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L.-A. Fraser,
G. Ioannidis,
J. D. Adachi,
L. Pickard,
S. M. Kaiser,
J. Prior,
J. P. Brown,
D. A. Hanley,
W. P. Olszynski,
T. Anastassiades,
S. Jamal,
R. Josse, D. Goltzman,
A. Papaioannou,
the CaMos Research Group
[show abstract]
[hide abstract]
ABSTRACT: SummaryCanadian women over 50years old were studied over a 10-year period to see if those who sustained a fracture (caused by minimal
trauma) were receiving the recommended osteoporosis therapy. We found that approximately half of these women were not being
treated, indicating a significant care gap in osteoporosis treatment.
IntroductionPrevalent fragility fracture strongly predicts future fracture. Previous studies have indicated that women with fragility
fractures are not receiving the indicated treatment. We aimed to describe post fracture care in Canadian women using a large,
population-based prospective cohort that began in 1995–1997.
MethodsWe followed 5,566 women over 50years of age from across Canada over a period of 10years in the Canadian Multicentre Osteoporosis
Study. Information on medication use and incident clinical fragility fractures was obtained during a yearly questionnaire
or interview and fractures were confirmed by radiographic/medical reports.
ResultsOver the 10-year study period, 42–56% of women with yearly incident clinical fragility fractures were not treated with an
osteoporosis medication. During year1 of the study, 22% of the women who had experienced a fragility fracture were on treatment
with a bisphosphonate and 26% were on hormone therapy (HT). We were not able to differentiate HT use for menopause symptoms
vs osteoporosis. Use of bisphosphonate therapy increased over time; odds ratio (OR) for use at year10 compared to use at
year1 was 3.65 (95% confidence interval (CI) 1.83–7.26). In contrast, HT use declined, with an OR of 0.07 (95%CI 0.02–0.24)
at year10 compared to year1 of the study.
ConclusionIn a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures.
Although bisphosphonate therapy usage improved over time, a substantial gap remains.
KeywordsBisphosphonates–Care gap–Fragility fracture–Osteoporosis–Postmenopausal women
Osteoporosis International 04/2012; 22(3):789-796. · 4.58 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A decrease in bone density at the hip or spine has been shown to increase the risk of fracture. A limitation of the bone mineral density (BMD) measurement is that it provides only a measure of a bone sample's average density when projected onto a 2D surface. Effectively, what determines bone fracture is whether an applied load exceeds ultimate strength, with both bone tissue material properties (can be approximated through bone density), and geometry playing a role. The goal of this project was to use bone geometry and BMD obtained from radiographs and DXA measurements respectively to estimate fracture risk, using a two-dimensional finite element model (FEM) of the sagittal plane of lumbar vertebrae. The Canadian Multicentre Osteoporosis Study (CaMos) data was used for this study. There were 4194 men and women over the age of 50 years, with 786 having fractures. Each subject had BMD testing and radiographs of their lumbar vertebrae. A single two dimensional FEM of the first to fourth lumbar vertebra was automatically generated for each subject. Bone tissue stiffness was assigned based on the BMD of the individual vertebrae, and adjusted for patient age. Axial compression boundary conditions were applied with a force proportional to body mass. The resulting overall strain from the applied force was found. Men and women were analyzed separately. At baseline, the sensitivity of BMD to predict fragility fractures in women and men was 3.77% and 0.86%, while the sensitivity of FEM to predict fragility fractures for women and men was 10.8% and 11.3%. The FEM ROC curve demonstrated better performance compared to BMD. The relative risk of being considered at high fracture risk using FEM at baseline, was a better predictor of 5 year incident fragility fracture risk compared to BMD.
Medical Engineering & Physics 09/2011; 34(4):478-84. · 1.62 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: We assessed vitamin D status and its correlates in the population-based Canadian Multicentre Osteoporosis Study (CaMos). Results showed that serum 25-hydroxyvitamin D levels <75 nmol/L were common. Given Canada's high latitude, attention should be given to strategies for enhancing vitamin D status in the population.
Inadequate vitamin D has been implicated as a risk factor for several clinical disorders. We assessed, in a Canadian cohort, vitamin D status and its correlates, based on serum 25-hydroxyvitamin D [25(OH)D], the best functional indicator of vitamin D status.
We studied 577 men and 1,335 women 35+ years from seven cities across Canada in the randomly selected, population-based Canadian Multicentre Osteoporosis Study (CaMos). Participants completed a comprehensive questionnaire. Serum 25(OH)D was measured by immunoassay. Multivariate linear regression modeling assessed the association between 25(OH)D and determinants of vitamin D status.
Participants (2.3%) were deficient in 25(OH)D (<27.5 nmol/L); a further 18.1% exhibited 25(OH)D insufficiency (27.5-50 nmol/L). Levels <75 nmol/L were evident in 57.5% of men and 60.7% of women and rose to 73.5% in spring (men) and 77.5% in winter (women); 25(OH)D <50 nmol/L was ≤10% year round for those supplementing with ≥400 IU vitamin D/day but was 43.9% among those not supplementing in winter and spring. The strongest predictors of reduced 25(OH)D for both men and women were winter and spring season, BMI ≥30, non-white ethnicity, and lower vitamin D supplementation and its modification by fall and winter.
In this national Canadian cohort, vitamin D levels <75 nmol/L were common, particularly among non-white and obese individuals, and in winter and spring. Vitamin D intake through diet and supplementation and maintenance of normal weight are key modifiable factors for enhancing vitamin D status and thus potentially influencing susceptibility to common chronic diseases.
Osteoporosis International 05/2011; 22(5):1389-99. · 4.58 Impact Factor
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L-A Fraser,
L Langsetmo,
C Berger,
G Ioannidis, D Goltzman,
J D Adachi,
A Papaioannou,
R Josse,
C S Kovacs,
W P Olszynski, [......],
S M Kaiser,
J Prior,
S Jamal,
N Kreiger,
J P Brown,
H Johansson,
A Oden,
E McCloskey,
J A Kanis,
W D Leslie
[show abstract]
[hide abstract]
ABSTRACT: A new Canadian WHO fracture risk assessment (FRAX®) tool to predict 10-year fracture probability was compared with observed 10-year fracture outcomes in a large Canadian population-based study (CaMos). The Canadian FRAX tool showed good calibration and discrimination for both hip and major osteoporotic fractures.
The purpose of this study was to validate a new Canadian WHO fracture risk assessment (FRAX®) tool in a prospective, population-based cohort, the Canadian Multicentre Osteoporosis Study (CaMos).
A FRAX tool calibrated to the Canadian population was developed by the WHO Collaborating Centre for Metabolic Bone Diseases using national hip fracture and mortality data. Ten-year FRAX probabilities with and without bone mineral density (BMD) were derived for CaMos women (N = 4,778) and men (N = 1,919) and compared with observed fracture outcomes to 10 years (Kaplan-Meier method). Cox proportional hazard models were used to investigate the contribution of individual FRAX variables.
Mean overall 10-year FRAX probability with BMD for major osteoporotic fractures was not significantly different from the observed value in men [predicted 5.4% vs. observed 6.4% (95%CI 5.2-7.5%)] and only slightly lower in women [predicted 10.8% vs. observed 12.0% (95%CI 11.0-12.9%)]. FRAX was well calibrated for hip fracture assessment in women [predicted 2.7% vs. observed 2.7% (95%CI 2.2-3.2%)] but underestimated risk in men [predicted 1.3% vs. observed 2.4% (95%CI 1.7-3.1%)]. FRAX with BMD showed better fracture discrimination than FRAX without BMD or BMD alone. Age, body mass index, prior fragility fracture and femoral neck BMD were significant independent predictors of major osteoporotic fractures; sex, age, prior fragility fracture and femoral neck BMD were significant independent predictors of hip fractures.
The Canadian FRAX tool provides predictions consistent with observed fracture rates in Canadian women and men, thereby providing a valuable tool for Canadian clinicians assessing patients at risk of fracture.
Osteoporosis International 03/2011; 22(3):829-37. · 4.58 Impact Factor
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W D Leslie,
L M Lix,
L Langsetmo,
C Berger, D Goltzman,
D A Hanley,
J D Adachi,
H Johansson,
A Oden,
E McCloskey,
J A Kanis
[show abstract]
[hide abstract]
ABSTRACT: We describe the creation of a FRAX® model for the assessment of fracture probability in Canadian men and women, calibrated from national hip fracture and mortality data. This FRAX tool was used to examine possible thresholds for therapeutic intervention in Canada in two large complementary cohorts of women and men.
To evaluate a Canadian World Health Organization (WHO) fracture risk assessment (FRAX®) tool for computing 10-year probabilities of osteoporotic fracture.
Fracture probabilities were computed from national hip fracture data (2005) and death hazards (2004) for Canada. Probabilities took account of age, sex, clinical risk factors (CRFs), and femoral neck bone mineral density (BMD). Treatment implications were studied in two large cohorts of individuals age 50 years and older: the population-based Canadian Multicentre Osteoporosis Study (4,778 women and 1,919 men) and the clinically referred Manitoba BMD Cohort (36,730 women and 2,873 men).
Fracture probabilities increased with age, decreasing femoral neck T-score, and number of CRFs. Among women, 10.1-11.3% would be designated high risk based upon 10-year major osteoporotic fracture probability exceeding 20%. A much larger proportion would be designated high risk based upon 10-year hip fracture probability exceeding 3% (25.7-28.0%) or osteoporotic BMD (27.1-30.9%), and relatively few from prior hip or clinical spine fracture (1.6-4.2%). One or more criteria for intervention were met by 29.2-34.0% of women excluding hip fracture probability (35.3-41.0% including hip fracture probability). Lower intervention rates were seen among CaMos (Canadian Multicentre Osteoporosis Study) men (6.8-12.9%), but in clinically referred men from the Manitoba BMD Cohort, one or more criteria for high risk were seen for 26.4% excluding hip fracture probability (42.4% including hip fracture probability).
The FRAX tool can be used to identify intervention thresholds in Canada. The FRAX model supports a shift from a dual X-ray absorptiometry (DXA)-based intervention strategy, towards a strategy based on fracture probability for a major osteoporotic fracture.
Osteoporosis International 03/2011; 22(3):817-27. · 4.58 Impact Factor
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L-A Fraser,
G Ioannidis,
J D Adachi,
L Pickard,
S M Kaiser,
J Prior,
J P Brown,
D A Hanley,
W P Olszynski,
T Anastassiades,
S Jamal,
R Josse, D Goltzman,
A Papaioannou
[show abstract]
[hide abstract]
ABSTRACT: Canadian women over 50 years old were studied over a 10-year period to see if those who sustained a fracture (caused by minimal trauma) were receiving the recommended osteoporosis therapy. We found that approximately half of these women were not being treated, indicating a significant care gap in osteoporosis treatment.
Prevalent fragility fracture strongly predicts future fracture. Previous studies have indicated that women with fragility fractures are not receiving the indicated treatment. We aimed to describe post fracture care in Canadian women using a large, population-based prospective cohort that began in 1995-1997.
We followed 5,566 women over 50 years of age from across Canada over a period of 10 years in the Canadian Multicentre Osteoporosis Study. Information on medication use and incident clinical fragility fractures was obtained during a yearly questionnaire or interview and fractures were confirmed by radiographic/medical reports.
Over the 10-year study period, 42-56% of women with yearly incident clinical fragility fractures were not treated with an osteoporosis medication. During year 1 of the study, 22% of the women who had experienced a fragility fracture were on treatment with a bisphosphonate and 26% were on hormone therapy (HT). We were not able to differentiate HT use for menopause symptoms vs osteoporosis. Use of bisphosphonate therapy increased over time; odds ratio (OR) for use at year 10 compared to use at year 1 was 3.65 (95% confidence interval (CI) 1.83-7.26). In contrast, HT use declined, with an OR of 0.07 (95%CI 0.02-0.24) at year 10 compared to year 1 of the study.
In a large population-based cohort study, we found a therapeutic care gap in women with osteoporosis and fragility fractures. Although bisphosphonate therapy usage improved over time, a substantial gap remains.
Osteoporosis International 03/2011; 22(3):789-96. · 4.58 Impact Factor
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W D Leslie,
C Berger,
L Langsetmo,
L M Lix,
J D Adachi,
D A Hanley,
G Ioannidis,
R G Josse,
C S Kovacs,
T Towheed,
S Kaiser,
W P Olszynski,
J C Prior,
S Jamal,
N Kreiger, D Goltzman
[show abstract]
[hide abstract]
ABSTRACT: A procedure for creating a simplified version of fracture risk assessment tool (FRAX®) is described. Calibration, fracture prediction, and concordance were compared with the full FRAX tool using two large, complementary Canadian datasets.
The Canadian Association of Radiologists and Osteoporosis Canada (CAROC) system for fracture risk assessment is based upon sex, age, bone mineral density (BMD), prior fragility fracture, and glucocorticoid use. CAROC does not require computer or web access, and categorizes 10-year major osteoporotic fracture risk as low (<10%), moderate (10-20%), or high (>20%).
Basal CAROC fracture risk tables (by age, sex, and femoral neck BMD) were constructed from Canadian FRAX probabilities for major osteoporotic fractures (adjusted for prevalent clinical risk factors). We assessed categorization and fracture prediction with the updated CAROC system in the CaMos and Manitoba BMD cohorts.
The new CAROC system demonstrated high concordance with the Canadian FRAX tool for risk category in both the CaMos and Manitoba cohorts (89% and 88%). Ten-year fracture outcomes in CaMos and Manitoba BMD cohorts showed good discrimination and calibration for both CAROC (6.1-6.5% in low-risk, 13.5-14.6% in moderate-risk, and 22.3-29.1% in high-risk individuals) and FRAX (6.1-6.6% in low-risk, 14.4-16.1% in moderate-risk, and 23.4-31.0% in high-risk individuals). Reclassification from the CAROC risk category to a different risk category under FRAX occurred in <5% for low-risk, 20-24% for moderate-risk, and 27-30% for high-risk individuals. Reclassified individuals had 10-year fracture outcomes that were still within or close to the original nominal-risk range..
The new CAROC system is well calibrated to the Canadian population and shows a high degree of concordance with the Canadian FRAX tool. The CAROC system provides s a simple alternative when it is not feasible to use the full Canadian FRAX tool.
Osteoporosis International 10/2010; 22(6):1873-83. · 4.58 Impact Factor
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R Eastell,
A Arnold,
M L Brandi,
E M Brown,
P D'Amour,
D A Hanley,
D Sudhaker Rao,
M R Rubin, D Goltzman,
S J Silverberg,
S J Marx,
M Peacock,
L Mosekilde,
R Bouillon,
E M Lewiecki
[show abstract]
[hide abstract]
ABSTRACT: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice.
Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies.
Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting.
Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies.
We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min.1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.
Journal of Clinical Endocrinology & Metabolism 03/2009; 94(2):340-50. · 6.50 Impact Factor
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ABSTRACT: Nitrates may have beneficial effects on bone. To determine if nitrates were associated with increased bone mineral density (BMD), we conducted a secondary analysis using data from subjects in a prospective study. Subjects reporting nitrate use had increased BMD compared with non-users, confirming that nitrates have positive BMD effects in women and men.
Prior studies suggest positive associations between nitrates and bone.
We used linear regression models, stratified by gender and adjusted for age, weight, and baseline differences, to determine the association between daily nitrate use and BMD among subjects participating in the Canadian Multicentre Osteoporosis Study. All results are reported as annualised percent change in BMD at the hip and spine among nitrate users compared to non-users.
We included 1,419 men (71 reported daily nitrate use) and 2,587 women (97 reported daily nitrate use). Male non-users had decreased hip BMD (-1.3%; 95% confidence interval [95%CI] = -1.6 to -1.1) and increased spine BMD (2.8%; 95%CI = 2.5 to 3.1). Male nitrate users had increased hip BMD (1.4%; 95%CI = 0.1 to 2.8) and spine BMD (4.5%; 95%CI = 3.2 to 5.7). Among women, non-users had decreased hip BMD (-1.9; 95%CI = -2.1 to -1.7) and increased spine BMD (2.1%; 95%CI = 1.9 to 2.4) whilst users had an increase in hip BMD (2.0%; 95%CI = 1.2 to 2.8) and spine BMD (4.1%; 95%CI = 3.4 to 4.9).
Nitrate use is associated with increased BMD at the hip and spine in men and women.
Osteoporosis International 10/2008; 20(5):737-44. · 4.58 Impact Factor
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A Papaioannou,
C C Kennedy,
G Ioannidis,
A Sawka,
W M Hopman,
L Pickard,
J P Brown,
R G Josse,
S Kaiser,
T Anastassiades, D Goltzman,
M Papadimitropoulos,
A Tenenhouse,
J C Prior,
W P Olszynski,
J D Adachi
[show abstract]
[hide abstract]
ABSTRACT: Using prospective data from the Canadian Multicentre Osteoporosis Study (CaMos), we compared health utilities index (HUI) scores after 5 years of follow-up among participants (50 years and older) with and without incident clinical fractures. Incident fractures had a negative impact on HUI scores over time.
This study examined change in health-related quality of life (HRQL) in those with and without incident clinical fractures as measured by the HUI.
The study cohort was 4,820 women and 1,783 men (50 years and older) from the CaMos. The HUI was administered at baseline and year 5. Participants were sub-divided into incident fracture groups (hip, rib, spine, forearm, pelvis, other) and were compared with those without these fractures. The effects of both time and fracture type on HUI scores were examined in multivariable regression analyses.
Men and women with hip fractures, compared to those without, had lower HUI measures that ranged from -0.05 to -0.25. Both women and men with spine fractures had significant deficits on the pain attributes (-0.07 to -0.12). In women, self-care (-0.06), mobility and ambulation (-0.05) were also negatively impacted. Women with rib fractures had deficits similar to women with spine fractures, and these effects persisted over time. In men, rib fractures did not significantly affect HUI scores. Pelvic and forearm fractures did not substantially influence HUI scores.
The HUI was a sensitive measure of HRQL change over time. These results will inform economic analyses evaluating osteoporosis therapies.
Osteoporosis International 10/2008; 20(5):703-14. · 4.58 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Observational studies are needed to quantify real-life effectiveness of antiresorptive therapy in the prevention of clinical fractures. Antiresorptive therapies were associated with an overall 32% reduction in low-trauma nonvertebral fracture risk among women 50 and older. Effectiveness may be lower among older women and those without risk factors.
Randomized controlled trials have shown that antiresorptive therapies reduce the risk of fracture in selected populations, but further study is needed to quantify their real-life effectiveness. The study objective was to determine the association between antiresorptive use and low-trauma nonvertebral fracture in women 50 and older.
The design was a retrospective nested case-control study (density-based sampling) within the Canadian Multicentre Osteoporosis Study. There were 5,979 eligible women with 453 cases and 1,304 matched controls.
The current use of antiresorptives was associated with a decreased risk of fracture with OR = 0.68, 95% CI: 0.52-0.91; where OR is the adjusted odds ratio and CI is the confidence interval. Subgroup analysis yielded OR = 0.61, 95% CI: 0.42-0.89 for ages 50-74; OR = 0.76, 95% CI: 0.50-1.17 for ages 75+; OR = 0.58, 95% CI: 0.40-0.83 for those with a major risk factor; and OR = 0.92; 95% CI: 0.59-1.42 for those without a major risk factor. Major risk factors were prevalent low-trauma fracture, vertebral deformity (grade 2+), and BMD T-score < or = -2.5.
Antiresorptive therapy is associated with a clinically important reduction in low-trauma nonvertebral fracture risk among community-dwelling women aged 50 and older. Antiresorptive therapy may be less effective for women 75 and older and women without major risk factors.
Osteoporosis International 06/2008; 20(2):283-90. · 4.58 Impact Factor
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A Papaioannou,
C C Kennedy,
G Ioannidis,
Y Gao,
A M Sawka, D Goltzman,
A Tenenhouse,
L Pickard,
W P Olszynski,
K S Davison,
S Kaiser,
R G Josse,
N Kreiger,
D A Hanley,
J C Prior,
J P Brown,
T Anastassiades,
J D Adachi
[show abstract]
[hide abstract]
ABSTRACT: We examined osteoporosis diagnosis/treatment in 2,187 community dwelling men age 50+. After five years in the study, 90% of men with fragility fractures remained undiagnosed and untreated for osteoporosis. The need to treat fragility fractures is well established in guidelines, and these numbers represent an important care gap.
Whether physicians in the community are recognizing and appropriately treating osteoporosis and fragility fractures in men remains unknown. We examined the rate of diagnosis and treatment in community dwelling men participating in the Canadian Multicentre Osteoporosis Study (CaMos).
Between February 1996 and September 2002, 2,187 participants were recruited from nine sites across Canada and prospectively followed. Information on osteoporosis diagnosis, fractures, medications were collected annually by a detailed questionnaire. DXA examination of lumbar spine (L1-4) and hip were conducted at baseline and year five.
Diagnosis and treatment in men with clinical fragility fractures was low: at baseline and year five only 2.3% and 10.3% of men with a clinical fracture reported an osteoporosis diagnosis, respectively. At year five, 90% of men with a clinical fragility fracture were untreated. Hip fractures were the most commonly treated (37.5% by year five). A diagnosis of osteoporosis resulted in greater treatment: 67% of participants with diagnosed osteoporosis were treated with a bisphosphonate and 87% were taking calcium and/or vitamin D (year five).
In this population-based study, both a diagnostic and therapeutic gap existed between knowledge and practice related to fragility fractures and osteoporosis in men aged >or=50 years.
Osteoporosis International 04/2008; 19(4):581-7. · 4.58 Impact Factor
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ABSTRACT: Hip fracture is associated with recurrent fractures and increased mortality. The results of our retrospective cohort study support the use of antiresorptive agents to prevent recurrent hip fractures in this population.
Hip fracture, the most serious consequence of osteoporosis, is associated with recurrent fractures and increased mortality. Antiresorptive therapy has proven efficacy in the prevention of fractures after vertebral fractures. It is unknown if it can prevent recurrent fractures after a hip fracture.
We designed a population based, retrospective cohort study, using administrative databases and identified patients hospitalized for a hip fracture between 1996 and 2002. The exposure was defined as being dispensed a prescription for an antiresorptive agent at any time following discharge. Multivariate Cox regression models were used to estimate the hazard ratio of recurrent hip fracture. Subgroup and propensity score analyses were performed.
A total of 20,644 patients were identified; 6,779 filled a prescription for antiresorptive agents. There were 992 recurrent hip fractures. Patients exposed to antiresorptives had a 26% reduction in the rate of recurrent fractures (adjusted hazard ratio 0.74; 95% CI, 0.64-0.86) compared to patients who were not. All subgroups experienced a reduction in recurrent fracture, except the very elderly. Propensity score analyses were consistent with the main analysis.
Antiresorptive therapy reduces the risk of recurrent hip fractures in elderly patients. These results provide evidence that this therapy should be considered for secondary prevention of hip fractures.
Osteoporosis International 01/2008; 18(12):1625-32. · 4.58 Impact Factor
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J A Kanis,
A Oden,
O Johnell,
H Johansson,
C De Laet,
J Brown,
P Burckhardt,
C Cooper,
C Christiansen,
S Cummings, [......],
L J Melton,
H Pols,
J Reeve,
K Sanders,
A-M Schott,
A Silman,
D Torgerson,
T van Staa,
N B Watts,
N Yoshimura
[show abstract]
[hide abstract]
ABSTRACT: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD.
Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score).
CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts.
The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.
Osteoporosis International 09/2007; 18(8):1033-46. · 4.58 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Recent studies in mice using genetic approaches have shed new light on the physiological effects of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and the vitamin D receptor (VDR) in skeletal and mineral homeostasis, and on their interaction with calcium. These studies in mice with targeted deletion of the 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha(OH)ase), and of the VDR or of double mutants, have shown the discrete effects of calcium in inhibiting parathyroid hormone secretion and in enhancing bone mineralization, but overlapping effects of calcium and 1,25(OH)(2)D on inhibiting parathyroid growth and on normal development of the cartilaginous growth plate. The 1,25(OH)(2)D/VDR system is essential, however, in enhancing intestinal calcium absorption and in optimally increasing osteoclastic activation. In addition, the 1,25(OH)(2)D/VDR system has important anabolic effects on bone, thus defining a dual role for this system in bone turnover. These studies are revealing functions of the vitamin D/VDR system which have relevance for new concepts of the pathophysiology of renal bone disease and, in particular, of the adynamic bone disorder, and for the development of new analogs of the active form of vitamin D, which have less calcemic activity and greater skeletal anabolic effects.
Kidney International 02/2006; 69(2):218-23. · 6.61 Impact Factor
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[hide abstract]
ABSTRACT: The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated to not only impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and, conversely, with decreased BMD in men.
The Canadian Multicentre Osteoporosis Study is a longitudinal, randomly selected, population-based community cohort. We present data from men (n=2,004) and postmenopausal women age 65 and older (n=2,776) who underwent a BMD measurement and structured interview in the 5th year of the study. The outcome measure was percent difference in BMD (g/cm(2)).
Daily COX-2 inhibitor use was reported by 394 subjects. In men, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites, with a percent difference of -3.1% [95% confidence interval (CI), -6.0, -0.3] between users and nonusers at total hip. In postmenopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites [percent difference at total hip: +3.0% (95% CI, 0.3, 5.8)]. These effects appeared to be dose-dependent.
COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, with a higher BMD in postmenopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in postmenopausal women if bone-selective analogs can be developed.
Osteoporosis International 02/2006; 17(9):1410-9. · 4.58 Impact Factor
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ABSTRACT: We evaluated the capacity of estradiol (E(2)) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E(2) caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E(2) tamoxifen. E(2) also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E(2) production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.
Endocrinology 08/2005; 146(7):2885-94. · 4.46 Impact Factor
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ABSTRACT: SOX9 is a transcription factor that is essential for chondrocyte differentiation and cartilage formation. We stably overexpressed SOX9 cDNA in the rat chondrocytic cell line CFK2. Compared with the vector control, a greater proportion of SOX9-transfected cells accumulated in the G0/G1 phase. This was associated with an increase in mRNA and protein expression of p21(cip1), an inhibitor of cyclin-dependent kinase activity. SOX9 enhanced p21(cip1) promoter activity in a luciferase reporter assay. CFK2 cells overexpressing SOX9 became more elongated and adhesive and demonstrated a shift in cytoplasmic F-actin distribution. N-cadherin mRNA levels were elevated in the SOX9-transfected cells, and SOX9 enhanced N-cadherin promoter activity. By electrophoretic mobility shift assay, nuclear extracts of SOX9-transfected CFK2 cells specifically bound an oligonucleotide comprising an N-cadherin promoter region containing a consensus SOX9-binding motif. The transcriptional activity of SOX9 depended upon nuclear localization signals required for SOX9 nuclear entry. Differentiation of transfected CFK2 cells was accelerated as evidenced by more rapid accumulation of alkaline phosphatase activity, increased production of proteoglycans, and increased calcium accumulation, and this was associated with decreased ERK1 expression. These studies demonstrate that SOX9 alters the rate of cell cycle progression of chondrocytes and their differentiation by enhancing or inhibiting the expression of selected genes, including p21(cip1) and ERK1, and that N-cadherin is an additional direct target of this transcriptional regulator.
Journal of Biological Chemistry 12/2001; 276(44):41229-36. · 4.77 Impact Factor
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ABSTRACT: We examined the capacity of PTHrP to modulate the terminal differentiation of the preadipocytic cell line, 3T3-L1. These cells express endogenous PTHrP and its receptor, but expression levels were undetectable after differentiation into mature adipocytes. Cells stably overexpressing PTHrP failed to differentiate when induced to undergo adipogenesis and proliferated at a faster rate. MAPK activity was elevated in PTHrP-transfected 3T3-L1 cells, and treatment with the PKA inhibitor H-8 decreased this activity. Inhibition of MAPK kinase with PD098059 permitted terminal differentiation of PTHrP-transfected 3T3-L1 cells to proceed. Although PPAR gamma gene expression levels remained relatively constant in the PTHrP-transfected cells, PPAR gamma phosphorylation was enhanced. Furthermore, the capacity of PPAR gamma to stimulate transcription in the presence of troglitazone was diminished by PTHrP. Expression of the PPAR gamma-regulated adipocyte specific gene aP2 transiently rose and then fell in PTHrP-transfected cells. These results indicate that PTHrP can increase MAPK activity in 3T3-L1 cells via the PKA pathway, thereby enhancing PPAR gamma phosphorylation. This modification can inactivate the transcriptional enhancing activity of PPAR gamma and diminish the expression of adipocyte-specific genes. These studies therefore demonstrate that PTHrP may inhibit the terminal differentiation of preadipocytes and describe a molecular pathway by which this action can be achieved.
Endocrinology 12/2001; 142(11):4900-9. · 4.46 Impact Factor
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ABSTRACT: Parathyroid hormone (PTH)-related peptide (PTHrP) can modulate the proliferation and differentiation of a number of cell types including osteoblasts. PTHrP can activate a G protein-coupled PTH/PTHrP receptor, which can interface with several second-messenger systems. In the current study, we have examined the signaling pathways involved in stimulated type I collagen and alkaline phosphatase expression in the human osteoblast-derived osteosarcoma cells, MG-63. By use of Northern blotting and histochemical analysis, maximum induction of these two markers of osteoblast differentiation occurred after 8 h of treatment with 100 nM PTHrP-(1-34). Chemical inhibitors of adenylate cyclase (H-89) or of protein kinase C (chelerythrine chloride) each diminished PTHrP-mediated type I collagen and alkaline phosphatase stimulation in a dose-dependent manner. These effects of PTHrP could also be blocked by inhibiting the Ras-mitogen-activated protein kinase (MAPK) pathway with a Ras farnesylation inhibitor, B1086, or with a MAPK inhibitor, PD-98059. Transient transfection of MG-63 cells with a mutant form of Galpha, which can sequester betagamma-subunits, showed significant downregulation of PTHrP-stimulated type I collagen expression, as did inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) by wortmannin. Consequently, the betagamma-PI 3-kinase pathway may be involved in PTHrP stimulation of Ras. Collectively, these results demonstrate that, acting via its G protein-coupled receptor, PTHrP can induce indexes of osteoblast differentiation by utilizing multiple, perhaps parallel, signaling pathways.
AJP Endocrinology and Metabolism 10/2001; 281(3):E489-99. · 4.75 Impact Factor
