Critical Issues in Osteoporosis Management


7 Critical Issues in Osteoporosis Management


Matthew Wong‐Pack BHSc MD (Cand)1, Kyra Cummings2, Arthur Lau MD FRCPC3, and Jonathan D. Adachi MD FRCPC3


1 Faculty of Medicine, University of Toronto, Toronto, ON, Canada


2 Western University, London, ON, Canada


3 Department of Medicine, McMaster University, Hamilton, ON, Canada


Clinical scenario



  • Seventy‐year‐old ambulatory postmenopausal Caucasian female who lives independently slips and falls in the bathtub.
  • She is unable to bear weight with her right leg and has significant pain in the right groin.
  • Radiographs in the Emergency Department reveal a femoral neck fracture and she is sent in for surgical repair of the fracture.
  • Following discharge, she is sent for bone mineral density (BMD) testing by dual energy x‐ray absorptiometry (DXA) and has blood tests to rule out secondary causes of osteoporosis (negative).
  • 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.
  • The patient discloses that she has had a prior wrist fracture at age 55 and that her mother had a hip fracture.
  • A complete dietary history reveals that the patient consumes 1 glass of milk (350 mg dietary calcium), 1000 mg of elemental calcium in the form of supplements, and 1000 IU of vitamin D per day.
  • The patient has since been started on calcium, vitamin D, and denosumab. Although upset about her recent fracture she is optimistic and eager to learn and has many questions.

Importance of the problem


Over 200 million people worldwide suffer from osteoporosis.1 Fragility fractures, the consequence of osteoporosis, are responsible for increased morbidity, mortality, chronic pain, and increased healthcare utilization.2 These fractures account for 0.83% of the global burden of noncommunicable disease.3 In postmenopausal women, fragility fractures are more common than stroke, myocardial infarction, and breast cancer combined.4


In the year 2000, there were an estimated 9 million fragility fractures worldwide, of which, 1.6 million were hip fractures, 1.7 million were forearm fractures and 1.4 million were vertebral fractures.3 It is projected that there will be an increase to 2.6 million hip fractures by 2020, and 4.5 million vertebral fractures by 2050.5 The lifetime risk of any fragility fracture is 40–50% in women and 13–22% in men.6


Hip fractures are the most severe type of fragility fracture as they require hospital admission and are associated with significant morbidity and mortality.6 At one year post hip fracture, mortality (in part due to other co‐morbidities) ranges from 12–20%,6 with the majority of deaths occurring within the first few months after fracture. An excess risk of death may persist for at least 5 years afterwards.7 Globally, there are approximately 740 000 deaths per year due to hip fracture and resulting complications.8


The long‐term costs associated with hip fractures are devastating. Available data on the economic burden of osteoporosis shows that currently, the cost of osteoporosis is 37 billion EUR per year in the European Union, 19 billion USD per year in the United States and $2.3–$3.9 billion per year in Canada.9–11 Due to the significant burden fragility fractures put on patients, their families, and the economy it is important to find the optimal pharmacotherapy to improve bone mass and prevent further traumatic injuries.


Top three questions



  1. In postmenopausal women aged >50 who have sustained fragility fractures, how does the diagnosis of osteoporosis determine the risk for future fracture?
  2. In postmenopausal women with low BMD or prior fragility fractures, which pharmacological therapies, compared to no medications, best reduce the risk for future fractures?
  3. In patients with low BMD or who have sustained a fragility fracture, what is the appropriate duration of pharmacotherapy to avoid adverse side effects?

Question 1: In postmenopausal women aged >50 who have sustained fragility fractures, how does the diagnosis of osteoporosis determine the risk for future fracture?


Rationale


The presence of a fragility fracture is a major risk factor for osteoporosis and is an important indicator for osteoporosis diagnosis and treatment.12


Orthopedic surgeons are in an ideal position either individually or collaboratively with colleagues to initiate and provide osteoporosis care for patients with fragility fractures, as they are the first physicians to make contact with the patient following fracture. It is estimated that the annual number of hip fractures worldwide will increase to 4.5–6.3 million by 2050.3,13,14 Therefore, identifying those who are at risk for future fractures is an important step in the management and prevention of osteoporosis.


Clinical comment


The diagnosis of osteoporosis is determined by measuring a patient’s BMD – the average concentration of bone mineral (g) per unit of bone area (cm2). Bone mineral density is measured using DXA, the gold standard method of measurement.2 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.15


Findings


A systematic review of 35 studies that evaluated practice patterns related to osteoporosis management after fragility fracture found that recognition and treatment of osteoporosis in these patients remained inadequate,16 confirming the persistence of an earlier identified global osteoporosis care gap.17 In this review, a clinical diagnosis of osteoporosis was reported in less than 30% of patients in the majority of studies. Further, DXA scans were performed in less than 15% of patients in studies that reported on BMD testing.


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. While low BMD is a strong and independent risk factor for fracture,18,19 it is not the only risk factor for fracture. Indeed, most fractures occur in women with osteopenia (T‐score between −1.0 and −2.5 SD) and not osteoporosis.15 A reason for this observation is that BMD measures bone quantity and does not take into account bone quality. Bone quality represents characteristics of bone tissue other than BMD that contribute to the strength of a bone, such as geometry, microarchitecture, remodeling, mineralization, and damage accumulation.20 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.


The Fracture Risk Assessment Tool (FRAX®), can be used to compute the 10‐year probability of fractures in men and women based on clinical risk factors for fracture, with or without the measurement of femoral neck BMD.21 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.22 The FRAX® tool calculates the 10‐year probability of a major fragility fracture (clinical spine, hip, forearm, or proximal humerus) and hip fracture calibrated to the fracture and death hazard of several countries.23


Moreover, there is the Osteoporosis Canada 10‐year Fracture Risk Assessment Tool which was developed by Osteoporosis Canada using the Canadian 2010 Osteoporosis Guidelines2 and the Canadian Association of Radiologists and Osteoporosis Canada (CAROC) system (http://www.osteoporosis.ca/health-care-professionals/clinical-tools-and-resources/fracture-risk-tool/). The Canadian Association of Radiologists and Osteoporosis Canada tool was calibrated using the same fracture data as the FRAX Canada calculator.24–26 The CAROC tool can be used on men and women over the age of 50, and stratifies them into three groups for risk of major fragility fracture within the next 10 years, low (<10%), moderate (10–20%), and high (>20%). The CAROC tool integrates age, sex, T‐score at the femoral neck, prior fragility fractures, and recent prolonged systemic glucocorticoid use.2


Resolution of clinical scenario


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 post fracture.
  • The FRAX and CAROC tools can and should be used to calculate the 10‐year probability of a major fragility fracture (clinical spine, hip, forearm, or proximal humerus) and hip fracture.

Question 2: In postmenopausal women with low BMD or prior fragility fractures, which pharmacological therapies, compared to no medications, best reduce the risk for future fractures?


Rationale


A number of different pharmacologic agents are available for the treatment of osteoporosis.27 Opinion among orthopedic 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 fragility fracture.


In a systematic review of 35 studies evaluating osteoporosis management after fragility fracture, more than half of the studies reported that no more than 30% of fracture patients were taking calcium and vitamin D and less than 15% of patients were receiving bisphosphonate therapy.17 As the majority of pivotal clinical trials were in postmenopausal women, data in men are limited and will not be reviewed.


Clinical comment


Recommended daily calcium and vitamin D intakes for populations vary between countries. The US National Osteoporosis Foundation (NOF) recommends an intake of 1200–1500 mg of calcium and 800–1000 IU of vitamin D per day for men and women aged 50 years and older.28


Available literature and quality of the evidence


Current opinion suggests that orthopedic surgeons prescribe one of the recommended anti‐osteoporotic drugs for the treatment of fragility fractures in addition to calcium, vitamin D, and exercise. The majority of pharmacological agents available for the treatment of osteoporosis are antiresorptive agents which include: bisphosphonates (oral or intravenous [IV]), hormone replacement therapy, raloxifene, denosumab, and to a lesser extent strontium ranelate. Other available anabolic agents are parathyroid hormone (PTH 1‐84), teriparatide (rh‐PTH 1‐34), and abaloparatide (PTHrP). A summary of the efficacy of pharmacologic agents on the relative risk reduction of hip fractures is presented in Table 7.1. As the majority of pivotal clinical trials were in postmenopausal women, data in men are limited. Several studies have examined the use of alendronate and risedronate for the treatment of osteoporosis in men.29–31 These medications have been shown to improve BMD and reduce the risk of vertebral fracture. However, given the limited number of studies, clinicians should refer men with osteoporotic fractures to a bone specialist for further recommendations and management.


Table 7.1 Efficacy of pharmacologic agents on the relative risk reduction of hip fractures in postmenopausal women.















































































Drug Description of Clinical Trial % Relative Risk Reduction for Hip Fracture
Oral bisphosphonates
Alendronate32–34 FIT‐1; n = 2027; postmenopausal women with low femoral neck BMD and ≥ vertebral fracture; alendronate 5 mg/d (then increased to 10 mg/d at 24 months) or placebo; 3 yr 51%

FIT‐2; n = 4432; postmenopausal women with low femoral neck BMD but no vertebral fracture; alendronate 5 mg/d (then increased to 10 mg/d at 24 mo) or placebo; 4 yr NS

FLEX; n = 1099; postmenopausal women from FIT‐1 and FIT‐2 trials; alendronate 5 mg/d or alendronate 10 mg/d or placebo; 5 yr NR
Risedronate35–38 VERT‐NA; n = 2458; postmenopausal women with ≥2 vertebral fractures or 1 vertebral fracture and low lumbar spine BMD; risedronate 2.5 mg/d (discontinued partway through trial) or risedronate 5 mg/d or placebo; 3 yr NR

VERT‐MN; n = 1226; postmenopausal women with ≥2 vertebral fractures; risedronate 2.5 mg/d (discontinued partway through trial) or risedronate 5 mg/d or placebo; 3 yr NR

VERT‐MN Extension; n = 265; risedronate 5 mg/d or placebo; 2 yr NR

HIP; n = 9331; postmenopausal women with osteoporosis at femoral neck and/or with ≥1 non‐skeletal risk factor for hip fracture; risedronate 2 mg/d or risedronate 5 mg/d or placebo; 3 yr 30%

BONE; n = 2946; postmenopausal women with 1 to 4 vertebral fractures and osteoporosis in ≥1 vertebra; ibandronate 2.5 mg/d or ibandronate 20 mg every other day for 12 doses every 3 mo or placebo; 3 yr NR
Intravenous bisphosphonates
Ibandronate39,40 DIVA; n = 1395; postmenopausal women with osteoporosis; 2 mg ibandronate injections every 2 mo plus oral placebo or 3 mg ibandronate injections every 3 mo plus oral placebo or 1 of 2 groups receiving oral ibandronate 2.5 mg/d plus placebo injections every 2 or every 3 mo; 1 yr NR
Zoledronic acid41,42 HORIZON – Pivotal Fracture Trial; n = 7765; postmenopausal women with osteoporosis at femoral neck with or without vertebral fracture or osteopenia with radiologic evidence of ≥2 mild vertebral fractures or 1 moderate vertebral fracture; single 5 mg infusion of zoledronic acid every 12 mo or placebo; 3 yr 41%

HORIZON – Recurrent Fracture Trial; n = 2127 men and women ≥50 yr who had undergone recent surgical repair of a low trauma hip fracture; single 5 mg infusion of zoledronic acid every year; 2 yr 30%
Other
Raloxifene43 MORE; n = 7705; postmenopausal women with osteoporosis; raloxifene 60 mg/d or raloxifene 120 mg/d or placebo; 3 yr NS
Denosumab44 FREEDOM; n = 7868; postmenopausal women with osteoporosis; denosumab 60 mg subcutaneously every 6 mo or placebo, 3 yr 40%
Calcitonin45 PROOF; n = 1255; postmenopausal women with osteoporosis; calcitonin 100 IU/d or calcitonin 200 IU/d or calcitonin 400 IU/d or placebo; 5 yr NS
Anabolic agents
Teriparatide (rh‐PTH 1‐34)46 n = 1637; postmenopausal women with prior vertebral fractures; PTH (1‐34) 20 μg/d or PTH (1‐34) 40 μg/d of or placebo; 1.8 yr NR
Parathyroid hormone [PTH (1‐84)]47 TOP; n = 2679; postmenopausal women with low BMD at hip or spine; recombinant human PTH (1‐84) 100 μg/d or placebo; 1.5 yr
Antiresorptive/Anabolic agents
Strontium ranelate48 TROPOS; n = 5091; postmenopausal women with osteoporosis; strontium ranelate 2 g/d or placebo; 3 y NS

BMD, bone mineral density; BONE, Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe; DIVA, Dosing Intravenous Administration Trial; FIT, Fracture Intervention Trial; FLEX, Fracture Intervention Trial Long‐Term Extension; FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; HIP, Hip Intervention Program Trial; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly; IU, international units; MN, multinational; MORE, Multiple Outcomes of Raloxifene Evaluation; n, total number of participants randomized; NA, North America; NR (separate hip data) no reported; NS, not statistically significant; PROOF, Prevent Recurrence of Osteoporotic Fractures Study; PTH, parathyroid hormone; TOP, Treatment of Osteoporosis Study; TROPOS, Treatment of Peripheral Osteoporosis Study; VERT, Vertebral Efficacy with Risedronate Therapy.


d, day; mo, month; yr, year.


Findings


Calcium and vitamin D


There is no clear evidence that calcium in combination with vitamin D reduces the risk of fragility fractures,49 but we do know that vitamin D on its own has no fracture risk benefit.50–53 That being said, there is strong evidence that calcium and vitamin D together are beneficial in patients with osteoporosis, especially postmenopausal women.51,52 The most severe adverse effect from taking calcium is the potential increased risk of cardiovascular events. At this time, there is no clear evidence to suggest that taking calcium with or without vitamin D increases one’s risk of cardiovascular events.54,55


Exercise


The mean BMD at the lumbar spine (1.77% [1.26–2.28%]) significantly increased after 18 months in the exercise group (p <0.001). There was also significant differences in BMD at both locations between the exercise and control groups (p <0.001).56 Tai chi has been investigated as well and has shown less BMD loss at the hip compared to controls (p <0.05) but did not show an overall increase in BMD.57 The most inclusive meta‐analysis of randomized control trials on the effect of resistance training 2–4 days/week for 15–90 minutes in postmenopausal women demonstrated a weighted mean difference in BMD of 0.012 g/cm2 (95% CI 0.002–0.022) at the lumbar spine and 0.014 g/cm2 (95% CI 0.003–0.025) at the femoral neck (p <0.001).58


Bisphosphonates


A recent review article 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.59 In the review, a total of 11 randomized placebo‐controlled trials were identified (three for alendronate, 32–34 four for risedronate,35–38 two for ibandronate,39,40 and two for zoledronic acid41,42). 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 by 20–51%, vertebral fractures by 41–70%, and nonvertebral fractures by 12–40% in postmenopausal women with low BMD and/or prior vertebral fracture.


The most common side effects from oral bisphosphonates are nausea, epigastric pain, esophagitis, and gastric ulcers.60 The most common adverse effects when taking zoledronic acid include pyrexia, myalgia, flu‐like symptoms, bone pain, and chills, which can be classified as acute phase response.61 This usually occurs after the first infusion, resolves in 3–4 days, and is less common with subsequent infusions.62 Acute anterior uveitis is associated with zoledronic acid therapy, usually occurs within three days of infusion, resolves with topical cyclopentolate, and has no lasting sequelae.63 The more severe adverse events include osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) has recently published a revised case definition for AFF as a fracture located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. Further criteria are provided in the ASBMR Task Force 2013 Revised Case Definition of AFFs.64 A systematic review and meta‐analysis of 11 studies, including five case controls and six cohorts, showed bisphosphonate use was associated with increased risk of subtrochanteric femoral shaft fractures (adjusted risk ratio [RR] = 1.70; 95% CI 1.22–2.37).65 The report concluded that, while the relative risk of patients with AFFs taking bisphosphonates is high, the absolute risk of AFFs in patients on bisphosphonates is low, ranging from 3.2 to 50 cases per 100 000 person years. However, long‐term use may be associated with higher risk (∼100 per 100 000 person years).64 They also published recommendations for orthopedic and medical management of AFFs (Table 7.2).64,66


Table 7.2 ASBMR Task Force on Atypical Femoral Fracture recommendations for orthopedic and medical management of atypical femoral fractures. Source: Modified from Shane, et al.64









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May 14, 2023 | Posted by in Uncategorized | Comments Off on Critical Issues in Osteoporosis Management

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