Osteoporosis complicating some inborn or acquired diseases.

Osteoporosis in chronic diseases is very frequent and pathogenetically varied. It complicates the course of the underlying disease by the occurrence of fractures, which aggravate the quality of life and increase the mortality of patients from the underlying disease. The secondary deterioration of bone quality in chronic diseases, such as diabetes of type 1 and type 2 and/or other endocrine and metabolic disorders, as well as inflammatory diseases, including rheumatoid arthritis - are mostly associated with structural changes to collagen, altered bone turnover, increased cortical porosity and damage to the trabecular and cortical microarchitecture. Mechanisms of development of osteoporosis in some inborn or acquired disorders are discussed.

Involvement of bone in systemic endocrine regulation.

The skeleton shows an unconventional role in the physiology and pathophysiology of the human organism, not only as the target tissue for a number of systemic hormones, but also as endocrine tissue modulating some skeletal and extraskeletal systems. From this point of view, the principal cells in the skeleton are osteocytes. These cells primarily work as mechano-sensors and modulate bone remodeling. Mechanically unloaded osteocytes synthetize sclerostin, the strong inhibitor of bone formation and RANKL, the strong activator of bone resorption. Osteocytes also express hormonally active vitamin D (1,25(OH)(2)D) and phosphatonins, such as FGF23. Both 1,25(OH)(2)D and FGF23 have been identified as powerful regulators of the phosphate metabolism, including in chronic kidney disease. Further endocrine cells of the skeleton involved in bone remodeling are osteoblasts. While FGF23 targets the kidney and parathyroid glands to control metabolism of vitamin D and phosphates, osteoblasts express osteocalcin, which through GPRC6A receptors modulates beta cells of the pancreatic islets, muscle, adipose tissue, brain and testes. This article reviews some knowledge concerning the interaction between the bone hormonal network and phosphate or energy homeostasis and/or male reproduction.

New molecules modulating bone metabolism - new perspectives in the treatment of osteoporosis.

In this review the authors outline traditional antiresorptive pharmaceuticals, such as bisphosphonates, monoclonal antibodies against RANKL, SERMs, as well as a drug with an anabolic effect on the skeleton, parathormone. However, there is also a focus on non-traditional strategies used in therapy for osteolytic diseases. The newest antiosteoporotic pharmaceuticals increase osteoblast differentiation via BMP signaling (harmine), or stimulate osteogenic differentiation of mesenchymal stem cells through Wnt/beta-catenin (icarrin, isoflavonoid caviunin, or sulfasalazine). A certain promise in the treatment of osteoporosis is shown by molecules targeting non-coding microRNAs (which are critical for osteoclastogenesis) or those stimulating osteoblast activity via epigenetic mechanisms. Vitamin D metabolites have specific antiosteoporotic potencies, modulating the skeleton not only via mineralization, but markedly also through the direct effects on the bone microstructure.

Hormonal and bone parameters in pubertal girls.

Here we analyzed associations between muscles mass, total bone mineral content (BMC), lumbar spine bone density (BMD L1-L4) and serum or urine hormones in healthy peripubertal girls. Total BMC and areal BMD L1-L4, muscle mass and fat were measured by dual-energy X-ray absorptiometry (DXA). Muscle force (N) was estimated by a dynamometer. Circulating estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 25-hydroxy vitamin D, parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), leptin, osteocalcin, bone isoenzyme of alkaline phosphatase (bALP) and total calcium and phosphorus were quantified as the nocturnal melatonin and serotonin urinary excretion. Partial correlations adjusted for height, Tanner score and physical activity confirmed positive relationships between BMC or BMD L1-L4 (Z-score) and lean mass or fat. Furthermore, positive relationship was observed between BMC or BMD L1-L4 (Z-score) and serum leptin. After adjustment for Tanner score and physical activity, positive associations were observed between lean mass and IGF-1, leptin levels or muscle force. We proved positive relationships between bone mass and serum leptin in peripubertal girls.

Trace elements have beneficial, as well as detrimental effects on bone homeostasis.

The protective role of nutrition factors such as calcium, vitamin D and vitamin K for the integrity of the skeleton is well understood. In addition, integrity of the skeleton is positively influenced by certain trace elements (e.g. zinc, copper, manganese, magnesium, iron, selenium, boron and fluoride) and negatively by others (lead, cadmium, cobalt). Deficiency or excess of these elements influence bone mass and bone quality in adulthood as well as in childhood and adolescence. However, some protective elements may become toxic under certain conditions, depending on dosage (serum concentration), duration of treatment and interactions among individual elements. We review the beneficial and toxic effects of key elements on bone homeostasis.

Hypercalcemia. Pathophysiological aspects.

The metabolic pathways that contribute to maintain serum calcium concentration in narrow physiological range include the bone remodeling process, intestinal absorption and renal tubule resorption. Dysbalance in these regulations may lead to hyper- or hypocalcemia. Hypercalcemia is a potentionally life-threatening and relatively common clinical problem, which is mostly associated with hyperparathyroidism and/or malignant diseases (90 %). Scarce causes of hypercalcemia involve renal failure, kidney transplantation, endocrinopathies, granulomatous diseases, and the long-term treatment with some pharmaceuticals (vitamin D, retinoic acid, lithium). Genetic causes of hypercalcemia involve familial hypocalciuric hypercalcemia associated with an inactivation mutation in the calcium sensing receptor gene and/or a mutation in the CYP24A1 gene. Furthermore, hypercalcemia accompanying primary hyperparathyroidism, which develops as part of multiple endocrine neoplasia (MEN1 and MEN2), is also genetically determined. In this review mechanisms of hypercalcemia are discussed. The objective of this article is a review of hypercalcemia obtained from a Medline bibliographic search.

Polymorphisms associated with low bone mass and high risk of atraumatic fracture.

Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In the pathogenesis of osteoporosis, except environment and internal factors, such as hormonal imbalance and genetic background, are also in play. In this study candidate genes for osteoporosis were classified according to metabolic or hormonal pathways, which regulate bone mineral density and bone quality (estrogen, RANKL/RANK/OPG axis, mevalonate, the canonical circuit and genes regulating the vitamin D system). COL1A1 and/or COL1A2 genes, which encode formation of the procollagen 1 molecule, were also studied. Mutations in these genes are well-known causes of the inborn disease 'osteogenesis imperfecta'. In addition to this, polymorphisms in COL1A1 and/or COL1A2 have been found to be associated with parameters of bone quality in adult subjects. The authors discuss the perspectives for the practical utilization of pharmacogenetics (identification of single candidate genes using PCR) and pharmacogenomics (using genome wide association studies (GWAS) to choose optimal treatment for osteoporosis). Potential predictors of antiresorptive therapy efficacy include the following well established genes: ER, FDPS, Cyp19A1, VDR, Col1A1, and Col1A2, as well as the gene for the canonical (Wnt) pathway. Unfortunately, the positive outcomes seen in most association studies have not been confirmed by other researchers. The controversial results could be explained by the use of different methodological approaches in individual studies (different sample size, homogeneity of investigated groups, ethnic differences, or linkage disequilibrium between genes). The key pitfall of association studies is the low variability (7-10 %) of bone phenotypes associated with the investigated genes. Nevertheless, the identification of new genes and the verification of their association with bone density and/or quality (using both PCR and GWAS), remain a great challenge in the optimal prevention and treatment of osteoporosis.

Bone tissue as a systemic endocrine regulator.

Bone is a target tissue for hormones, such as the sex steroids, parathormon, vitamin D, calcitonin, glucocorticoids, and thyroid hormones. In the last decade, other "non-classic" hormones that modulate the bone tissue have been identified. While incretins (GIP and GLP-1) inhibit bone remodeling, angiotensin acts to promote remodeling. Bone morphogenetic protein (BMP) has also been found to have anabolic effects on the skeleton by activating bone formation during embryonic development, as well as in the postnatal period of life. Bone has also been identified as an endocrine tissue that produces a number of hormones, that bind to and modulate extra-skeletal receptors. Osteocalcin occupies a central position in this context. It can increase insulin secretion, insulin sensitivity and regulate metabolism of fatty acids. Moreover, osteocalcin also influences phosphate metabolism via osteocyte-derived FGF23 (which targets the kidneys and parathyroid glands to control phosphate reabsorption and metabolism of vitamin D). Finally, osteocalcin stimulates testosterone synthesis in Leydig cells and thus may play some role in male fertility. Further studies are necessary to confirm clinically important roles for skeletal tissue in systemic regulations.

New insights into the physiology of bone regulation: the role of neurohormones.

Bone metabolism is regulated by interaction between two skeletal cells - osteoclasts and osteoblasts. Function of these cells is controlled by a number of humoral factors, including neurohormones, which ensure equilibrium between bone resorption and bone formation. Influence of neurohormones on bone metabolism is often bimodal and depends on the tissue, in which the hormone is expressed. While hypothalamic beta-1 and beta-2-adrenergic systems stimulate bone formation, beta-2 receptors in bone tissue activate osteoclatogenesis and increases bone resorption. Chronic stimulation of peripheral beta-2 receptors is known to quicken bone loss and alter the mechanical quality of the skeleton. This is supported by the observation of a low incidence of hip fractures in patients treated with betablockers. A bimodal osteo-tropic effect has also been observed with serotonin. While serotonin synthetized in brain has osteo-anabolic effects, serotonin released from the duodenum inhibits osteoblast activity and decreases bone formation. On the other hand, both cannabinoid systems (CB1 receptors in the brain and CB2 in bone tissue) are unambiguously osteo-protective, especially with regard to the aging skeleton. Positive (protective) effects on bone have also been shown by some hypophyseal hormones, such as thyrotropin (which inhibits bone resorption) and adrenocorticotropic hormone and oxytocin, both of which stimulate bone formation. Low oxytocin levels have been shown to potentiate bone loss induced by hypoestrinism in postmenopausal women, as well as in girls with mental anorexia. In addition to reviewing neurohormones with anabolic effects, this article also reviews neurohormones with unambiguously catabolic effects on the skeleton, such as neuropeptide Y and neuromedin U. An important aim of research in this field is the synthesis of new molecules that can stimulate osteo-anabolic or inhibiting osteo-catabolic processes.

[Regional migrating osteoporosis - a case report]. / Regionální migrující osteoporóza -  diferenciálne dia-gnostický problém.

Regional migrating osteoporosis (RMO) was observed in young man with episodes of bone pain in bearing joints, which migrated from hip to leg and subsequently to knee on the unilateral side. Dynamic scintigraphy (SPECT) carried out during relapse of pain demonstrated increased accumulation of radioizotope in Lisfrank joint, distal epiphysis of femur and proximal epiphysis of tibia on the unilateral side due to hyperperfusion and high metabolic turnover in these regions of the skeleton. Dia-gnosis of RMO was confirmed by magnetic resonance (MRI), which showed bone marrow edema of corresponding regions. Although RMO is relatively benign disease with spontaneous remissions, infection etiology or the more serious avascular necrosis should be taken into account.

[Drug induced osteoporosis]. / Léky indukovaná osteoporóza.

Loss of bone mass resulting from the treatment of chronic diseases is not unusual. However, osteoporosis in such patients is typically diagnosed too late, usually after a fracture appears. Particular attention should be given to glucocorticoids, which are commonly used in internal medicine. These hormones delay bone formation (via inhibition of osteoblast differentiation and osteoblast function) and activate bone resorption (through RANKL). Moreover, glucocorticoids inhibit calcium absorption from the intestines, which results in hypocalcemia. Following hyperparathyroidism further accelerates bone resorption. Severe damage to bone microstructure and its mechanical characteristics leads to atraumatic fractures. Bone loss sustained during glucocorticoid treatment occurs very early (3-5 % of bone mass in the first year and up to 1 % each year thereafter). Fortunately, most skeletal damage is reversible with early supplementation of vitamin D and calcium. Osteopenia (osteoporosis) complicates long-term treatment with supressive doses of thyroid hormone most often in females with hypoestrinism. L-thyroxine administered in doses > 0.093 mg/day leads to bone resorption, which is in part due to suppressed (low) levels ofTSH. Medications which pose a high risk of fracture are those which induce hypoestrinism (aromatase inhibitors) and antiandrogens (GnRH agonists). Similarly, some oral antidiabetics (such as thiazolindiones) promote adipogenesis to the detriment of osteogenesis, which increases bone loss. Fractures are also frequently observed in patients treated with selective serotonin reuptake inhibitors, anti-epileptics, diuretics, anticoagulation drugs and proton pump inhibitors. This review discusses the mechanisms of bone damage induced by the abovementioned pharmaceuticals.

[Soft tissues, hormones and the skeleton]. / Mekké tkáne, hormony a skelet.

Mechanical load activates bone modeling and increases bone strength. Thus physical activity is extremely important for overall bone health. Muscle volume and muscle contraction are closely related to bone mineral density in men and women, although these relationships are more significat in men. The muscle-bone unit has been defined as a functional system, in which both components are under control of the somatotropin-IGF-I system, androgens and D hormone. These endocrine systems play, via the muscle-bone unit, an important role in development of the skeleton and its stability in adulthood. That is why deficiency of any of these hormonal systems, or reduced physical activity (mainly in childhood) could seriously affect bone density and quality. Bone is also under control of adipose tissue, which modulates its metabolism via mechanical load and more importantly via adipocytokines (leptin, adiponectin and rezistin). Leptin increases bone formation by activation of osteoblasts. This direct effect of leptin is amplified by stimulation of the ß-1 adrenergic system, which inhibits the negative osteotropic effects of neuropeptide Y. On the other hand, leptin also activates ß-2 adrenergic receptors, which increase bone resorption. In humans, the overall osteo-anabolic effect of leptin tends to be dominant. Furthermore, leptin has a principal role in the start of puberty in girls and maturation, remodeling and development of the female skeleton. Adiponectin (and probably rezistin) has an unambiguous deteriorating effect on the skeleton. Further studies are needed to confirm the clinical importance of soft tissues relative to the integrity of the skeleton.

[Neuro-skeletal biology and its importance for clinical osteology]. / Neuro-skeletáirní biologie a její význam pro klinickou osteologii.

Bone remodeling is determined by function of two basic cell forms--bone resorbing osteoclasts and bone formation activating osteoblasts. Both cells are under control of a variety of endogenic and environmental factors, which ensure balance between bone resorption and bone formation. This article reviews the neuro-hormonal factors with osteoanabolic (central isoform of serotonin, melatonin, cannabinoids, beta 1 adrenergic system, oxytocin, ACTH and TSH) or osteocatabolic effects (neuropeptide Y, neuromedin U, beta2 adrenergic system). The dual effects of the beta-adrenergic system, serotonin and leptin are also discussed. The goal of studies focused on neuro-skeletal interaction is to synthesize new molecules, which can modify osteo-anabolic or osteo-catabolic pathways.

[Role of genetics in prediction of osteoporosis risk]. / Význam genetiky v predikci rizika osteoporózy.

Osteoporosis is in 60-80% a hereditary disease with a characteristic multifactorial pathogenesis during which the effects of many "weak" genes interact with external factors. To date, most information relating to the correlations between genes and bone parameter variability (density, quality and metabolism) has been provided by association studies of candidate genes for osteoporosis. The best known genes related to bone density have been identified as the genes for the vitamin D, estrogen and calcitonin receptor, LRP5 and LRP6. The genes for IL-1alpha and osteoprotegerin are responsible for the parameters of bone remodeling. Recently discovered genes related to bone phenotype include identified genes for hypolactasia, tetrafolate reductase and ALDH7A1. Bone size and dimensions are probably partially controlled by the PLCL1 gene. Candidate genes for osteoporosis probably also determine the production of calciotropic hormones (PTH, sex steroids) and even some extra-osseous phenotypes (inflammation, immunity, susceptibility to malignancies). On the contrary, genes that determine extra-osseous parameters (e.g. lipoprotein levels) are associated with the bone phenotype (the gene for ApoE is related to bone density). Association studies, though, have serious limitations. Among others, these include the influence of linkage disequilibrium associated with the close proximity of the identified genes within DNA, which may be one of the causes of false positive results. In children, where building of the skeleton is influenced predominantly by external factors (nutrition, physical activity), the relationship between candidate genes and bone mass is less close than in adults. This overview deals with the physiology and sexual differentiation of pubertal bone. It discusses the importance of identifying candidate genes in the prevention and targeted treatment of osteoporosis (pharmacogenetics) as well as the application of the FRAX (WHO) program in the ten-year prediction of fractures in osteopenic patients.

[Familial hypercalcemia and hypophosphatemia: importance in differential diagnosis of disorders in calcium-phosphate metabolism]. / Familiární hyperkalcemie a hypofosfatemie a jejich význam v diferenciální diagnostice poruch kalcium-fosfátového metabolizmu.

Hypercalcemia and hypophosphatemia are symptoms of two relatively rare hereditary diseases and are extraordinarily important from the standpoint of the differential diagnosis. Mutation in calcium sensing receptor gene (CaSR) clinically manifests as familial hypocalciuric hypercalcemia (FHH) or as the much more serious neonatal hyperparathyreosis. Hypercalciuric hypocalcemia is extremely rare. Prognosis for the most frequent mutations in the CaSR gene FHH is considered benign; nevertheless, if overlooked it can lead to an incorrect diagnosis of primary hyperparathyreosis, which has a fundamentally different prognosis and treatment. Familial hypophosphatemia sometimes occurs as hereditary rickets, which is a consequence of insufficient production of vitamin D-hormone or abnormal function of vitamin D receptors (VDR). The disease manifests as X-linked dominant hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets. Autosomal recessive form is very rare. Oncogenic hypophosphatemia should be excluded in differential diagnosis. In this review the issues of pathogenesis, differential diagnosis and treatment of FHH and hypophosphatemic rickets are discussed.

[Celiac disease and its relation to bone metabolism]. / Celiakie a její vztah ke kostnímu metabolismu.

Celiac disease (nontropical sprue) is autoimmune disorder of the intestinal mucose, which usually develops in humans hypersensitive to gluten. The disease can occur at any age, with the greatest occurrence in early adulthood. Besides intestinal symptomatology--abdominal pain, diarrhoea and weight loss--celiac disease is often accompanied by extra-intestinal complications including osteopenia or osteoporosis and osteomalacia. Overproduction of cytokines IL-1 alpha, IL-1 beta and TNF-alpha increases bone resorption, which is further accelerated by hyperparathyroidism connected with malabsorption of calcium and vitamin D. Interaction of both these mechanisms activated bone loss. Similarly as the classic (symptomatic) celiac disease, the occult form, commonly seen in the elderly, may be associated with a risk of osteoporosis or osteomalacia related fractures. Diagnosis is based on positivity of IgA and IgG antigliadin and endomysial antibodies and characteristic endoscopic detection of inflammation and atrophy of duodenal mucose. Areal screening of celiac disease in osteoporotic patients is very dubious. However, a methodical examination should be performed in all patients with unexplainable hyperparathyroidism or in those with various autoimmune diseases (type 1 diabetes, thyroiditis chronica), or in premenopausal women and men, who did not reach the appropriate peak bone mass. On the other hand, detailed analysis of calcium metabolism, including markers of bone remodlling and X-ray densitometry (DXA), are recommended in all patients with verified celiac disease. The effectiveness of a gluten-free diet and substitution with vitamin D and calcium, or treatment with bisphosphonates are discussed. The promising therapy appears to be new molecules with reparative effect on intestinal mucose such as AT-1001.

[Relationships of hormones of adipose tissue and ghrelin to bone metabolism]. / Vztah hormonu tukové tkáne a ghrelinu ke kostnímu metabolizmu.

Body adipose tissue influences bone metabolism through mechanical load, as well as via hormones released into circulation. Such hormones are adipocytokines--leptin, adiponectin, TNF-alpha, IL-6, resistin and visfatin. Some of them exert an osteoanabolic effect, while the others activate bone resorption. An increasingly discussed adipocytokine is leptin, which fundamental role is regulation of food intake ensuring survival of the organism during starvation. Leptin also stimulates osteoblasts and activates bone formation. The direct osteotropic effect of leptin is modulated by interaction with hypothalamic centers and neurohormones. Apparently, the most important leptin sensitive pathway involved in bone regulation is the beta-adrenergic system. While activation of beta-1-adrenergic receptors by leptin enhances bone formation, activation of beta-2-adrenergic receptors in hypothalamus and in the skeleton increases bone resorption. In humans, an anabolic effect on the skeleton prevails. In pubertal girls, leptin extensively released into circulation at the moment when adipose tissue reaches a critical volume, stimulates synthesis of GnRH and induces puberty, which is followed by striking increases in bone mass. Low leptin levels in anorexia nervosa are associated with amenorrhoea, which slows down increase of bone mass and may induce osteopenia. Important adipocytokine with an unambiguous negative effect on bone is adiponectin. Decreased production of this hormone explains in part the lower prevalence of osteoporosis in obese persons. In this article, the osteotropic importance ofleptin-sensitive neurohormonal mechanisms and other hormones related to adipose tissue are discussed. Clinical importance of the above mentioned hormones to integrity of the skeleton has not yet been verified.

[Pathogenetically complicated case of osteoporosis in a young man]. / Patogeneticky komplikovaný prípad osteoporózy u mladého muze.

Osteoporosis, is a serious disease both in women and men, with a high risk of fractures. However, its pathogenesis differs markedly, with the secondary form being more common in men. The aim of this case study is to demonstrate the complex pathogenesis of a severe osteoporosis in a 23-year-old heavy smoker with histiocytosis X, diabetes insipidus (DI), subclinical hypogonadism and low serum levels of IGF-I. Later, after normalization of sex hormones and IGF-I levels, vasopressin substitution, cessation of smoking and after long-term antiresorption therapy, adequate increase in bone density at the hip was documented, but insufficient and very slow increase at the lumbar spine was observed. Severe osteoporosis at the spine is most probably the consequence of the interaction of smoking with multiple hormone insufficiency during development of peak bone mass. The effect of additional, unidentified factor(s) (gene or hormone) is also likely. On the other hand, a direct causal association between histiocytosis X and osteoporosis was not confirmed histomorphometrically in this patient.

Increase of nocturnal melatonin levels in hemodialyzed patients after parathyroidectomy: a pilot study.

In hemodialyzed patients hormonal disturbances are known to occur. However, melatonin levels have not been completely studied. The aim of the study was to find whether changes in calcaemia affect melatonin secretion. For this reason we followed the nocturnal serum concentrations of melatonin and parathyroid hormone (PTH) in 9 hemodialyzed patients (6 women and 3 men, aged 37-65 years) both before and 1-3 months after parathyroidectomy at 6 p.m., 9 p.m., 11 p.m., 2 a.m., 5 a.m. and 7 a.m. At 6 p.m. blood samples to evaluate the levels of calcium and phosphate were also collected. Parathyroidectomy resulted in an increase in nocturnal melatonin levels. As expected, the parathyroidectomy was followed by considerable PTH decrease. PTH showed no nocturnal variation before or after parathyroidectomy. Calcium levels significantly decreased after the operation while phosphate levels increased. In summary, in hemodialyzed patients with hyperparathyroidism, parathyroidectomy significantly increases the nocturnal secretion of melatonin. Relationships between the pineal gland and parathyroid glands have yet to be elucidated.

Hormonal aspects of the muscle-bone unit.

Osteoporotic fractures are the result of low density and especially inferior bone quality (microarchitecture) caused by both internal (genes, hormones) and external (life style) influences. Bone mechanosensors are extremely important for the overall integrity of the skeleton, because in response to mechanical load they activate its modeling, resulting in an increase in bone density and strength. The largest physiological loads are caused by muscle contractions. Bone mass in adult men has a closer relationship to muscle mass than is case in women. The sexual differences in the relationship between bone and muscle mass are also apparent in children. Based on the mechanostatic theory, the muscle-bone unit has been defined as a functional system whose components are under the common control of the hormones of the somatotropin-IGF-I axis, sexual steroids, certain adipose tissue hormones and vitamin D. The osteogenic effects of somatotropin-IGF-I system are based on the stimulation of bone formation, as well as increase in muscle mass. Moreover, somatotropin decreases the bone mechanostat threshold and reinforces the effect of physical stress on bone formation. The system, via the muscle-bone unit, plays a significant role in the development of the childhood skeleton as well as in its stability during adulthood. The muscle and bone are also the targets of androgens, which increase bone formation and the growth of muscle mass in men and women, independently of IGF-I. The role of further above-mentioned hormones in regulation of this unified functional complex is also discussed.