Calcium sensing receptor and renal mineral ion transport.

Calcium sensing receptor (CaSR) is a component of the C family of the G protein-coupled receptors. It is ubiquitously expressed in human and mammal cells but is more expressed in parathyroid glands and kidney cells. It is located on the cell plasma membrane and senses the changes of extracellular calcium concentrations. Thus, it may modify cell functions according to serum calcium levels. CaSR has a key role in calcium homeostasis because it allows parathyroid glands and kidney to regulate PTH secretion and calcium reabsorption in order to keep serum calcium concentration within the normal range. CaSR appears as an important player in the regulation of renal calcium handling and body calcium metabolism. Thus, CaSR may protect human tissues against calcium excess. In kidneys, its protective effect includes the stimulation of diuresis and phosphate retention, along with the potential prevention of calcium precipitation and deposition in kidney tubules and interstitium.

Role of calcium-sensing receptor in bone biology.

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Carboxyl-terminal parathyroid hormone fragments: biologic effects.

Carboxyl-terminal PTH fragments (C-PTH), are generated by both direct secretion from parathyroids in relation to serum calcium levels and catabolism of PTH operated by the Kupffer cells in the liver. These molecular fragments have been till recently regarded as inert byproducts of PTH metabolism, since they do not interact with the PTH/PTH-related peptide (rP) receptor, which mediates the classical hormone actions. Current findings instead indicate that C-PTH would interact with a putative C-PTH receptor. This way, C-PTH seem to exert specific effects on calcium homeostasis and bone metabolism, opposite to those of the synthetic agonist of PTH/PTHrP receptor (i.e. PTH 1-34). In vitro and in vivo data actually indicate that C-PTH, by interacting with specific receptors, could have an anti-calcemic action, as well as a pro-apoptotic effect on both osteocytes and osteoclasts. This in turn could result in a reduced activity of the latter cells, with a consequent inhibition of bone resorption.

Asymptomatic primary hyperparathyroidism: surgical and medical management.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, frequently asymptomatic. Notwithstanding, mild PHPT may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. The definitive therapy for symptomatic and asymptomatic PHPT (aPHPT) is parathyroidectomy, which has been shown to increase BMD. In patients who choose not to be treated surgically or have contraindications for surgery, medical therapy should include drugs designed to protect the skeleton and/or to lower serum calcium, such as bisphosphonates, hormone replacement, and/or calcimimetic agents. However, there are currently no fracture data for any of these options. Obviously, there is the need for larger randomized controlled trials with fractures as end-points to evaluate the efficacy of medical treatment.

The role of PPARγ for the osteoblastic differentiation.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily and functions as a heterodimer with a retinoid X receptor by binding to PPAR responsive elements. PPARγ plays an important role in adipocyte differentiation and is activated by long-chain fatty acid, peroxisome proliferators, and thiazolidinedione (TZD). TZD are agonists of PPARγ, act as insulin-sensitizing agents, and are widely prescribed in the management of different conditions characterized by insulin resistance. Osteoblasts and marrow adipocytes derive from common multipotential mesenchymal stem cell (MSC) progenitors. Lineage commitment of MSC is determined by expression and/or activation of specific transcription factors, such as Runx2 and Osterix in the case of osteoblasts, and PPARγ in the case of adipocytes. Many evidences indicate an important role of PPARγ in bone metabolism. Heterozygous PPARγ-deficient (PPARγ +/-) mice exhibit enhanced bone formation with increased osteoblastogenesis. Embryonic stem cells derived from PPARγ +/- mice spontaneously differentiate into osteoblasts. In mice and rats, the activation of PPARγ by TZD treatment, such as rosiglitazone (Rosi), causes bone loss, which results from an increase of marrow adipocytes and a decrease of osteoblasts, leading to a reduction of bone formation rate. Human studies have shown that pre- and post-menopausal women treated with Rosi have an increased risk of fracture compared to women treated with metformin and glyburide. Moreover, the modulation of the PPARγ expression is also implicated in the effects of mechanical loading on bone and in age-related bone loss.

Bone fragility in men: where are we?

Osteoporosis in men is an increasingly important clinical issue. About one in three osteoporotic fractures occur in men, and the consequences of these fractures are generally more severe than in women. Despite these evidences, osteoporosis remains under-recognized and undertreated in men. This review provides a summary of recent developments about the causes, pathogenesis, and treatment of osteoporosis in men.

Skeletal effect of natural early menopause.

It is well-known that women with spontaneous or natural early menopause (NEM) (between ages of 40 and 45 yr) experience an increased risk of overall mortality, cardiovascular diseases, osteoporosis, neurological and/or psychiatric diseases, and other sequelae. On the contrary, the role of NEM is more contentious on the long-term bone consequences. The published data highlight that NEM has an ambiguous effect on bone mineral density, and is associated with an increased incidence of fractures, likely related to other risk factors rather than to osteoporosis. Therefore, an estrogen treatment should be considered for these women, especially if osteopenia is present at age of menopause.

Hyperhomocysteinemia: a biochemical link between bone and cardiovascular system diseases?

Homocysteine (HCY) is a sulfur-containing amino acid involved in two metabolic pathways, catalized by cystathionine-B-synthase and methionine synthase, depending on vitamin (vit) B6, B12, and folate levels and enzymatic activity of methylenetetrahydrofolate. High HCY levels (HHCY) are associated with cardiovascular (CV) and bone diseases, in particular osteoporosis (OP)/hip fracture. As regards the mechanisms involved in the link between HHCY, CV diseases (CVD), and OP, it has been proposed the role of lysyl-oxydase inhibition that might interfere with collagen crosslink formation. Some studies suggested the dysregulation of the osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK) ligand/RANK axis, others the involvement of oxidative stress. These mechanisms may act both on bone and CV system, but whether the common denominator is HCY itself or HCY is merely a marker, remains to be clearly established. Folate, vit B6, and B12 supplementation is associated with HCY reduction, but is unable to certainly reduce the incidence of OP/fracture and CVD, probably because, in the majority of patients, HCY is only moderately increased.

Salt intake, hypertension, and osteoporosis.

A high salt intake has been correlated with several pathological conditions such as hypertension, cardiovascular disease, renal calcium stones, and osteoporosis. Some of these diseases present a high prevalence in the elderly and common pathogenetic mechanisms are proposed for some of them. A high salt intake has been associated with hypertension as well as osteoporosis and one of the proposed pathogenetic mechanisms is an increased calcium excretion in urine. Urinary calcium loss induces a negative calcium balance that may predispose hypertensive subjects to developing greater bone loss. The gene which encodes for the thiazide- sensitive sodium-chloride cotransporter (NCCT) represents a possible link between hypertension and osteoporosis. Subjects heterozygous for an inactivating mutation of NCCT present a positive effect on bone density as shown by the significantly higher Z-scores at the lumbar spine and total femur. Recent clinical studies also support the benefit of ACE inhibitors in reducing fracture risk or improving bone metabolism. These data suggest that the renin-angiotensin system may be one of the several factors involved in bone metabolism. Hypertension, together with stroke, has been demonstrated to be a risk factor for osteoporosis. Although the risk associated with hypertension was limited in terms of relative risk, it may have a significant impact on the general population owing to the high prevalence of hypertension. The treatment of hypertension may thus be very useful in also giving protection against fractures.

Skeletal effects of oral anticoagulants.

Vitamin K antagonists (VKA) are often used as oral anticoagulants (OA) in order to prevent thromboembolic diseases. In bone, vitamin K reduces bone resorption and functions as a co-factor in the post-translational carboxylation of several bone proteins. Osteocalcin (OC), the most abundant of these bone matrix proteins, is produced by osteoblasts and released in small amounts in blood as a specific marker of bone formation. Carboxylated proteins have a high affinity for calcium and are important in the incorporation of calcium into bone and bone formation. The increased levels of undercarboxylated osteocalcin can bring about an alteration of the bone mineral density and the risk of fracture, even if contradictory results have been observed in several epidemiologic studies. However, some, but not all reports, find that vitamin K deficiency, induced by hydroxycoumarins, may be associated with low bone mass. Additionally, epidemiologic studies have found that the use of OA may be associated with either increased or no change in fracture risk. Such divergent results may imply that human studies are compromised by the physical illnesses for which OA were prescribed. Additional epidemiological or cohort studies are warranted in order to determine whether potential pharmacological effects of VKA on bone metabolism may have clinical consequences.

Bisphosphonates and atherosclerosis.

The relevance of association between osteoporosis and cardiovascular disease in clinical settings, and the evidence of a biological linkage between bone and vascular calcification, encourage the search of drugs that may act as dual-purpose therapies, concordantly enhancing bone density and reducing atherosclerosis. Bisphosphonates (BP) reduce bone resorption and fracture risk, and also seem to have the potential to reduce atherosclerotic process. This unexpected activity is the result of their interference with cholesterol synthesis, inflammatory progression, and oxidative stress. Although most animal studies show a clear anti-atherogenic activity of BP, data in humans are not consistent or conclusive, given the high affinity of BP for bone, which prevents them from accumulating in other tissues at the concentration required to exert a clear pharmacological effect.

Role of apoptosis in osteoporosis induced by glucocorticoids.

Glucocorticoid (GC)-induced osteoporosis (GIO) is a common and serious complication of prolonged systemic GC use. Bone loss with risk of fractures resulting from GC therapy is a relatively common disorder, and is the most prevalent form of secondary osteoporosis. It is generally accepted that GC can cause a rapid bone loss, decreasing bone formation and increasing bone resorption in vitro as well as in vivo. The decrease in bone formation has been mainly attributed to GC effects on osteoblastogenesis and osteocyte apoptosis, while the increase in bone resorption has been referred to an extension of the life-span of pre-existing osteoclasts. This article focuses on newer molecular aspects regarding the apoptotic mechanisms involved in the pathogenesis of GIO and is based on a presentation that was held at the 3rd Congresso Nazionale in Osteoporosi Secondarie e Endocrinopatie, in Ancona, Italy, October 2007.

Biochemical markers in glucocorticoid-induced osteoporosis.

Following the introduction of corticosteroids as therapeutic agents in the 1950s, their use has been expanded so that today glucocorticoids are widely used. There are few studies in the literature directly aimed at describing the changes of bone markers following glucocorticoid administration. The interpretation of some of these investigations may be hampered by a number of confounding factors, whose influence is not always taken into consideration. In general, the effects of glucocorticoid administration are represented by a reduction in bone formation markers (particularly considering serum osteocalcin levels) and a trend to an increase or no change in bone resorption markers. The inconsistency of this last finding may be related to the time at which the observation is carried out and to the marker employed.

Densitometry in glucocorticoid-induced osteoporosis.

The technique of choice for the measurement of bone mineral density (BMD) in patients with glucocorticoid-induced osteoporosis (GIOP) is dual X-ray absorptiometry (DXA), which has been demonstrated to be reliable in diagnosing osteoporosis and monitoring bone mass variations over time in GIOP. However, in patients with both exogenous (i.e. due to glucocorticoid therapy) and endogenous cortisol excess, the BMD decrease does not fully explain the high risk of fractures. Therefore, the BMD thresholds in guidelines for the prevention of GC-related fractures are different and debated. Quantitative computed tomography (QCT), which is useful to separately study cortical and trabecular bone and to measure true "volumetric" BMD, has been suggested to be a better predictor of vertebral fractures than DXA. However, QCT has the limit of the possible underestimation of bone mass and QCT T-scores may be lower as compared to DXA T-score values for the same skeletal site. Quantitative ultrasound, which is considered to reflect both BMD and structural properties of bone such as connectivity and elasticity, is able to diagnose low BMD in GIOP, but its role in monitoring BMD changes and in predicting fracture's risk remains unknown. Low BMD and high rate of bone loss have been suggested to be possible complications even of subclinical hypercortisolism regardless for gender and gonadal status. On the other hand, low BMD and vertebral fractures may be the initial presentation of an otherwise asymptomatic cortisol excess.

Adrenal incidentaloma: effects on bone metabolism.

The effects of clinically inapparent adrenal masses or adrenal incidentalomas (AI) on bone metabolism are a controversial clinical problem related to their activity. Most of these lesions are non-functioning tumors and only a small percentage of patients exhibits a subclinical hypercortisolism (SH). The degree of clinical appearance of SH varies with the extent of hormone overproduction. However, it is controversial, up to now, if this disorder is associated with long-term morbidity and if the treatment to reverse subtle glucocorticoid excess is beneficial. Patients with AI represent an ideal field to evaluate if alterations of bone turnover may be considered a precocious sign of an abnormal pattern of endogenous steroid secretion. Several small trials have highlighted in AI with and without SH reduced levels of osteocalcin (OC), probably due to a reducted bone formation induced by a subtle excess of glucocorticoids. In patients with AI with and without SH low levels of OC might be considered a precocious sign of an abnormal pattern of slight cortisol hypersecretion and could become one of the pivotal criteria to decide whether these tumors deserve surgical excision.

Effect of natural early menopause on bone mineral density.

OBJECTIVES: Early menopause (EM) is included among the risk factors for osteoporosis. Several studies have shown that women with early menopause have lower bone mineral density (BMD) than those with normal expected age of menopause. The aim of our cross-sectional study was to investigate the effects of time of menopause on vertebral bone mass in healthy postmenopausal women and to evaluate if early menopause is a risk factor for lower vertebral BMD. METHOD: We studied 782 who had never received drugs acting on bone mass. The study population was divided into three groups: women with early, normal (NM), and late (LM) menopause. Our study population was further categorized in 5-year age segments between 45 and >75. RESULTS: The three groups examined did not differ for age, age at menarche, body mass index (BMI), and vertebral BMD, while there were significant differences in age at menopause and years since menopause. Our study showed that women with EM presented significantly lower vertebral BMD than NM and LM in 50-54 age segments. Beyond 55 years, EM, NM, and LM women had no differences in lumbar BMD values. CONCLUSIONS: In conclusion, controversial data demonstrated that the absolute amount of bone loss is greater after early menopause than after normal or late menopause, even if a slight effect of early menopause on bone mass cannot be excluded.