measured by electrochemiluminescence assay on a Cobas 6000 Module e601 (Roche). At the time of enrollment all participants were questioned regarding any low traumatic fractures for the period of the disease. Patients underwent standard spinal radiographs in anterior-posterior and lateral positions of the vertebrae Th4−L4 (Axiom Icons R200 Siemens).Results: The median (Ме Q25; Q75) age of patients with CD was 33 (21; 43) years with no difference among the groups, p=0.936; BMI ― 29 (23; 34) kg/m2, p=0.094 and without differences by sex, p=0.254. The median 24hUFC in subjects with CD ― 825 (301; 2077) nmol/24h was significantly higher as compared to the control group (p0.001). We report increased levels of Wnt3a and Wnt10b in patients with CD: Wnt3а 0.15 (0.04; 0.23) ng/ml in patients with CD vs 0,04 (0.01; 0.13) ng/ml in control group (p=0.017) and Wnt10b 2621 (2226; 3688) pg/ml vs 1917 (1721; 2549) pg/ml (p=0.008).Conclusions: The serum level of Wnt3a and Wnt10b reflects the intensity of Wnt-signaling dysregulation, and therefore they may be considered as biomarkers of bone remodeling deterioration in hypercortisolism.

Excessive hormone secretion during hypercorticism and acromegaly results in significant disturbances in bone remodeling, decrease in bone quality, and bone fractures following small traumas. However, the mechanisms of the development of such changes are not clear. In the present study, we examined specimens of bone tissue from patients with endogenous hypercorticism (increased cortisol secretion) and acromegaly (increased growth hormone secretion) obtained during transnasal adenomectomy. Our main purpose was to analyze the expression of genes responsible for osteogenesis in the bone tissue specimens from patients with hypercorticism and acromegaly, targeting an assessment of pathogenetic aspects associated with bone complications. The study included 19 specimens of bone tissue from patients with pituitary tumors (samples with acromegaly, Cushing disease, and inactive pituitary adenomas; the latter served as a control group). We revealed 14 genes (ACP5, ALPL, BGLAP, BMP7, CD40, COL1A1, COL1A2, IGF1, IGFBP2, IL6, LEP, LTA, MMP2, WNT10B) which appeared to be the most important and require further detailed study. The present study confirmed the key role of the Wnt-signaling pathway in the osteogenic process. In addition, we present new data on molecular mechanisms of development of skeletal complications in the case of cortisol and growth hormone oversecretion in humans.

Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts.

The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.

This review describes the epigenetic regulation of osteoblastogenesis and osteoclastogenesis and its future implementation in the diagnosis and treatment of osteoporosis. A considerable part of the review is dedicated to the microRNAs (miRNAs). miRNAs are small regulatory factors that regulate gene expression, by post-transcriptional regulation of genes playing an important role in numerous cellular processes, including cell differentiation and apoptosis. Recently, a number of studies have revealed that miRNAs participate in bone homeostasis and their role in the pathogenesis of osteoporosis is practically evident. In this review, we highlight the miRNAs involved in bone remodelling and their roles in osteoporosis. miRNAs are stable molecules which make them promising potential markers for bone remodeling and osteoporosis.

This review discusses the recent evidence showing that the skeleton itself produces at least two hormones: fibroblast growth factor 23 (FGF23) and osteocalcin. FGF23 is secreted by osteocytes in bone and acts on the kidney to inhibit 1-alpha-hydroxilation ofvitamin D and promote phosphorous excretion. The affinity of FGF23 to FGF receptor is low, but FGF23 binds to FGF receptor-Klotho complex with more affinity. Therefore, Klotho determines the kidney-specific action of FGF23. Increase in FGF23 or Klotho levels due to genetic defects or ectopic production results in low serum phosphorous levels in humans. Contrary to this, low FGF23 or Klotho levels lead to hypophosphatemia and ectopic calcification. Mouse genetics studies revealed that osteoblast product, osteocalcin, in its undercarboxylated stage acts on the pancreatic beta-cells to enhance insulin production and on peripheral tissues to increase glucose utilization as a result of increased insulin sensitivity and to reduce visceral fat. In addition to this, undercarboxylated osteocalcin may also have another hormonal role, this time as a mediator of testosterone secretion. Osteocalcin was shown to induce testosterone production in Leydig cells of the testes both in ex vivo and in vivo studies. In both localizations, at the pancreas and at the testes osteocalcin acts through the GPCR6A receptor, this activates the cAMP response element-binding protein signaling pathway. Thus, this review reports the recent studies indicating bone ’s role as an endocrine organ.