Giovanni Adami

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.

Denosumab, cortical bone and bone erosions in rheumatoid arthritis

Takeuchi et al 1 demonstrate an additional inhibitory effect on the progression of bone erosions in rheumatoid arthritis (RA) with the addition to methotrexate of an anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, denosumab, confirming results already reported 8 years ago by Cohen and colleagues.2 Insufficient inhibition of structural joint damage by disease-modifying antirheumatic drugs (DMARDs) was reported despite clinical improvement,3–5 and recently two meta-analysis6 , …

Safety issues and adverse reactions with osteoporosis management

ABSTRACT Introduction: Osteoporosis is a disease that has spread worldwide and has become a relevant public health problem. Over the last 2 decades, a number of drugs have been licensed for its treatment owing to their efficacy in preventing fragility fractures. The safety profiles of these drugs are well defined with data from extensive programs of pharmacovigilance to support it. Areas covered: In this article we reviewed the long-term safety of Bisphosphonates, Calcium, Vitamin D, Selective Estrogen Receptor Modulators, Teriparatide and Denosumab. We excluded hormone replacement therapy that lost its indication for the treatment of osteoporosis. The license for the treatment of osteoporosis of Calcitonin was recently withdrawn and that of Strontium ranelate was severely limited. For both drugs, we report EMA statements about their safety profile. Expert opinion: The safety profile of most available drugs for the treatment of osteoporosis is well defined and the most serious adverse events are either rare or predictable. Osteoporosis treatment is a favorable choice in patients at moderate-high risk of fracture, while in patients at low risk pharmacological prevention should involve consideration of the balance between the beneficial effects of treatment, the probability of adverse effects and costs.

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 …

Circulating Dickkopf-1 and sclerostin in patients with Paget’s disease of bone

Paget disease of bone is a chronic metabolic bone disorder characterized by increased bone resorption and new bone formation. The aim of this study is defining the role of inhibitors of canonical Wnt/b-catenin signaling pathway in patients with Paget disease of bone. Scarce and contrasting results have been reported in literature. We studied 40 patients (15 females and 25 males) with radiological and scintigraphic evidence of Paget disease of bone and 40 healthy subjects matched by age and sex. N-propeptide of type I collagen, C-terminal telopeptide of type I collagen, sclerostin, and Dickkopf-related protein 1 (DKK1) were evaluated by blood samples in our laboratory. As expected, mean serum levels of bone turnover markers (N-propeptide of type I collagen and C-terminal telopeptide of type I collagen) were significantly higher in the Paget disease of bone group compared with the control group. No difference was observed between groups in Dickkopf-1 and sclerostin. Dickkopf-1 and sclerostin were never correlated with each other or with bone turnover markers. Sclerostin was positively correlated with age. In conclusion, our results suggest that the regulators of the Wnt-β catenin pathway are not altered in patients with Paget disease of bone. The positive correlation we found between sclerostin and age in Paget disease of bone patients indicates that in comparative studies, sclerostin serum levels must be adjusted for age.

Treatment with neridronate in children and adolescents with osteogenesis imperfecta: Data from open-label, not controlled, three-year Italian study

INTRODUCTION The present study assessed the long-term efficacy and safety of intravenous (i.v.) neridronate in children and adolescents affected by osteogenesis imperfecta (OI). METHODS 55 young patients (mean age 12.6±3.9years) affected by OI were included in the study. Neridronate was administered by i.v. infusion at a dose of 2mg/kg (maximum dose of 100mg) at intervals of three-months for three years. Dual X-ray absorptiometry of the lumbar spine, hip and ultradistal and proximal radius were evaluated every 6months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio were obtained at baseline and every 3months. Serum bone turnover markers total and bone alkaline phosphatase were performed every 12months in a proportion of patients. RESULTS Mean lumbar spine and total hip bone mineral density (BMD) and bone mineral content significantly increased from baseline compared to all subsequent time points (p<0.001). Mean ultradistal radius BMD significantly increased from month 18 (p=0.026). Levels of bone turnover markers significantly decreased from baseline to all post-baseline observation time points. There was no statistically significant effect on fracture risk (p=0.185), although a significant reduction was observed in the mean number of fractures occurring during treatment compared to pre-treatment values. The most frequent adverse events were arthralgia, fever, joint sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported serious adverse events was considered as treatment-related. CONCLUSION Long-term i.v. neridronate treatment has positive effects on BMD, bone turnover markers and fracture risk with a good safety profile.

An exploratory study on the role of vitamin D supplementation in improving pain and disease activity in rheumatoid arthritis

Rheumatology Unit, University of Verona, Verona, Italy; Rheumatology Unit, Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy; Rheumatology Unit, University of Foggia, Foggia, Italy; Rheumatology Unit, Gaetano Pini Institute, Milan, Italy; Rheumatology Unit, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Rheumatology Unit, University Federico II of Naples, Naples, Italy; Rheumatology Unit, Galateo San Cesario Hospital, San Cesari di Lecce, Italy

Correction to: The obesity paradox and osteoporosis

Unfortunately, the author’s first name and the family name were swapped and published in the original publication.