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1.  Utilization of DXA Bone Mineral Densitometry in Ontario 
Executive Summary
Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario.
Dual Energy X-ray Absorptiometry Bone Mineral Density Assessment
Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is >2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score <–2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score< –1 & ≥–2.5). DXA densitometry is presently an insured health service in Ontario.
Clinical Need
Burden of Disease
The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993.
Guidelines for Bone Mineral Density Testing
With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking.
Current Funding for Bone Mineral Density Testing
The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn).
Method of Review
This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement.
The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies.
Findings of Utilization Analysis
Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.
OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.
Women accounted for 90 % of all BMD tests performed in the province.
In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:
With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.
Repeat BMD made up approximately 41% of all tests. Most of the people (>90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.
18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.
Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.
Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.
In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years.
Findings of Systematic Review and Analysis
Serial Bone Mineral Density Testing for People Not Receiving Osteoporosis Treatment
A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ –1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test.
Serial Bone Mineral Density Testing in People Receiving Osteoporosis Therapy
Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.
Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.
There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.
Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.
A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions.
Bone Mineral Density Testing and Treatment After a Fragility Fracture
A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. A review of 10 systematic reviews of RCTs and 3 additional RCTs showed that therapy with antiresorptive drugs significantly reduced the risk of vertebral fractures by 40 to 50% in postmenopausal osteoporotic women and osteoporotic men, and 2 antiresorptive drugs also reduced the risk of nonvertebral fractures by 30 to 50%. Evidence from observational studies in Canada and other jurisdictions suggests that patients who had undergone BMD measurements, particularly if a diagnosis of osteoporosis is made, were more likely to be given pharmacologic bone-sparing therapy. Despite these findings, the rate of BMD investigation and osteoporosis treatment after a fracture remained low (<20%) in Ontario as well as in other jurisdictions.
Bone Mineral Density Testing in Men
There are presently no specific Canadian guidelines for BMD screening in men. A review of the literature suggests that risk factors for fracture and the rate of vertebral deformity are similar for men and women, but the mortality rate after a hip fracture is higher in men compared with women. Two bisphosphonates had been shown to reduce the risk of vertebral and hip fractures in men. However, BMD testing and osteoporosis treatment were proportionately low in Ontario men in general, and particularly after a fracture, even though men accounted for 25% of the hip and wrist fractures. The Ontario data also showed that the rates of wrist fracture and hip fracture in men rose sharply in the 75- to 80-year age group.
Ontario-Based Economic Analysis
The economic analysis focused on analyzing the economic impact of decreasing future hip fractures by increasing the rate of BMD testing in men and women age greater than or equal to 65 years following a hip or wrist fracture. A decision analysis showed the above strategy, especially when enhanced by improved reporting of BMD tests, to be cost-effective, resulting in a cost-effectiveness ratio ranging from $2,285 (Cdn) per fracture avoided (worst-case scenario) to $1,981 (Cdn) per fracture avoided (best-case scenario). A budget impact analysis estimated that shifting utilization of BMD testing from the low risk population to high risk populations within Ontario would result in a saving of $0.85 million to $1.5 million (Cdn) to the health system. The potential net saving was estimated at $1.2 million to $5 million (Cdn) when the downstream cost-avoidance due to prevention of future hip fractures was factored into the analysis.
Other Factors for Consideration
There is a lack of standardization for BMD testing in Ontario. Two different standards are presently being used and experts suggest that variability in results from different facilities may lead to unnecessary testing. There is also no requirement for standardized equipment, procedure or reporting format. The current reimbursement policy for BMD testing encourages serial testing in people at low risk of accelerated bone loss. This review showed that biannual testing is not necessary for all cases. The lack of a database to collect clinical data on BMD testing makes it difficult to evaluate the clinical profiles of patients tested and outcomes of the BMD tests. There are ministry initiatives in progress under the Osteoporosis Program to address the development of a mandatory standardized requisition form for BMD tests to facilitate data collection and clinical decision-making. Work is also underway for developing guidelines for BMD testing in men and in perimenopausal women.
Increased use of BMD in Ontario since 1996 appears to be associated with increased use of antiresorptive medication and a decrease in hip and wrist fractures.
Data suggest that as many as 20% (98,000) of the DXA BMD tests in Ontario in 2005/06 were performed in people aged less than 65 years, with no fracture in the current year, and coded as being at low risk for accelerated bone loss; this is not consistent with current guidelines. Even though some of these people might have been incorrectly coded as low-risk, the number of tests in people truly at low risk could still be substantial.
Approximately 4% (21,000) of the DXA BMD tests in 2005/06 were repeat BMDs in low-risk individuals within a 24-month period. Even though this is in compliance with current OHIP reimbursement policies, evidence showed that biannual serial BMD testing is not necessary in individuals without major risk factors for fractures, provided that the baseline BMD is normal (T-score < –1). In this population, BMD measurements may be repeated in 3 to 5 years after the baseline test to establish the rate of bone loss, and further serial BMD tests may not be necessary for another 7 to 10 years if the rate of bone loss is no more than 1% per year. Precision of the test needs to be considered when interpreting serial BMD results.
Although changes in BMD may not be the perfect surrogate for reduction in fracture risk as a measure of response to osteoporosis treatment, experts advised that it is presently the only reliable test for monitoring response to treatment and to help motivate patients to continue treatment. Patients should not discontinue treatment if there is no increase in BMD after the first year of treatment. Lack of response or bone loss during treatment should prompt the physician to examine whether the patient is taking the medication appropriately.
Men and women who have had a fragility fracture at the hip, spine, wrist or shoulder are at increased risk of having a future fracture, but this population is presently under investigated and under treated. Additional efforts have to be made to communicate to physicians (particularly orthopaedic surgeons and family physicians) and the public about the need for a BMD test after fracture, and for initiating treatment if low BMD is found.
Men had a disproportionately low rate of BMD tests and osteoporosis treatment, especially after a fracture. Evidence and fracture data showed that the risk of hip and wrist fractures in men rises sharply at age 70 years.
Some counties had BMD utilization rates that were only 10% of that of the county with the highest utilization. The reasons for low utilization need to be explored and addressed.
Initiatives such as aligning reimbursement policy with current guidelines, developing specific guidelines for BMD testing in men and perimenopausal women, improving BMD reports to assist in clinical decision making, developing a registry to track BMD tests, improving access to BMD tests in remote/rural counties, establishing mechanisms to alert family physicians of fractures, and educating physicians and the public, will improve the appropriate utilization of BMD tests, and further decrease the rate of fractures in Ontario. Some of these initiatives such as developing guidelines for perimenopausal women and men, and developing a standardized requisition form for BMD testing, are currently in progress under the Ontario Osteoporosis Strategy.
PMCID: PMC3379167  PMID: 23074491
2.  P1 - Maxillary Osteoporosis and Genetic Predisposition 
Osteoporosis is a form of dysmetabolic osteopathy of multifactorial origin, characterised by reduction of the bone matrix and mineral portion and, overall, of bone mass, leading to fragility and increased fracture risk.
AETIOPATHOGENESIS -ENDOCRINE FACTORS: ACTH, glycocorticoids, PTH, thyroxine, oestrogen, testosterone-GENETIC FACTORS: Major genes that regulate fundamental characteristics of bone, such as density and quality, and minor genes that regulate individual genetic background [lipoprotein receptor related protein (LRP5), TGF1, BMP, VDR, COL1A1, ER].
The DIAGNOSIS is based on history, clinical findings (vertebral or appendicular fractures), blood chemistry, conventional radiology and bone mass measurement. For the latter, it is possible to use DUAL-ENERGY X-RAY DENSITOMETRY which measures bone mineral content: according to the WHO definition, in osteoporosis bone mineral density (BMD) is more than 2.5 standard deviations below normal.
MAXILLARY OSTEOPOROSIS: because of their function as a support for teeth, which leads to the development of the alveolar process, and their role in mastication, the jawbones (maxilla and mandible) differ from all the other bones of the skeleton. This role, also involving the masticatory muscles, prompts bone trophism. In advancing age a marked reduction of the thickness of the maxillary cortical bone is observed, together with increased porosity and constant functional remodelling of the trabecular part, a phenomenon that, as it increases, leads to tooth loss. Only a mandibular area (a bucco-lingual area of cortical bone in front of the mental foramen) remains unmodified, independently of gender, age and tooth loss.
Materials and methods:
Kemifar® supplies a test which can be used to study several factors (Er, VDR, COL1A1) that predispose to the development of osteoporosis. OsteoResis®Type is a simple, non-invasive test that allows the complete determination, and interpretation, of several genotypes associated with the appearance of osteoporosis. The test requires a pinprick blood sample, taken from the fingertip: from this sample, which is placed on a special paper, the genetic material is extracted for subsequent analysis. The test supplies definitive data, does have to be repeated and can be carried out at any time.
Gene polymorphism influences the appearance of osteoporotic fracture risk: individuals with an absent enzyme restriction site have a markedly reduced osteoporotic fracture risk, therefore if capital “X” indicates absence of the restriction site, the XX subject has a resistant genotype as the site is not present on either chromosome, whereas Xx and xx subjects have a susceptible genotype.
A sample of 20 subjects randomly drawn from among patients referred to our department of oral and implant surgery underwent the above test.
Discussion and conclusions:
The genetic component is becoming increasingly important in the early diagnosis of osteoporosis. Even though there are many risk factors involved in the pathogenesis of the disease, the most important is still a positive family history. The single individual’s genetic makeup is important as regards bone mass peak, which is 50–60% genetically determined.
PMCID: PMC3213811
3.  WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk 
PLoS Genetics  2012;8(7):e1002745.
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13
Author Summary
Bone traits are highly dependent on genetic factors. To date, numerous genetic loci for bone mineral density (BMD) and only one locus for osteoporotic fracture have been previously identified to be genome-wide significant. Cortical bone has been reported to be an important determinant of bone strength; so far, no genome-wide association studies (GWAS) have been performed for cortical bone thickness (CBT) of the tibial and radial diaphysis or BMD at forearm, a skeletal site rich in cortical bone. Therefore, we performed two separated meta-analyses of GWAS for cortical thickness of the tibia in 3 independent cohorts of 5,878 men and women, and for forearm BMD in 5 cohorts of 5,672 individuals. We identified the 7q31 locus, which contains WNT16, to be associated with CBT and BMD. Four SNPs from this locus were then tested in 2,023 osteoporotic fracture cases and 3,740 controls. One of these SNPs was genome-wide significant, and two were genome-wide suggestive, for forearm fracture. Generating a mouse with targeted disruption of Wnt16, we also demonstrated that mice lacking this protein had substantially thinner bone cortices and reduced bone strength than their wild-type littermates. These findings highlight WNT16 as a clinically relevant member of the Wnt signaling pathway and increase our understanding of the etiology of osteoporosis-related phenotypes and fracture.
PMCID: PMC3390364  PMID: 22792071
Osteoporosis is the most common metabolic bone disorder of the elderly, affecting the normal bone turnover with an increased bone resorption and subsequent higher risk of fragility fractures. Collagen type 1 is the most represented protein in bone matrix. A genetic variation (Sp1) in intron 1 of COL1A1 gene has been associated to modulation of expression of the alpha 1 chain of collagen type 1 and it is considered a candidate polymorphism for predisposition to osteoporosis status and fragility fractures. Association studies, in ethnically different populations, are needed to strongly confirm the role of this polymorphism in bone metabolism.
Materials and methods
We enrolled over 2,000 Italian individuals and studied their bone mineral density (BMD) and fractures in relation to age, sex and body mass index (BMI). Moreover, we analyzed the distribution of Sp1 polymorphism in these individuals and associated it to normal bone status, osteopenic condition or osteoporosis diagnosis, BMD and the presence of low-trauma fractures.
The most rare ss genotype showed a trend for osteoporosis diagnosis with respect to both normal and osteopenic status. The same genotype resulted to be associated to lower values of BMD both at spine and femur sites. No association was found with fractures.
In conclusion the presence of the homozygote ss genotype seemed to predispose to osteoporosis diagnosis and to be more frequent in subjects with lower spine and femur BMD values.
PMCID: PMC3797002  PMID: 24133532
osteoporosis; bone mineral density; fragility fracture risk; collagen type 1; Sp1 polymorphism; osteoporosis prevention
PLoS Medicine  2008;5(10):1-12.
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
PMCID: PMC2566998  PMID: 18922041
PLoS Medicine  2006;3(4):e90.
Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.
Methods and Findings
Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm 2 (CI, 16 to 34 mg/cm 2) lower in TT homozygotes than the other genotype groups ( p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm 2 (CI, 1 to 42 mg/cm 2), ( p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses.
Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.
A large collaborative European study finds only weak links between a much studied potential genetic risk factor and bone mineral density or fracture risk.
PMCID: PMC1370920  PMID: 16475872
The EPMA Journal  2013;4(1):15.
Collagen type I is one of the key proteins involved in the maturation, development and mineralization of bone. Genetic polymorphisms of collagen type I alpha-1 chain (COL1A1) gene are associated with low bone mineral density and higher risk of fractures in adults and children. We hypothesize that the polymorphic alleles and genotypes of COL1A1 gene influence bone mineralization and metabolism in children with juvenile idiopathic arthritis (JIA).
We recruited 196 children with JIA in our study. Bone mineral density (BMD) was measured by lumbar spine dual-energy X-ray absorptiometry. Osteocalcin, Ca, Ca2+ and inorganic phosphate (Pi) were utilized for the assessment of bone metabolism. Molecular testing: Sp1 (rs1800012) and -1997G/T (rs1107946) polymorphisms of COL1A1 gene were detected RFLP.
No differences in genotype, allele and haplotype distribution of COL1A1 were detected among children with normal and low BMD (LBMD; <−2 standard deviation). The presence of GG genotype of Sp1 increased the incidence of LBMD in Tanner II to III children (odds ratio (OR) = 9.7 [95% confidence interval (CI), 1.2; 81.7], p = 0.02) as well as GG genotype of -1997G/T increased the frequency of LBMD in Tanner IV to V children (OR = 4.5 [95% CI, 0.9; 22.0], p = 0.048). Tanner I children with -1997GG genotype had lower Ca2+ and osteocalcin and higher Pi compared with carriers of -1997Т allele. Tanner IV to V children with -1997GG genotype had lower BMD and BMD-Z score than carriers of -1997Т.
The evaluation of the biologic effects of the GG Sp1 and GG of -1997G/T polymorphism of COL1A1 has shown negative effect on BMD and mineral turnover related to pubertal stage.
PMCID: PMC3693906  PMID: 23763832
Juvenile idiopathic arthritis (JIA); Bone mineral density (BMD); Bone densitometry; Collagen; Polymorphism
Age  2011;35(2):471-478.
Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G–G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.
PMCID: PMC3592947  PMID: 22174012
Bone mineral density; Polymorphisms; COL1A1; JAG1; Haplotypes; Postmenopausal Mexican-Mestizo women
Osteoporosis International  2012;23(7):1877-1887.
Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future.
The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis.
We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA).
Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the −2,327 bp upstream (P = 6.8 × 10−4) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA.
Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-011-1861-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3368110  PMID: 22215184
Association; BMD; CDX1; Periostin; Vertebral fracture
Annals of the Rheumatic Diseases  2004;63(5):544-548.
Objective: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene.
Methods: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested.
Results: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years.
Conclusions: Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested.
PMCID: PMC1754973  PMID: 15082485
Lancet  2008;371(9623):1505-1512.
Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.
In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.
We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density.
Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.
Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.
PMCID: PMC2679414  PMID: 18455228
Acta Pharmacologica Sinica  2011;32(7):947-955.
To study whether genetic polymorphisms of COL1A1 and COL1A2 genes affected the onset of fracture in postmenopausal Chinese women.
SNPs in COL1A1 and COL1A2 genes were identified via direct sequencing in 32 unrelated postmenopausal Chinese women. Ten SNPs were genotyped in 1252 postmenopausal Chinese women. The associations were examined using both single-SNP and haplotype tests using logistic regression.
Twenty four (4 novel) and 28 (7 novel) SNPs were identified in COL1A1 and COL1A2 gene, respectively. The distribution frequencies of 2 SNPs in COL1A1 (rs2075554 and rs2586494) and 3 SNPs in COL1A2 (rs42517, rs1801182, and rs42524) were significantly different from those documented for the European Caucasian population. No significant difference was observed between fracture and control groups with respect to allele frequency or genotype distribution in 9 selected SNPs and haplotype. No significant association was found between fragility fracture and each SNP or haplotype. The results remained the same after additional corrections for other risk factors such as weight, height, and bone mineral density.
Our results show no association between common genetic variations of COL1A1 and COL1A2 genes and fracture, suggesting the complex genetic background of osteoporotic fractures.
PMCID: PMC4003126  PMID: 21602843
COL1A1; COL1A2; polymorphism; bone fracture; osteoporosis
Background: The markers of bone remodelling, such as serum osteocalcin, may be used to assess osteoporosis and to predict the fracture risk in elderly persons, especially in women. The bone mineral density which reflects the bone mass and strength, also predicts osteoporotic related hip fractures. So, this work highlights the association between the bone turnover and the bone mass and strength.
Aim: To assess the association between the biochemical markers of bone remodeling and osteocalcin with the bone mineral density in non osteoporotic and osteoporotic women among post menopausal subjects.
Materials and Methods: Sixty postmenopausal women whose ages ranged from 55-65 years included in this study, were further divided into group 1 (thirty non osteoporotic subjects) and group 2 (thirty osteoporotic subjects). For all the subjects, serum osteocalcin was measured by ELISA. BMD was measured by the Dual Energy X- Ray Absorptiometry (DXA) scan. The women with osteoporosis were diagnosed, based on the T- score of the bone mineral density, by the DXA scan. The Student’s “t” test was performed between the variables of both the groups and a correlation test was also performed between osteocalcin and BMD by using SPSS.
Results: A negative correlation was found between the osteocalcin level and the bone mineral density in post menopausal women. The mean values of both serum osteocalcin and BMD between the osteoporotic and the non osteoporotic subjects were statistically significant.
Conclusion: An increased bone turnover coincides with the trabecular deterioration in osteoporotic women of the post menopausal age group. A combination of biochemical markers and BMD may be a better predictor of the fracture risk than when it was assessed by either alone. The biochemical markers of the bone turnover cannot be a substitute for the serial BMD measurement, but they may be useful when they are considered in conjunction with the BMD measurement.
PMCID: PMC3681044  PMID: 23814717
BMD; Osteocalcin; Osteoporosis
Postgraduate Medical Journal  1998;74(872):349-354.
This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.
PMCID: PMC2360948  PMID: 9799889
Lancet  2008;371(9623):1505-1512.
Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.
In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.
We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density.
Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.
PMCID: PMC2679414  PMID: 18455228
In Italy, 60–70 thousand people are affected by spinal cord lesions, which have an incidence of 20/25 new cases per million per year and a male:female ratio of 4:1. The age group most affected is 10–40 years. In 65% of cases the origin of the lesion is traumatic. According to the ASIA (American Spinal Injury Association) Impairment Scale (AIS), the lesion is defined complete or incomplete, depending on whether or not partial conservation of sensory and/or motor functions is found below the level of the lesion in the first 24 hours following the trauma. Patients with spinal injuries show alterations of phosphocalcic metabolism, with osteoporosis, neurogenic para-osteo-arthropathy and renal calculi. Even though post-lesion osteoporosis is traditionally considered secondary to reduced loading, it has characteristics different from those of primary osteoporosis and osteoporosis caused by endocrine disorders or by simple disuse. Indeed, there is usually no significant demineralisation of the bone segments above the level of the neurological lesion and the site and entity of the bone resorption are influenced by factors such as age, sex, muscle spasticity, but above all by lesion site, lesion severity, and post-lesion period.
Osteocytes (the mechanosensors in bone tissue), via extracellular and intracellular signal transmitters, transmit mechanical load signals to the osteoblasts, stimulating bone formation and inhibiting bone resorption by the osteoclasts.
A spinal injury results in prolonged limitation of both the loading and the movement of the lower limbs; this leads to marked muscle atrophy, inhibition of the osteoblasts and activation of the osteoclasts, and an inevitable loss of bone tissue. The increase in bone resorption following a spinal injury is reflected in increased urinary excretion of hydroxyproline, pyridinoline, deoxypyridinoline and type I collagen C-telopeptide. Significantly increased expression of RANKL mRNA and protein in cultures of osteoblast-like cells from spinal injured rats has also been observed, while OPG expression is significantly reduced and osteoclastogenesis increased. Spinal lesions are also associated with supplementary production, in the bone marrow, of cytokines like IL-6, potential mediators of bone mass loss.
Recent studies suggest that bone remodelling is also influenced by nervous signals: after denervation, due to a spinal lesion, there is a marked reduction in innervation density and in neuropeptides, such as VIP, PACAP, NPY, SP, CGRP, noradrenaline, glutamate and serotonin, mainly in bone segments below the level of the lesion; this upsets the balance between bone resorption and formation. In addition to its direct role in bone metabolism, denervation can induce alterations of vascular regulation: indeed, a complete spinal injury causes alterations of the sympathetic innervation with possible opening of intraosseous venous shunts that, leading to venous and capillary stasis with increase in local pressure, could favour the formation of osteoclasts, accelerating the process of bone resorption; osteopenia is indeed predominant in the meta-epiphyseal areas of long bones, which are highly vascularised.
In the first months following the injury, the demineralisation generally affects mainly the distal femur and proximal tibia, segments rich in trabecular bone, while the femoral and tibial diaphyses, which are rich in cortical bone, are relatively spared.
Paradoxically, in the lumbar spine, in which the trabecular component is prevalent, DXA scans do not reveal significant reductions in bone mineral density, independently of the lesion level or duration. This may be because the spinal column exerts an ongoing bodyweight-supporting action during wheelchair use. Nevertheless, on DXA studies, BMD at lumbar level can sometimes erroneously appear increased on account of the presence of osteophytes due to neuropathic spondylopathy. To overcome the limits of this approach, the most recent studies have used densitometric methods such as QCT (quantitative computerised tomography) to assess the density of trabecular and cortical bone in the distal radius and tibia.
Up to a third of spinal cord injured patients are liable to sustain fragility fractures. Although they are asymptomatic, these fractures can cause complications, such as abnormal bone callus formation, bedsores and increased spasticity, all factors that can further deteriorate the patient’s already precarious state of health.
Reduction of fracture risk through an appropriate treatment of osteoporosis after spinal cord injury is particularly important for the prognosis and quality of life of these patients. In this context, the application of diagnostic protocols, both haematological and instrumental, for the monitoring and therapeutic control of bone demineralisation over time could be an effective help.
PMCID: PMC3213781
Osteoporosis is a complex disease characterized by low bone mineral density (BMD), which is determined by an interaction of genetics and environmental factors. Collagen type alpha 1 (COL1A) and JAGGED (JAG1) genes have been implicated in relation to BMD. The aim of this study was to investigate possible association among BMD and rs2273061 of JAG1, rs1107946 and rs1800012 of Col1A1 polymorphisms, as well as their haplotypes with BMD in postmenopausal Chinese women. A structured questionnaire for risk factors was recorded and BMD in lumbar spine and total hip was measured by dual-energy X-ray absorptiomety. Genomic DNA was obtained from 367 postmenopausal Chinese women. Genomic DNA was extracted from EDTA-preserved peripheral venous blood by phenol-chloroform extraction method and analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). As a result, the rs1800012 polymorphism of COL1A1 showed an association with BMD of the lumbar spine under a dominant model. Besides, haplotype analysis of COL1A1 gene showed that G-G haplotype presented higher BMD in lumbar spine. No significant association between genotypes and alleles distributions of the rs1107946 polymorphism of COL1A1 and rs2273061 polymorphism of the JAG1 was found. In conclusion, our results suggest that the rs1800012 polymorphism of the COL1A1 and one haplotype were significantly associated with lumbar spine BMD variations in Chinese postmenopausal women.
PMCID: PMC4230153  PMID: 25400810
Bone mineral density; polymorphism; JAG1; COL1A1; haplotypes; Chinese postmenopausal women
World Journal of Gastroenterology : WJG  2014;20(39):14087-14098.
The authors revise the latest evidence in the literature regarding managing of osteoporosis in ulcerative colitis (UC), paying particular attention to the latest tendency of the research concerning the management of bone damage in the patient affected by UC. It is wise to assess vitamin D status in ulcerative colitis patients to recognize who is predisposed to low levels of vitamin D, whose deficiency has to be treated with oral or parenteral vitamin D supplementation. An adequate dietary calcium intake or supplementation and physical activity, if possible, should be guaranteed. Osteoporotic risk factors, such as smoking and excessive alcohol intake, must be avoided. Steroid has to be prescribed at the lowest possible dosage and for the shortest possible time. Moreover, conditions favoring falling have to been minimized, like carpets, low illumination, sedatives assumption, vitamin D deficiency. It is advisable to assess the fracture risk in all UC patient by the fracture assessment risk tool (FRAX® tool), that calculates the ten years risk of fracture for the population aged from 40 to 90 years in many countries of the world. A high risk value could indicate the necessity of treatment, whereas a low risk value suggests a follow-up only. An intermediate risk supports the decision to prescribe bone mineral density (BMD) assessment and a subsequent patient revaluation for treatment. Dual energy X-ray absorptiometry bone densitometry can be used not only for BMD measurement, but also to collect data about bone quality by the means of trabecular bone score and hip structural analysis assessment. These two indices could represent a method of interesting perspectives in evaluating bone status in patients affected by diseases like UC, which may present an impairment of bone quality as well as of bone quantity. In literature there is no strong evidence for instituting pharmacological therapy of bone impairment in UC patients for clinical indications other than those that are also applied to the patients with osteoporosis. Therefore, a reasonable advice is to consider pharmacological treatment for osteoporosis in those UC patients who already present fragility fractures, which bring a high risk of subsequent fractures. Therapy has also to be considered in patients with a high risk of fracture even if it did not yet happen, and particularly when they had long periods of corticosteroid therapy or cumulative high dosages. In patients without fragility fractures or steroid treatment, a medical decision about treatment could be guided by the FRAX tool to determine the intervention threshold. Among drugs for osteoporosis treatment, the bisphosphonates are the most studied ones, with the best and longest evidence of efficacy and safety. Despite this, several questions are still open, such as the duration of treatment, the necessity to discontinue it, the indication of therapy in young patients, particularly in those without previous fractures. Further, it has to be mentioned that a long-term bisphosphonates use in primary osteoporosis has been associated with an increased incidence of dramatic side-effects, even if uncommon, like osteonecrosis of the jaw and atypical sub-trochanteric and diaphyseal femoral fractures. UC is a long-lasting disease and the majority of patients is relatively young. In this scenario primary prevention of fragility fracture is the best cost-effective strategy. Vitamin D supplementation, adequate calcium intake, suitable physical activity (when possible), removing of risk factors for osteoporosis like smoking, and avoiding falling are the best medical acts.
PMCID: PMC4202340  PMID: 25339798
Ulcerative colitis; Osteoporosis; Fragility fracture; Bone mineral density; Trabecular bone score; Hip structural analysis; Fracture assessment risk tool; Dual energy X-ray absorptiometry
Calcified Tissue International  2011;90(2):76-89.
Osteoporosis is a common skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. We previously demonstrated that Col1a1-SOX9 transgenic mice, in which SOX9 specifically expresses in osteoblasts driven by a 2.3kb Col1a1 promoter, display osteopenia during the early postnatal stage. In this study, to further analyze the osteopenia phenotype and especially the effect of the osteoblast-specific expression of SOX9 on bone mechanical properties, we performed bone geometry and mechanical property analysis of long bones from Col1a1-SOX9 transgenic mice (TG) and wild type littermates (WT) at different time points. Interestingly, after body weight adjustment, TG mice have similar whole-bone strength as WT mice, but exhibit significantly thinner cortical bone, lower elastic modulus, and higher moment of inertia. Thus, osteoblast-specific SOX9 expression results in altered bone structure and material properties. Furthermore, the expression levels of Pcna, Col1a1, Osteocalcin, and the Opg/Rankl ratio in TG mice are significantly lower until 4 months of age compared with WT mice, suggesting that TG mice have dysregulated bone homeostasis. Finally, bone marrow stromal cells (MSCs) isolated from TG mice display enhanced adipocyte differentiation and decreased osteoblast differentiation in vitro, suggesting that osteoblast-specific expression of SOX9 can lead to altered mesenchymal stem cell differentiation potentials. In conclusion, our study implies that SOX9 activity has to be tightly regulated in adult skeleton to ensure optimal bone quality.
PMCID: PMC3272153  PMID: 22143895
SOX9; RUNX2; osteoporosis; bone mechanical property; marrow stromal cells (MSC)
Sex steroids are important regulators of bone physiology and play an essential role in the maintenance of bone health throughout the life. Hormonal replacement therapy (HRT) is a treatment commonly used to relieve symptoms and some undesirable consequences of menopause such as osteoporosis. Osteoporosis, characterized by the loss of bone mass and deterioration of microarchitecture with a consequent higher risk of fragility fractures, is under genetic influence. A tetranucleotide (TTTA)n microsatellite repeat polymorphism, at intron 4 of the CYP19 (aromatase) gene, has been previously associated with higher lumbar spine bone mineral density (LS-BMD) and lower risk of spine fracture in postmenopausal women. Moreover, the ERα encoded by the ESR1 gene is another important candidate for the regulation of bone mass of menopause. Moreover prospective analysis from >18.000 subjects at the GENOMOS study indicated that XX homozygotes genotype had a reduced risk of fracture independently from BMD.
In the present study, we investigated in postmenopausal Italian women, at baseline and after 1 year of HRT, whether ESR1 and CYP19 gene polymorphisms could affect BMD through different statistical models.
This study has been performed on 100 post-menopausal Italian women, from a larger group of 250. The study group was administred HRT and LS-BMD was measured at baseline and after 1 year of therapy. Genetic analysis evaluating ESR1 and CYP19 gene polymorphisms was performed.
Generalized Linear Models (GLMs) test showed that women with normal LS-BMD at the baseline had a major statistically significant BMD increase of 0.1426 gr/cm2 (p= 0.0001) with respect to the osteoporotic patients. In addition, subjects with genotype 1 and 2 of CYP19 gene had a lower modification in LS-BMD after 1 year of HRT (0.0837 gr/cm2 and 0,076 g/cm2; p=0.0470 and 0,0547 respectively) when compared to genotype 3. No influences of the aromatase genotypes were observed in the variable difference using both Anova and GLMs test. Regarding the ESR1 gene polymorphism, the LS-BMD after 1 year of HRT was influenced by the diagnosis at the baseline and height and ERα genotypes were able to influence difference with statistical significant results with both test.
In the present study, we have demonstrated that CYP19 gene polymorphism is able to influence the effect of 1 year HRT on LS-BMD with no influence on pre-/ and post-/HRT LS-BMD differences. Although ESR1 gene polymorphism is not able to influence the LS-BMD after 1 year HRT, it influences the observed modifications during the year of therapy. These data underlie the complexity of the genetics of the bone mass and its importance in influencing the response to HRT.
PMCID: PMC4064439  PMID: 25002878
CYP19 gene; ESR1 gene; polymorphism; Hormonal Replace Therapy (HRT)
Jama  2008;299(11):1277-1290.
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
PMCID: PMC3282142  PMID: 18349089
Clinics (Sao Paulo, Brazil)  2008;63(5):645-650.
We aimed to discuss the risk assessments for both patients with hip fractures due to fall-related, low energy traumas and non-fractured control patients by examining bone mineral density and genetic data, two features associated with femoral strength and hip fracture risk.
Twenty-one osteoporotic patients with proximal femur fractures and non-fractured, osteoporotic, age- and gender-matched controls were included in the study. Bone mineral density measurements were performed with a Lunar DXA. The COL1A1, ESR, VDR, IL-6, and OPG genes were amplified, and labeling of specific gene sequences was performed in a multiplex polymerase chain reaction using the osteo/check PCR kit from the whole blood of all subjects.
The bone mineral density (trochanteric and total bone mineral density values) of the fracture group was significantly decreased relative to the control group. We were not able to conduct statistical tests for the polymorphisms of the COL1A1, ESR, and VDR genes because our results were expressed in terms of frequency. Although they were not significant, we did examine differences in the IL-6 and OPG genes polymorphisms between the two groups. We concluded that increasing the number of cases will allow us to evaluate racial differences in femoral hip fracture risk by genotypes.
PMCID: PMC2664723  PMID: 18925325
Hip fractures risk; Osteoporosis; Gene polymorphism
Many fractures occur in individuals without osteoporosis defined by areal bone mineral density (aBMD). Inclusion of other aspects of skeletal strength may be useful in identifying at-risk subjects. We used surrogate measures of bone strength at the radius and tibia measured by peripheral quantitative computed tomography (pQCT) to evaluate their relationships with nonvertebral fracture risk. Femoral neck (FN) aBMD, measured by dual-energy X-ray absorptiometry (DXA), also was included. The study population consisted of 1143 white men aged 69+ years with pQCT measures at the radius and tibia from the Minneapolis and Pittsburgh centers of the Osteoporotic Fractures in Men (MrOS) study. Principal-components analysis and Cox proportional-hazards modeling were used to identify 21 of 58 pQCT variables with a major contribution to nonvertebral incident fractures. After a mean 2.9 years of follow-up, 39 fractures occurred. Men without incident fractures had significantly greater bone mineral content, cross-sectional area, and indices of bone strength than those with fractures by pQCT. Every SD decrease in the 18 of 21 pQCT parameters was significantly associated with increased fracture risk (hazard ration ranged from 1.4 to 2.2) independent of age, study site, body mass index (BMI), and FN aBMD. Using area under the receiver operation characteristics curve (AUC), the combination of FN aBMD and three radius strength parameters individually increased fracture prediction over FN aBMD alone (AUC increased from 0.73 to 0.80). Peripheral bone strength measures are associated with fracture risk and may improve our ability to identify older men at high risk of fracture. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179319  PMID: 20593412
peripheral QCT; men; bone strength; osteoporosis; fracture
PLoS Genetics  2010;6(1):e1000806.
Osteoporosis is a major public health problem. It is mainly characterized by low bone mineral density (BMD) and/or low-trauma osteoporotic fractures (OF), both of which have strong genetic determination. The specific genes influencing these phenotypic traits, however, are largely unknown. Using the Affymetrix 500K array set, we performed a case-control genome-wide association study (GWAS) in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip OF and 516 controls. We found that a SNP, rs13182402 within the ALDH7A1 gene on chromosome 5q31, was strongly associated with OF with evidence combined GWAS and replication studies (P = 2.08×10−9, odds ratio = 2.25). In order to explore the target risk factors and potential mechanism underlying hip OF risk, we further examined this candidate SNP's relevance to hip BMD both in Chinese and Caucasian populations involving 9,962 additional subjects. This SNP was confirmed as consistently associated with hip BMD even across ethnic boundaries, in both Chinese and Caucasians (combined P = 6.39×10−6), further attesting to its potential effect on osteoporosis. ALDH7A1 degrades and detoxifies acetaldehyde, which inhibits osteoblast proliferation and results in decreased bone formation. Our findings may provide new insights into the pathogenesis of osteoporosis.
Author Summary
Osteoporosis is a major health concern worldwide. It is a highly heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures. However, the specific genetic variants determining risk for low BMD or OF are largely unknown. Here, taking advantage of recent technological advances in human genetics, we performed a genome-wide association study and follow-up validation studies to identify genetic variants for osteoporosis. By examining a total of 11,568 individuals from Chinese and Caucasian populations, we discovered a susceptibility gene, ALDH7A1, which is associated with hip osteoporotic fracture and BMD. ALDH7A1 might inhibit osteoblast proliferation and decrease bone formation. Our finding opens a new avenue for exploring the pathophysiology of osteoporosis.
PMCID: PMC2794362  PMID: 20072603
PLoS Genetics  2013;9(2):e1003247.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Author Summary
Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
PMCID: PMC3578773  PMID: 23437003

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