Antiresorptive Agents -- Effect on Bone Crystal Size and Bone Quality

Ego Seeman, MD, PhD


February 18, 2003


A reduction in bone turnover rate will increase the average age of bone tissue and presumably lead to increased crystal size, which should produce weaker, more brittle bone for a given bone mineral density (BMD). Has larger crystal size been observed, and if so with what effect?

Donald R. White, PhD

Response from Ego Seeman, MD, PhD

This is an important and insightful question. To my knowledge, studies examining crystal size have not been done. At present there are no data to suggest that prolonged use of antiresorptive agents is associated with an increase in fracture risk. This work is ongoing, however, and your question might well be asked again next year.

A most important material property of bone is the degree of mineralization of its tissue. The greater the tissue mineral content or ash density, the greater the stiffness and peak stress the bone will tolerate. More is not always better, however; 100% mineralized bone is brittle and will not "give" during impact loading. Bone "toughness" declines as the tissue mineral content exceeds about 65% (percent volume of bone that is mineral ash). R.D. Blank (University of Wisconsin, Madison) and colleagues[1] reported at ASBMR this past year that collagen cross-link maturity and crystallinity account for differences in bone strength in strains of mice with similar BMD and differing in bone strength. They also showed that cross-link maturity and crystallinity were highly correlated. In other words, the protein and mineral components of the bone matrix are interdependent.

Not all bone remodeling or bone resorption is bad. Bone remodeling is most likely one of the most important ways that the skeleton removes damaged older bone and perhaps bone that is too highly mineralized for the function it is required to perform. This type of remodeling is referred to as targeted remodeling. This is distinct from the untargeted and rapid remodeling that occurs after estrogen withdrawal.

A consequence of aging is that the volumes of bone formed and replaced at each remodeling site or basic multicellular unit (BMU) become unbalanced as the volume of bone formed within each remodeling unit is reduced. Thus, a tiny amount of bone is lost, which over time leads to structural damage, such as cortical thinning, cortical porosity, trabecular thinning, and loss of connectivity. With loss of estrogen, the remodeling rate increases and the imbalance worsens so that the amount of bone lost increases for 2 reasons: the volume of bone removed increases and the volume of bone formed decreases even further. The high remodeling rate removes older, more densely mineralized bone and replaces it with young, less densely mineralized bone. The result is that the stiffness of bone diminishes. That is, it can bend more, which is not a good thing; if bone bends and deforms too much, microdamage occurs, which may increase the risk of complete fracture (the same loads on bone are relatively greater as they are acting on a lower cross-sectional area of bone).

The preamble above is needed to appreciate the good and the bad of the drugs we currently use to prevent and treat osteoporosis. The antiresorptive agents have great utility in that they reduce bone fragility. Drugs such as alendronate, risedronate, raloxifene, and estrogen reduce the rate of remodeling so there are fewer sites in bone "chewing away" at itself. There is some evidence now that these drugs do more than that. They also reduce the life span of the osteoclasts and probably increase the life span of the osteoblasts. Thus, with antiresorptive treatment, the negative bone balance becomes less negative or may be abolished so the volumes of bone formed and resorbed in each BMU become equal. The evidence for this is scant, but there are some data, at least in animals.

With slowing of remodeling there is more time for bone to undergo secondary mineralization. That is, instead of being removed, bone tissue has more time to undergo more complete secondary mineralization with enlargement of crystals and loss of water, which to some degree restores the impact strength of the bone. Now, if the remodeling is suppressed too much (and we don't know how much is "too much") 2 things may occur. First, as the bone becomes more completely mineralized and becomes more homogeneous and stiffer, it loses toughness and thus the ability to resist the progression of microdamage. The homogeneity in bone allows cracks to travel and create 2 new surfaces using less energy than would be required to create such surfaces in bone that is less homogenous in texture. The second problem is the failure to remove microdamage. As stated above, not all remodeling is bad; the resorptive process is partly targeted to microdamage, and if targeted remodeling is suppressed by antiresorptive agents, this may lead to accumulation of new microdamage and failure to remove old microdamage.

There are animal data supporting the above. An increase in microdamage occurs in dogs given high doses of the bisphosphonate alendronate or risedronate, but the relevance of this finding to human subjects is not clear at all. This should not deter clinicians from prescribing these agents, as they do reduce the risk for spine fractures (alendronate, risedronate, raloxifene, estrogen) and nonspine fractures (alendronate, risedronate, estrogen).


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