AD and Concomitant Conditions

Osteoporosis in the AD Patient Osteoporosis (OP) is a common disease that is characterized by low bone mass and microarchitectural disruption, which together lead to skeletal fragility, resulting in increased risk of fracture. Once a patient has fractured, their future risk of fracture is increased approximately four fold. Although adverse effects occur across the broad range of patients that suffer OP-related fractures, patients with Alzheimer’s disease may be even more susceptible to some of the adverse outcomes. By Brian Wirzba, MD, FRCPC

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steoporosis (OP) is a common condition that affects approximately 1.4 million Canadians. It has been termed “the silent thief” as it remains completely asymptomatic until the patient suffers a fracture, at which point it can have a major impact on morbidity and mortality. Despite this, its importance in the elderly is often minimized as some patients and even healthcare providers still consider it a “natural” part of the aging process. Although it is certainly true that declines in bone density and the associated increased risk of fractures progress with age, our current knowledge of OP and how to effectively treat it allows us to reduce the risk of fractures in the Brian Wirzba, MD, FRCPC Specialist in General Internal Medicine and Medical Director of the Grey Nuns Hospital, Osteporosis Program, Edmonton, Alberta.

same way we reduce the risk of other age-related conditions such as cardiac events, cognitive decline and cancer (to name a few). Of course, fracture elimination is not possible, but by treating those at highest risk and by reducing their risk we can significantly improve their quality of life. In recent years, the trend to utilize Fracture Assessment Tools to estimate the five- or 10-year risk of fracture has allowed primary-care physicians to assess their patients’ risk in a manner very similar to using the Framingham study data to estimate 10-year risk of a cardiac event. This not only allows physicians to reassure younger patients with few risk factors of their low-risk status (where lifestyle interventions alone may be adequate) but has also emphasized just how high the risk is in the frail elderly population. There is no clear link between OP and Alzheimer’s disease (AD)

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yet the two conditions often coexist. The understanding of the assessment and management of the OP patient is therefore essential for the physician caring for the AD patient. This article answers some of the most common questions asked about OP assessment and management of the elderly patient, and why patients with AD need their fracture risk assessed.

Why is Osteoporosis Something That Needs to be Considered in my AD Patients? Like many other disease states, we are often aware that the patient in our clinic may have some risk factors for OP but are not certain whether or not to be concerned about the likelihood of them eventually “suffering” from the condition. This is particularly true for asymptomatic conditions such as OP when the patient is not currently

Osteoporosis

being “bothered” by their disease and when they may have other conditions that are actively hindering their daily physical, mental or emotional wellbeing. However, the reality of the situation is that it is not the thinning of bones themselves that is the problem for the patient, rather it is the fact that thin bones fracture and these fractures can have a major impact on quantity and quality of life. Once a patient has fractured, their future risk of fracture is increased approximately four fold. We also know that 20% of patients die within one year after a hip fracture while only 50% return to their pre-fracture functional status— 20% require institutionalization.1 In an elderly patient with other comorbities their ability to recover is further hindered. Delirium may develop following fractures related to the pain associated with fractures, pain medication use, changes in environment (such as hospitalization) or altered functional capacity. Pulmonary and gastrointestinal compromise has also been described with progressive vertebral fractures and its associated kyphosis. Although these adverse effects occur across the broad range of patients that suffer OP-related fractures, patients with AD are not immune and may be more susceptible to some of the adverse outcomes, such as delirium.

Why Are the Elderly More Susceptible to Fracture? OP is a common disease that is characterized by low bone mass

and microarchitectural disruption, which together lead to skeletal fragility and resulting increased risk of fracture.2 Unfortunately the only test readily available to assess for OP is a Bone Density Scan (DEXA) which can estimate bone mass (or bone quantity) reasonably well. Despite significant interest and research into other radiologic or laboratory modalities, to date, no clinically useful test for the microarchitectural changes (or bone quality) has been identified. With age, the

estrogen deficiency-related postmenopausal OP which primarily affects trabecular bone (such as that found in vertebrae), and senile OP which more frequently affects cortical bone, predisposing older women and men to hip fractures.4 Although the former mechanism may lead to increased rapid bone loss for female patients in the early postmenopausal years, the latter process leads to a 0.5% per year bone density loss well into the elderly years. This loss occurs due to periosteal apposition from the out-

Changes in bone quality occur for a variety of reasons beginning at a young age when the skeleton is still maturing. Peak bone density and its optimal “strength” generally occur in the third and fourth decades of life, after which a gradual decline in quantity and quality occurs. rates of fracture increase exponentially, certainly more than would be expected based upon loss of bone mass alone. Changes in bone quality occur for a variety of reasons, beginning at a young age when the skeleton is still maturing. Peak bone density and its optimal “strength” generally occur in the third and fourth decades of life, after which a gradual decline in quantity and quality occurs. In their recent review of the mechanisms of senile OP, Duque and Troen3 describe the two main pathophysiological processes that generate bone loss. There is the more commonly recognized

side of bones (more pronounced in women compared to men) and endosteal bone resorption on the inside of the bone, both of which lead to a mechanically more fragile macroarchitecture. It has also been noted that senile OP involves the accumulation of bone marrow fat at the expense of osteoblastogenesis5 thereby negatively affecting the microarchitecture. One potentially preventable risk factor for microarchitectual changes that affects all ages but is particularly important in the frail or institutionalized elderly patient is vitamin D insufficiency. Despite being readily treatable, this condi-

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AD and Concomitant Conditions tion remains extremely common,6 particularly in the elderly who generally have decreased intake of vitamin D-rich foods, lower levels of sunlight exposure and, even if sunlight exposure does occur, suffer from the age-related reduced ability to metabolize vitamin D in

in risk of vertebral and non-vertebral fractures.10 At the same time, primary-care physicians have become very familiar with the use multifactorial risk assessment tools such as those based upon Framingham data to estimate a patient’s risk of a cardiac event.

One potentially preventable risk factor for microarchitectual changes that affects all ages but is particularly important in the frail or institutionalized elderly patient is vitamin D insufficiency. the skin.7 This hypovitaminosis D often leads to secondary hyperparathyroidism and its subsequent enhanced osteoclastic bone resorption.8

How Can a Patient’s Risk of Fracture Be Assessed? Despite all we know about OP and the risk factors of fracture, we do not have a crystal ball that tells us exactly who will fracture and when. Like every other area of medicine, we deal with risk and risk reduction (not elimination). With more than 80% of low trauma fractures occuring in people who do not have a T-score below -2.5 (the definition of “osteoporosis” utilized in bone mineral density [BMD] reports)9 it is very apparent that we need more than just BMD to estimate fracture risk. In addition, changes in bone density in people taking antiresorptive drugs explains only 4% to 30% of the reduction

Such tools allow for a more realistic estimate of what the individual patient’s risk really is if they do not undergo therapeutic interventions. Although a number of such tools are available for OP, including one that is suggested for use when reporting (dual-energy x-ray absorptiometry (DXA) results,11 perhaps one of the most robust tools has recently been published by the World Health Organization12 and is available online at www.shef.ac.uk/FRAX. This FRAXTM fracture assessment tool is based upon international data and, after entering some basic clinical risk factors (Table 1) and the femoral neck bone density (T-score or Z-score) a 10-year risk of hip fracture and major osteoporotic fracture (clinical spine, forearm, hip, or shoulder) is provided. Although this tool may have some drawbacks (such as the use of femoral neck BMD rather than potentially lower BMD sites, underestimation in patients with particularly strong per-

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sonal or family fracture histories, and the absence of a specific Canadian calculation tool), it is very simple to use and relatively intuitive, yet robust and well validated. The resulting 10-year fracture risk assessment can then be used to discuss with the patient or family member the magnitude of risk, with a value of approximately 15% risk of hip fracture being considered by many to be an appropriate treatment intervention threshold. The use of antiresorptive therapy would be expected to reduce the risk of fracture by 40% to 50% over the first three years (the duration of most randomized control trials). Their effect over 10 years (compared to placebo) is unknown and unstudied but they are thought to remain effective with such long-term use. As a result it is also important to note that once a patient is taking an antiresorptive agent their risk of fracture is reduced (assuming the medication is taken appropriately and appropriately absorbed), although the exact degree of reduction is unknown. By utilizing this method of assessment, one can avoid the overtreatment of the low-risk patient (10-year fracture risk < 10%) as well as the undertreatment of those at highest risk (10-year fracture risk > 20%)— two problems that are unfortunately all too common and propagated by an over-reliance on BMD values alone.

Osteoporosis What Are The Treatment Options for Osteoporosis? Exercise. Fracture risk-reduction treatment options include lifestyle measures as well as pharmacologic means. Bone density is known to be higher in physically active people and exercise does reduce the rate of age-related bone loss.13 Despite several studies in elderly patients that have shown surrogate endpoint benefit (BMD, bone turnover markers, balance, leg strength), none have been large enough or designed to demonstrated fracture reduction. Given that the strongest single risk of a fracture is falling and not bone density,14,15 it is unfortunate that larger studies looking at various exercise programs or balance improvement interventions have not been performed. Regardless, it is recommended that patients who have difficulty performing a simple sit-to-stand test or take longer than 13 seconds to complete a simple “up-and-go” test be referred for further assessment and management of their fall risk including an environmental assessment and strength and balance training.16,17 Calcium and vitamin D. Elderly patients demonstrate diminished absorption of calcium and reduced serum levels of vitamin D typically resulting in high parathyroid hormone (PTH) levels and subsequent bone loss. Despite this, the numerous trials that have looked at whether or not replacement is able to prevent fractures

have demonstrated varying results. Many of these studies were small, underpowered or involved lower-risk populations. In general however, studies in the highest-risk individuals do demonstrate benefit—the fact that supplementation was used in the treatment and placebo groups of all the randomized controlled trials testing antriresorptive agents makes supplementation important to recommend to all patients. The total daily intake of elemental calcium should be 1500 mg with most diets including 500 mg to 1000 mg per day depending on dairy product intake. As such, 500 mg to 1000 mg of supplemental calcium is recommended. Dietary vitamin D intake, however, is very low (often < 100 IU per day) and as such, 1000 IU as a single daily dose supplement is recommended for most patients. Patients with malabsorp-

Table 1

Clinical Risk Factors for FRAXTM Fracture Risk Assessment Tool • Age • Sex • Height and weight (for BMI) • Previous fracture • Paternal hip fracture • Current smoking • Glucocorticoid use • Rheumatoid arthritis • Secondary osteoporosis

the sunlight-deprived group having an increased risk of fracture at one year (odds ratio 3.7).18 Pharmacologic therapy. Antiresorptive therapies remain the mainstay of OP pharmacologic therapy. These agents reduce osteoclast-associated bone breakdown relative to the normal osteoblast-associated bone buildup. As we age the rate of breakdown

Antiresorptive therapies remain the mainstay of OP pharmacologic therapy. These agents reduce osteoclast-associated bone breakdown relative to the normal osteoblast-associated bone buildup. As we age the rate of breakdown overtakes buildup, leading to the gradual BMD decline associated with senile OP. tion syndromes should have serum vitamin D levels tested to ensure they are within the normal range of supplements. In one novel study, institutionalized patients with AD were randomized to regular sunlight exposure or deprivation for one year with

overtakes buildup, leading to the gradual BMD decline associated with senile OP. Some breakdown and buildup is desirable in order for the bone to repair damaged areas and microfractures. By slightly reducing the breakdown however, the overall BMD will

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AD and Concomitant Conditions stabilize and ideally increase while still preserving the bone’s self-repairing abilities. Bisphosphonates, such as cyclical etidronate, alendronate, risedronate, ibadronate (not available in Canada), and more recently intravenous zoledronate, regu-

such, it is essential that the tablets be taken on an empty stomach (> 2 hours after the last meal at minimum) and that no food or pills (other than water) be taken for at least 30 minutes (although our clinic recommends one hour) after the tablet.

The newest agent (zoledronate) is administered via 10- to 15-minute infusion yearly and may prove particularly useful in this patient population. This class of therapy is considered by many to be the first line of pharmacologic therapy for elderly patients at high risk for fracture. late bone resorption by reducing bone breakdown by the induction of osteoclasts apoptosis. Although commonly utilized in Canada, cyclical etidronate was developed prior to the medical field’s desire for RCT trials that demonstrate fracture reduction and, as such, we are not as certain of its benefits, while the newer nitrogen-containing bisphosphonates have all demonstrated fracture reduction for vertebral, hip and other clinical fractures. The most common side effect of the oral bisphosphonates is upper GI irritation, which can be managed in some patients by ensuring administration of the agents with a large glass of water and remaining upright after ingestion. Bioavailability of oral bisphosphonates is, however, very poor; approximately 2% under ideal circumstances. As

Although several agents are available with weekly or even monthly dosing, the precise method of ingestion that is required may still present a significant challenge for elderly patients who may already have a complex medication regimen. Use of dosettes, blister-packaged medications and even institution-based nursing distribution practices for medications are just a few examples where the very specific timing of administration may be problematic and potentially make the use of this class ineffective. The newest agent (zoledronate) is administered via 10- to 15-minute infusion yearly and may prove particularly useful in this patient population. This class of therapy is considered by many to be the first line of pharmacologic therapy for elderly patients at high risk for fracture.

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Selective Estrogen Receptor Modulators (SERMs), such as raloxifene or tamoxifene (not utilized for OP) stimulate or inhibit the various organ estrogen receptors in varying manners. By specifically stimulating the bonebased estrogen receptors, raloxifene can provide the proven estrogen bone-building and fracturereduction benefits. Compared to estrogen alone, there is no increase in uterine or breast cancer and no difference with regard to venous thromboembolic risk and an increased risk of vasomotor symptoms. Raloxifene does have proven vertebral fracture reduction data, but because it was studied in a younger population than other agents, there was a lower risk for hip fracture and no significant fracture benefit was observed. In the absence of other significant thromboembolic risk however, this agent remains a good and relatively underutilized treatment for patients with osteoporosis and, in particular, those intolerant to oral bisphosphonates. Anabolic treatments increase the amount of bone laid down in each remodeling unit by enhancing osteoblastogenesis, decreasing adipogenesis, or protecting osteoblasts against apoptosis. Currently, an analog of teriparatide, the recombinant 1-34 fragment of human parathyroid hormone, is the only approved anabolic treatment for OP in Canada. By intermittent daily dosing of PTH, anabolic effects

Osteoporosis

Table 2

Agents Approved for the Treatment of Osteoporosis in Canada Treatment

Pros

Cons

Bisphosphonates

Alendronate 10 mg po qd

Well proven fracture reduction data for most agents (including vertebral, non-vertebral and hip fracture reduction)

Oral agents MUST be taken on an empty stomach (including no other pills) due to poor bioavailability

Alendronate 70 mg po weekly

Reasonable cost

Poor adherence to therapy

Risedronate 5 mg po qd

Long-term safety record (> 15 years for some agents)

GI irritation (relatively common)

Simple administration with very few drug interations

No hip fracture data

Cyclical etidronate 400 mg po qd for two weeks every three months

Risedronate 35 mg po weekly Risedronate 75 mg po qd for two days each month

Very rare risk of osteonecrosis of the jaw (approximately 1/100,000 in OP patients)

Zoledronate 5 mg IV yearly SERMs Raloxifene 60 mg po qd

Does not require empty stomach Reasonable cost Cardiac-disease neutral

Increased risk of venous thromboembolic disease (the same as estrogen) Increased vasomotor symptoms in patients close to the age of menopause Not for male patients

Hormone Replacement Therapy Estrogen

Proven fracture reduction

Numerous other pros and cons involving other organs make use of hormone replacement therapy for OP alone, not advisable

Simple administration

Weaker quality data supporting fracture reduction

Calcitonin Nasal calcitonin 200 IU qd

Nasal irritation Well tolerated Anabolic Agents Teriparatide (rPTH 1-34) 20 µg sc qd for 18 months

are observed—rather than the marked bone resorption seen with continuous PTH exposure (such as primary hyperparathyroidism). Daily subcutaneous injection for 18 months has been shown to reduce vertebral and nonvertebral fractures—its cost, however, is prohibitive for many patients and the

Only anabolic agent available

Very high cost

Well proven fracture-reduction data

Requires subcutaneous injection

patient or caregiver must be able to administer the treatment. It is also imperative to ensure that the patient is not taking a bisphosphonate while receiving therapy and that an antiresorptive agent is initiated immediately upon stopping this treatment if optimal benefit is expected.

Summary Osteoporosis is common in elderly patients, including those with AD. The resultant fractures can have a major adverse effect on morbidity and mortality. By recognizing this risk and estimating its severity using a simple fracture risk assessment tool, the clinician can

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AD and Concomitant Conditions make an informed decision about which patients require pharmacologic therapy in addition to lifestyle management (with exercise, calcium and vitamin D) alone. Given the current treatment options that

have demonstrated excellent fracture-reduction capabilities available in a variety of administration methods, and with various pros and cons (Table 2), there is at least one agent that should suit every at-risk

patient. The future is also bright with newer agents and classes on the horizon (not discussed in this article), and with our understanding of aspects of bone quality ever improving.

References 1. Chrischilles EA, Butler CD, Davis CS, et al. A model of lifetime osteoporosis impact. Arch Intern Med 1991; 151(10):2026-32. 2. Kanis JA, Melton LJ 3rd, Christiansen C, et al. The diagnosis of osteoporosis. J Bone Miner Res 1994; 9(8):1137-41. 3. Understanding the Mechanisms of Senile Osteoporosis: New Facts for a Major Geriatric Syndrome. J Am Geriatr Soc 2008; 56(5):935-41. 4. Chan GK, Duque G. Age-related bone loss: Old bone, new facts. Gerontology 2002; 48(2):62-71. 5. Rosen CJ, Bouxsein ML. Mechanisms of disease: Is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol 2006; 2(1):35-43. 6. Lips P. Vitamin D status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol 2007; 103(3-5):620–5. 7. Kira M, Kobayashi T, Yoshikawa K. Vitamin D and the skin. J Dermatol 2003; 30(6):429–37. 8. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the eld

erly: Consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001; 22(4):477-501. 9. Stone KL, Seeley DG, Lui LY, et al. BMD at multiple sites and risk of fracture of multiple types: long-term results from the study of osteoporotic fractures. J Bone Miner Res 2003; 18(11):1947-54. 10. Seeman E. Is a change in bone mineral density a sensitive and specific surrogate of anti-fracture efficacy? Bone 2007; 41(3): 308-17. 11. K. Siminoski, et al. Recommendations for Bone Mineral Density Reporting in Canada. Can Assoc Radiol J 2005; 56(3):178-88. 12. J. Kanis, et al. FRAX and the assessment of fracture probability in men and women from the UK, Osteoporos Int 2008;19(4):385-97. 13. Szulc P, Beck TJ, Marchand F et al. Low skeletal muscle mass is associated with poor structural parameters of bone and impaired balance in elderly men— the MINOS study. J Bone Miner Res

2005; 20(5):721–9. 14. Kannus P, Niemi S, Parkkari J, et al. Why is the age-standardized incidence of low-trauma fractures rising in many elderly populations? J Bone Miner Res 2002;17(8):1363-7. 15. Kannus P, Sievanen H, Palvanen M, et al. Prevention of falls and consequent injuries in elderly people. Lancet 2005; 366(9500):1885-93. 16. Whitney JC, Lord SR, Close JC. Streamlining assessment and intervention in a falls clinic using the timed up and go test and physiological profile assessments. Age and Ageing 2005; 34(6):567-71 17. Järvinen TL, Sievänen H, Khan KM, et al. BMJ 2008; 336(7636):124-6. 18. Sato Y, Iwamoto J, Kanoko T, et al. Amelioration of Osteoporosis and Hypovitaminosis D by Sunlight Exposure in Hospitalized, Elderly Women With Alzheimer's Disease: A Randomized Controlled Trial, Journal of Bone and Mineral Research 2005; 20(8):1327-33.

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