Philip N Sambrook

Publications (92)412.12 Total impact

• Article: Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial.

  Jean-Yves Reginster, Janusz Badurski, Nicholas Bellamy, William Bensen, Roland Chapurlat, Xavier Chevalier, Claus Christiansen, Harry Genant, Federico Navarro, Evgeny Nasonov, Philip N Sambrook, Timothy D Spector, Cyrus Cooper
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  ABSTRACT: BACKGROUND: Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. METHODS: Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). RESULTS: The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. CONCLUSIONS: Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.
  Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
• Article: Serum Uric Acid plays a protective role for bone loss in peri- and postmenopausal women: A Longitudinal Study.

  Joanna Makovey, Monique Macara, Jian Sheng Chen, Christopher S Hayward, Lyn March, Markus J Seibel, Philip N Sambrook
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  ABSTRACT: OBJECTIVE: Oxidative stress has been linked to osteoporosis. Serum uric acid (UA), a strong endogenous antioxidant, has been associated with higher bone mineral density (BMD), lower bone turnover and lower prevalence of fractures in a large cross-sectional study of men. Whether this relationship is present in women and how UA relates to changes in BMD longitudinally has not been examined. METHODS: A sample of 356 peri- and postmenopausal women, mean age 60.5years was studied. Each individual had baseline BMD and body composition measurements by dual energy x-ray absorptiometry (DXA) and at least one repeat measure, on average 9.7years later. Annual rate of change in BMD (A%ΔBMD) was calculated. UA was measured at each DXA visit. Calciotropic hormones and bone turnover markers were measured at the final visit only. RESULTS: Cross-sectional data analyses revealed that women with higher UA levels had significantly higher absolute BMD measures at all skeletal sites. These women also had higher measures of body weight and its components such as lean mass (LM) and fat mass (FM). Results of multiple regression analyses showed a positive association between UA and BMD that remained significant even after accounting for possible confounders including LM and FM. Regression analyses of the longitudinal BMD data demonstrated significant associations between serum UA levels and annual rates of change in BMD at all skeletal sites. After adjustment associations remained significant for lumbar spine, forearm and whole body BMD but not for hip BMD. CONCLUSION: Higher serum UA levels appear to be protective for bone loss in peri- and postmenopausal women and this relationship is not affected by changes in body composition measures.
  Bone 10/2012; · 4.02 Impact Factor
• Article: High osteoporotic fracture risk and CVD risk co-exist in postmenopausal women.

  Joanna Makovey, Monique Macara, Jian Sheng Chen, Christopher S Hayward, Lyn March, Philip N Sambrook
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  ABSTRACT: INTRODUCTION: Osteoporosis related risk factors such as BMD have been associated with cardiovascular endpoints in previous studies but there have been no studies of integrated risk using risk factor algorithms. METHODS: A sample of 358 peri- and postmenopausal women, mean age 59.3 (range 45-74) years were studied. Each individual had bone mineral density (BMD) measurements by dual energy X-ray absorptiometry. Fracture risk was assessed using the WHO FRAX algorithm and cardiovascular disease (CVD) risk using the Framingham Risk Tool. RESULTS: Women with higher 10year risk of major osteoporotic had significantly higher cardiovascular risk (4.634% vs 8.36%, p=0.001). In multiple regression analysis, 5-year CVD risk was significantly associated with the 10-year risk of having major osteoporotic (β=0.095, p=0.001) and hip (β=0.055, p=0.001) fracture. Women with the highest CVD risk were 5.4 times more likely to have higher risk of major osteoporotic fracture. CONCLUSIONS: Fracture risk, determined by using a multiple risk factor algorithm such as FRAX, was positively associated with higher cardiovascular risk determined by using the Framingham Risk Tool. Awareness regarding these concurrent risk factors needs to be raised so that appropriate risk reduction can be implemented.
  Bone 09/2012; 52(1):120-125. · 4.02 Impact Factor
• Article: Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects.

  Frances M K Williams, Aruna T Bansal, Joyce B van Meurs, Jordana T Bell, Ingrid Meulenbelt, Pradeep Suri, Fernando Rivadeneira, Philip N Sambrook, Albert Hofman, Sita Bierma-Zeinstra, Cristina Menni, Margreet Kloppenburg, P Eline Slagboom, David J Hunter, Alex J Macgregor, Andre G Uitterlinden, Tim D Spector
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  ABSTRACT: OBJECTIVE: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. METHODS: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. RESULTS: This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10(-8), the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10(-8)) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10(-4), p=0.006). CONCLUSIONS: LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway.
  Annals of the rheumatic diseases 09/2012; · 8.11 Impact Factor
• Article: An increased rate of falling leads to a rise in fracture risk in postmenopausal women with self-reported osteoarthritis: a prospective multinational cohort study (GLOW).

  Daniel Prieto-Alhambra, Xavier Nogues, M Kassim Javaid, Allison Wyman, Nigel K Arden, Rafael Azagra, Cyrus Cooper, Jonathan D Adachi, Steven Boonen, Roland D Chapurlat, [......], Susan L Greenspan, Frederick H Hooven, J Coen Netelenbos, Johannes Pfeilschifter, Maurizio Rossini, Philip N Sambrook, Stuart Silverman, Ethel S Siris, Nelson B Watts, Adolfo Díez-Pérez
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  ABSTRACT: OBJECTIVES: Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women. METHODS: The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60 393 non-institutionalised women aged ≥55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, 'Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?', and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status. RESULTS: Of 51 386 women followed for a median of 2.9 years (interquartile range 2.1-3.0), 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)). CONCLUSIONS: Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.
  Annals of the rheumatic diseases 06/2012; · 8.11 Impact Factor
• Article: Associations between drug burden index and mortality in older people in residential aged care facilities.

  Nicholas M Wilson, Sarah N Hilmer, Lyn M March, Jian Sheng Chen, Danijela Gnjidic, Rebecca S Mason, Ian D Cameron, Philip N Sambrook
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  ABSTRACT: The Drug Burden Index (DBI), a measure of an individual's exposure to anticholinergic and sedative medications, is associated with functional impairment in community-dwelling, older people. In people from residential aged care facilities (RACFs), DBI score does not appear to be associated with functional impairment, but is associated with an increased risk of falls. We investigated the associations between increasing DBI score and mortality in older adults living in RACFs. Study participants (n = 602; 70.9% female), recruited from 51 RACFs in Sydney, Australia, had a mean ± standard deviation (SD) age of 85.7 ± 6.4 years and a mean ± SD DBI score of 0.58 ± 0.64. Exposure to anticholinergic medication was 33.6% and sedative medications 41.9%. All-cause mortality after a variable follow-up time (774-1269 days) was 36.2% (n = 218), with the leading causes of death classified as stroke (n = 46; 21.1%), ischaemic heart disease/cardiovascular system (n = 44; 20.2%) and pneumonia (n = 31; 14.2%). One-year mortality multivariate models showed that the DBI categories low (n = 260; hazard ratio [HR] 1.13; 95% CI 0.82, 1.57) and high (n = 153; HR 1.19; 95% CI 0.82, 1.74) were not associated with mortality. This lack of a significant association remained after dichotomization into the anticholinergic and sedative components of the DBI. We found that with high exposure to anticholinergic and sedative medications, there was no significant association between increasing DBI score and all-cause mortality in old individuals living in RACFs. Further research into the adverse effects of medication use on the mortality of institutionalized older individuals is needed.
  Drugs & Aging 02/2012; 29(2):157-65. · 2.67 Impact Factor
• Article: Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial

  Cyrus Cooper, Jean-Yves Reginster, Roland Chapurlat, Claus Christiansen, Harry Genant, Nicholas Bellamy, William Bensen, Federico Navarro, Janusz Badurski, Evgeny Nasonov, Xavier Chevalier, Philip N. Sambrook
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  ABSTRACT: Objective: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis.
  01/2012; 28(2):231-239.
• Article: Efficacy and safety of oral strontium ranelate for the treatment of knee osteoarthritis: rationale and design of randomised, double-blind, placebo-controlled trial.

  Cyrus Cooper, Jean-Yves Reginster, Roland Chapurlat, Claus Christiansen, Harry Genant, Nicholas Bellamy, William Bensen, Federico Navarro, Janusz Badurski, Evgeny Nasonov, Xavier Chevalier, Philip N Sambrook
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  ABSTRACT: OBJECTIVE: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis. RESEARCH DESIGN, METHODS, AND RESULTS: This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoral compartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2 g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ± 10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012. Clinical trial registration: The trial is registered on www.controlled-trials.com (number ISRCTN41323372). CONCLUSIONS: This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.
  Current Medical Research and Opinion 12/2011; 28(2):231-9. · 2.38 Impact Factor
• Article: Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women.

  Stephen Gehlbach, Kenneth G Saag, Jonathan D Adachi, Fred H Hooven, Julie Flahive, Steven Boonen, Roland D Chapurlat, Juliet E Compston, Cyrus Cooper, Adolfo Díez-Perez, [......], Andrea Z LaCroix, J Coen Netelenbos, Johannes Pfeilschifter, Maurizio Rossini, Christian Roux, Philip N Sambrook, Stuart Silverman, Ethel S Siris, Nelson B Watts, Robert Lindsay
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  ABSTRACT: Previous fractures of the hip, spine, or wrist are well-recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow-up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow-up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8-, 3.0-, and 4.8-fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1-fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR] = 7.3) and hip (HR = 3.5). Prior rib fractures were associated with a 2.3-fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2-fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8-fold risk of future fracture of a weight-bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2011; 27(3):645-53. · 6.04 Impact Factor
• Article: Obesity is not protective against fracture in postmenopausal women: GLOW.

  Juliet E Compston, Nelson B Watts, Roland Chapurlat, Cyrus Cooper, Steven Boonen, Susan Greenspan, Johannes Pfeilschifter, Stuart Silverman, Adolfo Díez-Pérez, Robert Lindsay, [......], J Coen Netelenbos, Stephen Gehlbach, Frederick H Hooven, Julie Flahive, Jonathan D Adachi, Maurizio Rossini, Andrea Z Lacroix, Christian Roux, Philip N Sambrook, Ethel S Siris
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  ABSTRACT: To investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW). This was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥ 55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications. Body mass index (BMI) and fracture history were available at baseline and at 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥ 30 kg/m(2)). Fracture prevalence in obese women at baseline was 222 per 1000 and incidence at 2 years was 61.7 per 1000, similar to rates in nonobese women (227 and 66.0 per 1000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in nonobese women, while the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report 2 or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than nonobese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone protective therapy, compared with 41% of nonobese and 57% of underweight women. Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures.
  The American journal of medicine 11/2011; 124(11):1043-50. · 4.47 Impact Factor
• Article: Bisphosphonates and glucocorticoid osteoporosis in men: results of a randomized controlled trial comparing zoledronic acid with risedronate.

  Philip N Sambrook, Christian Roux, Jean-Pierre Devogelaer, Kenneth Saag, Chak-Sing Lau, Jean-Yves Reginster, Christina Bucci-Rechtweg, Guoqin Su, David M Reid
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  ABSTRACT: We studied 265 men (mean age 56.4 years; range 18-83 years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5 mg/day or equivalent) (prevention arm, n=88) or continuing glucocorticoid therapy (treatment arm, n=177). Patients received either a single ZOL 5 mg infusion or RIS 5 mg oral daily at randomization, along with calcium (1000 mg) and vitamin D (400-1200 IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12 months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (β-CTx and P1NP), and overall safety. In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. -0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. -0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p=0.0024) and the treatment subpopulation (p=0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum β-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced β-CTx at all time-points, and P1NP at Month 3 (p=0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL. Once-yearly ZOL preserves or increases BMD within 1 year to a greater extent than daily RIS in men receiving glucocorticoid therapy.
  Bone 10/2011; 50(1):289-95. · 4.02 Impact Factor
• Article: Factors influencing adherence with therapeutic sunlight exposure in older people in intermediate care facilities.

  Seeta Durvasula, Philip N Sambrook, Ian D Cameron
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  ABSTRACT: PURPOSE OF RESEARCH: The purpose of this study was to investigate the factors influencing low adherence with therapeutic sunlight exposure in a randomized controlled trial conducted with older people living in intermediate care facilities. The study involved participants in the FREEDOM (Falls Risk Epidemiology: Effect of vitamin D on skeletal Outcomes and other Measures) study, a randomized controlled trial of therapeutic sun exposure to reduce falls in older people in intermediate care facilities. Semi-structured interviews were conducted with thirty participants in the FREEDOM trial, and with ten sunlight officers who were employed to facilitate the sun exposure. Two focus groups involving 10 participants in the FREEDOM trial were also held at the end of the intervention period. Common themes were derived from the interview and focus group transcripts. The study showed that the perceived health benefits did not influence adherence with the sun exposure. Factors such as socializing with others and being outdoors were more important in encouraging attendance. The main barriers to adherence included the perceived inflexibility and regimentation of daily attendance, clash with other activities, unsuitable timing and heat discomfort. This study showed that providing greater flexibility and autonomy to older people in how and when they receive sun exposure is likely to improve adherence.
  Archives of gerontology and geriatrics 09/2011; 54(2):e234-41. · 1.36 Impact Factor
• Article: Protease-activated receptor 2, rather than protease-activated receptor 1, contributes to the aggressive properties of synovial fibroblasts in rheumatoid arthritis.

  Meilang Xue, Yee-Ka Agnes Chan, Kaitlin Shen, Suat Dervish, Lyn March, Philip N Sambrook, Christopher J Jackson
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  ABSTRACT: To investigate whether protease-activated receptor 1 (PAR-1) and/or PAR-2 promotes the invasiveness/proliferation of synovial fibroblasts (SFs) and to determine the signaling mechanisms of these pathways. SFs were isolated from the synovial tissue of patients with rheumatoid arthritis (RA), patients with osteoarthritis (OA), and PAR-1- or PAR-2-knockout (KO) mice. Expression of PAR-1 and PAR-2 was detected by immunofluorescence and Western blotting. The invasion and proliferation of SFs were measured by invasion assay and MTT assay, respectively. Matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by zymography, and cytokines were measured by enzyme-linked immunosorbent assay. PAR-1 and PAR-2 were colocalized with SFs in RA and OA synovium and, to a considerably lesser extent, in normal synovium. Inhibition of PAR-2 by small interfering RNA (siRNA) inhibited RASF invasion and proliferation, whereas blocking of PAR-1 by siRNA had the reverse effects. SFs from PAR-2-KO mice exhibited slower rates of proliferation and invasion. SFs from PAR-1-KO mice produced less MMP-2 and, in response to tumor necrosis factor α (TNFα) stimulation, had increased MMP-9 secretion when compared to SFs from wild-type and PAR-2-KO mice. Inhibition of PAR-1, but not PAR-2, stimulated the secretion of interleukin-17 (IL-17) and TNFα by RASFs. Furthermore, PAR-1 and PAR-2 had opposing effects on the activation of ERK, p38, and NF-κB. Activation of PAR-1 stimulates MMP-2 secretion, inhibits RASF growth and invasion, and decreases production of IL-17 and TNFα by RASFs, whereas activation of PAR-2 stimulates RASF growth and invasion and increases production of TNFα. Thus, although PAR-1 and PAR-2 are coexpressed by RASFs, PAR-2 alone appears to be responsible for the aggressive properties of RASFs and is likely to contribute to the pathologic progression of RA.
  Arthritis & Rheumatism 09/2011; 64(1):88-98. · 7.87 Impact Factor
• Article: The role of fat and lean mass in bone loss in older men: findings from the CHAMP study.

  Kerrin Bleicher, Robert G Cumming, Vasikaran Naganathan, Thomas G Travison, Philip N Sambrook, Fiona M Blyth, David J Handelsman, David G Le Couteur, Louise M Waite, Helen M Creasey, Markus J Seibel
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  ABSTRACT: Weight loss is associated with bone loss; however, it is unclear whether loss of fat or loss of lean body mass plays the key role in this relationship. The aim of this longitudinal analysis was to clarify the relationship between hip BMD, hip BMC and whole body BMC with changes in fat and lean tissue mass in older men. The Concord Health and Aging in Men Project (CHAMP) is a population-based study in Sydney, Australia, involving 1705 men aged 70-97 years. Bone mineral density (BMD) of the total hip, and bone mineral content (BMC) of the hip and whole body (WB), lean mass and fat mass were measured with Dual X-ray Absorptiometry (DXA). Multivariate linear regression models were used to assess relationships. Over 2.2 years of follow-up, 368(33%) men lost at least 2% of their body weight, which included a mean loss of 0.8 kg/year of lean body mass and 0.9 kg/year of fat body mass. Fat loss was strongly associated with BMD loss in men who lost weight. As a group, weight losers lost 1.0% of hip BMD annually compared to 0.2% in men who gained weight, with each kilo of fat loss associated with 0.6%/year hip BMD loss (p<0.0001). Lean mass was not associated with hip BMD loss in weight losers, however, lean mass change was associated with BMD change in men who gained weight (0.3% hip BMD increase per kilo increase of lean mass p<0.01). Maintaining body weight is important for bone health in elderly men. Body fat plays an important role in this relationship, which may reflect the additional metabolic function of adipose tissue.
  Bone 09/2011; 49(6):1299-305. · 4.02 Impact Factor
• Article: Antiresorptive therapies for osteoporosis: a clinical overview.

  Jian Sheng Chen, Philip N Sambrook
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  ABSTRACT: Antiresorptive therapies are used to increase bone strength in individuals with osteoporosis and include five principal classes of agents: bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin and monoclonal antibodies such as denosumab. However, no head-to-head studies have compared different antiresorptive agents using fracture as an end point. Bisphosphonates, which have proven antifracture efficacy and a good safety profile, are the most widely used first-line antiresorptive therapy and are recommended for patients with osteoporosis, a prior fragility fracture or osteopenia, as well as individuals with a high risk of fracture. Denosumab, which also has good antifracture efficacy, is another possible first-line therapy, although long-term safety data are lacking. However, no single antiresorptive therapy is currently appropriate for all patients or clearly superior to other therapies. Antiresorptive agents such as estrogens, SERMs (in postmenopausal women) and calcitonin are considered to be second-line agents that are appropriate in special circumstances. Clinicians should determine the most appropriate pharmacological therapy after a careful assessment of the risk:benefit profiles of these drugs in each patient. In addition, patients should receive a detailed explanation of the treatment goals, so that the therapeutic benefit can be maximized through good compliance and persistence.
  Nature Reviews Endocrinology 09/2011; 8(2):81-91. · 9.97 Impact Factor
• Article: Predicting fractures in an international cohort using risk factor algorithms without BMD.

  Philip N Sambrook, Julie Flahive, Fred H Hooven, Steven Boonen, Roland Chapurlat, Robert Lindsay, Tuan V Nguyen, Adolfo Díez-Perez, Johannes Pfeilschifter, Susan L Greenspan, [......], Nelson B Watts, Cyrus Cooper, Christian Roux, Maurizio Rossini, Ethel S Siris, Stuart Silverman, Kenneth G Saag, Juliet E Compston, Andrea LaCroix, Stephen Gehlbach
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  ABSTRACT: Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self-reported clinical risk factors, excluding BMD, to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged 55 years or older from 723 primary-care practices in 10 countries. The population comprised 19,586 women aged 60 years or older who were not receiving antiosteoporosis medication and were followed annually for 2 years. Self-administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the C index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 "major fractures" (as defined by FRAX), and 583 "osteoporotic fractures" (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed a moderate ability to correctly order hip fracture times (C index for hip fracture 0.78 and 0.76, respectively). C indices for "major" and "osteoporotic" fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age + fracture history alone (C index for hip fracture 0.78). In conclusion, estimation of fracture risk in an international primary-care population of postmenopausal women can be made using clinical risk factors alone without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2011; 26(11):2770-7. · 6.04 Impact Factor
• Article: Ethnicity and falls in older men: low rate of falls in Italian-born men in Australia.

  Fiona F Stanaway, Robert G Cumming, Vasi Naganathan, Fiona M Blyth, David J Handelsman, David G Le Couteur, Louise M Waite, Helen M Creasey, Markus J Seibel, Philip N Sambrook
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  ABSTRACT: past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts. this study analysed data from 335 Italian-born and 848 Australian-born men aged 70 years and over participating in the Concord Health and Ageing in Men Project (CHAMP). Prospective falls data were collected by 4 monthly phone calls (mean follow-up time: 26.7 months). Negative binomial regression compared falls incidence rate ratios (IRR) between the two groups of men. there were 37 (11%) Italian-born men and 185 (22%) Australian-born men who had two or more falls during follow-up (P < 0.001). Negative binomial analysis demonstrated that Italian-born men had half the incidence rate of falls compared with Australian-born men (IRR = 0.51, 95% CI = 0.38-0.67). After adjustment for falls risk factors, Italian-born men remained significantly less likely to fall with a 43% lower fall rate (IRR = 0.57, 95% CI = 0.39-0.85). older male Italian-born immigrants are less likely to fall than their Australian-born counterparts. Differences in fall rates between the two groups are not explained by established falls risk factors.
  Age and Ageing 07/2011; 40(5):595-601. · 3.09 Impact Factor
• Article: Changes in reproductive hormone concentrations predict the prevalence and progression of the frailty syndrome in older men: the concord health and ageing in men project.

  Thomas G Travison, Anh-Hoa Nguyen, Vasi Naganathan, Fiona F Stanaway, Fiona M Blyth, Robert G Cumming, David G Le Couteur, Philip N Sambrook, David J Handelsman
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  ABSTRACT: Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. The objective of the study was to examine, using longitudinal measurements, the relations of serum androgens, estrogens, gonadotropins, and SHBG to the prevalence and progression of frailty in older men. Concord Health and Ageing in Men Project is an observational cohort study of 1705 men (aged 70 yr or older) living in the suburb of Concord, Sydney, Australia. Measurements were obtained at baseline (2005-2007) and 2-yr follow-up (2007-2009). Testosterone (T), dihydrotestosterone, estradiol, and estrone were obtained by liquid chromatography-tandem mass spectrometry, whereas SHBG, LH, and FSH were measured by immunoassay. Subjects from the general community were sampled. A total of 1645 subjects constituting a representative sample of community-dwelling men aged 70 yr old or older participated in the study. The frailty syndrome was measured according to the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fractures (SOF) indices. Androgens and estrogens showed significant age-adjusted associations with concurrent frailty. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting greater CHS frailty as compared with the highest T quintile (P < 0.001); results for dihydrotestosterone, estradiol, estrone, and calculated free T were similar, and were unchanged when the SOF frailty index was substituted for the CHS frailty index. A 1 sd, 2-yr decrease in T, calculated free T, or LH was associated with a 1.2- to 1.3-fold increase in the odds of progression (increase in severity) of frailty. The control for comorbid medical conditions did not affect results. Age-related changes in blood androgens and estrogens may contribute to the development or progression of frailty in men.
  The Journal of clinical endocrinology and metabolism 06/2011; 96(8):2464-74. · 6.50 Impact Factor
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  Available from: Alex Macgregor

  Article: Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study.

  Gregory Livshits, Maria Popham, Ida Malkin, Philip N Sambrook, Alex J Macgregor, Timothy Spector, Frances M K Williams
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  ABSTRACT: Low back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population. Material and A cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18-84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition. The major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (p<0.001) associated with non-specific LBP. The single most important risk factor was the amount of LDD. After adjustment for other risk factors, the individuals who exhibited advanced LDD (90% vs 10%) had 3.2 higher odds of manifesting LBP. The data also showed a significant (p<0.001) genetic correlation between the LBP and LDD measurements, suggesting that approximately 11-13% of the genetic effects are shared by LDD and LBP. The main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.
  Annals of the rheumatic diseases 06/2011; 70(10):1740-5. · 8.11 Impact Factor
• Article: Carpal tunnel syndrome and its relationship to occupation: a meta-analysis.

  Annica Barcenilla, Lyn M March, Jian Sheng Chen, Philip N Sambrook
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  ABSTRACT: To examine the association between work place exposure and CTS by meta-analysis, including analyses with respect to exposure to hand force, repetition, vibration and wrist posture. All relevant peer-reviewed articles published between January 1980 and December 2009 were identified by a systematic search using the MEDLINE, CINAHL and PubMed databases. Papers were critiqued independently by two researchers and the relevant exposure information was extracted. Using the raw data of exposed and unexposed cases, a cumulative effect of specific exposure risks were calculated for hand force, repetition, a combination of force and repetition, vibration and wrist posture using the statistical program, Stata version 11 (StataCorp, College Station, TX, USA). Heterogeneity, meta-regression, publication bias and subgroup sensitivity analyses were performed. Thirty-seven studies from English-language literature met the inclusion criteria. Using National Institute for Occupational Health and Safety criteria for case definition, a significant positive association between CTS and hand force, repetition, use of vibratory tools and wrist posture was observed with approximate doubling of risk for all exposures. Significant heterogeneity among studies was observed for most exposures and metaregression analyses identified CTS case definition, study design, country and risk of bias score to be the significant determinants. When a more conservative definition of CTS was employed to include nerve conduction abnormality with symptoms and/or signs, risk factors significantly associated with an increased risk of CTS among exposed workers were: vibration [odds ratio (OR) 5.40; 95% CI 3.14, 9.31], hand force (OR 4.23; 95% CI 1.53, 11.68) and repetition (OR 2.26; 95% CI 1.73, 2.94). There was a non-significant trend for the association between CTS and combined exposure to both force and repetition (OR 1.85; 95% CI 0.99, 3.45) and wrist posture (OR 4.73; 95% CI 0.42, 53.32). Occupational exposure to excess vibration, increased hand force and repetition increase the risk of developing CTS. Workplace strategies to avoid overexposure to these risk factors should be implemented.
  Rheumatology (Oxford, England) 05/2011; 51(2):250-61. · 4.24 Impact Factor