In patients aged 50 years or older who have sustained a hip or other fragility fracture, evidence suggests that:
• Many patients are not receiving appropriate evaluation and treatment for osteoporosis postfracture [overall quality:
high]
• Significant progress has been made towards developing and implementing programs to address this care gap [overall quality: high]
Question 2: How do I decide which fragility fracture patients are at high risk for future fracture and which patients to treat
pharmacologically?
Case clarification
The DXA scan reveals that the patient has a T-score of −2.0 at the lumbar spine (L1–L4), a T-score of −3.9 at the left femoral neck and a T-score of −4.1 at the left total hip. On further questioning, the patient discloses that she has had a prior wrist fracture at age 55 and that her mother had a hip fracture. She is not taking oral steroids, does not have rheumatoid arthritis, does not smoke, and drinks less than
C H A P T E R 7 Osteoporosis and Metabolic Disorders other than BMD that contribute to the strength of a bone such as geometry, microarchitecture, remodeling, minerali- zation and damage accumulation.30 It is the interplay between both quantitative and qualitative factors that ulti- mately determines the fragility of a bone and its suscepti- bility to fracture.31 For this reason, recent treatment guidelines have focused on evaluating a patient’s absolute fracture risk, which considers BMD as well as other clinical risk factors for fracture that are thought to capture some aspects of bone quality.
The World Health Organization (WHO) has developed an international Fracture Risk Assessment Tool (FRAX®), that can be used to compute the 10-year probability of fractures in men and women based on clinical risk factors for fracture (which represent bone quality), with or without the measurement of femoral neck BMD.32 The algorithms used in the FRAX model are based on a series of meta- analyses using primary data from population-based cohorts that have identified several clinical risk factors for frac- ture.33 The performance characteristics of the clinical risk factors have been validated in independent, population- based prospectively studied cohorts with over a million person years of observation.33 The FRAX tool calculates the 10-year probability of a major osteoporotic fracture (clinical spine, hip, forearm, or proximal humerus) and hip fracture calibrated to the fracture and death hazard of several countries.34
The FRAX calculation tool is available for public use online at http://www.shef.ac.uk/FRAX/index.htm. After selecting an appropriate country of origin, a patient’s 10- year fracture risk probability can be determined by answer- ing a simple set of 12 questions pertaining to the patient’s clinical risk factors for fracture (Table 7.2). Current fracture risk cutoffs for the tool are based on cost effectiveness. For example, low bone mass (T-score between −1.0 and −2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20% was shown to be cost- effective in the USA.35 In a study from the UK, the fracture risk in women with a history of osteoporotic fracture was selected as the treatment cutoff, corresponding to a risk level of 7.5%.32 It should be noted that cutoffs have not been established for all countries that can utilize the FRAX tool.
While the FRAX tool facilitates the determination of who is at high risk for fracture, by assessing quantity and indi- rectly quality, it does have several limitations. Although FRAX is an international tool, it is suitable for use only in those countries for which epidemiological data are availa- ble.36 The set of clinical risk factors used in the FRAX tool also has limitations. For instance, several risk factors can be indicated only as present or absent (“yes” or “no”) in the question set, such as glucocorticoid therapy or previous fracture. However, there is evidence that the risk associated with the use of glucocorticoids is dose responsive.37,38 In one drink per month. Blood tests to identify secondary
causes of osteoporosis were negative.
A T-score is the number of standard deviations (SD) above or below the mean value of BMD for young adults (20–30 years old). The World Health Organization (WHO) defines osteoporosis as a T-score of –2.5 or less at the hip or lumbar spine.
Relevance
Many patients who sustain a fragility fracture do not receive appropriate pharmacologic treatment for underly- ing osteoporosis.14 It is important to identify those at high risk for future fracture and those who would benefit from pharmacologic treatment in order to prevent future fractures.
Current opinion
Current opinion suggests that lack of education and train- ing about osteoporosis is an important barrier to ortho- pedic postfracture care. Opinion is divergent among orthopedic surgeons on which patients should be consid- ered for pharmacologic treatment.
Finding the evidence
• Cochrane Database with search terms: “osteoporosis and treatment guidelines”
• MEDLINE (1996 to August Week 1 2009) and Embase (1980 to 2009 Week 33) search strategy:
1 exp Osteoporosis/di [Diagnosis]
2 exp Practice Guideline/
3 2 and 1
4 limit 3 to (English language and humans)
• A review of reference lists of relevant articles for addi- tional published trials
Quality of the evidence
Level I• 8 systematic reviews or meta-analyses
• 3 clinical practice guidelines
Findings
Until recently, decisions about osteoporosis therapy were made based on the presence or absence of fractures and on T-score values ≤ −2.5 SD from DXA measurements of BMD.
Although low BMD is a strong and independent risk factor for fracture,27,28 it is not the only one. Indeed, most fractures occur in women with osteopenia (T-score between −1.0 and
−2.5 SD) and not osteoporosis.29 The main reason for this observation is that BMD measures bone quantity and does not take into account bone quality. Bone quality represents essentially all of the other characteristics of bone tissue
fracture risk zones (low, moderate, and high). An initial risk category is obtained from age, sex, and T-score at the femoral neck. Clinical risk factors—the presence of a prior fragility fracture after age 40 or recent prolonged systemic glucocorticoid use—increase fracture risk independent of BMD.
Recommendations
In patients aged 50 years or older who have sustained a fragility fracture, and have not received prior pharmaco- logic treatment, evidence suggests that:
• The FRAX tool can be used to calculate the 10-year prob- ability of a major osteoporotic fracture (clinical spine, hip, forearm, or proximal humerus) and hip fracture [overall quality: high]
• Alternative methods are also available to determine absolute fracture risk [overall quality: high]
• Treatment decisions should be patient specific and guidelines developed by the appropriate country of origin should be considered [overall quality: high]
Question 3: What medications reduce the risk of hip fracture?
Case clarification
A complete dietary history reveals that the patient con- sumes 1 glass of milk (350 mg dietary calcium), 1000 mg of elemental calcium in the form of supplements, and 800 IU of vitamin D per day. She is not currently taking any pre- scription medications.
addition, the risk of future fracture increases progressively with the number of prior fractures.39 Further, only femoral neck BMD is taken into account by FRAX, as it was the only site for which BMD data was available for all of the study cohorts. BMD measurement by DXA at the femoral neck site is difficult as accurate measurements require correct rotation of the femur and positioning of the region of inter- est by the technician. As a result, considerable variability in femoral neck BMD may occur. However, it should be noted that a patient’s fracture risk probability can be obtained without entering BMD data into the FRAX tool, emphasizing again the importance of factors other than BMD on future fracture risk. Additionally, the FRAX tool can only be used to assess previously untreated patients.
Although the FRAX tool is available for use internation- ally, it is not incorporated into all sets of treatment guide- lines for osteoporosis worldwide. Treatment guidelines for osteoporosis vary by country, and only some countries recommend the use of the FRAX tool. A summary of North American and European guidelines for fracture risk assessment and treatment of osteoporosis is presented in Table 7.3. The US National Osteoporosis Foundation (NOF)40 and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)41 both recommend the use of the FRAX tool to calculate absolute fracture risk in their treatment guidelines for oste- oporosis. The Osteoporosis Canada 2010 Guidelines42 suggest the use of one of two closely related tools for esti- mating 10-year risk of major osteoporotic fracture: the FRAX tool or the Canadian Association of Radiologists/
Osteoporosis Canada (CAROC) tool. Both were calibrated using the same Canadian fracture data and were validated in Canadians.43–45 The CAROC tool stratifies men and women over age 50 into three 10-year major osteoporotic
Table 7.2 List of clinical risk factors included in the WHO Fracture Risk Assessment Model (FRAX)
Clinical risk factor Geographic region Race
Sex Weight Height
Prior fragility fracture Parent with hip fracture
Glucocorticoid use (≥5 mg/day of prednisone for ≥3 mo ever) Rheumatoid arthritis
Secondary osteoporosis Current smoking
Alcohol intake (≥3 or more drinks/day) WHO, World Health Organization.
Recommended daily calcium and vitamin D intakes for pop- ulations vary by country. The Institute of Medicine (IOM) recommends a daily calcium intake of 1000 mg for men 51–70 years and 1200 mg for women. For men and women 71 years of age and older the recommendation is 1200 mg per day.
Vitamin D recommendations are 600 IUs a day for men and women 51–70 years of age and 800 IUs per day for men and women 71 years of age and older
Relevance
A number of different pharmacologic agents are available for the treatment of osteoporosis.46 Opinion among ortho- pedic surgeons is divergent on which pharmacologic agents are best to reduce the relative risk of hip fractures in postmenopausal women who present with low BMD or a prior fragility fracture.
Current opinion
Current opinion suggests that orthopedic surgeons pre- scribe a variety of different pharmacologic agents for the treatment of fragility fractures.
C H A P T E R 7 Osteoporosis and Metabolic Disorders
Table 7.3 North American and European guidelines for fracture risk assessment and treatment of osteoporosis
Continent Fracture risk assessment Treatment guidelines
North America (USA)a
WHO Fracture Risk Assessment Tool (FRAX) Postmenopausal women and men age 50 and older presenting with the following should be considered for treatment:
• A hip or vertebral (clinical or morphometric) fracture.
• T-score ≤−2.5 at the femoral neck or spine after appropri- ate evaluation to exclude secondary causes
• Low bone mass (T-score between −1.0 and −2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥3% or a 10-year probability of a major osteoporosis-related fracture ≥20% based on the US- adapted WHO algorithm
North America (Canada)b
Approach 1: WHO FRAX
Approach 2: Canadian Association of Radiologists/Osteoporosis Canada (CAROC)
1 Select the table appropriate for the patient’s sex 2 Identify the row that is closest to the patient’s age
3 Determine the patient’s absolute fracture risk category by using the lowest T-score from the recommended skeletal sites (lumbar spine, total hip, femoral neck, and trochanter, with forearm 1/3 radius if either spine or hip is not valid)
4 Evaluate clinical factors that may move the patient into a higher fracture risk category (fragility fractures after 40 yrs of age and current systemic glucocorticoid therapy >3 mo raise the patient to the next higher risk category; if both factors are present, move to high risk)
Determine the patient’s absolute fracture risk category
Approach 1
Determine fracture risk category using the WHO FRAX®
tool Approach 2
Absolute fracture risk categories:
• Low risk (<10%, 10-yr fracture risk)
• Moderate risk (10–20%, 10-yr fracture risk)
• High risk (>20%, 10-yr fracture risk)
In both approaches, a patient’s fracture risk category is the basis for deciding on treatment and frequency of BMD monitoring
Europec No universally accepted policy for population screening in Europe to identify patients with osteoporosis or those at high risk of fracture
Patients are identified opportunistically using a case-finding strategy on the finding of a previous fragility fracture or the presence of significant risk factors
Approach 1: BMD as intervention threshold Approach 2: WHO FRAX
Approach 1
• Postmenopausal women with a previous fracture can be considered for treatment without the need for a BMD test
• Postmenopausal women with other clinical risk factors should be considered for BMD testing, and treatment should be considered where the T-score for BMD at the femoral neck is −1.0 SD or lower for postmenopausal women with a parental history of hip fracture, −2.0 SDs in women committed to long-term oral glucocorticoids, and
−2.5 SD or lower for women with rheumatoid arthritis, who smoke or who drink 3 units of alcohol or more daily Approach 2
• Postmenopausal women with prior fragility fracture should be considered for treatment
• FRAX probability determines whether the patient is above or below the intervention threshold for treatment. The intervention threshold at each age is set at a risk equivalent to that associated with a prior fracture and therefore rises with age
BMD, bone mineral density; SD, standard deviation; WHO, World Health Organization.
a US National Osteoporosis Foundation Guidelines40.
b Canadian Association of Radiologist/Osteoporosis Canada Guidelines42.
c European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis Guidelines41.
Finding the evidence
• Cochrane Database with search terms: “osteoporosis and treatment and hip fracture”
• MEDLINE (1996 to August Week 1 2009) and Embase (1980 to 2009 Week 33) search strategy:
1 exp Bone Density Conservation Agents/tu [Therapeutic Use]
2 exp Hip Fractures/
3 1 and 2
4 limit 3 to (English language and humans)
• A review of reference lists of relevant articles for addi- tional published trials
Quality of the evidence
Level I• 8 systematic reviews or meta-analyses
• 18 randomized controlled trials
Findings
The majority of pharmacologic agents available for the treatment of osteoporosis are antiresorptive agents, which include bisphosphonates (oral or intravenous), hormone replacement therapy (HRT), raloxifene, denosumab, and calcitonin. Other available agents are parathyroid hormone (an anabolic agent) and strontium ranelate (a combination antiresorptive and anabolic agent).46 A summary of the effi- cacy of pharmacologic agents on the relative risk reduction of hip fractures is presented in Table 7.4. As the majority of pivotal clinical trials were in postmenopausal women, data in men is limited and will not be reviewed.
A recent review article47 summarized the efficacy results from pivotal clinical trials of four commonly prescribed bisphosphonates—alendronate, risedronate, ibandronate and zoledronic acid—for the treatment of postmenopausal osteoporosis. A total of 11 randomized placebo-controlled trials were identified (3 for alendronate,48–50 4 for risedro- nate,51–54 2 for ibandronate,55,56 and 2 for zoledronic acid57,58).
Compared with placebo controls, alendronate, risedronate, and zoledronic acid but not ibandronate (no available hip data) were found to reduce the relative risk of hip fractures in postmenopausal women with low BMD and/or prior vertebral fracture by 30% to 51%. Similarly, two rand- omized placebo-controlled trials looking at the fracture efficacy of HRT in postmenopausal women with59 and without60 hysterectomy demonstrated that HRT could reduce the relative risk of hip fracture by 39% and 30%
respectively. The clinical trial of denosumab reported a relative risk reduction of hip fracture with denosumab of 40%.61 In contrast, randomized placebo-controlled trials with raloxifene62 and calcitonin63 have failed to demon- strate successful relative risk reductions of hip fracture in postmenopausal women. Two pivotal trials64–71 have exam- ined the effects of hPTH(1–34) and hPTH(1–84) on fracture risk reduction in postmenopausal women. hPTH(1–34) was
shown to reduce the relative risk of nonvertebral frac- tures;71 however, the number of women with hip fractures was too small to estimate the incidence of hip fracture, and thus the specific relative risk reduction at the hip site.
Similarly, the hPTH(1–84) trial72 did not report on the spe- cific relative risk reduction of hip fractures, but the differ- ence in the number of reported nonvertebral fractures was not statistically significant between treated and untreated groups. Finally, four randomized placebo-controlled trials have evaluated the effects of strontium ranelate on fracture risk reduction in postmenopausal women.73–76 Only one of these trials specifically assessed the efficacy of the drug on the relative risk reduction of hip fractures,76 and failed to show a significant relative risk reduction.