CLINICAL OBSTETRICS AND GYNECOLOGY Volume 56, Number 4, 694–702 r 2013, Lippincott Williams & Wilkins
Osteoporosis: Therapeutic Guidelines. Guidelines for Practice Management of Osteoporosis SANA N. KHAN, MD*, LATASHA CRAIG, MDw and ROBERT WILD, MD* *University of Oklahoma Health Science Center; and w Department of REI, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Abstract: Therapeutic guidelines of osteoporosis are reviewed from North American Menopause Society, American Association of Clinical Endocrinologists, American College of Obstetrics and Gynecology, and the National Osteoporosis Foundation. The various guidelines are compared and discussed. Key words: osteoporosis, guidelines
Introduction Osteoporosis is a chronic, large-scale, escalating problem facing health care systems today. The goals of osteoporosis care are: to improve the diagnosis, prevention, and finally, treatment of this Correspondence: Sana N. Khan, MD, 420 James Circle, Royal Oak, MI 48067. E-mail: skhan421@ gmail.com The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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prevalent disorder. The way that this information is conveyed to providers on the frontlines is through guidelines. The aim of this chapter is to review current guidelines for osteoporosis from a variety of different organizations. We further seek to provide a practical discussion of the differences between the guidelines to produce take-away points for routine and special populations. A guideline is a recommended practice that allows some discretion or leeway in its interpretation, implementation, or use. Further defined in a medical context as a set of standards, criteria, or specifications to be used or followed in the performance of certain tasks. Guidelines often include evidence-based medical research, epidemiologic studies, and expert opinion. Here it is important to point out that VOLUME 56
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Osteoporosis: Therapeutic Guidelines guidelines stipulate that these directing principles are not fixed rules. That is to say that every decision needs to be individualized to a particular patient and situation. Different organizations’ guidelines often share features but differ as well; therefore a helpful resource if often a comparison of guidelines. The major organizations that produce guidelines on osteoporosis that will be presented here include: The North American Menopause Society (NAMS), The American Association of Clinical Endocrinologists (AACE), The American College of Obstetrics and Gynecology (ACOG), and The National Osteoporosis Foundation (NOF). The format of this article will be to review the major points of each of the guidelines in their original format to highlight the differences in presentation. After the review of the guidelines, there will be a discussion as the differences between the approach to guidelines from the different organizations and the value that each adds to therapeutic decision making. We list the grading system for each society and the level of evidence for each is delineated as a bolded numerical and/or letter grade. Evidence is graded by strength and level of evidence and the method of grading is provided when it is available.
Summary of Guidelines
(1) North American Menopause Society1 To construct the most recent position statement on the management of osteoporosis, a literature review was performed and priority was given to evidence from randomized-controlled clinical trials and meta-analyses of such trials, followed by evidence from controlled observational studies. Where evidence was contradictory (or inadequate) to form a conclusion, a consensus-based expert opinion was established. Because standards of care
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and available treatment options differ throughout the world, the focus is limited to therapies available in North America. Of note, the evidence is not specifically graded as other organizations have presented. NAMS recommends that all postmenopausal women be encouraged to employ lifestyle practices, which include: maintenance of healthy weight and diet, obtaining adequate calcium and vitamin D3, participating in appropriate exercise, avoiding excessive alcohol consumption, not smoking, and utilizing measures to prevent falls. These therapies may be sufficient in low-risk patients, when insufficient these strategies are encouraged with pharmacologic therapy. Osteoporosis drug therapy is recommended in the following populations. *
*
*
All postmenopausal women with a history of an osteoporotic vertebral or hip fracture. All postmenopausal women who have bone mineral density (BMD) values consistent with osteoporosis (ie, T scores < – 2.5) at the lumbar spine, femoral neck, or total hip region. All postmenopausal women who have a T score from – 1.0 to – 2.5 and a 10-year risk, based on the FRAX calculator, of a major osteoporotic fracture (spine, hip, shoulder, and wrist) of at least 20% or of a hip fracture of at least 3%.
NAMS comments that adherence to therapy is poor; therefore guidance is provided regarding how and when to periodically evaluate treatment efficacy. There are many therapies for osteoporosis, yet no studies have prospectively compared these therapies for antifracture efficacy. Bisphosphonates are the first-line drugs for osteoporotic postmenopausal women. They are very effective; however, www.clinicalobgyn.com
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there are significant adverse effects, and concerns of effects of long-term use are mentioned. The selective estrogen-receptor modulator Raloxifene should be considered for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis secondary to its favorable fracture reduction profile and decreased risk of invasive breast cancer. Other important agents are Denosumab, the monoclonal antibody, and each is described as very effective, having been shown to increase BMD at various skeletal sites as compared with Alendronate. Limited Teriparatide [parathyroid hormone (PTH) 1-34] therapy is an option for patients who are at high risk for fracture. Calcitonin is not a first-line drug for postmenopausal osteoporosis treatment, as its fracture efficacy is not strong. There is a brief discussion on each agent reviewing the mechanisms and negative effects. The primary indication for systemic estrogen or estrogen-progestin therapy (ET/EPT) is to treat moderate to severe menopause symptoms (eg, vasomotor symptoms). When symptoms are controlled or cease, continued hormone therapy can still be considered for bone effects, weighing its benefits and risks against those of alternative therapies. NAMS briefly discusses other agents that are not currently available in the United States such as Tibolone, as well as upcoming therapies, which include Strontium Ranelate, PTH 1-84 or the full-length PTH, Bazedoxifine, and Lasofoxifene. Data are inadequate to make definitive recommendations regarding combination or serial anabolic and antiresorptive drug therapies. NAMS provides parameters for follow-up BMD testing which includes: repeat imaging for patients receiving
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therapy no more frequently than 1 year, and repeat imaging in untreated patients between 2 and 5 years. (2) American Association of Clinical Endocrinologists2 (evidence obtained through Medline searches and other references. Expert opinion was used to evaluate the literature and grade references based on evidence level as noted below). Grading is as follows: A: homogeneous evidence from multiple well-designed randomized-controlled trials or cohortcontrolled trials with sufficient statistical power, or at least 1 level 1 publication demonstrating benefit greater than risk. B: Evidence from at least 1 well-designed clinical trial, cohort, case-controlled study or meta-analysis. At least 1 conclusive level 2 publication demonstrating benefit greater than risk. C: Evidence based on clinical experience, descriptive studies, or expert consensus opinion. At least 1 conclusive level 3 publication demonstrating benefit greater than risk. D: Not rated. What nonpharmacologic measures can be recommended for the treatment of osteoporosis? These measures include: maintenance of adequate protein intake, use of proper body mechanics, consideration of the use of hip protectors in individuals with a high risk of falling, taking measures to reduce the risk of falling, and referral for physical therapy when indicated. (B) Appropriate diet is recommended for all; however, it is important to consider special populations with inadequate intake of accelerated bone loss. Appropriate calcium intake varies by population; there are a variety of appropriate preparations for calcium repletion. In addition, it is important for providers to assess that patients are taking in an appropriate amount of calcium. (A) Vitamin D supplementation is important and the process begins in childhood therefore, younger patients
Osteoporosis: Therapeutic Guidelines
should be counseled. The amount of supplemental vitamin D depends on the age range. Other vitamins such as magnesium and vitamin A play a direct or indirect role in osteoporosis. (A) No conclusive evidence exists to support the use of isoflavones. Caffeine and alcohol should be avoided in excess, and exposure to tobacco smoke eliminated. (B) Who needs pharmacologic therapy? *
*
First priority: agents approved by the US Food and Drug Administration (FDA) for the prevention or treatment (or both) of osteoporosis. Second priority: agents not approved by the FDA but for which level 1 or 2 evidence for efficacy and safety is available. These agents may be appropriate for patients who are unable to take approved agents or who have complex and extenuating medical problems that preclude the effective use of approved agents.
The therapeutic goals in patients with osteoporosis are as follows: to prevent fractures by improving bone strength and reducing the risk of falling and injury, to relieve symptoms of fractures and skeletal deformity, and to maximize physical function. What drugs can be used to treat osteoporosis? *
* *
*
AACE has endorsed the 2010 NOF Clinician’s Guide to the Prevention and Treatment of Osteoporosis.
AACE and the American College of Endocrinology recommend the following pharmacologic agents when pharmacotherapy is indicated. (A) *
*
Use Alendronate, Risedronate, Zoledronic acid, and Denosumab as the first line of therapy. (A)
*
*
*
*
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Use Ibandronate as a second-line agent. Use Raloxifene as a secondline or third-line agent. (A) Use calcitonin as the last line of therapy. (C) Use Teriparatide for patients with very high fracture risk or patients in whom bisphosphonate therapy has failed. (A) AACE comments on the use of hormonal therapy for osteoporosis and quotes the FDA’s comment, ‘‘when prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom nonestrogen medications are not considered to be appropriate.’’ [X] Advise against the use of combination therapy, however, sequential therapy is discussed. (B) AACE also discusses therapies that are not currently approved or available in the United States including: Etidronate, Pamidronate, Strontium Ranelate, Clodronate, Tibolone, and the full-length molecule of PTH (1-84). AACE provides significant individual discussion regarding the data behind the mechanisms, preparations, risks and benefits, and duration of treatment of the various antifracture therapies available today. AACE also briefly discusses surgical therapy for osteoporotic fractures. How is treatment monitored?
*
Baseline dual-energy x-ray absorptiometry (DXA), and repeat DXA every 1 to 2 years until findings are stable. Continue with follow-up DXA every 2 years or at a less frequent interval. (B) www.clinicalobgyn.com
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AACE advocates for technical reproducibility. (B) Bone turnover markers can be used to follow the response to therapy (grade C).
What is successful treatment of osteoporosis (B)? *
* *
BMD is stable or increasing, and no fractures are present for patients taking antiresorptive agents, bone turnover markers at or below the median value for premenopausal women are achieved. One fracture is not necessarily evidence of failure. Consider alternative therapy or reassessment for secondary causes of bone loss for patients who have recurrent fractures while receiving therapy.
How long should patients be treated (C)? *
*
For treatment with bisphosphonates, if osteoporosis is mild, consider a ‘‘drug holiday’’ after 4 to 5 years of stability. If fracture risk is high, consider a drug holiday of 1 to 2 years after 10 years of treatment. Follow BMD and bone turnover markers during a drug holiday period, and reinitiate therapy if bone density declines substantially, bone turnover markers increase, or a fracture occurs.
When should patients be referred to clinical endocrinologists (C)? *
*
When a patient with normal BMD gets a fracture without major trauma. When recurrent fractures or continued bone loss occurs in a patient receiving therapy without obvious treatable causes of bone loss. When osteoporosis is
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*
unexpectedly severe or has unusual features. When a patient has a condition that complicates management (eg, renal failure, hyperparathyroidism, or malabsorption).
(3) American College of Obstetricians and Gynecologists3 Level A—Recommendations based on good and consistent scientific evidence. Level B—Recommendations based on limited or inconsistent evidence. Level C—Recommendations based on consensus or expert opinion. ACOG recommends that treatment be initiated when BMD T scores are r – 2.5. (A) For women in the low bone mass category (T score between – 1 and – 2.5), the FRAX calculator can be used to make an informed treatment decision. Women who are found to have a 10year risk of major osteoporotic fracture Z20% or a risk of hip fracture Z3% using the FRAX calculator are candidates for medical pharmacologic therapy. Women who have had a lowtrauma fracture (especially of the vertebra or hip) also are candidates for treatment even in the absence of osteoporosis on the DXA report. (A) ACOG states that isoflavones are unlikely to have a significant effect on BMD. ACOG recommends bisphosphonates as first-line therapy for osteoporosis; however, Raloxifine is recommended as a good choice for younger postmenopausal women secondary to the decreased risk of invasive breast cancer. (A) Denosumab is also recommended for patients with high fracture risk. (A) Teriparatide is reserved for severe or refractory cases of osteoporosis. (A) Calcitonin is considered a weaker therapy and should be used in mild cases or when other therapies are not tolerated. (A)
Osteoporosis: Therapeutic Guidelines Combination therapy is not recommended. Although there is no clear evidence regarding when to discontinue bisphosphonate therapy, prescribing trends appear to show 5- to 10-year duration of therapy. The FDA has recommended more guidance regarding duration of treatment and drug holidays from the manufacturers. ACOG has an in-depth discussion regarding hormonal therapy for osteoporosis. The women’s health initiative (WHI) study showed a significant decreased risk of fracture with either ET alone or combination estrogen and progestin therapy. There are several FDA-approved hormonal therapies for osteoporosis. The dose and duration of therapy needs to be individualized based on the patient’s risk factors for other conditions such as breast cancer, endometrial cancer, risk of heart disease, and venous thromboembolism. Although combination therapy is not recommended, switching from one type to another type of agent is advocated as this limits the adverse effects and therapeutic ceiling of and type of agent.
’
’
*
*
*
Advise a diet rich in fruits and vegetables and that includes adequate amounts of total calcium intake. ’ The NOF supports the Institute of Medicine recommendations for calcium intake.
*
Advise appropriate vitamin D intake, including supplements if necessary, for individuals aged 50 and older.
The NOF recognizes that different regimens of vitamin D may be needed for different populations. The NOF recommends adequate calcium and vitamin D intake after therapy initiation.
Recommend regular weight-bearing and muscle-strengthening exercise to improve agility, strength, posture, and balance and reduce the risk of falls and fractures. Assess risk factors for falls and offer appropriate modifications (eg, safety assessment, balance training, avoidance of certain medications, and bifocals use). Advise on cessation of tobacco smoking and avoidance of excessive alcohol intake. Measure height annually, preferably with a wall-mounted stadiometer.
Treatment recommendations: *
Initiate pharmacologic treatment in: ’ Those with hip or vertebral (clinical or asymptomatic) fractures. ’ Those with T scores < – 2.5 at the femoral neck, total hip or lumbar spine by DXA, after appropriate evaluation. ’ Postmenopausal women with low bone mass (T score between – 1.0 and – 2.5) at the femoral neck, total hip, or lumbar spine by DXA. ’ Postmenopausal women with a 10-year hip fracture probability > 3% or a 10-year major osteoporosis-related fracture probability > 20% based on the US-adapted World Health Organization absolute fracture risk model (FRAX).
*
Current FDA-approved pharmacologic options for osteoporosis
(4) National Osteoporosis Foundation4 Although the recommendations are based ‘‘mainly on evidence from randomized, controlled clinical trials’’; there is no individual grading for each recommendation provided. NOF provides general Universal Guidelines which include: *
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are bisphosphonates (Alendronate, Ibandronate, Risedronate, and Zoledronic acid), calcitonin, estrogen agonist/antagonist (Raloxifene), estrogen and/or hormone therapy, PTH 1-34 (Teriparatide), and RANKL inhibitor (Denosumab). ’ A detailed description of each agent, its mechanism, administration, risk and benefits, and side effects are discussed. ’ For hormonal therapy—the WHI study is referred to and a final statement is made: ‘‘When ET/HT use is considered solely for prevention of osteoporosis, the FDA recommends that approved nonestrogen treatments should first be carefully considered.’’ *
*
Ample information regarding non–FDA-approved medications is provided. No pharmacologic therapy should be considered indefinite in duration. After the initial 3- to 5-year treatment period, a comprehensive risk assessment should be performed. There is no uniform recommendation that applies to all patients and duration decisions need to be individualized.
Treatment efficacy monitoring includes: * * *
*
Ensuring compliance and reducing barriers to compliance. Annual review of continued medication to treat osteoporosis. Evaluation to discontinue treatment temporarily after a long duration, particularly after bisphosphonate administration. If treatment is discontinued, serial monitoring can include clinical assessment for fractures, falling, any interval chronic disease occurrence and consideration of serial BMD
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testing and possible use of biochemical markers.
Discussion Each of the guidelines is slightly different in some ways which highlight the nuances of what each individual organization focuses on when forming guidelines. The presentations were left to use the original format with either bullet points or question and answer as well as the organizations’ original wording where possible. There are many similarities and areas in which guidelines are shared from a common source or have come to the same conclusion from the available evidence. All guidelines use a system of rating for the evidence that has been used to form the guidelines. All organizations recommend appropriate weight-bearing exercise, balanced diet, and avoidance of excessive alcohol intake, smoking cessation, and fall prevention. The NOF and AACE go into significant detail on fall prevention. The NOF discusses home safety assessment and notes the importance of vision assessment. AACE discusses the use of physical therapy for fall and fracture prevention. All guidelines include a recommendation for calcium and vitamin D supplementation in patients with osteoporosis. AACE and NOF delve into more detail regarding the differences in calcium and vitamin D supplementation in different age groups and populations. The guidelines have similar recommendations for who should be treated; however, each with a particular approach. The organizations differ in their recommendations for first-line therapy. NAMS, AACE, and NOF do not necessarily recommend 1 agent or class of agents as firstline therapy. Rather, they discuss the evidence regarding decreased fracture risk and various sites and in various populations so that a provider may make an educated decision for an individual
Osteoporosis: Therapeutic Guidelines patient by referencing all guidelines. They recommend that bisphosphonates are very effective although other agents such as Raloxifine and Denosumab are as well. ACOG recommends bisphosphonates or Raloxifene as first-line therapy. AACE and NOF go into detailed descriptions of the mechanisms of available agents as well as preparations, and negative effects. AACE in addition to briefly discussing surgical options for osteoporosis also provides a section on when to refer a patient to a clinical endocrinologist, which is helpful for understanding and triaging patients with complex or refractory osteoporosis. All guidelines suggest that combination pharmacologic therapy is not superior to single-agent therapy for osteoporosis, although there are subtle differences in their recommendations for sequential therapy, duration, and discontinuation of therapy. There are some emerging areas for which no standard guidelines have been developed. One concept that falls into this category is the duration/cessation of treatment and drug holiday. These topics are important given emerging data on rare but serious effects including osteonecrosis of the jaw and atypical femur fractures. NAMS has recently released a Practice Pearls bulletin discussing drug interruptions or holidays. They cite the 2011 FDA discussion on bisphosphonate therapy and conclude that no clear recommendations can be made, as therapy needs to be individualized.5 However, evaluation for the cessation of treatment after 3 to 5 years is reasonable for low-risk patients, after 5 to 10 years for moderate-risk patients, and after 10 years for high-risk patients. This is possible secondary to the ‘‘lingering’’ effect of these therapies.6 The AACE recommends that bisphosphonates be discontinued after 4 to 5 years in cases of mild disease, for patients with higher fracture risk they recommend discontinuation of bisphosphonates for 1 to 2 years after 10
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years of therapy. Reinitiation of therapy is indicated for fracture, substantial decline in BMD, or an increase in bone turnover markers. The NOF states that there can be no uniform decisions on duration and that cases need to be individualized. They state that it is reasonable to discontinue bisphosphonate therapy and perform a comprehensive fracture assessment after 3 to 5 years in patients with a moderate risk of fracture or less, but that continued therapy or alternate therapy may be needed in patients with a high-risk of fracture. ACOG recalls that the FDA recommended more specific labeling regarding duration of treatment and treatment interruptions. They state it is reasonable to interrupt treatment after 5 to 10 years of bisphosphonate use and that it is difficult to assess risk of adverse outcome in the general population because adverse effects were more commonly reported in a very specific patient population. Most guidelines, however, do leave the duration of therapy and length of drug holiday at the discretion of the physician. Most organizations also provide recommendations regarding hormonal options for osteoporosis. In comparison, the recommendations of NAMS, ACOG, and NOF, regarding hormonal therapy for osteoporosis, are slightly varied. NAMS states that hormonal therapy can be continued for osteoporosis alone in the absence of vasomotor symptoms weighing its benefits and risks against those of alternative therapies. In contrast, ACOG does not recommend continuation of hormonal therapy for osteoporosis in the absence of vasomotor symptoms and recommends ‘‘using the lowest dose for the shortest amount of time.’’ The NOF comments that when ET/HT use is considered solely for prevention of osteoporosis, the FDA recommends that approved nonestrogen treatments should first be carefully considered. Therefore, a detailed understanding of the risks and benefits of www.clinicalobgyn.com
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hormone therapy, as well as an understanding of a patient’s situation and previous therapies, are imperative to make a decision on hormonal therapy for osteoporosis. The AACE, NOF, and NAMS also give specific information on the FDA approval of osteoporosis treatments. The AACE, NOF, and NAMS also discuss non–FDA-approved therapies, therapies not available in the United States currently, and upcoming therapies on medications for osteoporosis. All guidelines have similar recommendations on monitoring BMD after the diagnosis of osteoporosis is made and after treatment is initiated. The NOF and the AACE go into more detail and recommend the use of bone turnover markers for treatment surveillance. The NOF at the conclusion of their guidelines provides a list of unanswered and future questions regarding osteoporosis treatment. This unique addition provides information regarding gaps and directions in future research. All aforementioned guidelines provide valuable information. Much of it is overlapping; however, familiarization with all guidelines provides the best understanding of the available evidence regarding osteoporosis and the approach that different organizations take to answer common questions. The NAMS guidelines focus more on the osteoporotic female population. ACOGs guidelines provide more information regarding hormonal options for premenopausal and postmenopausal low bone density. The AACE guidelines focus on osteoporosis from an endocrinology standpoint and provide recommendations on referral for primary providers. The NOF guidelines are
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comprehensive and stress that the guidelines are not rules and that every patient encounter needs to be individualized to that patient’s situation and needs. We stress again that all guidelines are only loose recommendations for management and need to be tailored to each individual patient. Providers caring for osteoporotic patients need to familiarize themselves with all guidelines and which to apply to each patient.
References 1. North American Menopause Society. Position statement: management of osteoporosis in postmenopausal woman: 2010. Menopause. 2010;17: 25–54, quiz 55-6. 2. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis. 2010. Available at: https://www.aace. com/files/osteo-guidelines-2010.pdf. Accessed February 4, 2013. 3. American College of Obstetricians and GynecologistsHauk L. Osteoporosis. Practice Bulletin. Number 129. 2012. Available at: https://access. acog.org/eweb/dynamicpage.aspx?site = congress& webcode = LoginRequired&urlReq = http%3a% 2f%2fwww.acog.org%2fResources + And + Publi cations%2fPractice + Bulletins + List.aspx. Accessed January 16, 2013. 4. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: NOF; 2010. Available at: http://nof.org/files/nof/public/content/file/344/ upload/159.pdf. Accessed February 5, 2013. 5. FDA Drug Safety Communication: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures 2010. Available at: http://www.fda. gov/drugs/drugsafety/ucm229009.htm. Accessed March 2, 2013. 6. North American Menopause SocietyDiab DL, Watts NB. NAMS Practice Pearl: use of drug holidays in women taking bisphosphonates. Menopause. 2013. Available at: http://pdfs.journals.lww.com/meno pause journal/9000/00000/Use_of_drug_holidays_in_ women_taking.98549.pdf. Accessed March 2, 2013.
Osteoporosis: Therapeutic Guidelines. Guidelines for Practice Management of Osteoporosis SANA N. KHAN, MD*, LATASHA CRAIG, MDw and ROBERT WILD, MD* *University of Oklahoma Health Science Center; and w Department of REI, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Abstract: Therapeutic guidelines of osteoporosis are reviewed from North American Menopause Society, American Association of Clinical Endocrinologists, American College of Obstetrics and Gynecology, and the National Osteoporosis Foundation. The various guidelines are compared and discussed. Key words: osteoporosis, guidelines
Introduction Osteoporosis is a chronic, large-scale, escalating problem facing health care systems today. The goals of osteoporosis care are: to improve the diagnosis, prevention, and finally, treatment of this Correspondence: Sana N. Khan, MD, 420 James Circle, Royal Oak, MI 48067. E-mail: skhan421@ gmail.com The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
694 | www.clinicalobgyn.com
/
prevalent disorder. The way that this information is conveyed to providers on the frontlines is through guidelines. The aim of this chapter is to review current guidelines for osteoporosis from a variety of different organizations. We further seek to provide a practical discussion of the differences between the guidelines to produce take-away points for routine and special populations. A guideline is a recommended practice that allows some discretion or leeway in its interpretation, implementation, or use. Further defined in a medical context as a set of standards, criteria, or specifications to be used or followed in the performance of certain tasks. Guidelines often include evidence-based medical research, epidemiologic studies, and expert opinion. Here it is important to point out that VOLUME 56
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NUMBER 4
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DECEMBER 2013
Osteoporosis: Therapeutic Guidelines guidelines stipulate that these directing principles are not fixed rules. That is to say that every decision needs to be individualized to a particular patient and situation. Different organizations’ guidelines often share features but differ as well; therefore a helpful resource if often a comparison of guidelines. The major organizations that produce guidelines on osteoporosis that will be presented here include: The North American Menopause Society (NAMS), The American Association of Clinical Endocrinologists (AACE), The American College of Obstetrics and Gynecology (ACOG), and The National Osteoporosis Foundation (NOF). The format of this article will be to review the major points of each of the guidelines in their original format to highlight the differences in presentation. After the review of the guidelines, there will be a discussion as the differences between the approach to guidelines from the different organizations and the value that each adds to therapeutic decision making. We list the grading system for each society and the level of evidence for each is delineated as a bolded numerical and/or letter grade. Evidence is graded by strength and level of evidence and the method of grading is provided when it is available.
Summary of Guidelines
(1) North American Menopause Society1 To construct the most recent position statement on the management of osteoporosis, a literature review was performed and priority was given to evidence from randomized-controlled clinical trials and meta-analyses of such trials, followed by evidence from controlled observational studies. Where evidence was contradictory (or inadequate) to form a conclusion, a consensus-based expert opinion was established. Because standards of care
695
and available treatment options differ throughout the world, the focus is limited to therapies available in North America. Of note, the evidence is not specifically graded as other organizations have presented. NAMS recommends that all postmenopausal women be encouraged to employ lifestyle practices, which include: maintenance of healthy weight and diet, obtaining adequate calcium and vitamin D3, participating in appropriate exercise, avoiding excessive alcohol consumption, not smoking, and utilizing measures to prevent falls. These therapies may be sufficient in low-risk patients, when insufficient these strategies are encouraged with pharmacologic therapy. Osteoporosis drug therapy is recommended in the following populations. *
*
*
All postmenopausal women with a history of an osteoporotic vertebral or hip fracture. All postmenopausal women who have bone mineral density (BMD) values consistent with osteoporosis (ie, T scores < – 2.5) at the lumbar spine, femoral neck, or total hip region. All postmenopausal women who have a T score from – 1.0 to – 2.5 and a 10-year risk, based on the FRAX calculator, of a major osteoporotic fracture (spine, hip, shoulder, and wrist) of at least 20% or of a hip fracture of at least 3%.
NAMS comments that adherence to therapy is poor; therefore guidance is provided regarding how and when to periodically evaluate treatment efficacy. There are many therapies for osteoporosis, yet no studies have prospectively compared these therapies for antifracture efficacy. Bisphosphonates are the first-line drugs for osteoporotic postmenopausal women. They are very effective; however, www.clinicalobgyn.com
696
Khan et al
there are significant adverse effects, and concerns of effects of long-term use are mentioned. The selective estrogen-receptor modulator Raloxifene should be considered for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis secondary to its favorable fracture reduction profile and decreased risk of invasive breast cancer. Other important agents are Denosumab, the monoclonal antibody, and each is described as very effective, having been shown to increase BMD at various skeletal sites as compared with Alendronate. Limited Teriparatide [parathyroid hormone (PTH) 1-34] therapy is an option for patients who are at high risk for fracture. Calcitonin is not a first-line drug for postmenopausal osteoporosis treatment, as its fracture efficacy is not strong. There is a brief discussion on each agent reviewing the mechanisms and negative effects. The primary indication for systemic estrogen or estrogen-progestin therapy (ET/EPT) is to treat moderate to severe menopause symptoms (eg, vasomotor symptoms). When symptoms are controlled or cease, continued hormone therapy can still be considered for bone effects, weighing its benefits and risks against those of alternative therapies. NAMS briefly discusses other agents that are not currently available in the United States such as Tibolone, as well as upcoming therapies, which include Strontium Ranelate, PTH 1-84 or the full-length PTH, Bazedoxifine, and Lasofoxifene. Data are inadequate to make definitive recommendations regarding combination or serial anabolic and antiresorptive drug therapies. NAMS provides parameters for follow-up BMD testing which includes: repeat imaging for patients receiving
www.clinicalobgyn.com
therapy no more frequently than 1 year, and repeat imaging in untreated patients between 2 and 5 years. (2) American Association of Clinical Endocrinologists2 (evidence obtained through Medline searches and other references. Expert opinion was used to evaluate the literature and grade references based on evidence level as noted below). Grading is as follows: A: homogeneous evidence from multiple well-designed randomized-controlled trials or cohortcontrolled trials with sufficient statistical power, or at least 1 level 1 publication demonstrating benefit greater than risk. B: Evidence from at least 1 well-designed clinical trial, cohort, case-controlled study or meta-analysis. At least 1 conclusive level 2 publication demonstrating benefit greater than risk. C: Evidence based on clinical experience, descriptive studies, or expert consensus opinion. At least 1 conclusive level 3 publication demonstrating benefit greater than risk. D: Not rated. What nonpharmacologic measures can be recommended for the treatment of osteoporosis? These measures include: maintenance of adequate protein intake, use of proper body mechanics, consideration of the use of hip protectors in individuals with a high risk of falling, taking measures to reduce the risk of falling, and referral for physical therapy when indicated. (B) Appropriate diet is recommended for all; however, it is important to consider special populations with inadequate intake of accelerated bone loss. Appropriate calcium intake varies by population; there are a variety of appropriate preparations for calcium repletion. In addition, it is important for providers to assess that patients are taking in an appropriate amount of calcium. (A) Vitamin D supplementation is important and the process begins in childhood therefore, younger patients
Osteoporosis: Therapeutic Guidelines
should be counseled. The amount of supplemental vitamin D depends on the age range. Other vitamins such as magnesium and vitamin A play a direct or indirect role in osteoporosis. (A) No conclusive evidence exists to support the use of isoflavones. Caffeine and alcohol should be avoided in excess, and exposure to tobacco smoke eliminated. (B) Who needs pharmacologic therapy? *
*
First priority: agents approved by the US Food and Drug Administration (FDA) for the prevention or treatment (or both) of osteoporosis. Second priority: agents not approved by the FDA but for which level 1 or 2 evidence for efficacy and safety is available. These agents may be appropriate for patients who are unable to take approved agents or who have complex and extenuating medical problems that preclude the effective use of approved agents.
The therapeutic goals in patients with osteoporosis are as follows: to prevent fractures by improving bone strength and reducing the risk of falling and injury, to relieve symptoms of fractures and skeletal deformity, and to maximize physical function. What drugs can be used to treat osteoporosis? *
* *
*
AACE has endorsed the 2010 NOF Clinician’s Guide to the Prevention and Treatment of Osteoporosis.
AACE and the American College of Endocrinology recommend the following pharmacologic agents when pharmacotherapy is indicated. (A) *
*
Use Alendronate, Risedronate, Zoledronic acid, and Denosumab as the first line of therapy. (A)
*
*
*
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Use Ibandronate as a second-line agent. Use Raloxifene as a secondline or third-line agent. (A) Use calcitonin as the last line of therapy. (C) Use Teriparatide for patients with very high fracture risk or patients in whom bisphosphonate therapy has failed. (A) AACE comments on the use of hormonal therapy for osteoporosis and quotes the FDA’s comment, ‘‘when prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom nonestrogen medications are not considered to be appropriate.’’ [X] Advise against the use of combination therapy, however, sequential therapy is discussed. (B) AACE also discusses therapies that are not currently approved or available in the United States including: Etidronate, Pamidronate, Strontium Ranelate, Clodronate, Tibolone, and the full-length molecule of PTH (1-84). AACE provides significant individual discussion regarding the data behind the mechanisms, preparations, risks and benefits, and duration of treatment of the various antifracture therapies available today. AACE also briefly discusses surgical therapy for osteoporotic fractures. How is treatment monitored?
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Baseline dual-energy x-ray absorptiometry (DXA), and repeat DXA every 1 to 2 years until findings are stable. Continue with follow-up DXA every 2 years or at a less frequent interval. (B) www.clinicalobgyn.com
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AACE advocates for technical reproducibility. (B) Bone turnover markers can be used to follow the response to therapy (grade C).
What is successful treatment of osteoporosis (B)? *
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BMD is stable or increasing, and no fractures are present for patients taking antiresorptive agents, bone turnover markers at or below the median value for premenopausal women are achieved. One fracture is not necessarily evidence of failure. Consider alternative therapy or reassessment for secondary causes of bone loss for patients who have recurrent fractures while receiving therapy.
How long should patients be treated (C)? *
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For treatment with bisphosphonates, if osteoporosis is mild, consider a ‘‘drug holiday’’ after 4 to 5 years of stability. If fracture risk is high, consider a drug holiday of 1 to 2 years after 10 years of treatment. Follow BMD and bone turnover markers during a drug holiday period, and reinitiate therapy if bone density declines substantially, bone turnover markers increase, or a fracture occurs.
When should patients be referred to clinical endocrinologists (C)? *
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When a patient with normal BMD gets a fracture without major trauma. When recurrent fractures or continued bone loss occurs in a patient receiving therapy without obvious treatable causes of bone loss. When osteoporosis is
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unexpectedly severe or has unusual features. When a patient has a condition that complicates management (eg, renal failure, hyperparathyroidism, or malabsorption).
(3) American College of Obstetricians and Gynecologists3 Level A—Recommendations based on good and consistent scientific evidence. Level B—Recommendations based on limited or inconsistent evidence. Level C—Recommendations based on consensus or expert opinion. ACOG recommends that treatment be initiated when BMD T scores are r – 2.5. (A) For women in the low bone mass category (T score between – 1 and – 2.5), the FRAX calculator can be used to make an informed treatment decision. Women who are found to have a 10year risk of major osteoporotic fracture Z20% or a risk of hip fracture Z3% using the FRAX calculator are candidates for medical pharmacologic therapy. Women who have had a lowtrauma fracture (especially of the vertebra or hip) also are candidates for treatment even in the absence of osteoporosis on the DXA report. (A) ACOG states that isoflavones are unlikely to have a significant effect on BMD. ACOG recommends bisphosphonates as first-line therapy for osteoporosis; however, Raloxifine is recommended as a good choice for younger postmenopausal women secondary to the decreased risk of invasive breast cancer. (A) Denosumab is also recommended for patients with high fracture risk. (A) Teriparatide is reserved for severe or refractory cases of osteoporosis. (A) Calcitonin is considered a weaker therapy and should be used in mild cases or when other therapies are not tolerated. (A)
Osteoporosis: Therapeutic Guidelines Combination therapy is not recommended. Although there is no clear evidence regarding when to discontinue bisphosphonate therapy, prescribing trends appear to show 5- to 10-year duration of therapy. The FDA has recommended more guidance regarding duration of treatment and drug holidays from the manufacturers. ACOG has an in-depth discussion regarding hormonal therapy for osteoporosis. The women’s health initiative (WHI) study showed a significant decreased risk of fracture with either ET alone or combination estrogen and progestin therapy. There are several FDA-approved hormonal therapies for osteoporosis. The dose and duration of therapy needs to be individualized based on the patient’s risk factors for other conditions such as breast cancer, endometrial cancer, risk of heart disease, and venous thromboembolism. Although combination therapy is not recommended, switching from one type to another type of agent is advocated as this limits the adverse effects and therapeutic ceiling of and type of agent.
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Advise a diet rich in fruits and vegetables and that includes adequate amounts of total calcium intake. ’ The NOF supports the Institute of Medicine recommendations for calcium intake.
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Advise appropriate vitamin D intake, including supplements if necessary, for individuals aged 50 and older.
The NOF recognizes that different regimens of vitamin D may be needed for different populations. The NOF recommends adequate calcium and vitamin D intake after therapy initiation.
Recommend regular weight-bearing and muscle-strengthening exercise to improve agility, strength, posture, and balance and reduce the risk of falls and fractures. Assess risk factors for falls and offer appropriate modifications (eg, safety assessment, balance training, avoidance of certain medications, and bifocals use). Advise on cessation of tobacco smoking and avoidance of excessive alcohol intake. Measure height annually, preferably with a wall-mounted stadiometer.
Treatment recommendations: *
Initiate pharmacologic treatment in: ’ Those with hip or vertebral (clinical or asymptomatic) fractures. ’ Those with T scores < – 2.5 at the femoral neck, total hip or lumbar spine by DXA, after appropriate evaluation. ’ Postmenopausal women with low bone mass (T score between – 1.0 and – 2.5) at the femoral neck, total hip, or lumbar spine by DXA. ’ Postmenopausal women with a 10-year hip fracture probability > 3% or a 10-year major osteoporosis-related fracture probability > 20% based on the US-adapted World Health Organization absolute fracture risk model (FRAX).
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Current FDA-approved pharmacologic options for osteoporosis
(4) National Osteoporosis Foundation4 Although the recommendations are based ‘‘mainly on evidence from randomized, controlled clinical trials’’; there is no individual grading for each recommendation provided. NOF provides general Universal Guidelines which include: *
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are bisphosphonates (Alendronate, Ibandronate, Risedronate, and Zoledronic acid), calcitonin, estrogen agonist/antagonist (Raloxifene), estrogen and/or hormone therapy, PTH 1-34 (Teriparatide), and RANKL inhibitor (Denosumab). ’ A detailed description of each agent, its mechanism, administration, risk and benefits, and side effects are discussed. ’ For hormonal therapy—the WHI study is referred to and a final statement is made: ‘‘When ET/HT use is considered solely for prevention of osteoporosis, the FDA recommends that approved nonestrogen treatments should first be carefully considered.’’ *
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Ample information regarding non–FDA-approved medications is provided. No pharmacologic therapy should be considered indefinite in duration. After the initial 3- to 5-year treatment period, a comprehensive risk assessment should be performed. There is no uniform recommendation that applies to all patients and duration decisions need to be individualized.
Treatment efficacy monitoring includes: * * *
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Ensuring compliance and reducing barriers to compliance. Annual review of continued medication to treat osteoporosis. Evaluation to discontinue treatment temporarily after a long duration, particularly after bisphosphonate administration. If treatment is discontinued, serial monitoring can include clinical assessment for fractures, falling, any interval chronic disease occurrence and consideration of serial BMD
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testing and possible use of biochemical markers.
Discussion Each of the guidelines is slightly different in some ways which highlight the nuances of what each individual organization focuses on when forming guidelines. The presentations were left to use the original format with either bullet points or question and answer as well as the organizations’ original wording where possible. There are many similarities and areas in which guidelines are shared from a common source or have come to the same conclusion from the available evidence. All guidelines use a system of rating for the evidence that has been used to form the guidelines. All organizations recommend appropriate weight-bearing exercise, balanced diet, and avoidance of excessive alcohol intake, smoking cessation, and fall prevention. The NOF and AACE go into significant detail on fall prevention. The NOF discusses home safety assessment and notes the importance of vision assessment. AACE discusses the use of physical therapy for fall and fracture prevention. All guidelines include a recommendation for calcium and vitamin D supplementation in patients with osteoporosis. AACE and NOF delve into more detail regarding the differences in calcium and vitamin D supplementation in different age groups and populations. The guidelines have similar recommendations for who should be treated; however, each with a particular approach. The organizations differ in their recommendations for first-line therapy. NAMS, AACE, and NOF do not necessarily recommend 1 agent or class of agents as firstline therapy. Rather, they discuss the evidence regarding decreased fracture risk and various sites and in various populations so that a provider may make an educated decision for an individual
Osteoporosis: Therapeutic Guidelines patient by referencing all guidelines. They recommend that bisphosphonates are very effective although other agents such as Raloxifine and Denosumab are as well. ACOG recommends bisphosphonates or Raloxifene as first-line therapy. AACE and NOF go into detailed descriptions of the mechanisms of available agents as well as preparations, and negative effects. AACE in addition to briefly discussing surgical options for osteoporosis also provides a section on when to refer a patient to a clinical endocrinologist, which is helpful for understanding and triaging patients with complex or refractory osteoporosis. All guidelines suggest that combination pharmacologic therapy is not superior to single-agent therapy for osteoporosis, although there are subtle differences in their recommendations for sequential therapy, duration, and discontinuation of therapy. There are some emerging areas for which no standard guidelines have been developed. One concept that falls into this category is the duration/cessation of treatment and drug holiday. These topics are important given emerging data on rare but serious effects including osteonecrosis of the jaw and atypical femur fractures. NAMS has recently released a Practice Pearls bulletin discussing drug interruptions or holidays. They cite the 2011 FDA discussion on bisphosphonate therapy and conclude that no clear recommendations can be made, as therapy needs to be individualized.5 However, evaluation for the cessation of treatment after 3 to 5 years is reasonable for low-risk patients, after 5 to 10 years for moderate-risk patients, and after 10 years for high-risk patients. This is possible secondary to the ‘‘lingering’’ effect of these therapies.6 The AACE recommends that bisphosphonates be discontinued after 4 to 5 years in cases of mild disease, for patients with higher fracture risk they recommend discontinuation of bisphosphonates for 1 to 2 years after 10
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years of therapy. Reinitiation of therapy is indicated for fracture, substantial decline in BMD, or an increase in bone turnover markers. The NOF states that there can be no uniform decisions on duration and that cases need to be individualized. They state that it is reasonable to discontinue bisphosphonate therapy and perform a comprehensive fracture assessment after 3 to 5 years in patients with a moderate risk of fracture or less, but that continued therapy or alternate therapy may be needed in patients with a high-risk of fracture. ACOG recalls that the FDA recommended more specific labeling regarding duration of treatment and treatment interruptions. They state it is reasonable to interrupt treatment after 5 to 10 years of bisphosphonate use and that it is difficult to assess risk of adverse outcome in the general population because adverse effects were more commonly reported in a very specific patient population. Most guidelines, however, do leave the duration of therapy and length of drug holiday at the discretion of the physician. Most organizations also provide recommendations regarding hormonal options for osteoporosis. In comparison, the recommendations of NAMS, ACOG, and NOF, regarding hormonal therapy for osteoporosis, are slightly varied. NAMS states that hormonal therapy can be continued for osteoporosis alone in the absence of vasomotor symptoms weighing its benefits and risks against those of alternative therapies. In contrast, ACOG does not recommend continuation of hormonal therapy for osteoporosis in the absence of vasomotor symptoms and recommends ‘‘using the lowest dose for the shortest amount of time.’’ The NOF comments that when ET/HT use is considered solely for prevention of osteoporosis, the FDA recommends that approved nonestrogen treatments should first be carefully considered. Therefore, a detailed understanding of the risks and benefits of www.clinicalobgyn.com
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hormone therapy, as well as an understanding of a patient’s situation and previous therapies, are imperative to make a decision on hormonal therapy for osteoporosis. The AACE, NOF, and NAMS also give specific information on the FDA approval of osteoporosis treatments. The AACE, NOF, and NAMS also discuss non–FDA-approved therapies, therapies not available in the United States currently, and upcoming therapies on medications for osteoporosis. All guidelines have similar recommendations on monitoring BMD after the diagnosis of osteoporosis is made and after treatment is initiated. The NOF and the AACE go into more detail and recommend the use of bone turnover markers for treatment surveillance. The NOF at the conclusion of their guidelines provides a list of unanswered and future questions regarding osteoporosis treatment. This unique addition provides information regarding gaps and directions in future research. All aforementioned guidelines provide valuable information. Much of it is overlapping; however, familiarization with all guidelines provides the best understanding of the available evidence regarding osteoporosis and the approach that different organizations take to answer common questions. The NAMS guidelines focus more on the osteoporotic female population. ACOGs guidelines provide more information regarding hormonal options for premenopausal and postmenopausal low bone density. The AACE guidelines focus on osteoporosis from an endocrinology standpoint and provide recommendations on referral for primary providers. The NOF guidelines are
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comprehensive and stress that the guidelines are not rules and that every patient encounter needs to be individualized to that patient’s situation and needs. We stress again that all guidelines are only loose recommendations for management and need to be tailored to each individual patient. Providers caring for osteoporotic patients need to familiarize themselves with all guidelines and which to apply to each patient.
References 1. North American Menopause Society. Position statement: management of osteoporosis in postmenopausal woman: 2010. Menopause. 2010;17: 25–54, quiz 55-6. 2. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Postmenopausal Osteoporosis. 2010. Available at: https://www.aace. com/files/osteo-guidelines-2010.pdf. Accessed February 4, 2013. 3. American College of Obstetricians and GynecologistsHauk L. Osteoporosis. Practice Bulletin. Number 129. 2012. Available at: https://access. acog.org/eweb/dynamicpage.aspx?site = congress& webcode = LoginRequired&urlReq = http%3a% 2f%2fwww.acog.org%2fResources + And + Publi cations%2fPractice + Bulletins + List.aspx. Accessed January 16, 2013. 4. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: NOF; 2010. Available at: http://nof.org/files/nof/public/content/file/344/ upload/159.pdf. Accessed February 5, 2013. 5. FDA Drug Safety Communication: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures 2010. Available at: http://www.fda. gov/drugs/drugsafety/ucm229009.htm. Accessed March 2, 2013. 6. North American Menopause SocietyDiab DL, Watts NB. NAMS Practice Pearl: use of drug holidays in women taking bisphosphonates. Menopause. 2013. Available at: http://pdfs.journals.lww.com/meno pause journal/9000/00000/Use_of_drug_holidays_in_ women_taking.98549.pdf. Accessed March 2, 2013.
