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Too much sanity may be madness. And maddest of all, to see life as it is and not as it should be.

Miguel Cervantes, Don Quixote

A GENTLEMAN CAME OUT of a nightclub and encountered a drunk on his hands and knees. When asked what he was doing, the drunk replied, “I'm looking for my car keys.” The gentleman looked for a while, but soon was certain that the car keys were not there. When the drunk was asked why he was looking in that spot, he pointed to the street lamp overhead and said, “Because I can see over here. I think I dropped the keys on the other side of the street, but it's dark over there.”

Until about 10 years ago, osteoporosis was defined as a reduced amount of bone that was qualitatively normal (as opposed to osteomalacia, in which the bone was qualitatively abnormal). We now have accurate and precise ways to measure bone mass at a variety of skeletal sites. Bone mass measurement has become the “gold standard” for the prefracture diagnosis of osteoporosis. In untreated patients, there is an almost linear correlation between bone density and bone strength (based on biomechanical testing).(1–3) In older women, reduced bone mineral density (BMD) is associated with a high risk of fragility fracture.(4)

We know that the drugs used to treat osteoporosis increase bone mass and reduce fracture risk. It seemed logical to assume that the mechanism by which they reduce the risk for fracture is through increases in bone density. However, we now know that bone density does not tell the whole story. In untreated subjects with the same BMD, fracture risk varies with age(5) and perhaps with gender(6,7) and race.(8,9) Patients treated with agents that produce different effects on BMD at different skeletal sites have similar reductions in fracture at those sites; alendronate has little effect on BMD in the forearm, a somewhat greater effect in the hip, and the largest effect in the spine (Fracture Intervention Trial [FIT]-1) and yet reduces the risk of fractures by ∼50% at all three sites.(10)

Agents that have different effects on BMD in the spine (e.g., calcitonin,(11) raloxifene,(12) and bisphosphonates(10,13)) or different doses of the same agent that produce different effects on BMD (e.g., parathyroid hormone [PTH])(14) reduce the risk of vertebral fractures to a similar degree. The reduction in the risk of fracture is seen soon after treatment is begun, well before change in BMD has reached its maximum.(15–17) Patients receiving the same drug but have different effects on BMD may have similar reductions in fractures.(18–20)

A 1991 consensus conference produced a new definition of osteoporosis: “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility with susceptibility to fracture.”(21) To paraphrase this definition, osteoporosis is a disorder of bone quantity and bone quality. Although it has been >10 years since this “new” definition of osteoporosis, the definition of bone quality remains elusive.

Patients who have already had one or more fractures have a much higher risk of future fracture than patients with similar BMD but who have not had a fracture, even after adjusting for other risk factors.(22,23) The presence of a fracture might be considered a “field test” for poor quality. Is it possible to assess bone quality before the first fracture occurs?

It is intuitively obvious that microarchitecture is important for bone strength. The study by Borah et al.(24) in this issue of the Journal builds on work of others and adds some new methodology to help in our understanding. They evaluated vertebral core biopsy specimens from minipigs by microcomputed tomography and performed biomechanical testing of the same samples. Trabecular bone from the risedronate-treated animals was stronger than in the ovariectomized animals. Untreated minipigs showed significant deterioration of trabecular bone microarchitecture, and those treated with high-dose risedronate had more trabeculae that were thicker, better connected, and more platelike. Several of these parameters have no direct relationship to bone mass, emphasizing the role of microarchitecture in bone quality and a major factor in bone strength.

Bone microarchitecture in the risedronate-treated animals was more uniform, which means stronger bone. Most dramatically, the risedronate-treated animals showed preservation of cross-connecting trabeculae compared with loss of cross-struts in the ovariectomized animals. Cross-struts resist radial stress and prevent buckling of longitudinal trabeculae. These findings help explain how treatment with risedronate results in a greater reduction in fracture risk than would be expected based on the increase in bone mass alone.(25) These were growing animals treated with very high doses of risedronate. It is not clear if these findings pertain to effects observed in humans.

Clinical methods for assessing bone microarchitecture do not yet exist, and even a combination of bone mass and architecture as assessed by Borah et al. does not fully explain bone strength. Other possible factors that may be part of bone quality include reduced bone turnover(26) (reduction in the number and depth of resorption sites, which serve as stress risers), improved secondary mineralization, changes in cortical porosity, increases in bone size, and the health of osteocytes and other aspects of the bone microenvironment. It is likely that these factors have varying degrees of importance in different people and even in the same person at different times.

As recently as 4 years ago, the thought that something other than changes in bone density might account for antifracture effects of medications to treat osteoporosis was met with anger and incredulity. A respected colleague said (I hope in jest), “Bone quality is anything that can't be measured.” A continued search for important aspects of bone quality and clinically applicable methods for assessment is inevitable.(27) Now that the search has moved away from the street lamp, answers are beginning to appear.


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    Hochberg MC, Ross PD, Black D, Cummings SR, Genant HK, Nevitt MC, Barrett-Connor E, Muslin T, Thompson D, for the Fracture Intervention Trial Research Group. 1999 Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum 42:12461254.
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