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Monitoring Osteoporosis Therapy

Dr Omar Hussein Professor of Radiology Ain Shams University

Clinical Questions
Why monitor osteoporosis therapy? Will the results of the repeat DXA scan change your management? If a repeat DXA scan is ordered, how do you know if the change is real?

Rationale
Many factors that are not clinically apparent could lead to a suboptimal response to therapy : Long-term compliance and persistence with therapy is poor; only about 50 percent of patients who begin an osteoporosis drug continue therapy for at least one year. Some patients do not maintain a sufficient intake of calcium or vitamin D to achieve the full benefit of therapy.

Rationale
Malabsorption caused by a variety of GIT disorders, including asymptomatic celiac disease, may impair treatment effect. Other conditions with adverse skeletal effects, such as multiple myeloma or increased thyroid hormone levels, may be present but undetected before therapy, or may develop during therapy.

Rationale

Various circumstances may affect decisions about continuing or modifying treatments


Prognosis Responsiveness to treatment Possibility for changing to a lower-risk intervention Resident satisfaction with the benefits ofor concern about complications related to treatment
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BMD measurement:
1. Dual-Energy X-Ray Absorptiometry: Results expressed as T-SCORE is the number of SD the measurement is above or below the YOUNG-NORMAL MEAN BMD.
Z-SCORE is the number of SD the measurement is above or below the AGEMATCHED MEAN BMD. Sites used for measurement per WHO criteria: Total proximal femur Femoral neck Lumbar spine 33percent(1/3rd) radius Peripheral skeletal sites predict global # risk, however not used in WHO/FRAX criteria therefore limited value. Changes to therapy at these sites are slow.

Raisz L. N Engl J Med 2005;353:164-171

SQ Mild

SQ Severe
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Lateral Vertebral Assessment (using DXA):

Qualitative and quantitative

Semi-quantitative grading (Genant et al 1993)


0
Normal

Grade

1 (~20-25%)
Anterior

Middle Mild fracture

Posterior

2 (~25-40%)
Anterior Middle Moderate fracture Posterior

3 (~40%)
Anterior Middle Severe fracture Posterior

(Source: Genant HK et al, JBMR 1993; 8:1137-1148)

Using BMD to Monitor Therapy in Treating Osteoporosis:

Pro

Con

Pro Pro Pro

Many clinical practice guidelines, including those of the NOF1 the International Society for Clinical Densitometry, the Institute for Clinical Systems Improvement, American Association of Clinical Endocrinologists, North American Menopause Society , recommend the use of DXA to monitor osteoporosis therapy. The suggested interval between baseline and follow-up BMD testing is typically 1 to 2 years, with subsequent intervals determined according to clinical circumstances.

DXA is the only technology recognized by Medicare for monitoring patients treated for osteoporosis.

BMD is a surrogate marker for bone strength and fracture risk. Stability or a significant increase in BMD is an acceptable response to therapy and is associated with a reduction in fracture risk.
Lewiecki EM, Watts NB. Assessing response to osteoporosis therapy. Osteoporos Int. 2008;19(10):13631368.

Pro

A significant decrease in BMD suggests a suboptimal response to therapy and may require evaluation for factors contributing to bone loss and possibly changing treatment

Pro

Quantitative morphometric assessment of vertebral fracture follow up by lateral vertebral morphometry

Con Con

A valid quantitative comparison of BMD measurements requires that measurements be made on the same DXA machine (or different machines that have been cross-calibrated) according to well-established quality standards that include precision assessment and calculation of the least significant change, the smallest change in BMD that is statistically significant.2

If the least significant change has not been calculated, it is not possible to distinguish an apparent BMD change that is within the range of measurement error from one that is likely to be a genuine biologic change.

Con

An increase in BMD is associated with reduced fracture risk. However, the relationship between BMD and fracture risk is not a linear one. Fracture risk decreases soon after beginning therapy, even preceding a measurable improvement in BMD.

Con

Fracture risk can decrease with no change in BMD. Studies have even shown a decreased fracture risk despite a slight decrease in BMD.

What Is Precision Error?

PE reflects the reproducibility of a measurement when performed under identical circumstances in the setting of no real biologic change.

Factors that affect precision for DXA Scans


Equipment Number of Measurements Operator Dependent Variables

How To Calculate Precision?

Scan
15 individuals 3 times
30 individuals 2 times

Use patients representative of your typical patient population Reposition between each scan From these measurements radiologist is able to calculate precision for specific center
Bonnick SL, et al. J Clin Densit 2001; 4:105

Precision is Important because it allows Least Significant Change (LSC) to be calculated

What is Least Significant Change (LSC)?


Precision error at your center Desired confidence level (95%)

LSC = 2.8 x precision error

Only changes exceeding 2.8 times the precision error can be considered clinically significant within the 95% confidence interval.

Spine BMD with antiresorptive agents Dotted line indicates LSC at 1 and 2 years

Deal, Current Rheumatology Reports, 2002 - adapted from McClung

Hip BMD with antiresorptive agentsDotted line indicates LSC at 3 years

Deal, Current Rheumatology Reports, 2002 - adapted from McClung

Confounding Variables that affect DXA Scanning


Aortic calcifications Osteophytes Compression fractures Skeletal diseases ie. Pagets disease

Current recommendations for monitoring osteoporosis therapy

Organization

Recommendations

American Association of Clinical Endocrinologists

Repeat yearly until stable, then every two years

Institute for Clinical Systems Improvement

Acknowledges controversy; but if performed, repeat after one to two years of therapy

Organization

Recommendations

International Society for Clinical Densitometry

Repeat based on each patient's clinical status, usually one year after starting therapy with longer intervals once therapeutic effect established
Serial testing in accordance with medical necessity and expected response, and in consideration of local regulatory requirements; usually one to two years after starting therapy

National Osteoporosis Foundation

Organization

Recommendations

Scientific Advisory Council of the Osteoporosis Society of Canada

No specific recommendation

North American Menopause Society

Repeat every 2 years

Bone Markers

Bone forming markers

Bone resorption markers


Urinary hydroxyproline Urinary total pyridinoline (PYD) Urinary free deoxypyridinoline (DPD) Urinary collagen type 1 crosslinked N-telopeptide (NTX) Urinary or serum collagen type 1 cross-linked C-telopeptide (CTX) Bone sialoprotein (BSP) Tartrate-resistant acid phosphatase 5b

Serum total alkaline phosphatase Serum bonespecific alkaline phosphatase Serum osteocalcin Serum type 1 procollagen (Cterminal/N-terminal): C1NP or P1NP

Bone markers
Diagnosis of osteoporosis is not based on evaluation of bone markers, and bone mineral density (BMD) assessment is still the criterion standard for evaluation and diagnosis.

A study done by Kumar et al, 2008 showed that osteocalcin showed a significant correlation with BMD and other bone markers did not correlate with the underlying BMD. Even though changes in bone metabolism cannot be identified by the determination of a single bone marker, improved biochemical measurement may provide early information about osteoporosis. Because of the variability of bone turnover markers, BMD determination still remains the best modality currently available for evaluation of osteoporosis

Bone Markers and Bone Density, Endocr Pract 2008;14(No. 9)

Several studies confirmed that short-term reductions in bone turnover were associated with a reduction in vertebral and/or non-vertebral fracture risk in women.

Clin Biochem Rev. 2006 August; 27(3): 123138.Biochemical Markers of Bone Turnover Part II: Clinical Applications in the Management of Osteoporosis

There are data suggesting that biochemical markers of bone turnover are useful tools to evaluate therapeutic effects after a relatively short period of time, and that serial measurements of bone markers may help to decide whether or not a patient responds to a specific antiresorptive treatment. As bone turnover markers, in particular indices of bone resorption, decrease rapidly after initiation of treatment within three to six months, they might represent useful surrogate markers for monitoring patient compliance. Only few data, however, are available to support this theoretical approach.
Clin Biochem Rev. 2006 August; 27(3): 123138.Biochemical Markers of Bone Turnover Part II: Clinical Applications in the Management of Osteoporosis

To conclude
Precision and LSC must be considered to obtain reliable results from repeat DXA scans. Changes in BMD are more precisely measured at sites of trabecular bone, ie. the spine Increase in BMD is only part of the fracture risk reduction story.

To Conclude
A statistically significant BMD loss may lead to further evaluation and possibly a change in treatment. The strategy of monitoring therapy with BMD testing is supported by the medical evidence, consistent with clinical practice guidelines, and makes good clinical sense.