Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia

Osteoporosis in beta-thalassaemia is multifactorial; increased osteoclast function seems to play an important role in its pathogenesis. The aim of this study was to evaluate the effect of pamidronate on the osteoporosis of thalassaemia. To this effect we studied 26 patients who received this drug in doses of 30 or 60 mg i.v. once a month over 12 months. The effects were monitored by measuring bone mineral density (BMD) in association with markers of osteoclast function [soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), osteoprotegerin (OPG)] and of bone remodelling [N-telopeptide of collagen type-I (NTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), bone-alkaline phosphatase (bALP), and osteocalcin (OC)]. Thirty healthy individuals were also studied, as controls. NTX, TRACP-5b, bALP and OC levels were significantly higher in thalassaemic patients compared with controls; in contrast, OPG levels were significantly lower, while the levels of sRANKL varied within normal limits. Administration of pamidronate was followed by a clear decrease of NTX, TRACP-5b, OPG, and OC, and by a significant increase in the BMD of the lumbar spine, which was similar in patients of both treatment groups. These data suggest that pamidronate, at a monthly dose of 30 mg, is an effective treatment for thalassaemic osteoporosis.     

Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin–angiotensin system (RAS).     

A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients. The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA)

Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n = 24) showed a significantly increased IMT compared to those with the TC (n = 52, p = 0.007) and TT (n = 24, p = 0.009) genotype, in the hypertensive group only (mean ± SD for TT = 0.88 ± 0.21 mm, TC = 0.90 ± 0.16 mm, CC = 1.05 ± 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.     

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.     

Soluble Receptor Activator of Nuclear Factor-κB Ligand (sRANKL)/Osteoprotegerin Balance in Ageing and Age-Associated Diseases

Recently, novel members of the TNF/TNF receptor superfamily, receptor activator of nuclear factor- kappa B ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin (OPG), have been identified as paracrine mediators of both the immune system and bone functions. The balance of RANK/RANK-L and OPG is critical for osteoclastogenesis modulation and physiological bone remodeling. In order to evaluate whether RANKL/OPG balance is modified by ageing, we analyzed, by imunoassay, systemic levels of OPG and sRANKL in healthy elderly subjects (age range from 70 to over 90 years) and in patients affected by two age-related diseases, osteoarthritis (OA) and polymyalgia rheumatica (PMR), characterized by bone metabolism alteration and involvement of the immune system. We demonstrated that (a) plasma concentrations of OPG increased significantly with age; (b) conversely, sRANKL significantly declined in the group of subjects aged between 81 and 90 years, being similar to the young controls in the other age groups; (c) in OA and PMR, circulating OPG did not differ from plasma levels found in age-matched control groups, while sRANKL concentration was significantly increased compared to controls. Hence, in ageing, the sRANKL/OPG system appears to be modified, with prominent changes in circulating OPG levels; in OA and PMR, the sRANKL/OPG balance alteration was shown to be mainly due to the increase of plasma sRANKL concentration.     

Effects of Estrogen Deficiency and/or Caffeine Intake on Alveolar Bone Loss,Density, and Healing: A Study in Rats

Background: The aim of this study is to evaluate the effects of caffeine and/or estrogen deficiency on ligature‐induced bone loss (BL), trabecular bone area (TBA), and postextraction bone healing (BH). Methods: Rats were assigned into one of the following groups (15 each): 1) control = non‐ingestion of caffeine/sham surgery; 2) caffeine = ingestion of caffeine/sham surgery); 3) ovariectomized (OVX) = non‐ingestion of caffeine/ovariectomy; or 4) caffeine/OVX = ingestion of caffeine/ovariectomy. The rats were under caffeine administration for 65 days and/or estrogen deficiency for 51 days. On day 21 after ovariectomy, one first mandibular molar received a ligature and the contralateral tooth was not ligated. The first maxillary molars were extracted 8 days before sacrifice. BL, TBA, the positive cells for tartrate‐resistant acid phosphatase (TRAP), receptor activator of nuclear factor‐κB ligand (RANKL), and osteoprotegerin (OPG) were analyzed in the furcation area of mandibular molars. Histometric BH and gene expression of bone morphogenetic protein (BMP)‐2, BMP‐7, osteopontin, and bone sialoprotein were evaluated in alveolar sockets. Results: The caffeine group presented the greatest BL and the OVX group the highest number of TRAP‐positive (TRAP⁺) cells around ligated teeth (P <0.05). The control group presented higher TBA and BH than the other groups (P <0.05). All test groups presented higher RANKL/OPG⁺ cells than the control group around ligated/unligated teeth. The OVX and caffeine/OVX groups presented a greater number of TRAP⁺ cells around unligated teeth than the control group (P <0.05). There were no differences among groups for gene expression (P >0.05). Conclusions: Caffeine increased BL in ligated teeth. Caffeine and/or estrogen deficiency decreased TBA in the unligated teeth and reduced BH after tooth extraction.     

Gingival Crevicular Fluid,Serum Levels of Receptor Activator of Nuclear Factor‐κB Ligand,Osteoprotegerin, and Interleukin‐17 in Patients With Rheumatoid Arthritis and Osteoporosis and With Periodontal Disease

Background: This study is performed to evaluate gingival crevicular fluid (GCF) and serum levels of soluble receptor activator of nuclear factor‐κB ligand (sRANKL), interleukin (IL)‐17A, IL‐17E, IL‐17F, IL‐17A/F, and osteoprotegerin (OPG) in women with rheumatoid arthritis (RA), osteoporosis (OPR), and those who are systemically healthy (SH), all with periodontal disease. Methods: GCF and serum samples were obtained before any periodontal intervention from 17 women with RA, 19 with OPR, and 13 who were SH with periodontitis. Full‐mouth clinical periodontal measurements were recorded. sRANKL, OPG, and IL‐17 levels were determined by enzyme‐linked immunosorbent assay. Results: Clinical periodontal measurements were similar in the three study groups. Although the total amounts of GCF albumin, OPG, IL‐17A, and IL‐17A/F were similar in the study groups, there were statistically significant differences in GCF concentrations of sRANKL, OPG, IL‐17A, IL‐17E, IL‐17F, and IL‐17A/F. The sRANKL/OPG ratios were significantly higher in the RA group than in the OPR and SH groups (P <0.05). Serum sRANKL, sRANKL/OPG, and IL‐17A/IL‐17E ratios were significantly higher, whereas OPG concentrations were significantly lower in the RA group compared to other groups (P <0.05). Serum IL‐17A concentrations were significantly higher in the RA and OPR groups than in the SH group (P <0.05). Conclusion: Increased inflammatory mediator levels in patients with RA, despite the long‐term use of various anti‐inflammatory drugs, suggest that these patients may have a propensity to overproduce these inflammatory mediators.