P112 Teriparatide versus anti-resorptive treatment in rheumatoid arthritis patients with severe osteoporosis: an observational study

Background/Aims Patients with rheumatoid arthritis (RA) are at increased risk of developing osteoporosis (OP) and have a twofold increased risk of vertebral fracture compared with the general population. There is increasing evidence that teriparatide (TPTD) is superior to anti-resorptive medication in patients with severe spinal OP.The aim of this study was to compare the efficacy of TPTD with anti-resorptive treatment (ART) in RA patients with severe spinal OP. Methods Observational study of RA patients and controls with severe OP who were referred to a specialist osteoporosis clinic. Patients with a history of two vertebral fractures or a spinal BMD Tscore < -4 were offered either TPTD or standard care with either oral or parenteral ART. After completion of TPTD treatment patients were advised to commence ART. DEXA re-evaluation was usually performed after 1, 2 and 5 years. Results We studied 59 postmenopausal women with RA who had severe spinal OP. In the RA group 29 patients received TPTD treatment and 30 patients were started on ART (12 Zoledronic acid, 11 Alendronate, 3 Risedronate, 2 Denosumab, 1 Etidronate and 1 unknown).RA patients who were started on TPTD were on average 5 years younger (65.4 ±10.6) than patients who were started on ART (70.6±8.2; p = 0.041). Slightly more than half of TPTD RA patients (55.2%) had previously received bisphosphonates and 10.3% received low dose Prednisolone (mean± SD dose = 5.5 ± 3.3 mg). Baseline lumbar spine T-score was -4.25±0.57 in the RA TPTD group. Patients with RA who elected to have ART as opposed to TPTD had higher BMD values as compared with those who chose to have TPTD (T-score = -3.39±1.09; p = 0.001, from RA TPTD group).We found that increase in BMD with TPTD treatment was superior to ART in the RA group at increasing spine BMD after 2 years (+17.59% ± 9.63% vs 3.19 % ± 4.99% , p value<0.001). Assessment after 5 years following commencement of ART showed that spine BMD remained higher in the RA TPTD group than in the RA ART group alone (18.0% ± 11.6% vs 6.36 % ± 8.95%; p = 0.019). However, there was no significant difference between TPTD and ART on hip BMD change at 2 years (+ 3.6% ± 12.2 % vs -0.57% ± 5.96%, p = 0.237) or 5 years (+1.0% ± 10.9% vs -0.3% vs ± 7.8%, p = 0.724). Conclusion This real-world study confirms that TPTD treatment is more effective in treating severe spinal OP in RA patients than antiresorptive medication alone. Despite the fact that the majority of RA patients had been pre-treated with bisphosphonates the TPTD treatment effect in RA patients was robust. Anabolic treatment with TPTD is a good option for RA patients with severe spinal OP. Disclosure B. Hauser: Other; Dr Hauser has received fees for a promotional article from Gedeon Richter. K.M. Berg: None. J.A. Lambert: None. S.H. Ralston: Grants/research support; Prof Ralston has received grant funding from Lilly for an observational study and donation of Teriparatide for the TOPAZ trial in Osteogenesis Imperfecta.

Looking for new anabolic treatment from rare diseases of bone formation

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterized by altered bone erosion or formation. In this review we will describe some bone formation-related disorders as Sclerosteosis, Van Buchem disease, Hypophosphatasia and Camurati-Engelmann disease. In the past decades the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation

Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D–treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.

MicroRNA levels in bone and blood change during bisphosphonate and teriparatide therapy in an animal model of postmenopausal osteoporosis

ABSTRACTMicroRNAs control the activity of a variety of genes that are pivotal to bone metabolism. Therefore, the clinical utility of miRNAs as biomarkers and drug targets for bone diseases certainly merits further investigation. This study describes the use of an animal model of postmenopausal osteoporosis to generate a comprehensive dataset on miRNA regulation in bone tissue and peripheral blood during bone loss and specifically anti-resorptive and osteo-anabolic treatment.Forty-two Sprague-Dawley rats were randomized to SHAM surgery (n=10) or ovariectomy (OVX, n=32). Eight weeks after surgery, OVX animals were further randomized to anti-resorptive treatment with zoledronate (n=11), osteo-anabolic treatment with teriparatide (n=11), or vehicle treatment (n=10). After 12 weeks of treatment, bone and serum samples were used for microRNA analysis using next-generation sequencing (NGS), mRNA levels using RT-qPCR, and bone microarchitecture analysis using nanoCT.Ovariectomy resulted in loss of trabecular bone, which was fully rescued using osteo-anabolic treatment, and partially rescued using anti-resorptive treatment. NGS revealed that both, anti-resorptive and anabolic treatment had a significant impact on miRNA levels in bone tissue and serum: out of 426 detected miRNAs, 46 miRNAs were regulated by teriparatide treatment an d 10 by zoledronate treatment (p-adj. < 0.1). Interestingly, teriparatide and zoledronate treatment were able to revert miRNA changes in tissue and serum of untreated OVX animals, such as the up-regulation of miR-203a-3p, a known osteo-inhibitory miRNA. We confirmed previously established mechanisms of miR-203a by analyzing its direct target Dlx5 in femoral head.Our data reveal a significant effect of ovariectomy-induced bone loss, as well as the two major types of anti-osteoporotic treatment on miRNA transcription in femoral head tissue. These changes are associated with altered activity of target genes relevant to bone formation, such as Dlx5. The observed effects of bone loss and treatment response on miRNA levels in bone are also reflected in the peripheral blood, suggesting the possibility of minimally-invasive monitoring of bone-derived miRNAs using liquid biopsies.HighlightsmicroRNA expression in bone tissue is altered by osteo-anabolic and anti-resorptive therapy in OVX rats.microRNA changes in untreated OVX rats are reverted by anti-osteoporotic therapy.miR-203a is up-regulated during bone loss and down-regulated following therapy.Bone tissue and serum levels of miR-203a are highly correlated.

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

Urinary Concentrations of Steroids in Bulls under Anabolic Treatment by Revalor-XS® Implant

Despite the European ban of using anabolics in food-producing animals, growth promoters might still be illegally used in the European Union. To control the food chain and guarantee consumers’ health, there is a need of highly sensitive analytical methods for the identification of marker residues of such treatments. In the present study, a group of bulls (n=16) received trenbolone acetate (200 mg) and estradiol (40 mg) by a commercial ear implant during a time range of 71 days, and a second group (n=16) was kept for control. The aim of the research was to measure the residual urinary concentrations of the administered drugs (β-trenbolone andβ-estradiol), their main metabolites (α-trenbolone andα-estradiol), and possible alterations of the urinary profile of other endogenous hormones metabolically related. The analytical method was based on liquid chromatography-tandem mass spectrometry. Results showed average urinary concentrations ofα-trenbolone andα-estradiol during treatment in the range of (0.81÷2.1) ng mL−1and (0.96÷4.4) ng mL−1, respectively, whereasβ-trenbolone andβ-estradiol exhibit urinary concentrations lower than 0.22 ng mL−1in both cases. Data obtained from the urinary profiles of endogenous steroids indicate that they could be useful to indirectly detect the ongoing treatment.