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Thread: Osteoporosis: New Paradigms in Determining Fracture Risk

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  1. #1
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    Osteoporosis: New Paradigms in Determining Fracture Risk

    Introduction

    During the last decade, the Bone Mineral Density Measurement (BMD) has been used both as a diagnostic tool and to assess the efficacy of drugs that affect bone metabolism. Dual-energy x-ray absorptiometry (DXA), represents the "gold standard" method for this evaluation and for a number of years has served to classify/categorize patients according to their measurements for clinical trials. Initially, DXA measurements were used as the primary outcome in evaluating the efficacy of these drugs.

    However, DXA measurements only provide information about the bone mineral content in g/cm², and it became apparent that the size and volumetric measurement of the bone can not be adequately represented using this method. Further, it became obvious that bone density does not represent bone strength. By using clinical risk factors (e.g., age, personal and family history of fragility fracture, etc.) together with DXA measurements, one can significantly improve fracture risk assessment.

    In order to evaluate bone complexity, the definition of osteoporosis was modified to: "a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture."[1] By introducing this new concept, bone density, together with bone quality, comprise the two relevant components of bone strength.



    Section 1 of 4

    Clinical Review

    In view of these changes, what can we learn from BMD when it is used as a risk assessment for fragility fracture before and after treatment? How important is additional information about prior fragility fractures?

    BMD is the most readily quantifiable predictor of fracture risk for individuals who have not yet suffered a fragility fracture. However, BMD alone should not serve as an absolute indicator of fracture risk. For each standard deviation decrease in BMD from a baseline, the fracture risk approximately doubles. However, a T-score of -2.5 can represent a different level of risk for an individual who is 45-years of age, when compared to one who is 75 years old.

    Once the new fragility fracture became the acceptable primary outcome in the treatment efficacy assessment in clinical trials, it was possible to evaluate the role of a prior fracture. It is now clear that a prior fragility fracture is associated with an increased risk of sustaining a future fracture from 1.5 - 9.5 times (depending on an individual's age, as well as the number and site of prior fractures). [2-4]

    The presence of a vertebral fracture (VF) can mean a four fold greater risk of incurring a second VF.[5,6] Twenty percent of those who sustain a VF will experience a second VF within 1 year. [7] The presence of a VF can mean an increase in the risk of sustaining fractures at other sites (e.g., the hip). [6]

    A Quebec study that included about 7000 individuals found that there is "2.3 - 10 fold increased risk of experiencing a hip fracture in women over 45 years of age having previously sustained a fracture at the wrist or humerus, as compared to women with no prior fractures". [8]

    Both alendronate and risedronate have been shown to prevent hip fractures in as little as 18 months of therapy. [9,10] Therefore, proper intervention after an initial fragility fracture may significantly reduce the risk of a subsequent hip fracture.

    In follow-up therapy, BMD measurements can be used to evaluate the effectiveness of the treatment together with clinical information about a fragility fracture. Comparisons of different antiresorptive agents (i.e., estrogen, SERM, bisphosphonates) have clearly shown that a reduction in the fracture rates can be only partially explained by increases in BMD measurements. [11-15]

    Meta-analyses have reported that changes in BMD account for 23 - 54% of the fracture risk reduction.[15] The most potent antiresorptive drugs (bisphosphonates), particularly alendronate and risedronate, show stable and sustained reduction of fracture risk despite further gains in BMD.

    H.G. Bone, et al, recently reported the results of a multinational, randomized, double-blind study in which postmenopausal women with osteoporosis were treated with alendronate. Treatment with 10mg. of alendronate daily over 10 years produced significant increases in bone mineral density, which was gradually lost when discontinued. [16]

    The Fracture Intervention Trial (FIT) reported that treatment with alendronate reduced the incidence of vertebral (one or more), hip and wrist fractures by about 50% over 3 years in postmenopausal women with osteoporosis (NHANES adjusted), with a mean T-score <-1.5 and a least one vertebral fracture. [9]

    Data from a risedronate trial indicated a significant reduction of hip fractures in patients with low BMD by 40%. Sixty percent of those had experienced a prior vertebral fracture.[17]

    For this reason Osteoporosis Society of Canada recommends therapy for those with a T-score <-1.5 and the presence of a fragility fracture after age of 40, and/or other clinical risk factors. A positive response to therapy requires at least stabilization of BMD measurements and adequate prevention of the fragile bone fracture.

    So far, in bone evaluation, we can measure one component of bone strength, i.e., bone density. As well, we can estimate, indirectly, improved bone strength by the reduction of fractures.

    Can we measure bone quality (most probably responsible for discrepancies between increases in BMD e.g., 2, 5, and 7%, and a fracture risk reduction of 30-60%)?

    There are a number of components that determine bone strength, including:

    1. Bone mineral density
    2. Mineralization
    3. Organic constituents of bone
    4. Crystallinity
    5. Microarchitecture
    6. Macroarchirtecture
    7. Cortical porosity
    8. Remodeling
    9. Microdamage

    However, this list is probably far from complete. There is growing interest in developing clinically useful methods to further assess bone quality. Thus far, in "every day" clinical practice, we don't have a generally accepted method, but quantitative ultrasound and biochemical markers are gaining interest and undergoing intensive investigations.

    The utility of measuring biochemical markers of bone remodeling has been tested in a number of clinical trials.[17-20] Bone tissue is constantly remodeling itself through bone resorption and formation, and as a result, certain substances are continuously released. Their levels in the blood and urine reflect the rate of bone turnover. The exact names of those substances are beyond the scope of this review but are available on request.



    Can we use biochemical markers to identify individuals at risk for osteoporotic fracture?

    There is no general consensus, mainly because of the population studied, i.e., most individuals had been diagnosed with osteoporosis already. However, it has been hypothesized that those with the highest rates of bone turnover, are at the highest risk of bone fracture. [21,22]



    Can we use biochemical markers in treatment follow-up?

    The results from trials using antiresorptive therapies are showing rapid and significant decreases in biochemical markers in the first 3 months of therapy, and a sustained reduced level indicates an adequate response to therapy, particularly with alendronate and risedronate. A lack of response and a continuously high level of markers of bone resorption should raise the question of drug efficacy.

    An interesting observation came from a risedronate trial where reduction in the most commonly available markers of bone resorption (telopeptides - CTX and NTX) was associated with the reduction in new vertebral fracture risk at the first and third years of observation.[17]

    In a meta-analysis of 18 trials, approximately 70,000 women were treated with antiresorptive therapy. The authors concluded that a 70% reduction in resorption would reduce vertebral fracture risk by 40%. Further, a 50% reduction in formation would reduce the risk of fracture by 44%. [20]

    There is a question of optimal bone suppression and the theoretical consequences of "oversuppression" of the bone. Thus far, there is no evidence in clinical practice and no clinically relevant data to indicate that available antiresorptive agents may have a negative effect on bone quality, providing they are used in the recommended doses.



    Section 2 of 4

    Conclusion

    * BMD is a very valuable method of risk assessment for osteoporosis.
    * Additional clinical information about preexisting fractures will significantly improve identification of those individuals who can benefit the most from active therapy (even if the BMD is not in the range of osteoporosis).
    * Reduction of fracture incidence together with BMD stabilization provides the best proof of drug effectiveness.
    * Bisphosphonates, particularly alendronate and risedronate have the largest, long-term data (i.e., 10 years for alendronate and 5 years for risedronate) of sustained antifracture effect as well as adequate safety data.
    * New methods of bone quality assessment, like ultrasound and particularly biochemical markers are promising. It seems that biochemical markers have great potential in assessing a patient's response to therapy.

    Source - Registration may be req.

  2. #2
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    Had my yearly Bone Scan done yesterday - results are very encouraging. I take Actonel (by prescription a year and half now) and Calcium/Magnesium with Vit D. for past 2 years.

    I encourage all with SCI to get theirs done.

    Yaw

  3. #3
    Just as a note, please do not copy entire articles to this site (see Dr. Young's copyright information posted on the Announcements forum), esp. from a restricted source such as this as it could get CareCure into a copyright infringement suit.

    In relationship to the topic, keep in mind that osteoporosis in SCI may have an additional mechanism not understood at this time. It is not just due to lack of weight bearing. Studies on the effectiveness of the etidronate drugs (such as Fosamaz or Actonel) in people with SCI have not found them to be effective unless combined with dynamic standing (ie, vibration therapy or FES).

    In addition, people with SCI tend to have the most severe osteoporosis in their distal femur, proximal tibia and hip (in that order) and rarely have it in their wrists or lumbar spine, which is the most common places for ABs with osteoporosis and usually the areas measured by most DEXA machines. If you have a DEXA scan it must be done for your femur and tibia to really tell you what your risks are in those areas.

    Be careful applying any AB research in this area to people with SCI...you cannot assume that treatment or effectiveness will be the same.

    (KLD)

  4. #4
    Senior Member MikeC's Avatar
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    SCI Nurse, I just had my annual physical at the VA. They did not have me scheduled for a bone density test but I requested one because of what I've read on this site. When they were doing the test they did it on my hips and lower back. I asked the technician to do my legs but she said that they "don't do that." I found out yesterday that my results were "not good." I've got an appointment with an SCI doctor in a few weeks and he will go over my results in detail (the nurse said he could only tell me if the results were good). Was wondering if I need to press for more testing (of my legs) when I meet with the doctor. Thanks.

    T12 Incomplete - Walking with Crutches, Injured in Oct 2003

  5. #5
    If it was your hips that were done, this is probably sufficient. Ask your physician at the VA why their machine is not programmed for distal femur and proximal tibia. It is not that the machine cannot do it, but that they have not subscribed to the computer software that allows them to analyze the results for the less common sites. The SCI Center can put pressure on the radiology department to do this, and it should be available in a SCI center VA medical center.

    (KLD)

  6. #6
    BMD- routine-done on atleast on one leg, one wrist, and back.In SCI patients, it should certainly be done on both legs or atleast alternate each time it is done.
    You can share my personal story- nothing terribly exciting, but I do not have a SCI, did have back surgery 10 years ago but I am female & seem to be getting old, but not that old. Let's just say over 29.
    I was having some left shoulder pain off & on (old age-not??)& probably didn't use my left arm as much as my right but I did use it.
    My first "routine" BMD showed osteopenia in my left wrist.
    Calcium & Vit D I am taking twice a day.I like the mint chocolate best. I just saw a sugar free brand at the dollar store I want to try.
    So, be persistent or just take the calcium & Vit D prophylactically. Need to drink lots of water! The pills are huge, so I like the chews.
    1200-1500 of Calcium is recommended per day with Vit D.
    It is definitely one of the underutilized tests!

    Be persistent- you are right!


    CWO

  7. #7
    Senior Member MikeC's Avatar
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    Thanks KLD - always appreciate your quick responses. Mike

    T12 Incomplete - Walking with Crutches, Injured in Oct 2003

  8. #8
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    Thank you nurse - forgot about the copyright thing.


    I did have the scan on my lumbar, wrist, hip and tibia. All have increased in density. My Lumbar for instance went from a T -2.4 to a T -1.9. I think its part of an on going study here concerning BMD and SCI. (Lyndhurst Centre Toronto)

    Also similarly to Mike it was at my insistence and on a whim that I had the scan done. While spending 3 months as an inpatient in Rehab (after a month in Hospital) and being bored (there was a facility in the rehab centre).

    I was expecting good results because I used to be a fitness/nutrition freak (competed in Provincial Weightlifting and Powerlifting - high joint load should lead to higher bone density I guess) I was shocked at my scores which bordered on osteoporosis. I'm glad I got it done.
    Yaw

  9. #9
    ....it became obvious that bone density does not represent bone strength.There are a number of components that determine bone strength, including:

    1. Bone mineral density
    2. Mineralization
    3. Organic constituents of bone
    4. Crystallinity
    5. Microarchitecture
    6. Macroarchirtecture
    7. Cortical porosity
    8. Remodeling
    9. Microdamage
    Hmmm, so is it possible to have a low fracture risk and be osteoporotic if other risk factors aren't present.

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