Distal phalangeal bone erosions observed by HR-pQCT in patients with psoriatic onycholysis.

OBJECTIVES: PsA prevalence among skin psoriasis is ∼30%. Nail psoriasis, especially onycholysis, is present in >70% of PsA and the risk of developing PsA is more than doubled in patients with nail involvement. We hypothesized that onycholysis may be associated with early bone erosions of the DIP joint without harbouring PsA symptoms. METHODS: We compared tendon thickness, assessed by US, and bone erosions, assessed by high-resolution peripheral quantitative CT, of the DIP joint in patients with psoriatic onycholysis without PsA (ONY) with those in patients with cutaneous psoriasis only (PSO). We used patients with PsA as reference (PsA group), and healthy age-matched controls (CTRL). Differences between groups were assessed by analysis of variance tests followed by post hoc analysis using the Scheffe method. RESULTS: Mean (s.e.m.) age of the 87 participants (61% males) was 45.2 (1.3) years. The mean extensor tendon thickness was significantly larger in ONY than in PSO patients. In the PsA group, 68% of patients exhibited erosions of three different shapes: V-, Omega- and U-shape. Association with erosions was greater in the ONY group than in the PSO group (frequency: 57 vs 14%; P < 0.001; mean number of erosions: 1.10 (0.35) vs 0.03 (0.03); P < 0.001). CONCLUSION: Onycholysis was associated with significant enthesopathy and bone erosions in our cohort. These data support the pathogenic role of enthesopathy in PsA. Onycholysis may be considered as a surrogate marker of severity in psoriasis. TRIAL REGISTRATION: ClinicalTrails.gov, https://clinicaltrials.gov, NCT02813720.

The role of biochemical markers of joint tissue remodelling to predict progression and treatment efficacy in inflammatory rheumatic diseases.

Structural damage is a hallmark in RA, spondyloarthropy (SpA) and psoriatric arthritis (PsA). Its progression is difficult to predict and current radiological or inflammatory biological markers lack sensitivity. Biochemical markers of bone, cartilage and synovial tissues provide a dynamic indication of the anabolism and catabolism of joint tissues and can be easily measured by immunoassays. Novel biochemical markers including post-translational modifications of matrix proteins and enzyme-generated neoepitopes with increased tissue and/or biological pathway specificity have been developed. Their evaluation in clinical trials of novel biologic therapies and epidemiological studies indicated that their measurements could be useful to predict progression of structural damage and treatment efficacy, independently of current clinical, radiological and biological indices of disease activity. In this paper we briefly describe the latest developments in biochemical markers and critically analyse the clinical data assessing the utility of established and novel biochemical markers in RA, SpA and PsA.

Balancing benefits and risks in the era of biologics.

Biologics are substances synthetized from biological sources used in the prevention and treatment of several diseases. Rheumatologists have many years of experience with biologics for the treatment of immune-mediated diseases and osteoporosis. Randomized clinical trials and postmarketing studies have demonstrated that treatment with biologics can result, albeit infrequently, in serious adverse events. To date, several risk mitigation strategies have been identified and implemented. The objective of the present perspective review is to examine the risk mitigation strategies of biologic treatments, with special focus on anti-tumor necrosis factors and denosumab.

Relationship Between Sex Steroids and Deterioration of Bone Microarchitecture in Older Men: The Prospective STRAMBO Study.

In older men, low estrogen levels are associated with poor bone microarchitecture. Data on androgens are discordant. We studied the link between baseline sex steroid levels (total 17ß -estradiol [17ßE2], total testosterone [tT], calculated bioavailable 17ßE2 [bio-17ßE2], and apparent free testosterone concentration [AFTC]) and bone microarchitecture deterioration assessed prospectively in a 820 older men followed for 8 years. Bone microarchitecture was assessed by HR-pQCT at baseline, then after 4 and 8 years. At both the skeletal sites, the bone microarchitecture deterioration rate did not correlate with serum levels of tT and 17ßE2. At the distal radius, cortical area (Ct.Ar) decreased more rapidly in the lowest versus the highest AFTC quartile. At the distal tibia, cortical thickness (Ct.Th) decreased and trabecular area (Tb.Ar) increased more rapidly in the highest versus the lowest AFTC quartile. At the tibia, bone mineral content (BMC), total volumetric bone mineral density (Tt.vBMD), Ct.Th, and Ct.Ar decreased, whereas Tb.Ar increased faster in the lowest versus the highest bio-17ßE2 quartile. In men who had both AFTC and bio-17ßE2 in the lowest quartile (high-risk group), distal radius cortical vBMD (Ct.vBMD) decreased more rapidly compared with men who had both hormones in the three upper quartiles (reference group). At the distal tibia, Tt.vBMD, Ct.Th, Ct.Ar, and Ct.vBMD decreased, whereas Tb.Ar increased more rapidly in the high-risk group versus the reference group. In men receiving androgen deprivation therapy (ADT) for prostate cancer, BMC, Tt.vBMD, Ct.Th, Ct.Ar, and Ct.vBMD decreased, whereas Tb.Ar increased more rapidly than in men not receiving ADT at both the skeletal sites. Thus, in older men followed up prospectively, low levels of bio-17ßE2, and to a smaller extent AFTC, are associated with accelerated cortical bone deterioration. Cortical bone deterioration was strongly accelerated in men receiving ADT who had very low levels of all sex steroids. © 2019 American Society for Bone and Mineral Research.

Bone Microarchitecture Assessed by HR-pQCT as Predictor of Fracture Risk in Postmenopausal Women: The OFELY Study.

Several cross-sectional studies have shown that impairment of bone microarchitecture contributes to skeletal fragility. The aim of this study was to prospectively investigate the prediction of fracture (Fx) by bone microarchitecture assessed by high-resolution peripheral computed tomography (HR- pQCT) in postmenopausal women. We measured microarchitecture at the distal radius and tibia with HR-pQCT in the OFELY study, in addition to areal BMD with dual-energy X-ray absorptiometry (DXA) in 589 women, mean ± SD age 68 ± 9 years. During a median [IQ] 9.4 [1.0] years of follow-up, 135 women sustained an incident fragility Fx, including 81 women with a major osteoporotic Fx (MOP Fx). After adjustment for age, women who sustained Fx had significantly lower total and trabecular volumetric densities (vBMD) at both sites, cortical parameters (area and thickness at the radius, vBMD at the tibia), trabecular number (Tb.N), connectivity density (Conn.D), stiffness, and estimated failure load at both sites, compared with control women. After adjustment for age, current smoking, falls, prior Fx, use of osteoporosis-related drugs, and total hip BMD, each quartile decrease of several baseline values of bone microarchitecture at the radius was associated with significant change of the risk of Fx (HR of 1.39 for Tb.BMD [p = 0.001], 1.32 for Tb.N [p = 0.01], 0.76 for Tb.Sp.SD [p = 0.01], 1.49 [p = 0.01] for Conn.D, and 1.27 for stiffness [p = 0.02]). At the tibia, the association remained significant for stiffness and failure load in the multivariate model for all fragility Fx and for Tt.BMD, stiffness, and failure load for MOP Fx. We conclude that impairment of bone microarchitecture-essentially in the trabecular compartment of the radius-predict the occurrence of incident fracture in postmenopausal women. This assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone, to benefit from a therapeutic intervention. © 2017 American Society for Bone and Mineral Research.

Lower serum osteocalcin is associated with more severe metabolic syndrome in elderly men from the MINOS cohort.

BACKGROUND: Bone has emerged as an endocrine organ regulating energy metabolism through secretion of osteocalcin. In epidemiological studies, presence of metabolic syndrome (MetS) was associated with lower osteocalcin level. OBJECTIVES: We evaluated whether osteocalcin level was associated with MetS severity in men and whether it was more strongly associated with MetS compared with N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP), and C-terminal telopeptide of type I collagen (ßCTX). METHODS: We included 798 men aged 51-85 years for total osteocalcin measurement. Number of MetS criteria was used to define severity. We used polytomous logistic regression to assess the relationship between MetS severity and osteocalcin level. RESULTS: Thirty percent of men had MetS. In patients with MetS, the higher the number of MetS traits were present, the lower was the average osteocalcin level (0-2 criteria: 551 men: 19.5±6.7 ng/ml, three criteria: 155 men: 19.3±7.4 ng/ml, four criteria: 72 men: 17.3±5.7 ng/ml, and five criteria: 20 men: 15.0±5.1 ng/ml; P for trend=0.002).In the polytomous logistic regression model, an increase in osteocalcin level of 10 ng/ml was associated with lower prevalence of severe MetS: three criteria (odds ratio (OR)=0.93 (0.70-1.24)), four criteria (OR=0.54 (0.34-0.84)), and five criteria (OR=0.28 (0.10-0.82)) in comparison with no MetS (P for trend=0.008).After adjustment, using stepwise analysis of the polytomous logistic regression model, we observed that osteocalcin, age, and apparent free testosterone entered in the model but not other bone markers (PINP, ßCTX, and BAP). CONCLUSION: In older Caucasian men, total osteocalcin level was associated with MetS severity. Osteocalcin was more strongly associated with MetS severity than other bone turnover markers.

Etanercept may induce neurosarcoidosis in a patient treated for rheumatoid arthritis.

BACKGROUND: TNFα blockers have drastically improved rheumatoid arthritis prognosis by preventing joint destruction in DMARD resistant patients. Altering cytokine balance in immune diseases may expose to paradoxical adverse events. CASE PRESENTATION: We present the case of a 40-year-old woman, with a confirmed erosive and seropositive RA, successfully treated by TNFα blocker (etanercept) for seven years, and who developed a severe neurosarcoidosis. She had lymphocytic meningitis, bilateral peripheral facial paralysis and anosmia, associated with bilateral hilar lymph nodes, papilloedema, anterior uveitis and elevated serum angiotensin-converting enzyme level. Magnetic resonance imaging showed a bilateral thickening of the Gasser's ganglia walls and enhanced signal of the vestibulocochlear, the facial and the proximal portion of trijeminal nerves. CONCLUSION: This case raised the issue of the imputability of etanercept in the development of neurosarcoidosis. Neurological symptoms onset in patients on TNFα blockers should lead to exclude infections, induced lupus but also paradoxical neurosarcoidosis.

Higher serum osteocalcin is associated with lower abdominal aortic calcification progression and longer 10-year survival in elderly men of the MINOS cohort.

CONTEXT: Abdominal aortic calcification (AAC) is an indicator of cardiovascular risk, especially in the diseases characterized by insulin resistance such as type 2 diabetes. Osteocalcin is a bone-secreted hormone that favors insulin sensitivity and insulin secretion. OBJECTIVES: We investigated whether total serum osteocalcin level at baseline is associated with AAC progression and 10-year all-cause mortality in elderly men. DESIGN AND PARTICIPANTS: We assessed 774 men aged 51-85 years from the MINOS cohort who had osteocalcin measurement and lumbar spine radiographs at baseline. They were followed-up prospectively for 10 years. Among them, 615 patients had a follow-up radiograph at 3.5 or 7 years. MAIN OUTCOME MEASURES: Serum total osteocalcin was measured with an immunoradiometric assay on morning fasting serum collected at baseline. Kauppila's AAC score was assessed from lumbar spine radiographs. AAC progression rate was calculated as the difference between AAC on the last available radiograph and AAC at baseline divided by the follow-up time. Death status was collected over 10 years. RESULTS: In multivariate analysis, higher baseline total osteocalcin was associated with lower AAC progression rate (odds ratio = 0.74 [0.57-0.97] per 10 ng/mL variation; P = 0.029). At the 10-year follow-up, there were 599 men alive (77%), 181 dead (23%), and 2 lost to follow-up. Higher osteocalcin was associated with lower 10-year all-cause mortality (hazard ratio = 0.62 [0.44-0.86] per 10 ng/mL variation; P = 0.005). CONCLUSION: Higher baseline total osteocalcin concentrations were associated with lower AAC progression rate and lower mortality. These data suggest that osteocalcin level might be an independent indicator of cardiovascular risk and global health in elderly Caucasian men.

Pathophysiology and medical treatment of pain in fibrous dysplasia of bone.

One of the most common complications of fibrous dysplasia of bone (FD) is bone pain. Usual pain killers are often of inadequate efficacy to control this bone pain. The mechanism of bone pain in FD remains uncertain, but by analogy with bone tumors one may consider that ectopic sprouting and formation of neuroma-like structures by sensory and sympathetic nerve fibers also occur in the dysplastic skeleton. Bone pain has been reported in up to 81% of adults and 49% of children. It affects predominantly the lower limbs and the spine. The degree of pain is highly variable and adults reports more pain than children. Bisphosphonates have been shown to reduce bone pain in uncontrolled studies. Their influence on bone strength remains unknown. In a randomized trial testing alendronate, bone pain was not significantly improved. Another trial assessing the effect of risedronate is ongoing. Possible future therapies include tocilizumab, denosumab and drugs targeting nerve growth factor and its receptor TrkA.

Modifications of bone material properties in postmenopausal osteoporotic women long-term treated with alendronate.

OBJECTIVE: Given recent concern about long-term safety of bisphosphonate (BP) therapy, the effects of long-term alendronate (ALN) therapy on intrinsic bone properties were studied among postmenopausal osteoporotic (PMOP) women. DESIGN AND METHODS: Transiliac bone biopsies were obtained from 32 outpatient clinic PMOP women treated with oral ALN for 6.4 ± 2.0 years. Variables reflecting bone mineralization were measured both at tissue level using quantitative microradiography and at crystal level by Fourier transform infrared microspectroscopy. Bone microhardness was investigated by Vickers indentation tests. RESULTS: were compared with those from 22 age-matched untreated PMOP women. Results Long-term treatment with ALN was associated with a 84% (P<0.001) lower remodeling activity compared with untreated PMOP women, leading to an increased degree of mineralization in both cortical and trabecular bone (+9 and +6%, respectively, P<0.05). Despite a more mature and more mineralized bone matrix, after treatment, cortical and trabecular microhardness and crystallinity were lower than that measured in untreated patients. None of the variables reflecting material properties were significantly correlated to the duration of the treatment. CONCLUSION: Increased degree of mineralization associated with lower crystallinity and microhardness in ALN long-term-treated PMOP women suggests that ALN could alter the quality of bone matrix. The study also suggested that after 3 years of treatment, the changes in material properties are not dependent on the duration of the treatment. Further studies are requested to assess the short-term (<3 years) effects of BPs on bone intrinsic properties.

Fibrous dysplasia of bone and McCune-Albright syndrome.

Fibrous dysplasia of bone is a genetic, non-inheritable disease, characterized by bone pain, bone deformities and fracture, involving one or several bones. It is caused by mis-sense mutations occurring post-zygotically in the gene coding for the alpha-subunit of the stimulatory G-protein, Gs, in the guanine nucleotide binding, alpha stimulating (GNAS) complex locus in chromosome 20q13. This mutation results in osteoblastic differentiation defects, and bone resorption is often increased. The bone lesions may be associated with endocrine dysfunctions and café-au-lait spots; this is known as McCune-Albright syndrome. Patients with polyostotic fibrous dysplasia often have renal phosphate wasting. The disease, however, has a wide clinical spectrum, so many patients are asymptomatic. Diagnosis relies on radiographs and pathology. Bisphosphonates have been used in the treatment of fibrous dysplasia to relieve bone pain and improve lytic lesions, but they are still under clinical evaluation. Calcium, vitamin D and phosphorus supplements may be useful in some patients. Surgery is also helpful to prevent and treat fracture and deformities.

Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study.

UNLABELLED: We sought whether microdamage could rise in postmenopausal osteoporotic women on long-term bisphosphonates, as suggested by recent animal studies. We found few microcracks in iliac bone biopsies, despite a marked reduction in bone turnover. INTRODUCTION: Animal studies suggest that bisphosphonates (BPs) could increase microdamage frequency in a dose-dependent manner, caused by excessively suppressed bone turnover. However, there is limited data in humans receiving BP therapeutic doses for >3 yr. MATERIALS AND METHODS: We measured microcrack frequency and histomorphometry parameters on transiliac bone biopsies in 50 postmenopausal osteoporotic women (mean age = 68 yr) who had received BP therapy (3 on intravenous pamidronate, 37 on oral alendronate, and 10 on oral risedronate) for at least 3 yr (mean treatment duration = 6.5 yr). We compared these results with transiliac bone biopsies obtained from 12 cadavers. We used bulk staining with green calcein as a fluorochrome. The microcracks were quantified in three 100-microm-thick sections using optic microscopy and were confirmed by laser confocal microscopy. Microcrack frequency (number of microcracks/mm2 of bone tissue) was compared between treated women and controls using nonparametric tests. We also explored predictors of microcrack frequency, including age, duration of BP therapy, and activation frequency. RESULTS: Among treated women, cancellous bone microcrack frequency was low (mean, 0.13 microcracks/mm2) and did not differ significantly from that observed in controls (0.05 microcracks/mm2; p = 0.59). Of note, 54% of the treated women and 58% of the controls had no observable microcracks. There was no association between microcrack frequency and the duration of BP therapy (for microcracks/mm2 and duration, Spearman r = 0.04, p = 0.80) and between patients' ages and the number of microcracks (Spearman r = -0.09, p = 0.61). Although bone remodeling parameters were suppressed in treated women, we found no relationship between microcrack density and activation frequency (Spearman r = -0.003, p = 0.99). Also, microcrack frequency was not increased in women with prevalent vertebral fracture compared with those without fractures. CONCLUSIONS: Among postmenopausal osteoporotic women on long-term BPs, microcrack frequency in the iliac bone is low, despite a marked reduction of bone turnover.

Medical therapy in adults with fibrous dysplasia of bone.

UNLABELLED: In open studies, bisphosphonate therapy (pamidronate, alendronate) reduced bone pain associated with fibrous dysplasia of bone and was associated to some radiological improvement. Calcium, vitamin D, and phosphorus supplements may be useful in patients with deficiency. We are awaiting results from controlled trials testing bisphosphonates. INTRODUCTION: Fibrous dysplasia of bone (FD), a rare disease caused by osteoblastic lineage differentiation defects, is associated with bone pain, fracture, and bone deformity, but few therapeutic options are available. MATERIALS AND METHODS: We reviewed published data on the treatment of FD with bisphosphonates (pamidronate, alendronate), calcium, vitamin D, and phosphorus. We also present new results on FD therapy with a more potent bisphosphonate, zoledronic acid, given intravenously at the dose of 4 mg every 6 months. RESULTS: Pamidronate therapy, given intravenously every 6 months at a dose of 180 mg in adults, relieved bone pain, decreased bone resorption, and improved the radiological aspect (filling of lytic lesions and/or thickening of cortices) in approximately 50% of patients. BMD in affected sites was also significantly increased after pamidronate treatment. Those results have been obtained only in open studies, without controls, by several research groups. In a series of nine patients on long-term pamidronate treatment, but resisting to this medication and switched to intravenous zoledronic acid, no substantial improvement was observed. There is some biological rationale supporting the use of calcium and vitamin D in patients with deficiency to improve FD lesions by limiting secondary hyperparathyroidism. Phosphorus supplementation may prevent mineralization defects in those patients who have both FD and renal phosphate wasting. However, we are lacking clinical evidence for the efficacy of such supplements. CONCLUSIONS: Bisphosphonate treatment reduces increased osteoclastic activity in FD and probably improves bone pain, but their use should be better studied in randomized controlled trials.