Angelo Fassio

New strategies for the prevention and treatment of systemic and local bone loss; from pathophysiology to clinical application

Bone loss is the result of a negative unbalance between bone formation ad bone resorption. In the last years, the studies on the Wnt canonical pathway have highlighted its crucial role in bone balance through its influence on the activity and maturation of the osteoblast line and in the Receptor Activator of Nuclear Factor κ B (RANK) - RANK ligand (RANKL)/Osteoprotegerin (OPG) system. These mechanisms are involved not only in the pathological processes inducing not only systemic bone loss (i.e. Postmenopausal osteoporosis, glucocorticoid- induced osteoporosis, etc.), but also at a local level, as happens in Rheumatoid Arthritis (RA). Recently, several new drugs for the treatment of bone loss have been approved, while some others are still under development. The most promising new drugs in the treatment of osteoporosis include the antibody that neutralizes RANKL (denosumab, DMAb), monoclonal antibodies against sclerostin and parathyroid hormone-related protein analogue. Other new strategies for the prevention and treatment of bone loss include calcilytics, cathepsin K inhibitor or the combination or the sequential use of the current drugs. New insights concerning the treatment of the local bone loss in RA and in Complex Regional Pain Syndrome type I are also provided in this review.

In psoriatic arthritis Dkk-1 and PTH are lower than in rheumatoid arthritis and healthy controls

Psoriatic Arthritis (PsA) is characterized by bone erosive damage often associated with exuberant bone formation especially in enthesial sites. Dkk-1 and sclerostin are the main inhibitors of the WNT/β-catenin signaling pathway and play a key role in the regulation of both bone formation and resorption. We performed this study in order to compare the serum levels of the WNT-pathway regulators along with bone turnover markers (BTM) and parathyroid hormone (PTH) between three different groups: one group of female patients affected by PsA, one group of female patients affected by rheumatoid arthritis (RA), and healthy female controls (HC). This is a cross-sectional study including 33 patients with PsA classified with the CASPAR criteria, 35 HC, and 28 patients with RA classified with the ACR/EULAR 2010 criteria. Intact N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), Dickkopf-related-protein 1 (Dkk-1), sclerostin, PTH, and 25OH-vitamin D serum levels were dosed. The PsA group showed significantly lower Dkk-1 levels when compared to the HC and RA groups. Dkk-1 in the RA group was significantly higher than HC. A similar trend was documented for PTH. In the PsA group, CTX-I was found to be lower than in both the RA and HC groups. This study demonstrated for the first time that Dkk-1 levels in PsA are lower than HC, in contrast with RA, in which they are increased. These results might contribute to explain the different bone involvement of the two different diseases.

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.

The negative bone effects of the disease and of chronic corticosteroid treatment in premenopausal women affected by rheumatoid arthritis

Osteoporosis is a well-known extra-articular complication in rheumatoid arthritis (RA). The chronic corticosteroid treatment, the functional impairment associated with RA and the disease itself appear to be the most relevant determinants. Most of the previous studies involved postmenopausal women, in whom the estrogenic deficiency might amplify the negative effect towards bone of both RA and corticosteroid therapy. We decided to evaluate bone health in a cohort of premenopausal RA patients. The study population includes 47 premenopausal women attending our outpatient clinic for RA and twice as many healthy age-matched control women selected from the hospital personnel. The bone density at the spine and femoral neck were significantly lower in patients with RA as compared with controls. When spine bone mineral density (BMD) values were adjusted for the cumulative glucocorticoid (GC) dose alone and for the cumulative GC dose plus body mass index (BMI) the mean differences between two groups decreased but they remained statistically significant. We found no difference when the spine BMD was adjusted for cumulative GC dose, BMI and health assessment questionnaire. The difference in femoral neck BMD remained statistically significant also after all the same adjustments. In conclusion, our study shows that a BMD deficiency is frequent also in premenopausal women affected by RA, especially at femoral site and that the main determinants of this bone loss are not only the disease-related weight loss, corticosteroid therapy and functional impairment, but also the systemic effects of the disease itself.

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.

A case of mandible Paget’s disease of the bone treated with intravenous neridronate

Pagets disease of bone (PDB) is a focal disorder of osteoclasts, leading to chaotic bone remodelling, and it is characterized by the presence of focal areas of excessive bone formation alongside with areas of focal bone resorption. The typical radiographic feature is the cotton wool appearance. To date, bisphosphonates are the mainstay of the treatment. We hereby report the case of a young woman presenting with mandible PDB, with a relevant diagnostic delay and mistakenly treated for five years with chronic oral corticosteroids. After our evaluation, the patient received treatment with intravenous neridronate (an amino-bisphosphonate licensed in Italy for the treatment of this disease), with achievement of clinical remission.

Bone Geometry, Quality, and Bone Markers in Children with Type 1 Diabetes Mellitus

Adults with Type 1 diabetes mellitus show a high risk of bone fracture, probably as a consequence of a decreased bone mass and microarchitectural bone alterations. The aim of the study was to investigate the potential negative effects of type 1 diabetes on bone geometry, quality, and bone markers in a group of children and adolescents. 96 children, mean age 10.5 ± 3.1 years, agreed to participate to the study. Bone geometry was evaluated on digitalized X-rays at the level of the 2nd metacarpal bone. The following parameters were investigated and expressed as SDS: outer diameter (D), inner diameter (d), cortical area (CA), and medullary area (MA). Bone strength was evaluated as Bending Breaking Resistance Index (BBRI) from the geometric data. Bone turnover markers (PINP, CTX-I, and BAP), sclerostin, Dkk-1, PTH, and 25OH-Vitamin D were also assessed. A group of healthy 40 subjects of normal body weight and height served as controls for the bone markers. D (− 0.99 ± 0.98), d (− 0.41 ± 0.88), CA (− 0.85 ± 0.78), and MA (− 0.46 ± 0.78) were all significantly smaller than in controls (p < 0.01). BBRI was significantly lower (− 2.61 ± 2.18; p < 0.0001). PTH, PINP, and BAP were higher in the diabetic children. Multiple regression analysis showed that CA and D were influenced by insulin/Kg/day and by BMI, while d was influenced by PINP only. Type 1 diabetic children show smaller and weaker bones. The increased bone turnover could play a key role since it might amplify the deficit in bone strength associated with the inadequate osteoblastic activity caused by the disease itself.

Effects of secukinumab on serum adipocytokines: preliminary data

Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects joints, connective tissues and the axial skeleton. Metabolic syndrome is an independent risk factor for psoriasis (Pso) development and is associated with more severe forms of Pso. Adipocytokines are secreted by white adipose tissue and are thought to link obesity with the development of metabolic and cardiovascular diseases. Secukinumab is a new monoclonal antibody with a different mechanism of action. This antibody selectively binds to and neutralizes interleukin-17 (IL-17) and it has shown efficacy in the treatment of PsA. The aim of this study was to evaluate the possible interferences of secukinumab on different adipocytokines. We enrolled 28 patients with PsA, classified with the CASPAR criteria. Serum samples were stored at baseline and then at the first, the third and the sixth month of therapy. Resistin, chemerin, adiponectin and C-reactive protein (CRP) were dosed. When tested globally, none of the adipokine tested showed any statistically significant variation. However, when the male group was tested, both resistin and chemerin at M6 showed a significant decrease from baseline. CRP did not show any variation at any time point. Our study demonstrated that treatment with secukinumab has little influence on the levels of adipokines tested within the first six months of treatment even though it might exert different influence between males and females from a metabolic perspective. Further studies with greater numbers of patients are needed to determine whether these preliminary results have clinical relevance.

Drug-induced osteonecrosis of the jaw: the state of the art

Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (>90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.