In 1991, osteoporosis was defined as a metabolic bone disease characterised by ‘low bone mass, microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk’.¹ However, the current conception of osteoporosis is as a disease of compromised bone strength that predisposes an individual to an increased risk of fracture.² In this new definition, osteoporosis is a dynamic, rather than an anatomical, condition. The disease is thus low bone mass and deteriorated bone quality, and fracture is the clinical consequence of the disease.

The ‘bone strength’ component of the definition refers to the integration of bone mass and bone quality. ‘Bone quality’ primarily refers to bone architecture, metabolic turnover, damage accumulation (e.g. microfractures) and demineralisation. At present, the most clinically relevant indicator of bone quality is a history of personal fracture. The current definition of osteoporosis represents it as both a disease and a risk factor, and this has important implications for the pathogenesis, prevention and treatment of the disease.

Osteoporosis is highly prevalent in the general population. Using the operational definition of osteoporosis (based on measurement of bone mineral density (BMD)), the prevalence of osteoporosis in Australian men and women aged 60 years and above was estimated to be 11% and 27% respectively.³ As expected, the prevalence of osteoporosis increases with advancing age, from approximately 5% (men) and 13% (women) at 60 years of age to over 28% (men) and 63% (women) at age 80 or above.⁴ With a rapidly ageing population, it is expected that osteoporosis will be an even greater problem in the next 20 years or so.

The outcome of osteoporosis is fragility fracture. Fractures are a major public health problem because of their high incidence rate in the population, and because individuals with fracture are at increased risk of mortality and morbidity and reduced quality of life, and incur significant healthcare costs. In several population-based epidemiological studies, all major fractures were associated with increased mortality, especially in men.⁵ Even in healthy older women, clinical vertebral fractures, commonly manifested as asymptomatic fracture, and hip fractures, are substantially associated with increased mortality.^6,⁷ A more recent study demonstrated that asymptomatic vertebral deformity is a major risk factor for subsequent fracture and mortality.⁸

The increase in fracture cases will result in a significant increase in healthcare costs. The annual cost of treatment of fractures and associated sequelae has been estimated at $10–20 billion in the United States and £3 billion in England and Wales. Within the next 50 years the cost of hip fracture alone in the United States may exceed $240 billion.⁹ In Canada, the annual cost of hip fracture is estimated at $650 million and is expected to rise to $2.4 billion by 2041.¹⁰ In Australia, the direct and indirect costs of fracture have been estimated at $7.5 billion.¹¹

EPIDEMIOLOGY OF FRACTURES

Theoretically, any fracture related to low bone density may be considered an osteoporotic fracture. Fractures of the spine (vertebrae), hip and wrist (distal forearm) have long been regarded as typical osteoporotic fractures.¹²^–¹⁶ Most types of fracture occur more often in patients with low BMD,^17,¹⁸ and therefore most types of age-related fractures are osteoporotic in nature. According to this definition, the following fracture types are considered osteoporotic:

• in women—vertebrae, hip and other femoral, wrist–forearm, humeral, rib, pelvic, clavicle, scapula, sternum, tibia and fibula

In both women and men, fractures occurring at the skull and face, hands and fingers, feet and toes, ankle and patella are classified as not due to osteoporosis.¹⁹

Because fragility or osteoporotic fracture is defined as fracture-related with minimal trauma (i.e. a fall from standing height or less),^20,²¹ in the research setting, fractures clearly due to major trauma (such as motor vehicle accidents) or due to underlying diseases (such as cancer or bone-related diseases) were excluded from analysis.^5,^16,^18,²²^–²⁶

Overall, the incidence of any fracture in women and men increases with advancing age, and is greater in women than in men. The incidence of fracture also varies according to geographic variations between and within countries. Fracture rates in women aged 60 or older are six times higher than those in women aged 35–59 years; in men aged 60 or older the rate is 1.4-fold greater than in men less than 60 years of age.²⁷

Overall fracture rates are greater in urban than in rural areas.^28,²⁹ The difference is more pronounced in those aged 60 years or over, suggesting that environmental factors have an impact on bone health.

The magnitude of osteoporosis-related fracture can be quantified by the lifetime risk of fracture. In developed countries it is estimated that the residual lifetime risk of any fracture for men and women from age 60 is approximately a quarter and just under a half respectively.¹⁶ For individuals with osteoporosis, the mortality-adjusted lifetime risk of any fracture is probably over 40% for men and 65% for women.³ The three most common sites are hip, vertebral and Colles’ fracture.

TYPES OF FRACTURE

Hip fracture

Hip fractures include femoral neck, intertrochanteric or subtrochanteric fractures. Hip fracture is the most serious consequence of osteoporosis because it incurs many subsequent complications, including pain and disability.³⁰

It is estimated that, from the age of 60 years, 11 out of 100 women will sustain a hip fracture during their remaining lifetime. This risk is higher than the risk of being diagnosed with breast cancer (around 10%). Approximately 17% of women and 30% of men who have sustained a fracture will die within 12 months after the event.³¹ However, the exact causes of death among these individuals are not clear. Among women who survive the fracture, over 20% require long-term care and over a third are unable to return to their prior work,³² and have a significantly reduced quality of life.³³

Vertebral fracture

Osteoporosis has sometimes been referred to as a ‘silent disease’ because individuals often do not have apparent symptoms and pain until a fracture occurs. Asymptomatic vertebral fracture can be considered a silent disease, because patients do not realise that they have a fracture and do not seek medical attention. Currently, there is no ‘gold standard’ for the identification of vertebral fracture ^34,³⁵; estimates of its overall prevalence and incidence rate in elderly women and men depends in part on the definition used.³⁶

Asymptomatic vertebral fracture can be detected by conventional radiology, but it is not an attractive means of large-scale screening, because of cost and radiation exposure. In a large-scale study,³⁷ vertebral fracture was present in 12% of women and men. As expected, the prevalence of vertebral fracture increases with age, more sharply in women.³⁸ The use of corticosteroid therapy doubles the risk.³⁹ Studies have found that about 33% of vertebral fractures or deformities are symptomatic⁴⁰ and that only 23% of vertebral deformities in women were diagnosed clinically.⁴¹ In other words, there are many ‘silent’ vertebral fractures that produce no obvious symptoms. Vertebral deformities, whether clinically recognised or not, are related to an increase in chronic back pain and disability,^42,⁴³ and to low health-related quality of life⁴⁴ and an increase in mortality.^8,⁴⁵

Distal forearm fracture

A fracture of the distal forearm is one that occurs through the distal third of the radius and/or ulna. It is frequently and typically seen in women.^46,⁴⁷ Although its consequence is less serious than that of a hip fracture, it is associated with significant pain and may be associated with severe and long-term complications.^48,⁴⁹ The incidence increases rapidly with advancing age in women (but less so with men), for up to 10 years following menopause, and tends to slow thereafter.⁵⁰

CLINICAL ASSESSMENT OF OSTEOPOROSIS

The clinical assessment of osteoporosis and fracture risk is based on assessment of:

• clinical risk factors, including the possibility of secondary causes of osteoporosis or bone loss

• bone strength.

Risk factors

Risk factors can be broadly classified into modifiable and non-modifiable risk factors (listed in Box 23.1). Of these, the four key risk factors are:

• advancing age

• personal history of a fragility fracture

• family history of fracture

• low BMD (or osteoporosis).

A prior fragility fracture substantially elevates an individual’s risk of future fracture.^5,^8,^51,⁵² The elevated risk is 1.5- to 9.5-fold depending on age at assessment, number of prior fractures and the site of the incident fracture. A pre-existing asymptomatic vertebral fracture increases the risk of a second vertebral fracture and non-vertebral fracture at least four-fold.⁸ A study of a placebo group showed that 20% of those who experienced a vertebral fracture during the period of observation had a second vertebral fracture within 1 year. Patients with a hip fracture are at increased risk of a second hip fracture. The risk of subsequent fracture among those with a prior fracture at any site is 2.2 times that of people without a prior fragility fracture.⁵² A family history of osteoporotic fracture is also a major risk factor for fracture.

Although most studies have focused on the index person’s mother or other female family members, the genetic influence on risk of osteoporosis is multifactorial, and one should not ignore a history of osteoporotic fracture in first- or second-degree male relatives. Therefore, other family members should be included during assessment of genetic contribution to osteoporosis risk.

Bone strength

At present there is no direct method for reliably measuring bone strength. However, BMD, measured by dual-energy X-ray absorptiometry (DXA), provides a benchmark for bone strength. BMD measurement could account for up to 70–75% of variance in bone strength.⁵³ BMD is often standardised by expressing it as a T-score, i.e. the number of standard deviations (SD) from the young normal mean, taken as aged between 20 and 30 years.

There is a strong, continuous and consistent relationship between BMD and fracture risk, such that each SD lowering in BMD is associated with a 1.6-fold increase in fracture risk in both men and women.⁵⁴ In Chinese women, the relative risk of fracture for each SD lowering in femoral neck BMD was two-fold.⁵⁵ There is evidence that the magnitude of association between BMD and hip fracture risk (with relative risk being 2.2⁵⁶ to 3.6⁵⁷) is equivalent to or even stronger than the association between serum cholesterol and cardiovascular disease. Measurement of BMD is therefore considered the gold standard for diagnosis of osteoporosis in elderly men and postmenopausal women.

An operational definition of osteoporosis, by which a postmenopausal woman is considered to have osteoporosis, is if her femoral neck BMD (which is more reliable than lumbar spine measurements) is decreased by at least 2.5 SD compared with the mean value in young adults.⁵⁸ The WHO classification also includes definitions of osteopenia and normal BMD (Table 23.1). The operational criteria of osteoporosis for women has also been adopted for men.⁵⁹ These classifications do not apply to children.

TABLE 23.1 WHO diagnostic categories for BMD in postmenopausal women

Category	Projected proportion of population^*
Normal	BMD not more than 1 SD below peak BMD in young adult mean (T-score > −1)
Osteopenia	BMD 1–2.5 SD below young adult mean (T-score −1 to −2.5)
Osteoporosis	BMD 2.5 SD or more below young adult mean (T-score at or below −2.5)
Established osteoporosis	BMD 2.5 SD or more below young adult mean, and the presence of one or more fragility fractures

* Urban, 2020 (%). SD: standard deviation. BMD: bone mineral density.

Source: Nolla et al. 2002⁶⁰

Who should have a BMD measurement?

Mass screening using DXA scanning is not recommended or feasible without some selection of the target population. One important and difficult question is how to decide which women should undergo BMD measurement and further evaluation based on the results of BMD scan. It is suggested that a case-finding strategy be adopted, to identify individuals ideally eligible for a BMD scan ⁶¹—that is:

• women aged > 65 years, or men aged > 70 years

• women aged < 65 years, or men aged < 70 years, with risk factors for fracture (as in Box 23.1).

In the absence of BMD measurement, a number of clinical prediction rules, including the Osteoporosis Self-assessment Tool for Asians (OSTA), have been developed,^62,⁶³ to identify ‘candidates’ for a BMD scan. Most of these scores, based only on age and body weight, are a simple prediction rule that can potentially be useful in identifying women at high risk of osteoporosis. These scoring systems^64,⁶⁵ can be useful in ruling out osteoporosis.

Quantitative ultrasonography (QUS) is a portable, less expensive, less time-consuming and radiation-free technology, although there is limited evidence of its clinical usefulness.

Bone turnover markers

Bone is a net result of two counteracting processes of bone resorption and bone formation, often referred to as bone remodelling.

• Bone remodelling is a normal, natural process that maintains skeletal strength, enables repair of microfractures and is essential for calcium homeostasis. During the remodelling process, osteoblasts produce a number of cytokines, peptides and growth factors that are released into the circulation. Their concentration thus reflects the rate of bone formation.

• Bone formation markers include serum osteocalcin, bone-specific alkaline phosphatase and procollagen I carboxyterminal propeptide (PICP).

• Most biochemical indices of bone resorption are related to collagen breakdown products such as hydroxyproline or the various collagen cross-links and telopeptides. Bone resorption markers include urinary hydroxyproline, urinary pyridinoline (PYR), urinary deoxypyridinoline (D-PYR) as well as collagen type I cross-linked N telopeptide (NTX) and collagen Type I cross-linked C telopeptide (CTX).

Bone turnover rate in postmenopausal women correlates negatively with BMD, and markers of bone resorption are associated with fracture risk.⁶⁶ A reduction in biochemical markers appears to be correlated with a decrease in vertebral fracture incidence⁶⁷ in some studies, but is not necessarily always predictive of response to therapies. Nevertheless, the predictive value of biomarkers in assessing an individual patient can be limited by their high variability within individuals.⁶⁸

Assessment of absolute fracture risk

At any given level of BMD, fracture risk varies widely in relation to the burden of other risk factors ⁵⁶ (some modifiable), such as:

• advancing age

• low dietary calcium intake

• low vitamin D levels and inadequate sunlight

• family history of fracture

• steroid use

• low BMI

• increased propensity to fall

• smoking

• chronic stress and poor mental health

• excessive alcohol ingestion.

Thus, for any one individual, the likelihood of fracture depends onavv a combination of risk factors. This means that two individuals, both with osteoporosis, can have different risks of fracture because they have different non-BMD risk profiles. Likewise, an osteoporotic individual can have the same risk of fracture as a non-osteoporotic individual. A logical and appropriate assessment of fracture risk for an individual should therefore take into account the individual’s risk profile, including BMD and a history of fracture. A multivariable-based nomogram such as the one developed by Nguyen and colleagues ^69,⁷⁰ and the WHO’s FRAX model⁷¹ can be used to estimate an individual’s absolute risk of fracture, and help select patients suitable for intervention.

The critical question of who should be treated can only be answered by a complete evaluation of an individual’s risk profile. Treatment is cost-effective if an individual’s 10-year risk of hip fracture is between 1.2% and 9.0%, depending on age.⁷² To facilitate the estimation of this threshold, a nomogram (Figure 23.1) is used to estimate the probability of fracture based on age, BMD and history of fractures and falls.

FIGURE 23.1 Nomogram for predicting 5-year and 10-year probability of hip fracture.⁶⁹ To use, mark the age of an individual on the ‘Age’ axis and take a vertical line up to the ‘Points’ axis. Repeat this process for each additional risk factor, then sum the points. Locate the final sum on the ‘Total points’ axis and take a vertical line down to the 5-year and 10-year risk lines to determine the individual’s probability of sustaining a hip fracture within these timeframes

TREATMENT

Nutrition and supplements

Nutrition

Preventive nutrition begins in early childhood. Adequate levels of calcium intake can maximise the positive effect of physical activity on bone health during the growth period of children. Adequate dietary magnesium and calcium intake throughout life is essential to bone health.

Higher dietary protein intake is associated with a lower rate of age-related bone loss,⁷³ and fruit and vegetable intake is positively associated with bone density in men and women.⁷⁴

Salt intake should be reduced.

Calcium and vitamin D

A combination of calcium and vitamin D reduces the incidence of hip and non-vertebral fractures.⁷⁵^–⁷⁷ Elderly women (aged 69+ years) taking calcium (1200 mg/day) and vitamin D (800 IU) for 18 months had their risk of hip fracture reduced by 43% and non-vertebral fracture by 32%, although in a recent meta-analysis it was shown that the use of calcium or calcium plus vitamin D reduced fracture risk by 12%.⁵⁵ In summary, calcium and vitamin D appear to be efficacious in reducing the risk of hip fracture and non-vertebral fractures. There is some evidence, however, that calcium supplements can lead to a moderately increased risk of myocardial infarction. Regular moderate sun exposure should also be remembered as a valuable way of maintaining adequate vitamin D levels. If vitamin D levels are very low (< 50 nmol/L²), a large loading dose of vitamin D of up to 50,000 IU per month until the level is at least > 75 nmol/L² and then a maintenance dose of 2000 IU daily with 3-monthly monitoring.⁷⁸ Some advocate a larger loading dose of 100,000 IU as being helpful in bringing up the levels more quickly, followed by a supplement of 1000–5000 IU daily, monitored at 3-monthly intervals until normal range is achieved. Then maintenance of 1000 IU daily if sun exposure has not increased.

Pharmacological

During the past two decades, several major advances in the treatment of osteoporosis have been made. There are now more therapeutic options available than at any time before. Anti-fracture therapies can be broadly divided into two groups: anti-resorptive and bone-forming (anabolic) agents. The former reduces bone turnover, while the latter increases bone formation. Both agents have been shown to reduce fracture risk for some, although not necessarily all, fragility fractures. It is difficult to assess the relative anti-fracture efficacy of the various therapies, as there have not been any head-to-head comparative trials.

Hormone therapy

Hormone therapy (HT) has been used in treating osteoporosis for some time, despite there having been no randomised controlled trial or large-scale prospective studies of the efficacy of HT in postmenopausal women with osteoporosis or a pre-existing fracture. The Women’s Health Initiatives (WHI) study found that HT reduced the risk of hip fracture by an average of 34%, vertebral fracture by 34% and all fractures by 24%.⁷⁹^–⁸¹ However, women on HT in the HERS study (designed to evaluate the effect of oestrogen plus progestin on the risk of coronary heart disease) found no significant reduction in hip fracture risk and any fracture.⁸⁰ Still, a recent meta-analysis of women who had been treated with HT for 12–120 months showed that HT could reduce non-vertebral fracture risk by 28% and vertebral fracture risk.⁸² Although these data collectively suggest that HT may reduce fracture risk with a modest efficacy, its anti-fracture benefit must be weighed against other adverse effects such as increased risk of breast cancer, thromboembolic disease and stroke.

Selective oestrogen receptor modulators

In postmenopausal women suffering from osteoporosis, raloxifene (at the dose of 60 mg/day) has been shown to significantly reduce the risk of vertebral fracture by as much as 50%.^83,⁸⁴ However, its effects on hip and non-vertebral fractures have not been consistent. Raloxifene could also reduce the risk of non-vertebral fractures in women with severe osteoporosis. The drug is mostly used in younger postmenopausal women who have bone loss predominantly at the spine, not the hip.

Calcitonin

Calcitonin (generally given as a nasal spray), due to its antiresorptive properties, has been used in the treatment of osteoporosis for many years, with significant beneficial effects in reducing bone loss and fracture risk, possibly up to 33% when combined with calcium (1000 mg/day) and vitamin D (400 IU per day).⁸⁵ Similar risk reduction was also observed in those with a pre-existing vertebral fracture.⁸⁵ A meta-analysis including four studies conducted between 1966 and 2000 found that calcitonin reduced vertebral fracture risk by 54%. However, its effect on non-vertebral fractures has not been shown. Calcitonin is also associated with pain relief in patients following acute osteoporotic vertebral fractures.

Bisphosphonates

Bisphosphonates are currently a mainstay of pharmacological therapy for the treatment of osteoporosis in both postmenopausal women and elderly men. Bisphosphonates inhibit bone resorption through their effects on osteoclasts, and other complex cellular mechanisms that are not well understood. Their potential benefits need to be weighed against the risk of side effects, including jaw necrosis in long-term use.

There are a number of agents in this class, and based on their mode of action they can be classified into two main groups: those that closely resemble pyrophosphate (clodronate and etidronate), and nitrogen-containing bisphosphonates (alendronate, risedronate and ibandronate). Currently, alendronate (Fosamax®), risedronate (Actonel®) and ibandronate (Boniva®) are FDA-approved for osteoporosis treatment.

• Alendronate—has been extensively studied in the treatment and prevention of fracture. In a three-year study of postmenopausal women ⁸⁶ it significantly reduced the incidence of new fractures, possibly by up to 47% over three years.⁸⁷ In this group of patients it also reduced the risk of hip fracture and wrist fracture. It is effective in the treatment of glucocorticoid-induced osteoporosis, increases BMD^88,⁸⁹ and decreases the incidence of vertebral fractures at 2 years (6.8% vs 0.7%) in glucocorticoid-treated men and women.⁸⁹ It also has beneficial effects in men.⁹⁰

• Risedronate—in women with osteoporosis, treatment with risedronate (5 mg/day) for 3 years reduced the incidence of vertebral fractures by 41–49% and non-vertebral fractures by 39–33%.⁹¹^–⁹³ Among those with a prior vertebral fracture, it reduced hip fracture by 60%, although no significant reduction of hip fracture may be seen in elderly women who were selected on the basis of clinical risk factors other than low BMD.

• Other bisphosphonates—etidronate is not FDA-approved for the prevention or treatment of osteoporosis, but it may reduce the risk of vertebral fracture by up to 37%.⁹⁴ Nevertheless, concerns about its efficacy and safety have limited its use. Ibandronate is FDA-approved for the prevention and treatment of postmenopausal osteoporosis at a dose of 2.5 mg/day, and may reduce vertebral fracture and increase BMD.⁹⁵

• Zoledronic acid is more potent than other bisphosphonates such as alendronate and risedronate, and has been approved by the FDA for the treatment of hypercalcaemia of malignancy, multiple myeloma, and bone metastases from solid tumours. It has been found to reduce the incidence of vertebral fractures by 70%, clinical vertebral fracture by 77%, and hip fracture by 41%.⁹⁶

Parathyroid hormone

Parathyroid hormone (PTH) is an anabolic agent ⁹⁷ and is FDA-approved for the treatment of postmenopausal osteoporosis. Although it has been found to reduce the incidence of fractures in men and women,⁹⁸ there is concern regarding osteosarcomas in long-term use. PTH also has a beneficial effect on bone health in men^99,¹⁰⁰ and in women with glucocorticoid-induced osteoporosis.^101,¹⁰²

Duration of treatment

The best duration of treatment is not known yet. Most randomised clinical trials followed patients for 3 years, with the longest study running for 7 years.¹⁰² Therefore, from the principle of evidence-based medicine, it seems that 3-year duration is the logical answer. However, stopping treatment could result in increased bone remodelling, bone loss, structural damage and increased fracture risk. It has been suggested that if treatment restores BMD to the normal range, it may be reasonable to consider stopping treatment and monitoring bone turnover markers and rates of bone loss.¹⁰⁸

Monitoring response to drug therapy

Testing may be recommended, to monitor a patient’s response to osteoporosis therapy. This may include measurement of BMD, or laboratory tests that indicate bone turnover (i.e. rate of new bone formation and breakdown). Testing is typically done before treatment begins, to get a baseline measurement. Laboratory testing may be repeated 3 months after treatment begins, while bone density testing may be repeated after 2 years.

Side effects of bisphosphonates

Most individuals who take bisphosphonates for prevention or treatment of osteoporosis do not have any serious side effects related to the medication. However, there has been concern about a risk from bisphosphonates in patients who require invasive dental work. A problem known as avascular necrosis or osteonecrosis of the jaw has rarely developed in a small number of people who used bisphosphonates in cancer therapy. The risk of this problem is small in patients who take bisphosphonates for osteoporosis prevention and treatment. However, there is a slightly higher risk of this problem when higher doses of bisphosphonates are given intravenously during cancer treatment. Bisphosphonates are not recommended for premenopausal women who could become pregnant, because of the unknown effects on a developing fetus.

Alternative or adjunct therapies

Vitamin K and ipriflavone (a synthetic phyto-oestrogen) are the only alternative therapies for which sufficient data on BMD and fracture outcomes are available for evaluation. Phyto-oestrogens are weak oestrogen-like chemicals produced by plants, which have been shown to have oestrogen agonist and antagonist properties. There are three major groups of naturally occurring phyto-oestrogens: isoflavones (found principally in soybeans and other legumes), lignans (found principally in flax seed, fruits and vegetables) and coumestans (found in bean sprouts and fodder crops). Ecological studies have shown that communities with a high phyto-oestrogen intake (such as Asians living in Asia) have lower rates of hip fracture than North Americans.¹⁰⁹ However, direct epidemiological and clinical evidence for a protective effect of natural phyto-oestrogens in humans is not yet conclusive. Although vitamin K may be efficacious in slowing bone loss in postmenopausal women with osteoporosis, it has not been shown to be superior to calcium and vitamin D. It is not efficacious in preventing bone loss associated with medication-induced ovarian failure.¹¹⁰ In summary, the data available to date suggest that vitamin K may be efficacious in the treatment of postmenopausal women with severe osteoporosis, but has not been shown to be superior to calcium and vitamin D.¹¹¹

DHEA

Low dehydroepiandrosterone (DHEA) levels have been associated with decreased bone mineral density ¹¹² and an increased risk of fracture. DHEA supplementation is indicated where there is demonstrated to be a low serum DHEA level. Dose begins at 10 mg orally per day, reviewed monthly. The aim is to achieve normal serum level. Excessive levels should be avoided because of potential for androgenic side effects.

OSTEOPOROSIS IN MEN

Because of its oestrogen-related mechanism, osteoporosis has been commonly perceived as a disease of postmenopausal women. However, emerging evidence in recent years suggests that this perception is an oversight, because men are also susceptible to osteoporosis. Indeed, approximately one-third of all fracture cases in the general population occur in men.¹¹³ Furthermore, the lifetime risk of fracture in men is 1 in 4.^3,¹¹⁴ Outcomes of fracture in men are often worse than in women. For instance, men who have sustained a fracture have an increased risk of mortality compared to women.⁵ Men are twice as likely as women to die in hospital after a hip fracture.¹¹⁵ However, most studies of osteoporosis have largely been conducted in women and, as a result, osteoporosis in men has not been well documented.

Men have, on average, higher BMD and lower rate of bone loss than women ^4,¹¹⁶ and they tend have a lower risk of fracture at a later age than women.¹¹⁷ Major risk factors for osteoporosis in men include:

• a history of atraumatic fracture

• osteopenia on radiograph

• glucocorticosteroid use > 5 mg/day

• hypogonadism

• hyperparathyroidism ^24,^118,¹¹⁹

• use of anticonvulsant drugs

• excessive alcohol consumption

• tobacco use

• rheumatoid or other inflammatory arthritis

• multiple myeloma or lymphoma

• family history of osteoporosis

• concomitant diseases (e.g. Cushing’s disease, chronic liver or kidney disease, pernicious anaemia, gastric resection)

• nutritional calcium, magnesium and/or vitamin D deficiency

Although reduced testosterone is a risk factor for fracture in men,⁷⁰ lower level of oestrogen is also a risk factor for low bone mass and fracture.¹²⁰^–¹²² Low BMD is a major risk factor for fracture;^18,^56,¹²³ therefore, evaluation of BMD by DEXA and radiograph can be used to make a diagnosis of osteoporosis in men. It has been estimated that approximately 10% of men aged 60 years or above have osteoporosis.⁴ Prognostic models that take into account various simple risk factors can be used to estimate the risk of fracture for a man.⁶⁹ In randomised controlled clinical trials, bisphosphonates^89,¹²⁴ (alendronate and risedronate) and PTH¹²⁵ (teriparatide, recombinant parathyhroid hormone) have been shown to be effective in reducing fracture risk in men. Calcium and vitamin D supplementation can also be useful in preventing osteoporosis and fracture in men.¹¹⁸

PREVENTION

Calcium

Calcium is an important component of fracture prevention. Although calcium alone may not prevent osteoporosis, having adequate calcium, whether through food or supplementation, is an important and practical way to maintain bone health. Low dietary calcium intake is associated with lower BMD and increased fracture risk.⁴ Up to 75% of women may have a calcium intake (including supplemental calcium) less than the recommended daily intake.¹²⁶ Although a lower calcium intake is associated with greater risk of hip fracture,¹²⁷ calcium supplementation appears to improve BMD.^128,¹²⁹ Despite this limited evidence, the public health message is that people should have adequate dietary calcium intake throughout life (Table 23.2). More recently, concerns have arisen regarding a potentially increased risk of myocardial infarction among people taking calcium supplements over the long term.

TABLE 23.2 Recommended daily calcium intakes ^*

Age/gender	Recommended daily calcium intake (mg)
< 6 months	300
6 months − 1 year	500
1–3 years	700
4–7 years	900
Girls:
8–11 years	900
12–15 years	1000
16–18 years	800
Women:
19–54 years	800
> 54 years	1000
pregnant	1100–1200
Boys:
8–11 years	800
12–15 years	1200
16–18 years	1000
Men:
19–64 years	800
> 64 years	800

* Australia, National Health and Medical Research Council

Source: NHMRC 1991¹³⁰

Vitamin D

Although most calcium is deposited in bone, bone is not just calcium, and calcium does not function in isolation but in interaction with vitamin D—adequate vitamin D is important for bone health, as it regulates the efficiency of calcium absorption. Vitamin D here includes cholecalciferol (vitamin D₃) and ergocalciferol (vitamin D₂). Despite the common perception of Australia as ‘sunshine country’, there is a high prevalence of vitamin D deficiency among elderly people. For example, a study of institutionalised or housebound individuals found that up to 80% of women and 70% of men were deficient in vitamin D and, of these, 97% had a blood level of vitamin D below the median value of the healthy reference range.^131,¹³²

People with vitamin D deficiency may need a loading dose, depending on the vitamin D levels, and supplementation with 3000–5000 IU vitamin D₃ per day for 12 weeks, before repeating the test o fvitamin D levels and reviewing.¹³³

Lifestyle and dietary factors

Lifestyle and dietary factors, including caffeine, alcohol, smoking and salt intake, have been shown to be associated with fracture risk.¹³⁴^–¹³⁸ In Caucasian populations, heavy caffeine ingestion (> 4 cups coffee/day) has been shown to be associated with hip fracture in men and women.^139,¹⁴⁰ The effect of sodium on bone health remains unclear; however, studies have shown a significant negative effect¹⁴¹ when daily intake exceeds 2100 mg (90 mmol). Cigarette smoking is a significant risk factor for hip fracture.¹³⁴ Modification of lifestyle, including reducing or stopping smoking, and reducing alcohol, caffeine and salt intake, is recommended as a practical way to slow the progression of osteoporosis or to reduce the risk of fracture. Other factors such as dietary magnesium and protein are also important.

Physical activity

Adequate physical activity is an important factor in reducing the risk of fracture and falls ¹⁴²; however, excessive physical activity can be harmful to bone health.¹⁴³ It is recommended that older adults maintain regular physical activity such as jogging, field and racquet sports and swimming to reduce bone loss and fracture risk. Weight-bearing exercise is the most useful in osteoporosis prevention and management. Appropriate resistance exercise is also recommended.

Fall prevention

In the elderly, approximately one-third of women and 20% of men fall each year.¹⁴⁴ About half of falls occur indoors, mainly in the living room (30%), bathroom/toilet (23%), dining room (14.4%) and bedroom (12.3%). Falls are an important risk factor for fracture.⁵⁶ Over 90% of hip fractures are a result of a fall¹⁴⁵ but only 1–2% of all falls of the elderly lead to a hip fracture.^146,¹⁴⁷ Therefore, fall prevention is an important approach, to reduce the risk of fracture in the elderly.

Practical strategies of fall prevention include:

• modifying the home to remove slippery surfaces and dangerous furniture

• correcting poor vision

• installing appropriate aids in the bathroom

• modifying medications such as sedatives.

Physical therapies aimed at improving strength and balance, including resistance training and t’ai chi, have been found to be beneficial in reducing falls in the elderly.

POST-FRACTURE MANAGEMENT

An existing fracture increases the risk of subsequent fractures.^8,^148,¹⁴⁹ Individuals with a personal history fracture—with or without osteoporosis—should be considered for treatment. However, several studies have suggested a very low uptake of treatment. In a study of 502 hip-fracture patients in a hospital setting, only 14% underwent BMD scan, 13% received calcium/vitamin D, and only 18% received HRT, calcitonin or bisphosphonates.¹⁵⁰ Other studies have reported that only 5% of patients with recent hip fractures left the hospital with a new medication prescribed to reduce the risk of subsequent fractures.¹⁵¹^–¹⁵³ Most women attending primary care physicians who reported a fracture after menopause are not on any specific anti-osteoporotic therapy.¹⁵³ 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 therefore not treated. An information-based intervention could increase the uptake of anti-fracture treatment among high-risk patients.¹⁵⁴ Other strategies for improving treatment uptake include fracture discharge pathways, increased nurse contact and patient education.

There was a concern that anti-resorptive therapies may interfere with the bone healing process; however, there is no consistent evidence that the use of anti-resorptive agents soon after fracture impairs fracture healing. There is a view that older patients with a pre-existing fracture may not benefit from treatment. However, evidence from clinical trials clearly indicates that older patients with fracture benefit from anti-osteoporosis therapy, similarly to younger individuals.

RICKETS

Rickets is a condition associated with softening of bones, leaving them vulnerable to deformity and fracture. The main cause is vitamin D deficiency, although a significant and prolonged poor intake or malabsorption of calcium can also cause it.

Rickets was a once common bone disease of children and it is still common in poorer countries where nutrition is inadequate. Although far less common until recently in developed countries, it is now making a comeback in many places around the world, probably due to inadequate sun exposure leading to inadequate vitamin D levels. This rise in the incidence of rickets can be contributed to by a predominance of indoor activities, physical inactivity and an over-aggressive approach to sun protection. The breastfeeding children of mothers with inadequate vitamin D levels are also more likely to develop rickets. Dark-skinned children, especially those living in countries with relatively low levels of sunlight, are at greater risk, as are children who are not consuming milk. Vitamin D deficiency can also result in hypocalcaemia and hyperexcitability of muscles.

DIAGNOSIS

Rickets is classically diagnosed on the clinical picture in association with the following tests.

• X-rays—revealing classic deformities listed above

• low serum calcium and serum phosphorus

• high serum alkaline phosphatase (ALP)

• low vitamin D.

MANAGEMENT

If diagnosed and managed in childhood, the problems associated with rickets respond well without long-term disability or deformity. If not managed, however, the deformities can become permanent.

Clinically evident rickets requires co-management with a paediatric endocrinologist.

Neonates and infants under 3 months:

• vitamin D level 25–50 nmol/L—400 IU vitamin D₃ (cholecalciferol daily)

• vitamin D level < 25 nmol/L—1000 IU daily for 3 months.

Infants 4–12 months:

• vitamin D level 25–50 nmol/L—50,000 IU stat or 400 IU daily for 3 months, then maintenance 400 IU daily

• vitamin D level < 25 nmol/L—100,000 IU stat or 1000 IU daily for 3 months, then maintenance 400 IU daily.

Children and adolescents 1–18 years:

• vitamin D level 25–50 nmol/L—150,000 IU stat or 1000–2000 IU daily for 3 months

• vitamin D level < 25 nmol/L—150,000 IU stat repeated at 6 weeks, or 1000–2000 IU daily for 6 months plus regular moderate safe sun exposure (ultraviolet B).

For all ages, re-check vitamin D, calcium, phosphate and ALP at 3 months, then vitamin D and ALP annually.

Cod liver oil is also a good source of vitamin D but should not be considered for high-dose vitamin D, because of concerns about vitamin A toxicity. Generally speaking, 10–20 minutes per day is sufficient exposure on a regular basis, with the amount of sun exposure with skin unprotected by sunscreen and/or glass varying according to the season, colour of the skin and latitude. Avoiding sunburn is of course advisable, to avoid the risk of melanoma; and if a child is going to be out in the sun for a more prolonged period of time, particularly in the summer months of the year, then all the usual measures for sun protection should be undertaken. Increasing the dietary intake of calcium is also advisable.

OSTEOMALACIA

Osteomalacia is a milder form of rickets seen in adults. It is also a softening of the bone due to vitamin D deficiency causing poor bone mineralisation. It is associated with diffuse bone pain, weakness and a tendency to fracture. Adults at particular risk of osteomalacia are those who have inadequate ultraviolet B exposure, such as those with dark skin who are living in countries with low levels of sunlight, those who cover their skin for cultural reasons and institutionalised elderly perople who rarely go outdoors. It can also be found in people with a poor diet or who are unable to absorb vitamin D from their food due to malabsorption or coeliac disease. Patients with chronic renal failure and renal tubular acidosis can also suffer from osteomalacia.

The symptoms of and laboratory tests for osteomalacia are similar to those for rickets and osteoporosis. A technetium bone scan will indicate increased bone activity, and X-rays may also show pseudofractures (Looser’s zones).

Management of osteomalacia is by administration of vitamin D₃. A very low vitamin D level can be an indication for a larger stat dose of vitamin D, for example 100,000 IU IM or orally as drops, followed by a maintenance dose of 10,000–20,000 IU per week until the vitamin D levels are again adequate. A lower maintenance dose may then be required, particularly if the cause of vitamin D deficiency cannot be resolved. Malabsorption syndromes may require vitamin D injections rather than oral administration.

PAGET’S DISEASE

Paget’s disease (osteitis deformans) is a condition of bone that tends to affect the elderly. About 10% of 90-year-olds have it, although a great proportion of these will be asymptomatic. Paget’s disease is of uncertain origin, although a viral aetiology is suspected. A genetic predisposition may also play a role, and men are more commonly affected than women.

The pathological process in Paget’s disease involves bone resorption by osteoclasts, followed by new, softer bone being laid down by osteoblasts—that is, there is an increase in bone turnover. The new bone being laid down tends to be more disorganised—the so-called ‘mosaic’ pattern—and is hypervascular, which can cause problems during surgery.

SYMPTOMS

Some patients with Paget’s disease will be diagnosed based on tests taken for other reasons, such as X-ray findings or serum ALP levels. For patients who are symptomatic, the following are common symptoms:

• bone pain—in affected bones, most commonly the spine; it is like a deep aching feeling, often worse at night, causing disturbed sleep.

• joint pain and osteoarthritis—particularly of the hip or knee

• headaches—can be associated with Paget’s disease of the skull

• sometimes growth of the bones of the skull can also cause hearing loss or pressure on other cranial or spinal nerves

• bone deformity—such as enlargement of the skull, spreading of the teeth or bowing of the tibia

• gait problems

• cardiovascular complications—including calcification of the aortic valve and cardiac failure, in severe Paget’s disease

• kidney stones—more common in people with Paget’s disease.

DIAGNOSIS

Diagnosis can be made clinically and confirmed by the following tests where indicated:

• X-ray or skeletal survey showing areas of dense and thickened bone

• raised ALP—can also be useful in monitoring the level of disease activity

• normal calcium and phosphate levels

• radioisotope bone scans—can help to gauge the level of disease activity.

Although an uncommon presentation, bony metastases from prostate cancer can mimic X-ray lesions suggestive or Paget’s disease, and so it will be helpful to exclude this before confirming a new diagnosis of Paget’s disease in an elderly male. Osteogenic sarcoma is also a rare complication of Paget’s disease.

MANAGEMENT

If treated early, the outcome for Paget’s disease patients is good, in terms of slowing the progression of the condition and associated symptoms. The disease process, however, and the secondary impact of it, will not go away.

General measures as outlined in the chapter on pain management (Ch 38) will be useful for those with more severe and chronic pain. The mainstays of medical management are aimed at reducing pain and minimising deformities that can lead to complications such as hearing loss. Drugs commonly used for Paget’s disease (see the section above on osteoporosis) are:

• bisphosphonates—generally considered first-line therapy

• calcitonin.

Surgery can sometimes be necessary for those who have severely involved joints, after fractures or when bone deformity is causing significant problems.

Lifestyle measures such as adequate vitamin D₃ intake (a supplement of 1000 IU daily may be beneficial), regular moderate sun exposure and calcium intake are recommended. Regular exercise is important for maintaining healthy weight, mobility and bone integrity. Patients should discuss the appropriate level and form of exercise with a healthcare professional.