COMMENTARY Bone Densitometry: The Best Way to Detect Osteoporosis and to Monitor Therapy

0021-972X/99/$03.00/0 Vol. 84, No. 6 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 1999 by The Endocrine Society COMMENTARY Bone Densitometry: The Best Way to Detect Osteoporosis and to Monitor Therapy PAUL D. MILLER, CAROL ZAPALOWSKI, CAROLINA A. M. KULAK, AND JOHN P. BILEZIKIAN Colorado Center for Bone Research (P.D.M., C.Z.), Lakewood, Colorado 80227; the Departments of Medicine (C.A.M.K., J.P.B.) and Pharmacology (J.P.B.), Columbia University College of Physicians and Surgeons, New York, New York 10032; and the Department of Endocrinology, Federal University of Parana, Hospital de Clinicas (C.A.M.K.), Curitiba, Brazil The development of objective, noninvasive, and highly sensitive techniques to quantitate bone mineral density (BMD) has provided the clinician with a powerful diagnostic tool. Bone mass measurement is the best way to make the diagnosis of osteoporosis, one of the major diseases of our time. Using this technology, osteoporosis can now be detected well before it is obvious by conventional x-rays or when fractures eventuate. The definition of osteoporosis by the World Health Organization (WHO) is a BMD that is 2.5 sd or more below the mean of a young, normal reference population (1). This definition offers the practitioner an objective standard by which to make a diagnosis and to make subsequent management decisions. It has also profound therapeutic implications. Fortuitously, the advent of this technology has been accompanied by an exciting array of new, effective therapies to prevent and treat osteoporosis. The therapeutic optimism resulting from these pharmacological breakthroughs has fueled discussions about the potential widespread applicability of bone mass measurement to the entire population at risk. It has sparked controversy over how widely bone mass measurement modalities should be applied to detect the population at risk and what devices should be used to this end. In this article we provide a perspective on these issues. Defining the population at risk The aging population is inevitably going to become more osteoporotic unless we intervene first with diagnostic tools and then with preventive therapy. The National Osteoporosis Foundation has estimated that the number of postmenopausal women in this country will double from 40 to 80 million over the next 20 yr (2). Projections also call for a tripling of the number of osteoporotic fractures by 2040 from current annual estimates of 1.3 million. Staggering costs are surely going to exceed the 1995 figure of 13.8 billion dollars Received January 22, 1999. Accepted February 11, 1999. Address all correspondence and requests for reprints to: John P. Bilezikian, M.D., Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. by countless billions more. The need is clear both to discover the population with osteoporosis and, more importantly, to identify those at risk for the disease. Importance of bone mass measurement Measurement of bone mass is the single best predictor of fracture risk (3 5). The advent of this technology into the clinical arena over the past 15 years is similar in importance to the development of the sphygmomanometer and assays for serum cholesterol. As blood pressure and cholesterol determinations are predictors of stroke and cardiovascular disease, so bone density predicts fracture risk (2 5). In fact, the measurement of bone mass is a much more powerful indicator of fracture risk than cholesterol determination is a predictor of myocardial infarction. Epidemiological studies indicate that the totality of risk for fracture, as represented by bone mass measurement, is 60 70% (6). Because of its predictive power, it is, thus, the most important information to gain about fracture risk. Other independent predictors of fractures are readily known, such as age, history of previous fracture, and low body weight. Together, the risk profile of an individual can be rather accurately determined as long as the BMD is known. Bone mass measurement techniques The most widely used technique is dual energy x-ray absorptiometry (DXA). DXA can measure central sites, such as lumbar spine and hip, as well as peripheral sites, such as distal forearm, heel, and phalanges. DXA is noninvasive, rapid, accurate, and safe. The high precision of the technique usually allows DXA testing of central sites (not peripheral sites) to be used for monitoring as well as diagnosis. The effectiveness of therapy with bisphosphonates is well correlated with changes in bone mass (7). Most of the recent literature with respect to treatment response is based upon central measurements (8 10). It is the gold standard with which all other technologies are compared. Other approaches to bone mass measurement have been developed (11). Quantitative computed tomography (QCT) measures lumbar spine (12) and more recently has been 1867

1868 MILLER ET AL. JCE&M 1999 Vol 84 No 6 adapted to measure peripheral sites as well (13). The potential advantage of QCT over DXA is in its ability to measure true volumetric density (grams per cm 3 ) compared with DXA, which gives an areal density (grams per cm 2 ). Moreover, QCT measures cancellous bone of the lumbar spine exclusively, devoid of the cortical envelope. It is less likely, therefore, to detect artifacts of aging, such as osteophytes and aortic calcifications, than DXA. On the other hand, changes in the bone marrow space with aging can confound the lumbar spine density measurement by QCT. Other disadvantages of QCT are the cost of the machines, poor availability, cost of the test, and, to a certain extent, radiation exposure, the latter of which becomes a consideration when patients are monitored. Fracture prediction by QCT is as good as but no better than that by DXA (14). A number of less costly and more portable devices that measure peripheral sites have been developed and approved by the FDA (15). The rationale to develop these densitometers rests with the fact that central machines are relatively expensive and, in some settings, not readily accessible. Some believe that central densitometers are unlikely to proliferate sufficiently or to be distributed proportionately throughout the United States so as to be accessible to all who are in need of bone mass measurement. There are currently about 5000 central DXA machines in the United States. As noted, DXA and QCT have been adapted to peripheral sites. In addition, the radius can be measured by single energy absorptiometry (16), and the phalanges can be measured by radiogrammetric absorptiometry (17) and DXA. In addition to machines that use ionizing radiation, the technique of ultrasound has been developed to measure bone mass (18). Ultrasound can measure the speed of sound as well as broadband ultrasonic attenuation of the site in question. These indexes give a measure of bone mass, although it is still not clear whether ultrasound may also detect certain qualitative aspects of bone. The machines available in the United States at this time detect bone mass in heel and proximal tibia. Ultrasound machines are attractive because they are small, portable, relatively inexpensive, and do not use ionizing radiation. The heel is of particular interest, because its composition, primarily cancellous bone, is similar to the composition of the spine. An example of how useful ultrasound can be in the quest to detect the population at risk is in Japan, where the introduction of ultrasound was associated with a 30% increase in diagnosis (19). What site(s) should be measured to detect the population at risk? The technologies described above give highly accurate and reproducible information. In general, bone mass at peripheral sites correlates well with measurements at more central (and more important) sites, such as hip and spine. Correlation coefficients between peripheral and central sites in general will be between 0.6 0.70 (Fig. 1). These reasonably good correlations seem to be the case regardless of the sites and the devices compared. Such correlations have led to arguments for and against the use of peripheral measurements to discover the population at risk. General optimism (15, 20) has led to views by some that peripheral sites can be used in FIG. 1. The relationship between bone mineral measurements at a peripheral site (distal radius) and a central site (spine). The study population consisted of 172 postmenopausal and osteoporotic women. Solid lines show the WHO thresholds for the definition of osteoporosis (t score, 2.5). Data are rom Ref. 36. selected subsets and that some therapeutic decisions can be based on them (21). More tempered opinions have questioned the potential utility of peripheral measurements (22 23). The facts that the machines that measure peripheral sites can be portable and are less expensive are an important part of the argument to use peripheral techniques. If we are going to discover the millions of Americans who are at risk, we must use screening approaches that are the easiest and the most affordable. In these respects, peripheral devices are most attractive. If one can identify a large number of individuals who would otherwise not be discovered and do it in a cost-effective manner, a major point against screening the at-risk population, namely cost, is minimized. Within limits, this argument has merit. The good correlation between peripheral and central measurements is precisely the genesis of the counterargument, namely that peripheral sites will miss a substantial number of individuals with osteopenia or osteoporosis. Significant concordance between sites with r values from 0.6 0.70 is not good enough when it comes to predicting bone mass from one site to another in a particular individual (24 26). This discordance has the potential to be a real problem. An individual with normal bone mass at a peripheral site could have substantial reductions at a central site and, therefore, need additional testing for these to be discovered (20). In general, measurement of the site in question gives the best predictive value of the risk of fracture at that site (3). For example, measurement of hip bone density (at any of the five sites: femoral neck, trochanter, intertrochanter, Wards area, and total hip) gives much better predictive information about hip fracture than does measurement of the spine, distal radius, or heel (Fig. 2). This is generally true for the spine also except for older individuals in whom osteoarthritic changes may give artifactually elevated values in the anterio-posterior projection. For these individuals, the lateral spine or hip measurement is a better predictive index than the anterioposterior spine bone density. One point on which most experts agree at this time is that

BONE DENSITOMETRY 1869 FIG. 2. Risk ratio values for hip fracture as determined by bone densitometry at the hip and other sites. Measurements of bone density were obtained at five different hip regions, two forearms regions, the heel, and the spine. Although relative risk (RR) for hip fracture was related to bone mass measurement at any site ( 1), at every hip site, the RR showed much higher values ( 2.5). Data are from Ref. 36. peripheral measurements have not yet been shown to be useful to monitor the course of therapy (20, 27). For this important feature of bone mass measurement technology, central sites need to be used. This point raises an important problem. Certainly, peripheral measurement can be used, at least in some individuals, to discover osteoporosis. Bone density at osteoporotic levels in the radius, for example, does define a problem that needs attention (14, 3), particularly in older individuals, in whom bone mass is likely to be low at all skeletal sites. However, the best way to monitor that patient when therapy is established is to use central sites, where remodeling occurs at a more substantial pace. Thus, changes in bone mass can be detected more readily in the course of therapy. A peripheral site, such as the heel, comprised of similar cancellous bone as the lumbar spine, has a greater potential to be used for monitoring purposes, but to date the data are not conclusive, nor has the FDA yet approved this site for monitoring the course of therapy. The FDA has recognized that the precision error of the heel is low enough to be capable of monitoring, but the responsiveness of this site to therapy has not yet been established. At the present time, therefore, it would appear that central sites will have to be measured both at baseline and thereafter if densitometry is going to be used to monitor patients. Discordance among skeletal sites is not surprising, as the composition and metabolism of bone are not uniform from site to site. Different hormonal and mechanical influences lead to differential changes in bone mass as a specific function of site. For example, early postmenopausal bone loss is going to affect the cancellous skeleton first, a feature of estrogen deficiency. In this setting, therefore, a central site will show bone loss first. As osteoporosis is primarily a disorder of postmenopausal women, these central sites have reasonably been emphasized more. With age, the concordance between peripheral and central sites tends to improve, but in women in their early postmenopausal years, a discordance between peripheral and central sites is a source of concern. From the forgoing discussion, there will be a number of individuals whose peripheral measurement is normal, but whose hip or spine is osteopenic or osteoporotic. Miller et al. (20) recently suggested a group of individuals for whom one is encouraged to test beyond the peripheral site simply because they are at much greater risk. For example, any postmenopausal individual with significant risk factors for osteoporosis or a history of fragility fractures should have central measurements (Table 1), even if a peripheral site is normal. An early postmenopausal woman not taking estrogen replacement therapy who is concerned about low bone mass and would consider preventive therapy should also have a central measurement if the peripheral site measured is normal. Another important consideration is the rate of bone metabolism. If bone turnover is elevated, as determined by measurements of biochemical bone markers, these subjects, too, should have the benefit of central measurements even if the peripheral site(s) is normal. The case for selective screening Ideally, one would like to test all individuals at risk for osteoporosis. As all postmenopausal individuals are at risk for developing osteoporosis if they live long enough, one would like to develop an approach that allows the entire population to be screened. Such an approach has important precedents with respect to other widely pervasive diseases, such as hypertension, diabetes, hyperlipidemia, and breast and cervical cancer. In contrast to these conditions, for which inexpensive screening tests have been developed, are readily available, or have simply been accepted, there is no such equivalent with respect to surveying the population for osteoporosis. Nevertheless, osteoporosis is a disorder that meets requirements for which a screening approach is justifiable. It is a common disease associated with high cost, it causes major morbidity and mortality, accurate and safe diagnostic tests are available, and therapy is efficacious. As more densitometers become available at a lower cost, the concept of screening the population will gain more support. At the moment, the more acceptable approach to this issue is to consider the case for selective screening. The carriers who provide reimbursement for bone densitometry have understandably been slow in developing TABLE 1. Normal peripheral screening and indication for central bone mass measurement Postmenopausal women not receiving HRT, who would consider treatment or prevention if low bone mass was diagnosed Maternal history of hip fracture Personal history of fragility fracture Smoker, tall ( 5 7 ) and thin ( 125 lb) Taking medications such as: steroids, antiseizure and GnRH agonists Diseases or conditions associated with bone loss: hyperthyroidism, posttransplantation, malabsorption, hyperparathyroidism, prolactinoma, immobilization Presence of high markers of bone resorption Adapted from Miller et al. (20).

1870 MILLER ET AL. JCE&M 1999 Vol 84 No 6 guidelines for reimbursement, but do agree with the concept of selective screening. The Bone Mass Measurement Act of 1998 detailed, for the first time, a set of uniform indications for bone measurement for which reimbursement is justified (Table 2). They include an estrogen-deficient women at risk for osteoporosis. Although the regulation is somewhat ambiguous on this point, it is reasonable to expect that estrogendeficient subjects at risk include those with a family history of osteoporosis, low body weight, history of anorexia, amenorrhea for at least 1 yr during the reproductive years, associated diseases associated with bone loss and certain medications. Other indications contained in the Bone Mass Measurement Act include any individual with a vertebral abnormality, receiving long term glucocorticoid therapy, or with primary hyperparathyroidism and for the purposes of monitoring a patient s response to an FDA-approved therapy for osteoporosis. The National Osteoporosis Foundation (NOF) has just issued its document, Osteoporosis: review of the evidence for prevention, diagnosis, and treatment and cost-effective analysis (2). In that report, the NOF proceeds one step beyond the Health Care Finance Administration guidelines. It defines three categories of individuals who should have a bone mass measurement: all women over age 60 65 yr, all women with vertebral fracture, and all woman, 50 60 yr old, with at least one important risk factor. As we further refine and define our criteria for bone mass measurement and as technologies become more user-friendly, available, and affordable, it is clear that bone mineral densitometry is going to be even more widely application to the population. One looks forward to the day when bone mass measurement will be as much a standard of preventive care as is measurement of blood pressure, blood sugar, and cholesterol and mammography. Monitoring therapy of osteoporosis with bone densitometry Bone mass measurement is indispensable to the early diagnosis of osteoporosis. Early recognition of this disease, before the first or next fracture occurs, is leading to a therapeutic imperative, namely to intervene. With new approaches to prevention and therapy, it is important to be able to monitor the effectiveness of the therapy that has been instituted. It is not enough to state simply that the therapy has been shown to work and that all one has to do is to follow the therapeutic plan. The end point of therapy is a reduction in fracture incidence. Certainly, this end point can be monitored in large clinical trials, but it is relatively useless in the individual patient. It is logical to expect that as bone TABLE 2. Bone mass measurement act: a effective July 1, 1998 (HCFA) Indications for bone mass measurement 1) An estrogen-deficient woman at clinical risk for osteoporosis 2) An individual with vertebral abnormalities 3) An individual receiving long term glucocorticoid therapy ( 7.5 mg prednisone/day for 3 months) 4) An individual with primary hyperparathyroidism 5) An individual being monitored to assess the response to or the efficacy of a FDA-approved drug for osteoporosis therapy a Ref. 35. mass measurement defines risk of fracture, it should be useful as an index of therapeutic effectiveness. Indeed, the large clinical trial experience with the bisphosphonate, alendronate, has shown clearly that impressive increases in bone mass in the lumbar spine are associated with a substantial reduction in fracture incidence (9, 10). Recent analysis of these data also suggests that there is a significant relationship between the magnitude of the change in bone mass and the magnitude of the reduction in fractures (7). These data have led to acceptance of bone mass measurement as a surrogate marker for the true end point, fracture reduction. The bone mass measurement act of 1998 acknowledges this point by providing reimbursement for monitoring the therapeutic course of an osteoporotic subject. The use of bone densitometry to monitor the population receiving agents to prevent or treat osteoporosis is clearly important. However, recent evidence suggests that changes in bone mass do not account for the entire risk reduction associated with a specific therapeutic intervention. In the EPIDOS (28) and SOF (29) studies, large epidemiological studies in Europe and the United States, respectively, changes in bone mass have been shown to account only in part for the reduction in fracture incidence. An additional, important predictive index is the change in bone markers. A reduction in indexes of bone turnover contributes importantly and independently to fracture risk reduction. In a carefully conducted, double blind, placebo-controlled study of calcium and vitamin D, Dawson-Hughes et al. (30) have shown that fracture incidence is significantly reduced over a 3-yr period. This reduction in fracture incidence is associated with minimal changes in bone mass. Bone turnover is reduced, however, by calcium and vitamin D administration. The results of the large multicenter study of nasal calcitonin (PROOF study) show that fracture incidence is reduced, but neither bone density nor bone markers change substantially (31). Also recently, data from a large clinical trial with raloxifene, a selective estrogen receptor modulator, have shown that changes in bone mass and bone markers are much less than one would expect considering the major reduction in fracture incidence (32). These newer data do not negate the value of monitoring changes in bone mass with therapy, but emphasize, rather, that there are other factors that will be helpful in assessing the overall response to therapy. In some cases, the evaluation of bone markers will provide not only confirmatory evidence that a biological effect is occurring and that bone mass will increase over time, but also will provide independent data to substantiate the risk reduction afforded by the change in bone mass. Greenspan et al. have shown, for example, that the extent of reduction of the resorption marker, N-telopeptide of collagen, predicts the ultimate change in lumbar spine and hip density (33). Recognition of the potential value of bone markers has led the Health Care Finance Administration to propose a set of guidelines for their use in the context of FDA-approved therapy (34). They include two baseline determinations, a 3 month posttherapy determination, and yearly measurements thereafter.

BONE DENSITOMETRY 1871 Summary The revolution in the field of osteoporosis has been aided and abetted by the advent of bone mass measurement technologies. As they become more widely applicable and more affordable, it is evident that we have the potential to discover the millions of individuals at risk for or with the disease. With effective therapies at hand, it is now possible to prevent and treat osteoporosis. There is every reason, therefore, to apply bone mass measurements as widely as possible to discover those subjects at risk for osteoporosis in a manner that is effective and affordable. References 1. Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR. 1998 Associations between low levels of serum estradiol, bone density and fractures among elderly women: the study of osteoporotic fractures. J Clin Endocrinol Metab. 83:2239 2243. 2. National Osteoporosis Foundation. 1998 Osteoporosis: prevention, diagnosis, and treatment. Osteop Int. 8(Suppl 4):S1 S88. 3. Cummings SR, Black DM, Nevitt MC, et al. 1993 Bone density at various sites for prediction of hip fractures. Lancet. 341:72 75. 4. Hui SL, Slemenda CW, Johnston Jr C. 1988 Age, and bone mass as predictors of fracture in a prospective study. J Clin Invest. 81:1804 1809. 5. Black DM, Cummings SR, Genant HK, Nevitt MC, Palermo L, Browner W. 1992 Axial and appendicular bone density predict fractures in older women. J Bone Miner Res. 7:633 638. 6. Ross PD. 1998 Risk factors for osteoporotic fracture. Endocrinol Metab Clin North Am. 27:289 301. 7. Hochberg MC, Ross PD, Cummings SR, et al. 1998 Larger increases in bone mineral density with alendronate therapy are associated with lower risk of new vertebral fractures. Osteop Int. 8(Suppl 3):13. 8. Watts NB, Harris ST, Genant HK, et al. 1990 Intermittent cyclic etidronate treatment of postmenopausal osteoporosis. N Engl J Med. 323:73 77. 9. Liberman UA, Weiss SR, Broll J, et al. 1995 Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 333:1437 1443. 10. Black DM, Cummings SR, Karpf DB, et al. 1996 Randomised trial of effect of alendronate on risk fracture in women with existing vertebral fractures. Lancet. 348:1535 1541. 11. Blake GM, Fogelman I. 1996 Principles of bone densitometry. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. New York: Academic Press; 1313 1332. 12. Genant HK, Cann CE, Ettinger B, Gordan GS. 1982 Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med. 97:699 705. 13. Grampp S, Lang P, Jergas M, Gluer CC, Takada M, Engelke K, Genant HK. 1994 Peripheral quantitative computed tomography: short term in vivo precision and comparison to forearm DXA. J Bone Miner Res. 9:A368. 14. Ross PD, Genant H, Davis JD, Miller PD, Wasnich R. Predicting vertebral fracture incidence from prevalent fractures and bone density among nonblack, osteoporotic women. 1993 Osteop Int. 3:120 126. 15. Blake GM, Patel R, Fogelman I. 1998 Peripheral or axial density measurement. J Clin Densitometry. 1:55 63. 16. Kelly TL, Crane G, Baran DT. 1994 Single x-ray absorptiometry of the forearm: precision, correlation and reference data. Calcif Tissue Int. 54:212 218. 17. Yates AJ, Ross PD, Lydick E, Epstein RS. 1995 Radiographic absorptiometry in the diagnosis of osteoporosis. Am J Med. 98:41 47. 18. Gluer CC, Genant HK, Hans D, et al. 1997 Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement and current status. J Bone Miner Res. 12:1280 1288. 19. Baran DT. 1998 A sound strategy for bones. J Clin Densitometry. 1:209 210. 20. Miller PD, Bonnick SL, Johnston CC, Kleerekoper M, Lindsay RL, Sherwood LM, Siris ES. 1998 The challenges of peripheral bone density testing. Which patients need additional central density skeletal measurements? J Clin Densitometry. 1:211 217. 21. Eastell R, Wahner HW, O Fallon WM, Amadio PC, Melton III LJ, Riggs BL. 1989 Unequal decrease in bone density of lumbar spine and ultradistal radius in Colles and vertebral fracture syndrome. J Clin Invest. 83:168 174. 22. WHO Study Group. 1994 Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Tech Rep Ser 843. Geneva: WHO; 1994. 23. Drinka PJ, DeSmet AA, Bauwens SF, Rogot A. 1992 The effect of overlying calcification on lumbar bone densitometry. Calcif Tissue Int. 50:507 510. 24. Grampp S, Genant HK, Mathur A, et al. 1997 Comparisons of noninvasive bone mineral measurements in assessing age related loss, fracture discrimination, and diagnostic classification. J Bone Miner Res. 12:697 711. 25. Melton III LJ, Chrischilles EA, Cooper C, Lane AW, Riggs BL. 1992 How many women have osteoporosis? J Bone Miner Res. 7:1005 1010. 26. Arlot ME, Sornay-Rendu E, Garnero P, Vey-Marty B, Delmas PD. 1997 Apparent pre- and postmenopausal bone loss evaluated by DXA at different skeletal sites in women: the OFELY cohort. J Bone Miner Res. 12:683 690. 27. Bouxsein M, Parker RA, Greenspan SL. 1998 Forearm bone mineral densitometry cannot be used to monitor improvements in hip and spine bone density after 2.5 years of alendronate therapy. Bone. 23(Suppl):S312. 28. Garnero P, Hausherr E, Chapuy MC, et al. 1996 Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res. 11:1531 1538. 29. Cummings SR, Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B. 1998 Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med. 339:733 738. 30. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. 1997 Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med. 337:670 676. 31. Chesnut C, Silverman SL, Andriano K, et al. 1998 Salmon calcitonin nasal spray reduces the rate of new vertebral fractures independently of known major pre-treatment risk factors: acrrued 5 years analysis of the PROOF study. Bone. 23:S290. 32. Ensrud K, Black D, Recker R, et al. 1998 The effect of 2 and 3 years of raloxifene on vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. Bone. 23:S174. 33. Greenspan SL, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey, Karpf DB. 1998 Early changes in biochemical markers of bone turnover predict the long term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res. 13:1431 1438. 34. DHHS. 1998 Medicare program: recommended medicare national coverage policy for collagen crosslinks, any method. Federal Register. Washington DC: U.S. Government Printing Office. 35. DHHS. 1998. Medicare program: medicare coverage of and payment for bone mass measurements. Federal Register. Washington DC: U.S. Government Printing Office; 63(121)34320 34328. 36. Blake GM, Patel R, Fogelman I. 1998 Peripheral or axial bone density measurements? J Clin Densitometry. 1:55 63.