Long-term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review [Entered Retrospectively]

Project Summary Title and Description

Title
Long-term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review [Entered Retrospectively]
Description
Objective. To summarize evidence on outcomes of long-term osteoporosis drug therapy to prevent fractures, on continuing versus discontinuing osteoporosis drug therapy (i.e., placebo drug holidays), and on whether osteoporosis drug intervention effects vary as a function of patient, bone, or drug characteristics. Data sources. MEDLINE, Embase and Cochrane databases from 1995 to June 2018; ClinicalTrials.gov; bibliographies of relevant systematic reviews Review methods. Long-term osteoporosis drug therapy was defined as >3 years and drug holiday as osteoporosis drug discontinuation for ≥1 year after ≥1 year of prior osteoporosis drug use. Two reviewers independently rated risk of bias (ROB) and strength of evidence (SOE), resolving discrepancies by consensus. Included studies were English-language trials for incident fractures and harms and controlled observational studies for additional harms outcomes. For low or medium ROB studies, one reviewer extracted data and a second verified accuracy. Results. Of 56 eligible publications, 44 had low or medium ROB, including 32 publications of trials (7 unique studies) and 12 publications of observational studies (10 unique studies). Nearly all studies were comprised of postmenopausal women. Mean participant age was 72 years; all but 2 studies had a mean age <80 years. In postmenopausal women with osteoporosis, compared with placebo, 4 years of alendronate or raloxifene reduced risk of incident vertebral fractures (high SOE), 4 years of alendronate reduced risk of incident clinical fractures (moderate SOE). In postmenopausal women with past fractures, compared with placebo, both long-term estrogen and long-term estrogen/progestin reduced risk of incident clinical fractures and long-term estrogen reduced risk of incident hip fractures (all low SOE). Alendronate, denosumab and raloxifene for 4 years each significantly increased total hip and lumbar spine bone mineral density (BMD) versus placebo. Continuation versus discontinuation of alendronate after 5 years reduced risk of incident clinical vertebral fractures in one large trial (10 vs. 5 years, moderate SOE), but not in another smaller trial (7 vs. 5 years, low SOE). Continuation versus discontinuation of zoledronic acid (6 vs. 3 years) reduced risk of incident radiographic vertebral fractures (moderate SOE), but evidence was insufficient about risk of incident clinical vertebral fractures. Neither alendronate nor zoledronic acid continuation reduced risk of nonvertebral fractures (low SOE) versus discontinuation; for both, continuation was associated with generally stable hip BMD compared to small, but significant declines with discontinuation. Based primarily on observational studies, long-term bisphosphonates may increase risks of radiologically confirmed atypical femoral fractures (AFF), subtrochanteric or femoral shaft fractures without confirmed AFF features, and osteonecrosis of the jaw (ONJ). Limitations. Minimal data for men or individuals with comorbidities. Low power to assess risks of incident clinical fractures. No data compared long-term effects of sequential treatments (e.g., anabolic followed by anti-resorptive) or different durations of drug holidays. Analyses of possible treatment effect modifiers almost entirely post hoc. Observational studies used variable drug treatment and control exposures and harms definitions. Conclusions. For postmenopausal women with osteoporosis by BMD or past fractures, long-term alendronate and raloxifene reduced risk of incident vertebral fractures; long-term alendronate, estrogen, and estrogen/progestin reduced risk of clinical fractures; and long-term estrogen reduces risk of incident hip fractures. Longer-term use of bisphosphonates versus discontinuation may lower vertebral fracture risk and stabilize hip BMD, but doesn’t reduce nonvertebral fracture risk and may increase risk of AFF and ONJ. Long-term estrogen and estrogen/progestin increased risk of cardiovascular disease, and long-term estrogen increased risk of dementia and breast cancer. To address remaining knowledge gaps, future trials and observational studies should enroll diverse populations (sex, comorbidity), examine the effects of sequential treatments and compare drug holidays of different durations, be powered for clinical fractures, and use standard AFF and ONJ definitions. A priori analyses to examine whether treatment outcomes vary by patient, bone and drug treatment characteristics may inform individualized treatment decisions.
Attribution
N/A
Authors of Report
N/A
Methodology description
N/A
PROSPERO
CRD42018087006
DOI
10.26300/k9rp-0g62
Notes
Entered Retrospectively. File "osteoporosis data study characteristics ROB results outcomes.docx" contains study characteristics, risk of bias, and outcomes data.
Funding Source
Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA2902015000081)

Key Questions

1. Key Question 1. Among men and postmenopausal women aged ≥50 years with osteoporosis* or osteopenia/low bone mass†, what is the efficacy of long-term (>3 years) osteoporosis drug therapy in reducing risk of incident fracture and on change in BMD? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
2. Key Question 2. Among men and postmenopausal women aged ≥50 years with osteoporosis* or osteopenia/low bone mass†, does efficacy of long-term osteoporosis drug therapy for reducing risk of incident fracture vary as a function of patient, bone, or osteoporosis drug characteristics§? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
3. Key Question 3. Among men and postmenopausal women aged >50 years with osteoporosis* or osteopenia/low bone mass†, what is the risk of harms associated with long-term (>3 years) osteoporosis drug therapy? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
4. Key Question 4. Among men and postmenopausal women aged >50 years with osteoporosis* or osteopenia/low bone mass†, does the risk of harms associated with long-term (>3 years) osteoporosis drug therapy vary as a function of patient, bone, or osteoporosis drug characteristics§? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
5. Key Question 5. Among men and postmenopausal women aged ≥50 years currently receiving drug therapy (≥1 year) started for osteoporosis* or osteopenia/low bone mass† to prevent fracture, what is the effect of osteoporosis drug treatment holidays (≥1 year) on incident fracture risk and change in BMD? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
6. Key Question 6. Among men and postmenopausal women aged ≥50 years currently receiving drug therapy (≥1 year) started for osteoporosis* or osteopenia/low bone mass† to prevent fracture, does the effect of osteoporosis drug treatment holidays (≥1 year) on incident fracture risk vary as a function of patient, bone or osteoporosis drug characteristics§? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
7. Key Question 7. Among men and postmenopausal women aged ≥50 years currently receiving drug therapy (≥1 year) started for osteoporosis* or osteopenia/low bone mass† to prevent fracture, what is the risk of harms of osteoporosis drug treatment holidays (≥1 year)? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).
8. Key Question 8. Among men and postmenopausal women aged >50 years currently receiving drug therapy started for osteoporosis* or osteopenia/low bone mass† to prevent fracture, does risk of harms associated with osteoporosis drug treatment holidays vary as a function of patient, bone, or osteoporosis drug characteristics? *Osteoporosis defined by hip or lumbar spine DXA BMD T-score <-2.5, past clinical hip or vertebral fracture, or prevalent radiographic vertebral fracture. †Osteopenia/low bone mass defined by hip or lumbar spine DXA BMD T-score < -1.0 and > -2.5. § Patient characteristics (age, sex, race, osteoporosis status*, fracture history [clinical fractures, radiographic vertebral fractures], calculated fracture risk [e.g. FRAX®], comorbid conditions); Bone characteristics (BMD, biomarkers); Osteoporosis drug characteristics (dose, frequency, treatment duration, delivery route).

Associated Extraction Forms

Associated Studies (each link opens a new tab)

TitleAuthorsYear
Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study.2009
Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis.2010
Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study.2016
Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial.
Raloxifene and risk for stroke based on the framingham stroke risk score.2009
Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial.
Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial.2000
Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial.2006
Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur.2010
The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).2012
The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).2015
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.2006
Ten years' experience with alendronate for osteoporosis in postmenopausal women.2004
Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation.
Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.2003
Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial.2005
The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene.2014
Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to discontinue treatment?2014
Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.-- Not Found --
Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.
Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial.2012
Vascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: incidence, patient characteristics, and effect of raloxifene.
Effect of raloxifene on cardiovascular adverse events in postmenopausal women with osteoporosis.2006
Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.
Oral bisphosphonates are associated with increased risk of subtrochanteric and diaphyseal fractures in elderly women: a nested case-control study.
Effect of Raloxifene on all-cause mortality.
Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.
Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial.2006
Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial.2007
Raloxifene reduces risk of vertebral fractures corrected in postmenopausal women regardless of prior hormone therapy.
Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort.2011
Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial.2015
Incidence Rate of Atypical Femoral Fracture after Bisphosphonates Treatment in Korea.2018
Incidence and risk of osteonecrosis of the jaw among the Taiwan osteoporosis population.2014
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.
Safety assessment of raloxifene over eight years in a clinical trial setting.
Increasing occurrence of atypical femoral fractures associated with bisphosphonate use.2012
Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study.2012
Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial.2008
Association of prevalent vertebral fractures, bone density, and alendronate treatment with incident vertebral fractures: effect of number and spinal location of fractures. The Fracture Intervention Trial Research Group.1999
Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women.2011
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.2005
Does a history of non-vertebral fracture identify women without osteoporosis for treatment?2008
Risk of atypical femoral fracture during and after bisphosphonate use.2015
Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial.2010
Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.
Benefits and risks of raloxifene by vertebral fracture status.2010
Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience.2003
Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis.2004
Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group.2000
Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene.2011
Risk of atrial fibrillation associated with use of bisphosphonates and other drugs against osteoporosis: a cohort study.2010
Oral bisphosphonate use increases the risk for inflammatory jaw disease: a cohort study.2012
The Association Between Long-Term Bisphosphonate Use and the Risk of Fracture Among Women Aged 50 or Older with Osteoporosis.2016
A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis.1998
Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study.2018
The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects.2018
Incidence, risk factors, and fracture healing of atypical femoral fractures: a multicenter case-control study.2018
Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8 years’ experience in a single center2017

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