Amir Qaseem, MD, PhD, MHA; Mary Ann Forciea, MD; Robert M. McLean, MD; Thomas D. Denberg, MD, PhD; for the Clinical Guidelines Committee of the American College of Physicians (*)
Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations.
Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.
Disclosures: Dr. Fitterman chairs the test writing committee for internal medicine for the American Board of Internal Medicine and receives a consultation fee for this work. Authors not named here have disclosed no conflicts of interest. Authors followed the policy regarding conflicts of interest described at www.annals.org/aim/article/745942. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1361. All financial and intellectual disclosures of interest were declared, and potential conflicts were discussed and managed. Dr. Wilt participated in the discussion for this guideline but was recused from voting on the recommendations because of active indirect financial and intellectual conflicts. A record of disclosures and management of conflicts of interest is kept for each CGC meeting and conference call and can be viewed at www.acponline.org/about-acp/who-we-are/leadership/committees-boards-councils/clinical-guidelines-committee/disclosure-of-interests-for-clinical-guidelines-committee.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106: e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Qaseem: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Forciea: University of Pennsylvania Health System, 3615 Chestnut Street, Philadelphia, PA 19104.
Dr. McLean: Yale School of Medicine, 46 Prince Street, Suite 302, New Haven, CT 06519.
Dr. Denberg: 7480 East 5th Avenue, Denver, CO 80230.
Author Contributions: Conception and design: A. Qaseem, R.M. McLean, T.D. Denberg, M. Cooke.
Analysis and interpretation of the data: A. Qaseem, M.A. Forciea, R.M. McLean, T.D. Denberg, M. Cooke, L.L. Humphrey, D. Kansagara.
Drafting of the article: A. Qaseem, R.M. McLean, T.D. Denberg, M. Cooke.
Critical revision of the article for important intellectual content: A. Qaseem, M.A. Forciea, R.M. McLean, T.D. Denberg, M. Cooke, L.L. Humphrey, D. Kansagara, H.J. Schünemann.
Final approval of the article: A. Qaseem, M.A. Forciea, R.M. McLean, T.D. Denberg, M. Cooke, N. Fitterman, L.L. Humphrey, D. Kansagara.
Statistical expertise: A. Qaseem.
Obtaining of funding: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem.
This guideline updates the 2008 American College of Physicians (ACP) recommendations on treatment of low bone density and osteoporosis to prevent fractures in men and women. This guideline is endorsed by the American Academy of Family Physicians.
The ACP Clinical Guidelines Committee based these recommendations on a systematic review of randomized controlled trials; systematic reviews; large observational studies (for adverse events); and case reports (for rare events) that were published between 2 January 2005 and 3 June 2011. The review was updated to July 2016 by using a machine-learning method, and a limited update to October 2016 was done. Clinical outcomes evaluated were fractures and adverse events. This guideline focuses on the comparative benefits and risks of short- and long-term pharmacologic treatments for low bone density, including pharmaceutical prescriptions, calcium, vitamin D, and estrogen. Evidence was graded according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.
The target audience for this guideline includes all clinicians. The target patient population includes men and women with low bone density and osteoporosis.
ACP recommends that clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures in women who have known osteoporosis. (Grade: strong recommendation; high-quality evidence)
ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence)
ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. (Grade: weak recommendation; low-quality evidence)
ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low-quality evidence)
ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence)
ACP recommends that clinicians should make the decision whether to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. (Grade: weak recommendation; low-quality evidence)
Appendix Table 1. Evidence Table for New Randomized, Controlled Trials Identified in the Update
Appendix Table 2. Evidence Table for Post hoc and Subgroup Analyses and Follow-up Studies Identified in the Update
Table 1. The American College of Physicians Guideline Grading System*
Summary of the American College of Physicians Guideline on the treatment of low bone density or osteoporosis to prevent fractures in men and women.
BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; FRAX = World Health Organization Fracture Risk Assessment Tool; GI = gastrointestinal.
Table 2. Summary of Evidence on Pharmacologic Treatments for Low Bone Density and Osteoporosis
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Emily Frank, MD
St. Vincent Medical Group
May 9, 2017
Helpful yet flawed guidelines
I direct a thriving bone health practice as well as a fracture intervention service, seeing over 1000 new bone health patients annually. While I appreciate the updated guidelines and evidence-based summary provided, I must note some inconsistencies in your work. First, I am concerned that SERMs are not recommended for treatment of anyone with postmenopausal osteoporosis. Certainly they carry some increased risk of cerebrovascular and thrombotic events, but in the low risk patient who is within the first decade following menopause, they can be used safely and effectively to lower vertebral fracture risk. These women often lose bone density in their lumbar spine first and their femoral neck BMD may be only mildly osteopenic. Furthermore, clinicians' pharmacologic options are extremely limited at this point, especially in women who are in their fifties. They are reticent to take bisphosphonates because of the negative press they've received and insurance won't cover denosumab or teriparatide. Many of these women took oral contraceptives for decades without thromoembolic event and the likelihood they'll develop one whle using raloxifene (in the absence of a hypercoagulable condition) is extremely low. SERMs aren't as effective in my experience in older women and as they age their risk of vascular complications would obviously increase. But a global recommendation against their use is, in my opinion, irresponsible. A few other comments; teriparatide is primarily an anabolic, not an antiresorptive therapy. In fact, urine NTX increases while on Forteo. This is inaccurately stated in several places. Ten thousand patients turn 65 in the US each day. Clinicians who care for patients with osteopenia and osteoporosis need accurate, up to date and relevant guidelines to help them provide the most appropriate patient care. Thank you for your work.
Saitama Medical University
May 11, 2017
Skeletal adaptation to mechanical strain: a key role in osteoporosis
American College of Physicians (ACP) recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years and suggests that continuing treatment after the initial 5 years may be beneficial for some patients and may be appropriate after reassessing the risks and benefits of continuing therapy (1). The primary target audience is non-expert clinicians and I would therefore like to introduce a natural homeostatic system in the skeleton (2-5) to avoid misunderstanding.Wolff’s law confirms that mechanical environment is the major determinant of skeletal architecture; well-known examples are bone loss in the weight-bearing sites of astronauts during space flight and bone gain in the dominant arms of professional tennis players. The skeleton normally responds to physical activity to maintain resultant elastic deformation (strain) while increased bone strength by pharmacologic treatment with osteoporosis drugs results in decreased bone strain, suggesting that the effect of osteoporosis therapy is limited by adaptation of bone to mechanical strain (2, 3). Consequently, it is important to note that, after the withdrawal of pharmacologic treatment with osteoporosis agents, areal bone mineral density measured by dual-energy x-ray absorptiometry would return to its pre-treatment level through the negative mechanical strain-related feedback control. There appears to be no exception regardless of their mechanisms of action and the speed of this return theoretically depends on how long the effect of pharmacologic therapy can continue after discontinuing.In addition, ACP suggests that calcium and vitamin D may be added as dietary supplements to osteoporosis treatment regimens, although the effectiveness of these regimens on fracture prevention is unclear (1); the limitation of osteoporosis therapy mentioned above might partly explain ACP evaluation that the overall effect of calcium or vitamin D alone on fracture risk is uncertain (2). However, there should be no doubt that appropriate calcium and vitamin D are essential to prevent osteomalacia in adults.Finally, ACP suggests that evidence is insufficient to conclusively show the effect of physical activity on fracture risk (1), but age-related fragility fracture is closely associated with reduced physical activity (4). It is useful to know some fundamental rules of mechanical strain-related stimulus in the skeleton during physical activity (5). First, bone gain induced by mechanical loading positively correlates with the peak strain. Second, the strain rate is another critical determinant; bone responds to dynamic, but not static, mechanical loading. Third, the number of cycles of mechanical loading required to maximally stimulate bone is surprisingly small.References1. Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. [Epub ahead of print 9 May 2017].2. Sugiyama T. Vitamin D and calcium supplementation to prevent fractures in adults. Ann Intern Med. 2013;159:856.3. Sugiyama T, Kim YT, Oda H. Osteoporosis therapy: a novel insight from natural homeostatic system in the skeleton. Osteoporos Int. 2015;26:443-7.4. Sugiyama T, Kono Y, Sekiguchi K, Kim YT, Oda H. Age-related fragility fracture: insights from the natural homeostatic system in the skeleton. Arch Osteoporos. 2015;10:45.5. Sugiyama T, Watarai K, Oda T, Kim YT, Oda H. Exercise for the skeleton in postmenopausal women: fundamental rules of mechanical strain-related stimulus. Osteoporos Int. 2016;27:1927-8.
University of Washington
May 14, 2017
Long-term bisphosphonate not helpful even in high risk patients
In the section about duration of pharmacologic therapy there was a mistake. In the post hoc analysis of the study in women who took alendronate therapy for 5 versus 10 years (reference 242) the subjects were divided into 6 groups based on presence or absence of baseline vertebral fractures and bone density T-score lower than -2.5, between -2.0 and -2.5, and better than -2.0. The group with the highest risk of fractures was the group with T score lower than -2.5 and prevalent vertebral fracture, but in that group there was no difference in fracture rates (nonvertebral: 31.6% in placebo and 33.3% in alendronate groups; vertebral: 27.5% in placebo and 25.4% in alendronate groups). Furthermore, in women with T-score below -2.5, an analysis done by the FDA(1) found no benefit to fracture reduction with ten years of alendronate compared to five years. Therefore, there is no evidence that alendronate is beneficial when used longer than 5 years even in women with high risk. On the other hand, there is evidence of increasing atypical fractures with longer use (reference 256). While waiting for more data to come in, I recommend that after five years of antiresorptive treatment, the very high risk patients, especially those who have had a fracture despite bisphosphonates, should be treated with an anabolic agent instead of further antiresorptive treatment.1. Food and Drug Administration. Background document formeeting of Advisory Committee for Reproductive Health Drugsand Drug Safety and Risk Management Advisory Committee. 2011(http://www .fda .gov/ downloads/ AdvisoryCommittees/ CommitteesMeetingMaterials/ Drugs/ DrugSafetyandRiskManagementAdvisoryCommittee/ UCM270958 .pdf).
E. Michael Lewiecki
New Mexico Clinical Research & Osteoporosis Center
May 20, 2017
Conflict of Interest:
Guideline Committee Member, National Osteoporosis Foundation, American Association of Clinical Densitometry
New ACP guidelines for osteoporosis may do more harm than good
It has been said that all guidelines are wrong, but good ones are useful. The recent ACP update of guidelines for treatment of low bone density or osteoporosis to prevent fractures in men and women (1) are consistent with the former but not the latter. I fear these guidelines may do more harm than good by failing to reduce, and perhaps exacerbating, the already very large osteoporosis treatment gap (2). Despite the availability of excellent tools to diagnose osteoporosis, such as dual-energy X-ray absorptiometry (DXA), algorithms to assess fracture risk, such as FRAX, and an array of medications to reduce fracture risk, most patients with osteoporosis not being treated to reduce fracture risk. This represents a major public health concern that has reached crisis proportions (3). An analysis of Medicare claims data suggests that hip fracture rates in the US in recent years are higher than projected (4), with a large personal burden of suffering and substantial healthcare costs for Medicare. The well-intentioned but misguided ACP guidelines do not address important unmet needs in the care of osteoporosis and may serve to confuse physicians more than enlighten them. As an example, Recommendation 2 is to treat for 5 years, not recognizing that there is good evidence to support treating for more than 5 years in high risk patients and not recognizing that stopping treatment with a non-bisphosphonate, such as denosumab, is followed by rapid loss of efficacy (5). Recommendation 4 is against monitoring bone density during 5 years of treatment. This is counter-intuitive and contradicts current best practices. Patients with suboptimal response to therapy due to malabsorption, poor adherence to therapy, or development of an unrecognized confounding disease or condition will not be recognized, placing them at high risk for fractures that might otherwise have been prevented. Patients expect and deserve to have osteoporosis treatment monitored, just as patients treated for hypertension expect and deserve to have blood pressure monitored. There are other evidence-based clinical practice guidelines for the management of osteoporosis, such as those of the National Osteoporosis Foundation and the American Association of Clinical Endocrinologists, that are far more nuanced and comprehensive. I suggest physicians look there for guidance rather than with the updated ACP guidelines.References1. Qaseem A, Forciea MA, McLean RM, Denberg TD, Clinical Guidelines Committee of the American College of P. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians. Ann Intern Med. 2017.2. Solomon DH, Johnston SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29(9):1929-37.3. Khosla S, Shane E. A Crisis in the Treatment of Osteoporosis. J Bone Miner Res. 2016;31(8):1485-7.4. Lewiecki EM, Adler RA, Curtis JR, Gagel R, Saag KG, Singer AJ, et al. Hip fractures and declining DXA testing: at a breaking point? J Bone Miner Res. 2016;31(Suppl):S26.5. Brown JP, Ferrari S, Gilchrist N, Beck Jensen J-E, Pannacciulli N, Recknor C, et al. Discontinuation of Denosumab and Associated Fracture Incidence: Analysis From FREEDOM and its Extension. J Bone Miner Res. 2016;31(Suppl):S32.
Qaseem A, Forciea MA, McLean RM, Denberg TD, for the Clinical Guidelines Committee of the American College of Physicians. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians. Ann Intern Med. [Epub ahead of print 9 May 2017]:. doi: 10.7326/M15-1361
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