Bone densitometry was originally developed to diagnose a high risk for fragility fractures in older postmenopausal women who may have primary osteoporosis. Its widespread availability, however, has led to its use in healthy peri- and premenopausal patients and the unexpected findings of low bone density in this group of patients. Their low bone density caused much uncertainty about the likelihood of fracture risk and what treatment might be needed. Conceptually, bone density reflected bone strength, and so a low density reflected increased fracture risk. Clinical experience and the results of pivotal studies of therapy for osteoporosis suggested that bone density was only partly responsible for skeletal strength. Many structural and material properties of bone, not measured by bone density, made it resist fracturing. Clinical risk factors helped determine these characteristics, albeit imperfectly, and aided clinicians decide whether and what treatment was needed. But now, new fracture risk assessment protocols (namely, FRAX, the WHO risk assessment tool) are available to help resolve this dilemma. This paper reviews some of the clinical observations that led to rethinking the concept bone density and bone strength and how it changes the clinical approach to therapy for the healthy young patient.
For over 2 decades, bone densitometry (DXA) has been used to diagnose osteoporosis and monitor treatment efficacy. Although originally developed for assessing the risk of fragility fractures in postmenopausal woman over the age of 65, it is now used across all genders and age-groups to assess bone mass and fracture risk. Practitioners now find young healthy patients with abnormal DXA results and are faced with the question of what to do. The following clinical vignette typifies the challenge facing practitioners.
A 50-year-old perimenopausal woman (weight 110 lbs, height 64 in) is concerned about osteoporosis after her elderly mother developed a hip fracture. The patient is healthy, exercises daily, and takes mineral and vitamin supplements. She has had normal menstrual cycles and has 2 children. Her right hip bone density was 0.75 g/cm 2 and the T score −2.1. She questions whether she needs drug treatment like her mother received.
This case raises a number of timely issues–what information does DXA provide about the pathology and diagnosis of osteoporosis, what factors make bone strong apart from the bone density, and whether pharmacologic intervention is appropriate whenever T-scores are abnormal.
The challenge of diagnosing disease with T-scores
Patients with a low bone density, or osteopenia, constitute a large number of referrals for the diagnostic and therapeutic problem they pose. As a group they are the source of the largest number of fractures in the population, even greater than those classified as osteoporotic by densitometry. Their seemingly benign bone density contradicts the present orthodoxy about fracture risk and serves to show the complex nature of using bone density to predict fractures. DXA is useful predictor of fracture at the population level but can be poor at the individual patient level.
Because of the widespread availability of DXA technology, practitioners have used T-scores to diagnose a high risk for fragility fractures in all patients, regardless of age. But, the original application of the T-score was to identify a high risk for fragility fracture in the older postmenopausal, white women. A T-score of −2.5 or less confirmed this risk. Furthermore, it was a surrogate marker for diagnosing primary osteoporosis because the prevalence of the disease was highest in this age group. Consequently, this number became the diagnostic criterion for the disease and the intervention threshold for pharmaceutic treatment. Experience showed that this T-score cutoff alone was insufficient for diagnosing fracture risk and deciding on treatment intervention, when applied to patients outside the cohort for which it was developed, especially noted when applied to premenopausal patients. What was not appreciated was that the relationship of fracture risk and T-score was continuous. There was no discrete cutoff separating disease from no disease as this specific score implied. Individual patients could fracture at any score but, from population statistics, had the highest risk at very low values. Studies ultimately showed that the greatest number of fractures occurred in patients with moderate decreases in T-score values, commonly called osteopenia.
As the technology became more widely used in various age groups, more abnormal results were found in young patients. Questions arose about what these observations actually meant. Originally, clinicians believed that bone strength or the resistance to fracture was only related to bone density. A high bone density predicted strong healthy bones which resisted fracturing, and a low bone density implied the reverse. Many clinical observations contradicted this notion ( Table 1 ) and forced reassessment of this widely held belief.
| • Similar BMD in young and old does not carry the same fracture risk (ie, age and bone quality). |
| • Vertebral fracture reduction with various antiresorption therapies is very similar across all drug classes but the increases in bone density are different. |
| • Significant reduction of vertebral fractures occurs within the first year of antiresorption therapy in pivotal studies but bone density does not change significantly. |
| • Bone density and fracture risk are discordant with glucocorticoid use. |
| • Increased BMD does not always coincide with increased strength (ie, sodium fluoride, osteopetrosis, diabetes mellitus). |
The first clinical observation reported over 2 decades ago was that age was an independent risk factor for fragility fractures. This early study showed that both young and old individuals had a distribution of bone density values ranging from low to high. However, at every point along the curve of fracture risk and bone mineral density (BMD), the young person has a negligible risk for fractures compared with the older patient. Qualitative differences in “young bone” made it resist fracturing even when it had similar BMD values as “old bone.” In other words, a low density in an older person carried with it substantial risk for fracture that was not present in a younger person with equivalent bone density. Bone density may indicate how much bone was present, but it did not tell how strong or well constructed it was.
Randomized pharmaceutic trials evaluating therapies for osteoporosis noted several unexpected findings. Antiresorptive drugs reduced spinal fractures to a greater degree than predicted from the change in bone density. Bone density increase of 1-6% with several different drugs decreased fracture risk 35-50%, significantly greater results from the expected 4% fracture reduction with a 1% increase in density. For raloxifene and risedronate, spinal fracture risk decreased as early as 6 months into treatment, at a time when there was minimal change in bone density. The improvement in spinal density with alendronate or risedronate explained only 16-18% of the reduction in fracture risk. A similar finding occurred with estrogen treatment. More sophisticated imaging techniques showed estrogen altered hip structural geometry and made it stronger despite minimal changes in bone density.
Clinical observations from the use of glucocorticoids also brought into question the relationship between bone density, fractures, and bone strength. Fractures developed at higher values of density than expected. Men and women treated with these drugs fractured at a higher spinal bone density than matched controls or had a greater number fractures than attributable to the bone density. A T-score of −1.5 identified the largest number (60%) of immunosuppressed heart transplant patients with fractures compared with the usual score −2.5, which captured only 13%. Such discordance of bone density and fracture is also seen in a recent report in the pediatric literature wherein intermittent steroid use for nephritic syndrome led to vertebral fractures in a patient with normal Z-scores. Newer forms of bone imaging show these steroidal drugs can affect bone strength separately from changes in density by decreasing trabecular connectivity and increasing trabecular perforation.
Other clinical observations also cast doubt about bone density being the only factor in bone strength. Osteopetrosis is a disease characterized by high bone density and yet fracture risk is increased. Sodium fluoride was used to treat primary osteoporosis several decades ago because it alone could markedly increase bone density. Unfortunately, it also increased fracture rate. Experimental studies later showed that fluoride altered bone mineral quality and made it weaker. Type 2 diabetes mellitus also increases fracture risk at the spine and the hip, but bone density is inadequate to assess this risk. Increased porosity of trabecular bone as well as glycosylated end products of collagen may contribute to the higher risk.
All these data led to the realization that bone strength was related to other variables besides bone density and that disease could alter the architecture and structural material of bone. These nondensity factors were operationally defined as bone quality, a collection of skeletal characteristics, apart from the measured density, which made bone resist fracturing. These qualitative properties arose from the microscopic structure of bone such as the integrity of the trabecular network, accumulation of microdamage, the quality of bone mineral itself, alterations in collagen, turnover of remodeling sites (activity of osteoclasts/osteoblasts), and the actual loads imposed on the bone from the activities of daily living. Routine DXA testing did not discern these properties. At best these “qualities” could be approximated from evaluation of clinical risk factors, which practitioners could subjectively apprise. The result was the present definition of bone strength ( Table 2 ), a composite of skeletal density and other properties, which together made bone resist fractures from the activities of daily living. Herein lies glimmerings of the answer to the diagnostic dilemma of the young patient with a low bone density. Is the bone weak? Does it need drug therapy in addition to the traditional nonpharmacologic treatments?
| • The accuracy of patient–provided data affects the calculation very markedly. |
| • Only untreated patients should be analyzed since the original data bases estimate risk in drug-treatment−naive populations. |
| • The hip density is the input variable and may not predict fractures at other sites accurately. |
| • Secondary diseases are not weighted in the risk analysis for individual diagnoses, severity, mutiple combinations, duration. |
| • Some clinical variables were not considered or poorly quantitated such as physical activity; calcium and vitamin D status; quantitation/duration of tobacco, alcohol, steroid use; multiplicity and timing of fractures; balance-gait disturbances, falls, high/low bone turnover. |
| • Racial and ethnic differences are not adequately assessed. |
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