Non-invasive and/or non-destructive techniques can provide structural information about bone, beyond simple bone densitometry. While the latter provides important information about osteoporotic fracture risk, many studies indicate that BMD only partly explains bone strength. Quantitative assessment of macro- and microstructural features may improve our ability to estimate bone strength. Methods for quantitatively assessing macrostructure include (besides conventional radiographs) DXA and CT, particularly volumetric quantitative CT (vQCT). Methods for assessing microstructure of trabecular bone non-invasively and/or non-destructively include high-resolution CT (hrCT), microCT (microCT), high-resolution magnetic resonance (hrMR) and microMR (microMR). vQCT, hrCT and hrMR are generally applicable in vivo; microCT and microMR are principally applicable in vitro. Despite recent progress made with these advanced imaging techniques, certain issues remain. The important balances between spatial resolution and sampling size, or between signal-to-noise and radiation dose or acquisition time, need further consideration, as do the complexity and expense of the methods vs their availability and accessibility. Clinically, the challenges for bone imaging include balancing the advantages of simple bone densitometry vs the more complex architectural features of bone or the deeper research requirements vs the broader clinical needs. The biological differences between the peripheral appendicular skeleton and the central axial skeleton must be further addressed. Finally, the relative merits of these sophisticated imaging techniques must be weighed with respect to their applications as diagnostic procedures, requiring high accuracy or reliability, compared with their monitoring applications, requiring high precision or reproducibility.

If bone strength was the only requirement of skeleton, it could be achieved with bulk, but bone must also be light. During growth, bone modelling and remodelling optimize strength, by depositing bone where it is needed, and minimize mass, by removing it from where it is not. The population variance in bone traits is established before puberty and the position of an individual's bone size and mass tracks in the percentile of origin. Larger cross-sections have a comparably larger marrow cavity, which results in a lower volumetric BMD (vBMD), thereby avoiding bulk. Excavation of a marrow cavity thus minimizes mass and shifts the cortex radially, increasing rigidity. Smaller cross-sections are assembled by excavating a smaller marrow cavity leaving a relatively thicker cortex producing a higher vBMD, avoiding the fragility of slenderness. Variation in cellular activity around the periosteal and endocortical envelopes fashions the diverse shapes of adjacent cross-sections. Advancing age is associated with a decline in periosteal bone formation, a decline in the volume of bone formed by each basic multicellular unit (BMU), continued resorption by each BMU, and high remodelling after menopause. Bone loss in young adulthood has modest structural and biomechanical consequences because the negative BMU balance is driven by reduced bone formation, remodelling is slow and periosteal apposition continues shifting the thinned cortex radially. But after the menopause, increased remodelling, worsening negative BMU balance and a decline in periosteal apposition accelerate cortical thinning and porosity, trabecular thinning and loss of connectivity. Interstitial bone, unexposed to surface remodelling becomes more densely mineralized, has few osteocytes and greater collagen cross-linking, and accumulates microdamage. These changes produce the material and structural abnormalities responsible for bone fragility.

This review updates our current knowledge on the mechanism of action of strontium ranelate and analyses the way it rebalances bone turnover and how it influences bone biomechanics. Strontium ranelate is able to increase pre-osteoblast replication, osteoblast differentiation, collagen type I synthesis and bone matrix mineralization probably through a calcium-sensing receptor (CaR)-dependent mechanism. Paralleling this anabolic effect there is inhibition of osteoclast differentiation and activity mediated by an increase in osteoprotegerin (OPG) and a decrease in RANK ligand (RANKL). The overall effect is a rebalanced bone turnover in favour of improved bone geometry, cortical thickness, trabecular bone morphology and intrinsic bone tissue quality, which translates into enhanced bone strength.

HIV infection and AIDS have protean and multisystem manifestations throughout the various stages of infection. Progression from HIV infection to AIDS is associated with a gradual loss of immunocompetence and the occurrence of opportunistic infections and malignancies; it is also associated with immune dysregulation and persistent, prolonged immune activation that leads to autoimmune phenomena such as vasculitis and serological abnormalities. In people who are infected with HIV, the recognition of autoinflammatory disorders, their differentiation from infections or lymphoproliferative malignancies and their treatment using potentially immunosuppressive drugs is a challenging clinical scenario. The spectrum of rheumatologic diseases reported in HIV-infected individuals has changed dramatically since the introduction of highly active antiretroviral therapy in 1995. Complications such as metabolic abnormalities, osteoporosis, and immune restoration inflammatory syndrome have emerged.

In healthy cartilage, effective weight-bearing requires a high concentration of intact aggrecan. Degradation and loss of aggrecan are features of osteoarthritis (OA). It is unclear whether ADAMTS-4, ADAMTS-5, or both of these aggrecanases from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzyme family, are responsible for aggrecanolysis in human OA, and at what stage of disease these enzymes are active. Several potential disease-modifying agents for OA include glucosamine and chondroitin sulfate, diacerhein, and pentosan polysulfate; although their mechanisms of action in vivo are unknown, data from in vitro studies and animal models suggest that their efficacy might be partly due to inhibition of proinflammatory pathways that lead to downregulation of ADAMTS enzymes. Some histone deacetylase inhibitors that are successfully used to treat cancer can block ADAMTS-5 expression; however, these inhibitors will only be considered as potential therapies for OA if their toxicity is markedly reduced. ADAMTS inhibitors currently in development are expected to show excellent specificity now that crystal structures for several ADAMTS enzymes are available to guide drug design. ADAMTS-4 and ADAMTS-5 are appropriate targets for OA therapies, but ultimately, inhibitors of these enzymes will form only part of a larger arsenal of therapies.

To evaluate the post hoc study power of randomized controlled trials (RCTs) in the treatment of non-renal SLE and to determine the generalizability of these RCTs using an SLE database.

SLE primarily affects young females of childbearing age and fertility is generally conserved. SLE is a predominantly Th2-mediated disease and a progressive Th1/Th2 cytokine shift is seen in the fetal-maternal unit as well as in maternal circulation. Whether this fact affects pregnancy is unknown. Pregnancy represents a challenge for lupus patients and their physicians. However, the majority of SLE patients can now have successful pregnancies and deliver healthy babies, a result of our knowledge of the risks that SLE patients have to face during pregnancy, the preventive and therapeutic measures that we adopt, when necessary, and the close and appropriate rheumatological, obstetric and neonatal monitoring. All of these aspects are discussed in this review.

Certain autoantibodies which are found in autoimmune diseases including CTDs can impair fertility. Reproductive failure may present as pregnancy loss, either as miscarriage, intrauterine fetal death or stillbirth. There are also late obstetric complications such as intrauterine growth restriction, pre-eclampsia and pre-term birth. This review summarizes the possible influences of autoantibodies in reproductive failure, and particularly their predictive value (if available). The aPLs detectable by lupus anticoagulant, anti-cardiolipin or anti-beta2 glycoprotein I assays are associated with pregnancy loss and have a positive predictive value (PPV) of 75%. In spite of the general consensus on the management of pregnant aPL-positive women, few well-designed clinical trials have been reported and there is also insufficient data about the PPV of treatment. Anti-thyroid antibodies have been associated with pregnancy loss, and indeed have a PPV of 40%. However, no antibody is pathognomic for pregnancy loss. It may be more appropriate to assess a combination of antibodies rather than one antibody. However, a large meta-analysis of published trials is required in order to determine the prevalence of each particular autoantibody and different combinations of antibodies in different forms of reproductive failure.

Fertility in patients with SLE and other systemic autoimmune disease is usually unaltered. However, fertility may be impaired by anovulation during episodes of active disease or chronic renal failure, administration of NSAIDs, high dose of corticosteroids and cyclophosphamide. Early pregnancy loss occurs in SLE patients with aPLs. An association of autoimmune disease with infertility has been suggested, but the studies are not conclusive. Ovulation stimulation as a fertility treatment could theoretically induce SLE. However, two recent studies did not find previous use of fertility drugs and in vitro fertilization to be more frequent in the history of SLE patients when compared with controls. Patients with SLE or primary APS, who are undergoing infertility treatment, could be at risk of flare or thrombosis. In the past 10 yrs, many reports have been published regarding the risk of lupus exacerbation associated with controlled ovarian hyperstimulation; not all found excess risk. At the moment we do not have any prospective study in this field. A trend towards a worse prognosis in cases of SLE patients undergoing assisted reproductive techniques (ARTs) for pregnancy rate, live-birth rate and maternal complications can be seen. If hormonal ovarian stimulation is useful, well-advised management would administer a low effective gonadotropin dose in a patient whose disease has been silent preferably for at least 6 months. Further data are needed to establish safety and efficacy of ART in SLE patients.

The incidence of congenital heart block (CHB) in the offspring of anti-Ro-positive women is approximately 1-2%, and the risk of recurrence is 10 times higher in the following pregnancies. Non-fluorinated steroids (prednisone, prednisolone and methylprednisolone) are recommended only for maternal indications, not for prevention of CHB in anti-Ro/SSA-positive women. Fluorinated steroids (dexamethasone or bethametasone) are not metabolized by the placenta and are available to the fetus in an active form. Routine prophylactic therapy with fluorinated steroids is not recommended even in women who previously had children with CHB or skin rash since this therapy has its own side-effects. Intravenous immunoglobulin had been used to prevent the development of CHB in 8 high risk mothers (anti-Ro/SSA positive and previous pregnancy with CHB), and in one case CHB recurred (12.5%). At present, the only sure recommendation that can be made in these women is that in the presence of reliable positivity for anti-Ro/SSA antibodies serial echocardiograms and obstetric sonograms should be performed at least every 2 weeks starting from the 16th week of gestational age: the goal is to detect early fetal abnormalities, such as premature atrial contractions or moderate pericardial effusion, that might precede complete atrioventricular block and that might be a target of preventive therapy. Fluorinated steroids should not be used in the absence of symptoms; in the presence of alarming symptoms, betamethasone seems safer than dexamethasone.

Antenatal exposure to immunosuppressive drugs given to mothers during pregnancy to treat autoimmune diseases raises some questions about the fetal development and the long-term outcome of children. Studies in humans showed that glucocorticoids (GCs), CsA and HCQ do not seem to increase the risk of congenital abnormalities; in contrast, cyclophosphamide, LEF and MTX are contraindicated during pregnancy. The risk of gestational complications, including pre-term delivery, intrauterine growth retardation (IUGR) and low birth weight (LBW), is higher in autoimmune diseases rather than in the general population and probably this finding is related to both maternal disorder and immunosuppressive therapy. Recently, results of our studies suggest that immunosuppressants given during pregnancy do not impair significantly the development of immunity in exposed children. Moreover, preliminary data on neurodevelopmental outcome seem to exclude a causative role of in utero exposure to immunosuppressive agents on the cognitive impairment observed in some of these children; however, our data need to be confirmed with further observations.

A consensus paper concerning the interaction of anti-rheumatic drugs and reproduction was published in 2006, representing data collected during the year 2004 and 2005. Because of an increasing use of biological agents in women of fertile age, the information was updated for the years 2006 and 2007. Experts disagree whether TNF-inhibitors should be stopped as soon as pregnancy is recognized or may be continued throughout pregnancy. Pregnancy experience with abatacept and rituximab is still too limited to prove their safety for the developing fetus. They must be withdrawn before a planned pregnancy. LEF has not been proven to be a human teratogen. Registries of transplant recipients have shown that cyclosporin (CsA) and tacrolimus do not increase the rate of congenital anomalies, whereas mycophenolate mofetil (MMF) clearly carries a risk for congenital anomalies. Prophylactic withdrawal of drugs before pregnancy is mandatory for abatacept, rituximab, LEF and MMF. Data remain insufficient for gonadal toxicity of immunosuppressive drugs in men and for excretion of these drugs in human breast milk.

Immunological and epidemiological evidences suggest that female sex hormones play an important role in the aetiology and pathophysiology of chronic inflammatory diseases; however, whether (or when) oestrogens are friends or foes in inflammatory/immune-mediated rheumatic diseases is still a matter of debate. Several significant factors generate confusion and opposite conclusions in evaluating the role of oestrogens in inflammatory/immune diseases. These factors include the relatively superficial translation done from the animal studies to the human condition, the different effects of oestrogens on their different receptors or on different target cells, the different oestrogen concentrations employed and finally, opposite effects (especially on cell proliferation) exerted by different peripheral oestrogen metabolites. However, as supported by the higher prevalence of rheumatic autoimmune diseases in women, oestrogens are generally considered as enhancers of cell proliferation and humoral immune response.

While in the past, pregnant SSc patients were thought to be at high risk for poor fetal and maternal outcome, at present, careful planning, close monitoring and appropriate therapy allows these patients to have a successful pregnancy. Retrospective studies clearly show an increased frequency of pre-term births and small full-term infants but the frequency of miscarriage and neonatal survival rate did not differ from healthy controls. The worst life-threatening complication of a pregnancy is scleroderma renal crisis: despite the fact that ACE inhibitors are associated with congenital abnormalities and are relatively contraindicated in pregnancy, in this case their use is recommended. In order to avoid complications, pregnancies in SSc should be planned when the disease is stable, and should be avoided in rapidly progressing diffuse SSc as such patients are at a greater risk for developing serious cardiopulmonary and renal problems early in the disease. HCQ, intravenous immunoglobulins (if blood pressure is not high and renal function is normal) and low doses of steroids may be safely used. In case of rapid worsening of disease activity, elective termination in the first trimester and an induced pre-term birth in the last trimester may be suggested. In order to minimize risks, a multidisciplinary team should assist scleroderma patients to suggest the best timing for a pregnancy and to tailor adequate supportive treatment during the pregnancy.

The knowledge about the risk of pregnancy in vasculitides mostly derives from single case reports or at best from retrospective studies with all the caveats that these observations include. Primary systemic vasculitides are uncommon, encompassing a broad spectrum of severity, from mild to life-threatening manifestations and with different natural histories, from self-limiting to relapsing or chronic active disease. The treatments require a cautious use of immunosuppressants tailored to each specific condition. Furthermore, most of the cytotoxic drugs necessary to treat vasculitis act by modifying the cell cycle and cell differentiation, biological effects that are particularly hazardous for the foetus. In order to have an uncomplicated pregnancy, conception should be planned when the disease is inactive. Moreover, organ failure or damage, due to previous disease activity, must also be taken into account since it can lead to adverse obstetrical and fetal outcomes.

The Wnt/beta-catenin pathway regulates multiple biological events during embryonic development, including bone formation. Fracture repair recapitulates some of the processes of normal bone development, such as the formation of bone from a cartilaginous template, and many cell-signaling pathways that underlie bone development are activated during the repair process. The Wnt/beta-catenin signaling pathway is activated during fracture repair, and dysregulation of this pathway alters the normal bone-healing response. In early pluripotent mesenchymal stem cells, Wnt/beta-catenin signaling needs to be precisely regulated to facilitate the differentiation of osteoblasts; by contrast, beta-catenin is not needed for chondrocyte differentiation. Once mesenchymal stem cells are committed to the osteoblast lineage, activation of Wnt/beta-catenin signaling enhances bone formation. This activity suggests that the Wnt/beta-catenin pathway is a therapeutic target during bone repair. Indeed, treatments that activate Wnt/beta-catenin signaling, such as lithium, increase bone density and also enhance healing.

Clinical trials in rheumatology are necessarily associated with an array of ethical issues that vary according to the type of trial under consideration. Difficult questions arise related to the appropriateness of enrolling normal volunteers or patients with disease in early phase toxicity studies of new agents. Prevention studies raise important questions regarding the exposure of a population of patients to an intervention with known adverse effects, even though prevention is not ensured. Postmarketing studies, although critically important in determining the true and long-term effects of therapies in a real-world setting, are sometimes designed solely for marketing purposes that do not contribute to meeting such goals. Regardless of the type of trial, selecting the appropriate control arm, the outcome measure, and 'rescue' or withdrawal provisions requires attention to pragmatic as well as ethical concerns. In addition, randomization is only ethically appropriate when, in addition to other conditions, clinical equipoise pertains to the treatment arms. Additional formative research is needed to improve the design of clinical trials and the informed consent processes for them. Finally, training in clinical research methods, which encompasses research ethics, is needed for rheumatologist investigators to ensure that participants are protected and that the results obtained from studies will be sound and ultimately applicable to clinical care.

The introduction of targeted biologic agents directed against tumor necrosis factor (TNF) has represented a novel and exciting avenue for investigation into therapies for the vasculitic diseases. In vasculitic diseases that are associated with granuloma formation, anti-TNF agents are a particularly attractive approach to treatment in that their mechanism of action targets immunologic pathways that are thought to have a role in disease pathogenesis. To date, a number of important trials have investigated the use of anti-TNF agents in patients with a vasculitic disease: most notably, Wegener's granulomatosis, giant-cell arteritis, Takayasu's arteritis, and Behçet's disease. Randomized, placebo-controlled trials of anti-TNF therapies for vasculitic diseases have advanced our knowledge not only in terms of their clinical results but also by demonstrating that networks of researchers can conduct multicenter trials in these uncommon diseases. Experience with the use of anti-TNF agents in patients with Wegener's granulomatosis or giant-cell arteritis has emphasized the crucial role of randomized trials in determining whether a treatment is effective, even in the face of promising preliminary data. Caution is necessary in clinical practice until such data become available.

Accumulating evidence suggests that RA is a T-cell-mediated autoimmune disease. Early attempts at disease modulation using strategies such as CD4 mAbs were severely hampered by a lack of biomarkers of autoreactivity. Recently, however, co-stimulation blockade has emerged as an effective treatment for RA. Alongside a greatly improved mechanistic understanding of immune regulation, this has rekindled hopes for authentic and robust immune programming. The final pieces of the jigsaw are not yet in place for RA but, in other disciplines, emerging treatment paradigms such as non-mitogenic anti-CD3 mAbs, autoantigenic peptides and even cellular therapies are providing hope for a future in which immunopathology can be specifically and vigorously curtailed.

Many randomized clinical trials (RCTs) are labelled efficacy and safety while due consideration for power is provided only for efficacy outcomes. This in turn necessitates a discussion of the inadequacy of sample size (type II error) for identifying harm. This is particularly important in RCTs of TNF inhibitors as harm related to these agents is still a matter of debate.