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The relationship between the immune system, estrogen deficiency and bone loss is an intriguing and, as yet, unexplained challenge of the past two decades. Here we summarize the evidence that links immune cells, inflammation, cytokine production and osteoclast formation and activity with particular regard to humans.

Background Iloprost has been suggested to possess anti-inflammatory and immunomodulating actions and it is widely use as a vasodilatator in systemic sclerosis (SSc). In this study we evaluate the effect of iloprost on immune response in SSc patients. To this extend we enrolled 15 women affected by SSc and infused iloprost for 5 days. The effect of iloprost on T cells and monocytes was measured by flow cytometry, Real time PCR and measuring cytokines production in vivo and in vitro by ELISA. Results Our results demonstrate that Iloprost reduces T cell and TNF alpha production both in vivo and in vitro. It reduces T regulatory cells number, but increases their activity after immune stimulation. It increases serum IL-2 and this increase persists 28 days after the last infusion, also RANKL was increased both in vivo and in vitro. We observed no effect on IFN gamma production. Conclusions These results suggest that iloprost has anti-inflammatory and immunomodulating effects, reducing TNF alpha production by T cells and the number of T regulatory cells and increasing IL-2 and RANKL.

Fracture healing is a complex process that involves several cell types; as a previous report suggested an increase in osteoblast (OB) precursors in peripheral blood during this process, this paper examines the role of circulating bone cell precursors in this process in the light of a prior suggestion that OB precursors are increased. Nine healthy men less than 60 years old with traumatic fractures were enrolled. The parameters circulating OB precursors (osteocalcin+/alkaline phosphatase+/CD15- cells) and osteoclast precursors (CD14+/CD11b+/vitronectin receptor + cells) were measured by flow cytometry; bone formation markers and TGFbeta1, by ELISA; and PTH, by RIA in serum on arrival at the emergency department (baseline) and 15 days after fracture. Bone cell precursors behaved differently during healing. TGFbeta1 was inversely correlated with OB number, but increased their degree of maturation at baseline. Bone formation markers and TGFbeta1 were increased after fracture, whereas PTH was decreased. The TGFbeta1 increase was directly correlated with age, whereas age was not correlated with the precursors. In conclusion, we confirm the role of TGFbeta1 in fracture healing; and its possible role in the control of pre-OB homeostasis. There was no variation in circulating precursor cells during healing, though the increase in TGFbeta1 may suggest increased pre-OB maturation and homing to the injured site.

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength.To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength.In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated.Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p0.01) and QCT (5.7%, p0.0001). Between-treatment differences were significant for trabecular spine (p = 0.0017) [non-parametric test], trabecular trochanter (10.7%, p0.0001), total hip (10.8%, p0.0001), and compressive strength indices at femoral neck (8.6%, p = 0.0001), and trochanter (14.1%, p0.0001).Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength.

This study evaluates the effect of alendronate on osteoclastogenesis, cytokine production, and bone resorption in postmenopausal women. We suggest that it acts on mature bone resorbing osteoclasts after 3 months of treatment, whereas, after 1 year, it diminishes their formation by reducing their precursors and serum RANKL.Osteoclasts are the target cells of bisphosphonates, though the most drug-sensitive steps of their formation and activity have not been determined. The present study evaluates the effect of alendronate on osteoclastogenesis, cytokine production, and bone resorption in postmenopausal women.The study was conducted on 35 osteoporotic women; 15 were pretreated with alendronate 70 mg/week, whereas, 20 were treated with calcium 1 g/day and vitamin D 800 IU/day. After 3 months, 30 received alendonate 70/mg, vitamin D 2800 IU/week, and calcium 1 g/day for 12 months (combined therapy), whereas, the other five patients remained on calcium 1 g/day and vitamin D 800 IU/day. The following parameters were assessed before and after therapy: changes in bone resorption markers, circulating osteoclast precursors, formation of osteoclasts in peripheral blood mononuclear cell cultures, their viability, and variations in cytokines production.After 3 months of alendronate, there was no significant reduction in the number of osteoclast precursors, osteoclast formation and viability, and cytokine levels, whereas, there was a significant reduction of bone resorption markers. One year of the combined therapy, on the other hand, reduced osteoclast precursors, osteoclast formation, and serum RANKL, whereas, calcium plus vitamin D alone had no effect.We suggest that alendronate mainly acts on mature bone resorbing osteoclasts in the short term, whereas, its long-term administration diminishes their formation by reducing their precursors and serum RANKL.

It has been suggested that iron-deficient rats have lower bone mass than iron-replete animals, but a clear association between bone and iron repletion has not been demonstrated in humans. A growing body of evidences also suggests a relation between lipid oxidation and bone metabolism and between iron metabolism and LDL oxidation. Iron availability to cells also depends on haptoglobin (Hp) phenotypes. Hp has also important antioxidant properties according to its phenotype, hence we evaluate whether Hp phenotype could influence bone density, iron metabolism and lipid oxidation. This cross-sectional study enrolled 455 postmenopausal women affected by osteoporosis (260) or not (195). Bone mineral density, markers of bone and iron metabolism, levels of oxidized LDL (oxLDL) and Hp phenotype were measured in all the subjects. Hp 1.1 and 2.2 frequency was higher and Hp 2.1 was lower in the patients with fragility fractures (80) compared with the controls. We therefore evaluate different Hp phenotypes as risk or protective factors against fragility fracture: Hp 2.1 is a protective factor against fracture while 1.1 is an important and 2.2 a moderate risk factor for fragility fractures. Lower serum iron was associated with elevated transferrin in patients with Hp 1.1; moreover patients had relative iron deficiency compared with the controls and fractured patients had higher level of oxLDL. We found that both iron metabolism and oxLDL varies according to Hp phenotypes and are predictive of bone density. Our data indicate that Hp 2.1 is a protective factor for fragility fractures, depending on its role on iron metabolism and its antioxidant properties.

There is evidence that bone turnover in women is more rapid during the first years after menopause than in subsequent years. The assessment of deoxypyridinoline (DPD) cross-links in a fasting urine sample is considered a specific index of bone resorption by osteoclasts and also can be used for monitoring the response to pharmacologic antiresorption treatment. The interpretation of results, however, is hampered by biological and other preanalytical variability (1)(2)(3)(4). Specific degradation products of the bone matrix, such as DPD and pyridinoline (PYD), closely reflect the rate of bone metabolism. Vesper et al. (1) reported mean within-day variabilities of 67% for DPD (range, 53%–75%) and 71% for PYD (57%–78%). The mean between-day variability was 16% for both PYD and DPD (ranges, 5%–24% and 12%–21% for DPD and PYD, respectively). The mean between-person variabilities across different studies were 34% for DPD (8%–98%) and 26% for PYD (12%–63%) in healthy premenopausal women and 40% (27%–54%) and 36% (22%–61%), respectively, in postmenopausal women. Specimen instability and errors in creatinine measurements were additional sources of variability(1). Some authors have reported that the variability can be reduced by collecting urine for 24 h (or longer) instead of using single voids and by expressing the results as ratios to creatinine(5)(6). The usefulness of urinary markers of bone turnover in monitoring therapy depends on the within-person variability of these markers compared with their changes in response to treatment (7). Thus, the biological and laboratory variabilities of DPD cross-links are important considerations for clinical evaluation. We evaluated the biological variability of DPD cross-link concentrations in fasting morning urine specimens collected during a 2-week period from women in their first years of menopause. We examined 64 postmenopausal women (mean age, 53 years; range, 49–57 …

Objectives . Abnormalities of insulin sensitivity are increasingly reported in HIV infection. Considering that cytokines (particularly TNF-α and IL-1β) can induce insulin resistance in infections, we investigated the relationship between insulin sensitivity and cytokine release from peripheral blood mononuclear cells (PBMCs) in HIV-infected patients. Methods . Fourteen HIV-positive patients treated with dual-NRTI (nucleosidic reverse transcriptase inhibitors) regimens, and fourteen healthy controls were studied. Insulin resistance was assessed by homeostatic model for insulin resistance (HOMA-IR). Cytokine production by PBMCs ex vivo was measured. Results . Plasma glucose levels did not differ in HIV patients and in controls. Insulin concentrations and HOMA-IR were significantly higher in HIV-infected patients than in controls (respectively, 11.4±4.3 vs. 7.86±1.1mIU, P =0.005; 2.27±0.91 vs. 1.6±0.2, P =0.025). A significant positive linear correlation was observed between HOMA-IR and TNF-α concentrations in the supernatants of unstimulated PBMC cultures in HIV patients (r=0.771;P=0.001), but not in controls. Conclusions . Our results are in accordance with previous findings showing that insulin resistance may indeed be present in PI-naive HIV patients, and suggest that either TNF-α, or other mediators released in parallel with this cytokine may induce a state of insulin resistance, unrelated to highly active antiviral treatments, in poorly controlled HIV disease.

CRH inhibits the secretion of gonadotropins by activating endogenous opioids, whereas alpha MSH, which displays various behavioral and neuroendocrine effects contrary to those of the opioids, stimulates their release. To evaluate the possible interaction of CRH and alpha MSH, eight women in the luteal phase underwent the following tests: 1) ovine CRH infused at 100 micrograms/h for 3 h, 2) alpha MSH (2.5 mg as an iv bolus 60 min after the start of saline infusion), 3) CRH plus alpha MSH (injected 60 min after the start of CRH infusion), and 4) placebo. LH, FSH, PRL, ACTH, and cortisol were determined every 15 min for 180 min. CRH significantly (P < 0.001) reduced serum LH. alpha MSH alone significantly (P < 0.001) increased LH to a peak within 15-30 min (baseline, 3.3 +/- 0.7 mIU/mL; maximum increase, 3.5 +/- 0.9 mIU/mL) and induced an even greater rise when injected during the CRH infusion (baseline, 2.8 +/- 03 mIU/mL; maximum increase 7.5 +/- 1.6 mIU/mL; P < 0.05 vs. alpha MSH alone). FSH was always unaffected. ACTH and cortisol increased (P < 0.001) during the CRH infusion and fell significantly (P < 0.001) during the placebo infusion. alpha MSH had no effect on these changes. PRL fell during the placebo infusion (P < 0.001). No changes were induced by CRH or alpha MSH. In conclusion, alpha MSH antagonizes CRH inhibition of LH secretion. This finding lends support to the view that differential posttranslational processing of POMC contributes to the regulation of LH secretion. Further investigation is needed to clarify the mechanism of the antagonism between alpha MSH and CRH.

SYNOPSIS Since in migraineurs a change in dopaminergic tone has been hypothesized and since in man prolactin secretionby the lactotroph cells is controlled by hypothalamic inhibitory factors (of which dopamine is the best known), wedecided to investigate plasma prolactin (PRL) response to L-Dopa in a group of migraineurs.We tested 5 women suffering from common migraine and 5 healthy women as controls.A different behaviour of PRL secretion was observed in the two groups. In migraineurs the inhibition of PRLsecretion was less marked than in normals, with a statistically significant difference at 30 and 60 minutes.This difference might suggest a reduced responsiveness of the pituitary lactotroph cells to the action ofdopaminergic agents. The mechanisms accounting for this peculiar behaviour of PRL secretion in migraineurs arestill to be elucidated.

It now appears to be accepted that oestrogens and progestogens can help to prevent post-menopausal bone loss. This study accordingly evaluated vertebral bone mineral content (BMC) patterns and changes in calcitonin (CT) secretion in 12 women who had been ovariectomized in the previous 6 mth and in 12 others who had had a natural menopause, all of whom received oestrogen-progestogen replacement therapy for 12 mth. We also studied 12 oophorectomized and 21 normal-menopause women who did not receive any treatment and hence constituted the corresponding control groups. A significant difference was found between the lumbar BMC in the treated women and the controls. Moreover, the CT levels rose significantly after replacement therapy in both the oophorectomized and the natural-menopause subjects. It was concluded that combined oestrogen-progestogen treatment can prevent post-menopausal bone loss and increase CT secretion.

The aim of our study was to assess the predictive value of the Singh index (SI), which estimates bone architecture, and bone density (BMD) when dealing with the mechanical competence of bone and to analze possible differences in bone properties between gender in humans. The relationship between SI, BMD, and mechanical competence was analyzed in 106 bone cylinders from 37 human femoral heads obtained during hip-joint replacement surgery for low energy fracture or for osteoarthritis. Bones from osteoporotic patients are less dense and more brittle compared with bones from osteoarthritic patients, as expected. Among osteoporotic patients female bones were more brittle than those from males, although BMD was similar. In osteoarthritic patients there were no significant differences among sexes. Bone mechanical competence varies according to BMD and to SI categories. Thus, our study suggests that bone strength is predicted by both BMD and bone architecture.