Giovanni Orsolini

Bone Involvement and Osteoporosis in Mastocytosis

Bone involvement is frequent in patients with systemic mastocytosis. Osteoporosis is the most prevalent bone manifestation, but diffuse osteosclerosis or focal osteolytic or osteosclerotic lesions are not infrequent. The risk of osteoporotic fractures is high, especially at the spine and in men. Routine measurements of bone mineral density and vertebral morphometry are warranted. The bone turnover markers indicate the involvement of complex bone metabolism in mastocytosis-related manifestations. Bisphosphonates represent the first-line treatment for osteoporosis-related mastocytosis.

Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.

Zoledronic Acid in Osteoporosis Secondary to Mastocytosis

BACKGROUND Osteoporosis is the prevalent manifestation of bone involvement in patients with systemic mastocytosis. Mastocytosis-related osteoporosis is characterized by both absolute and relative prevalence of osteoclastic activity, consistent with the positive results reported in small series of patients with antiresorptive drugs, such as bisphosphonates. The aim of this study is to investigate the efficacy of zoledronic acid in patients with mastocytosis-related osteoporosis. METHODS Twenty-five patients with osteoporosis secondary to indolent systemic mastocytosis were given a single intravenous infusion of 5 mg zoledronic acid dissolved in 100 mL of 0.9% saline over 60 minutes. RESULTS After 1 year, the mean increase in bone mineral density was 6.0% ± 4.4% at the spine and 2.4% ± 3.2% at the total hip. Serum levels of bone turnover markers decreased versus baseline: bone alkaline phosphatase -34% and -35%, and C-terminal telopeptide -68% and -56% at 6 and 12 months, respectively. None of the patients reported new fractures during the year of follow-up. In all the first 20 treated patients, a transitory acute phase response was observed, but this was prevented in 4 of 5 subsequent patients in whom acetaminophen was given systematically during the 3 days post-infusion. CONCLUSIONS A single 5 mg zoledronic acid intravenous infusion in patients with osteoporosis secondary to indolent systemic mastocytosis is associated with significant increases in spine and hip bone mineral density and decreases of bone turnover markers over at least 1 year. Yearly zoledronic acid might represent a therapeutic option for indolent systemic mastocytosis-associated osteoporosis.

Titer-Dependent Effect of Anti-Citrullinated Protein Antibodies On Systemic Bone Mass in Rheumatoid Arthritis Patients

Bone loss in rheumatoid arthritis (RA) is a key feature both local and systemic. Anti-citrullinated protein antibodies (ACPA) have recently been found to directly induce differentiation and activation of osteoclasts and therefore contribute to periarticular bone loss. The aim of this study was to analyze the effect of ACPA on systemic bone mineral density (BMD) in patients with established RA. This is a cross-sectional study with a single-center RA population. BMD was measured with Dual X-ray absorptiometry at lumbar and femoral sites. ACPA were measured by EIA. Multivariate analysis was performed adjusting for the main confounding variables. One hundred twenty-seven RA patients were enrolled. In univariate analysis, ACPA-positive patients showed lower BMD Z-score (SD below the age- and gender-matched mean reference value) at femoral sites (p < 0.01). A negative correlation between ACPA titer and BMD Z-score at all sites was observed (p < 0.01). The multivariate analysis adjusted for the main confounding variables confirmed the negative effect of ACPA at femoral sites (p < 0.05), but not at lumbar spine BMD. No significant effect of rheumatoid factor has been observed. ACPA have a negative titer-dependent effect on BMD at femoral sites, mainly constituted by cortical bone. ACPA-positive patients, especially if at high titer, should undergo bone investigations and be treated with bone protecting agents. Disease-modifying anti-rheumatic drugs lowering ACPA titer might have positive effects on systemic bone mass.

Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab

Notch receptors play a central role in skeletal development and homeostasis. Hajdu Cheney Syndrome (HCS) is a rare disease associated with mutations of NOTCH2 that lead to the translation of a truncated, presumably stable, NOTCH2 protein. As a consequence, a gain-of-NOTCH2 function is manifested. We report a subject presenting with HCS and her child, both harboring a new heterozygous mutation in Exon 34 of NOTCH2 upstream of the PEST domain. The subject presented with osteoporosis, fractures, acroosteolysis and splenomegaly but did not have neurological complications, cardiovascular defects or polycystic kidneys. Sequencing of genomic DNA revealed a previously unreported mutation at nucleotide 6667C>T leading to a Gln2223Ter protein product in the subject and her son. Preclinical studies have demonstrated that the bone loss in HCS is secondary to enhanced osteoclastogenesis and bone resorption, and the same mechanism may operate in humans. Accordingly, the case we report was treated and responded to therapy with denosumab with an increase in bone mineral density (BMD). However, acroosteolysis progressed and was not modified by denosumab. In conclusion, we report a case of HCS associated with a novel mutation in NOTCH2 and its response to denosumab on BMD.

Osteoporosis treatment: why ibandronic acid?

Introduction: In this article, we have summarized the specific evidence on ibandronic acid (or ibandronate) efficacy, tolerability, and feasibility acquired from trials and clinical use. Areas covered: This critical review focuses on evidence from randomized controlled clinical trials, meta-analyses, surrogate markers, bridging trials, long-term extension studies, observational studies, clinical experiences in osteoporosis in addition to postmenopausal treatment adherence in clinical practice, and safety profile of ibandronic acid. Expert opinion: Pivotal studies on ibandronic acid efficacy in terms of antifracture effects on nonvertebral fractures had some intrinsic limitations. However, a large body of indirect evidence suggests that ibandronate has significantly sustained vertebral and nonvertebral antifracture efficacies in women with postmenopausal osteoporosis, in comparison to those observed with other nitrogen-containing bisphosphonates. Discrepancies in efficacy between the available bisphosphonate regimens appear to be a function of dose rather than to inherent differences in their respective therapeutic potential. Drugs or treatment regimens that minimize the risk of osteoporotic fractures and make the treatment of osteoporosis more convenient and suitable for patients are preferred: ibandronic acid marketed at oral doses of 150 mg once monthly and 3 mg quarterly as intravenous injection has these characteristics. The safety profile of ibandronic acid treatment appears to be good overall and in some cases better than that of other nitrogen-containing bisphosphonates.

Clinical profile and outcome of patients with rheumatoid arthritis and abnormally high aortic stiffness

Objectives Ascending aorta has an increased stiffness (AoSI) in rheumatoid arthritis (RA) patients due to their chronic inflammatory status. We assessed prevalence and factors associated with increased AoSI and its prognostic role in a large cohort of RA patients. Methods We prospectively analysed 226 RA patients without overt cardiac disease compared with 226 non-RA patients matched for cardiovascular risk factors (non-RA controls). Abnormally high AoSI was diagnosed if AoSI > 6.07% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation as part of a thorough echocardiography performed in all patients. Results AoSI was significantly higher in the RA patients than non-RA controls (6.3 ± 4.5% vs. 4.6 ± 3.5%, p < 0.001); it was related to older age, higher systolic blood pressure and RA disease. Predictors of AoSI in RA patients were older age, higher systolic blood pressure and the non-prescription of non-steroidal anti-inflammatory drug and/or immunomodulatory/anti-cytotoxic agents. Abnormally high AoSI was diagnosed in 41% RA patients and 21% non-RA controls (p < 0.001). The RA phenotype with abnormally high AoSI was a > 60 years old subject with systolic blood pressure > 129 mmHg, mitral annular calcification who was not receiving non-steroidal anti-inflammatory drug. By multivariate Cox regression analysis abnormally high AoSI independently predicted death or all-cause hospitalization (hazard ratio 2.85 (95% confidence interval 1.03–7.85)) at 12-month follow-up. Conclusions Increased AoSI is common, can be predicted by an ordinary clinical assessment and is a strong predictor of adverse clinical outcome at mid-term follow-up in patients with RA.

Regional differences of vitamin D deficiency in rheumatoid arthritis patients in Italy

Vitamin D deficiency is very common in patients with rheumatoid arthritis (RA). Aim of this study was to evaluate the prevalence of vitamin D deficiency among the different Italian regions and whether these variations are associated with different severity of the disease. The study includes 581 consecutive RA patients (464 women), not taking vitamin D supplements, from 22 Italian rheumatology centres uniformly distributed across Italy. Together with parameters of disease activity (disease activity score 28), functional impairment (activities of daily living and health assessment questionnaire disability index) and mean sun exposure time, all patients had serum 25-hydroxyvitamin D (25OHD) measured in a centralized laboratory. Vitamin D deficiency (25OHD level <20 ng/mL) was very frequent among RA patients; its prevalence was 60%, 52% and 38% in southern, central and northern Italy, respectively. Mean disease activity and disability scores were worse in southern regions of Italy. These scores were inversely related to 25OHD levels and this correlation remained statistically significant after adjusting for both body mass index (BMI) and sun exposure time. However, disease severity remained significantly higher in southern regions versus central-northern Italy after adjustment also for serum 25OHD levels, age and BMI. In RA Italian patients there are significant regional differences in the prevalence of vitamin D deficiency explained by different BMI, and sun exposure time, and inversely associated with disease activity and disability scores.

Osteoporosis: an Independent Determinant of Bone Erosions in Rheumatoid Arthritis?

We read with great interest the article by Simon and colleagues “Ageand Sex-Dependent Changes of Intra-Articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis.” The postmenopausal state and rheumatoid arthritis (RA) lead to a significant decrease of both cortical and trabecular intra-articular bone density. This process in RA patients is a sign for a severe disease course predicting erosive disease. Bone erosion is an important complication of RA and is associated with deformities and disabilities. Insufficient inhibition of structural joint damage by disease-modifying antirheumatic drugs (DMARDs) represents an unsolved problem and was reported despite clinical improvement. Erosion mainly affects intra-articular cortical bone and results from unpaired bone resorption and formation. It is clear that the main trigger of articular bone erosions is inflammation. Proinflammatory cytokines such as TNF-a, interleukin 1 (IL-1), and interleukin 6 (IL-6) play a pivotal role in bone complications throughout the activation of osteoclasts, mainly via the RANK/ RANKL/osteoprotegerin system. Moreover, Dickkopf-1 (DKK-1), a Wnt system inhibitor, hasanemerging role inbonemetabolismand bone complications of RA. DKK-1 is implicated in joint remodeling and in inflammation-induced bone loss. DKK-1 serum levels have been found to be elevated in RA and related with erosions and lower bone mineral density (BMD). Recent evidence has also linked higher parathyroid hormone (PTH) levels to bone damage in RA, and we have observed that PTH appears to be an important determinant of bone resorption and DKK-1 serum levels in RA patients. It is well known that chronic high serum levels of PTH decreases thickness and increases porosity of cortical bone. Simon and colleagues showed that the alterations of bone quantity and microstructure of intra-articular bone, measured with high-resolution peripheral quantitative computed tomography (HR-pQCT), could be not only secondary to RA disease, but also secondary to aging and/or loss of estrogen. Indeed, intra-articular bone in RA has similar composition as in postmenopausal women older than 60 years. The latter evidence suggests a new hypothesis: osteoporosis, as well as RA, may be an independent determinant in the development of erosions. Simon and colleagues found a strong correlation between intra-articular bone in the metacarpal heads and extra-articular bone in the radius, which is in accordance with previous findings. It is known that low BMD, measured with digital X ray techniques or dual-energy X-ray absorptiometry (DXA), is significantly associated with bone erosions in RA patients. Recently, cortical thinning and fenestration have been observed before the clinical onset of arthritis in subjects with anti-citrullinated protein antibodies (ACPAs), and ACPAs have a negative titer-dependent effect on BMD. ACPA titer is a well-known risk factor for bone erosions in RA. Many other factors are related with higher risk of erosions in RA, includingdisease activity, cigarette smoking, alcohol consumption, hypovitaminosis D, low body mass index (BMI), corticosteroid use, andaging; all of thesearewell-known risk factors forosteoporosis too! Therefore, we could speculate that the correlation with bone erosions might also be mediated by osteoporosis. On the other hand, the described protective effect of obesity on radiographic joint damage might be due to the wellknown positive correlation between BMI and BMD. Denosumab, a drug for osteoporosis treatment, achieved important results in the prevention of erosions in RA; of note, denosumab has no effect on inflammation but only positive effects on cortical BMD and porosity. In conclusion, osteoporosis might be an important and independent determinant of bone erosions in RA. We need a deeper bone investigation in RA patients. The poor response to the DMARDs, in terms of progression of bone erosions, might depend on the concomitant osteoporosis and on other risk factors of bone loss.

Rheumatoid arthritis, γδ T cells and bisphosphonates

We read with great interest the results of the study of Mo et al .1 The authors suggest that γδ T cells are involved in the pathogenesis of rheumatoid arthritis (RA). The study showed a significant reduction, in patients with RA, of peripheral total γδ T cells (particularly Vδ2 T cells, the major population of peripheral blood γδ T cells). The percentage of peripheral Vδ2 T cells of RA was negatively correlated with the levels of inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate as well as the Disease Activity Score in 28 joints. The peripheral reduction of Vδ2 …