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Bisphosphonates for Treatment and Prevention of Osteoporosis

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General Information

Description

  • bisphosphonates are 1 pharmacological option used for prevention and treatment of osteoporosis with the goal of inhibiting bone resorption, increasing bone strength, and decreasing risk of osteoporosis fractures1,2,3
  • other options for prevention and treatment of osteoporosis include1,2,3
    • hormonal replacement therapy
    • estrogen agonist/antagonist (such as raloxifene)
    • receptor activator of nuclear factor kappa-B (RANK) inhibitor (denosumab)
    • parathyroid hormone 1-34 (teriparatide) or parathyroid hormone related peptide (PTHrP[1-34]) analog (abaloparatide)
    • see Medications in Osteoporosis for additional information
  • patients with osteoporosis or at risk for osteoporosis should be advised on1,3
    • risk of osteoporosis-related fractures
    • decision to initiate bisphosphonates, which should be based on clinical judgment and patient preferences
    • importance of calcium, vitamin D, and exercise as part of any treatment program for osteoporosis
  • an effective treatment reduces fracture risk, but does not necessarily eliminate fracture risk

Definitions and classifications

  • osteoporosis - generalized skeletal disorder characterized by low bone density, deterioration of bone quality, and compromised bone strength, often leading to fragility fracture due to excessive bone loading from a fall or certain activities of daily living1
  • fragility (low trauma) fracture - fracture from minor trauma (for instance, fall from standing height or less) or that occurs spontaneously (28293453Eur J Rheumatol 2017 Mar;4(1):46OpenInNewfull-textOpenInNew)
  • z-score - bone mineral density (BMD) score representing number of standard deviations above or below mean value for age-, race-, ethnicity-, and sex-matched persons4
  • T-score - BMD score representing number of standard deviations above or below mean for normal young white women4
  • classification of bone health according to T-score for postmenopausal women and men ≥ 50 years old (1, mnh26280231pcxh108836713pmdc26280231pAm Fam Physician 2015 Aug 15;92(4):261OpenInNewfull-textOpenInNew)
    Classification BMD T-score
    NormalWithin 1 SD of mean level for young-adult reference population T-score ≥ -1.0
    Low bone mass (osteopenia)Between 1 and 2.5 SD below mean level for young-adult reference populationT-score between -1 and -2.5
    Osteoporosis ≥ 2.5 SD below mean level for young-adult reference population T-score ≤ -2.5
    Severe or established osteoporosis ≥ 2.5 SD below mean level for young-adult reference population plus fragility fractures T-score ≤ -2.5 plus ≥ 1 fracture
    Abbreviations: BMD, bone mineral density; SD, standard deviation.
  • Fracture Risk Assessment (FRAX)OpenInNew - risk calculator used to estimate 10-year probability of hip fracture and 10-year probability of major osteoporosis fracture (such as clinical vertebral, hip, proximal humerus, and distal forearm fractures), based on femoral neck BMD (if available) and presence of clinical risk factors; intended for postmenopausal women and men ≥ 50 years old1,4
  • treatment failure - significant reduction in BMD or recurrent fractures in patient who is compliant to therapy4
  • antiresorptive medications - suppress bone turnover and increase BMD; antiresorptive only medications include

References

General references used

  1. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81OpenInNewfull-textOpenInNew, correction can be found in Osteoporos Int 2015 Jul;26(7):2045OpenInNew, commentary can be found in JAMA 2015 Apr 14;313(14):1467OpenInNew
  2. Compston J, Cooper A, Cooper C, et al; National Osteoporosis Guideline Group (NOGG). UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 2017 Dec;12(1):43OpenInNew full-textOpenInNew
  3. Maraka S, Kennel KA. Bisphosphonates for the prevention and treatment of osteoporosis. BMJ. 2015 Sep 2;351:h3783OpenInNew, commentary can be found in BMJ 2015 Nov 4;351:h5868OpenInNew
  4. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016 Sep 2;22(Suppl 4):1-42OpenInNew

Recommendation grading systems used

  • American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) and American Association of Clinical Endocrinologists/The Obesity Society/American Society for Metabolic & Bariatric Surgery (AACE/TOS/ASMBS) grading recommendations
    • recommendation grade
      • Grade A - evidence from multiple, well-designed, randomized, cohort controlled trials with sufficient statistical power; ≥ 1 conclusive level 1 publications demonstrating benefit greater than risk
      • Grade B - evidence from ≥ 1 well-designed clinical trial, cohort- or case-controlled analytic study, or meta-analysis; no conclusive level 1 publication; ≥ 1 conclusive level 2 publications demonstrating benefit greater than risk
      • Grade C - evidence based on clinical experience, descriptive studies, or expert consensus opinion; no conclusive level 1 or 2 publications; ≥ 1 conclusive level 3 publications demonstrating benefit greater than risk, no risk, or no benefit
      • Grade D - no conclusive level 1, 2, or 3 publications demonstrating risk greater than benefit; conclusive level 1, 2, or 3 publication demonstrating risk is greater than benefit
    • Best evidence level (BEL)
      • BEL 1 - strong evidence
        • subject factor impact
          • none - grade A
          • negative - grade B
      • BEL 2 - intermediate evidence
        • subject factor impact
          • positive - grade A
          • none - grade B
          • negative - grade C
      • BEL 3 - weak evidence
        • subject factor impact
          • positive - grade B
          • none - grade C
          • negative - grade D
      • BEL 4 - no evidence
        • subject factor impact
          • positive - grade C
          • none - grade D
    • References -
  • American College of Rheumatology (ACR) recommendation system
    • Strong recommendation - confidence that desirable effects of recommendation outweigh undesirable effects (or vice versa), course of action would apply to all or almost all patients
    • Conditional recommendation - desirable effects of recommendation probably outweigh undesirable effects, course of action would apply to majority of the patients
    • Good practice recommendation - benefits of proceeding with guidance outweigh the harms, but supporting evidence is indirect
    • Reference - ACR guideline for prevention and treatment of glucocorticoid-induced osteoporosis (cxh124315756t pmdc28585373pArthritis Rheumatol 2017 Aug;69(8):1521OpenInNew)
  • Endocrine Society uses Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system
    • strength of recommendation
      • Strong recommendation - guideline panel members have high confidence that desirable effects of recommendation outweigh undesirable effects (or vice versa)
      • Weak recommendation - guideline panel members conclude with less confidence that desirable effects of recommendation probably outweigh undesirable effects, or benefits and harms are finely balanced, or appreciable uncertainty
    • quality of evidence
      • High-quality evidence - consistent evidence from well-performed randomized controlled trials, or exceptionally strong evidence from unbiased observational studies
      • Moderate-quality evidence - randomized controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise evidence), or unusually strong evidence from unbiased observational studies
      • Low-quality evidence - ≥ 1 critical outcome from observational studies, randomized controlled trials with serious flaws, or indirect evidence
      • Very low-quality evidence - ≥ 1 of the critical outcomes from unsystematic clinical observations or very indirect evidence
  • National Osteoporosis Guideline Group (NOGG) grading recommendations
    • levels of evidence for studies of intervention
      • Ia - meta-analysis of randomized controlled trials (RCT)
      • Ib - from ≥ 1 RCT
      • IIa - from ≥ 1 well-designed controlled study without randomization
      • IIb - from ≥ 1 well-designed quasi-experimental study
      • III - from well-designed nonexperimental descriptive studies (comparative studies, correlation studies, case-control studies)
      • IV - reports from expert committees, opinions, or clinical experience
    • quality of recommendations
      • Grade A - evidence levels Ia and Ib; validated by use as inclusion criteria in RCT
      • Grade B - evidence levels IIa, IIb, III; does not adversely affect fracture outcomes in randomized controlled trials
      • Grace C - evidence level IV; untested or adversely affect intervention outcomes
  • Osteoporosis Canada (OC) level of evidence criteria
    • treatment and intervention
      • 1+ - systematic overview of meta-analysis of randomized controlled trials (RCTs)
      • 1 - RCT with adequate power
      • 2+ - systematic overview or meta-analysis of level 2 RCTs
      • 2 - randomized controlled trial that does not meet level  1  criteria
      • 3 - nonrandomized controlled trial or cohort study
      • 4 - before/after study, cohort study with noncontemporaneous controls, case-control study
      • 5 - case series without controls
      • 6 - case report or case series < 10 patients
    • grades of recommendation
      • Grade A - support level 1 or 1+ evidence plus consensus
      • Grade B - support level 2 or 2+ evidence plus consensus
      • Grade C - support level 3 evidence plus consensus
      • Grade D - any lower level of evidence supported by consensus
    • Reference - 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada (mnh20940232pmdc20940232pCMAJ 2010 Nov 23;182(17):1864OpenInNew)

Synthesized Recommendation Grading System for DynaMed

  • DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based MethodologyOpenInNew).
  • Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see where guidelines agree and where guidelines differ from each other and from the current evidence.
  • In DynaMed (DM), we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to provide recommendations to support clinical decision-making in the Overview & Recommendations section.
  • We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE)OpenInNew to classify synthesized recommendations as Strong or Weak.
    • Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
    • Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and harms). Weak recommendations are used when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their judgments. Weak recommendations are also used when the range of patient values and preferences suggests that informed patients are likely to make different choices.
  • DynaMed (DM) synthesized recommendations (in the Overview & Recommendations section) are determined with a systematic methodology:
    • Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and the recommendations from guidelines.
    • Recommendations are phrased to match the strength of recommendation. Strong recommendations use "should do" phrasing, or phrasing implying an expectation to perform the recommended action for most patients. Weak recommendations use "consider" or "suggested" phrasing.
    • Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a qualified group has explicitly deliberated on making such a recommendation. Group deliberation may occur during guideline development. When group deliberation occurs through DynaMed-initiated groups:
      • Clinical questions will be formulated using the PICO (Population, Intervention, Comparison, Outcome) framework for all outcomes of interest specific to the recommendation to be developed.
      • Systematic searches will be conducted for any clinical questions where systematic searches were not already completed through DynaMed content development.
      • Evidence will be summarized for recommendation panel review including for each outcome, the relative importance of the outcome, the estimated effects comparing intervention and comparison, the sample size, and the overall quality rating for the body of evidence.
      • Recommendation panel members will be selected to include at least 3 members that together have sufficient clinical expertise for the subject(s) pertinent to the recommendation, methodological expertise for the evidence being considered, and experience with guideline development.
      • All recommendation panel members must disclose any potential conflicts of interest (professional, intellectual, and financial), and will not be included for the specific panel if a significant conflict exists for the recommendation in question.
      • Panel members will make Strong recommendations if and only if there is consistent agreement in a high confidence in the likelihood that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. Panel members will make Weak recommendations if there is limited confidence (or inconsistent assessment or dissenting opinions) that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. No recommendation will be made if there is insufficient confidence to make a recommendation.
      • All steps in this process (including evidence summaries which were shared with the panel, and identification of panel members) will be transparent and accessible in support of the recommendation.
    • Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in recommendation drafting or development, with explicit confirmation that Strong recommendations are adequately supported.
    • Recommendations are published only after consensus is established with agreement in phrasing and strength of recommendation by all editors.
    • If consensus cannot be reached then the recommendation can be published with a notation of "dissenting commentary" and the dissenting commentary is included in the topic details.
    • If recommendations are questioned during peer review or post publication by a qualified individual, or reevaluation is warranted based on new information detected through systematic literature surveillance, the recommendation is subject to additional internal review.

DynaMed Editorial Process

Special acknowledgements

  • Alan Malabanan, MD (Assistant Professor of Medicine, Harvard Medical School; Director, Endocrinology Fellowship and Director of Clinical Education, Endocrinology, Beth Israel Deaconess Medical Center; Massachusetts, United States)
  • Dr. Malabanan declares no relevant financial conflicts of interest.
  • Esther Jolanda van Zuuren, MD (Head of Allergy, Dermatology, and Venereology, Leiden University Medical Centre; Netherlands)
  • Dr. van Zuuren declares no relevant financial conflicts of interest.
  • William Aird, MD (Deputy Editor of Hematology, Nephrology, and Oncology; Professor of Medicine, Harvard Medical School; Massachusetts, United States)
  • Dr. Aird declares no relevant financial conflicts of interest.
On behalf of the American College of Physicians
  • Barbara Turner, MD, MSEd, MACP, ACP Deputy Editor, Clinical Decision Resource, as part of the ACP-EBSCO Health collaboration, managed the ACP peer review of the Overview and Recommendations section and related clinical content in this topic.
  • Marcy B. Bolster, MD (Clinical Professor of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina; Associate Professor of Medicine, Harvard Medical School; Associate Physician, Division of Rheumatology, Allergy and Immunology, Director, Rheumatology Fellowship Training Program, and Medical Lead, Fracture Liaison Service, Massachusetts General Hospital; Massachusetts, United States)
  • Dr. Bolster declares no relevant financial conflicts of interest.
  • DynaMed topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.
  • Editorial Team role definitions
    Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic Editors also serve as consultants for the internal DynaMed Editorial Team during the writing and editing process, and review the final topic drafts prior to publication.
    Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.
    Recommendations Editors provide explicit review of DynaMed Overview and Recommendations sections to ensure that all recommendations are sound, supported, and evidence-based. This process is described in "Synthesized Recommendation Grading."
    Deputy Editors are employees of DynaMed and oversee DynaMed internal publishing groups. Each is responsible for all content published within that group, including supervising topic development at all stages of the writing and editing process, final review of all topics prior to publication, and direction of an internal team.
Choosing Wisely Canada acknowledges dissemination of their recommendations through DynaMed Plus to reach the point of clinical decision-making.

How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):

  • DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T900139, Bisphosphonates for Treatment and Prevention of Osteoporosis; [updated 2018 Dec 03, cited place cited date here]. Available from https://www.dynamed.com/topics/dmp~AN~T900139. Registration and login required.
  • KeyboardArrowRight

    Overview and Recommendations

    • Background

    • Indications and bisphosphonate options

    • Treatment monitoring and duration of therapy

  • Related Summaries

  • KeyboardArrowRight

    General Information

    • Description

    • Definitions and classifications

  • Bone Remodeling and Bisphosphonate Mechanism of Action

  • KeyboardArrowRight

    Indications for Bisphosphonate Therapy

    • KeyboardArrowRight

      Postmenopausal women and men ≥ 50 years old

      • National Osteoporosis Foundation

      • Osteoporosis Canada

      • American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE)

      • Endocrine Society

    • Glucocorticoid-induced osteoporosis

    • Other (secondary osteoporosis)

  • Pretreatment Patient Evaluation

  • Contraindications and Precautions for Bisphosphonates

  • KeyboardArrowRight

    Bisphosphonate Formulations and Dosing

    • General information

    • Alendronate

    • Ibandronate

    • Risedronate

    • Zoledronic acid

    • Etidronate

  • KeyboardArrowRight

    Efficacy of Bisphosphonates for Prevention and Treatment of Osteoporosis

    • Overview of efficacy

    • KeyboardArrowRight

      Postmenopausal women

      • KeyboardArrowRight

        Treatment of osteoporosis

        • Drug class efficacy

        • Alendronate

        • Ibandronate

        • Risedronate

        • Zoledronic acid

        • Etidronate

        • Comparative efficacy

      • KeyboardArrowRight

        Prevention of osteoporosis

        • Alendronate

        • Risedronate

        • Zoledronic acid

        • Etidronate

        • Comparative efficacy

    • KeyboardArrowRight

      Men with osteoporosis

      • Alendronate

      • Risedronate

      • Zoledronic acid

      • Comparative efficacy

    • KeyboardArrowRight

      Glucocorticoid-induced osteoporosis

      • Drug class efficacy for steroid-induced osteoporosis

      • Alendronate

      • Risedronate

      • Zoledronic acid

      • Etidronate

      • Comparative efficacy

  • KeyboardArrowRight

    Monitoring and Follow-up

    • Monitoring during treatment

    • Bisphosphonate failure

  • KeyboardArrowRight

    Duration of Bisphosphonate Treatment and Drug Holiday

    • KeyboardArrowRight

      Guidance on treatment duration and drug holiday

      • General considerations

      • Postmenopausal women and older men

      • Glucocorticoid-induced osteoporosis

    • Evidence for treatment duration and drug holiday

  • KeyboardArrowRight

    Adverse Effects of Bisphosphonates

    • Overview of adverse effects

    • Gastrointestinal adverse effects

    • Acute-phase reaction

    • KeyboardArrowRight

      Atypical femoral fracture

      • General information

      • Evidence for bisphosphonates and risk of atypical femoral fractures

      • Evaluation of atypical femoral fractures

      • Treatment for atypical femoral fractures

    • KeyboardArrowRight

      Medication-related osteonecrosis of the jaw (MRONJ)

      • General information

      • Evidence for bisphosphonates and risk of MRONJ

      • Evaluation of osteonecrosis of the jaw

      • Treatment of osteonecrosis of the jaw

    • Other adverse effects

    • Outcomes that may not be adverse effects

  • KeyboardArrowRight

    Quality Improvement

    • Quality and Outcomes Framework Indicators

    • Choosing Wisely Canada

  • KeyboardArrowRight

    Guidelines and Resources

    • KeyboardArrowRight

      Guidelines

      • International guidelines

      • United States guidelines

      • United Kingdom guidelines

      • Canadian guidelines

      • European guidelines

      • Mexican guidelines

      • Central and South American guidelines

      • Australian guidelines

      • Middle Eastern guidelines

    • Review articles

  • Patient Decision Aids

  • Patient Information

  • KeyboardArrowRight

    References

    • General references used

    • Recommendation grading systems used

    • Synthesized Recommendation Grading System for DynaMed

    • DynaMed Editorial Process

    • Special acknowledgements

    • How to cite

Topic Editor
Alan Malabanan MD
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Affiliations

Assistant Professor of Medicine, Harvard Medical School; Massachusetts, United States; Director, Endocrinology Fellowship and Director of Clinical Education, Endocrinology, Beth Israel Deaconess Medical Center; Massachusetts, United States

Conflicts of Interest

Dr. Malabanan declares no relevant financial conflicts of interest.

Recommendations Editor
Esther Jolanda van Zuuren MD
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Affiliations

Head of Allergy, Dermatology, and Venereology, Leiden University Medical Centre; Netherlands

Conflicts of Interest

Dr. van Zuuren declares no relevant financial conflicts of interest.

Deputy Editor
William Aird MD
KeyboardArrowDown
Affiliations

Deputy Editor of Hematology, Nephrology and Oncology, Dynamed; Massachusetts, United States; Professor of Medicine, Harvard Medical School; Massachusetts, United States

Conflicts of Interest

Dr. Aird declares no relevant financial conflicts of interest.

Produced in collaboration with American College of Physicians

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Fractures of the left and right femurs

Fractures of the left and right femurs

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