Monday, May 2, 2011

FRAX Index and osteoporosis prevention: clinical application of risks stratification studies.


        


Vertebral fractures

 

Accurate detection of vertebral fracture is essential for risk assessment of individual patients in clinical practice, for determining the drug efficacy in clinical trials and for evaluating the prevalence and incidence of osteoporotic disease in a given population.

A prevalent vertebral fracture is the strongest predictor of subsequent vertebral fracture as well’s of any subsequent osteoporotic fracture.

A vertebral fracture results in a 4.4 fold increase risk of future vertebral fracture in people with a prevalent fracture.

Although bone mass is an important component of the risk of fracture, other abnormalities occur in the skeleton that contribute to fragility fractures.

In addition, a variety of nonskeletal factors, such as the liability to fall and force of impact, contribute to fracture risk. In this view an accurate assessment of fracture risk should ideally take into account other readly measured indices of fracture risk, including in particular those adding more informations to that provided by Bone Mineral Density measurement.

It has been suggested that the ability of Bone Mineral Density to predict a fracture is comparable to the use of blood pressure measurements to predict stroke and better than serum cholesterol levels to predict myocardial infarction.

At the age of 50 years, the proportion of women with osteoporosis who will fracture their hip, spine, forearm or proximal humerus in the next 10 years is about 45%. However the detection rate of these fractures (i.e. sensitivity) is low, and 90% of such fractures would occur in women without osteoporosis.

Low sensitivity is one of the reasons why widespread population-based screening is not widely recommended in women at the time of menopause.

Vertebral fractures assessment

The problem is besides all the definition of vertebral fracture, at present there’s no Consensus Giudelines on osteoporotic vertebral fracture definition.

Identification of vertebral fracture can be very difficult, because the shape of normal vertebral bodies varies widely between individuals. Vertebral bodies can be present abnormal features because non-osteoporotic deformities and errors in radiological projection can induce a misdiagnosis of fractured body.

We have to remember that about 50% of vertebral fractures are asymptomatic and therefore are only casually identified. They are not the source of pain !Even when chest radiographs or vertebral images are correctly obtained only 35 to 50% of all radiographic vertebral fractures are correctly reported. It has been estimated that only 19% of these fractures reach clinical attention and can be correctly treated with a antiosteoporotic treatment. In view of high radiation exposure routine chest and lumbar radiographs are not recommended, but the availability of vertebral imaging using DEXA take the advantage of utilize an image of near radiographic quality available with a low fraction of the radiation dose.

Imaging vertebral fractures using DXA is called Vertebral Fracture Assessment (VFA).

The disadvantage of VFA is poor image resolution compared to conventional radiography, CT or MRI and the increased difficulties in imaging the thoracic spine, expecially above T7. Between 5 to 15% of thoracic vertebrae can be visualized only by conventioonal radiography.

The sensitivity and specicificty of this approach compared with conventional radiography varies with the kind of approach used to definy a vertebral fracture:

- Morphometric

- Semiquantitative (SQ)

- Visual identification

Irrespective of the approach, sensitivity is only moderated for for mild fractures corresponding to Genant grade 1 vertebral fracture showing a sensitivity of 54%, due to low imge resolution of this technique.

The sensitivity for identifying moderate to severe vertebral fractures (corresponding to Genant grade 2 and 3 fractures ) is substantial higher ranging from 90 to 94%.

Specificity is high, with a result between 94 to 99%, compared to conventional radiography.

Morphometric and visual identification using DXA images in children can be especially problematic because currently available software cannot detect the vertebrae in most children. That’s why we use total body DXA evaluation in children.

One advantage of DXA imaging is that the scan are not subjected to the same degree of projection distortion as conventional radiography because the X-ray beam is always orthogonal to the spine. Reducing the X ray diffraction effect.

Moreover DXA reduces the frequency that soft tissue obscure the endplates compared to single energy mode.

Side-by-side viewing facilitates the identification of incidental vertebral fractures.

Morphometrical analysis

It uses the measurement of vertebral height to define vertebral fractures. A normative daatabase is established against which the vertebrae are compared, There are a number of different morphometric approaches that vary with the criteria by which they define a vertebral fracture and in the reference data used, The most widely used approaches to identify prevalent and incidental vertebral fractures are the two different algorithms proposed by McCloskey et al (3) and Eastell R et al (4). Morphometric analysis has a high sensitivity and moderate high specificity in discriminating between normal vertebrae and fractured vertebrae. Moreover, all the morphometric approaches for defining prevalent and incident vertebral fractures are correlated with clinical risk factors for vertebral fractures.

The approach used can ahve a significant impact on the prevalence of vertebral fractures identified, varying from 3% to 90%.

A loss of vertebral height of 20 to 25 % is usually used to define an incident vertebral fracture; using this definition comparable ability to identify any vertebral frcture is present irrespective of aproach used to define a baseline fracture.

As mentioned above VFA is more effective in identifying moderate to severe deformities with a sensitivity of 81.6% for grade 2 deformities, whereas mild grade 1 deformities identifiation has a sensitivity as low as 22%.

Finally , the precision error is small if compared with the reduction in vertebral height of 20 to 25% threshold used to define vertebral fractures and it is less using conventional radiology than using VFA.

Semiquantitative analysis

SQ analysis combines measurements of vertebral height with subsequent evaluation of all vertebrae with a short vertebral height by an expert reader. This combined approach enables the identification of non-osteoporotic fracture vertebral deformities, which are not identified using morphometric analysis alone. As a consequence, SQ analysis is able to reduces false positive results.

The most widely used SQ analysis is that of Genant HK (6). Baseline or prevalent vertebral fractures are graded from “0” equal to normal to “3” equal to severe fracture, and incident fractures are defined as an increase of more than or equal than 1 grade on follow-up radiographs.

Genant grade 1 corresponds to an 20 to 25% reduction in anterior, middle or posterior height

Genant grade 2 corresponds to a 25 to 40% reduction in any height

Genant grade 3 corresponds to more than 40% reduction in any vertebral height

Mild grade 1 SQ vertebral deformities are frequently not associated with low BMD values.

The interobserver agreement for conventional radiographs or DXA images is similar with a K score of 0.53 and 0.51 respectively.

This approach is currently those recommended by International Society of Clinical Densitometry for diagnosing vertebral fractures with VFA.

Visual Identification by an expert reader (Algorithm Based Qualitative Approach)

ABQ approach differs from SQ analysis because the last one is based only on variations of vertebral height; not considering variations on endplates cracks or breaks as the primary event with a subsequent evaluation of vertebral height. ABQ focus more attention on the vertebral endplate alterations rather than on short vertebral height. Using ABQ we have a greater association with low BMD and interobserver agreement for radiography and DXA images of 0.74 and 0.65 respectively. So that mild vertebral fractures identified with ABQ are more strngly associated with osteoporosis than when this mild fractures are identified with SQ method.

The definition of vertebral fractures includes the presence of breaks in the cortex of vertebral body; these breaks always occurs in the center or either the superior or inferior endplates that are the weakest area of endplate because it is more distant from the strong outer vertebral ring. As a consequence, the endplate buckles or collapses under pressure because of interventebral disc and it results in a concave appearance to the superior and/or inferior endplate. If the concavity extend beyond the inner border of the vertebral ring , it is unlikely to represent an osteoporotic fracture. A vertebral fracture initially involves a crack of the superior or inferior endplate with or without the simultaneous loss of vertebral height. As severity of the fracture progresses, the vertebral ring fractures resulting in loss of height and buckling of the anterior, lateral and occasionally posterior cortex. It is important to outlined these aspects because there is considerable variation in vertebral shape resulting in osteoporotic and non osteoporotic deformities that can result in considerable intraobserver error even among expert readers.

Commonly we can see wedge deformity fracture associated with endplate fracture where is present a fracture of the anterior cortex of vertebral body.

A true compression fracture associated with endplate fracture is an osteoporotic compression fracture of superior endplate associated with fracture of anterior and posterior cortex of vertebral body.

It is also important to identify the different characteristics of high trauma burst fractures. There is usually an history of high trauma injury (such as a car accident, fall from a significant height) immediately resulting in acute, severe, localized back pain with localized tenderness.

Also the presence of intravertebral edema during MRI, used in the studies under discussion is not universally accepted target of vertebral osteoporotic fracture. Such as CT scan, also MRI, are usually only required in the presence of localized pain, focal neurological signs, or symptoms suggesting cord compression or a radiculopathy, or the clinical suspicion of primary or metastatic lesions, but not in osteoporotic patients.

Osteoporotic fractures are rare above T4 and in this settings, it is very important to consider metastatic lesions and , if appropriate to investigate for a primary neoplastic lesion.

Variations in shape or size of the vertebrae or of the vertebral endplate can be caused by degenerative diseases (osteoarthrosis), congenital deformities and metastatic lesions.

In addition, the aging skeleton, particularly in women, may develop slight wedging because of remodelling without depression or break in the endplate or cortex.

Scheuermann’s disease is frequently associated with a short anterior vertebral height in combination with irregularity of the whole superioe and/or inferior endplates. It appears to be isolated in a single vertebral body or involving adjacent vertebrae.

Schmorl’s nodes consist of a rounded flash-like break in the superior or inferior endplatein either the anteroposterior or lateral view, which rarely affects more than 25% of the endplate. They are found in about 35-75% of population and are formed by extrusion or erniation of the nuclear material from the interventebral disk into the vertebral body.

Degenerative osteomalacic changes are present in a vertebral body involved by an uniform or symmetrical concavity of the superior and inferior endplates. It is associated with a generalized thinning and reduced density of all vertebral bodies.

Clinical recommendations for screening for vertebral fractures

The current recommendations for using fracture assessment through DXA imaging (VFA) by the International Society of Clinical Densitometry are:

  1. When the results may influence clinical management
  2. If BMD is indicated then consider performing VTA if clinically indicated in:

- Documented height loss greater than 2 cm

- Historical height loss greater than 4 cm since young adult

- History of fracture after 50 years old

- Commitment to long term oral or parental glucocorticoid therapy

- History or findings suggestive of vertebral fracture not documented by previous radiographic imaging

Althoough risk factors can provide guidance to identify which patients require screening for osteoporosis, very few subjects would be prepared to initiate long-term therapy to prevent a fracture without confirmation of a diagnosis of osteoporosis using DXA scan.

If a patient has osteopenia and a fragility fracture at any site, the majority of physicians would intervene with therapy.

Therefore, it is reasonable to screen all patients with osteopenia using VFA, if it will alter the management of the patient. In a study at Mayo Clinic 16% of patients 60 to 69 years old and 45% of those older than 70 years had a previously undiagnosed vertebral fracture on VFA.

Fracture Risk Quantification

Concurrent considerations of risk factors that operate independently of BMD improuve evaluation of fracture risk.

The best example is age. The same T-score (i.e. the number of Standard Deviations from BMD found on people 35 years old) has different significance at different ages. For any BMD value, fracture risk is much higher in the elderly than in the young people. This is because age contributes to fracture risk indepently of BMD.

In general, risk factor scores show relative poor specificity and sensitivity in predicting either BMD or fracture risk. However, some risk factors vary in importance according to age. For example risk factors for falling, such as reduced mobility, sedatives use, visual impairment are more strongly predictive of fracture in the elderly than in younger individuals.

A series of meta-analyses has been undertaken to identify clinical risk factors that could be used in case finding strategies with or without the use of BMD measurement:

  1. Low body mass index (BMI): A low BMI is a significant risk factors for hip fracture. 20 kg/m2 vs 25 kg/m2 shows a RR of 1.27, whereas 30 Kg/m2 vs 25 Kg/m2 shows a RR of 0.89.
  2. Fragility fracture after 50 years of age : RR 1.86. In other words the presence of prior vertebral fracture approximately doubles the risk of having another fracture.
  3. Parental history of hip fracture : RR 1.54 an increase in risk independent from BMD value.
  4. Smoking is a RR 1.29
  5. Ever use of corticosteroids: RR 1.65
  6. Alcohol intake shows an increase in fracture risk that is dose dependent. Where the alcohol intake is on average 2 Units or less daily,there is no increase in risk. Intakes of 3 or more Units daily are associated with a dose-dependent increase in risk. RR 1.38
  7. Rheumatoid Arthritis RR 1.56. In contrast to many causes of secodary forms of osteoporosis rheumatoid arthritis causes an increase in fracture risk indenpendently of BMD and the use of glucocorticoids.

The multiplicity of these risk factors poses problems in the units of risk to be used. Also if the Relative Risk can be used, the best suited for clinician is the absolute risk ( or probability ) of fracture. The absolute risk dependes on age and life expenctancy, as well’s from the current relative risk. In general lifetime risk of fracture decreases with age, in particular after 70 years of age, because the risk of death with age outweight the increasing incidence of fracture. Estimates of lifetime risk are less relevant in assessing individual clinical risk of fracture in order to choose a therapeutic intervention. So that it has been recommended the use of a short term absolute risk ( i.e. a probability over 10-year interval), 10 years interval covers the likely duration of treatment and average life expectancy in elderly 60 year or older.

What about heart failure ?

Recently Heart failure has been identified such a risk factor for fragility fractures in two large studies by Ezekowitz JA on 2008 and by Carbone L on 2010.

Heart Failure is a leading cause of hospitalization and mortality in Europe and North America. Successfully enhanced treatment rates of hypertension and survival after myocardial infarction have produced a delay in the incidence in heart failure. So that the median age of heart failure patients in clinical trials and large epidemiological studies ranges between 65 and 75 years of age. Such patients are notably at risk for other co-morbid conditions causally related or not such as bone fracture.

Osteoporosis is one of such co-morbidity affecting 1 in 4 women and 1 in 8 men over 50 years old and it is known to be clinically evident with fragility fractures.

A central unanswered question is now evident: does heart failure lead to osteoporosis and fragility fractures or is it a passive participant in a population at risk of both diseases ?

A first answer comes on 1997 in a description of 101 patients with endstage heart failure awaiting cardiac transplantation, low bone mass was common, as vitamin D deficiency and Hyperparathyroidism.

What are the possible links between osteoporosis, fragility fractures, and heart failure ? Many scientists point to shared risk factors for both diseases such as older age, smoking, diabetes, renal dysfunction, inactivity, and poor nutrition.

An interesting role in linking bone loss to heart failure should be hyperaldosteronism always present in heart failure.

Elevated aldosterone levels have been associated with urinary magnesium and calcium wasting, causing secondary hyperparathyroidism.

Heart failure patients treated with spironolactone, a known aldosterone antagonist, showed few fractures compared to matching heart failure affected patients. It is not established if the consequent reduction in hyperparathyroidism is the cause of increased bone repair, increased mineralization, or mineral retentions in particular calcium and magnesium.

Future researches are needed in order to examine biomarkers, imaging, and clinical outcomes related to bone health after carefully clinically phenotyping patients with heart failure.

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