At this year's annual meeting of the American College of Rheumatology (ACR), a variety of studies examined the potential role of bone anabolic agents in the treatment of osteoporosis. Other studies illustrated that increased bone mineral density (BMD) screening and treatment among women at high risk for osteoporosis can save money in the Medicare budget, which could possibly offset higher copayment costs for the screened and treated women. Studies of patients with rheumatoid arthritis (RA) revealed that hand BMD measurements may be accurate and standardizable markers of worsening disease. Other studies suggest that RA patients treated with corticosteroids or methotrexate may have increased risk of fracture.

Emerging Bone Anabolic Treatments for Postmenopausal Osteoporosis

A variety of treatments with proven efficacy for the management of postmenopausal osteoporosis are now available. Nevertheless, existing antiresorptive (ie, slow bone resorption) treatments have important limitations, fueling the continued search for new therapies. Bisphosphonates, such as alendronate and risedronate, have been shown to reduce vertebral fracture risk in older women by 50% or more and to reduce the risk of nonvertebral fractures by 30% to 40%.

However, these agents are associated with gastrointestinal adverse effects in some patients. Selective estrogen receptor modulators (SERMs) and estrogen also provide substantial protection against vertebral fractures but are associated with increases in certain cardiovascular adverse effects, such as deep venous thrombosis. SERMs' effect on nonvertebral fractures is uncertain. Recent data from the Women's Health Initiative^[1] randomized trial found that the cardiovascular and breast cancer risks from long-term use of conjugated estrogen plus medroxyprogesterone, the most widely used estrogen and progestin preparation, probably outweigh its beneficial skeletal effects. Finally, all of these approved antiresorptive agents offer partial protection against new fractures, a welcome benefit for patients with osteoporosis. However, many investigators believe that bone anabolic agents, those capable of increasing bone mass to a greater extent than antiresorptive agents, will offer even greater protection against the risk of fractures.

One such anabolic agent under investigation is strontium ranelate (SR), a bone-seeking compound that has a dual effect on bone metabolism, both stimulating bone formation and inhibiting bone resorption. Results from phase 2 and phase 3 randomized trials of SR, reported at recent scientific meetings and in publications,^[2] have shown substantial increases in spine BMD (up to 3% per year increases at the 2-g/d dose), femoral neck BMD, and prevention of new vertebral fractures. At this year's ACR meeting, Dr. Reginster and colleagues presented further data from the SOTI trial bearing on the fracture prevention efficacy of SR.^[3] The purpose of this multicenter, double-blinded, randomized, placebo-controlled study was to examine the efficacy of SR (2 g/d) in preventing new vertebral fractures during 3 years in 1649 postmenopausal women (mean age, 70 years) with established spinal osteoporosis.

All women received a daily supplement of elemental calcium and vitamin D. Bone density at the spine increased by more than 11% after 3 years in the women receiving 2 g/d of strontium compared with a loss of 1.3% in the placebo group. The incidence of new vertebral fractures was reduced by 41%, as reported at the June 2002 meeting of the World Congress on Osteoporosis in Lisbon. New results presented at the ACR showed that after just 1 year, the SR-treated women had fewer new vertebral fractures: 44 (6.1%) compared with 85 (11.8%) in the placebo group (relative risk [RR], 0.51; 95% confidence interval [CI], 0.35-0.73). In addition, antifracture efficacy was maintained during the third year of treatment, with the SR-treated women having fewer fractures (RR, 0.49; 95% CI, 0.33-0.74). Fewer of the women receiving strontium had new clinical vertebral fractures as well during the first year (RR, 0.47; 95% CI, 0.28-0.79).

These data for SR treatment and vertebral fracture are similar to what has been found for the bisphosphonates alendronate and risedronate. However, in contrast to the 30% to 40% reduction in nonspine fracture risk demonstrated for the latter 2 agents, no data are available addressing the effect of SR on nonspine fractures. So it is not yet clear what will differentiate this treatment from the already approved bisphosphonates and other anabolic agents under development. One possibility is a different adverse effect profile. In this large study, SR was well tolerated and no specific adverse events were observed, but more information is needed on long-term use. In addition, SR appears to increase markers of bone formation while simultaneously decreasing markers of bone resorption,^[2] suggesting that it may be possible to achieve maximum BMD increases with continuous use and without combined therapy with an antiresporptive agents. This is in contrast to parathyroid hormone (PTH), another promising anabolic agent, which dramatically increases bone formation while increasing bone resorption in a coupled fashion. Achieving the optimal skeletal effect with PTH may entail combining it in some way with an antiresorptive therapy,^[4] and exactly how this should be done is under investigation. Current PTH treatments are delivered by injection, but oral forms are under development.

PTH is a rising star among bone anabolic agents because of its large impact on bone density at trabecular rich sites and proven ability to reduce vertebral fractures.^[5,6] A study presented by Erikson and colleagues^[7] at the ACR suggests that the mechanisms by which the anabolic effects of PTH increase bone strength include inducing a more platelike structure in trabecular bone and an increase in cortical thickness. Both of these morphometric properties are related to increased bone strength. Using iliac crest bone biopsy specimens obtained 18 months after treatment in patients who received PTH (20 and 40 mcg of teriparatide [TPTD, rhPTH (1-34)]) or placebo, the authors used 3-dimensional computed tomography to compare 3-dimensional microarchitecture in the 2 groups. PTH increased trabecular bone volume by 60% vs -2% in placebo. Trabecular connectivity density increased by 40% in the treated groups and declined by 0.5% in the placebo group, whereas cortical thickness increased by 29% in the PTH group and decreased by 2% in the placebo groups. The authors conclude that these changes in cancellous and cortical bone morphologic findings "explain the increased biomechanical competence and reduced vertebral and nonvertebral fracture incidence after teriparatide treatment."

Getting Effective Interventions to Patients With Osteoporosis

Despite growing recognition of the adverse impact of fractures on the health and well-being of older women and men, several barriers continue to impede access to effective treatments by those in need. These barriers include underuse of bone density measurements among patients with risk factors (eg, a previous fracture), uncertainty about diagnosis in nonwhite women, and the costs of diagnosis and treatment.

Dr. Chhabra and colleagues^[8] reported on an education intervention study designed to improve diagnostic screening for postmenopausal osteoporosis in primary care practice. Primary care residents attended lectures on osteoporosis and learned how to use the Osteoporosis Risk Assessment Instrument (ORAI)^[9] screening instrument to identify women in need of bone density screening. Before the intervention, only 25% of women 45 years and older with ORAI scores that indicated a high risk for osteoporosis were referred for bone density tests. Importantly, the educational intervention appeared to have little impact on the referral rate among high-risk women. Lack of insurance coverage was cited as a primary factor in those not referred for testing. Clearly, access to BMD testing is constrained by the health insurance context and the costs of uncovered tests and treatments. This issue was addressed for the Medicare population in a study presented by Dr. King and colleagues^[10] that examined the costs and benefits of increased BMD testing for women in the Medicare-covered population.

The authors point out that only about 12% of the more than 15 million women 65 years and older who have low bone density or osteoporosis undergo BMD testing paid for by Medicare. They estimated that an increase in the number tested by 10% would result in a net savings of $15 million to the Medicare budget (reduction in medical costs due to fractures prevented minus testing costs and costs of adverse events from treatment). However, net costs to the Medicare patients were increased by almost $15 million (savings from copayments for fractures prevented minus copayments for BMD tests, bone-sparing medications, and treatment of adverse events). They recommend that Medicare take steps to increase BMD testing and use the savings to the program from fracture prevention to help offset the increased copay costs to the patients.

The ratio of benefits to costs in using BMD testing to screen for osteoporosis depends on how well the tests can be targeted to those at greatest risk. Many studies have addressed risk factors for low BMD in white women, and results from these studies have been used to develop screening questionnaires, such as the ORAI,^[9] to help select women for BMD testing. However, there is little information on how such risk factor screening might work in older nonwhite women, who have a lower but not insubstantial risk of fractures. Using data from the recent National Health and Nutrition Examination Survey (NHANES) III study, Drs. Magnus and Broussard^[11] evaluated how well low values for body mass index (BMI), physical activity, and calcium intake can identify white, African American, and Mexican women with BMD values indicative of osteoporosis (T-scores of -2.5 or less). T-score cutoffs for each group were derived from racial/ethnic-specific distributions for total femur among BMD among young, healthy women aged 20-35 years from the NHANES III data set. Using this approach, 9%, 12%, and 13% of the African American, Mexican American, and white women, respectively, ages 50-79 years were defined as having osteoporosis. In each racial/ethnic group, women with a low BMI had a 7- to 13-fold increased risk of osteoporosis. Of interest, calcium intake and physical activity were not consistently associated with either osteoporosis or osteopenia (T-scores of -2.5 to -1) in the nonwhite women. These results suggest that low weight or BMI may be useful in selecting older African America and Mexican American women for BMD testing. Additional work is needed to identify the best BMI or weight cutoffs for defining those at risk.

The use of racial/ethnic-specific BMD cutpoints for osteoporosis is controversial, since it is not known whether the risk of fracture in groups defined by these cutpoints is similar across racial/ethnic lines. An alternative approach is to use T-score cutpoints based on young normal reference populations for white women as the definition of osteoporosis regardless of race/ethnicity. If the risk of fracture at absolute BMD values is the same across racial/ethnic lines, then the same absolute cutpoints (in grams per square centimeters) that are used to diagnosis osteoporosis in white women could be used in nonwhite women. This would increase the proportion of minority women identified as having osteoporosis and at risk of fracture. However, until data definitively addressing this question are available, the conservative approach is to use racial/ethnic-specific T-scores.

Perhaps the biggest challenge facing osteoporosis treatment in the future will be competition for medical resources from other common debilitating and life-threatening diseases of aging. Although the number of hip fractures will continue to climb as the population ages, so will the number of elderly persons with dementia, cancer, heart disease, and other geriatric illness. Competition for scarce health care resources will increase the need for public health interventions for prevention of osteoporosis and fractures, which are inexpensive, safe, and widely applicable in the population. Dr. Silverman and colleagues^[12] reported the results of a study looking at psychosocial factors that influence whether postmenopausal women are likely to adopt positive bone health behaviors, including exercise, taking calcium and vitamin D supplements, managing chronic pain, and taking medicine for osteoporosis. One of the aims of the study was to test whether self-efficacy -- the belief that one is able to successfully undertake a course of action or reach a goal -- influences the adoption of these bone health behaviors. The authors reported that belief in the ability to perform any of the specific bone health behaviors was strongly related to belief in the ability to perform one or more of the other behaviors. In addition, more general "self-efficacy beliefs," such as belief in the ability to improve bone health and belief in the ability to manage stress, also predicted belief in the ability to perform the bone health behaviors. The value of this work is that it suggests ways in which education about osteoporosis prevention and treatment can be more effective, for example, by combining education with positive role modeling and support group discussion.

Bone-Related Issues of Special Relevance to the Rheumatic Diseases

RA is a chronic disease characterized by synovial inflammation that results in structural damage to the joint, including extensive erosion of bone around the joint margins. The severity of periarticular bone erosions in the finger joints is an important marker of disease activity and outcome in RA and a key component of radiologic scales measuring joint damage in RA, such as the Larsen score.^[13] A number of studies have examined the relationship between hand radiologic damage and BMD in patients with RA, seeking to determine if there is an association between disease activity and overall skeletal health. Another line of investigation has sought to determine if bone loss in the hand proceeds in parallel with radiographic hand joint damage and whether changes in hand bone density might serve as a useful early marker of disease activity. Haugeberg and colleagues^[14] studied 135 women with longstanding RA (mean duration, 17 years) and measured bone density in the hand using digital x-ray radiogammetry (DXR) of conventional hand x-ray films and DEXA of the hip and spine. In this cross-sectional study, the Larsen score was strongly correlated with hand BMD (r = 0.62), modestly correlated with total hip BMD (r = 0.26, P = .003), and weakly related to spine BMD (r = 0.10, P = .26). This preferential association of hand joint damage score with hand BMD confirms the findings of a previous study.^[15] The ACR presenters also determined that the hand BMD-Larsen score association was independent of age, BMI, disease duration, and deformed joint count. These findings support a possible role of hand BMD as a surrogate marker of cumulative disease activity. Hand BMD measurement has the potential to provide faster and more standardized information about RA progression compared with methods based on scoring of hand radiographs.

In a related abstract,^[16] the same group presented data from a 5-year longitudinal study of 102 RA patients with disease duration of fewer than 4 years. Hand BMD was measured sequentially using computerized radiogammetry (Pronosco X-posure system), and sequential hand x-ray films were read for joint damage using the Sharp score. Hand BMD declined rapidly, with a 3.4% loss by 2 years and a cumulative 5.4% loss at 5 years. Progressive structural deterioration was also seen in the Sharp score. Decline in hand BMD was strongly associated with decreases in Sharp score and was 3 times as great in hands showing structural progression as in those that did not progress. Decline in hand BMD after 2 years independently predicted 5-year change in Sharp score. The authors conclude that rapid hand bone loss in early RA predicts radiographic progression and hand BMD loss may be a useful marker of disease activity. Further investigation is needed to validate hand BMD as a marker of RA progression.

Patients with RA not only experience hand bone loss and joint damage but also are thought to have an increased risk of fractures. Bone loss and increased fracture risk in RA patients may result from loss of mobility, treatment with corticosteroids and other disease-modifying drugs, and inflammation.^[17] However, there are few studies that specifically examine risk factors for fracture in RA patients. Dr. Hochberg and colleagues^[18] used data from the largest longitudinal study of RA patients (n = 8076) to date to investigate factors associated with fractures during follow-up in the Vioxx Gastrointestinal Outcomes Research study. Fractures occurred at a rate of 2.7 per 100 patient-years during the study. They found not only that a number of risk factors for fracture in the RA patient are the same as in the general population (female sex, older age, white race, previous fracture) but also that use of specific treatments for RA, including corticosteroids and methotrexate, also increased fracture risk. Since BMD was not measured in this study, it is not clear if these treatments affected fracture risk by causing bone loss. It is possible that these treatments are also markers for more severe disease, and the functional disability that results may also be a factor in the greater fracture risk. Nevertheless, these results underscore the need to evaluate RA patients, particularly those treated with corticosteroids and methotrexate, for osteoporosis and to initiate osteoporosis therapy for those with low bone density or for whom long-term treatment with corticosteroids or methotrexate is needed.

Summary

• Despite the availability of several approved antiresorptive treatments for osteoporosis, including bisphosphonates and SERMs, there is a large-scale effort under way to develop bone anabolic agents that can achieve even greater fracture protection.
  
  
• At this year's ACR meeting, studies were presented showing that treatment of postmenopausal osteoporotic women with SR, a bone anabolic agent that appears to slow bone resorption, results in a rapid (1-year) and sustained (2-3 years) reduction in the risk of vertebral fractures comparable to that seen with the bisphosphonates. No data are available yet related to the effect of this treatment on risk of nonvertebral fractures, which are substantially reduced by the bisphosphonates alendronate and risedronate.
  
  
• PTH (1-34), another promising but not yet approved bone anabolic treatment for osteoporosis, reduces fracture risk by returning osteoporotic trabecular bone to a more normal platelike structure and thickening of cortical bone.
  
  
• Increased BMD screening and treatment among elderly women at high risk for osteoporosis is estimated to save money in the Medicare budget. These savings could be used to offset higher copayment costs for the screened and treated women.
  
  
• Patients with RA have increased bone loss in the hand, which is highly correlated with the progression of radiographic damage to the hand joints. Hand BMD measurements have promise as an easily standardizable marker of RA worsening.
  
  
• Patients with RA receiving either corticosteroids or methotrexate have an increased risk of fracture.
  
  

References

1. Writing Group for the Women's Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
2. Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis -- a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab. 2002;87:2060-2066.
3. Reginster J-Y, Sawicki A, Devogelaer JP, et al. Rapid and sustained anti-fracture efficacy of strontium ranelate in postmenopausal osteoporosis. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1571.
4. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet. 1997;350:550-555.
5. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.
6. Kurland E, Cosman F, McMahon D, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab. 2000;85;3069-3076.
7. Eriksen EF, Wang O, Genant HK, et al. Two- and 3-dimensional analysis of cancellous and cortical bone in a multicenter, double-blind, randomized and placebo-controlled study of teriparatide. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1570.
8. Chhabra A, McNearney TA, Shepherd A, Hussain N, Goel N. Low priority of diagnostic screening of osteoporosis by primary care residents. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 157.
9. Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Joseph L, Brown JP. Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry. JAMA. 2001;286:57-63.
10. King AB, Saag K, Burge RT, Balda EP, Pisu M, Goel N. The budget impact of current bone mineral density testing rates in the Medicare program. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1567.
11. Broussard DL, Magnus JH. Does a single osteoporosis screening profile work in three racial/ethnic groups of women? Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 967.
12. Silverman S, Gold DT, Conditt MK, Miller BE. Bone health behaviors and self-efficacy beliefs. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1044.
13. Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn. 1977;18:481-491.
14. Haugeberg G, Lodder MC, Lems WF, et al. Hand bone mineral density is associated with radiographic hand joint damage in patients with longstanding rheumatoid arthritis (RA). Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1398.
15. Ardicoglu O, Ozgocmen S, Kamanli A, Pekkutucu I. Relationship between bone mineral density and radiologic scores of hands in rheumatoid arthritis. J Clin Densitom. 2001;4:263-269.
16. Haugeberg G, Uhlig T, Strand A, Smedstad LM, Kvien TK. Hand bone loss in rheumatoid arthritis (RA) predicts subsequent radiographic hand joint damage. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1602.
17. Haugeberg G, Orstavik RE, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone loss in patients with rheumatoid arthritis: results from a population-based cohort of 366 patients followed up for two years. Arthritis Rheum. 2002;46:1720-1728.
18. Hochberg MC, Kvien TK, Schnitzer TJ, Krupa D, Reicin A, and the VIGOR Steering Committee. Risk factors for fracture in patients with rheumatoid arthritis. Program and abstracts of the American College of Rheumatology 66th Annual Scientific Meeting; October 25-29, 2002; New Orleans, Louisiana. Abstract 1605.