Cover Story

Managing bone loss

By Lois E. Wehren, MD, and Ethel S. Siris, MD

Drug therapy isn't recommended for all women with osteopenia, a precursor to osteoporosis. Clinicians need to identify, early on, the patients with low bone mass at additional risk for future osteoporotic fractures.

Nearly 30 million women have either osteoporosis or low bone mass and the numbers are rising. Preventing osteoporosis is more than an issue of deteriorating quality of life. For an ever-growing number of baby boomers, it may even be a matter of life and death, considering that there's a 20% increase in mortality in the year following hip fracture. And fracture risk is part and parcel of the very definition of this major public health problem: "a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture."¹

A chronic disease, osteoporosis is silent for years or decades before a fracture occurs. Although most common among postmenopausal Caucasian women, it affects women of other races—and men, too. An estimated 43.6 million men and women aged 50 and older currently have osteoporosis or low bone mass, according to the National Osteoporosis Foundation (NOF).² Women make up 29.6 million of this total; 7.8 million have osteoporosis and 21.8 million have low bone mass.

Approximately 1.5 million fragility fractures occur each year, including 700,000 vertebral fractures, 300,000 hip fractures, and 200,000 fractures of the distal forearm.³ Because of increasing life expectancy and rising age-specific fracture rates, the prevalence of both osteoporosis and fracture is expected to soar over the next several decades. For example, by 2020 the prevalence of osteoporosis and low bone mass in the United States will rise by 41%, to 61.4 million, according to NOF estimates.² The incidence of hip fracture worldwide is expected to double in women and triple in men by 2035.⁴

These escalating numbers highlight the importance of addressing osteoporosis and fracture risk in postmenopausal patients, especially when you consider the personal, societal, and economic consequences of fracture. Nearly two thirds of women who fracture their hips sustain permanent losses in functional ability and, as noted earlier, approximately 20% die within the next year.^5,6 Long-term effects on quality of life may also follow other osteoporotic fractures.⁷ In 1995 alone, $13.8 billion were spent on medical costs of osteoporotic fractures, of which non-hip fractures accounted for $5.1 billion (36.9%).⁸

Diagnosing osteoporosis

Asymptomatic until fracture occurs, osteoporosis has a preclinical period that may last for decades. Although risk factor screening alone is insufficient to diagnose osteoporosis, bone mineral density (BMD) testing can readily do so. Bone strength also depends on the rate of bone turnover (i.e., the rates of bone resorption and of new bone formation), macro- and microarchitecture of bone, accumulated microdamage within bone, and the extent of mineralization of bone.¹ However, these parameters either cannot be measured noninvasively at present or have not yet been shown to predict BMD or fracture well.

Several simple screening instruments can help determine which patients to refer for BMD testing. Among these are the Simple Calculated Osteoporosis Risk Estimation (SCORE), the Osteoporosis Risk Assessment Instrument (ORAI), and the Osteoporosis Self-assessment Test (OST).^9-11 Each instrument has demonstrated good sensitivity (correctly identifying patients whose BMD will be found to be low when tested) and moderate specificity (correctly identifying people with normal BMD). Use of such a screening test can, therefore, help to identify women who do not need BMD testing, as well as those who constitute a high-risk group.

Because substantial bone loss occurs during the initial postmenopausal years and age-related losses continue thereafter, guidelines of both the United States Preventive Services Task Force (USPSTF) and the NOF recommend BMD testing for all women aged 65 or older.^12,13 If risk factors are present, testing is recommended for all postmenopausal women over age 50 (NOF) or 60 (USPSTF). Again, use a risk factor screening instrument to help you decide who should have BMD testing.

Although BMD at the hip is considered the gold standard, measurements at peripheral sites can also be used for diagnosis and prediction of fracture risk.^12-14 Measurements are typically reported as T-scores. The T-score describes the degree to which an individual's BMD differs from the average of the young adult population, in terms of standard deviation (SD) units: a T-score of -1.0 is, therefore, 1 SD below the young adult average. Table 1 shows the diagnostic categories proposed by the World Health Organization (WHO) in the early 1990s.¹⁵ In addition, women with low BMD who have had a previous fragility fracture are considered to have "severe" or "established" osteoporosis.

TABLE 1
Diagnostic classification of BMD measurements using World Health Organization definitions

Z-scores may also be reported; these are also standardized scores, but are more of a peer-group comparison. They compare the BMD of the woman being measured to the average BMD of women her own age. Z-scores are generally less useful than T-scores for diagnosing subjects at risk because, as previously mentioned, BMD declines progressively throughout life, and because fracture risk seems to be more closely related to the absolute amount of bone present. Many clinicians, however, use the Z-score as a basis for evaluating women for secondary factors that may contribute to low bone mass. If a patient's Z-score is lower than -1.5, her bone loss may be due to more than menopause- and age-related changes, and she should have further evaluation to exclude other medical disorders.

Factors impacting treatment decisions

An assessment of fracture risk guides treatment decisions in osteoporosis. BMD explains about 60% to 80% of variation in fracture risk and predicts fracture better than hypertension predicts stroke or hypercholesterolemia predicts cardiovascular events.¹³ Regardless of the site at which BMD is measured, overall skeletal fracture risk approximately doubles for each SD decrease below young adult normal.^{14, 16} However, measurement at the hip may best predict hip fractures.¹⁷ Assessment of clinical risk factors for fracture also enters into treatment decisions. The first four of the risk factors listed in the NOF guidelines (Table 2) are the most important.¹³ A personal history of fracture has the greatest effect on fracture risk. Independently of BMD and regardless of previous fracture site, future fracture is about twice as likely in women with such a history.¹⁸

NOF guidelines recommend treating all women who have osteoporosis and some women who have osteopenia. According to the guidelines, all women whose T-scores are <-2.0 are candidates for treatment, as are women whose T-scores are <-1.5, if any of the above-listed risk factors are present.¹³ These recommendations highlight the important distinction to be made between diagnostic BMD thresholds (WHO guidelines) and fracture risk/treatment thresholds and emphasize the additive effect of risk factors.

Should you consider treating women with osteopenia?

Osteopenia, as defined by the WHO, describes BMD values between 1 and 2.5 SD below the average of the young adult normal population. According to this definition, approximately 16% of the young adult normal population will have T-scores consistent with either osteopenia (15.4%) or osteoporosis (0.6%). In healthy younger women, these low values typically reflect lower than average peak bone mass rather than bone loss of the type associated with menopause. Because the distribution of average BMD values shifts lower with advancing age, progressively larger segments of older groups have low T-scores, so that approximately 40% (~13 million) of all women over age 50 have osteopenia and another 20% (~7 million) have osteoporosis.¹⁹ This represents a very large population at risk of fracture who deserve evaluation and treatment.

The association between BMD and fractures has no threshold. In other words, the risk of fragility fracture increases progressively as BMD declines and no level of BMD is associated with a complete absence of risk. One would, therefore, infer that osteopenia is associated with a greater risk of fracture than with normal BMD. This was, in fact, recently reported in both the Study of Osteoporotic Fractures (SOF) and the National Osteoporosis Risk Assessment (NORA) cohorts.^14,20 Using classification based on hip or spine measurements or both, SOF investigators reported that 74%, 60%, and 53%, respectively, of all nonvertebral fractures reported during 10 years of follow-up occurred in women whose T-scores were > -2.5.

One could argue that a good proportion of this elderly female population would have moved from osteopenia to osteoporosis during those 10 years and that, in fact, women with full-blown osteoporosis were the ones having the fractures. In NORA, however, within approximately 1 year after BMD measurement at peripheral skeletal sites (forearm, heel, or finger), the fracture rates of women who had been identified as osteopenic were 1.8 times those seen in women with normal BMD. (The fracture rates of women with osteoporosis were four times higher than those of women with normal BMD.) Even after adjusting for multiple risk factors, the osteopenic women were 70% more likely to sustain fragility fractures of the hip, spine, rib, wrist, or forearm. In fact, women with T-scores between -1.0 and -2.5, who comprised 40% of the study population, experienced more than half of the 2,258 fractures reported during follow-up.

Specific management recommendations

Comprehensive management of osteoporosis includes providing recommendations for modifying behavioral risk factors, for getting adequate weight-bearing exercise, and taking in adequate calcium (1,200 to 1,500 mg/day) and vitamin D (400 to 800 IU/day), as well as a drug prescription. Each of the drugs approved for managing osteoporosis—estrogen, raloxifene, the bisphosphonates, alendronate and risedronate, calcitonin, and teriparatide—has shown at least some efficacy in reducing fractures.^21-25 However, because the clinical trials were conducted in high-risk groups (women with very low BMD and/or prevalent fragility fractures) in order to more readily demonstrate fracture reduction, we have little direct evidence from clinical trials that any of these agents will reduce the risk of fracture in all women with osteopenia.

It is of considerable interest, in this context, to note that the WHI study showed a reduction in the risk of clinical fractures and hip fractures in a population not selected for having osteoporosis.²¹ This suggests that estrogen will reduce fractures in a lower-risk population. Moreover, researchers have reported stabilization or increased BMD with estrogen or estrogen/progestin, raloxifene, alendronate, and risedronate in early postmenopausal women who do not have osteoporosis.^26-29 (Calcitonin is indicated only in women who are at least 5 years postmenopausal and who have osteoporosis.)

Although BMD correlates well with fracture risk in osteoporotic populations, that has not been established in randomized interventional trials. This association, therefore, must be considered uncertain, even though guidelines advise therapy for some women whose BMD is in the osteopenic range. It is intuitively appealing to treat women with scores in that range to prevent bone loss, given evidence suggesting that the microarchitectural damage to bone caused by bone loss may compromise bone strength and may be irreversible with currently available antiresoptive treatments.³⁰ Especially damaging is the disruption of trabecular connectivity (an important cause of bone fragility).³⁰ Certainly we can recommend to all women general measures like modifying lifestyle behaviors (stopping smoking) and using calcium and vitamin D supplements to minimize bone loss. But these measures, in and of themselves, are insufficient to completely protect the skeleton, especially in the several years immediately following menopause.

NOF recommendations for pharmacologic treatment were derived from a cost-benefit analysis, which in addition to considering the absolute risk of fracture, also takes into account the costs of treatment (and available resources) and risks associated with it. This analysis implicitly assumed that the effects of treatments on fracture incidence could be generalized beyond populations studied in clinical trials.

We also don't know how long to treat osteopenic women to reduce fractures. NOF clinical guidelines do recommend pharmacologic agents for some of the osteopenic population. Specifically, they recommend treatment for women with T-scores below -2 and also between -1.5 and -2 when there are additional risk factors for fracture. True consensus does not yet exist, however, for a treatment "threshold," largely because evidence to establish one is inadequate. Future research may more precisely identify women with osteopenia who are at particular risk of fracture, sparing large numbers of women who will not fracture in the near future from undergoing unnecessary drug treatment. At present, the NOF recommendations appear to provide reasonable guidance to the clinician.

Conclusions

Osteoporosis is a common disease among postmenopausal women, and its clinical consequences—fragility fractures—are associated with substantial morbidity, mortality, and cost. We can easily and noninvasively diagnose osteoporosis through BMD testing, and can use clinical risk-factor algorithms to help identify women who are most likely to need BMD measurement. Comprehensive management of the disease is directed toward decreasing the risk of fracture, and includes modification of behavioral risk factors, adequate exercise, appropriate nutrition (including calcium and vitamin D), and medication.

Several drugs have been shown to reduce the risk of fracture in women with osteoporosis. The action of these drugs is largely mediated through increases in BMD and decreases in rates of bone turnover. The risk of fragility fracture increases progressively as BMD declines, so women with osteopenia are at greater risk of fracture than are women with normal BMD. Although current treatment guidelines do not recommend drug therapy in all women with osteopenia, ob/gyns should consider treatment, in accordance with NOF guidelines, for two groups of women with osteopenia: those in whom additional risk factors are present and, perhaps, those who are losing bone rapidly during the first few years after menopause.

Dr. Wehren is on the Gynecology Advisory Board and Speakers' Bureau of Merck & Company, Inc. Dr. Siris is a paid consultant to Merck, Procter & Gamble, and Eli Lilly.

REFERENCES

1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795.

2. National Osteoporosis Foundation. America's Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, D.C.: National Osteoporosis Foundation; 2002.

3. Riggs BL, Melton LJ 3rd. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone. 1995;17(5 suppl):505S-11S.

4. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7:407-413.

5. US Congress, Office of Technology Assessment. Hip Fracture Outcomes in People Age 50 and Over - Background Paper. OTA-BP-H-120. Washington, DC: U.S. Government Printing Office; 1994.

6. Cummings SR, Kelsey JL, Nevitt MC, et al. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev. 1985;7:178-208.

7. Wehren LE, Barrett-Connor E. Quality of life in postmenopausal women with a history of fracture of the rib, spine, wrist, or hip: evidence from NORA. J Bone Miner Res. 2002;17(suppl 1):S359.

8. Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:24-35.

9. Lydick E, Cook K, Turpin J, et al. Development and validation of a simple questionnaire to facilitate identification of women likely to have low bone density. Am J Manag Care. 1998;4:37-48.

10. Cadarette SM, Jaglal SB, Kreiger N, et al. Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry. CMAJ. 2000;162:1289-1294.

11. Geusens P, Hochberg MC, van der Voort DJ, Siris E, et al. Performance of risk indices for identifying low bone density in postmenopausal women. Mayo Clin Proc. 2002;77:629-637.

12. Screening for postmenopausal osteoporosis. File Inventory, Systematic Evidence Review Number 17. Rockville, Md: Agency for Healthcare Research and Quality; 2002. Available at: http://www.ahcpr.gov/clinic/prev/ostscinv.htm .

13. Osteoporosis: review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis. Introduction. Osteoporos Int. 1998;8(suppl 4):S7-S80.

14. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 2001;286:2815-2822.

15. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Technical Report No. 843. Geneva, Switzerland: World Health Organization, 1994.

16. Black DM, Cummings SR, Genant HK, et al. Axial and appendicular bone density predict fractures in older women. J Bone Miner Res. 1992;7:633-638.

17. Cummings SR, Black DM, Nevitt MC, et al. Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993;341:72-75.

18. Klotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739.

19. Looker AC, Johnston CC Jr, Wahner HW, et al. Prevalence of low femoral bone density in older U.S. women from NHANES III. J Bone Miner Res. 1995;10:796-802.

20. Wainwright SA, Phipps KR, Stone JV, et al. A large proportion of fractures in postmenopausal women occur with baseline bone mineral density T-score >-2.5. J Bone Miner Res. 2001;16(suppl 1):S155.

21. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

22. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637-645.

23. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85:4118-4124.

24. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344-1352.

25. Chesnut CH 3rd, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109:267-276.

26. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI. JAMA. 1996;276:1389-1396.

27. Johnston CC Jr, Bjarnason NH, Cohen FJ, et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 double-blind, randomized, placebo-controlled trials. Arch Intern Med. 2000;160:3444-3450.

28. Hosking D, Chilvers CE, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med. 1998;338:485-492.

29. Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab. 1998;83:396-402.

30. Marcus R, Majumdar S. The nature of osteoporosis. In: Marcus R, Feldman D, Kelsey JL, eds. Osteoporosis. 2nd ed. San Diego, Calif: Academic Press; 2001:3-17.

Dr. Wehren is a Postdoctoral Fellow, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Md. Dr. Siris is Madeline C. Stabile Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons, and Director, Toni Stabile Osteoporosis Center, New York Presbyterian Hospital, New York, N.Y.

Key points

• Topping the National Osteoporosis Foundation's (NOF) list of risk factors for osteoporosis is a personal history of fracture during adulthood. Independently of bone mineral density (BMD) measurement and the site of previous fracture, these women are about twice as likely to experience a future fracture.

• Some 7.8 million women have osteoporosis, 21.8 million have low bone mass, and the numbers are escalating as baby boomers age. NOF recommends treating all women who have osteoporosis and some women with osteopenia.

• NOF recommendations make an important distinction between diagnostic BMD thresholds (WHO guidelines) and fracture risk/treatment thresholds and emphasize the added effect of risk factors.

• Although BMD measurements at the hip are considered the gold standard, measurements at peripheral sites are also used to diagnose and predict fracture risk.

• Regardless of the BMD site measured, overall skeletal fracture risk approximately doubles for each standard deviation decrease below the norm for young adults.

Lois Wehren, Ethel Siris. Cover Story: Managing bone loss.

Contemporary Ob/Gyn

Jul. 1, 2003;48:42-52.