Osteoporosis: underrated, underdiagnosed and undertreated

Osteoporosis, one of the more common diseases in ageing populations, is a major public health problem because of its age-associated exponential increase in prevalence, and its serious consequences in terms of mortality, morbidity and economic costs. Osteoporotic fractures, commonly of the hip, spine, humerus, forearm and wrist, are typically sustained with little or no antecedent trauma. Vertebral fractures, which can vary from mild wedge compressions to complete crush fractures, are clinically silent in two-thirds of women. However, they are associated with considerable morbidity, increased risk of mortality, and indicate a greatly increased risk of further fractures, including hip fractures. The combined lifetime risk for hip, forearm and vertebral fractures coming to clinical attention is around 40%, equivalent to the risk for cardiovascular disease.1 In white women, the lifetime risk of hip fracture, the most serious consequence of osteoporosis, is 1 in 6, compared with a 1-in-9 risk of a diagnosis of breast cancer.2 In Australia alone, direct costs attributable to osteoporotic fractures were estimated at $700 million in 1994.3 More recent estimates, taking into account all types of fractures and all types of costs, both direct and indirect, have been estimated at about $7 billion annually.4 Death is relatively common in the months immediately after a hip fracture.5,6 Moreover, all major osteoporotic fractures are associated with a twofold increase in age-adjusted mortality in women and a threefold increase in men.6 Hip fracture survivors have an increased risk of dependence, with 50% requiring help with daily living activities and 15%–25% entering long-term care.7,8

Fracture risk is a function of trauma sustained (eg, in falls) and bone strength (which depends on both the quantity of bone and its architecture). Bone mass, assessed by bone mineral density (BMD), is a good predictor of fracture risk, with each standard deviation (SD) decrease in BMD being associated with at least a twofold increase in the risk of fracture.8-10 The relationship between BMD and fracture applies throughout the skeleton, with some site specificity (ie, hip fracture risk is more related to BMD measurements at the hip than at the lumbar spine or forearm). The strength of the relationship between fracture risk and BMD is stronger than that between stroke and blood pressure or between cholesterol level and myocardial infarct. Although low-trauma fracture is the hallmark of osteoporosis, it is usually classified in terms of BMD values. In 1994, an expert panel of the World Health Organization (WHO) proposed that osteoporosis be defined by BMD values relative to those of young adult females, with those more than 2.5 SDs below being classed as osteoporosis, and those between 1 and 2.5 SDs below being classified as osteopenia.11 By these criteria, in Australia, about 11% of men and 27% of women aged 60 or more years are osteoporotic, and another 42% of men and 51% of women are osteopenic.12 Of course, BMD is a continuous variable and the lower the BMD, the greater the relative risk of fracture. Absolute risk of fracture depends on BMD, bone shape and other poorly defined characteristics of bone “quality”, and the likelihood of trauma. Quantitative ultrasound measurements, such as broadband ultrasound attenuation (BUA) and speed of sound (SOS), have been shown to identify some people at increased risk of fracture in both cross-sectional and longitudinal studies.13-16 However, these people are not the same as those identified by BMD measurement, and they have not been shown to benefit in interventional clinical trials of fracture risk.

Common risk factors for osteoporosis include familial predisposition, lifestyle, hormonal, medications and illnesses and falls (see Box 1). Inherited factors play an important role in osteoporosis risk. In studies of twins, 70%–80% of differences in BMD (measured at the lumbar spine and femoral neck) between individuals is attributable to genetic factors.17-19 Various studies have found significant inherited components of fracture risk (eg, 25% of liability for Colles’ fracture, a twofold hip fracture risk with a maternal hip fracture, a threefold risk of hip and other fractures with a paternal wrist fracture).20,21 Certain key genes have been reported as contributors to this inherited risk, with variants of each being associated with a doubled risk of osteoporotic fracture (eg, the vitamin D receptor, collagen Ia1, the Wnt-Frizzled pathway, and bone morphogenetic protein 2).

Hormonal and reproductive factors influence osteoporosis risk, as do medications and certain underlying diseases. Oestrogen deficiency, from natural or surgically induced menopause, or resulting from excessive exercise or undernutrition, accelerates bone loss. Women with late menarche and/or early menopause, and thus a shorter exposure to normal reproductive hormones, may be at increased risk.22-25 Many of these factors are not amenable to intervention; hormone replacement therapy is the exception, but its use has decreased greatly following recent studies relating oestrogen use to (modestly) increased risk of breast cancer and cardiovascular and cerebrovascular outcomes.

People with a history of prior fracture are at significantly increased risk of subsequent fracture. For instance, women with pre-existing vertebral fractures have a risk of subsequent vertebral fractures about 4 times greater than those without prior fractures, and the risk increases with the number of prior vertebral fractures.26

Nutrition and lifestyle also affect the skeleton, although this may be more relevant at the extremes of variables such as nutrition and exercise than within normal ranges. Thinness is an important risk factor for low BMD. Indeed, of all anthropometric factors, body weight is the strongest predictor of BMD. The positive relationship between increased weight and increased BMD may be partly attributable to increased mechanical forces on the bone,27 but neural control factors may also play a part.28 An adequate dietary calcium intake and a physically active lifestyle in later decades of life could translate into a reduction in the risk of osteoporosis. For example, women in the top third for both quadriceps muscle strength and dietary calcium intake had 15% higher BMD than those in the lowest third. Among people in the lowest third for body mass index (< 23–24 kg/m2), quadriceps strength and dietary calcium intake (< 465 mg/day), about two-thirds of women and almost half of men had osteoporosis by WHO BMD criteria.29

Smoking is associated with lower BMD and increased fracture risk in postmenopausal women30-32 and in men.31 However, a positive effect in bone, as assessed by BMD, is associated with modest alcohol intake (ie, about 3–4 units per week in premenopausal and postmenopausal women31,33). Some medications may modify osteoporosis risk, including, particularly, excessive thyroxine replacement therapy and oral glucocorticoid use; the latter has been associated with increased risk of spine and forearm fractures.34

Change in BMD is the result of the bone remodelling process (or bone turnover), in which microscopic amounts of bone tissue are removed (bone resorption) and then replaced with new tissue (bone formation).35 In adulthood, with an increased rate of bone turnover, the rate of bone resorption is greater than the rate of bone formation, resulting in net bone loss both in trabecular and cortical bone. At present, most pharmacological therapies for treating osteoporosis aim to inhibit this excessive bone resorption.36 These agents (see Box 2), which include bisphosphonates and raloxifene, as well as oestrogen replacement therapy, reduce the rate of bone turnover (particularly bone resorption), reduce bone loss and increase BMD measurements. In randomised studies of varying quality, these agents have been shown to reduce fracture risk. In postmenopausal women with low BMD who have or have not had previous vertebral fracture, hormone replacement therapy (HRT),37-39 raloxifene,40-42 and bisphosphonates such as alendronate43-45 and risedronate46,47 have each been shown to increase BMD and reduce fracture risk by between 30% and 60%. Parathyroid hormone (PTH [1-34]), which stimulates bone formation, has also been shown to increase BMD, improve bone structure, and decrease the risk of vertebral and non-vertebral fractures.48 The efficacy of combination therapies has also been investigated,49,50 but data are scarce and study sizes too small to determine whether fracture risk would be significantly reduced compared with monotherapy.

Vitamin D3 and calcium have been shown in some (but not all) randomised clinical trials to reduce hip fractures by 43% and other non-vertebral fractures by 32% in ambulatory women living in nursing homes, and to reduce non-vertebral fractures in men and women aged 65 years or older living in the community.51-53 Vitamin D treatment is logical in institutionalised or housebound elderly people, in whom vitamin D deficiency is common. Hip protectors have been reported to reduce hip fractures in some, but not all, clinical trials.54,55 Also, compliance with wearing hip protectors can be a problem, primarily because of discomfort.

It is generally agreed that individuals with low BMD, and particularly those with a history of fracture (with osteoporosis or osteopenia), should be considered for treatment. However, recent studies have shown that these high-risk individuals are not being diagnosed or treated. Among hospitalised women aged 60 or older with spine radiographs showing severe vertebral deformities, only 17% had mention of the fracture in their medical records or discharge summary.56 A study of women aged 55 years or more with wrist fractures in a managed-care setting reported that 23% had been started on some form of osteoporosis-specific therapy, and less than 3% had had a BMD scan.57 The situation for hip fracture is more disturbing. In a study of 502 hospitalised hip-fracture patients, only 14% had BMD scans, 13% received calcium and/or vitamin D, and only 18% received HRT, calcitonin, or bisphosphonates.58 Other studies have reported that only 5% of patients with recent hip fractures left the hospital with a new medication prescribed for reducing the risk of subsequent fractures.59,60 In Australia, the situation is no better. In a recent survey of more than 88 000 women attending 927 primary care physicians, of those who reported a fracture postmenopause less than 20% were on any specific antiosteoporotic therapy (personal data). Thus, despite both the magnitude of the problem and the introduction of osteoporosis treatment guidelines, most high-risk individuals (possibly 80%) are still not identified, and thus not treated. It may be reasonable to infer that many otherwise preventable fractures are occurring daily in Australia, as well as around the world.