Bone Mineral Density Testing in Clinical Practice Screen & Intervene Critical Challenges in Osteoporosis and Women’s Health

Outline Background Diagnosis of osteoporosis BMD and fracture risk Indications for BMD testing Interpretation of BMD tests Combining BMD and clinical risk factors Selecting patients for treatment Serial BMD testing Peripheral bone density testing

Osteoporosis is a Silent Disease No symptoms No findings on physical exam No laboratory abnormalities Increase in fracture risk Fractures have serious consequences Treatment can reduce fracture risk Challenge: To identify and treat patients at risk for fracture before the first fracture occurs

Consequences of Fractures Increased risk of future fractures Chronic pain Surgery Loss of height Impaired pulmonary function Abdominal symptoms Medical expenses / lost income Hospitalization Surgery Rehab hospital Nursing home Loss of self-esteem Depression Loss of independence Disability Death

Relative Risk of Death Following Clinical Fractures Fracture Intervention Trial (FIT): 6459 postmenopausal women aged 55-81 years followed for an average of 3.8 years Any Symptomatic Nonspine Other Forearm Spine Hip 0.3 1.0 2.0 5.0 16.0 10.0 6.7 8.6 Osteoporotic fracture is also associated with significant mortality in postmenopausal women. These data summarize results from 6459 postmenopausal women followed for an average of 3.8 years in the Fracture Intervention Trial (FIT). There was an approximate 2-fold increase in risk of death following any clinical fracture, primarily due to a 6-fold increase in mortality following hip fracture and an 8-fold increase in mortality following vertebral fracture. In contrast, there was no increase in risk of mortality associated with forearm fracture or fractures at sites other than the spine, wrist, or hip. These data suggest that clinical fractures, particularly vertebral fractures, are associated with an increased risk of mortality in postmenopausal women. Interestingly, the mortality following vertebral fracture is comparable to or greater than that associated with hip fractures. “The observed excess mortality among women who experience a clinical vertebral fracture widens the public health impact of these fractures.” 1   1. Cauley JA et al., Osteoporos Int 2000;11:556-61 Age-Adjusted Relative Risk (95% CI) Cauley JA et al. Osteoporos Int. 2000;11:556-561.

Diagnosis of Osteoporosis Densitometric Diagnosis Dual-energy X-ray absorptiometry (DXA) World Health Organization (WHO) criteria Clinical Diagnosis Fragility fracture

What DXA measures: bone mineral content (BMC) in grams & area in cm2 “Areal” BMD is calculated in g/cm2 (aBMD = BMC/Area) “T-score” is calculated using the patient’s BMD and a reference database

Calculation of T-score Patient’s BMD – Young-Adult Mean BMD SD of Young-Adult BMD in g/cm2 Example: T-score = 0.7 g/cm2 - 1.0 g/cm2 0.1 g/cm2 = - 3.0

WHO Classification of BMD T-score Normal -1.0 or greater Low Bone Mass (Osteopenia) Between -1.0 and -2.5 Osteoporosis -2.5 and below Severe Osteoporosis -2.5 and below with history of fragility fracture WHO Study Group 1994.

Why is a T-score of -2.5 or less used to diagnose osteoporosis? “Such a cutoff value identifies approximately 30% of postmenopausal women as having osteoporosis using measurements made at the spine, hip or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites.” Kanis JA et al. J Bone Miner Res. 1994;9:1137.

L1-L4 T-score = -2.6

Left Femoral Neck T-score = -2.6

Use Clinical Judgment T-score greater than -2.5 does not eliminate the possibility of osteoporosis Clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture T-score -2.5 or less does not always mean that osteoporosis is present Primary disease may be something else (e.g., osteomalacia, multiple myeloma)

DXA is the “Gold Standard” Widely used in epidemiological studies from which prevalence data is derived WHO criteria based on BMD measured by DXA Correlation with fracture risk Low radiation Excellent precision

Clinical Uses of DXA Diagnose osteoporosis Predict fracture risk Monitor changes in BMD

Indications for BMD Testing Official Position Indications for BMD Testing Screening Women aged 65 and older. Men aged 70 and older. Risk Factors Postmenopausal women under age 65 with risk factors. Adults with a fragility fracture. Adults with a disease or condition associated with low bone mass or bone loss. Adults taking medications associated with low bone mass or bone loss. Treatment Anyone being considered for pharmacologic therapy. Anyone being treated, to monitor treatment effect. Anyone not receiving therapy in whom evidence of bone loss would lead to treatment. Women discontinuing estrogen should be considered for bone density testing according to the indications listed above.

Bone Mass Measurement Act, 7/1/98 Five Categories of Medicare Covered Services Estrogen-deficient women at clinical risk for osteoporosis Individuals with vertebral abnormalities Individuals receiving long-term glucocorticoid therapy Individuals with primary hyperparathyroidism Individuals being monitored to assess the response to or efficacy of an FDA-approved osteoporosis drug therapy Vertebral abnormalities = x-ray evidence of VF, osteopenia, or osteoporosis Federal Register, Volume 63, Number 121, June 24, 1998.

Diagnosis in Postmenopausal Women and in Men Age 50 and Older Official Position Diagnosis in Postmenopausal Women and in Men Age 50 and Older Osteoporosis may be diagnosed in postmenopausal women and in men age 50 and older if the T-score of the lumbar spine, total hip or femoral neck is -2.5 or less:* In certain circumstances the 33% radius (also called 1/3 radius) may be utilized. *Note: Other hip regions of interest, including Ward’s area and the greater trochanter, should not be used for diagnosis. Application of recommendation may vary according to local requirements.

Diagnosis in Premenopausal Women and Men Younger than Age 50 Official Position Diagnosis in Premenopausal Women and Men Younger than Age 50 Z-scores, not T-scores are preferred. This is particularly important in children. A Z-score of -2.0 or lower is defined as “below the expected range for age” and a Z-score above -2.0 is “within the expected range for age.”

Bone Density and Fracture Risk Relative Risk for Fracture Exponential Relationship Bone Density (T-score) Adapted from Faulkner KG. J Bone Miner Res. 2000;15:183-187.

Age is an Independent Risk Factor for Fracture Ten Year Fracture Probability (%) Age 80 70 60 50 Probability of first fracture of hip, distal forearm, proximal humerus, and symptomatic vertebral fracture in women of Malmö, Sweden. Adapted from Kanis JA et al. Osteoporosis Int. 2001;12:989-995.

Predicting Hip Fractures: Relative Risk vs. Fracture Probability Age* Hip T-score Relative Risk (a) (2.6)2.5 10-Year Probability (b) 50 -2.5 17.6 1.9% 80 19.4% Relative Risk = (RR per SD)T-score or Z-score Difference 10-Year Probability from Swedish National Bureau of Statistics *Postmenopausal Woman (a) Marshall D et al. BMJ. 1996;32:1254-1259. (b) Kanis JA et al. Osteoporos Int. 2001;12:417-427.

Prior Fracture Increases Relative Risk of Subsequent Fractures Site of Subsequent Fracture Site of Prior Fracture Wrist Vertebra Hip 3.3 1.7 1.9 1.4 4.4 2.3 NA 2.5 Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721-739.

BMD and Clinical Risk Factors Predict Hip Fractures Age ≥ 80 Family Hx Hip Fx Any Fx Except Hip Since Age 50 Fair, Poor or Very Poor Health Hx Hyperthyroidism Anticonvulsant Therapy Current Benzodiazepine Rx Current Weight < Age 25 Weight Caffeine > 2 Cups Coffee per Day On Feet ≤ 4 hours per Day No Walking for Exercise Can’t Rise From Chair Without Using Arms Lowest Quartile Depth Perception Lowest Quartile Contrast Sensitivity Heart Rate > 80 (per 1000 woman-years) Rate of Hip Fracture No. of Risk Factors Calcaneal Bone Density SOF in 9516 white women over age 65 with no previous hip fracture Cummings SR et al. N Engl J Med. 1995;332:767-773.

NOF Treatment Guidelines Initiate therapy to reduce fracture risk in women with T-Score less than -2.0, regardless of risk factors† T-score between -1.5 and -2.0, if at least one risk factor is present Previous vertebral or hip fracture †Major risk factors = fracture as an adult, first degree relative with fragility fracture, weight less than 127 lbs., current smoking, glucocorticoid therapy more than 3 mo. Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation. 2003.

Most Fractures Occur in Patients with T-score Greater Than -2.5 Study of Osteoporotic Fractures (SOF) 8,065 postmenopausal women age 65 or older 54% of women with hip fracture had baseline T-scores greater than -2.5 (total hip) National Osteoporosis Risk Assessment (NORA) 149,524 postmenopausal women with mean age of 65 82% of 2,259 women with fragility fractures had baseline T-scores greater than -2.5 (peripheral) Wainwright SA et al. J Clin Endocrinol Metab. 2005;90:2787-2793. Siris ES et al. Arch Intern Med. 2004;164:1108-1112.

WHO Project Goal: To develop a standardized methodology for expressing fracture risk and intervention thresholds for men and women worldwide Method: Study correlations of BMD and clinical risk factors with fracture outcomes in large prospective observational studies, and apply cost utility analysis to set intervention thresholds

Fracture Risk Reporting Since the goal of osteoporosis therapy is fracture prevention, patient selection is best based on fracture risk T-score alone does not provide a complete assessment of fracture risk Combination of clinical risk factors with BMD may provide a better way of identifying patients for treatment

Selection of Clinical Risk Factors Independent of BMD (if BMD is known) Validated in multiple populations (sex, ethnicity, country) Easily obtainable Amenable to intended treatment Intuitive Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

Clinical Risk Factors Femoral neck T-score + Age Previous low trauma fracture Current cigarette smoking Rheumatoid arthritis High alcohol intake (> 2 units/day) Parental history of hip fracture Prior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

Intervention Threshold A fracture probability above which it is cost-effective to treat with pharmacological agents Based on statistical modeling using many medical, social, and economic assumptions

Decision to Treat Fracture probability Cost-effectiveness Efficacy Safety Expected adherence to therapy Non-skeletal risks and benefits Patient beliefs and preferences

Why do serial BMD testing? To monitor response to therapy by finding an increase or stability of bone density, and To evaluate for non-response by finding loss of bone density- suggesting the need for re-evaluation of treatment and evaluation for secondary causes of osteoporosis J Clin Densitom. 2002;5(Suppl):S1-S45.

When should repeat BMD testing be done? When expected change in BMD equals or exceeds the “Least Significant Change” (LSC) Intervals between BMD testing should be determined according to each patient’s clinical status Consider 1 year after initiation or change of therapy Longer intervals once therapeutic effect is established Shorter intervals when rapid bone loss is expected typically 1year after initiation or change of therapy is appropriate, with longer intervals once therapeutic effect is established. In conditions associated with rapid bone loss, such as glucocorticoid therapy, more often is appropriate. J Clin Densitom. 2002;5(Suppl):S1-S45.

Never Compare T-scores Always Compare BMD Never Compare T-scores

BMD Values from Different Manufacturers are Not Comparable Different dual energy methods Different calibration Different detectors Different edge detection software Different regions of interest

Vertebral Fracture Assessment (VFA) Recognition of vertebral fracture may Change diagnostic classification Change estimate of fracture risk Change treatment decisions Normal Vertebral Fx

Peripheral Measuring Devices

Peripheral Bone Density Measurement Good prediction of fracture risk Good tool for skeletal health education Cannot be used with the WHO criteria for diagnosis of osteoporosis Not useful for monitoring bone density changes J Clin Densitom. 2002;5(Suppl):S1-S45.

Summary BMD testing can diagnose osteoporosis, predict fracture risk, and monitor changes in BMD over time Combination of BMD and clinical risk factors is as better predictor of fracture risk than BMD or clinical risk factors alone Patients at high risk for fracture are most likely to benefit from therapy