Concluding Remarks for Session I and Questions for the Future Dennis Black, PhD, San Francisco, California

ENDPOINTS IN STUDIES OF OSTEOPOROSIS: BMD, FRACTURE, OR QUALITY OF LIFE?

For a number of years, change in bone mineral density (BMD) has been used as the endpoint in os- teoporosis studies. There are a number of advan- tages to this endpoint: (1) Importantly, studies of BMD can be done with a fairly small sample size and at comparat ively low cost. For example, a 2-year clinical trial of hormone rep lacement therapy might require only about 100 patients in each t rea tment group; (2) BMD can be precisely measured; (3) Use of BMD as an endpoint seems sensible because we know that women with higher BMD are at lower risk for fracture.

It has become evident, however, that there are sig- nificant disadvantages to the use of BMD. A munber of studies have suggested that a given increase in BMD associated with a particular t rea tment may not be easily translated into reduced fracture risk.~ For example, resultant increases in BMD underes t imate the antifracture efficacy of estrogen, bisphosphona- tes, and other antiresorptive therapies: Increases in BMD account for only about 40-70% of the observed reduction in risk of ver tebral fracture seen in estro- gen- and bisphosphonate- t rea ted patients. Con- versely, a large s tudy of fluoride demonst ra ted very large increases in BMD; however, there was no cor- responding decrease in fracture risk. '~ In fact, frac- ture may even have increased in those taking fluo- ride. Thus, the FDA and other regulatory agencies have begun to require more clinically meaningful endpoints than BMD (for example, fracture) for reg- istration of new products.

Occurrence of fracture is considered to be the best endpoint for os teoporosis studies; however, quality of life is what we hope to affect by treating osteo- porosis. Quality-of-life studies are required by some governments for registration of a t reatment. Back pain is another important consequence of osteopo- rosis. However, it may not be feasible as an endpoint

From the Departments of Epidemiology and Biostatistics, University of California, San Francisco, California.

Requests for reprints should be addressed to Dennis Black, PhD, De- partments of Epidemiology and Biostatistics, University of California, San Francisco, 74 New Montgomery Street, Suite 600, San Francisco, Cali- fornia 94105.

in os teoporosis studies because back pain is a dis- ease with multiple causes. A t rea tment that elimi- nates ver tebral f ractures may not measurably affect back pain. As important as quality of life and back pain appear to be, these endpoints may not be read- ily measurable, and they may be costly to assess.

IDENTIFICATION OF PATIENTS AT HIGH RISK FOR FRACTURE

BMD is currently our best predic tor of fracture. Although BMD at any site is predictive, of part icular value is BMD at the hip, which is a very strong pre- dictor of hip f rac tureJ What other tools can we use to predict f racture risk? Recent studies of ul trasound of bone have shown it to be predictive of fracture; however, it is a weaker predic tor of hip fracture than is hip BMD. Nonetheless, in situations in which dual- energy x-ray absorpt iometry is not available, ultra- sound may be useful.

Epidemiologic risk factors may be useful as screening tools. To be useful on a populat ion basis, risk factors mus t be strongly associated with frac- ture and must occur frequently. At present, risk fac- tors for hip fracture are bet ter unders tood than those for other types of fracture. For example, history of pos tmenopausa l fracture, maternal history of hip fracture, smoking, and neuromuscular impairment have all recently been shown to be independent pre- dictors of hip fracture. 4

One risk factor that has not been much discussed is the presence of a morphomet r ic ver tebral fracture. Women with ver tebral f ractures are 4 - 5 t imes more likely to suffer new vertebral fracture and twice as likely to exper ience hip fracture as w o m e n without ver tebral f rac tu res ) Moreover, we know that w o m e n with multiple vertebral fractures exper ience greater overall pain and disability than those without. Fur- thermore, we know from the Fracture Intervent ion Trial that women with ver tebral f ractures can benefit f rom therapy. 6 Should we be assessing ver tebral frac- tures as par t of BMD screening or as par t of osteo- porosis screening? Currently, a ssessment of verte- bral f racture usually requires a radiograph and a radiologist 's reading. However, new technologies al- low us to assess ver tebral f ractures using bone den- si tometers. In the future, ver tebral fracture assess- ment may be easily done along with measu remen t of BMD.

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SYMPOSIUM ON OSTEOPOROSIS/BLACK

How should risk factors be used in combinat ion for the selection of patients for t rea tment of osteo- porosis? The t rea tment of patients with high choles- terol is an interesting analogy. Dr. David Eddy at Kai- ser in southern California has compared two strategies for selecting patients for t rea tment to pre- vent coronary artery disease: (1) t reat all individuals with low-density l ipoprotein (LDL) >130 mg/dL or (2) t reat individuals with other risk factors, in addi- tion to elevated LDL. Assunting a fixed amount of resources to be used for t reatment, he found that pat ient selection using risk factors in conjunction with LDL level (strategy number 2) prevents 10-20 t imes the number of cases of coronary artery disease as are prevented by treating for elevated LDL level alone (unpublished calculations).

Can similar strategies, which combine various risk factors, be developed for osteoporosis? How can we best use information pert inent to all of these factors? The National Osteoporosis Foundat ion is currently developing screening and t rea tment guidelines that combine information about BMD, ver tebral fracture, and other risk factors. For example, the guidelines will suggest different BMD thresholds for t reatment, depending on the value of other risk factors. These guidelines will be published in 1997 and may create a clinically useful way of combining risk factors.

GLOBAL CONSIDERATIONS Will os teoporosis screening strategies developed

in one country be useful in another country or re- gion? Even within Europe, fracture incidence differs regionally, and predictors of fracture are probably different, as, for example, be tween Sweden and The Netherlands. Dr. Johnell made the point that in- creased hip fracture numbers in Asia and the devel- oping world over the next 50 years will exceed those in developed countries. The best screening strategies and the mos t reliable predictors of f r a c ~ r e in de- veloping countries are not known. Moreover, mea- surement of BMD is less practical in countries with limited resources. More work is needed to identify risk factors in non-Western countries.

COLLES' FRACTURES There is interesting work to be done on Colles'

fractures; they seem to be unusual. Dr. Lips pointed out that the epidemiology with advancing age is not as expected. The incidence of these f ractures does not increase with age. Instead, the incidence pla- teaus after 65 years of age in women, and there is no apparent increased incidence with age in men. These pat terns may in par t be related to declining neuro- muscular function that results instead in hip frac- ture. As Dr. Cooper noted, unlike with hip and ver- tebral fractures, there is no increased mortali ty

associated over the long te rm with Colles' fractures. Moreover, the fact that these fractures are not pre- dicted by ver tebral fractures is not support ive of the Type I - T y p e II hypothesis, which s tates that verte- bral and wrist f ractures have similar etiologies. 7 More research into Colles' f ractures is needed. A bet- ter understanding of the epidemiology of these frac- tures may result in a be t ter understanding of osteo- porosis in general.

OPTIMAL AGE TO START TREATMENT Now that b isphosphonates and estrogen are avail-

able for the t rea tment of osteoporosis , we need to determine how best to use these agents. The optimal age for starting t rea tment of individuals at risk for fracture is not known. Is it justified to t reat a 50-year- old woman? Can we predict her risk, and do we know that we can modify her risk? Is it be t ter to wait until 60 or 70 years of age when the risk of fracture is greater?

SUMMARY AND CONCLUSIONS In designing future clinical trials, we need to con-

sider the appropr ia te endpoint. Clearly, f racture end- points are preferable to BMD but may require very large and expensive trials. Quality-of-life endpoints are also important in clinical trials, but they are chal- lenging to measure.

We have made great progress in identifying women at high risk for fracture. We now need to develop methods for optinlally applying this infor- mation. We also need to determine which risk fac- tors best predict long-term (10-30 years) risk of frac- ture.

We have to deternfine whether t rea tments work, how they can best be used, and the mos t reliable risk factors for identifying high risk of fracture over the very long term. These are issues that need to be ad- dressed by synthesizing some of the work that has been done.

DISCUSSION Incidence of Vertebral Fractures in Women with Prevalent Fractures Ego Seeman, MD (Melbourne, Australia): In one study there was a halving of ver tebral fracture rates f rom 6.2% to 3.2% over 3 years among pat ients re- ceiving alendronate, s Therefore, the incidence of vertebral fracture in pat ients with os teoporosis is 2% per year. We have to r emember that figure when de- signing drug trials. If there is a drug that is possibly efficacious, not 50% but 30%, it still may be quite a good drug. However, a large number of pat ients must be t reated to take advantage of that beneficial effect if the underlying ver tebral fracture rate is 2% in peo- ple with no underlying fracture but bone mineral

28S August 18, 1997 The American Journal of Medicine ® Volume 103 (2A)

density (BMD) ->2.5 s tandard deviations lower than peak density. I know that fracture rates of 6% and 10% are reported, however. Dennis Black, PhD (San Francisco, California): Six percent per year is a consis tent ver tebral fracture rate anlong high-risk women. Note that the Liberman study s enrolled a mixed group of patients with and without baseline fractures. For pat ients with existing vertebral f ractures at baseline, 6% per year is a good est imate of incidence of new ver tebral fractures. David B. Karp f , MD ( R a h w a y , New Jersey): Hav- ing the first morphomet r ic vertebral fracture dra- matically increases the risk of having new vertebral or hip fractures. That tells me that it is important to prevent that first ver tebral fracture. Steven Cummings, MD (San Francisco, Califor- nia): Presumably, it is not the vertebral fracture it- self that is causing the increased risk of subsequent vertebral and hip fractures. If the vertebral fracture is just a marker , then it is important to prevent what- ever leads to the first and subsequent fractures. Dr. Karpf : Vertebral fractures are a marker for mi- croarchitectural deterioration of bone. If we institute therapy and prevent the first vertebral fracture, we will p resumably also affect whatever else is being confounded by it.

Do Benefits Remain After Treatment Is Discontinued? Charles Slemenda, DrPH (Indianapolis, Indi- ana): Can we justify treating someone who is 55 or 60 years old? Do the benefits of therapy remain after it is s topped? If a drug has produced increased bone density, or if it has improved whatever is the true measure of efficacy by 5-6%, and if that difference is maintained for the rest of the pat ient 's life, then 2 - 3 years ' t rea tment to bring about that difference is a wonderful thing, and it should be provided for everyone. Moreover, it would be the mos t cost-effec- tive option because the continual reduction in frac- ture risk throughout life adds up. However, if the beneficial effects d isappear when therapy is stopped, then therapy is much less effective. I think there is a t remendous need for pos t t rea tment follow-up. Anthony Lyons, FRCS (Nottingham, United Kingdom): There is a well-designed Merck study

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called EPIC that addresses that issue to a certain extent for BMD by means of the p lacebo groups that are built in. Certainly in the Nott ingham and Copen- hagen groups, we will be following pat ients af ter s tudy complet ion until we can no longer follow them to record fracture incidence and BMD. Dr. Cummings: Will that s tudy have sufficient power to look at f ractures as the endpoint? Dr. Karpf : It includes a very low-risk population.

Accelerated Loss of Bone with Aging Is Probably Underestimated Dr. Seeman: I think a message that should go across very clearly is that rates of bone loss do not decel- erate; if anything, they accelerate with age. Dr. Black: Another point is that, even though this is a rigorous study, 'J in fact we looked at bone loss only in the women who actually came back to the clinic. The women who did not come back to the clinic tended to be older and presumably were losing even more bone. So, we probably underes t imated that ac- celeration in bone loss.

REFERENCES 1. Cummings SR, Black DM, Vogt TM, et al, for the Study of Osteoporotic Fractures Research Group. Changes in BMD substantially underestimate the anti-fracture effects of alendronate and other antiresorptive drugs. J Bone Min- eral Res. 1996;1 l(suppl 1):$102. 2. Riggs BL, Hodgson SF, O'Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med. 1990;322:802-809. 3. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. Lancet. 1993;341:72-75. 4. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl .I Med. 1995;332:767-773. 5. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med. 1991;114:919-923. 6. Black DM, Cummings SR, Thompson D, et al, for the Fracture Intervention Trial Research Group. Alendronate reduces risk of vertebral and clinical frac- tures in women with existing vertebral fractures: Results of the Fracture Inter- vention Trial. J Bone Mineral Res. 1996;1 l(suppl 1):$151. 7. Riggs BL, Melton LJ. Evidence for two distinct syndromes of involutional osteoporosis. Am J Med. 1983;75:899-901. 8. Liberman UA, Weiss SR, Broil J, et al. Effects of three years treatment with oral alendronate on fracture incidence in women with postmenopausal osteo- porosis. N Engl J Med. 1995;333:1437-1443. 9. Ensrud KE, Palermo L, Black DM, et al. Hip and calcaneal bone loss increase with advancing age: longitudinal results from the study of osteoporotic frac- tures. J Bone Miner Res. 1995;10:1778-1787.

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