Analysis of 1-year vertebral fracture risk reduction data in treatments for osteoporosis. (Review Article).

Abstract: One-year vertebral fracture risk reduction from clinical trials in adults with postmenopausal or glucocorticoid-induced osteoporosis is reviewed. Data were obtained by conducting a literature search of osteoporosis medications using the MEDLINE database, bibliographies of selected citations, and recent meeting abstracts. The methodologic quality of the trials was assessed using recently published criteria for ranking evidence. In prospective analyses, the 1-year risk of new morphometric vertebral fractures was reduced by risedronate 5 mg/d in two 3-year studies in postmenopausal women with prevalent vertebral fracture, and in two 1-year studies in patients with or at risk for glucocorticoid-induced osteoporosis. The 1-year risk of clinical vertebral fractures was reduced by alendronate and raloxifene in post hoc analyses. Reduction of morphometrically identified vertebral fracture risk is a more stringent therapeutic goal than clinical vertebral fracture risk. Therefore, more weight should be given to data from studies that use the morphometry to assess vertebral fracture incidence.

Key Words: bisphosphonates, glucocorticoid-induced osteoporosis, osteoporosis, postmenopausal osteoporosis, vertebral fracture

**********

Key Points

* The prevalence of vertebral fracture approaches 20% in the white female population by age 70 years, and two-thirds of the patients are asymptomatic.

* The presence of asymptomatic vertebral fractures is a strong risk factor for future vertebral and hip fractures in untreated patients.

* The presence of a fragility vertebral fracture is diagnostic of osteoporosis, regardless of the patient's bone mineral density (BMD) or T-score.

* Patients 60 years of age and older who have lost height should undergo spinal radiography to identify fragility fractures.

* Risedronate has been shown to rapidly reduce the risk of new vertebral fractures within 1 year of treatment in prospective clinical trials.

* Alendronate and raloxifene have been shown in post hoc analysis of clinical trials to reduce the incidence of clinical vertebral fractures (captured as adverse events in case report forms) within 1 year of therapy.

* Physicians should assess patients for the presence of vertebral deformities, regardless of their BMD or T-scores.

Osteoporosis is a disorder characterized by microarchitectural deterioration of bone tissue leading to reduced bone mass, bone fragility, and an increased risk of fracture. (1) Currently, it is estimated that 10 million people in the United States have osteoporosis, and an additional 18 million have low bone mass. (2) In the United States, up to 30% of white postmenopausal women have osteoporosis according to World Health Organization (WHO) bone density criteria, and an additional 54% have low bone mineral density (BMD). (3)

Aging and reduced gonadal function are common risk factors for primary osteoporosis. (4) Declining estrogen levels at menopause result in increased bone turnover that favors resorption and loss of bone mass. (4) Secondary osteoporosis results from conditions or drugs that accelerate bone loss. The most common cause of secondary osteoporosis is the use of long-term oral glucocorticoid therapy. (5) Bone loss occurs even with low doses of glucocorticoids but is most rapid and extensive at prednisone doses of at least 5.0 mg/d or equivalent. (6) Loss of bone mass is most rapid during the first year of glucocorticoid therapy in areas containing the greatest proportion of trabecular bone (ie, spine, hip, distal radius, pelvis, ribs), and significant decreases can be seen as soon as 3 months after the initiation of therapy. (7)

Vertebral fractures are the most common type of osteoporotic fracture and are associated with deformity and morbidity. (8) The prevalence of women with vertebral fractures increases with age, from less than 15% for patients younger than 60 years old to 32% among those aged 75 years and older. (9) Approximately 30 to 50% of women and 20 to 30% of men develop vertebral fractures during their lifetimes, and approximately one-half of these individuals develop multiple fractures. (8,10) Vertebral fractures, as detected by radiography, occur in one of six patients within 1 year of initiating long-term glucocorticoid therapy with prednisone 7.5 mg/d or its equivalent. (11)

Clinically, vertebral fracture is suspected in patients with either back pain, vertebral deformities as assessed during a physical examination (kyphosis), or loss of height. Symptomatic or clinical vertebral fractures in osteoporotic patients are associated with pain and disability, which lead to loss of functional activity and quality of life. (12) The risk of pain and disability increases progressively with the number and severity of vertebral deformities and is multiplied several times with each additional fracture. (8,13,14) However, even women with asymptomatic vertebral deformities were more likely to have a history of increased back pain and back disability. (13) These data underscore the negative impact that even asymptomatic vertebral deformities have on affected individuals.

Asymptomatic vertebral deformities are often noted on routine chest x-rays. Nearly three-fourths of vertebral deformities are asymptomatic (15); therefore, the only valid methods to diagnose vertebral fracture in most patients are with a standard radiograph or with lateral morphometric views obtained with the use of newer dual x-ray absorptiometry (DXA) units. Instant vertebral assessment (IVA) and lateral vertebral assessment (LVA) are new technologies using advanced fan-beam DXA to provide rapid assessment of vertebral fractures and are highly correlated with vertebral fractures, as assessed on standard lateral spine x-rays. (16,17)

Once patients experience a vertebral fracture, including asymptomatic vertebral fractures, their risk of sustaining another vertebral fracture increases markedly. Patients with an existing vertebral deformity have a more than 12-fold risk during a 10-year period of sustaining another vertebral fracture as compared with control patients (ie, those without prevalent vertebral deformity). (18) Vertebral fractures increase the risk of experiencing another vertebral fracture or other osteoporotic fractures in affected individuals. One in five postmenopausal women with a vertebral fracture will experience another vertebral fracture within the next year even while receiving calcium and vitamin D supplementation. (15) Women with preexisting vertebral fractures have an approximate fourfold greater risk of subsequent vertebral fractures than those without prior fractures (19,20) and have an increased risk of hip fracture as well. (21) A symptomatic or an asymptomatic vertebral fracture increases the risk of subsequent hip fracture by 2.3-fold and distal forearm (Colles) fracture by 1.6-fold during a 10-year period. (18) Mortality rates are also higher in women who experience clinical vertebral fractures. (22-24)

The significant morbidity and mortality associated with vertebral fractures, the associated risk of further osteoporotic vertebral fractures in the year after initial fracture, and the high risk of this fracture during the first year of long-term glucocorticoid therapy are compelling reasons for physicians to reduce vertebral fracture risk as rapidly as possible in patients with osteoporosis. The objectives of this systematic review are to assess and summarize the literature concerning 1-year vertebral fracture risk reduction data from osteoporosis clinical trials and to make recommendations concerning treatment.

Methods

A literature search was conducted to identify studies published in English-language journals since 1990 concerning treatment to reduce vertebral fracture risk. The MEDLINE electronic database, bibliographies of selected citations, and recent meeting abstracts were used to identify potential studies. MEDLINE search terms included osteoporosis, treatment, and the generic names of medications currently approved for the treatment of osteoporosis in the United States (ie, risedronate, alendronate, raloxifene, salmon calcitonin). Treatment studies in patients with osteoporosis or in those at risk for developing osteoporosis were identified. The studies selected for review included those that had 1-year vertebral fracture data (eg, fracture incidence, relative risk reduction, absolute risk reduction data). The number needed to treat (NNT) is an increasingly popular indicator of fracture efficacy and reflects the number of patients that need to be treated to prevent one event. (25) In a therapeutic trial, the NNT is the inverse of the absolute benefit of intervention, that is, the difference between the proportion of events in the control group (Pc) and the proportion of events in the intervention group (Pi): NNT = 1 / (control group [Pc] -- intervention group [Pi]).

Because NNT is often used by physicians to justify the use of one particular drug over another, NNT data are provided where possible and represent the number of patients that need to be treated for 1 year to prevent one vertebral fracture. Study quality was also rated according to a recently published evidence scale (26) in which Level A represents high-quality randomized, controlled studies or meta-analyses; Level B represents other evidence, including well-designed, nonrandomized clinical trials, low-quality randomized, controlled trials (eg, post hoc subgroup analyses), or data presented in abstract form; and Level C represents consensus or expert opinion.

Results

During the past 5 years, a number of well-designed prospective clinical trials assessing the efficacy of treatments for osteoporosis have been conducted in postmenopausal women and in patients receiving long-term glucocorticoids (Table 1). Because regulatory authorities in the United States and Europe require 3-year fracture data for osteoporosis drug approval, the majority of studies conducted in postmenopausal women have had a 3-year duration. One-year vertebral fracture data were prospectively analyzed in 2 of these studies in postmenopausal women, (27,28) while these data were obtained via post hoc analysis in other studies. In the studies conducted in postmenopausal women, most had established osteoporosis (ie, prevalent vertebral fracture at baseline and/or had [less than or equal to]-2.0 at one of the skeletal sites tested). Studies conducted in patients receiving long-term glucocorticoids have typically had a 1-year duration and reported vertebral fracture incidence for this time frame. Patients in al l of the studies shown in Table 1 received calcium supplementation and vitamin D supplementation if needed.

Vertebral fracture risk reduction was a primary outcome measure in the postmenopausal osteoporosis studies and was a secondary outcome measure (along with change in BMD) assessed in the glucocorticoid-induced osteoporosis studies. Because only approximately one-fourth of vertebral fractures identified radiographically are recognized clinically, (15) it is important to consider the method used to assess vertebral fracture incidence when evaluating osteoporosis treatment studies. Although assessment of the spine for vertebral fractures on the basis of conventional radiographs is a traditional approach, inconsistent criteria for defining vertebral fracture by x-ray have led to the development of methods based on vertebral morphometry. (29) Quantitative and semiquantitative morphometry provides a precise method for defining vertebral fracture or deformity, is more accurate and reproducible than qualitative assessment of spinal radiographs, detects more vertebral fractures, and accordingly, is frequently used in clinical research and epidemiological studies. (30-32)

Most estrogen data showing fracture benefit are case controlled, (33-36) with the exception of the recent Women's Health Initiative (WHI) randomized controlled trial. (37) Other currently approved osteoporosis treatments (risedronate, alendronate, raloxifene, and salmon calcitonin nasal spray) have demonstrated a reduction in the risk of vertebral fractures in postmenopausal women over the long term (3-5 years) in well-designed prospective clinical trials. (27,28,38-41) The following discussion focuses on available data on 1-year vertebral fracture risk reduction with these drugs.

Postmenopausal Osteoporosis

Risedronate. Risedronate is approved for both prevention and treatment of postmenopausal and glucocorticoid-induced osteoporosis and is available in both once-daily (5 mg) and once-weekly (35 mg) formulations. (42) In randomized studies of postmenopausal women with osteoporosis, risedronate reduced the risk of radiologically detected vertebral fracture within 1 year (Table 1). The Vertebral Efficacy with Risedronate Therapy (VERT) studies evaluated the effect of risedronate on fracture risk in postmenopausal women with osteoporosis. The North American study (VERT-NA) enrolled 2,458 patients with at least 2 vertebral fractures at baseline or 1 vertebral fracture and lumbar spine T-score [less than or equal to]-2 at baseline(28); the multinational study (VERT-MN) assessed 1,226 patients with at least 2 vertebral fractures at baseline.(27) These studies prospectively assessed 1-year vertebral fracture risk reduction. Risedronate 5 mg/d significantly reduced the risk of morphometric vertebral fractures by 65 and 61% (NNT = 25 and 21) after 1 year of treatment in the VERT-NA and VERT-MN studies, respectively (Table 1).

In an abstract that reported the results of a combined analysis of the VERT studies, risedronate 5 mg/d produced a statistically significant 69% reduction in the risk of clinical vertebral fractures after 1 year among risedronate 5 mg/d recipients.(43) In addition, this analysis found a significant reduction in the risk of vertebral fractures diagnosed clinically after 6 months of therapy (P < 0.01).(43) A recent abstract containing the results of a meta-analysis of 5 trials (including the VERT studies) reported that risedronate 5 mg/d reduced the 1-year risk of new morphometric vertebral fractures by 64% (NNT = 21).(44)

The large Hip Intervention Program (HIP) study assessed the effect of risedronate on 3-year hip fracture risk in 9,331 women aged 70 to 79 years with established osteoporosis by WHO criteria (T score [less than or equal to]2.5) and in women at least 80 years of age with at least one nonskeletal risk factor for hip fracture or low BMD at the femoral neck.(45) In a post hoc analysis of HIP study data (in abstract form), treatment with risedronate 5 mg/d significantly reduced the 1-year risk of new morphometric vertebral fractures by 55% (NNT 37).(46)

Alendronate. Alendronate is approved for prevention and treatment of postmenopausal osteoporosis and for treatment of glucocorticoid-induced osteoporosis and is available in the following formulations: for the treatment of postmenopausal women once daily (10 mg) and once weekly (70 mg) and for prevention in postmenopausal women once daily (5 mg) and once weekly (35 mg).(47) Most of the alendronate studies reported vertebral fracture risk reduction after 3 or more years of treatment. In an early Phase III study, lateral spine radiographs were done after 1, 2, and 3 years of therapy to detect vertebral fractures and progression of vertebral deformities; however, only 3-year fracture risk data were reported.(48) The Fracture Intervention Trial (FIT) studied the effect of alendronate on the incidence of vertebral and nonvertebral fractures in postmenopausal women with low femoral neck BMD using the Hologic database (T-score at least -2.0 and at least one vertebral fracture)(38) or T-score at least -2.0 and no ve rtebral fracture).(39) When the data were reanalyzed using T-scores derived from the Third National Health and Nutrition Examination Survey (NHANES III), the threshold T-score for inclusion in FIT was -1.6.(49)

Efficacy data were reported in two separate arms of the FIT trial, a 3-year arm in 2,027 patients with at least 1 vertebral fracture at baseline (FIT 1)(38) and a 4-year arm in 4,432 patients with no vertebral fractures at baseline (FIT 2).(39) The dose of alendronate used in these studies was 5 mg/d for the first 2 years, then 10 mg/d for the subsequent years. Spinal radiographs were obtained at 2 and 3 years after randomization in FIT 1 and at 4 years in FIT 2; therefore, 1-year morphometric fracture data are not available for either study. Two post hoc analyses of FIT data reported a significant reduction in the 1-year risk of new clinical fractures with alendronate in women with confirmed postmenopausal osteoporosis (Table 1).(49,50) Clinical vertebral fractures were defined as those that came to the medical attention of the investigators (most often because of back pain). Fracture incidence was not reported in these analyses; therefore, absolute risk reduction and NNT data are not available.

Another post hoc analysis using alendronate reported a significant 100% (P = 0.044) reduction in the risk of multiple clinical fractures at 6 months.(50) One problem with using multiple vertebral fractures as an outcome is that it ignores the first new vertebral fracture during the observation period. In the case of the 6-month clinical fracture data described above, this means that patients had already experienced 1 clinical vertebral fracture (and perhaps multiple fractures had they been assessed morphometrically). Similar clinical vertebral fracture results were obtained in a third analysis of FIT data presented in abstract form.(51) In this analysis, the relative risk of new clinical vertebral fractures was reduced by 68% in 942 patients who had a morphometrically defined vertebral fracture at baseline and by 54% in 2,799 patients who did not have a preexisting vertebral fracture (P values not available).

Raloxifene. Raloxifene is a selective estrogen receptor modulator approved for the prevention and treatment of osteoporosis in postmenopausal women.(41,52,53) Raloxifene 60 mg/d significantly reduced vertebral fracture risk after 3 years in a preplanned analysis of 7,705 postmenopausal women With osteoporosis.(41) In a post hoc analysis, raloxifene significantly reduced the 1-year incidence of new clinical vertebral fractures by 68% in the overall study population and by 66% among women with prevalent vertebral fracture (Table 1).(54) Absolute risk reduction and NNT data were not available in this analysis, which was presented in abstract form.

Salmon Calcitonin. The nasal spray formulation of calcitonin salmon is approved for the treatment of women with osteoporosis who are more than 5 years postmenopausal.(54) Fracture risk after treatment with calcitonin nasal spray was assessed in a 5-year trial of 1,255 postmenopausal women with established osteoporosis.(40) Based on a graph of cumulative percentage of participants with at least 1 fracture, vertebral fracture risk was not significantly reduced after 1 year of therapy with salmon calcitonin nasal spray (100, 200, or 400 IU/d) and was significantly reduced after 5 years only in the 200 IU/d group.

Estrogen Replacement Therapy (ERT). ERT is approved for prevention of bone loss but not for treatment of postmeno-pausal osteoporosis. The antifracture efficacy of ERT has only recently been assessed in 1 large prospective randomized clinical trial conducted by the WHI; however, most data are based almost entirely on observational studies.

The WHI conducted a large randomized trial to determine whether estrogen plus progestin had favorable outcomes on coronary heart disease incidence and on overall risks in predominantly healthy postmenopausal women. A subanalysis of the WHI studied the effects of estrogen plus progestin on fracture risk. Results indicate that estrogen plus progestin reduced the observed hip and clinical vertebral fracture rates by one-third compared with placebo. (37) This is the first trial with definitive data supporting the hypothesis that postmenopausal hormones may prevent fractures at hip, vertebrae, and other sites. However, this trial was stopped early because of the increased risk of breast cancer and cardiac disease associated with combined estrogen and progesterone treatment. (37)

There is further evidence of reduction in nonspine fracture risk among ERT users who initiate therapy early (before age 60) and continue it over the long term. (35) A trial conducted to study the effects of hormone replacement therapy (HRT) on heart disease recruited more than 2,700 postmenopausal women and also collected data on fracture occurrence. Only 20% of the women had osteoporosis by WHO criteria. No significant difference in fracture risk was identified between those receiving HRT and those receiving placebo (mean follow-up, 4.1 yr). (35) Prospective clinical data assessing ERT in glucocorticoid-induced osteoporosis are limited to a subgroup analysis of 42 postmenopausal women with rheumatoid arthritis who received low-dose corticosteroids: ERT recipients had a significant increase in lumbar spine BMD relative to control patients. (55)

Glucocorticoid-induced Osteoporosis

Risedronate. Risedronate 5 mg/d also reduced the risk of vertebral fracture after 1 year of therapy in studies of patients receiving oral glucocorticoids (prednisone [greater than or equal to]7.5 mg or its equivalent). (11,56) Two randomized, placebo-controlled, 1-year studies for the prevention (11) and treatment (56) of glucocorticoid-induced osteoporosis were conducted (Table 1). The prevention study included 224 men and women who had begun taking glucocorticoids (prednisone [greater than or equal to]7.5 mg/d or equivalent) within the previous 3 months and who were expected to continue treatment for another 12 months. (11) The treatment study included 290 men and women who had been receiving oral glucocorticoids (mean daily dose of prednisone [greater than or equal to]7.5 mg or equivalent) for at least 6 months. (56) The 1-year risk of new vertebral fractures was reduced by 71% (NNT = 9) in the prevention study (11) and by 70% (NNT = 10) in the treatment study. (56) When data from the populations of these two studies were combined, risedronate 5 mg/d produced a significant 70% (P = 0.01; NNT = 10) reduction in 1-year radiographic vertebral fractures relative to placebo. (57)

Alendronate. One year of treatment with alendronate did not reduce the risk of vertebral fracture in patients receiving glucocorticoids. (58) In 477 patients who underwent glucocorticoid therapy ([greater than or equal to]7.5 mg/d prednisone or equivalent), alendronate 5 or 10 mg/d for 48 weeks did not significantly reduce the risk (40%; not significant) of morphometrically defined new vertebral fractures. (58)

Discussion

Fracture is the most serious clinical manifestation of osteoporosis and, accordingly, fracture prevention is the most meaningful and clinically relevant health benefit of osteoporosis prevention or treatment. (59) There is significant morbidity and mortality associated with osteoporotic vertebral fractures, even those that do not come to clinical attention, that is, asymptomatic vertebral fractures. (21,22,60) The significance of these asymptomatic vertebral fractures (detected by radiography) on future risk has only recently been examined. (14,15) The common occurrence of vertebral fracture within 1 year after prior vertebral fracture (15) or after beginning glucocorticoids (oral prednisone [greater than or equal to]7.5 mg/d or equivalent) (11) indicates that interventions having the potential to reduce fracture risk within 1 year have clinical utility.

A number of therapies available for the management of osteoporosis (ie, risedronate, alendronate, raloxifene, salmon calcitonin nasal spray) have been shown to reduce the risk of vertebral fractures in postmenopausal women over the long term (3-5 years). However, despite the fact that osteoporosis is a rapidly progressive disease, few data from prospective clinical trials assess vertebral fracture risk reduction at 1 year or less, and much of these data are derived from post hoc analyses using clinical vertebral fracture as the end point. Post hoc analyses are prone to a number of methodological shortcomings, especially with regard to patient selection bias (ie, analyzing subgroups of patients most likely to have a favorable outcome). (61,62) Moreover, clinical detection (ie, pain) followed by radiographic confirmation underestimates vertebral fracture incidence and is the less rigorous alternative to prospective radiographic/morphometric detection of vertebral fractures since most vertebral fractures do not cause pain. Therefore, antifracture data from subgroup analyses, particularly those that use clinical vertebral fracture as the main end point, need to be interpreted with caution.

In postmenopausal women and patients receiving long-term glucocorticoids, 1 year of treatment with risedronate produced a statistically significant reduction in the risk of morphometrically detected vertebral fractures in preplanned analyses. (27,28,56) Data supporting a 1-year vertebral fracture risk reduction for alendronate and raloxifene are post hoc analyses of clinical (painful) vertebral fractures. (49,50,54) Vertebral fracture risk was not reduced after 1 year of treatment with salmon calcitonin nasal spray. (40)

Careful assessment of how rapidly a treatment shows antifracture effect in clinical trials will facilitate selection of the most appropriate and effective therapy for patients with osteoporosis and those who are at risk for its development. Patients with asymptomatic vertebral fractures not treated have a one in five chance of having another vertebral fracture within 12 months. Risedronate has provided the best prospective data to date to support a rapid (1-year) reduction in morphometric vertebral fracture risk in postmenopausal and glucocorticoid-induced osteoporosis. In post hoc analyses, both alendronate as well as risedronate have been shown to reduce clinical vertebral fractures within 1 year of treatment.

Table 1.

Summary of 1-year vertebral fracture data from osteoporosis clinical
trials (a)


                             Type of analysis
Series (ref. no.)            (level of evidence) (b)

Postmenopausal osteoporosis

 Harris et al, 1999 (28)     Primary analysis (A)
  (VERT-NA)


 Black et al, 2000 (51)      Post hoc analysis of subset
                             of FIT (B)




 Cohen et al, 2000 (46)      Post hoc analysis of HIP
                             data (B)




 Quandt, 2000 (51)           Post hoc analysis of subset
                             of FIT (B)

 Reginster et al, 2000 (27)  Primary analysis (A)
  (VERT-MN)


 Pols et al, 2001 (54)       Post hoc analysis of MORE (B)





 Watts et al, 2001 (43)      Post hoc analysis of VERT (B)




 Chesnut et a], 2002 (44)    Meta-analysis of five
                             trials (B)





 Levis et al, 2002 (50)      Post hoc analysis of subset
                             of FIT (B)




Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)       Primary analysis (A)



 Cohen et al, 1999 (11)      Primary analysis (A)



 Reid et al, 2000 (56)       Primary analysis (A)



 Wallach et al, 2000 (57)    Post hoc analysis of
                             data from Cohen
                             et al (11) and Reid et al (56)



                             Full study or
Series (ref. no.)            abstract data

Postmenopausal osteoporosis

 Harris et al, 1999 (28)      Full study
  (VERT-NA)


 Black et al, 2000 (51)       Full study





 Cohen et al, 2000 (46)        Abstract





 Quandt, 2000 (51)             Abstract


 Reginster et al, 2000 (27)   Full study
  (VERT-MN)


 Pols et al, 2001 (54)         Abstract





 Watts et al, 2001 (43)        Abstract




 Chesnut et a], 2002 (44)      Abstract






 Levis et al, 2002 (50)       Full study





Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)        Full study



 Cohen et al, 1999 (11)       Full study



 Reid et al, 2000 (56)        Full study



 Wallach et al, 2000 (57)     Full study




                             Baseline osteoporosis
                             characteristic (no. of
Series (ref. no.)            patients)

Postmenopausal osteoporosis

 Harris et al, 1999 (28)     [greater than or equal to]1
  (VERT-NA)                  vertebral fracture (1,329)


 Black et al, 2000 (51)      [greater than or equal to]1
                             vertebral fracture or
                             femoral neck T-score
                             [less than or equal to]-2.5
                             (3,658)

 Cohen et al, 2000 (46)      Age 70-79 yr with osteoporosis
                             or age 80-89 yr with low
                             femoral neck BMD or risk
                             factor for hip fracture (9,331


 Quandt, 2000 (51)           Femoral neck T-score between
                             -2.5 and -1.6 (3,741)

 Reginster et al, 2000 (27)  [greater than or equal to]2
  (VERT-MN)                  vertebral fractures (667)


 Pols et al, 2001 (54)       [greater than or equal to]1
                             vertebral fracture or
                             femoral neck/lumbar
                             spine T-score [less than
                             or equal to]-2.5 (7,705)

 Watts et al, 2001 (43)      [greater than or equal to]1
                             vertebral fracture at
                             baseline (1,996)


 Chesnut et a], 2002 (44)    [greater than or equal to]1
                             vertebral fracture or
                             femoral neck T-score
                             [less than or equal to]-2.5
                             (3,331)


 Levis et al, 2002 (50)      [greater than or equal to]1
                             vertebral fracture or femoral
                             neck T-score
                             [less than or equal to]-2.5
                             (3,658)

Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)       Men/women initiating/receiving
                             long-term GC (477)


 Cohen et al, 1999 (11)      Men/women initiating
                             long-term GC (224)


 Reid et al, 2000 (56)       Men/women receiving
                             long-term GC (290)


 Wallach et al, 2000 (57)    Men/women initiating/receiving
                             long-term GC (518)





Series (ref. no.)            Regimen

Postmenopausal osteoporosis

 Harris et al, 1999 (28)     RIS 5 mg/d
  (VERT-NA)
                             Placebo

 Black et al, 2000 (51)      ALEN 5 mgld for 2 yr,
                              then 10 mg/d




 Cohen et al, 2000 (46)      RIS 5 mgld



                             Placebo

 Quandt, 2000 (51)           ALEN 5 mg/d for 2 yr,
                              then 10 mg/d

 Reginster et al, 2000 (27)  RIS 5 mg/d
  (VERT-MN)
                             Placebo

 Pols et al, 2001 (54)       RAL 60 or 120 mg/d





 Watts et al, 2001 (43)      RIS 5 mg/d


                             Placebo

 Chesnut et a], 2002 (44)    RIS 5 mg/d




                             Placebo

 Levis et al, 2002 (50)      ALEN 5 mg/d for 2 yr,
                              then 10 mg/d




Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)       ALEN 5 or 10 mgld

                             Placebo

 Cohen et al, 1999 (11)      RIS 5 mgld

                             Placebo

 Reid et al, 2000 (56)       RIS 5 mg/d

                             Placebo

 Wallach et al, 2000 (57)    RIS 5 mg/d


                             Placebo

                               Patients with new        Method of
                             (ie, first) vertebral    assessment of
Series (ref. no.)                fracture (%)       vertebral fracture

Postmenopausal osteoporosis

 Harris et al, 1999 (28)             2.4%              Morphometric
  (VERT-NA)
                                     6.4%

 Black et al, 2000 (51)               NR                 Clinical





 Cohen et al, 2000 (46)              2.3%              Morphometric



                                     5.0%

 Quandt, 2000 (51)                    NR                 Clinical


 Reginster et al, 2000 (27)          5.6%              Morphometric
  (VERT-MN)
                                     13.0%

 Pols et al, 2001 (54)                NR                 Clinical





 Watts et al, 2001 (43)              0.6%                Clinical


                                     1.7%

 Chesnut et a], 2002 (44)            3.3%              Morphometric




                                     8.1%

 Levis et al, 2002 (50)               NR                 Clinical





Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)               2.3%              Morphometric

                                     3.7%

 Cohen et al, 1999 (11)              5.7%              Morphometric

                                     17.3%

 Reid et al, 2000 (56)               5.0%              Morphometric

                                     15.0%

 Wallach et al, 2000 (57)            5.4%              Morphometric


                                     16.2%


                                 RRR vs         ARR vs
Series (ref. no.)              placebo (%)    placebo (%)  NNT

Postmenopausal osteoporosis

 Harris et al, 1999 (28)     65% (P < 0.001)     4.0%      25
  (VERT-NA)


 Black et al, 2000 (51)      59% (P < 0.001)      NR       NR





 Cohen et al, 2000 (46)      55% (P < 0.001)     2.7%      37





 Quandt, 2000 (51)           60% (P = 0.005)      NR       NR


 Reginster et al, 2000 (27)  61% (P = 0.001)     7.4%      14
  (VERT-MN)


 Pols et al, 2001 (54)        68% (P [less        NR       NR
                              than or equal
                                to] 0.05)



 Watts et al, 2001 (43)      69% (P = 0.009)     1.1%      91




 Chesnut et a], 2002 (44)    64% (P < 0.001)     4.8%      21






 Levis et al, 2002 (50)      61% (P = 0.021)      NR       NR





Glucocorticoid-induced
osteoporosis

 Saag et al, 1998 (58)          40% (NS)         1.4%      71



 Cohen et al, 1999 (11)      71% (P = 0.072)     11.6%      9



 Reid et al, 2000 (56)       70% (P = 0.125)     10.0%     10



 Wallach et al, 2000 (57)    70% (P = 0.01)      10.8%     10




(a) ALEN, alendronate; ARR, absolute risk reduction; FIT, Fracture
Intervention Trial; GC, glucocorticoids; HIP, Hip Intervention Program;
MORE, Multiple Outcomes of Raloxifene Evaluation; NNT, number needed to
treat; NR, not reported; NS, not significant; RAL, raloxifene; RIS,
risedronate; RRR, relative risk reduction; VERT-MN. Vertebral Efficacy
with Risedronate Therapy-multinational study; VERT-NA, Vertebral
Efficacy with Risedronate Therapy-North American study.

(b.) Study quality was rated using a recently published scale. (26)
Level A represents high-quality, randomized, controlled studies or
metaanalyses, Level B is other evidence, including well-designed,
nonrandomized clinical trials; low-quality, randomized, controlled
trials; (eg, post hoc subgroup analyses), or data presented in abstract
form. Level C represents consensus and/or expert opinion.

Accepted February 27, 2003.

References

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From the University of Colorado Health Sciences Center and the Colorado Center for Bone Research, Lakewood, CO.

Reprint requests to Paul Miller, MD, Medical Director, Colorado Center for Bone Research, 3190 S. Wadswarth Boulevard, Suite 250, Lakewood, CO 80227. Email: [e-mail]

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