Teriparatide increases the maturation of circulating osteoblast precursors.

UNLABELLED: This study shows that teriparatide promotes the circulating osteoblast (OB) precursor degree of maturation in patients affected by postmenopausal osteoporosis. INTRODUCTION: Anabolic treatment with teriparatide has proven effective for the therapy of postmenopausal osteoporosis and significantly reduces the risk of non-vertebral fragility fractures. The aim of this study was to investigate the effect of teriparatide on circulating OB precursors. METHODS: We evaluated by flow cytometry and real-time PCR the expression of OBs typical markers in peripheral blood mononuclear cells during treatment with teriparatide plus calcium and vitamin D, raloxifene plus calcium and vitamin D or calcium and vitamin D alone at various time points. Serum bone alkaline phosphatase and osteocalcin (OC) were measured as markers of bone turnover. RESULTS: Our results show that circulating OB precursors are more numerous and more immature in patients affected by fragility fractures than in osteoporotic patients without fractures. We also show that teriparatide treatment increases the expression of alkaline phosphatase and of OC in OB precursors; thus, it increases their degree of maturation. CONCLUSIONS: We suggest that teriparatide acts as anabolic agents also by promoting the maturation of OB precursors.

HDL cholesterol and bone mineral density in normal-weight postmenopausal women: is there any possible association?

AIM: Epidemiological investigation of the association between lipid profile, atherosclerosis and bone mass has produced conflicting RESULTS: The present paper reports the assessment of the lipid profile, bone mineral density (BMD) and turnover in a cohort of Italian women. METHODS: In this cross sectional study we enrolled 173 women in menopause (101 osteoporotic and 72 normal). In each subject the authors evaluated BMD, bone turnover, lipid profile (total cholesterol, high density lipoprotein [HDL], low density lipoprotein [LDL] and triglycerides), and risk factors for osteoporosis, cardiovascular diseases and eating habits using a questionnaire. RESULTS: HDL was significantly higher in osteoporotic patients than in controls and the risk of osteoporosis was significantly higher in women with higher level of HDL. The authors suggest that the level of HDL could be used as screening for postmenopausal osteoporosis: the cut-off points recommended are HDL >61 mg/dL to detect women with a high risk (sensitivity 74%) and <45 mg/dL to detect those with a low risk (specificity 83%). CONCLUSION: This study provides evidences of the relation between HDL, but not total cholesterol or LDL levels with BMD in a cohort of normal-weight women and equally distributed cardiovascular risks. It also suggests that a proatherogenic lipid profile is associated with higher bone mineral density, and that HDL can be used in deciding whether a patient's BMD should be measured.

Acute adrenal crisis and hypercalcemia in a patient assuming high liquorice doses.

Two months after monolateral adrenalectomy, a 47-year-old woman stopped taking corticosteroid replacement therapy in the first 15 days of therapy. She was admitted to the Department of Internal Medicine because of hypertension, severe hypercalcemia, uncompensated metabolic alkalosis and clinical symptoms of acute adrenal insufficiency. The presence of hypokalemia and hypernatremia precluded a diagnosis of hypocortisolism, therefore no corticosteroids were given during the time required to investigate the cause of hypercalcemia, which resulted negative. Administration of intravenous saline infusion produced no improvement in her clinical condition. Despite electrolyte alterations, hydrocortison (100 mg i.v.) and zoledronate (4 mg i.v.) were also administered, leading to a rapid and marked improvement in her clinical picture within a few hours, with normalization of the calcemia and the other electrolytic disturbances. After her neurological condition had fully normalized, the patient admitted she had been assuming large amounts of liquorice as a laxative for many years; this compound very likely compensated the adrenal insufficiency by inhibiting 11 b steroid-dehydrogenase and disguised the clinical presentation at the time of admission. This case report confirms that, though rare, hypercalcemia may be a finding in acute adrenal insufficiency and can be rapidly corrected by corticosteroid administration. Furthermore, excessive liquorice intake can induce a clinical picture resembling that of primary hyperaldosteronism. In patients with adrenal insufficiency, it can, at least in part, disguise its metabolic effects and delay diagnosis and treatment.

[Fractures and chronic renal insufficiency]. / La patologia fratturativa nei diversi gradi di insufficienza renale cronica.

Chronic renal insufficiency (CRI) causes important modifications in the metabolism of phosphorus and calcium, to which frequently resulting in serious disorders of the skeleton, including demineralization, reduction of the bone resistance and a higher risk of fractures. Renal osteodystrophy is the term used to describe these disorders; they are generally heterogeneous and are classified according to the state of bone turnover into secondary hyperparathyroidism, adynamic bone, and osteomalacia. The incidence of hip fractures in the patients with CRI is higher than in the general population. Hip fractures are an important cause of morbidity and mortality. The evaluation of the fracture risk in the patients with different degrees of CRI is problematic, in particular because of the difficulty in identifying fractures, especially vertebral ones. The instrumental index that best expresses the fracture risk in the general population is bone mineral density (BMD); however, the relationship between low BMD and CRI is disputed. Bone disorders in patients with CRI have in fact a multifactorial pathogenesis and low BMD is not the only risk factor for fractures. Besides densitometric evaluation, also that vertebral morphometric evaluation would be desirable in patients with CRI. The fracture risk increases progressively with the severity of chronic renal disease and it is especially high in patients with renal insufficiency in more advanced-stages CRI (creatinine clearance<15-20 mL/min). However, not only in patients with severe CRI undergoing dialysis, but also in those with milder renal disease is the risk of bone fractures high.

Protein intake: the impact on calcium and bone homeostasis.

Bone density depends on various factors such as age, hormonal status, genetics factors and lifestyle: a balanced diet plays a fundamental role in the prevention of osteoporosis. The role of protein intake on bone health is still controversial: this review is focused on the relation between protein intake and bone metabolism.

Effects of lifestyle and risk factors on bone mineral density in a cohort of Italian women: suggestion for a new decision rule.

In this study the authors analyzed the role of risk factors in postmenopausal osteoporosis in a cohort of Italian women and evaluated predictive values of decision rules for early identification of osteoporotic women. Furthermore, the authors investigated the prevalence of secondary osteoporosis in this population. Women who underwent bone densitometry were asked to answer a questionnaire about the common risk factors for osteoporosis. Patients were classified as nonosteoporotic, nonosteopenic, and osteoporotic. Risk factors were compared among the groups by use of analysis of variance (ANOVA). National Osteoporosis Foundation (NOF) recommendation, Osteoporosis Risk Assessment Instruments (ORAIs), Osteoporosis Self-Assessment Tools (OST) score, and weight criterion were applied to this population. The authors proposed a new decision rule based on a new score. A total of 525 women received the questionnaire: 47.4% women were osteoporotic, 32.2% were osteopenic, and 20.4% nonosteoporotic. Risk factors that differed significantly between these groups were: age, age at menarche, postmenopausal period, and body mass index (BMI); the aforementioned risk factors appear to be significant predictors of bone density (BMD) in linear regression model. The incidence of secondary osteoporosis was 13%. In conclusion, the authors (1) confirmed the role played by nonmodifiable risk factors in determining BMD; (2) showed that the use of NOF guidelines, ORAI, OST score, and weight criterion is not satisfactory in our cohort; (3) suggested a new score, based upon the features that were significantly different between patients and controls; and (4) demonstrated the relatively high prevalence of secondary osteoporosis and suggest a primary screening for secondary osteoporosis in all patients with low BMD.

Is leptin the link between fat and bone mass?

Leptin is a cytokine-like hormone which is considered the link between fat and bone; it is produced by adipocytes and osteoblasts, regulates food intake via specific receptors located in the central nervous system (CNS) and bone mass through alternate pathways: one involving a direct stimulatory effect on bone formation; and another indirect effect through the CNS that suppresses bone formation. Leptin exerts a direct stimulatory effect on osteoblast differentiation and on bone growth if directly administered, while it exerts an inhibitory effect on bone formation if administered in the CNS. It is therefore unclear whether leptin should be considered an antiosteogenic factor or an anabolic agent for bone formation: in all probability, leptin has a broader role in human physiology and in particular its action has evolved in order to synchronize periods of bone growth, mineral accretion and fertility with periods of food availability, while it restricts growth and reproduction during periods of nutritional stress.

Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency.

Many study in literature have suggested a possible role of T cells and tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of bone loss that occurs in pathological conditions, such as systemic inflammatory diseases; the molecular bases through which this phenomenon occurs and the relevance of this mechanism also in estrogen deficiency induced bone loss remain unclear. In our study we observed that TNF-alpha knock-out mice (TNF-/-), as well as transgenic mice without thymus (and therefore without mature T cell), do not lose bone after ovariectomy like observed for mice of normal genetic background (wild type, WT). Moreover, after transfer into athymic mice of T cell isolated from WT ovariectomized animals (and so stimulated by estrogen deficiency to proliferate and to produce TNF-alpha), ovariectomy recovers its ability to induce bone loss; whereas there is no change in bone density after injection into athymic mice of T-cell purified from TNF-/- animals which, even if mature, are unable to produce TNF-alpha. Therefore the presence of TNF-alpha producing T-cell is essential for estrogen deficiency to influence bone metabolism. In the following study of the research group of Prof. Pacifici it has been shown that the increased activation of TNF-alpha producing T-cell in the ovariectomized mice is due to increased INF-gamma levels, resulting from ovariectomy-induced enhanced secretion of IL-12 and IL-18 by macrophages. INF-gamma promotes expression in immunocompetent cells of class II transactivator (CIITA), that, up-regulating expression of the major system of histocompatibility of class II, makes the macrophages more active in antigen presentation to T-cells, which in turn start producing TNF. For the first time an immune mechanism is involved in the pathogenesis of post-menopausal osteoporosis; nevertheless the applicability of these conclusions also in humans remains still to be proved.

Hypoparathyroidism and co-existing celiac disease.

A 62-yr-old woman with idiopathic hypoparathyroidism was admitted to our hospital for severe anemia (Hb 5.6 gr/dl) and hypoalbuminemia (3.2 gr/dl). Hypoparathyroidism was diagnosed when she was 33 yr old, because of repeated hypocalcemic tetanic crises, low calcium and high phosphate levels. Since then she has been treated with oral calcium gluconate and calcitriol, with satisfactory clinical balance and normalization of calcium serum levels. After menopause, despite this therapy, the patient still had frequent hypocalcemic tetanic crises, resolving with iv administration, in high doses, of calcium gluconate. The anemia, for which the patient came to our attention, was hypochromic microcytic and in the past she had been treated with iron and transfusion therapy. The patient's recent history also revealed recurrent long lasting episodes of diarrhea, hyporexia and weight loss. The clinical presentation seemed related to a malabsorption syndrome: a celiac disease (CD) diagnosis was confirmed, based upon the finding, at duodenal biopsy, of a severe villous atrophy. A bone mineral density (BMD) evaluation showed a limited reduction of femoral values classified as osteopenia according to the World Health Organization (WHO) criteria. Thereafter, the patient was instructed to follow a gluten-free diet which rapidly led to an improvement of the nutritional parameters and to a reduction of calcium and vitamin D requirements. Difficult clinical and metabolic control in hypoparathyroidism patients may suggest the possible co-existence of both endocrine and extra-endocrine autoimmune diseases, such as CD. Moreover, bone density, normally reduced in celiac patients, seems to be preserved (maintained) by the lack of parathyroid secretion.

Effect of raloxifene and clodronate on bone density in postmenopausal osteoporotic women.

The aim of the present study was to determine the safety and efficacy of combined therapy with raloxifene (RLX) and clodronate (CLD) in postmenopausal women. We enrolled 45 women with postmenopausal osteoporosis. The patients were randomly assigned to two different therapeutic groups: RLX 60 mg/day (n = 23) and RLX 60 mg/day plus CLD 100 mg intramuscularly (i.m.) once every 10 days (n = 22); 1 g of calcium and 800 IU of vitamin D3 were also given daily to both groups. Lumbar and femoral bone mineral density (BMD) were assessed at baseline and after 12 months of therapy using the dual X-ray absorptiometry technique (Norland XR36). We measured the bone turnover markers NTx and CTx, bone alkaline phosphatase (BAP) and osteocalcin at baseline and after 12 months of therapy. Our data demonstrate that 1 year of combined RLX+CLD therapy induced a higher increase in lumbar BMD than treatment with RLX alone as well as a major decrease in bone resorption markers, suggesting an additive effect of CLD on bone mass and inhibition of bone turnover. Furthermore, after 1 year of therapy levels of bone formation markers (osteocalcin and BAP) had increased in both groups, but the increase in osteocalcin and BAP was significantly higher in the RLX+CLD treated group, suggesting that, in addition to its inhibitory effects on resorption, CLD might also have stimulatory effects on mature osteoblast activity.