Osteoporosis is a progressive disorder of bone, defined as a condition resulting in an increased risk of skeletal fractures due to a reduction in bone mass and deterioration of skeletal microstruture.27 It is characterized by low bone mass, microstructural deterioration, and porous bone, which collectively are associated with higher fracture risk.4 Although osteoporosis has a higher overall prevalence in women, it is also a concern in men. Beyond aging and the menopause, there are other well-defined conditions that lead to bone loss (see discussions in section 3).28
The National Osteoporosis Foundation reported an overall 10.3% prevalence of osteoporosis in American adults aged 50 years or older, based on bone mineral density (BMD) at the femoral neck and lumbar spine.29 In 2010, this translated to 10.2 million individuals. An additional 43.4 million Americans (prevalence 43.9%) in the same age group were estimated to have low bone mass (osteopenia).29 Altogether, osteoporosis is thought to cause an estimated 2 million fractures each year in the US.
In 2013, it was reported that osteoporosis affects 8 million US women.30 As osteoporosis can manifest as fractures occurring at multiple skeletal sites, the incidence of fractures is a barometer of overall prevalence. Table 6 shows the rate of incident fractures among US men and women. Overall, the lifetime risk of wrist, hip, or vertebral fracture was estimated to be 30-40% in developed countries, nearly the same risk as that for coronary heart disease.1
|≥ 85 years||338,788||100,222|
Source: Burge et al. 20074
Data from NHANES III suggest that more than half of Americans age ≥ 50 years have osteoporosis or low bone mass at the femur neck or lumbar spine (Table 7).
|Low bone mass (osteopenia)||49%|
Source: Looker et al. 19973
As mentioned above, about 75-80% of Americans with osteoporosis are women,% an association with reduced fractures and increased BMD, and recommended assessing patients with T-scores > -2.5 at the end of treatment for possible drug discontinuation with continued monitoring.58 A retrospective analysis of a US claims database that included 57,913 postmenopausal women age ≥ 55 years who filled one or more pharmacy claims for a bisphosphonate or non-bisphosphonate (e.g., raloxifene, calcitonin, or teriparatide) found that only 23,430 (40.5%) subjects were compliant. Noncompliant participants had a 20% greater risk of fracture and 13% higher medical costs.59 These results confirm and expand findings from an earlier and similar study in Canada that reported a 16% lower osteoporosis-related fracture rate among medication-compliant women age >50 years.6020and most are postmenopausal.31 At age 50 years, the lifetime risk of developing osteoporosis-related fractures is about 40% for Caucasian women and 13% for Caucasian men.32 By age 60 years, approximately 50% of US women have osteopenia (low bone mass) or osteoporosis.3 In addition, it is estimated that more than 20% of postmenopausal women exhibit prevalent vertebral fractures.33 Table 8 summarizes the prevalence of low BMD at the femoral neck in postmenopausal US women by race/ethnicity.
Source: Looker et al. 19973
Estimates suggest that by 2025 the incidence of osteoporosis will rise by 50%, and over 87% of this increase will occur among those age 65-74 years.4 Other researchers have highlighted the negative outcomes associated with recurrent fractures and observed that first and repeat fractures increased by 60-70% per decade of age in a study population age 50-90 years; in this group, repeat fractures were more common among patients with low BMD.34
Data presented in Table 2 suggest that increasing age is a risk factor for the increased cost of osteoporosis. In addition, Table 7, which includes data about age, race, and incidences of osteoporosis, suggests that the total number of fractures alone is not directly correlated with costs.
Table 9 shows the cost burden of osteoporosis by race/ethnicity in 5-year increments from 2005-2025. In this time period, costs are expected to rise 175% among Hispanic and other race/ethnic groups, 79% among African-Americans, and 37% among Caucasians.4
Source: Burge et al. 20074
Fracture is the most significant clinical manifestation of osteoporosis. While fractures may occur in any bone, they tend to occur at sites of low BMD.2 Hip fractures are the most serious complication of osteoporosis, with almost 50% of patients requiring assistance with activities of daily living such as walking 1 year after occurrence.35 Table 10 summarizes data on 1-year mortality rates associated with osteoporotic hip and vertebral fractures.
|Fracture||Data Source||Population||1-Year Mortality||Reference|
|Hip fracture||Population-based, prospective, matched-pair cohort study (1986-1995), US||Adults age ≥ 50 years||> 31%||17%||Forsen et al. 199936|
|Vertebral fracture||Health Insurance Review Assessment Service (2005-2009), Korea||Adults age ≥ 50 years||14.6%||7.16%||Lee et al. 2012 37|
Abbreviations: US, United States
Among Thai men age ≥ 50 years who sustained a hip fracture following a simple fall, 1-year mortality was 21.1%, approximately 9.3 times the expected mortality rate for this age group. Delayed treatment or the absence of treatment for osteoporosis correlated with higher mortality.38 A similar study of Thai adults age ≥ 50 years, who sustained a hip fracture following a simple fall, reported a 1-year mortality rate of 31% in men, and 16% among women. This study reported that greater mortality was associated with men, age ≥ 70 years, and non-operative treatment.39
Due in part to their greater BMD as compared to Caucasian American women, African American women have about half the rate of hip and vertebral fractures. Even so, mortality following hip fracture is greater among African American women than their Caucasian counterparts, possibly because the former tend to be older at the time of fracture, to have more comorbidities, or to face greater disparities in care. While Caucasian women are about twice as likely to experience hip fractures compared to Caucasian men.40
While osteoporotic fractures are usually precipitated by a fall, they may also occur during routine daily activities. In addition, incident non-traumatic fractures at typical osteoporotic sites (i.e. hip, vertebral, and upper arm fractures) are associated with increased mortality.41 Table 11 presents data on mortality rates in men and women who experienced incident fractures in osteoporotic sites including hip, vertebrae, wrist, and humerus.
|Data Source||Population||Type Of Fracture||Post-Fracture Mortality Rate||Reference|
|Healthcare databases for the Province of Manitoba (1986 -2007; 15-year follow-up), Canada||Adults age ≥ 50 years||Hip, vertebral, humerus, wrist, among others *||50.1%||44.8%||Morin et al. 201041|
|Multicenter osteoporosis study (1995-1997; 5-year follow-up), Canada||Adults age ≥ 50 years||Hip||23.5%||23.5%||Loannidis et al. 200942|
|Forearm or wrist||11.5%||8.1%|
Note: *, 66% of fractures were located at sites other than hip and vertebrae
A 34-year prospective observational study assessing the correlation of early menopause and risk of osteoporosis reported that women who underwent menopause before age 47 years had a greater risk of osteoporosis (RR 1.83, 95% CI 1.22-2.74), fragility fracture (RR 1.68, 95% CI 1.05–2.57), and mortality (RR 1.59, 95% CI 1.04-2.36), by age 77 years.43
Measuring BMD is the primary technique for diagnosing and monitoring osteoporosis for postmenopausal women and men age ≥ 50 years.7 Table 12 shows the WHO operational criteria for classifying osteoporosis based on BMD, expressed as a T-score. In brief, the T-score compares a subject’s BMD with the mean value for young normal adult subjects and expresses the difference as a standard deviation.
|Normal||0 to -0.99|
|Osteopenia (low bone density)||-1.0 to -2.49|
|Severe or established osteoporosis||< -2.5 with fracture|
Source: World Health Organization. 19941
Some authors have objected to overreliance on T-scores and have pointed out that factors such as family history, laboratory results, genetic influences, or the presence of fragility fractures should be considered along with T-scores.44,45 It has been suggested that additional data be considered when physicians evaluate T-scores.46 For example, the WHO fracture risk assessment tool (FRAX) incorporates dual-energy x-ray absorptiometry (DXA) as well as seven independent risk factors for the assessment of fracture risk in subjects with osteopenia.7,47
As per the Bone Mass Measurement Act of 1998, all US women age >65 years, and men age >70 years are expected to undergo BMD testing. In addition, the 2013 Position Development Conference of the International Society for Clinical Densitometry recommended bone density tests in the presence of risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or diseases or conditions associated with bone loss for both postmenopausal women age <65 years and men age < 70 years.48
Systematic reviews published in 2012 and 2014 addressed the effects of long-term hormone therapy for perimenopausal and postmenopausal women and the effects of steroidal contraceptives on bone fractures in women.49,50 The first review acknowledged that hormone therapy can be effective in preventing postmenopausal osteoporosis, but also noted that the treatment is recommended only for women who are at elevated risk for osteoporosis and have no contraindications, and when non-estrogen therapies are not suitable. The second review examined 19 randomized controlled trials that evaluated the effectiveness of various steroidal contraceptives and noted that none had fracture as an outcome. Reviewers concluded that, based on existing information in 2014, they could not determine if steroidal contraceptives influence fracture risk.
The US Food and Drug Administration (FDA) drugs approved for the treatment of osteoporosis include: calcitonin; bisphosphonates (alendronate, alendronate with cholecalciferol [vitamin D3], ibandronate, risedronate, and zoledronic acid); raloxifene, an estrogen agonist/antagonist; conjugated estrogens/bazedoxifene, a tissue-selective estrogen complex; teriparatide, the 1-34 fragment of parathyroid hormone; and denosumab, an antibody directed against receptor activator of nuclear factor κB ligand (RANKL).51
A review published in 2009 discussed emerging treatments, including agents that show antiresorptive effects and anabolic effects and an agent that may combine both mechanisms of action.52 Other authors have reviewed emerging biologic agents that may help stimulate new bone formation.53
Table 13 summarizes the main currently available pharmacotherapies for treating osteoporosis in the US, along with their benefits and some potential associated adverse effects.54
|Bisphosphonates||Decreased vertebral, non-vertebral, and hip fractures||GI symptoms with oral bisphosphonates; acute-phase reactions with IV bisphosphonates|
|Raloxifene||Decreased vertebral fractures||Increased risk of VTE and mortality|
|Teriparatide||Decreased vertebral and non-vertebral fractures||Injection site reactions, nausea, dizziness|
|Denosumab||Decreased vertebral, non-vertebral, and hip fractures||Eczema, increased risk of cellulitis (in phase 3 clinical trial)|
|Hormone therapy||Decreased vertebral, non-vertebral, and hip fractures||Increased risk of VTE, breast cancer, and CV disease in women > 10 years after menopause|
Even though older men are twice as likely as women to die after hip fracture,55 osteoporosis is usually considered a “woman’s disease” due to higher overall prevalence in women.56 Due to its higher prevalence, pharmaceutical companies target new drug candidates for the primary prevention of fractures almost exclusively for registration purposes in postmenopausal women.56 Accordingly, there is more evidence on the effects of osteoporosis medications in women than in men.
An Australian study of 1,223 women and 819 men aged ≥ 60 years who were treated with bisphosphonates, hormone therapy (women only), and calcium with or without vitamin D found reduced mortality among women and men who received bisphosphonates.57 A systematic review on the use of bisphosphonates beyond 3 years showed