SOGC CLINICAL PRACTICE GUIDELINEAbstractObjective: To provide guidelines for the health care provider on the prevention, diagnosis, and clinical management of postmenopausal osteoporosis.Outcomes: Strategies for identifying and evaluating high-risk individuals, the use of bone mineral density (BMD) and bone turnover markers in assessing diagnosis and response tomanagement, and recommendations regarding nutrition, physical activity, and the selection of pharmacologic therapy to prevent and manage osteoporosis.Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library on August 30 and September 18, 2012, respectively. The strategy included the use ofappropriate controlled vocabulary (e.g., oteoporosis, bone density, menopause) and key words (e.g., bone health, bone loss, BMD). Results were restricted to systematic reviews, practice guidelines, randomized and controlled clinical trials, and observational studies published in English or French. The search was limited to the publication years 2009 and following, and updates were incorporated into the guideline to March 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.Values: The quality of the evidence was rated using the criteriadescribed by the Canadian Task Force on Preventive Health Care (Table 1).Sponsors: The Society of Obstetricians and Gynaecologists of Canada.RECOMMENDATIONS For Postmenopausal Women1. Health care providers should be aware that the goals ofosteoporosis management include assess m ent of fracture risk and prevention of fracture. (I-A) 2. Health care providers should understand that a stable orincreasing bone mineral density reflects a response to therapy in the absence of low-trauma fracture or height loss due to vertebral-compression fracture. A pro g ressive decrease in bone mineral density, with the magnitude of bone loss being greater than the precision error of the density assessment, indicates a lack of response to current ther a py. Management should be reviewed and modified appropriately. (I-A)No. 312, September 2014 (Replaces No. 222, January 2009)Osteoporosis in MenopauseThis clinical practice guideline has been prepared by the Menopause and Osteoporosis Working Group, reviewed by the Clinical Practice Gynaecology and Family Physician Advisory Committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.PRINCIPAL AUTHORS Aliya Khan, MD, Hamilton ON Michel Fortier, MD, Quebec QC MENOPAUSE AND OSTEOPOROSIS WORKING GROUPMichel Fortier, MD (Co-Chair), Quebec QC Robert Reid, MD (Co-Chair), Kingston ON Beth L. Abramson, MD, Toronto ON Jennifer Blake, MD, Toronto ON Sophie Desindes, MD, Sherbrooke QC Sylvie Dodin, MD, Quebec QC Lisa Graves, MD, Toronto ON Bing Guthrie, MD, Yellowknife NT Shawna Johnston, MD, Kingston ON Aliya Khan, MD, Hamilton ON Timothy Rowe, MB BS, Vancouver BC Namrita Sodhi, MD, Toronto ON Penny Wilks, ND, Dundas ON Wendy Wolfman, MD, Toronto ONDisclosure statements have been received from all contributors.The literature searches and bibliographic support for this guideline were undertaken by Becky Skidmore, MedicalResearch Analyst, Society of Obstetricians and Gynaecologists of Canada.Key Words : Osteoporosis, prevention, treatment, diagnosis, bone mineral density, dual energy x-ray absorptiometry, bone turnover markers, vertebral fractures, fragility fractures, antiresorptive, hormone therapy, selective estrogen-receptor modulator, bisphosphonates, calcitonin, anabolic, bone forming agentJ Obstet Gynaecol Can 2014;36(9 eSuppl C):S1–S15SOGC CLINICAL PRACTICE GUIDELINE3. Health care providers should identify the absolute fracture riskby integrating the key risk factors for fracture; namely, age,bone mineral density, prior fracture, and glucocorticoid use.These risk factors allow estimation of fracture risk using the tool of the Canadian Association of Radiologists and Osteoporosis Canada. (I-A)4. The Fracture Risk Assessment tool of the World HealthOrganization (FRAX) has now been validated in a Canadianpopulation and may also be used and incorporates additionalrisk factors; namely, low body mass index, parental history offracture, smoking status, alcohol intake, and the presence ofsecondary causes of osteoporosis. (I-A)5. Health care providers should be aware that a fragility fracturemarkedly increases the risk of a future fracture and confirms the diagnosis of osteo p orosis irrespective of the results of the bone density assessment, (I-A) and that the presence of a low-trauma fracture of a vertebra or hip or more than 1 fragility fractureconfirms a high fracture risk regardless of the bone mineraldensity. (I-A)6. Treatment should be initiated according to the results of the10-year absolute fracture risk assessment. (I-A)Calcium and Vitamin D7. Adequate calcium and vitamin D supplementation is keyto ensuring prevention of progressive bone loss. Forpostmenopausal women a total daily intake of 1200 mg ofelemental calcium from dietary and supplemental sourcesand daily supplementation with 800 to 2000 IU of vitamin Dare recommended. Calcium and vitamin D supplementationalone is insufficient to prevent fracture in those withosteoporosis; however, it is an important adjunct topharmacologic intervention with antiresorptive and anabolictherapy. (I-B)Hormone Therapy8. Hormone therapy should be prescribed for symptomaticpostmenopausal women as the most effective option formenopausal symptom relief. (I-A) It represents a reasonablechoice for the prevention of bone loss and fracture in this patient population. (I-A)9. Physicians may recommend low- and ultralow-dosage estrogentherapy to symptomatic women for relief of menopausalsymptoms (I-A) but should inform their patients that, despitethe fact that such therapy has demonstrated a beneficial effectin osteoporosis preven t ion, (I-A) no data are yet available onreduction of fracture risk.Bisphosphonates10. Alendronate, risedronate, and zoledronic acid are valuablefirst-line agents of choice in the treatment of postmenopausalosteoporosis and should be considered to decrease the risk ofvertebral, non-vertebral, and hip fractures. (I-A)11. Etidronate is a weak antiresorptive agent and is notrecommended as a first-line agent of choice for the treatmentof osteoporosis. (I-D)RANKL Inhibitor12. Denosumab is an effective antiresorptive agent, shown toreduce the risk of vertebral, non-vertebral, and hip fractures, (I-A) and should be considered as a first-line agent of choice in thetreatment of postmenopausal osteoporosis in women at a highfracture risk. (I-A)Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health CareQuality of evidence assessment*Classification of recommendations†I: Evidence obtained from at least one properly randomizedcontrolled trialA. There is good evidence to recommend the clinical preventive actionII-1: Evidence from well-designed controlled trials withoutrandomizationB. There is fair evidence to recommend the clinical preventive actionII-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group C. The existing evidence is conflicting and does not allow to make arecommendation for or against use of the clinical preventive action;however, other factors may influence decision-makingII-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results inuncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category D. There is fair evidence to recommend against the clinical preventive actionE. There is good evidence to recommend against the clinical preventiveactionIII: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees L. There is insufficient evidence (in quantity or quality) to makea recommendation; however, other factors may influencedecision-making*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.89†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.89ABBREVIATIONSAFF atypical femoral fractureBMD bone mineral densityET estrogen therapyFIT Fracture Intervention TrialHR hazard ratioHT hormone therapyONJ osteonecrosis of the jawRANKL receptor activator of nuclear factor kappa-B ligandRCT randomized controlled trialSERM selective estrogen-receptor modulatorWHI Women’s Health InitiativeOsteoporosis in MenopauseSelective Estrogen-Receptor Modulators13. Treatment with raloxifene may be considered to decrease the riskof vertebral fractures, bearing in mind that this agent has not been shown to be effective in reducing the risk of non-vertebral or hipfractures. (I-A)Parathyroid Hormone14. Treatment with teriparatide should be considered to decrease therisk of vertebral and non-vertebral fractures in postmenopausalwomen with severe osteoporosis (I-A) and should also beconsidered in postmenopausal women experiencing bone loss ora new fracture despite antiresorptive therapy. (I-A) INTRODUCTIONO steoporosis is defined as an impairment in bone strength due to an abnormal quantity and/or quality of bone. Quantity is evaluated by measuring BMD. Quality is affected by many factors, including the degree of mineral i zation, the rate of bone remodelling, the connectivity of the bony trabeculae, the quality of the collagen fibres, and the health of the bone cells. The 3 types of bone cells are osteoblasts, osteoclasts, and osteocytes. The osteocytes function as “mechanostats”, sensing the degree of microdamage and triggering remodelling in areas of stress and strain, thus allowing continual renewal, repair, and replacement of bone. This process of remodelling maintains bone strength.Adequate calcium and vitamin D intake is necessary to attain and maintain normal bone quantity and quality and thus achieve optimal bone strength. Early assessment of skeletal health and then initiation of appropriate calcium and vitamin D supplementation and an exercise program are essential in the prevention and treatment of osteoporosis. Individuals at increased risk for fracture should also be offered pharmacologic therapy in order to reduce the fracture risk. Absolute frac t ure risk is identified by integrating age and BMD with other key risk factors for fracture including prior fracture history and use of glucocorticoid therapy. The decision to treat is based on the risk of fracture, and the quantification of absolute fracture risk enables targeting of treatment to those at greatest risk.RISK ASSESSMENT AND MANAGEMENTBone strength is determined by both bone quantity and bone quality. Bone densitometry provides information on BMD, which is a reflection of bone quantity. Bone quality is determined by a number of factors, including the rate of remodelling, bone mineralization, function of the bone cells, and quality of the collagen fibres. It is necessary to identify risk factors for fracture that may be present and the risk of falls. The timed “get up and go” test is valuable in assessing gait stability and is a reflection of fall risk. Risk factors for osteoporosis have been identi fi ed (Table 2),1 and the presence of risk factors in a postmenopausal woman justifies bone densitometry.2In 2005 Osteoporosis Canada recommended identifying absolute fracture risk by integrating the key risk factors for fracture; namely, age, BMD, prior fracture, and glucocorticoid use.3 The 10year risk of fragility fractures is thus determined (Figure)1and defined as high if it is greater than 20%, moderate if it is 10% to 20%, and low if it is less than 10%.4 The additional effect of a preexisting fragility fracture or glucocorticoid use moves the patient 1 risk category higher. These guidelines were based on Swedish data and have been recalibrated using Canadian hip fracture data. The version developed by the Canadian Association of Radiologists and Osteoporosis Canada4 has now been validated in 2 Canadian cohorts and has close to 90% agreement with the FRAX5 score (the FRAX tool can be downloaded from the Osteoporosis Canada website, http://www.osteoporosis.ca). The presence of a vertebral or hip fracture or more than 1 fragility fracture increases the fracture risk to high. Fracture risk is evaluated on the basis of femoral neck BMD and age and is modified by the presence of prior fragility fracture or the use of glucocorticoid therapy (7.5 mg for 3 months or longer); these modifiers increase the fracture risk to the next risk category.1 A BMD Tscore of −2.5 or less at either the lumbar spine or the femoral neck denotes at least a moderate risk of fracture.1 Height should be measured annually, and a decrease in measured height of more than 2 cm should be further evaluated by radiographs of the thoracic and lumbar spine with exclusion of vertebral fractures.6A more comprehensive calculation of the 10year absolute fracture risk, now available from the World Health Organization, incorporates additional risk factors: parental history of hip fracture, current tobacco smoking, rheumatoid arthritis or other secondary causes of bone loss, and alcohol intake of 3 or more units daily.5It is recommended that absolute fracture risk be calculated using the tool of either the Canadian Association of Radiologists and Osteoporosis Canada or FRAX and the decision to treat be based on the absolute fracture risk. Younger individuals at a low risk of fracture are appropriately managed with lifestyle changes and strategies designed to prevent bone loss.Osteoporosis is diagnosed in a postmenopausal woman on the basis of a BMD Tscore of less than −2.5 at theSOGC CLINICAL PRACTICE GUIDELINElumbar spine, hip (femoral neck or total hip), or radius (distal third). Clinically it is diagnosed in a postmenopausal woman in the presence of a lowtrauma fracture. In a premenopausal woman osteoporosis is diagnosed only in the presence of fragility fractures; BMD alone cannot be used for diagnosis.7In premenopausal women a normal BMD is defined as being within 2 standard deviations of the agematched reference mean. Comparison with the agematched reference range is represented by the Z score, and in premenopausal women Z scores should be used instead of T scores. Low bone density is defined as a BMD Z score 2 or more standard deviations below the mean agematched reference value.7Pharmacologic therapy is considered in postmenopausal women after exclusion of secondary causes of low bone density. If the 10year absolute fracture risk is greater than 20% (high), then drug therapy is advised. In those with a moderate risk (10% to 20%), management decisions are indi v idualized. Those with a low fracture risk (< 10%) can be treated conservatively after exclusion of secondary causes of bone loss with prevention strategies based on ensuring adequate calcium and vitamin D supplementation. It is also important to emphasize regular exercise and reduced con s umption of alcohol (fewer than 2 drinks/d) and coffee (fewer than 4 cups/d). Smoking cessation should also be strongly advised.Failure of therapy is confirmed by the development of a lowtrauma fracture or significant bone loss despite pharmacologic therapy for 2 years. In these individuals it is necessary to ensure that there are no secondary causes of bone loss. It is also important to ensure adequate adherence to therapy.8ADVANCES IN PHARMACOLOGIC THERAPYIn addition to adequate calcium, vitamin D, and exercise, options for the prevention and treatment of osteoporosis include antiresorptive and anabolic agents.9 Antiresorptive (anticatabolic) agents inhibit osteoclast activity and reduce bone turnover.9,10 The various agents have different mechanisms of action. Bisphosphonates reduce the rate of bone turnover, providing a longer time for bone to mineralize. Bisphosphonate therapy is thus associated with modest increases in BMD. Estrogen acts through the estrogen receptors on both osteoblasts and osteoclasts, suppressing receptor activator of nuclear factor κB ligand (RANKL)induced osteoclast differentiation and thereby decreasing bone remodeling.11 Raloxifene, a SERM, can bind to estrogen receptors, with tissuespecific agonist or antagonist effects. Raloxifene decreases bone remodelling in addition to its extraskeletal effects. Osteoclastic bone resorption is also inhibited by calcitonin acting on calcitonin receptors. Denosumab is a monoclonal antibodyTable 2. Risk factors for osteoporosis: indications for measuring BMDOlder adults (age ≥ 50 years)Younger adults (age < 50 years)Age ≥ 65 years (both women and men) Fragility fractureClinical risk factors for fracture(menopausal women and men age 50 to 64 years)Prolonged use of glucocorticoids* Fragility fracture after age 40 years Use of other high-risk medications†Prolonged use of glucocorticoids*Hypogonadism or premature menopause(age < 45 years)Use of other high-risk medications Malabsorption syndromeParental hip fracture Primary hyperparathyroidismVertebral fracture or osteopenia identified on radiography Other disorders strongly associated with rapid bone loss and/or fractureCurrent smokingHigh alcohol intakeLow body weight (< 60 kg) or major weight loss(> 10% of body weight at age 25 years)Rheumatoid arthritisOther disorders strongly associated withosteoporosis*At least 3 months’ cumulative therapy in the previous year at a prednisone-equivalent dose ≥ 7.5 mg daily.†For example, aromatase inhibitors or androgen deprivation therapy.Reproduced with permission of the Canadian Medical Association from Papaioannou A et al.1Osteoporosis in Menopauseto RANKL (receptor activator of nuclear factor κB) and binds to RANKL, lowering values to premenopausal levels. This results in a decrease in the formation, function, and survival of osteoclasts.Antiresorptive agents are effective in reducing frac t ure risk by approximately 30% to 68% in postmenopausal women. However, fractures may still occur, and anabolic therapy can complement antiresorptive therapy in the prevention of further fractures. Anabolic therapy can result in new bone formation, with increases in cortical thickness and trabecular connectivity, leading to major improvements in the quality and quantity of bone. Anabolic therapy can increase the production of new bone matrix by enhancing osteoblast function. Teriparatide (recombinant human parathyroid hormone, amino acid sequence 1 through 34) decreases the release of sclerostin from osteocytes. Sclerostin is a protein that decreases bone formation by inhibiting the Wnt signalling pathway in the osteoblast. With a decrease in this inhibitor of bone formation, there is an increase in new bone formation. Teriparatide, 20 μg daily, has been shown to reduce the risks of vertebral and nonvertebral fragility fractures by approximately 65% and 53%, respectively, over 18 months in postmenopausal women with osteoporosis.12 Teriparatide is the only anabolic agent available in Canada.CALCIUM AND VITAMIN D SUPPLEMENTATION The effectiveness of calcium and vitamin D supplementation in preventing hip fractures was evaluated in the WHI.13 The trial involved 36 282 postmenopausal women who daily received either 1000 mg of elemental cal c ium as calcium carbonate and 400 IU of vitamin D, or a placebo, for an average of7 years. Patients were allowed to take additional daily supplements of up to 1000 mg of cal c ium and 600 IU of vitamin D; approximately 38% of subjects took more than 1200 mg of elemental calcium daily. Personal use of bisphosphonates, calcitonin, SERMs, and ET was also permitted. The calcium and vita m in D study arm overlapped with the HT arm; thus, approximately 51% of women were receiving estrogen.Treatment compliance was poor: by the end of the study, only 59% of the women were taking 80% or more of their supplements. As compared with those taking placebo, the women taking 1000 mg of calcium and 400 IU of vitamin D daily showed a 1.06% increase in hip BMD (P < 0.01). In the treatmentcompliant group, the HR for hip fracture was 0.71 (95% CI 0.52 to 0.97), representing a statistically significant 29% reduction in hip fracture risk among the women taking 80% or more of their calcium and vitamin D supplements. Estrogen use was associated with a 42% Assessment of basal 10-year risk of fracture with the 2010 tool of the Canadian Association of Radiologist and Osteoporosis Canada.Reproduced with permission of the Canadian Medical Association from Papaioannou A et al.1The T-score for the femoral neck should be derived from the National Health and Nutrition Education Survey III reference database for white women. Fragility fracture after age 40 or recent prolonged use of systemic glucocorticoids increases the basal risk by one category (ie, from low to moderate or moderate to high). This model reflects the theoretical risk for a hypothetical patient who is treatment-naive; it cannot be used to determine risk reduction associated with therapy. Individuals with fragility fracture of a vertebra or hip and those with more than one fragility fracture are at high risk of an additional fracture.WomenLow risk (< 10%)High risk (> 20%)Moderate riskAge (year)T–score,femoralneck0.0–1.0–2.0–3.0–4.050 55 60 65 70 75 80 85MenLow risk (< 10%)High risk (> 20%)Moderate riskAge (year)T–score,femoralneck0.0–1.0–2.0–3.0–4.050 55 60 65 70 75 80 85SOGC CLINICAL PRACTICE GUIDELINEreduction in hip fracture risk. A small but significant 17% increase in the risk of renal stones was noted in the treatment group as compared with the placebo group: the HR was 1.17 (95% CI 1.02 to 1.34). Inadequate blood levels of vitamin D were also noted in the WHI study and may have contributed to the findings. In the nested case–control study, the mean serum 25hydroxy vitamin D level at baseline was 46.0 nmol/L in the women who had sustained hip fractures as compared with 48.4 nmol/L in their control subjects (P = 0.17). Vitamin D supplementation of more than 600 IU daily may have reduced the fracture risk, as has been demonstrated in other clinical trials.Calcium supplements have been linked to a possible increase in the risk of cardiovascular events.14 A recent 5year RCT of 1200 mg of elemental calcium carbonate daily versus placebo in 1460 postmenopausal women did not demonstrate any difference in rates of death or hospitalization due to coronary events.15 In the EPIC study of 23 980 people between the ages of 35 and 64 years followed for 11 years with questionnaires, those with a calciumenriched diet had a lower risk of myocardial infarction (HR 0.69; 95% CI 0.5 to 0.94), whereas those using a calcium supplement had a higher risk (HR 1.86; 95% CI 1.17 to 2.96).16Data from the WHI among those not using personal calcium or vitamin D supplements at baseline did not show an adverse effect of such supplementation on the risk of myocardial infarction, coronary heart disease, total heart disease, stroke, or overall cardiovascular disease.17 These RCT data are the best evidence currently available and do not support an increased risk of coronary events with calcium and vitamin D supplementation.It is recommended that the daily calcium requirement of 1200 mg be met ideally from dietary sources; if this is not possible, then supplements may be safely used. Calcium carbonate and calcium citrate are the supplements of choice.Ensuring adequate vitamin D supplementation is a key component of the prevention and treatment of osteoporosis. Although it might not be sufficient as the sole means of therapy for osteoporosis, routine supplementation with calcium (1000 mg/d) and vitamin D 3 (800 to 2000 IU/d) is still recommended as a mandatory adjunct to the main pharmacologic agents (antiresorptive and anabolic drugs). Vitamin D in doses of 800 IU daily has been shown to be effective in reducing the risk of falls by 49% over a 12week period of therapy.18 Vitamin D supplementation at a dose of 10 000 IU once weekly has been suggested for women unable to take daily supplements in areas wheresuch a preparation is available. Doses of 100 000 IU ofvitamin D 3 given orally every 4 months have been shownto be effective in reducing the risk of osteoporotic fractures.19Vitamin D levels depend on a number of factors, including dietary intake, sun exposure, skin pigmentation, body mass index, and smoking status.20 Extraskeletal benefits are currently being evaluated and may include a reduction in the risk of certain malignant diseases as well as autoimmune disorders.HORMONE THERAPYEstrogen has significant antiresorptive effects. Spe c ifically, it enhances the osteoblastic production of osteoprotegerin, which has antiosteoclastic properties because of its ability to bind to RANKL and subsequently to block the RANKL/RANK interaction required for osteoclast recruitment and activation.21,22 Estrogen also decreases RANKL expression from the osteoblast. In the WHI, a pri m ary prevention trial, the estrogenonly arm demonstrated a 30% to 39% reductionin fracture rates.23 This trial theref ore confirmed the antifracture effects of ET suggested by previous clinical trials.24,25The combined estrogen/progestogen arm of the WHI had similar results: an increase in total hip BMD, together with a 34% reduction in hip and vertebral fractures and a 24% reduction in total osteoporotic fractures.26 In earlypostmenopausal women, the combined therapy resulted in increases in BMD of 2% to 3% at the hip and spine over 2 years of therapy.24 A decline in the markers of bone turnover in response to HT was also seen in earlypostmenopausal women.25HT (with estrogen alone or combined with a progestogen) is still considered the most effective therapy for the medical management of meno p ausal symptoms. Bone protection with HT at a usual dosage is considered an added benefit. Recent studies designed to test various dosages of estrogen for bone pro t ection have shown a linear dose response of the skeleton from the lowest to the highest dosages tested.24,27,28 These RCTs have shown that lowdosage ET can prevent postmenopausal osteoporosis, and ultralowdosage ET has beneficial skeletal effects. However, no fracture trial has yet been carried out with low and ultralowdosage HT. A low dose is 0.3 mg of conjugated estrogen or its equivalent (e.g., 0.5 mg of micronized estradiol); half this amount is considered ultralow.29SERM THERAPYSERMs have demonstrated tissuespecific estrogenagonistic or estrogenantagonistic effects.30 In the Multiple。
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