0
Reviews |

Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis FREE

Catherine MacLean, MD, PhD; Sydne Newberry, PhD; Margaret Maglione, MPP; Maureen McMahon, MD; Veena Ranganath, MD; Marika Suttorp, MS; Walter Mojica, MD; Martha Timmer, MS; Alicia Alexander, MD; Melissa McNamara, MD; Sheetal B. Desai, MD, MS; Annie Zhou, MS; Susan Chen, BA; Jason Carter, BA; Carlo Tringale, BA; Di Valentine, JD; Breanne Johnsen, BA; and Jennifer Grossman, MD
[+] Article and Author Information

From the Southern California Evidence-based Practice Center, which includes RAND, Santa Monica, and the Greater Los Angeles Veterans Administration Healthcare System and the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California.


Disclaimer: Dr. MacLean is employed by WellPoint. This paper and its content reflect the views of Dr. MacLean and have not been reviewed or endorsed by WellPoint.

Acknowledgment: The authors acknowledge the guidance provided by the Technical but have Expert Panel members: Marc C. Hochberg, MD, MPH; Lee J. Melton III, MD, MPH; Paul D. Miller, MD; Marcel E. Salive, MD, MPH; and Katherine Sherif, MD. They also acknowledge the careful work of the reviewers, and the invaluable assistance of Julie Newell, Jianglai Zhang, Scott Hiromoto, Yuyan (Sabrina) Shi, and Zhen (Frank) Wang.

Grant Support: Prepared under contract with the Agency for Healthcare Research and Quality (contract no. 290-02-003).

Potential Financial Conflicts of Interest:Stock ownership or options (other than mutual funds): J. Grossman (Johnson & Johnson).

Requests for Single Reprints: Margaret Maglione, MPP, RAND Corporation, 1776 Main Street, Santa Monica, CA 90401; e-mail, maglione@rand.org.

Current Author Addresses: Dr. MacLean: WellPoint, 4553 LaTienda Drive, M/S CAT102-C003, Thousand Oaks, CA 91362.

Dr. Newberry, Ms. Maglione, Ms. Suttorp, Ms. Timmer, Ms. Zhou, Ms. Chen, Mr. Carter, Mr. Tringale, Ms. Valentine, and Ms. Johnsen: RAND Corporation, 1776 Main Street, Santa Monica, CA 90407-2138.

Drs. McMahon, Ranganath, Desai, and Grossman: University of California, Los Angeles, 1000 Veteran Avenue 32-59, Los Angeles, CA 90095.

Dr. Mojica: Kaiser Permanente, 393 Walnut Center, Pasadena, CA 91188.

Dr. Alexander: c/o Margaret Maglione, MPP, RAND Corporation, 1776 Main Street, Santa Monica, CA 90401.

Dr. McNamara: Arthritis and Rheumatology Center, 5601 Norris Canyon Road, Suite 340, San Ramon, CA 94583.


Ann Intern Med. 2008;148(3):197-213. doi:10.7326/0003-4819-148-3-200802050-00198
Text Size: A A A

Background: Although several agents are available to treat osteoporosis, the relative efficacy and toxicity of these agents when used to prevent fractures has not been well described.

Purpose: To compare the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis.

Data Sources: MEDLINE (1966 to November 2007) and other selected databases were searched for English-language studies.

Study Selection: For the efficacy analysis, investigators selected studies that reported the rate of or risk for fractures. For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thromboembolic, or upper gastrointestinal events; malignant conditions; and osteonecrosis.

Data Extraction: Using a standardized protocol, investigators abstracted data on fractures and adverse events, agents and comparators, study design, and variables of methodological quality.

Data Synthesis: Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen–progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding.

Limitation: Few studies have directly compared different agents or classes of agents used to treat osteoporosis.

Conclusion: Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.

Editors' Notes
Context

  • Sorting through the proven benefits and harms of the agents available for treating osteoporosis is difficult.

Contribution

  • This systematic review of 76 randomized trials and 24 meta-analyses found good evidence that multiple agents, including alendronate, zoledronic acid, and estrogen, prevented vertebral and hip fractures more than placebo. Harms included increased risk for thromboembolic events with raloxifene, estrogen, and estrogen–progestin and increased gastrointestinal symptoms with bisphosphonates. No large trials directly compared 2 or more agents and established superiority of any agent.

Implication

  • Available data insufficiently characterize the benefits and harms of various therapies for osteoporosis relative to one another.

—The Editors

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (1). Approximately 44 million people in the United States are affected by osteoporosis and low bone mass (2). The clinical complications include fractures, disability, and chronic pain. About 54% of women age 50 years or older will have an osteoporotic fracture during their lifetime (3). Furthermore, approximately 4% of patients older than 50 years of age who have a hip fracture die while in the hospital and 24% die within 1 year after the hip fracture (4).

The economic burden of osteoporosis is large and growing. Most estimates are based on the cost of fracture alone: A 1995 estimate of costs incurred by osteoporotic fractures in the United States was $13.8 billion (5). A 2003 review estimated the total costs in the United States at $17 billion (6). Although the bulk of these costs were incurred by retired individuals older than age 65 years, direct costs and work loss are significant among employed postmenopausal women (7). The increasing prevalence and cost of osteoporosis have heightened interest in the efficacy and safety of the many agents available to treat the loss of bone mineral associated with osteoporosis.

This systematic review, developed under the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program, describes the benefits in fracture reduction and the harms from adverse events among and within the various classes of pharmacotherapies for osteoporosis. The agents evaluated were bisphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid), calcitonin, estrogen, teriparatide, selective estrogen receptor modulators (raloxifene and tamoxifen), testosterone, and vitamins (vitamin D) and minerals (calcium).

We followed a standardized protocol for the review. The full technical report (8) provides detailed methods, evidence tables, and risk estimates for individual studies. The full report also enumerates studies included in the meta-analyses described in this review.

Data Sources and Study Selection

We searched MEDLINE (1966 to December 2006), the ACP Journal Club database, the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews (no date limits), and the Web sites of the National Institute for Health and Clinical Excellence (no date limits) and Health Technology Assessment Programme (January 1998 to December 2006) for materials pertaining to the specified agents, limiting our searches to English-language publications and human studies. We first identified systematic reviews and meta-analyses of trials that reported pooled estimates of the effect of the agents on fracture risk. When such reviews were identified for specific agents, we truncated our searches for randomized trials to include only those published after the last search date used in the review or meta-analysis. We manually searched reference lists of all review articles obtained for any reports of original research not already identified, and we reviewed U.S. Food and Drug Administration (FDA) medical and statistical reviews, scientific information packets from pharmaceutical companies, and additional studies recommended by our technical expert panel and by stakeholders during a public review period. To supplement the information in systematic reviews on estrogen, we reviewed the Women's Health Initiative and Heart and Estrogen/progestin Replacement Study trials, as suggested by our technical expert panel. Finally, we conducted an additional search for large observational studies that reported any of the following adverse events: 1) cardiovascular events (myocardial infarction and stroke); 2) thromboembolic events (pulmonary embolism and venous thromboembolic events); 3) malignant conditions (breast cancer, colon cancer, lung cancer, and osteosarcoma); 4) upper gastrointestinal events (perforations, ulcers, bleeding, and esophageal ulcerations); and 5) osteonecrosis. The search was updated for this paper, but not for the full report, by searching MEDLINE (1 January 2007 to 10 November 2007) for large clinical trials that reported fracture outcomes for the specified agents.

For information on efficacy, we selected meta-analyses that reported pooled risk estimates for fracture and randomized trials that compared any of the agents with placebo or with each other and reported fracture outcomes. For information on harms, we selected systematic reviews, randomized trials, and large case–control or cohort studies with more than 1000 participants. We also reviewed cases of osteonecrosis at AHRQ's request.

Data Extraction and Study Quality

Two physicians independently abstracted data about study populations, interventions, follow-up, and outcome ascertainment by using a structured form. For each group in a randomized trial, a statistician extracted the sample size and number of persons who reported fractures. Two reviewers, under the supervision of the statistician, independently abstracted information about adverse events. Disagreements were resolved by the statistician or the principal investigator. Adverse events were recorded onto a spreadsheet that identified numbers of participants in each trial group and the description of the adverse event as listed in the original article. Each event was counted as if it represented a unique individual. Because an individual may have experienced more than 1 event within a category of adverse events (for example, both stroke and myocardial infarction), this assumption may have overestimated the number of people who had an adverse event in that category. If a trial report mentioned a particular type of adverse event but did not report data on it, we did not include the trial in that particular event's analysis. In other words, we did not assume an occurrence of zero events unless it was specifically reported as such. By taking this approach, we may have overestimated the number of patients for whom a particular adverse event was observed. We used predefined criteria to assess the quality of systematic reviews and randomized trials, based on internal and external validity assessment detailed in the QUOROM (Quality of Reporting of Meta-Analyses) statement (9), and items related to randomization, blinding, and accounting for withdrawals and dropouts (1011). Each element is detailed in appendices to the full report (8). For this review, we characterized the overall strength of evidence for estimating fracture risk as good, fair, or weak on the basis of the characteristics previously described, as well as the number of studies, total number of participants across studies, whether fractures were a primary outcome, reproducibility of results across studies, and precision of the CIs surrounding the point estimates. Evidence was classified as good if the total sample size was greater than 1000, the results across all studies were consistent, and the studies were of high methodological quality. Evidence was classified as fair if results were inconsistent across the studies. The evidence was classified as weak if no studies assessed fracture as a primary outcome, the total sample size across studies was less than 500, and the CIs around the point estimates were wide and crossed null.

Data Synthesis and Statistical Analysis

Comparisons of interest were single agent versus placebo and single agent versus another agent for agents within the same class and across classes. We also compared estrogen–progestin versus placebo or single drugs. Studies that included either calcium or vitamin D in all study groups were classified as comparisons between the other agents in each group; for example, alendronate plus calcium versus risedronate plus calcium would be classified as alendronate versus risedronate.

In this review, we summarize data on vertebral, nonvertebral, and hip fractures; data on total, wrist, and humerus fractures are included in the full report (8). The number of people with at least 1 fracture was our primary outcome of interest. Because fractures rarely occurred and zero events were often observed in at least 1 treatment group, we calculated odds ratios (ORs) by using the Peto method (12). Trials with zero events in both groups have an undefined OR. Because fractures are rare events, the OR approximates the relative risk (RR) for fracture. We combined data from multiple study groups in an individual study to calculate a single OR for comparisons of interest. In these instances, the same outcome had been reported for each group, and the individuals in each group were unique. For example, to develop an OR for the risk for vertebral fractures regardless of dose, we combined the participants in the various dose groups and compared them with those in the placebo group. We conducted the meta-analysis by using StatXact PROCs (Cytel, Cambridge, Massachusetts) for SAS software (SAS Institute, Cary, North Carolina).

Recognizing that characteristics of the study population may affect risk for fracture, we defined risk groups to categorize the study populations included in each meta-analysis and randomized, controlled trial on the basis of the risk factors that could be abstracted from these studies (Table 1). Based primarily on bone mineral density (13), the expected lifetime risk for fracture in the high-, intermediate-, and low-risk groups would be approximately 33%, 21%, and less than 10% to 21%, respectively. The 10-year risks would range from at least 3% at age 50 years to 10% at age 70 years, at least 1% at age 50 years to 4% at age 70 years, and less than 1% at age 50 years to approximately 2% at age 70 years for the high-, intermediate-, and low-risk groups, respectively.

Table Jump PlaceholderTable 1.  Risk Groups for Likelihood of Fracture*

For the analyses of adverse events, we compared agent versus placebo and agent versus agent for agents within the same class and across classes. We compiled a list of all unique adverse events that were reported in any study, and a physician grouped them into clinically sensible categories and subcategories. For groups of events that occurred in 3 or more trials, we estimated the pooled OR and its associated 95% CI. Because many events were rare, we used exact conditional inference to perform the pooling rather than applying the usual asymptotic methods that assume normality.

Role of the Funding Source

Although AHRQ formulated the initial study questions, it did not participate in the literature search, determination of study eligibility criteria, data analysis, or interpretation. Staff from AHRQ reviewed and provided comments on the report from which this paper is derived.

We identified 2641 titles through various sources (Figure 1). After reviewing available titles and abstracts, we ordered 1835 articles and could not obtain 10 articles.

Grahic Jump Location
Figure 1.
Study flow diagram.

PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Articles are not mutually exclusive.

Grahic Jump Location

Of the 1825 articles screened, we excluded 1721 from efficacy analyses for reasons detailed in Figure 1. Because comprehensive systematic reviews had recently been conducted for alendronate, risedronate, etidronate, raloxifene, calcitonin, parathyroid hormone (PTH), and estrogen, we did not reanalyze 166 articles on trials of these drugs. We included 76 randomized, controlled trials, 4 of which were identified in the updated search, and 24 meta-analyses in the efficacy analyses. Our analyses of adverse events included 493 articles, representing 417 randomized trials, 25 other controlled clinical trials, 11 open-label trials, 31 large observational studies, and 9 articles reporting cases of osteonecrosis among bisphosphonate users.

Comparative Benefits in Fracture Reduction
Drug versus Placebo Comparisons

For 9 of the 14 agents (alendronate, etidronate, risedronate, calcitonin, estrogen, PTH, raloxifene, calcium, and vitamin D), we identified 24 meta-analyses (1438) and 35 additional randomized trials that were published after the meta-analyses (3973) and described the effect of the agent compared with placebo on fracture incidence. For 4 of the 5 agents for which we did not identify meta-analyses (ibandronate, pamidronate, zoledronic acid, and tamoxifen), we identified 14 randomized trials (7487) that described the effect on the risk for fracture compared with that of placebo. We found no studies that reported fracture rates for testosterone. For calcium plus vitamin D—the only agent combination evaluated for this report—we identified 3 randomized trials that evaluated the risk for fracture compared with that of placebo (39, 8889).

Table 2 summarizes the key findings from all studies. Figures 2, 3, and 4 display the risk for vertebral, nonvertebral, and hip fracture of the agents compared with placebo for high-risk populations for studies that provided information on risk groups. Appendix Figures 1, 2, and 3 display the risk for vertebral, nonvertebral, and hip fracture of the agents compared with placebo for populations not described as high risk in those studies. Data include pooled risk estimates from published meta-analyses, where available. The full report provides (8) complete details, including the calculated point estimates and CIs for all comparisons.

Table Jump PlaceholderTable 2.  Effect of Agents on Fracture Risk Reduction Compared with Placebo, by Agent*
Grahic Jump Location
Figure 2.
Risk for vertebral fractures relative to placebo for participants who are at high risk for fracture, by agent.

PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Pooled risk estimate calculated by authors; restricted to studies with >12 months of follow-up. ‡Risk estimate calculated from cited individual studies. §Insufficient data to calculate risk.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Risk for nonvertebral fractures relative to placebo for participants who are at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Pooled risk estimate calculated by authors; restricted to studies with >12 months of follow-up. ‡Risk estimate calculated from cited individual studies. §Insufficient data to calculate risk.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Risk for hip fractures relative to placebo for participants who are at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.
Risk for vertebral fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator; WHI = Women's Health Initiative. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Risk for nonvertebral fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Risk for hip fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator; WHI = Women's Health Initiative. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location

We found good evidence from more than 1 randomized trial or meta-analysis that alendronate, etidronate, ibandronate, risedronate, calcitonin, PTH (1-34), and raloxifene, compared with placebo, prevent vertebral fractures. Good evidence from multiple trials and meta-analyses also indicate that both alendronate and risedronate, compared with placebo, prevent nonvertebral and hip fractures. Two large randomized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk populations (85, 87). The risk for hip fracture was reduced in both trials, although the reduction was statistically significant in only 1 trial (85). A smaller trial was not powered to detect a fracture risk reduction with zoledronic acid (84). Although 1 large randomized trial detailed in a systematic review showed that PTH (1-34) prevents nonvertebral fractures (90), 2 smaller trials did not (69, 91).

Good evidence suggests that estrogen by itself is associated with a reduced incidence of vertebral (28, 92), nonvertebral (93), and hip fractures compared with placebo (92). Among 3 meta-analyses that assessed the effect of estrogen on the risk for vertebral fracture in postmenopausal women, the pooled sample size in 1 meta-analysis was too small to detect even large differences in fracture risk among groups (22). Of the remaining 2 meta-analyses, the one with the largest pooled sample size (n = 6723) showed that estrogen reduced fracture risk more than placebo (RR, 0.45 [95% CI, 0.45 to 0.98]) (28), and the other (29) demonstrated a reduction in risk that was not statistically significant (RR, 0.68 [CI, 0.41 to 1.07]).

A published meta-analysis (24) and several large randomized trials (39, 7273, 94) showed no statistically significant difference between calcium alone and placebo in preventing vertebral, nonvertebral, and hip fractures in postmenopausal women. The risk for vertebral fracture for calcium versus placebo among all participants ranged from 0.70 (CI, 0.42 to 1.14) in a trial with 1471 participants (73) to 2.77 (CI, 0.39 to 19.65) in a trial with 2643 participants (39). The magnitude of risk reduction for nonvertebral and hip fractures was similar. In 1 trial that performed a preplanned, per-protocol analysis of the effect of adherence, the risk for vertebral fractures for calcium versus placebo was lower among the 830 participants (56.8%) who consumed 80% of their study tablets than among the participants who did not, with the risk reduction reaching statistical significance for nonvertebral fracture (RR, 0.63 [CI, 0.41 to 0.96]) (72).

The risks for vertebral, nonvertebral, and hip fractures were not significantly reduced by standard vitamin D (vitamin D2, vitamin D3, or 25-hydroxyvitamin D) versus placebo in 4 meta-analyses (pooled RR range, 0.33 [CI, 0.01 to 8.05] to 1.13 [CI. 0.05 to 2.55]) (22, 2526, 33). Likewise, risk for vertebral fracture (RR, 1.17 [CI, 0.71 to 1.95]) or hip fracture (RR, 1.14 [CI, 0.75 to 1.75]) was not significantly reduced for vitamin D3 (800 IU/d) versus placebo in 1 large trial performed after the 4 meta-analyses (39). In contrast to these findings, a fifth meta-analysis reported a significantly reduced pooled risk for nonvertebral fractures (RR, 0.77 [CI, 0.68 to 0.87]) and hip fractures (RR, 0.74 [CI, 0.61 to 0.88]) for vitamin D2 or D3 (700 to 800 IU/d) compared with placebo. For vitamin D analogues (1,25-hydroxyvitamin D and 1-hydroxyvitamin D), the risk for vertebral fracture was significantly reduced compared with placebo (pooled RR range, 0.52 [CI, 0.41 to 0.67] to 0.64 [CI, 0.44 to 0.92]) in 3 meta-analyses (25, 33, 36). For nonvertebral and hip fractures, the pooled risk for vitamin D analogues compared with placebo ranged from 0.16 (CI, 0.04 to 0.69) to 0.87 (CI, 0.29 to 2.59), with vitamin D analogues showing significant decreases in risk in 4 of 7 reported comparisons.

Within- and Between-Class Comparisons

We identified 9 randomized trials that compared different bisphosphonates (42, 95102) and 1 randomized trial that compared different selective estrogen receptor modulators (103). Sixteen randomized trials included head-to-head comparisons of agents from different classes (3941, 4951, 68, 100101, 104110). Most were designed to compare changes in intermediate outcomes, such as bone mineral density and changes in markers of bone turnover, but were too small and too short to detect clinically important differences in fracture incidence between groups. We identified only 2 head-to-head trials designed to compare fracture outcomes. One found no difference between risedronate and etidronate for the prevention of vertebral fractures (RR, 0.66 [CI, 0.32 to 1.36]) (95). The other, which compared raloxifene and alendronate (108), did not recruit enough participants to test differences in fracture outcomes. This study found no difference in the incidence of hip, wrist, or total vertebral fractures, but it was not powered to do so. However, a significant difference in moderate-to-severe vertebral fractures (3 of 713 alendronate recipients with fractures, 0 of 699 raloxifene recipients with fractures; P = 0.04) was found in a prespecified analysis.

Thus, the head-to-head studies had 3 key findings: 1) within the bisphosphonate class, superiority for prevention of fractures has not been shown for any agent; 2) superiority for the prevention of vertebral fractures has not been demonstrated for bisphosphonates compared with calcitonin, calcium, or raloxifene; and 3) on the basis of 6 inadequately powered randomized trials, fracture prevention did not differ between bisphosphonates and estrogen.

Effects in Different Risk Groups

Of the 24 meta-analyses that we reviewed, 6 evaluated the effect of therapy for groups at varying risk for fracture (14, 16, 18, 22, 26, 38). The criteria used to define risk groups in these studies overlapped but were not identical. In addition, because the risk groups were not always identical to those that we defined for this report, we used expert judgment to match each with one of our risk groups.

Low-Risk Populations

Four meta-analyses (14, 16, 22, 38) included a group categorized as low risk according to our criteria, which corresponds approximately to a 10-year risk for fracture of up to 2% and a lifetime risk of up to 21%. Summary estimates from 2 of these analyses suggested possible reductions in the risk for vertebral fracture (RR, 0.45 [CI, 0.06 to 3.15]) and nonvertebral fracture (RR, 0.79 [CI, 0.28 to 2.24]) with alendronate versus placebo (14) and a decrease in the risk for vertebral fracture with etidronate (RR, 0.61 [CI, 0.29 to 1.26]) versus placebo (16), but the width of the 95% CIs suggests that these agents may in fact have had no effect on or increased the risk for fracture.

For estrogen compared with placebo, 1 meta-analysis reported insignificant results with very wide confidence bounds for vertebral fracture risk (RR, 2.05 [CI, 0.71 to 5.97]) (22). This study and another meta-analysis suggested that estrogen reduced nonvertebral fractures more than placebo (RR, 0.86 [CI, 0.72 to 1.02] vs. 0.67 [CI, 0.46 to 0.98]) (22, 38). The first meta-analysis also found that the selective estrogen receptor modulator raloxifene reduced the risk for vertebral fractures more than placebo (RR, 0.53 [CI, 0.35 to 0.79]) and that vitamin D possibly reduced vertebral fractures more than placebo (RR, 0.86 [CI, 0.72 to 1.02]) (22). The Women's Health Initiative found a nonsignificant difference in hip fracture risk (hazard ratio, 0.17 [CI, 0.02 to 1.43]) among women at relatively low risk (based on age) who were taking estrogen (66, 92). When women were assigned a composite risk score and were stratified by those scores, women in the lowest risk group had a reduction in total fracture risk (hazard ratio, 0.82 [nominal CI, 0.66 to 1.02]) (66).

Two randomized trials in low-risk groups, 1 on the use of calcitonin and 1 on the use of selective estrogen receptor modulators, were completed after publication of the 2 meta-analyses just described. In the first trial, none of 49 calcitonin recipients had fractures at 24 months, compared with 2 of 52 placebo recipients (63). In the second trial, 19 747 postmenopausal women with increased risk for breast cancer (but not selected for fracture risk) were assigned to receive raloxifene or tamoxifen. After 60 months, the proportion of fractures was similar for the 2 groups (104 of 9726 raloxifene recipients with fractures and 96 of 9745 tamoxifen recipients with fractures; RR, 1.09 [CI, 0.82 to 1.44]) (103).

Specific Patient Populations
Men.

Few studies assessed the effect of agents to reduce fracture risk among men. Among 9 studies that included men (39, 50, 5962, 64, 70, 111), 2 demonstrated a reduction in fracture risk: 1 for hip fractures with risedronate (RR, 0.25 [CI, 0.08 to 0.78]) (60) and 1 for vertebral fractures with calcitonin (RR, 0.09 [CI, 0.01 to 0.96]) (64). An additional study found a reduced risk for total fractures (RR, 0.16 [CI, 0.04 to 0.65]) and a possible reduced risk for vertebral fractures (OR, 0.44 [CI, 0.18 to 1.09]) with teriparatide (70). Among the remaining studies, only 1 had a sufficient sample size to assess even a large effect of agents on fracture (39). In the study, which included 672 men and 3809 women, calcium did not decrease the risk for fractures compared with placebo (331 [12.6%] of 2617 vs. 367 [13.7%] of 2675 participants with fractures; hazard ratio, 0.94 [CI, 0.81 to 1.09]). Subgroup analyses found no difference in risk between men and women (hazard ratio, 1.04 [CI, 0.57 to 1.90]).

Patients at Increased Risk for Falls.

We found 7 studies that involved patients at increased risk for falling. These included patients with stroke and hemiplegia (55, 60, 112), Alzheimer disease (54), a recent hip fracture (47, 87), or Parkinson disease (46). A reduced risk for vertebral fractures was reported for zoledronic acid compared with placebo among participants who had undergone repair of a hip fracture (hazard ratio, 0.54 [CI, 0.32 to 0.92]) (87). The risk for nonvertebral fractures was also reduced for zoledronic acid versus placebo in this study population (hazard ratio, 0.73 [CI, 0.55 to 0.98]) (87). Nonvertebral fractures were reduced for risedronate compared with placebo among persons with Alzheimer disease (RR, 0.29 [CI, 0.15 to 0.57]) (54). Risk for an additional hip fracture among patients with a recent hip fracture was reduced, although not significantly, for zoledronic acid versus placebo in 1 study (hazard ratio, 0.70 [CI, 0.41 to 1.19]) (87). In another study, no fractures were detected for patients treated with either etidronate or placebo (47). Compared with placebo, risedronate reduced hip fractures in patients with Alzheimer disease (RR, 0.29 [CI, 0.13 to 0.66]) (54) and in patients with stroke and hemiparesis (RR, 0.22 [CI, 0.05 to 0.88] and 0.25 [CI, 0.08 to 0.78]) (55, 60). Compared with placebo, alendronate reduced hip fractures in patients with Parkinson disease (RR, 0.30 [CI, 0.12 to 0.78]) (46), as did vitamin D in patients with stroke and hemiparesis (RR, 0.12 [CI, 0.02 to 0.90]).

Patients with Renal Insufficiency.

We identified 1 trial on the efficacy of alendronate for fracture prevention in patients with renal insufficiency compared with those without renal insufficiency. In a retrospective analysis of the Fracture Intervention Trial (113), treatment with alendronate reduced the risk for clinical fractures to a similar degree in patients with and without reduced renal function (RR, 0.78 [CI, 0.51 to 1.21] vs. 0.80 [CI, 0.70 to 0.93]; P for interaction = 0.89). Treatment with alendronate reduced the risk for spine fractures to a similar degree in patients with and without reduced renal function (RR, 0.72 [CI, 0.31 to 1.70] vs. 0.50 [CI, 0.32 to 0.76]; P for interaction = 0.44).

Patients with Long-Term Glucocorticoid Use.

We identified 1 systematic review (114) and 6 randomized trials published after it (50, 52, 109, 115117) that evaluated the effect of bisphosphonates on fracture incidence among patients treated with glucocorticoids. The systematic review identified 9 trials (118126) published before 1999 that reported fracture data. Of the 6 included trials (118123) that compared fracture risk between treatment and placebo groups, 3 showed possible rate reductions in vertebral fracture with treatment (118, 120121) and 1 demonstrated a decrease of approximately 10% in vertebral fractures among patients treated with risedronate versus a control group (121).

Among the 6 randomized trials published after the systematic review, 3 found that bisphosphonates reduced fracture rate more than placebo (115117). One trial of risedronate demonstrated a statistically significant reduction in the absolute risk and RR for incident radiographic vertebral fractures (11% and 70%, respectively) after 1 year (117). The study included data from a trial (121) that was included in the systematic review described in the previous paragraph. Another randomized, controlled trial (116) demonstrated a significant reduction in the risk for incident radiographic vertebral fractures for alendronate compared with placebo (0.7% vs. 6.8%; P < 0.05). The third trial found a significant (70%) reduction in the incidence of vertebral fractures for risedronate compared with placebo (115). The remaining 3 trials reported no significant difference in fracture risk between etidronate (50, 52) or calcium (50) and placebo, between calcium and etidronate (50), and between calcium and pamidronate (109).

A meta-analysis (17) that pooled the results of 4 trials to assess the effect of calcitonin compared with placebo in preventing and treating glucocorticoid-induced osteoporosis found no significant effect for vertebral fractures (256 patients; OR, 0.71 [CI, 0.26 to 1.89]) or nonvertebral fractures (208 patients; OR, 0.52 [CI, 0.14 to 1.96]).

Short- and Long-Term Harms (Adverse Effects) of Agents

We assessed adverse events by the system affected. Key findings are summarized in the Appendix Table.

Table Jump PlaceholderAppendix Table.  Pooled Risk for Adverse Events for Bisphosphonates Compared with Placebo, by Agent*
Cardiovascular

Across many randomized trials, we found no clinically important differences in the rates of serious cardiac events when calcium, vitamin D, calcitonin, or PTH was compared with placebo. One placebo-controlled trial reported an increased risk for serious atrial fibrillation with zoledronic acid versus placebo (1.3% vs. 0.5% [93 of 3876 vs. 144 of 3889 participants with atrial fibrillation]; P < 0.001) (85). However, another large trial did not (1.1% vs. 1.3%; P = 0.84) (87). Another placebo-controlled trial suggested a possible increased risk for atrial fibrillation with alendronate (absolute risk, 128 of 3236 vs. 102 of 3223 participants with atrial fibrillation; OR, 1.26 [CI, 0.96 to 1.66]) (127).

The pooled odds of a cerebrovascular accident from 3 randomized trials was increased with estrogen compared with placebo (absolute risk, 185 of 6546 vs. 144 of 7226 participants with cerebrovascular accident; OR, 1.34 [CI, 1.07 to 1.68]) (92, 128129). Participants treated with combined estrogen–progestin in 2 studies had higher pooled odds of reported stroke than did participants who received placebo (OR, 1.28 [CI, 1.05 to 1.57]) (67, 130).

We pooled the findings of 2 studies on the risk for selective estrogen receptor modulators for pulmonary embolism. Compared with placebo, raloxifene increased the risk for pulmonary embolism (absolute risk, 24 of 5153 vs. 2 of 2600 participants with pulmonary embolism; OR, 6.26 [CI, 1.55 to 54.80]) (131132).

Pooled findings from 7 studies showed that raloxifene increased the risk for thromboembolic events (absolute risk, 167 of 6878 vs. 41 of 3667 participants with thromboembolic events; OR, 2.08 [CI, 1.47 to 3.02]) (131, 133138) and mild cardiac events (including chest pain, palpitations, tachycardia, and vasodilatation) (6 trials pooled) (absolute risk, 86 of 1658 vs. 39 of 1028 participants with mild cardiac events; OR, 1.53 [CI, 1.01 to 2.35]) (135136, 138141). Pooled findings from 4 studies showed an increased risk for thromboembolic events for estrogen compared with placebo (absolute risk, 105 of 6639 vs. 79 of 7139 participants with thromboembolic events; OR, 1.36 [CI, 1.01 to 1.86]) (40, 92, 128129). Similar results were obtained when the findings from 3 trials of estrogen–progestin were pooled (OR, 2.27 [CI, 1.72 to 3.02]) (66, 130, 142).

Gastrointestinal

Trials of all bisphosphonates, except zoledronic acid, reported esophageal ulcerations; however, only 1 trial found a significantly higher risk with etidronate than with placebo (absolute risk, 128 of 3236 vs. 102 of 3223 participants with esophageal ulcerations; OR, 1.33 [CI, 1.05 to 1.68]) (143). Perforations, ulcerations, or bleeding episodes were reported in trials of all bisphosphonates, except zoledronic acid. A pooled analysis of 3 trials found that etidronate users were at increased risk compared with a placebo group (absolute risk, 123 of 8066 vs. 186 of 16 083 participants with perforations, ulcerations, or bleeding episodes; OR, 1.32 [CI, 1.04 to 1.67]) (47, 143144), and a pooled analysis of 2 trials found that daily oral ibandronate recipients were at lower risk than placebo recipients (absolute risk, 12 of 2445 vs. 17 of 1137 participants with perforations, ulcerations, or bleeding episodes; OR, 0.33 [CI, 0.14 to 0.74]). Pooled analyses found no significant effects for other bisphosphonates (75, 145).

We categorized such conditions as acid reflux, esophageal irritation, nausea, vomiting, and heartburn as mild upper gastrointestinal events. Pooled analyses of 18 trials of etidronate versus placebo showed that etidronate increased the risk for these events (absolute risk, 880 of 8842 vs. 1248 of 16 814 participants with mild upper gastrointestinal events; OR, 1.33 [CI, 1.21 to 1.46]) (4852, 118119, 125126, 143, 146153). Pooled analyses of 7 trials also showed an increased risk for these events with pamidronate (absolute risk, 125 of 340 vs. 44 of 253 participants with mild upper gastrointestinal events; OR, 3.14 [CI, 1.93 to 5.21]) (79, 81, 154158). Pooled analyses found no difference between alendronate, ibandronate, risedronate, or zoledronic acid and placebo. However, pooled analysis of 3 head-to-head trials showed that alendronate users had a higher risk for mild upper gastrointestinal events than did etidronate users (absolute risk, 18 of 132 vs. 3 of 105 participants with mild upper gastrointestinal events; OR, 5.89 [CI, 1.61 to 32.7]). Similarly, in 4 head-to-head trials, alendronate recipients had a greater risk for mild upper gastrointestinal events than did calcitonin recipients (absolute risk, 56 of 413 vs. 13 of 288 participants with mild upper gastrointestinal events; OR, 3.42 [CI, 1.79 to 7.00]) or estrogen recipients (absolute risk, 78 of 255 vs. 68 of 306 participants with mild upper gastrointestinal events; OR, 1.57 [CI, 1.00 to 2.46]).

Cancer

Pooled analysis of the results of 5 trials that assessed the risk for breast cancer among women taking estrogen compared with placebo found a lower risk for breast cancer among estrogen users (absolute risk, 238 of 12 124 vs. 312 of 12 742 participants with breast cancer; OR, 0.79 [CI, 0.66 to 0.93]) (92, 128129, 159160). Conversely, in pooled analysis of 3 studies, women who used estrogen–progestin compared with placebo had an increased risk for breast cancer (absolute risk, 202 of 9922 vs. 152 of 9524 participants with breast cancer; OR, 1.28 [CI, 1.03 to 1.60]) (67, 130, 154). One study showed that women who used estrogen–progestin compared with placebo had a lower risk for colon cancer (absolute risk, 45 of 8506 vs. 67 of 8102 participants with colon cancer; OR, 0.64 [CI, 0.43 to 0.95]) (92). Risk for osteosarcoma was reported in 1 study, a head-to-head trial of raloxifene versus tamoxifen; differences between the groups were not significant (103).

Osteonecrosis

We found several published cases of osteonecrosis of the jaw in patients with cancer who were taking large doses of bisphosphonates intravenously. Cases involved pamidronate, zoledronic acid, and alendronate. Incidence rates and probability of this adverse event could not be calculated (see the Discussion section).

This report summarizes the meta-analyses and subsequent randomized trials that have evaluated the effect of various agents on the risk for osteoporotic fractures. These analyses support a role for many of these agents in reducing the risk for fracture compared with placebo. We did not identify any studies that demonstrated superiority of 1 agent over another in preventing fractures. However, no trial with head-to-head comparisons of 2 or more agents enrolled sufficient sample sizes to detect even large differences in risk.

Consistent with FDA requirements to demonstrate reduced fracture risk to obtain approval of an agent for osteoporosis treatment, many trials were powered to detect a difference in fracture risk among postmenopausal osteoporotic women. These studies provide good evidence that the bisphosphonates alendronate, etidronate, ibandronate, and risedronate, as well as the hormones calcitonin and teriparatide and the selective estrogen receptor modulator raloxifene, prevent vertebral, nonvertebral, or hip fractures in this high-risk group. Each of these agents, with the exception of etidronate, has been approved by the FDA for osteoporosis treatment. Also, consistent with FDA requirements to obtain approval for the prevention of osteoporosis—that is, demonstration of an improvement in bone mineral density, but not necessarily fracture risk reduction, in a population that has not yet shown evidence of osteoporosis—few studies assessed fracture as a primary outcome among these lower-risk individuals. A meta-analysis reported that raloxifene (30) reduces the risk for vertebral fractures in low-risk populations, and 1 trial demonstrated that ibandronate reduces the risk for any fracture in this group (74). These 2 agents have been approved by the FDA for osteoporosis prevention.

Estrogen is also approved by the FDA for preventing osteoporotic fractures in postmenopausal women. However, the evidence on fracture risk reduction for estrogen is more complex than that for bisphosphonates. The evidence suggests that estrogen reduces the risk for vertebral and hip fracture; however, the effect of estrogen on nonvertebral fracture risk is less clear. Among the 3 meta-analyses that assessed the effect of estrogen on the risk for vertebral fracture in postmenopausal women, only 1 showed an effect that achieved statistical significance (22, 26, 29). Likewise, the Women's Health Initiative showed that estrogen significantly reduced the risk for hip fracture (67), and a meta-analysis that included data from the Women's Health Initiative showed a reduction in risk for hip fracture that was nonsignificant (22). Among the 3 meta-analyses that evaluated the risk for nonvertebral fractures, all reported that estrogen reduced risk, but the significance of the results was lower for the 2 meta-analyses with smaller sample sizes (n = 7316 and 5383) (22, 29). The analysis with the largest sample size (n = 8774) was the only one that showed a significant effect of estrogen (38).

Neither tamoxifen nor testosterone is approved by the FDA for the treatment or prevention of osteoporosis. Consistent with this fact, we did not identify any evidence that these agents reduce the risk for fractures. One large trial provides evidence that tamoxifen is not associated with fracture risk reduction (86). We did not identify any studies that assessed the effect of testosterone on fracture.

Zoledronic acid is approved by the FDA for the treatment, but not the prevention, of osteoporosis. On the basis of 2 large trials that evaluated the effect of zoledronic acid compared with placebo among postmenopausal women at high risk for fracture, the evidence for a reduced risk for vertebral and nonvertebral fractures is good and that for hip fractures is fair (85, 87).

The evidence for fracture risk reduction is less clear for calcium and vitamin D. For calcium, several large, high-quality trials could not demonstrate a reduction in fractures among postmenopausal women (39, 7273). However, many studies have demonstrated that adherence to calcium treatment is low (39, 7273, 8889), and a prespecified analysis in 1 randomized trial demonstrated a reduction in fracture risk among participants who adhered to calcium supplementation (72).

Across a large body of literature, the effects of vitamin D varied depending on analogue, dose, and fracture type. Among many meta-analyses, some reported a reduced risk for standard vitamin D compared with placebo (25, 27, 33, 36) and some did not (22, 2526). The studies included in the meta-analyses contained some overlap, although each included some unique studies. The findings regarding fracture risk were not related to the size of the pooled sample in the meta-analyses. Notably, 1 meta-analysis reported a reduction in fracture risk for standard vitamin D (D2 and D3) for doses of 700 to 800 IU/d (27). However, in a large, high-quality trial published after these meta-analyses, 800 IU of vitamin D3 did not reduce fracture risk compared with placebo among ambulatory patients age 70 years or older with a history of fracture (39). In another trial published after these meta-analyses, 1000 IU of vitamin D reduced hip fracture risk for postmenopausal women with hemiplegia due to stroke (54). For vitamin D analogues (1,25-hydroxyvitamin D and 1-hydroxyvitamin D) compared with placebo, the risk for vertebral fracture was significantly reduced in 3 meta-analyses (25, 33, 36). For nonvertebral and hip fractures, the evidence was mixed. Together, these data do not prove a universal reduction of fracture risk with vitamin D. However, they do suggest that vitamin D analogues reduce the risk for vertebral fractures and that, in high enough doses, standard vitamin D may prevent fractures in some high-risk populations. The fact that fracture risk reduction was observed among postmenopausal women with hemiplegia suggests that vitamin D might prevent fractures by reducing falls. Indeed, vitamin D–treated patients in the study had a 59% reduction in falls compared with the placebo group, consistent with the vitamin D–associated reduction in falls reported in other studies (161).

Although evidence suggests that many agents reviewed in our report reduce the risk for fracture among postmenopausal women with a high risk for fracture—that is, women with T-scores less than −2.5 SD or a previous osteoporotic fracture—data on other patient populations are limited. More research is needed to determine whether and which osteoporosis agents reduce fracture risk among transplant recipients. Among lower-risk populations, data are limited on whether osteoporosis agents reduce the risk for fracture among women with osteopenia and among men. Coupled with good evidence that all osteoporosis agents are associated with adverse effects ranging from mild to serious, further research is needed to determine whether the benefits of treatment in these lower-risk populations outweigh the risks. Demonstration of fracture risk reduction could lead to broader use of these agents in these populations and reduced fracture rates; the opposite could lead to discontinuation of these agents in these populations, with a concomitant reduction in associated adverse events and unnecessary health care spending. A practical challenge in determining whether osteoporosis agents reduce the risk for fracture in lower-risk populations is that large sample sizes will be required. Given that the time to develop fractures is longer in lower-risk populations, trials designed to assess fracture risk would require larger sample sizes and longer follow-up than those of typical osteoporosis trials.

Our report also presents the evidence for selected short- and long-term harms (adverse effects) of the various agents. Among cardiac events, an increased risk for serious atrial fibrillation was found in 1 placebo-controlled trial of zoledronic acid (85). However, this finding was contradicted by the findings of another large trial that was published in the same year (87). Another placebo-controlled trial suggested a possible increased risk for atrial fibrillation with alendronate (127). The increased risk for cerebrovascular events reported for estrogen users was also borne out in 3 separate trials (92, 128129).

Among oral bisphosphonate users, the risk for gastrointestinal adverse events has been a concern. The pooled analyses showed a slight increase in esophageal ulcers, as well as mild gastrointestinal events, such as acid reflux. Whereas a pooled analysis of 3 trials also showed a slightly increased risk for more serious adverse events, such as perforations, ulcerations, and bleeding, with etidronate, another pooled analysis showed a decreased risk with daily oral ibandronate. One possible reason for the discrepancy between the apparent risks observed in smaller studies and those of the larger clinical trials is that the larger trials may have enrolled patients who are more likely to adhere to instructions for taking these agents. Alternatively, given the widespread concerns about gastrointestinal side effects, patients enrolled in the large clinical trials may have been given more explicit dosing instructions.

Finally, although we found multiple published cases of osteonecrosis of the jaw in patients with cancer who receive large doses of bisphosphonates intravenously, we could not calculate the risk for this event. A 2006 systematic review (162) identified before preparation of our report analyzed the risk for osteonecrosis of the jaw with bisphosphonate therapy. The researchers found that 94% of published cases were among patients being treated intravenously for cancer. They concluded that although the risk for osteonecrosis of the jaw among patients taking oral bisphosphonates is uncertain, the possible link warrants further investigation (162). Concerned about the apparently mounting evidence that bisphosphonates increase the risk for osteonecrosis of the jaw, the American Society for Bone and Mineral Research appointed a multidisciplinary task force to address the proposed link. After developing a case definition and reviewing all pertinent literature, the task force concluded in their 2007 report (163) that even though the risk for osteonecrosis of the jaw in patients taking oral bisphosphonates for osteoporosis seemed to be low (in contrast to patients taking the agents intravenously for cancer), the incidence might be higher than that suggested by the literature to date. It outlined an agenda for further research in the area (163).

The findings reported here should be viewed in the context of the limitations of this study and the research in the field. Although our literature search procedures were extensive and included canvassing experts from academia and industry for studies, other trials may have appeared in non–English-language publications or may have not been published. Publication bias may occur, resulting in an overestimation of the efficacy of these treatments. As for the research itself, many studies of agents to treat osteoporosis measure only changes in bone mineral density and not fracture risk. Most trials that measured fracture risk were inadequately powered to detect even large differences. Most were heterogeneous with respect to study design (criteria for participation, dosing, duration of administration, length of follow-up, or control group), and few considered adherence to the medication regimens. With regard to the assessment of adverse events, the counts of adverse events were limited to those that were explicitly reported in the reviewed studies. Consequently, if many studies failed to report a particular adverse event (because it did not occur in those studies), our analysis would have no way to capture this “nonoccurrence,” which could result in our overestimating the risk for that adverse event.

As for our selection of a method to estimate risk differences, both for fracture risk and for the adverse event risk, we chose to use the Peto OR because it has been shown to be the least biased method for estimating rates of rare events, especially compared with the DerSimonian and Laird OR and risk difference methods (164). The Peto method can be limited if the sample size between the 2 treatment groups is largely imbalanced. As is the case when any OR or risk ratio estimate is being calculated, studies with zero events in the denominator group cannot be calculated by using the Peto OR (12).

In summary, although good evidence indicates that many agents are effective in preventing osteoporotic fractures, data are insufficient to determine the relative efficacy or safety of these agents. Such studies are unlikely to be performed unless they are required as part of the approval process for these agents.

.  Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993; 94:646-50. PubMed
CrossRef
 
Lindsay R.  Osteoporosis: A Guide to Diagnosis, Prevention, and Treatment. New York: Raven Pr; 1992.
 
Chrischilles EA, Butler CD, Davis CS, Wallace RB.  A model of lifetime osteoporosis impact. Arch Intern Med. 1991; 151:2026-32. PubMed
 
U.S. 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; July 1994.
 
Ray NF, Chan JK, Thamer M, Melton LJ 3rd.  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. PubMed
 
Keen RW.  Burden of osteoporosis and fractures. Curr Osteoporos Rep. 2003; 1:66-70. PubMed
 
Sasser AC, Rousculp MD, Birnbaum HG, Oster EF, Lufkin E, Mallet D.  Economic burden of osteoporosis, breast cancer, and cardiovascular disease among postmenopausal women in an employed population. Womens Health Issues. 2005; 15:97-108. PubMed
 
MacLean C, Alexander A, Carter J, Chen S, Desai SB, Grossman J, et al.  Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis. Comparative Effectiveness Review No. 12. (Prepared by the Southern California/RAND Evidence-based Practice Center under contract 290-02-0003). Rockville, MD: Agency for Healthcare Research and Quality; December 2007. Available athttp://www.effectivehealthcare.ahrq.gov/reports/final.cfm.
 
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF.  Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999; 354:1896-900. PubMed
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ. et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12. PubMed
 
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M. et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998; 352:609-13. PubMed
 
Yusuf S, Peto R, Lewis J, Collins R, Sleight P.  Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985; 27:335-71. PubMed
 
Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J. et al.  The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007; 18:1033-46. PubMed
 
Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev. 2002; 23:508-16. PubMed
 
Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S. et al.  Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA. 1997; 277:1159-64. PubMed
 
Cranney A, Welch V, Adachi JD, Guyatt G, Krolicki N, Griffith L. et al.  Etidronate for treating and preventing postmenopausal osteoporosis. Cochrane Database Syst Rev. 2001; CD003376. PubMed
 
Cranney A, Welch V, Adachi JD, Homik J, Shea B, Suarez-Almazor ME. et al.  Calcitonin for the treatment and prevention of corticosteroid-induced osteoporosis. Cochrane Database Syst Rev. 2000; CD001983. PubMed
 
Papapoulos SE, Quandt SA, Liberman UA, Hochberg MC, Thompson DE.  Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporos Int. 2005; 16:468-74. PubMed
 
Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002; 23:517-23. PubMed
 
Cranney A, Tugwell P, Zytaruk N, Robinson V, Weaver B, Shea B. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002; 23:540-51. PubMed
 
Kanis JA, McCloskey EV.  Effect of calcitonin on vertebral and other fractures. QJM. 1999; 92:143-9. PubMed
 
Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J.  A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess. 2005; 9:1-160. PubMed
 
Schachter HM, Clifford TJ, Cranney A, Barrowman NJ, Moher D.  Raloxifene for primary and secondary prevention of osteoporotic fractures in postmenopausal women: a systematic review of efficacy and safety evidence. Ottawa, Ontario, Canada: Canadian Coordinating Office for Health Technology Assessment; 2005.
 
Shea B, Wells G, Cranney A, Zytaruk N, Robinson V, Griffith L. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev. 2002; 23:552-9. PubMed
 
Papadimitropoulos E, Wells G, Shea B, Gillespie W, Weaver B, Zytaruk N. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002; 23:560-9. PubMed
 
Avenell A, Gillespie WJ, Gillespie LD, O'Connell DL.  Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2005; CD000227. PubMed
 
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B.  Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005; 293:2257-64. PubMed
 
Torgerson DJ, Bell-Syer SE.  Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskelet Disord. 2001; 2:7. PubMed
 
Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev. 2002; 23:529-39. PubMed
 
Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD.  Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int. 2006; 17:313-6. PubMed
 
Nguyen ND, Eisman JA, Nguyen TV.  Anti-hip fracture efficacy of biophosphonates: a Bayesian analysis of clinical trials. J Bone Miner Res. 2006; 21:340-9. PubMed
 
Sawka AM, Papaioannou A, Adachi JD, Gafni A, Hanley DA, Thabane L.  Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women. BMC Musculoskelet Disord. 2005; 6:39. PubMed
 
Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY.  Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int. 2005; 76:176-86. PubMed
 
Palmer S, McGregor DO, Strippoli GF.  Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2005; CD005015. PubMed
 
Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE.  Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res. 2005; 20:2105-15. PubMed
 
Richy F, Ethgen O, Bruyere O, Reginster JY.  Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int. 2004; 15:301-10. PubMed
 
Boonen S, Laan RF, Barton IP, Watts NB.  Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int. 2005; 16:1291-8. PubMed
 
Torgerson DJ, Bell-Syer SE.  Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA. 2001; 285:2891-7. PubMed
 
Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC. et al.  Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005; 365:1621-8. PubMed
 
Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW. et al.  Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab. 2000; 85:720-6. PubMed
 
Greenspan SL, Resnick NM, Parker RA.  Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA. 2003; 289:2525-33. PubMed
 
Hosking D, Adami S, Felsenberg D, Andia JC, Välimäki M, Benhamou L. et al.  Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised, placebo-controlled study. Curr Med Res Opin. 2003; 19:383-94. PubMed
 
McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH. et al.  Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006; 354:821-31. PubMed
 
Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM.  Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005; 80:343-9. PubMed
 
Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P. et al.  Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology. 2005; 42:762-71. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Alendronate and vitamin D2 for prevention of hip fracture in Parkinson's disease: a randomized controlled trial. Mov Disord. 2006; 21:924-9. PubMed
 
Sato Y, Kanoko T, Yasuda H, Satoh K, Iwamoto J.  Beneficial effect of etidronate therapy in immobilized hip fracture patients. Am J Phys Med Rehabil. 2004; 83:298-303. PubMed
 
Sato Y, Honda Y, Iwamoto J.  Etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone. 2006; 39:1080-6. PubMed
 
Wimalawansa SJ.  A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med. 1998; 104:219-26. PubMed
 
Campbell IA, Douglas JG, Francis RM, Prescott RJ, Reid DM.  Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids. Thorax. 2004; 59:761-8. PubMed
 
Ishida Y, Kawai S.  Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med. 2004; 117:549-55. PubMed
 
Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T. et al.  Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year followup. J Rheumatol. 2003; 30:2673-9. PubMed
 
Sorensen OH, Crawford GM, Mulder H, Hosking DJ, Gennari C, Mellstrom D. et al.  Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003; 32:120-6. PubMed
 
Sato Y, Kanoko T, Satoh K, Iwamoto J.  The prevention of hip fracture with risedronate and ergocalciferol plus calcium supplementation in elderly women with Alzheimer disease: a randomized controlled trial. Arch Intern Med. 2005; 165:1737-42. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Risedronate therapy for prevention of hip fracture after stroke in elderly women. Neurology. 2005; 64:811-6. PubMed
 
Palomba S, Orio F Jr, Manguso F, Falbo A, Russo T, Tolino A. et al.  Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease. Osteoporos Int. 2005; 16:1141-9. PubMed
 
Hooper MJ, Ebeling PR, Roberts AP, Graham JJ, Nicholson GC, D'Emden M. et al.  Risedronate prevents bone loss in early postmenopausal women: a prospective randomized, placebo-controlled trial. Climacteric. 2005; 8:251-62. PubMed
 
Greenspan SL, Bhattacharya RK, Sereika SM, Brufsky A, Vogel VG.  Prevention of bone loss in survivors of breast cancer: A randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab. 2007; 92:131-6. PubMed
 
Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y. et al.  The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits. Bone. 2004; 35:418-24. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med. 2005; 165:1743-8. PubMed
 
Kanaji A, Higashi M, Namisato M, Nishio M, Ando K, Yamada H.  Effects of risedronate on lumbar bone mineral density, bone resorption, and incidence of vertebral fracture in elderly male patients with leprosy. Lepr Rev. 2006; 77:147-53. PubMed
 
Trovas GP, Lyritis GP, Galanos A, Raptou P, Constantelou E.  A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. J Bone Miner Res. 2002; 17:521-7. PubMed
 
Ushiroyama T, Ikeda A, Sakai M, Higashiyama T, Ueki M.  Effects of the combined use of calcitonin and 1 alpha-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: a prospective study of long-term and continuous administration with low dose calcitonin. Maturitas. 2001; 40:229-38. PubMed
 
Tóth E, Csupor E, Mészáros S, Ferencz V, Németh L, McCloskey EV. et al.  The effect of intranasal salmon calcitonin therapy on bone mineral density in idiopathic male osteoporosis without vertebral fractures—an open label study. Bone. 2005; 36:47-51. PubMed
 
Hay JE, Malinchoc M, Dickson ER.  A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2001; 34:292-8. PubMed
 
Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ. et al.  Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA. 2003; 290:1729-38. PubMed
 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML. et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33. PubMed
 
Reid IR, Eastell R, Fogelman I, Adachi JD, Rosen A, Netelenbos C. et al.  A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women. Arch Intern Med. 2004; 164:871-9. PubMed
 
Gallagher JC, Genant HK, Crans GG, Vargas SJ, Krege JH.  Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005; 90:1583-7. PubMed
 
Kaufman JM, Orwoll E, Goemaere S, San Martin J, Hossain A, Dalsky GP. et al.  Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int. 2005; 16:510-6. PubMed
 
Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R. et al.  Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev. 2000; CD001347. PubMed
 
Prince RL, Devine A, Dhaliwal SS, Dick IM.  Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006; 166:869-75. PubMed
 
Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U. et al.  Randomized controlled trial of calcium in healthy older women. Am J Med. 2006; 119:777-85. PubMed
 
Ravn P, Clemmesen B, Riis BJ, Christiansen C.  The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone. 1996; 19:527-33. PubMed
 
Chesnut CH III, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A. et al.  Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004; 19:1241-9. PubMed
 
Recker R, Stakkestad JA, Chesnut CH 3rd, Christiansen C, Skag A, Hoiseth A. et al.  Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004; 34:890-9. PubMed
 
Grotz W, Nagel C, Poeschel D, Cybulla M, Petersen KG, Uhl M. et al.  Effect of ibandronate on bone loss and renal function after kidney transplantation. J Am Soc Nephrol. 2001; 12:1530-7. PubMed
 
Kim SH, Lim SK, Hahn JS.  Effect of pamidronate on new vertebral fractures and bone mineral density in patients with malignant lymphoma receiving chemotherapy. Am J Med. 2004; 116:524-8. PubMed
 
Ninkovic M, Love S, Tom BD, Bearcroft PW, Alexander GJ, Compston JE.  Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation. J Hepatol. 2002; 37:93-100. PubMed
 
Aris RM, Lester GE, Renner JB, Winders A, Denene Blackwood A, Lark RK. et al.  Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Am J Respir Crit Care Med. 2000; 162:941-6. PubMed
 
Reid IR, Wattie DJ, Evans MC, Gamble GD, Stapleton JP, Cornish J.  Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1994; 79:1595-9. PubMed
 
Kananen K, Volin L, Laitinen K, Alfthan H, Ruutu T, Välimäki MJ.  Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate. J Clin Endocrinol Metab. 2005; 90:3877-85. PubMed
 
Coco M, Glicklich D, Faugere MC, Burris L, Bognar I, Durkin P. et al.  Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate. J Am Soc Nephrol. 2003; 14:2669-76. PubMed
 
Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. et al.  Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002; 346:653-61. PubMed
 
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA. et al.  Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356:1809-22. PubMed
 
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM. et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90:1371-88. PubMed
 
Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C. et al.  Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007; 357:1799-809. PubMed
 
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE. et al.  Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354:669-83. PubMed
 
Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T. et al.  Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ. 2005; 330:1003. PubMed
 
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY. et al.  Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001; 344:1434-41. PubMed
 
Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A. et al.  The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003; 18:9-17. PubMed
 
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H. et al.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291:1701-12. PubMed
 
Homik JE, Cranney A, Shea B, Tugwell P, Wells G, Adachi JD. et al.  A metaanalysis on the use of bisphosphonates in corticosteroid induced osteoporosis. J Rheumatol. 1999; 26:1148-57. PubMed
 
Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B. et al.  Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int. 2007; 18:811-8. PubMed
 
Kushida K, Fukunaga M, Kishimoto H, Shiraki M, Itabashi A, Inoue T. et al.  A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial. J Bone Miner Metab. 2004; 22:469-78. PubMed
 
Fukunaga M, Kushida K, Kishimoto H, Shiraki M, Taketani Y, Minaguchi H. et al.  A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial. Osteoporos Int. 2002; 13:971-9. PubMed
 
Guañabens N, Parés A, Ros I, Alvarez L, Pons F, Caballería L. et al.  Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol. 2003; 98:2268-74. PubMed
 
Iwamoto J, Takeda T, Ichimura S, Uzawa M.  Comparative effects of treatment with etidronate and alendronate on bone resorption, back pain, and activities of daily living in elderly women with vertebral fractures. Keio J Med. 2003; 52:230-5. PubMed
 
Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S. et al.  Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res. 2005; 20:141-51. PubMed
 
Muscoso E, Puglisi N, Mamazza C, Lo Giudice F, Testai M, Abbate S. et al.  Antiresorption therapy and reduction in fracture susceptibility in the osteoporotic elderly patient: open study. Eur Rev Med Pharmacol Sci. 2004; 8:97-102. PubMed
 
Tauchmanovà L, De Simone G, Musella T, Orio F, Ricci P, Nappi C. et al.  Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 37:81-8. PubMed
 
Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM. et al.  Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab. 2006; 91:2631-7. PubMed
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN. et al.  Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006; 295:2727-41. PubMed
 
Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A. et al.  A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:4528-35. PubMed
 
Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon J. et al.  Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis. Menopause. 2004; 11:405-15. PubMed
 
Garcia-Delgado I, Prieto S, Gil-Fraguas L, Robles E, Rufilanchas JJ, Hawkins F.  Calcitonin, etidronate, and calcidiol treatment in bone loss after cardiac transplantation. Calcif Tissue Int. 1997; 60:155-9. PubMed
 
Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P. 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; 338:485-92. PubMed
 
Recker RR, Kendler D, Recknor CP, Rooney TW, Lewiecki EM, Utian WH. et al.  Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone. 2007; 40:843-51. PubMed
 
Boutsen Y, Jamart J, Esselinckx W, Stoffel M, Devogelaer JP.  Primary prevention of glucocorticoid-induced osteoporosis with intermittent intravenous pamidronate: a randomized trial. Calcif Tissue Int. 1997; 61:266-71. PubMed
 
Uchida S, Taniguchi T, Shimizu T, Kakikawa T, Okuyama K, Okaniwa M. et al.  Therapeutic effects of alendronate 35 mg once weekly and 5 mg once daily in Japanese patients with osteoporosis: a double-blind, randomized study. J Bone Miner Metab. 2005; 23:382-8. PubMed
 
Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A. et al.  The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003; 18:9-17. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005; 20:187-92. PubMed
 
Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A. et al.  Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res. 2007; 22:503-8. PubMed
 
Blair MM, Carson DS, Barrington R.  Bisphosphonates in the prevention and treatment of glucocorticoid-induced osteoporosis. J Fam Pract. 2000; 49:839-48. PubMed
 
Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S. et al.  Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res. 2000; 15:1006-13. PubMed
 
Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E. et al.  Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 2001; 44:202-11. PubMed
 
Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF. et al.  Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int. 2000; 67:277-85. PubMed
 
Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R. et al.  Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997; 337:382-7. PubMed
 
Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S. et al.  Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. Ciblos Study Group. J Clin Endocrinol Metab. 1998; 83:1128-33. PubMed
 
Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S. et al.  Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med. 1998; 339:292-9. PubMed
 
Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M. et al.  Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 1999; 42:2309-18. PubMed
 
Jencen D, Reid D, Devogelaer JP, et al.  Risedronate is safe and well tolerated in treating corticosteroid-induced osteoporosis [Abstract]. Presented at the second joint meeting of the American Society for Bone and Mineral Research–International Bone and Mineral Society, San Francisco, California, 1-6 December 1998.
 
Skingle SJ, Moore DJ, Crisp AJ.  Cyclical etidronate increases lumbar spine bone density in patients on long-term glucocorticosteroid therapy. Int J Clin Pract. 1997; 51:364-7. PubMed
 
Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, Cawley MI.  The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate. Scand J Rheumatol. 1999; 28:152-6. PubMed
 
Geusens P, Dequeker J, Vanhoof J, Stalmans R, Boonen S, Joly J. et al.  Cyclical etidronate increases bone density in the spine and hip of postmenopausal women receiving long term corticosteroid treatment. A double blind, randomised placebo controlled study. Ann Rheum Dis. 1998; 57:724-7. PubMed
 
Cortet B, Hachulla E, Barton I, Bonvoisin B, Roux C.  Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum Engl Ed. 1999; 66:214-9. PubMed
 
Cummings SR, Schwartz AV, Black DM.  Alendronate and atrial fibrillation [Letter]. N Engl J Med. 2007; 356:1895-6. PubMed
 
Mosekilde L, Beck-Nielsen H, Sørensen OH, Nielsen SP, Charles P, Vestergaard P. et al.  Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas. 2000; 36:181-93. PubMed
 
Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H. et al.  Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002; 360:2001-8. PubMed
 
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B. et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280:605-13. PubMed
 
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A. et al.  Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004; 104:837-44. PubMed
 
Smith MR, Fallon MA, Lee H, Finkelstein JS.  Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89:3841-6. PubMed
 
Jolly EE, Bjarnason NH, Neven P, Plouffe L Jr, Johnston CC Jr, Watts SD. et al.  Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause. 2003; 10:337-44. PubMed
 
Michalská D, Stepan JJ, Basson BR, Pavo I.  The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2006; 91:870-7. PubMed
 
Zheng S, Wu Y, Zhang Z, Yang X, Hui Y, Zhang Y. et al.  Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in postmenopausal women: a randomized clinical trial in Beijing. Chin Med J (Engl). 2003; 116:1127-33. PubMed
 
Johnston CC Jr, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak BH. 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; 160:3444-50. PubMed
 
Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S. et al.  Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group. Osteoporos Int. 1999; 10:330-6. PubMed
 
Kung AW, Chao HT, Huang KE, Need AG, Taechakraichana N, Loh FH. et al.  Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women. J Clin Endocrinol Metab. 2003; 88:3130-6. PubMed
 
Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E.  Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:985-92. PubMed
 
Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C.  A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996; 11:835-42. PubMed
 
Rubin MR, Lee KH, McMahon DJ, Silverberg SJ.  Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:1174-8. PubMed
 
Recker RR, Davies KM, Dowd RM, Heaney RP.  The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999; 130:897-904. PubMed
 
van Staa T, Abenhaim L, Cooper C.  Upper gastrointestinal adverse events and cyclical etidronate. Am J Med. 1997; 103:462-7. PubMed
 
Sato Y, Asoh T, Kaji M, Oizumi K.  Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner Res. 2000; 15:2487-94. PubMed
 
McClung MR, Wasnich RD, Recker R, Cauley JA, Chesnut CH 3rd, Ensrud KE. et al.  Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res. 2004; 19:11-8. PubMed
 
Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I.  The prevention of early postmenopausal bone loss by cyclical etidronate therapy: a 2-year, double-blind, placebo-controlled study. Am J Med. 1997; 103:92-9. PubMed
 
Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R.  Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up). J Clin Endocrinol Metab. 1997; 82:2784-91. PubMed
 
Pouilles JM, Tremollieres F, Roux C, Sebert JL, Alexandre C, Goldberg D. et al.  Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy. Osteoporos Int. 1997; 7:213-8. PubMed
 
Heath DA, Bullivant BG, Boiven C, Balena R.  The effects of cyclical etidronate on early postmenopausal bone loss: an open, randomized controlled study. J Clin Densitom. 2000; 3:27-33. PubMed
 
Adami S, Bruni V, Bianchini D, Becorpi A, Lombardi P, Campagnoli C. et al.  Prevention of early postmenopausal bone loss with cyclical etidronate. J Endocrinol Invest. 2000; 23:310-6. PubMed
 
Pitt P, Li F, Todd P, Webber D, Pack S, Moniz C.  A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment. Thorax. 1998; 53:351-6. PubMed
 
Silberstein EB, Schnur W.  Cyclic oral phosphate and etidronate increase femoral and lumbar bone mineral density and reduce lumbar spine fracture rate over three years. J Nucl Med. 1992; 33:1-5. PubMed
 
Geusens P, Vanhoof JS, Joly J, Dequeker J, Nijs J, Rauss J.  Cyclic etidronate increases bone density in the spine and hip in postmenopausal women on chronic corticosteroid treatment. A double-blind controlled study. Bone. 1997; 20:9S.
 
Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowicz MA, Lane AW. et al.  Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992; 117:1-9. PubMed
 
Reid IR, King AR, Alexander CJ, Ibbertson HK.  Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (APD). Lancet. 1988; 1:143-6. PubMed
 
Ryan PJ, Blake GM, Davie M, Haddaway M, Gibson T, Fogelman I.  Intermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safety. Osteoporos Int. 2000; 11:171-6. PubMed
 
Lees B, Garland SW, Walton C, Ross D, Whitehead MI, Stevenson JC.  Role of oral pamidronate in preventing bone loss in postmenopausal women. Osteoporos Int. 1996; 6:480-5. PubMed
 
Brumsen C, Papapoulos SE, Lips P, Geelhoed-Duijvestijn PH, Hamdy NA, Landman JO. et al.  Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension. J Bone Miner Res. 2002; 17:1057-64. PubMed
 
Notelovitz M, John VA, Good WR.  Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause. 2002; 9:343-53. PubMed
 
Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED. et al.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006; 295:1647-57. PubMed
 
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY. et al.  Effect of vitamin D on falls: a meta-analysis. JAMA. 2004; 291:1999-2006. PubMed
 
Woo SB, Hellstein JW, Kalmar JR.  Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006; 144:753-61. PubMed
 
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D. et al.  Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research [Editorial]. J Bone Miner Res. 2007; 22:1479-91. PubMed
 
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A.  Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007; 26:53-77. PubMed
 

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Articles are not mutually exclusive.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Risk for vertebral fractures relative to placebo for participants who are at high risk for fracture, by agent.

PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Pooled risk estimate calculated by authors; restricted to studies with >12 months of follow-up. ‡Risk estimate calculated from cited individual studies. §Insufficient data to calculate risk.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Risk for nonvertebral fractures relative to placebo for participants who are at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Pooled risk estimate calculated by authors; restricted to studies with >12 months of follow-up. ‡Risk estimate calculated from cited individual studies. §Insufficient data to calculate risk.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Risk for hip fractures relative to placebo for participants who are at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.
Risk for vertebral fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator; WHI = Women's Health Initiative. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Risk for nonvertebral fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Risk for hip fracture relative to placebo for participants who are not at high risk for fracture, by agent.

NR = not reported; PTH = parathyroid hormone; SERM = selective estrogen receptor modulator; WHI = Women's Health Initiative. *Pooled risk estimate from cited meta-analysis or systematic review. †Insufficient data to calculate risk. ‡Risk estimate calculated from cited individual studies.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Risk Groups for Likelihood of Fracture*
Table Jump PlaceholderTable 2.  Effect of Agents on Fracture Risk Reduction Compared with Placebo, by Agent*
Table Jump PlaceholderAppendix Table.  Pooled Risk for Adverse Events for Bisphosphonates Compared with Placebo, by Agent*

Audio

Audio Summary

Other Audio Options: Download MP3

References

.  Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993; 94:646-50. PubMed
CrossRef
 
Lindsay R.  Osteoporosis: A Guide to Diagnosis, Prevention, and Treatment. New York: Raven Pr; 1992.
 
Chrischilles EA, Butler CD, Davis CS, Wallace RB.  A model of lifetime osteoporosis impact. Arch Intern Med. 1991; 151:2026-32. PubMed
 
U.S. 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; July 1994.
 
Ray NF, Chan JK, Thamer M, Melton LJ 3rd.  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. PubMed
 
Keen RW.  Burden of osteoporosis and fractures. Curr Osteoporos Rep. 2003; 1:66-70. PubMed
 
Sasser AC, Rousculp MD, Birnbaum HG, Oster EF, Lufkin E, Mallet D.  Economic burden of osteoporosis, breast cancer, and cardiovascular disease among postmenopausal women in an employed population. Womens Health Issues. 2005; 15:97-108. PubMed
 
MacLean C, Alexander A, Carter J, Chen S, Desai SB, Grossman J, et al.  Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis. Comparative Effectiveness Review No. 12. (Prepared by the Southern California/RAND Evidence-based Practice Center under contract 290-02-0003). Rockville, MD: Agency for Healthcare Research and Quality; December 2007. Available athttp://www.effectivehealthcare.ahrq.gov/reports/final.cfm.
 
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF.  Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999; 354:1896-900. PubMed
 
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ. et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12. PubMed
 
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M. et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998; 352:609-13. PubMed
 
Yusuf S, Peto R, Lewis J, Collins R, Sleight P.  Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985; 27:335-71. PubMed
 
Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J. et al.  The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007; 18:1033-46. PubMed
 
Cranney A, Wells G, Willan A, Griffith L, Zytaruk N, Robinson V. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev. 2002; 23:508-16. PubMed
 
Karpf DB, Shapiro DR, Seeman E, Ensrud KE, Johnston CC Jr, Adami S. et al.  Prevention of nonvertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study Groups. JAMA. 1997; 277:1159-64. PubMed
 
Cranney A, Welch V, Adachi JD, Guyatt G, Krolicki N, Griffith L. et al.  Etidronate for treating and preventing postmenopausal osteoporosis. Cochrane Database Syst Rev. 2001; CD003376. PubMed
 
Cranney A, Welch V, Adachi JD, Homik J, Shea B, Suarez-Almazor ME. et al.  Calcitonin for the treatment and prevention of corticosteroid-induced osteoporosis. Cochrane Database Syst Rev. 2000; CD001983. PubMed
 
Papapoulos SE, Quandt SA, Liberman UA, Hochberg MC, Thompson DE.  Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women. Osteoporos Int. 2005; 16:468-74. PubMed
 
Cranney A, Tugwell P, Adachi J, Weaver B, Zytaruk N, Papaioannou A. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002; 23:517-23. PubMed
 
Cranney A, Tugwell P, Zytaruk N, Robinson V, Weaver B, Shea B. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis. Endocr Rev. 2002; 23:540-51. PubMed
 
Kanis JA, McCloskey EV.  Effect of calcitonin on vertebral and other fractures. QJM. 1999; 92:143-9. PubMed
 
Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J.  A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess. 2005; 9:1-160. PubMed
 
Schachter HM, Clifford TJ, Cranney A, Barrowman NJ, Moher D.  Raloxifene for primary and secondary prevention of osteoporotic fractures in postmenopausal women: a systematic review of efficacy and safety evidence. Ottawa, Ontario, Canada: Canadian Coordinating Office for Health Technology Assessment; 2005.
 
Shea B, Wells G, Cranney A, Zytaruk N, Robinson V, Griffith L. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev. 2002; 23:552-9. PubMed
 
Papadimitropoulos E, Wells G, Shea B, Gillespie W, Weaver B, Zytaruk N. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002; 23:560-9. PubMed
 
Avenell A, Gillespie WJ, Gillespie LD, O'Connell DL.  Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2005; CD000227. PubMed
 
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B.  Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005; 293:2257-64. PubMed
 
Torgerson DJ, Bell-Syer SE.  Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskelet Disord. 2001; 2:7. PubMed
 
Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N. et al.  Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev. 2002; 23:529-39. PubMed
 
Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD.  Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int. 2006; 17:313-6. PubMed
 
Nguyen ND, Eisman JA, Nguyen TV.  Anti-hip fracture efficacy of biophosphonates: a Bayesian analysis of clinical trials. J Bone Miner Res. 2006; 21:340-9. PubMed
 
Sawka AM, Papaioannou A, Adachi JD, Gafni A, Hanley DA, Thabane L.  Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women. BMC Musculoskelet Disord. 2005; 6:39. PubMed
 
Richy F, Schacht E, Bruyere O, Ethgen O, Gourlay M, Reginster JY.  Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int. 2005; 76:176-86. PubMed
 
Palmer S, McGregor DO, Strippoli GF.  Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2005; CD005015. PubMed
 
Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE.  Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res. 2005; 20:2105-15. PubMed
 
Richy F, Ethgen O, Bruyere O, Reginster JY.  Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int. 2004; 15:301-10. PubMed
 
Boonen S, Laan RF, Barton IP, Watts NB.  Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int. 2005; 16:1291-8. PubMed
 
Torgerson DJ, Bell-Syer SE.  Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA. 2001; 285:2891-7. PubMed
 
Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC. et al.  Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005; 365:1621-8. PubMed
 
Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW. et al.  Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. J Clin Endocrinol Metab. 2000; 85:720-6. PubMed
 
Greenspan SL, Resnick NM, Parker RA.  Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA. 2003; 289:2525-33. PubMed
 
Hosking D, Adami S, Felsenberg D, Andia JC, Välimäki M, Benhamou L. et al.  Comparison of change in bone resorption and bone mineral density with once-weekly alendronate and daily risedronate: a randomised, placebo-controlled study. Curr Med Res Opin. 2003; 19:383-94. PubMed
 
McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH. et al.  Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006; 354:821-31. PubMed
 
Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM.  Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005; 80:343-9. PubMed
 
Zein CO, Jorgensen RA, Clarke B, Wenger DE, Keach JC, Angulo P. et al.  Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology. 2005; 42:762-71. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Alendronate and vitamin D2 for prevention of hip fracture in Parkinson's disease: a randomized controlled trial. Mov Disord. 2006; 21:924-9. PubMed
 
Sato Y, Kanoko T, Yasuda H, Satoh K, Iwamoto J.  Beneficial effect of etidronate therapy in immobilized hip fracture patients. Am J Phys Med Rehabil. 2004; 83:298-303. PubMed
 
Sato Y, Honda Y, Iwamoto J.  Etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone. 2006; 39:1080-6. PubMed
 
Wimalawansa SJ.  A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med. 1998; 104:219-26. PubMed
 
Campbell IA, Douglas JG, Francis RM, Prescott RJ, Reid DM.  Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids. Thorax. 2004; 59:761-8. PubMed
 
Ishida Y, Kawai S.  Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med. 2004; 117:549-55. PubMed
 
Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T. et al.  Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year followup. J Rheumatol. 2003; 30:2673-9. PubMed
 
Sorensen OH, Crawford GM, Mulder H, Hosking DJ, Gennari C, Mellstrom D. et al.  Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003; 32:120-6. PubMed
 
Sato Y, Kanoko T, Satoh K, Iwamoto J.  The prevention of hip fracture with risedronate and ergocalciferol plus calcium supplementation in elderly women with Alzheimer disease: a randomized controlled trial. Arch Intern Med. 2005; 165:1737-42. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Risedronate therapy for prevention of hip fracture after stroke in elderly women. Neurology. 2005; 64:811-6. PubMed
 
Palomba S, Orio F Jr, Manguso F, Falbo A, Russo T, Tolino A. et al.  Efficacy of risedronate administration in osteoporotic postmenopausal women affected by inflammatory bowel disease. Osteoporos Int. 2005; 16:1141-9. PubMed
 
Hooper MJ, Ebeling PR, Roberts AP, Graham JJ, Nicholson GC, D'Emden M. et al.  Risedronate prevents bone loss in early postmenopausal women: a prospective randomized, placebo-controlled trial. Climacteric. 2005; 8:251-62. PubMed
 
Greenspan SL, Bhattacharya RK, Sereika SM, Brufsky A, Vogel VG.  Prevention of bone loss in survivors of breast cancer: A randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab. 2007; 92:131-6. PubMed
 
Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y. et al.  The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits. Bone. 2004; 35:418-24. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med. 2005; 165:1743-8. PubMed
 
Kanaji A, Higashi M, Namisato M, Nishio M, Ando K, Yamada H.  Effects of risedronate on lumbar bone mineral density, bone resorption, and incidence of vertebral fracture in elderly male patients with leprosy. Lepr Rev. 2006; 77:147-53. PubMed
 
Trovas GP, Lyritis GP, Galanos A, Raptou P, Constantelou E.  A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. J Bone Miner Res. 2002; 17:521-7. PubMed
 
Ushiroyama T, Ikeda A, Sakai M, Higashiyama T, Ueki M.  Effects of the combined use of calcitonin and 1 alpha-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: a prospective study of long-term and continuous administration with low dose calcitonin. Maturitas. 2001; 40:229-38. PubMed
 
Tóth E, Csupor E, Mészáros S, Ferencz V, Németh L, McCloskey EV. et al.  The effect of intranasal salmon calcitonin therapy on bone mineral density in idiopathic male osteoporosis without vertebral fractures—an open label study. Bone. 2005; 36:47-51. PubMed
 
Hay JE, Malinchoc M, Dickson ER.  A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 2001; 34:292-8. PubMed
 
Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ. et al.  Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA. 2003; 290:1729-38. PubMed
 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML. et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33. PubMed
 
Reid IR, Eastell R, Fogelman I, Adachi JD, Rosen A, Netelenbos C. et al.  A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women. Arch Intern Med. 2004; 164:871-9. PubMed
 
Gallagher JC, Genant HK, Crans GG, Vargas SJ, Krege JH.  Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005; 90:1583-7. PubMed
 
Kaufman JM, Orwoll E, Goemaere S, San Martin J, Hossain A, Dalsky GP. et al.  Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int. 2005; 16:510-6. PubMed
 
Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R. et al.  Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev. 2000; CD001347. PubMed
 
Prince RL, Devine A, Dhaliwal SS, Dick IM.  Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006; 166:869-75. PubMed
 
Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U. et al.  Randomized controlled trial of calcium in healthy older women. Am J Med. 2006; 119:777-85. PubMed
 
Ravn P, Clemmesen B, Riis BJ, Christiansen C.  The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study. Bone. 1996; 19:527-33. PubMed
 
Chesnut CH III, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A. et al.  Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004; 19:1241-9. PubMed
 
Recker R, Stakkestad JA, Chesnut CH 3rd, Christiansen C, Skag A, Hoiseth A. et al.  Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone. 2004; 34:890-9. PubMed
 
Grotz W, Nagel C, Poeschel D, Cybulla M, Petersen KG, Uhl M. et al.  Effect of ibandronate on bone loss and renal function after kidney transplantation. J Am Soc Nephrol. 2001; 12:1530-7. PubMed
 
Kim SH, Lim SK, Hahn JS.  Effect of pamidronate on new vertebral fractures and bone mineral density in patients with malignant lymphoma receiving chemotherapy. Am J Med. 2004; 116:524-8. PubMed
 
Ninkovic M, Love S, Tom BD, Bearcroft PW, Alexander GJ, Compston JE.  Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation. J Hepatol. 2002; 37:93-100. PubMed
 
Aris RM, Lester GE, Renner JB, Winders A, Denene Blackwood A, Lark RK. et al.  Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Am J Respir Crit Care Med. 2000; 162:941-6. PubMed
 
Reid IR, Wattie DJ, Evans MC, Gamble GD, Stapleton JP, Cornish J.  Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1994; 79:1595-9. PubMed
 
Kananen K, Volin L, Laitinen K, Alfthan H, Ruutu T, Välimäki MJ.  Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate. J Clin Endocrinol Metab. 2005; 90:3877-85. PubMed
 
Coco M, Glicklich D, Faugere MC, Burris L, Bognar I, Durkin P. et al.  Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate. J Am Soc Nephrol. 2003; 14:2669-76. PubMed
 
Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. et al.  Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002; 346:653-61. PubMed
 
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA. et al.  Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356:1809-22. PubMed
 
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM. et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90:1371-88. PubMed
 
Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C. et al.  Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007; 357:1799-809. PubMed
 
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE. et al.  Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354:669-83. PubMed
 
Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T. et al.  Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ. 2005; 330:1003. PubMed
 
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY. et al.  Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001; 344:1434-41. PubMed
 
Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A. et al.  The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003; 18:9-17. PubMed
 
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H. et al.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291:1701-12. PubMed
 
Homik JE, Cranney A, Shea B, Tugwell P, Wells G, Adachi JD. et al.  A metaanalysis on the use of bisphosphonates in corticosteroid induced osteoporosis. J Rheumatol. 1999; 26:1148-57. PubMed
 
Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B. et al.  Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int. 2007; 18:811-8. PubMed
 
Kushida K, Fukunaga M, Kishimoto H, Shiraki M, Itabashi A, Inoue T. et al.  A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial. J Bone Miner Metab. 2004; 22:469-78. PubMed
 
Fukunaga M, Kushida K, Kishimoto H, Shiraki M, Taketani Y, Minaguchi H. et al.  A comparison of the effect of risedronate and etidronate on lumbar bone mineral density in Japanese patients with osteoporosis: a randomized controlled trial. Osteoporos Int. 2002; 13:971-9. PubMed
 
Guañabens N, Parés A, Ros I, Alvarez L, Pons F, Caballería L. et al.  Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol. 2003; 98:2268-74. PubMed
 
Iwamoto J, Takeda T, Ichimura S, Uzawa M.  Comparative effects of treatment with etidronate and alendronate on bone resorption, back pain, and activities of daily living in elderly women with vertebral fractures. Keio J Med. 2003; 52:230-5. PubMed
 
Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S. et al.  Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res. 2005; 20:141-51. PubMed
 
Muscoso E, Puglisi N, Mamazza C, Lo Giudice F, Testai M, Abbate S. et al.  Antiresorption therapy and reduction in fracture susceptibility in the osteoporotic elderly patient: open study. Eur Rev Med Pharmacol Sci. 2004; 8:97-102. PubMed
 
Tauchmanovà L, De Simone G, Musella T, Orio F, Ricci P, Nappi C. et al.  Effects of various antireabsorptive treatments on bone mineral density in hypogonadal young women after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 37:81-8. PubMed
 
Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SM. et al.  Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab. 2006; 91:2631-7. PubMed
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN. et al.  Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006; 295:2727-41. PubMed
 
Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz A. et al.  A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:4528-35. PubMed
 
Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon J. et al.  Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis. Menopause. 2004; 11:405-15. PubMed
 
Garcia-Delgado I, Prieto S, Gil-Fraguas L, Robles E, Rufilanchas JJ, Hawkins F.  Calcitonin, etidronate, and calcidiol treatment in bone loss after cardiac transplantation. Calcif Tissue Int. 1997; 60:155-9. PubMed
 
Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich R, Ross P. 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; 338:485-92. PubMed
 
Recker RR, Kendler D, Recknor CP, Rooney TW, Lewiecki EM, Utian WH. et al.  Comparative effects of raloxifene and alendronate on fracture outcomes in postmenopausal women with low bone mass. Bone. 2007; 40:843-51. PubMed
 
Boutsen Y, Jamart J, Esselinckx W, Stoffel M, Devogelaer JP.  Primary prevention of glucocorticoid-induced osteoporosis with intermittent intravenous pamidronate: a randomized trial. Calcif Tissue Int. 1997; 61:266-71. PubMed
 
Uchida S, Taniguchi T, Shimizu T, Kakikawa T, Okuyama K, Okaniwa M. et al.  Therapeutic effects of alendronate 35 mg once weekly and 5 mg once daily in Japanese patients with osteoporosis: a double-blind, randomized study. J Bone Miner Metab. 2005; 23:382-8. PubMed
 
Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A. et al.  The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003; 18:9-17. PubMed
 
Sato Y, Iwamoto J, Kanoko T, Satoh K.  Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005; 20:187-92. PubMed
 
Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A. et al.  Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res. 2007; 22:503-8. PubMed
 
Blair MM, Carson DS, Barrington R.  Bisphosphonates in the prevention and treatment of glucocorticoid-induced osteoporosis. J Fam Pract. 2000; 49:839-48. PubMed
 
Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S. et al.  Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res. 2000; 15:1006-13. PubMed
 
Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E. et al.  Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 2001; 44:202-11. PubMed
 
Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF. et al.  Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int. 2000; 67:277-85. PubMed
 
Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R. et al.  Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med. 1997; 337:382-7. PubMed
 
Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S. et al.  Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. Ciblos Study Group. J Clin Endocrinol Metab. 1998; 83:1128-33. PubMed
 
Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S. et al.  Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med. 1998; 339:292-9. PubMed
 
Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M. et al.  Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 1999; 42:2309-18. PubMed
 
Jencen D, Reid D, Devogelaer JP, et al.  Risedronate is safe and well tolerated in treating corticosteroid-induced osteoporosis [Abstract]. Presented at the second joint meeting of the American Society for Bone and Mineral Research–International Bone and Mineral Society, San Francisco, California, 1-6 December 1998.
 
Skingle SJ, Moore DJ, Crisp AJ.  Cyclical etidronate increases lumbar spine bone density in patients on long-term glucocorticosteroid therapy. Int J Clin Pract. 1997; 51:364-7. PubMed
 
Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, Cawley MI.  The prevention of corticosteroid-induced bone loss with intermittent cyclical etidronate. Scand J Rheumatol. 1999; 28:152-6. PubMed
 
Geusens P, Dequeker J, Vanhoof J, Stalmans R, Boonen S, Joly J. et al.  Cyclical etidronate increases bone density in the spine and hip of postmenopausal women receiving long term corticosteroid treatment. A double blind, randomised placebo controlled study. Ann Rheum Dis. 1998; 57:724-7. PubMed
 
Cortet B, Hachulla E, Barton I, Bonvoisin B, Roux C.  Evaluation of the efficacy of etidronate therapy in preventing glucocorticoid-induced bone loss in patients with inflammatory rheumatic diseases. A randomized study. Rev Rhum Engl Ed. 1999; 66:214-9. PubMed
 
Cummings SR, Schwartz AV, Black DM.  Alendronate and atrial fibrillation [Letter]. N Engl J Med. 2007; 356:1895-6. PubMed
 
Mosekilde L, Beck-Nielsen H, Sørensen OH, Nielsen SP, Charles P, Vestergaard P. et al.  Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas. 2000; 36:181-93. PubMed
 
Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H. et al.  Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002; 360:2001-8. PubMed
 
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B. et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998; 280:605-13. PubMed
 
Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A. et al.  Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Obstet Gynecol. 2004; 104:837-44. PubMed
 
Smith MR, Fallon MA, Lee H, Finkelstein JS.  Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89:3841-6. PubMed
 
Jolly EE, Bjarnason NH, Neven P, Plouffe L Jr, Johnston CC Jr, Watts SD. et al.  Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause. 2003; 10:337-44. PubMed
 
Michalská D, Stepan JJ, Basson BR, Pavo I.  The effect of raloxifene after discontinuation of long-term alendronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2006; 91:870-7. PubMed
 
Zheng S, Wu Y, Zhang Z, Yang X, Hui Y, Zhang Y. et al.  Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in postmenopausal women: a randomized clinical trial in Beijing. Chin Med J (Engl). 2003; 116:1127-33. PubMed
 
Johnston CC Jr, Bjarnason NH, Cohen FJ, Shah A, Lindsay R, Mitlak BH. 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; 160:3444-50. PubMed
 
Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S. et al.  Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group. Osteoporos Int. 1999; 10:330-6. PubMed
 
Kung AW, Chao HT, Huang KE, Need AG, Taechakraichana N, Loh FH. et al.  Efficacy and safety of raloxifene 60 milligrams/day in postmenopausal Asian women. J Clin Endocrinol Metab. 2003; 88:3130-6. PubMed
 
Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E.  Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002; 87:985-92. PubMed
 
Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C.  A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996; 11:835-42. PubMed
 
Rubin MR, Lee KH, McMahon DJ, Silverberg SJ.  Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:1174-8. PubMed
 
Recker RR, Davies KM, Dowd RM, Heaney RP.  The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999; 130:897-904. PubMed
 
van Staa T, Abenhaim L, Cooper C.  Upper gastrointestinal adverse events and cyclical etidronate. Am J Med. 1997; 103:462-7. PubMed
 
Sato Y, Asoh T, Kaji M, Oizumi K.  Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner Res. 2000; 15:2487-94. PubMed
 
McClung MR, Wasnich RD, Recker R, Cauley JA, Chesnut CH 3rd, Ensrud KE. et al.  Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res. 2004; 19:11-8. PubMed
 
Herd RJ, Balena R, Blake GM, Ryan PJ, Fogelman I.  The prevention of early postmenopausal bone loss by cyclical etidronate therapy: a 2-year, double-blind, placebo-controlled study. Am J Med. 1997; 103:92-9. PubMed
 
Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R.  Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up). J Clin Endocrinol Metab. 1997; 82:2784-91. PubMed
 
Pouilles JM, Tremollieres F, Roux C, Sebert JL, Alexandre C, Goldberg D. et al.  Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy. Osteoporos Int. 1997; 7:213-8. PubMed
 
Heath DA, Bullivant BG, Boiven C, Balena R.  The effects of cyclical etidronate on early postmenopausal bone loss: an open, randomized controlled study. J Clin Densitom. 2000; 3:27-33. PubMed
 
Adami S, Bruni V, Bianchini D, Becorpi A, Lombardi P, Campagnoli C. et al.  Prevention of early postmenopausal bone loss with cyclical etidronate. J Endocrinol Invest. 2000; 23:310-6. PubMed
 
Pitt P, Li F, Todd P, Webber D, Pack S, Moniz C.  A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment. Thorax. 1998; 53:351-6. PubMed
 
Silberstein EB, Schnur W.  Cyclic oral phosphate and etidronate increase femoral and lumbar bone mineral density and reduce lumbar spine fracture rate over three years. J Nucl Med. 1992; 33:1-5. PubMed
 
Geusens P, Vanhoof JS, Joly J, Dequeker J, Nijs J, Rauss J.  Cyclic etidronate increases bone density in the spine and hip in postmenopausal women on chronic corticosteroid treatment. A double-blind controlled study. Bone. 1997; 20:9S.
 
Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowicz MA, Lane AW. et al.  Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. 1992; 117:1-9. PubMed
 
Reid IR, King AR, Alexander CJ, Ibbertson HK.  Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (APD). Lancet. 1988; 1:143-6. PubMed
 
Ryan PJ, Blake GM, Davie M, Haddaway M, Gibson T, Fogelman I.  Intermittent oral disodium pamidronate in established osteoporosis: a 2 year double-masked placebo-controlled study of efficacy and safety. Osteoporos Int. 2000; 11:171-6. PubMed
 
Lees B, Garland SW, Walton C, Ross D, Whitehead MI, Stevenson JC.  Role of oral pamidronate in preventing bone loss in postmenopausal women. Osteoporos Int. 1996; 6:480-5. PubMed
 
Brumsen C, Papapoulos SE, Lips P, Geelhoed-Duijvestijn PH, Hamdy NA, Landman JO. et al.  Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension. J Bone Miner Res. 2002; 17:1057-64. PubMed
 
Notelovitz M, John VA, Good WR.  Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women. Menopause. 2002; 9:343-53. PubMed
 
Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED. et al.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006; 295:1647-57. PubMed
 
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY. et al.  Effect of vitamin D on falls: a meta-analysis. JAMA. 2004; 291:1999-2006. PubMed
 
Woo SB, Hellstein JW, Kalmar JR.  Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006; 144:753-61. PubMed
 
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D. et al.  Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research [Editorial]. J Bone Miner Res. 2007; 22:1479-91. PubMed
 
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A.  Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007; 26:53-77. PubMed
 

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Want to Subscribe?

Learn more about subscription options

<