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Sridharan M.,The London Clinic | Cheung J.,St. Thomas Hospital | Moore A.E.,Osteoporosis Screening Unit | Frost M.L.,Osteoporosis Screening Unit | And 3 more authors.
Calcified Tissue International | Year: 2010

Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1-34) for 18 months. Bone mineral density (BMD) was measured at 6 and 18 months at the lumbar spine (LS) and total hip (TH). Blood samples were obtained at baseline, 1-3, 6-9, and 12-18 months. Serum calcium, phosphate, PTH, 25(OH)vitamin D, 1,25(OH) 2vitamin D, markers of bone turnover, FGF-23, and sclerostin were measured. BMD increased at both the LS (11.6%, P < 0.001) and TH (2.5%, P < 0.01). The bone formation marker P1NP increased early (baseline mean [SD] 39.9 [24.4] μg/l, 1-3 months 88 [37.9] μg/l; P < 0.001) and remained higher than baseline throughout 18 months. FGF-23 also increased, with a peak response at 6-9 months (increase 65%, P = 0.002). Serum phosphate remained stable. A significant increase in 1.25(OH)2vitamin D (P = 0.02) was seen at 1-3 months only. A small but significant reduction in sclerostin was seen at 6-9 (P = 0.02) and 12-18 months (P = 0.06). There was a positive correlation between changes in P1NP and FGF-23 (6-9 months r = 0.78, P < 0.001). FGF-23 is increased by intermittent PTH(1-34). This is related to early changes in P1NP, suggesting that the skeletal effects of PTH may involve FGF-23. Further studies are required to elucidate this. © 2010 Springer Science+Business Media, LLC.

Manghat P.,St. Thomas Hospital | Souleimanova I.,St. Thomas Hospital | Cheung J.,St. Thomas Hospital | Wierzbicki A.S.,St. Thomas Hospital | And 8 more authors.
Bone | Year: 2011

Vascular calcification (VC) is highly prevalent in CKD and leads to increased vascular stiffness and cardiovascular disease (CVD). Non-traditional cardiovascular risk factors include abnormal bone turnover and/or dysregulation of the calcification inhibitors, although their relative contribution remains unclear. We investigated the association between bone turnover, the calcification inhibitors (matrix gla protein; MGP and Fetuin-A), and the phosphate regulating hormone; fibroblast growth factor-23 (FGF-23) and arterial stiffness in pre-dialysis CKD patients. One hundred and forty-five patients with CKD stages 1-4 (74 M, 71 F) aged (mean [SD]) 53 [14] years were studied. Bone turnover markers (bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRACP)) and MGP, Fetuin-A and FGF-23 were determined. BMD was measured at the lumbar spine (LS), femoral neck (FN), forearm (FARM) and total hip (TH). Arterial stiffness was assessed by contour analysis of digital volume pulse (SIDVP). There was a significant positive correlation between TRACP:BALP ratio and SIDVP ( r=0.19, p=0.023). Following multi-linear regression analysis, significant associations were seen between serum BALP (p=0.037), TRACP (p=0.009) and TRACP:BALP ratio (p=0.001) and SIDVP independently of traditional CVD risk factors. No significant relationship between SIDVP and MGP, Fetuin-A and FGF-23 was observed. A significant negative correlation was seen between BMD at the FARM and SIDVP in CKD stage 4 (r=-0.35, p=0.024). The association remained significant following correction for age, gender and cardiovascular risk factors (p=0.029). Our data suggest a link between imbalances in bone turnover and arterial stiffness in pre-dialysis CKD. Longitudinal studies are needed to evaluate the clinical usefulness of these bone turnover markers as predictors of CVD in CKD. © 2011 Elsevier Inc.

Sandhu S.K.,Osteoporosis Screening Unit | Hampson G.,Osteoporosis Screening Unit
Journal of Clinical Pathology | Year: 2011

With an increasingly ageing population, osteoporosis and osteoporosis-related fractures is fast becoming an important public health problem placing a considerable economic burden on health service resources. This does not account for the substantial pain, disability and indeed mortality incurred after a fracture, particularly a hip fracture. Osteoporosis is a systemic skeletal disorder which results from an imbalance in bone remodeling. This leads to a reduction in bone strength and increased susceptibility to fracture. It affects up to 1 in 2 women and 1 in 5 men. In the past 2 decades, there have been significant advances in bone biology which have helped in the understanding of the pathogenesis of osteoporosis and have led to improved therapies. In developing strategies for fracture prevention, it is important to identify those individuals with the highest fracture risk who will require pharmacological intervention. Treatment is aimed at fracture prevention and includes modification of general lifestyle factors which have been linked to fractures in epidemiological studies and ensuring optimum calcium and vitamin D intake as adjunct to active anti-fracture therapy. A number of drugs are now approved for the treatment of osteoporosis. This review article will describe the pathogenesis of osteoporosis and focus on the methods currently in use for the identification of patients at high fracture risk and will highlight their usefulness and limitations. The existing anti-fracture pharmacotherapies and those in development will be reviewed. Assessment of their effectiveness including the use of biochemical markers of bone turnover in this clinical context will be reviewed.

Hampson G.,Osteoporosis Screening Unit | Fogelman I.,Osteoporosis Screening Unit
International Journal of Women's Health | Year: 2012

Bisphosphonates (BPs) are synthetic analogues of pyrophosphate. They inhibit bone resorption and are therefore widely used in disorders where there are increases or disruptions in bone resorption. This includes postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease of bone, and malignancy-related bone loss. To best understand the clinical application of BPs, an understanding of their pharmacokinetics and pharmacodynamics is important. This review describes the structure, pharmacology and mode of action of BPs, focusing on their role in clinical practice. Controversies and side effects surrounding their use will also be discussed. © 2012 Hampson and Fogelman, publisher and licensee Dove Medical Press Ltd.

Ishtiaq S.,Osteoporosis Screening Unit | Fogelman I.,Osteoporosis Screening Unit | Hampson G.,Osteoporosis Screening Unit
Journal of Endocrinological Investigation | Year: 2015

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/ 1.73 m2. Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and antisclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention. © Italian Society of Endocrinology (SIE) 2014.

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