Bone Mass, Bone Loss, and Osteoporosis Prophylaxis

Throughout most of the 20th century, reduced bone mass was central to the definition of osteoporosis. Indeed, the very etymology of the word osteoporosis connotes a reduction in bone mass. At the 1990 Consensus Conference on Osteoporosis, however, the disorder was redefined as a condition of “skeletal fragility due to decreased bone mass and to microarchitectural deterioration of bone tissue, with a consequent increase in risk of fracture” [1]. Reduced bone mass was thereby relegated to the status of a risk factor for fragility.

This redefinition was a conceptually important shift, inasmuch as it placed the emphasis squarely on fragility fractures and facilitated recognition of other predisposing factors and development of a comprehensive approach that encompassed all factors-extraskeletal as well as skeletal-leading to fragility. Although bone mass is certainly the most extensively studied of the fragility factors, low bone mass is not the whole of the osteoporosis story and may not even be its most important component (despite frequent assertions to the contrary). If one could magically normalize bone mass in everyone, would one eliminate osteoporotic fractures? The best answer that can be given today is “no.” There would be fewer such fractures, but there would still be many, especially hip fractures.

It is both sobering and important to realize that even a young normal hip, when struck just so with approximately the force sustained in a fall from standing height, will fracture [2]. Hui and colleagues [3], while showing the expected increase in fracture risk with declining bone mass, also showed that with bone mass held constant, fracture risk increased with age. More to the point, the effect of age was larger than the effect of bone mass. Age, of course, is simply a surrogate for a host of influences, such as deterioration in balance and coordination, falling more often, falling to the side, and deterioration in bone material quality (for example, accumulated fatigue damage and remodeling errors). The relatively recent recognition of these factors has led to an appropriate increase in attention to how falls occur [4] and to such strategies as the development of protective hip pads [5].

This is not to argue against the manifest importance of bone mass, nor to suggest that it is not valuable to attempt to optimize and maintain bone mass. Even given a multiplicity of fragility factors, it is clear both in theory and in practice that when one falls, dense bones offer more protection than flimsy ones. That truism is, after all, the principal rationale for estrogen prophylaxis at menopause and for maintenance of optimal calcium and vitamin D intakes throughout life. At the same time, however, it is helpful to remember that all of our eggs are not, in fact, carried in the bone mass basket.

The foregoing helps situate the information contained in McClung and colleagues' study [6] in this issue. The authors report that modest doses of the bisphosphonate alendronate reduce or block entirely the bone loss that would otherwise occur in early postmenopausal women. This was a necessary study, and it provides welcome information. Still, its findings are hardly surprising. All bone loss occurs because of an excess of the resorptive component of remodeling over the formative component, and it is to be expected that such an agent as a bisphosphonate, which suppresses remodeling, would thereby reduce bone loss.

Moreover, because the bisphosphonates act on the resorptive side of remodeling (affecting both the differentiation and the work of osteoclasts), they effectively act as antagonists of parathyroid hormone action on bone and evoke a calcium-conserving increase in production of parathyroid hormone. Thus, one would expect not just a slowing of bone loss but, at the right dose, full protection of bone mass and even a modestly positive bone remodeling balance, as has been described for the therapeutic use of bisphosphonates [7]. One of the strengths of McClung and colleagues' study is that it was dose-ranging. Alendronate at 1 mg/d reduced, but did not completely eliminate, estrogen-deficiency bone loss; 5 mg/d effectively blocked bone loss; and 10 and 20 mg/d may have produced slight bone gains. (The manufacturer of alendronate has sought U.S. Food and Drug Administration approval of the 5-mg/d dosage for use as protection against menopausal bone loss.)

An interesting feature of McClung and colleagues' report is the relatively rapid loss of the protective effect of the agent after cessation of treatment, despite the many-year residence time of the drug in bone. This seeming discordance is explained by the fact that influences on osteoclast work derive mainly from factors in the adjacent extracellular fluid, both blood-borne and paracrine. In contrast, the bulk of the bony material is chemically isolated from the rest of the body by virtue of the nearly complete absence of free water in the extracellular material of mature bone. Thus, substances adsorbed to form hydroxyapatite crystals during bone mineralization effectively disappear from the body as further bone deposition buries them. They reappear, as it were, many years later when bone resorption attacks the region concerned and releases its contents into the circulation. Thus, one would expect osteoclast activity to increase and the remodeling space to reexpand when treatment with a remodeling suppressor stops, simply because osteoclast exposure to the agent declines as the body fluids lose their bisphosphonate content. Similar remodeling behavior is seen after estrogen withdrawal. This means that, to maintain the bone protection provided by either agent, therapy has to be continuous and indefinite.

That very need raises important questions about the long-term use of such agents in healthy women, most of whom would not develop osteoporosis if left untreated. We have no truly long-term experience with bisphosphonate exposure, and certainly none in healthy persons. The total skeletal burden of bisphosphonate after many years of therapy could become large. As the bulk of bone remodeling ultimately reaches bone deposited earlier during therapy and releases its content of drug, will the appropriate oral dose decrease? Will such bone even be resorbable? If so, will we reach a state in which there is ongoing life-long drug delivery from internal stores alone? Could we stop that if we wanted to? How could we reduce that body burden if it should prove to be harmful? Answers to these questions are not yet available. At the same time, the 20-year-plus safety record of bisphosphonate use in Paget disease provides reassurance (although use of the drug in this disease tends to be intermittent rather than continuous) and has certainly involved fewer persons that the legions of postmenopausal women who may be candidates for osteoporosis prophylaxis.

What seems incontrovertible is that physicians should take osteoporosis prophylaxis seriously. That means screening perimenopausal women for low bone mass and encouraging vigorous exercise, adequate intakes of calcium and vitamin D, and hormone replacement therapy. This combination is as effective as any present or projected pharmacologic intervention, if less glamorous than some. Although McClung and colleagues' study involved typical postmenopausal women, one would not be inclined to think of a bisphosphonate as the first choice for osteoporosis prevention in women who, for example, are in the upper half of the bone mass distribution or who are willing and able to take estrogen. But for women who are at high risk for fragility fracture and who cannot or will not take estrogen, bisphosphonate protection of their skeletal status seems to offer more benefit than risk. Happily, still other regimens will be available soon. These include 1) the selective estrogen receptor modulators [such as raloxifene], which have the bone protective effect of estrogen but function as estrogen antagonists for the tissues in which the hormone functions as a cancer promoter, and 2) reduced-dosage estrogen in combination with calcium.

The target of all of these regimens is preservation of bone mass-still the mainstay of our approach. One hopes that the other age-related fragility factors will be addressed as effectively in the not-too-distant future. Simply put, our approach to this disorder must be as multifaceted as the condition itself is multifactorial.

• Copyright ©2004 by the American College of Physicians