- Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: Update of a 2007 Report [Entered Retrospectively]
- Objectives: To update a 2007 systematic review on the effectiveness and safety of treatments to prevent fractures in persons with low bone density or osteoporosis and factors affecting adherence to these treatments, and to assess whether monitoring helps identify those most likely to benefit from treatment and the benefits of long-term treatment. Data Sources: MEDLINE®, Embase, the Cochrane Database of Systematic Reviews, and Clinical Trials.gov were searched from January 2005 through March 2011. Review Methods: After review by two investigators against predetermined inclusion/exclusion criteria, we included existing systematic reviews, randomized controlled clinical trials, and large observational studies, where appropriate, for assessment of treatment efficacy, safety, and adherence. Results: Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide reduce the risk of vertebral and nonvertebral fractures among postmenopausal women with osteoporosis. Ibandronate and raloxifene reduce the risk of vertebral but not nonvertebral fractures. Alendronate, risedronate, zoledronic acid, and denosumab prevent hip fractures among postmenopausal women with osteoporosis. Risedronate decreases the risk of vertebral and nonvertebral fracture among men with osteoporosis. Among those treated with glucocorticoids, fracture risk reduction was demonstrated for risedronate and alendronate compared to placebo; and for teriparatide compared to alendronate. Few studies have compared osteoporosis therapies head-to-head. Adherence to pharmacotherapy is poor in patients with osteoporosis, as with other chronic conditions. Many factors affect adherence to medications, including dosing frequency, side effects of medications, knowledge about osteoporosis, and cost. Age, prior history of fracture, and concomitant medication use do not appear to have an independent association with adherence. Dosing frequency appears to affect adherence: Adherence is improved with weekly compared to daily regimens, but evidence is lacking to show that monthly regimens improve adherence over that of weekly regimens. Decreased adherence to bisphosphonates is associated with less than optimal reduction in the risk of fracture. Insufficient evidence is available to make conclusions about how adherence to and persistence with newer osteoporosis therapies compare to that with bisphosphonates. Assessment of adverse effects finds that raloxifene is associated with an increased risk for pulmonary embolism and vasomotor flushing; and limited data support a possible association between bisphosphonate use and atypical subtrochanteric fractures of the femur. Evidence is limited on the utility of monitoring and long-term treatment. Conclusions: There is a high level of evidence that shows that fracture risk reduction is greatest in women with a diagnosis of osteoporosis and/or prevalent fractures. The level of evidence is low to moderate for fracture risk reduction in postmenopausal women with osteopenia and without prevalent fractures. The evidence is low for benefits of treatment for other populations, including men; for the benefits and risks of long-term treatment; and for the need (if any) for monitoring bone density; and mixed with regard to factors that influence adherence.
- Authors of Report
- Methodology description
- Search Strategy:
Our basic search strategy used the National Library of Medicine’s Medical Subject Headings (MeSH) keyword nomenclature. Using the same basic search rules used for the original report (with the addition of several new terms for additional drugs), we searched MEDLINE® for the period from January 2005 through March 2011. We also searched Embase, the American College of Physicians (ACP) Journal Club database, the Cochrane controlled trials register, and relevant pharmacological databases.
In searching for efficacy and effectiveness studies, we used terms for osteoporosis, osteopenia, low bone density, and the drugs listed in Key Question 1. In our search for the key adverse events (AE), we used terms for the AE and each of the drugs of interest. In our search for studies of adherence and persistence, we used terms for adherence and persistence and the drugs of interest. In all cases, both generic and trade names were used. In our search for studies on the effects of monitoring, we searched on terms related to monitoring and DXA in combination with the drugs of interest.
For new drugs, we reviewed the list of excluded studies from the original report to retrieve articles that had been rejected on the basis of drugs that were now included within the scope of the update, to find studies prior to 2005. The search was not limited to English-language publications and not limited by study design (e.g., reports of randomized controlled trials (RCT), observational studies, systematic reviews). The texts of the major search strategies are given in Appendix A.
To identify additional systematic reviews not captured in our primary search strategy, we also searched MEDLINE®, the Cochrane Database of Systematic Reviews, the websites of the National Institute for Clinical Excellence, and the NHA Health Technology Assessment Programme. We also manually searched the reference lists of review articles obtained as part of our search ("reference mining").
To augment those searches, the EPC’s Scientific Resource Center (SRC) conducted several "grey literature" searches, including a search of relevant trials in the NIH Clinical Trials database, the Web of Science, FDA Medwatch files, and Health Canada files.
Each title list was screened separately by two reviewers with clinical training and experience in systematic review to eliminate obviously irrelevant titles. Abstracts were obtained for all selected titles. Full text articles were then obtained for all selected abstracts. The reviewers then conducted a second round of screening to ascertain which articles met the inclusion criteria and would go on to data abstraction. Selections at this stage were reconciled, and disagreements were settled by consensus (with the project leaders resolving remaining disagreements).
During the second round of screening, we imposed inclusion criteria based on the particular Key Question(s) addressed by the study. For effectiveness/efficacy questions (Key Questions 1, 2, and 5), we accepted any abstracts that indicated the manuscript might include information on the treatment/prevention of osteoporotic fracture (but not bone density alone). Controlled clinical trials and large observational studies (N>1,000) that reported fracture outcomes for one or more of the drugs of interest were accepted for the efficacy analysis and went on to data extraction.
Study level details, such as population characteristics, comorbidities, inclusion and exclusion criteria, interventions, and outcomes assessed, were extracted and recorded onto specially designed forms.
- This systematic review of the literature will address the following key questions:
Key Question 1. What are the comparative benefits in fracture risk reduction among the following therapeutic modalities for low bone density: bisphosphonate medications (specifically: Alendronate (Fosamax®, oral); Risedronate (Actonel®; oral once-a-week); Ibandronate (Boniva®); Zoledronic acid (Reclast®, Zometa®, oral and IV).), Denosumab (Prolia®), Menopausal Estrogen therapy for women (numerous brands and routes of administration), Parathyroid hormone (PTH) (specifically: 1-34 (teriparatide) (Forteo®)), Selective estrogen receptor modulators (SERMs), (specifically: Raloxifene (Evista®)), Calcium, Vitamin D, Combinations or sequential use of above, and Exercise in comparison to above agents.
Key Question 2. How does fracture risk reduction resulting from treatments vary between individuals with different risks for fracture as determined by the following factors: Bone mineral density, FRAX or other risk assessment score, Prior fractures (prevention vs. treatment), Age, Sex, Race/ethnicity, Glucocorticoid use, Other factors (e.g., community dwelling vs. institutionalized, vitamin D deficient vs. not).
Key Question 3. Regarding treatment adherence and persistence: a) What are the levels of adherence and persistence with medications for the treatment and prevention of osteoporosis? b) What factors affect adherence and persistence? c) What are the effects of adherence and persistence on the risk of fractures?
Key Question 4. What are the short- and long-term harms (adverse effects) of the above therapies (when used specifically to treat or prevent low bone density/osteoporotic fracture), and do these vary by any specific subpopulations (e.g., the subpopulations identified in Key Question 2)?
Key Question 5. With regard to treatment for preventing osteoporotic fracture: a) How often should patients be monitored (via measurement of bone mineral density) during therapy, how does bone density monitoring predict antifracture benefits during pharmacotherapy, and does the ability of monitoring to predict antifracture effects of a particular pharmacologic agent vary among the pharmacotherapies? b) How does the antifracture benefit vary with long-term continued use of pharmacotherapy, and what are the comparative antifracture effects of continued long-term therapy with the various pharmacotherapies?
*** The systematic review data of this published project was retrospectively imported into SRDR by the Brown EPC on behalf of the Southern California Evidence-based Practice Center-RAND Corporation and the Agency for Healthcare Research and Quality (AHRQ). For access to the full report available on the AHRQ website, follow this link: http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1007 ***
- Funding Source
- The Agency for Healthcare Research and Quality (AHRQ)