Osteoporosis in adults with cerebral palsy

Authors


  • CONFLICTS OF INTEREST
    The author declares no conflicts of interest.

Kevin J Sheridan at Department of Pediatrics, Gillette Children’s Specialty Care, 200 University Avenue, Saint Paul, MN 55101, USA. E-mail: ksheridan@gillettechildrens.com

Abstract

Life expectancy for the 400 000 adults with cerebral palsy (CP) in the USA is increasing. Although there is a perception of increased fractured rate in the adult with CP, it has not been well studied. Low bone mineral density is found in more than 50% of adults with a variety of disabilities, including CP. Dual-energy X-ray absorptiometry scanning is commonly used to assess bone mineral density, but is limited by positioning and other artifacts in adults with CP. Novel scanning regions of interest, such as the distal femur, are not yet standardized in adults. Nutritional assessment and physical activity, the basis of most fracture prevention programs, are difficult to do in the adult with CP. A better understanding of the ‘muscle-bone unit’ physiology and its exploitation may lead to better treatment modifications. Clinical research trials with bisphosphonates (e.g. pamidronate), estrogen, selective estrogen receptor modulators, parathyroid hormone analogs, and growth hormone need to be targeted to the adult with CP. Longitudinal studies of fracture risk factors, genetic research in bone and neuromuscular biology, and the development of treatment surrogates for physical activity are additional areas of needed expertise. This could be facilitated by an adult CP registry and the centralization of clinical research efforts.

LIST OF ABBREVIATIONS
BMD

Bone mineral density

DXA

Dual-energy X-ray absorptiometry

FDA

Food and Drug Administration

PTH

Parathyroid hormone

ORAI

Osteoporosis Risk Assessment Instrument

QCT

Quantitative computed tomography

QUS

Quantitative ultrasound

SCORE

Simple Calculated Osteoporosis Risk Estimation

SERM

Selective estrogen receptor modulator

Cerebral palsy (CP) has been described as ‘a term of convenience applied to a group of motor disorders of central origins’ and is the most well-known of the neurological disorders that start in childhood and continue through adulthood.1 It is a static neurological condition resulting from brain injury incurred during central nervous system development. Seventy to eighty percent of cases are acquired prenatally from unknown causes, the remainder from birth complications (6%) and postnatal acquisition (10–20%).2 Life expectancy for the individual with CP is shorter than that of the general population, especially if its complications are severe.1

In 2001, the United Cerebral Palsy Foundation estimated that 764 000 children and adults in the USA have one or more symptoms of CP.3 Each year 8000 newborns and 1500 to 2500 children are recognized with CP. The precise number of adults is more difficult to assess, although estimates of 400 000 cases in the USA have been suggested. The life expectancy of children with CP has increased over the past three to four decades. Today, 95% of children with diplegia and 75% of children with quadriplegia survive until the age of 30 years.4 Survival to the age of 20 in individuals with CP is now 90%. The epidemiology is clear: there are more adults with CP, and they are surviving longer.

Children with CP face a number of medical complications during their growing years: gastrointestinal reflux, aspiration syndromes, respiratory infections, seizures, and contractures. These problems continue into adulthood. However, as adults, they experience additional degenerative complications from the chronic stress and wear and tear on muscles, tendons, and joints resulting from the dynamics of abnormal mechanics. Additionally, they are exposed to common age-related conditions such as atherosclerosis, dementias, muscle wasting, osteoarthritis, bone loss, and low-trauma fractures. The aging individual with CP is as susceptible to these health problems as the abled adult; the major difference is that problems are likely to occur at a younger age, and with more severity, in the individual with CP.

In a study of excess mortality of 45 292 Californians with disabilities from 1986 to 1995, Strauss et al.1 found an 8.4 standardized mortality ratio, with a threefold increase in breast cancer and an increased mortality due to brain cancer, circulatory diseases, and digestive diseases. Although osteoporosis was not cited as a cause of increased mortality in this disabled cohort, there is concern, by analogy to the elderly disabled, that osteoporosis increases the morbidity of other health problems in the aging adult with CP. It has already been established in the elderly that bone fractures do not directly cause death, but their impact on morbidity is high (p. 91).5

In the abled population, bone diseases accounted for a tiny fraction of the 2.4 million deaths reported nationally in 1999 (p. 91).5 A recent analysis of data from the National Health and Nutrition Examination Survey I (NHANES I) found that over a follow-up period of 8 to 22 years, each standard deviation decrease in bone density was associated with a 10 to 40% increase in mortality.6 In one study, 20% of all patients died within 1 year of a hip fracture; the hip fracture, however, was not directly cited as the cause of death.7 Studies in Europe have shown increased mortality after spine fractures as well as after hip fractures.8

Osteoporosis affects more than 10 million people in the USA and will affect over 14 million over the age of 50 by 2020.9 Hip fractures are the most devastating type of fracture. A 2005 estimate suggested that there are approximately 1.5 million hip fractures per year.9 By 2050, there will be almost 6.3 million. In the United States, almost all hip fracture patients are hospitalized, representing almost half of all hospitalizations for outpatient fractures. Even in the abled population, more than one in four (26%) of individuals suffering from a hip fracture becomes disabled the following year (p. 97).5 The cost for outpatient fractures was $12.2 to $17.9 billion in 2002 dollars.10 It is estimated that the cost will rise to $50 billion by 2040.

Only a small fraction of these patients will have CP as comorbidity. But as already noted, CP patients are surviving longer. As a result, they are experiencing an earlier susceptibility to the ‘diseases of aging:’ diabetes mellitus, heart disease, and osteoporosis.

This article reviews the current literature as it pertains to CP and bone fractures. The primary focus is adults. There are many studies of fracture rate, fracture risk, and treatments for osteoporosis in the abled population. In contrast, there have been more studies in children with CP than in the adult with CP. It will, therefore, be necessary to discuss some of the pediatric studies as they relate to the adult population. Although most of these studies involved children and adolescents, a few included both adults and children.

This article has four goals: (1) To review the epidemiology of spontaneous fracture in CP, in terms of prevalence and incidence of fractures; (2) To describe the risk factors associated with spontaneous fractures; (3) To review methodologies for assessing bone strength, e.g. bone mineral density (a proxy for bone strength) imaging with central and peripheral dual energy X-ray absorptiometry, peripheral and central quantitative computed tomography, ultrasound, and magnetic resonance imaging; and (4) To review the relevance and effectiveness of treatments for individuals with severely reduced bone strength.

The article concludes with some speculation about future clinical and research directions.

Epidemiology of spontaneous fracture in CP

The epidemiology of spontaneous fractures in children and adults is not well characterized. The reasons are multiple. First, not all fractures require hospitalization, are clinically documented, or are even identified as ‘fracture.’ The definition of ‘spontaneous fracture’ is also somewhat imprecise, given the heterogeneity of clinical fragility in persons with ‘cerebral palsy.’ A number of small studies have correlated clinical risk factors with fractures.11–13 However, large, population-based studies are few. An assumption of susceptibility to spontaneous fractures in the CP population is based on anecdotes, personal clinical experience, and limited surveys in select groups. In the population at large, 1.5 million individuals annually suffer fractures caused by bone disease. For white females at age 50, the lifetime risk is 39.7% for a fracture; for white males, the risk is 13.1%. Fractures of the hip have the greatest morbidity, with an annual incidence under the age of 35 of 2 per 100 000 white females; this incidence increases to over 3000 per 100 000 in white females over age 84 (p. 69–71).5 Falls account for the majority of hip and forearm fractures and for a quarter of spine fractures.

Can these rates translate directly to the relatively non-ambulatory or minimally ambulatory adult with CP? Are these fractures associated with morbidities in excess of those seen in the general population? These are unanswered questions. The following, however, is known. Although epidemiological studies in children with CP found a fracture rate similar to that of normal children, the fracture incidence was still highest in the most severely impaired individuals.14 Brunner and Doderlein15 reviewed the clinic records of 4000 patients with CP from two pediatric orthopedic centers. From 1976 to 1993, they reported 37 patients with 54 fractures. This translates to an estimated 2.7 fractures per year.

Risk factors

There are few studies examining the prevalence, let alone the incidence, of fracture in adults with CP. Most epidemiological studies are in children, with a few studies combining children and young adults. Extrapolating from conclusions reached in the pediatric studies to the adult raises some important considerations: (1) the longitudinally growing pediatric bone, which experiences both modeling (i.e. cortical bone growth in width and length) and remodeling (i.e. mainly trabecular bone restructuring), may have a different fracture threshold than the predominantly remodeling adult bone; (2) the child, who is lighter than the adult and therefore more frequently transferred or handled, is more likely to be exposed to stresses that can cause fractures; and (3) the adult has a longer cumulative exposure to abnormal bone mechanics, multiple joint surgeries, seizure medications, and the cumulative stresses of nutritional deficiencies and other diseases.

Despite these uncertainties, clinicians might assume a greater fracture risk in adults with CP than in children, as the expected aging decline in bone mass is superimposed upon an already compromised bone strength. The morbidity that accompanies a fracture may also be greater.

The following is a brief review of some of the epidemiological studies addressing risk factors for bone fractures in CP.

In Brunner and Doderlein’s study noted above, fractures correlated with low bone mineral density (BMD), stiff joints, poor balance, and violent seizures.15 In another study more than 40 years ago, the cause of the fracture could not be identified in over 50% of the childhood cases.16 Taken together, the major risk factors for fractures are ambulatory status, nutritional state, extent of neurological injury, degree of physical disability, dietary intake of calcium and vitamin D, and periods of immobilization.

Henderson et al.,17 using stepwise regression analysis, found, in decreasing order of importance, the following risk factors for lower bone mineral density in the distal femur of children with disabilities: severity of neurological impairment, increased feeding difficulty, use of anticonvulsants, and lower triceps skin-fold measurement.

In a combined adult and pediatric study of non-ambulatory individuals with spastic quadriplegia, out of 48 had a previous fracture and a low lumbar spine bone mineral density Z-score.14

Henderson et al.18 attempted to identify risk factors that predicted a low BMD in adults and children. In the 107 participants in this study, weight z score was the best predictor of bone mineral density z score. Therefore, a weight z score 2SD below the mean predicted a bone mineral density z score that was also at best 2SD below the mean. Prior fracture, use of anticonvulsants, and feeding difficulties further reduced the predicted bone mineral density.

A few small studies have looked at BMD as a risk factor in adults with CP. Jaffe and Timell19 found that 51% of a population of 108 institutionalized men with developmental disabilities had a quantitative ultrasound index (a measure of BMD risk) more than 2SD below the mean. Smeltzer and Zimmerman20 performed peripheral BMD screening in a descriptive, cross-sectional, community-based study of 429 females with different disabilities, twenty-five of whom had CP. The females were given a self-reported risk-factor survey. Among these females, 53.1% had evidence of low BMD, regardless of whether or not they had gone through menopause. The risk factors identified for low BMD were white race, lack of exercise, and medication use.

Tools for risk-factor assessment

BMD has been the most studied risk factor for spontaneous fractures in the abled and non-abled populations. However, it is impractical to measure BMD in the population as a whole. As a result, risk-factor assessment tools have been developed and adopted by various consensus panels. These tools are designed to select those who would benefit from further risk assessment, e.g. the measuring of BMD.

The National Osteoporosis Foundation Checklist for Individual Assessment, the Osteoporosis Risk Assessment Instrument (ORAI), the Simple Calculated Osteoporosis Risk Estimation (SCORE) index, the Osteoporosis Self-Assessment Tool, and the FRACTURE index are examples of such tools. The ORAI calculates scores based on age, weight, and current estrogen use. It has a sensitivity of 93%, but a poor specificity of 39%, for predicting abnormal BMD. The SCORE index addresses six factors – age, race, weight, estrogen use, rheumatoid arthritis, and personal fracture history – and has a sensitivity of 91% but a poor specificity of 40%. It has been evaluated by Smeltzer and Zimmerman20 in 307 females with disabilities. Its sensitivity in predicting BMD more than 2SD from the mean was 62.6% and specificity was 63%. This incorrectly categorized 40% of these females and was considered unacceptable.

The usefulness of these tools as predictors of low BMD has not been adequately studied in the adult with CP.

Assessment of bone mass

The variability of the risk factors that have been associated with fractures in select populations highlights the many aspects of bone biology that affect bone strength. Bone mass, bone size, bone geometry, and material properties of bone, as well as the nature of a particular trauma, contribute in some way to this susceptibility.21

It has been difficult to quantitatively and reproducibly assess each of these bone properties to fully assess fracture risk. BMD remains the most widely measured property of bone. In the laboratory, bone strength is strongly correlated to BMD and remains a strong independent predictor of fracture risk. BMD has been shown to correlate well with the load-bearing capacity of the hip and spine and with the risk of fracture.22 For each standard deviation decrease in BMD, the risk of fracture increases 1.5 to 2.5 times.23 (Each spine z score standard deviation decrease equals a 10 to 20% decline in BMD.) In fact, the relationship between BMD and fracture is stronger than the relationship between cholesterol and heart attack (p. 198).5

There are a number of ways to measure BMD. They include single- and dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), magnetic resonance imaging (MRI), quantitative ultrasound (QUS), radiogrammetry, and radiographic absorptiometry. DXA is by far the most widely used method for the assessment of bone mass and density in children and adults. It is safe and involves levels of X-radiation lower than those received in a transcontinental flight across the USA or from one chest X-ray. Because of its lower radiation exposure and excellent precision, DXA permits monitoring over time.

DXA does, however, has limitations. The most important one is that it cannot distinguish trabecular or cancellous bone from cortical bone. Likewise, it is limited in assessing certain structural characteristics of bone that affect strength. Nor can DXA characterize the material (other than calcium) properties of bone that affect strength (e.g. protein content, bone quality). Some of these limitations have more-profound consequences in select populations, such as children, adolescents, and, especially, individuals with neuromuscular diseases.

Some of the less commonly used methods of bone assessment address these DXA limitations. For example, QUS can evaluate microarchitecture of bone at peripheral sites. QCT can evaluate the three-dimensional aspects of bone and, unlike DXA, can distinguish trabecular from cortical bone.

In the adult population, most fractures occur in the spine and hip – the sites most commonly measured with DXA. These sites are also the most appropriate for monitoring therapy effectiveness, showing more gain in bone mineral density from treatment than peripheral sites such as the forearm. Peripheral DXA measurements, however, do have some ability to predict central (i.e. hip and spine) fractures.

In children and adolescents, DXA has an additional limitation. It directly measures the bone mineral content in a two-dimensional area of projected bone. Bone density is in fact calculated as an ‘areal,’ and not a true ‘volumetric,’ density. A larger bone would yield a falsely greater BMD than a smaller bone. This effect of bone size on the DXA areal bone density is a problem in the growing bones of children and adolescents. The smaller bones of the adult with CP would present a similar difficulty in interpretation. The measurement of whole-body bone mineral density and whole-body bone mineral content lessens this artifact and is the preferred approach in the growing child. Whole-body bone mineral content obtained from DXA scans agrees well with other methods.

In CP, unfortunately, measuring whole body, spine, hip, or even forearm sites is not possible because of acquired or intrinsic bone-related pathology or the presence of surgical hardware. The inability to properly position the region to be scanned, because of severe contractures or artifacts from muscle movement, adds to the difficulty of using DXA. Further interference from artifacts from previous surgeries, abnormally healed fractures, or the presence of surgically placed metallic hardware may preclude efforts to assess bone mass in the individual with CP. This has led to a practical interest in the use of less-involved peripheral sites and of sites where positioning is simpler, such as the lateral distal femur. At least in children with CP, this is also a common site of fracture.

This alternative site for DXA scanning was developed specifically for children with quadriparesis who demonstrated difficulty with the classic DXA scanning sites.24 It is well tolerated in many children with CP. In many cases this has been the only site from which a clinically useful DXA scan is obtained. Henderson et al.25 published a reference database of 256 healthy children between the ages of 3 and 18 years.

In this technique, three regions in the distal femur are scanned. Region 1, the metaphysis just proximal to the physis, is mostly trabecular bone. Region 3, the most distal site scanned, is mostly cortical bone. Region 2 is a transitional site between the metaphyseal cancellous bone and the diaphyseal cortical bone.

In a retrospective study of 85 non-ambulatory pediatric patients who had distal femoral scans, the average BMD of these three regions correlated with BMD and fracture occurrence. Twenty-six of the participants had a history of fracture. Using a regression model comparing the presence of fracture with body mass index (BMI) and dividing these 85 patients into high BMI (>17) or a low BMI (<17), an estimate was made of the BMD at which a 33% fracture risk occurred. If the BMI was low, this fracture-risk threshold would be reached at a lower BMD of 0.38g/cm2, whereas in the high-BMI group the threshold would be reached at a BMD of 0.74g/cm2. The authors noted that the z score should not be used to predict fracture risk in children as it has not been correlated with fracture rate in children with CP.11 In adults, the T score, not the z score, is used to estimate the BMD at which fracture risk increases, but only in postmenopausal females and males older than age 50. In children, the authors argue, fracture occurrence is predicated on the strength of the bone relative to the force applied, regardless of age or pubertal state.26

The distal femur site in adults with CP has not been extensively investigated. There are no large published reference standards, for example, in adults with or without CP; moreover, there are difficulties in developing such a reference. For example, this site may not be as accessible in adults as it is in children because of aging-related musculoskeletal problems (e.g. degenerative arthritis, worsening contractures, or cumulative effects of fractures or surgeries). On the other hand, DXA scanning is widely available, is relatively cheap to use (albeit with high start-up costs), and has been the bone characteristic most studied in many clinical trials. These advantages favor the initial use of DXA techniques adapted to the adult with CP. However, its limitations may eventually outweigh its advantages, and additional methods will need to be developed.

Alternative peripheral scanning techniques used in research studies and individual clinical settings include the following:

Peripheral Dual-energy X-ray absorptiometry XA techniques

The heel and finger, in addition to the forearm, have been used to screen individuals who will further benefit from BMD testing. The main advantage is the greater accessibility of the heel and finger in quadriplegic patients, although severe peripheral contractures can be limiting. Whether using peripheral DXA as a ‘risk-factor’ tool is more cost-effective or more predictive of low whole-body bone mass than the risk-factor questionnaire assessment is unknown.

Quantitative computed tomography

QCT involves almost 10 times more radiation exposure than DXA; however, it is much better in evaluating the three-dimensional structure of bone and bone geometry. A true volumetric bone mineral density can be calculated with QCT. Hip and spine QCT have been described as the criterion standard for measuring bone mineral density at these sites.27 The problem of the growth effect on bone size in the child is obviated with QCT. The procedure, however, is not widely available and is not appropriate for longitudinal assessments. There are also limited pediatric reference ranges. Its use in adults, especially in those with CP, is limited to research studies for similar reasons.

Peripheral QCT involves less radiation exposure but is not widely available. It suffers from even more limited reference data than QCT. It is used mainly in research.

Quantitative ultrasound

QUS is not associated with X-irradiation. It uses sound waves to measure bone mass. It does not measure bone density but rather speed of sound (m/s) in the bone, which is dependent on bone mass and bone ultrasound attenuation, which can be correlated with cancellous bone microarchitecture. It is used at peripheral sites such as the calcaneus, tibia, radius, and phalanges. It is affordable and portable, but less precise than DXA. Reference data for children are scant. It usefulness as a predictor for the common fractures in adults and children with CP is unknown.

Other X-ray methods (radiogrammetry, radiographic absorptiometry, single X-ray absorptiometry)

Radiogrammetry is a standard X-ray of the hand that compares cortical thickness with the total bone width in the mid-shaft of at least two metacarpal bones. Radiographic absorptiometry (photodensitometry) uses a standard X-ray of the hand to measure density of the middle phalanges of the second, third, and fourth fingers. Single X-ray absorptiometry measures density peripherally in the heel and forearm.

All three of these are older techniques that have not been well studied in the population in general or in individuals with CP. Their utility may be their low cost and availability, especially in parts of the world where resources are limited.

MRI

MRI is used to assess the trabecular microarchitecture of the peripheral skeleton. There is no X-irradation, and interstudy reliability is good. Modlesky et al.28 used MRI to study the distal femur in children with CP. Using MRI-defined parameters, a lower ‘quality’ of trabecular bone was noted in the children with CP compared to controls. MRI is expensive and not readily available. The requirement for minimal movement with MRI may be even more problematic than with DXA. This is not a widely used modality for assessment of BMD in adults with CP.

Treatment

Throughout life, bone adapts to the stresses of an external environment superimposed upon an internally fluctuating physiology. A variety of studies suggest that genetic factors may be responsible for determining 50 to 90% of an individual’s bone mass.5 The remainder is influenced by (1) normal daily physical activities, (2) cyclic metabolic fluctuations. and (3) accumulated acquired physiological stressors, including chronic illnesses, inflammatory diseases, neuromuscular diseases, nutritional compromise, and use of medications (prescribed and otherwise).

Treatment options aimed at modifying or reversing some of the genetic factors (e.g. in Paget’s disease or osteogenesis imperfecta), while important theoretically, are at present clinically non-existent. This paper therefore focuses on those non-genetic factors that are modified in order to maximize bone mass and their relevance to the disabled adult. Although these non-genetic factors play a minor role in overall bone mass, their effect on bone health may be great. It has been estimated that a 10% increase in bone mass can reduce fracture risk by as much as 50%.5

Fractures in adults with CP need to be treated (i.e. prevent additional fractures in individuals who have already had one) or prevented (i.e. prevent any fractures if a risk exists). Treatment options range from simple to complex and experimental. The following discussion is divided into two parts: (1) interventions that maximize the effects of daily activities and metabolism (i.e. nutrition), and (2) treatments that target the physiological aberrations leading to bone disease.

The life cycle of bone

Much of the evidence for the effect of physical activity and nutritional intervention on bone mass comes from large population studies in mostly abled adults. The impact of physical activity and nutrition on bone mass varies according to the life phase of the bone. In the growth phase of childhood and adolescence, bone mass and size increase. This is followed by the maintenance phase of adulthood, where bone is removed and replaced cyclically. Bone mass loss occurs throughout the remainder of life, developing slowly during the maintenance phase and more rapidly in the senescent phase.

As these phases develop in the adult with CP there may be greater overlap of each phase than in the individual without CP. In addition, the bone-mass decline in CP probably occurs at a younger chronological age. For example, during the growth phase in children with CP, the growing bone may experience many insults. Examples include such stressors as seizures, drugs used to treat seizures, multiple surgeries, immobility, poor nutrition, drugs used to treat spasticity, and pubertal delay. This may prevent an adequate peak bone mass in adulthood.

The increased deformities and muscle weaknesses accruing with age lead to further immobility. Superimposing the cumulative effects of bone injuring medications such as steroids and anti-seizure drugs, bone-mass preservation is dramatically hindered in the maintenance phase. The rapid loss of bone typically seen in the senescent phase may then occur earlier, especially in prematurely menopausal women and men with hypogonadism. The role of nutrition and physical activity is even more important in these adults.

Nutrition

An adequate, well-balanced diet may be the most important modifier of normal bone mass. Caloric intake adequate for the level of physical activity (or energy output) determines body weight, which in turn maximizes bone health. Adults with CP are challenged nutritionally to maintain such a body weight. Inability to chew or swallow, gastroesophageal reflux disease, and malabsorption may limit caloric intake.

The energy requirements for participants with CP have been studied. For years the poor weight gain and BMI in children and adults with CP was assumed to be due to the increased energy expenditure from spasticity and athetosis (if present). However, Stallings et al.29 found that energy requirements for both ambulatory and non-ambulatory adolescents were lower than those of a control group of normal adolescents. However, the type of paralysis could influence resting energy expenditure.30 For example in a study of adults with CP, athetosis increased the resting metabolic rate by an average of 524kcal/day.31

Once adequate caloric intake is established, food composition becomes important. Calcium and vitamin D are the dietary components that have the greatest effect bone quality. Many other nutrients (e.g. protein, phosphorus, magnesium, sodium) also influence bone health, though mostly through their effect on calcium balance.

In 1997, the Institute of Medicine conducted a major review of bone-related nutrients and developed a set of evidence-based recommendations for calcium and vitamin D intake.32 The recommendations state that the level of nutrient intake for healthy individuals should prevent the development of the chronic disease associated with the lack of that nutrient. Prevention occurs, according to the guidelines, when calcium intake is maximal at 1300mg/day for ages 9 to 18, 1000mg/day for ages 19 to 50, and 1200mg/day for those over age 50. A maximal intake of 2500mg/day could be tolerated. Vitamin D intake should be maximal at 200IU/day for all under age 50, 400IU/day for ages 50 to 70 years, and 600IU/day for those over age 70. Vitamin D intake may be partly spared by the influence of sunlight on the skin’s ability to make vitamin D, but many adults with CP do not get adequate sun exposure.

Adequate calcium and vitamin D intake is important during the growth phase of bone and may be an important determinant of adult peak bone mass. A meta-analysis in 2000 concluded that higher calcium intake increases BMD in cortical bone in children and adolescents, especially in populations at risk of low baseline intakes, but does not persist past the intake period.33

A meta-analysis of older adults (mostly elderly and postmenopausal females) concluded that calcium supplements reduced bone loss by approximately 2% after 2 years of use and led to a statistically significant 23% reduction in the risk of spine fractures.34 Additional studies have suggested calcium supplementation may have a positive effect on physical activity and muscle strength. It may also enhance drugs that reduce bone loss, such as estrogens and the bisphosphonates.

A meta-analysis examining the effect of vitamin D on bone density and fracture risk concluded that vitamin D reduced the risk of spine fractures by approximately 37%, which, by a direct effect on muscle strength, may be due in part to decreased falls.35 Whether vitamin D is acting independently of calcium was less clear. All these studies were done in otherwise healthy individuals without neuromuscular disease.

Studies examining the effect of calcium and/or vitamin D supplementation on BMD, fracture risk, or orthopedic complications in individuals with CP are notably lacking. Small, retrospective studies of fracture rates in children and a few young adults with CP have cited the risk factors of poor nutrition and low calcium intake in those who experienced fractures.12,36,37 Other studies have found no statistical difference in the calcium intake of a group of CP patients with fractures compared to age-matched controls without fractures.38

The effects of other nutrients on bone health have been studied. Both phosphorus deficiency and excess can have adverse effects on bone.39 Parathyroid hormone (PTH) enhances bone quality by influencing the growth of hydroxyapatite crystals. Magnesium is important to ensure adequate PTH secretion to maintain a normal serum calcium and balance. Fluorides are well-known to reduce tooth decay and will increase BMD; however, bone quality may be compromised by increased ‘brittleness.’ Other vitamins, such as K, E, A, and C, and the micronutrients copper, manganese, zinc, and iron play a role in the development and maintenance of a normal bone matrix.

Inadequate protein intake negatively affects the health of bone in the elderly and diminishes their ability to repair fractures. Excess intake of protein, caffeine, phosphorus, or sodium may also have negative effects. In adult females, each gram of excess sodium consumed per day has increased bone loss by 1% per year.40 Higher calcium intakes may offset this.

Depending upon the severity of the disability in adults with CP, these nutritional deficiencies or excesses may be accentuated. Even the assessment of adequate protein or micronutrient intake in this population is difficult.

Physical activity

Physical activity is cited as one of the ‘leading health indicators’ in Healthy People 2010, which sets forth health objectives for the USA during this decade.41 It is considered one of the most important modifiable lifestyle changes leading to reduced risk of heart disease, diabetes, and some cancers. Physical activity can also influence bone health by (1) increasing or maintaining bone mass, especially with weight-bearing or impact activities, and (2) decreasing falls through improved balance, coordination, and muscle mass. The US Surgeon General recommends 30 minutes of moderate-intensity physical activity on most, if not all, days of the week.42 This is in addition to strength-developing exercises at least two times per week. Many Americans without disabilities fall far short of these goals (p. 123).5 Gaskin and Morris,43 investigating the relationship between physical activity and quality of life, state that ‘the few studies published on CP and physical activity suggest that adults with CP are also not engaging in sufficient physical activity to meet the recommendations for the general population.’

The effect of physical activity on bone health in adults with CP may be more critical than it is in the general population because of the decline in function resulting from premature aging phenomena such as sarcopenia (muscle wasting) and degenerative arthritis in individuals with CP. There is also progression of the disability itself, with worsening contractures, spasticity, reduced mobility, increased pain, and psychosocial isolation, all of which can lead directly or indirectly to fractures.

An understanding of the effect of physical activity on bone-mass preservation has been hampered by the difficulty in performing such studies in many adults with CP. The wide variability in the tolerance of a particular exercise intervention, as well as individual misperceptions about what constitutes ‘exercise’ per se, are some of the challenges faced in community-based clinical studies.

Longitudinal observational studies in the general population have documented a link between physical activity and reduced fracture risk. For example in the Nurses Health study, walking 4 hours/week was associated with a 41% lower risk of hip fracture compared with walking less than an hour per week.44 In a large study of elderly females, higher levels of leisure-time physical activity and household chores were associated with a 36% reduction in hip fracture. There were similar associations in males. Whether these observations are directly applicable to the disabled population is unknown.

The impact of physical activity on bone mass (assessed as BMD) has been studied in randomized intervention trials. As a whole, these studies suggest that (1) bone mass does improve with exercise but only at the skeletal site of impact, (2) the benefit lasts only as long as the exercise itself, and (3) the effect is greater in those who were more sedentary at the start of the activity. Aerobic, weight-bearing, and resistance exercises were all effective in increasing BMD at the spine, while walking was effective in increasing it at the hip and spine. Both premenopausal and postmenopausal females, as well as elderly men, enjoyed these benefits. Large, well-controlled prospective trials of physical activity on BMD in adults with CP are lacking.

Physical activity surrogates

The kinds of physical activities and exercises noted above may not be feasible in the disabled adult. Therefore, surrogates for the muscle-loading effects of physical activity on bone have been studied in a series of small, mostly observational trials using standers or whole-body vibration techniques.

The ‘muscle-bone unit’ paradigm has helped conceptualize the effect of physical activity on bone strength. The physical activity forces can be static, as with gravitational or weight, or intermittent, as with mechanical strain or muscular forces. The muscle-bone unit concept suggests that the control of bone strength is largely dependent upon the muscle load on that bone. The so-called Utah paradigm explains how the bone strength–muscle strength relationship works.45 The mechanostat model suggests that mechanical loads result in bone strains that, when they exceed a modeling threshold, cause osteoblasts and osteoclasts to stimulate bone modeling, favoring a microarchitecture that increases bone strength. If the bone strains are below this threshold, remodeling removes bone next to the marrow, resulting in a thinner cortex. Bone strength seems to adapt more to the peak momentary (isometric) muscle forces. Thus, low-force activities done to exhaustion increase muscle endurance but not bone strength, while maximal force activities increase bone strength. The clinical implication for bone strength in adults with CP is that standers, favoring static weight-bearing loads, may not have as much impact on BMD or bone strength as the more intense short spurts of repetitive muscular contractions. Such short muscular bursts may, however, also increase fracture risk.

On the other hand, animal studies have demonstrated that high-frequency (10–90Hz), but very low-magnitude (<100 microstrain), strain stimuli are strongly anabolic to trabecular bone and that brief exposure to these low-level signals can inhibit a disuse osteopenia. Maintenance of skeletal health may then depend as much on the persistent barrage of these mechanical loads arising from, e.g. standing, as on the relatively large, but far less frequent, low-frequency, high-amplitude loads associated with walking.

Vibration studies

In a pilot study in 2004, Ward et al.46 took 20 disabled but ambulatory children and randomly assigned them to either (1) standing on an active, vertical, ground-based vibration device, oscillating at 90HZ (an audible sound) that delivered 0.3g (gravitational force of 9.8m/s2) or (2) a non-vibrating but audibly toned device. The proximal tibia and second lumbar spine volumetric BMD were measured with QCT after 6 months of observation. In the group who received the vibrations, there was a net 17.7% improvement in BMD compared with those who did not receive any vibrations. In the spine, the net benefit was 6.72%. No effect was seen on diaphyseal bone or on muscle. In similar studies in postmenopausal females, the effects were less clear. A 1-year prospective, randomized, double-blind, placebo-controlled trial in 70 postmenopausal females demonstrated that low-level vibration applied during quiet standing has a modest benefit in BMD (+3.35%) in the lightest CP (<65kg).47

Little else is known about the possible effect of standing alone or whole-body vibration exposure on bone strength in the adult with CP.

Bisphosphonates

Perhaps the most effective treatment for osteoporosis in postmenopausal females, Men over 50, and select populations of younger adults and children has been the bisphosphonates, which are inhibitors of osteoclast function in bone. Bisphosphonates bind to the surface of bone and are taken up by osteoclasts, thereby blocking the production of essential lipid compounds inside the cell, leading to its death and inhibiting bone loss or breakdown. The aminobisphosphonates, pamidronate and alendronate, are 10 times more powerful than etidrodronate (an example of an earlier class of bisphosphonates) and lack the mineralization defect caused by these earlier agents. Oral alendronate has been shown to increase BMD by 6 to 8% at the spine and by 3 to 6% at the hip over a 3-year period in postmenopausal females with osteoporosis. This was associated with a 50% decrease in fracture risk.48 Risedronate, ibandronate, and zoledronic acid are more-potent bisphosphonates with demonstrated benefits on BMD. All of these bisphosphonates are poorly absorbed and have had some rare side effects, such as gastroesophageal irritation and osteonecrosis of the jaw, that limit their use in some patients.

The effect of bisphosphonates on bone density and, to a smaller extent, on fracture rate has been studied in participants with CP and other neuromuscular diseases. A series of observational studies in the 1990s and the early part of this decade examined the effect of intravenous pamidronate on bone mineral density.17,49–52 Many of the participants in these studies were pre- or peri-pubertal children. The growing bone (modeling and remodeling) may have different responses to treatment than the adult bone (remodeling). This may limit extrapolating the findings to adults. It is instructive nonetheless to review some of these studies in participants with CP.

Many studies have demonstrated that pamidronate improves BMD and prevents fractures in children with osteogenesis imperfecta, a genetic disorder of bone. The dose of pamidronate used was approximately 12mg/kg/year.

In a randomized, placebo-controlled, double-blind trial, Henderson et al.17 studied the effect of 12mg/kg/year of intravenous pamidronate in six non-ambulatory children and adolescents with quadriplegic CP paired to age-, sex-, and race-matched controls. They demonstrated that pamidronate increased BMD by 89% (SD 21) in the metaphyseal region of the distal femur compared to 9% (SD 6) in the controls. The z scores improved from −4 (SD 0.6) to −1.8 (SD 1) with pamidronate. These participants had BMD z scores less than 2SD below the mean at the start of the study. Plotkin et al.52 performed another study of 23 children with severe spastic quadriplegic CP, and using a lower dose of pamidronate (approximately 4mg/kg/year), demonstrated, after 12 months of treatment, that the mean bone mineral density z score increased (SD) 1.6 for the femoral neck and (SD) 1.9 for the lumbar spine. PTH serum levels increased and N-telopeptide cross-linked products decreased in this study. All participants had initial BMD z scores less than 3SD below the mean. There were some observational comments about the occurrence of fractures in this small number of study participants. At the beginning of the study in Henderson et al.’s trial, three of the 14 participants had a history of at least one fracture. However, in the 18 months of the study there were no fractures in the group treated with pamidronate compared to three fractures in the placebo group. In Plotkin’s group. the fracture rate prior to the study was 0.08 fractures per year; that rate decreased to 0.004 fractures per year after 1 year of pamidronate. The difference was not statistically significant. Although the goal of treatment was to prevent fractures, the trials were designed to look at the effect of pamidronate on BMD, not on fracture rate.

These studies were performed in disabled, but growing, children. The effect on BMD may be more rapidly seen in a growing child than in an adult. Although bisphosphonates have been much more extensively studied in the non-disabled adult population, much less is known about their usefulness in the adult with CP.

Other treatment options have been studied in the adult with osteoporosis, especially in postmenopausal females and males older than 50. For females, estrogen replacement and selective estrogen receptor modulators have been the most studied. For females and males calcitonin, PTH injections (Forteo), and growth hormone have been investigated.

Estrogen and sex steroids

Estrogen replacement therapy in postmenopausal or hypogonadal females and testosterone replacement in hypogonadal males have demonstrated clear benefit in maintaining, or even improving, BMD.

Since 1972, the US Food and Drug Administration (FDA) has approved the use of estrogen to treat postmenopausal females with osteoporosis. One meta-analysis demonstrated that hormone replacement therapy increased BMD in the spine by 3.5 to 7%, in the hip by 2 to 4%, and in the forearm by 3 to 4.5%.53

Another meta-analysis suggested that estrogen reduced the risk of non-spine fractures by 27% and spine fractures by 33%. The safety of hormone replacement therapy in postmenopausal females was questioned in the Women’s Health Initiative. In this study estrogen therapy was associated with a one-third reduction in hip and spine fractures but was seen only during treatment.5

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) interact with estrogen receptors throughout the body. They affect some of the cellular activity seen with estrogen binding. Examples of SERMs include tamoxifen, currently used in the treatment of breast cancer, and raloxifene, the only FDA-approved SERM.

In a large-scale clinical trial in postmenopausal females, raloxifene increased BMD in the spine by 2 to 3% and hip BMD by 2.5% after 3 years of use. The benefit on fracture-rate reduction was seen only in the spine (50% reduction). The effect lasted 4 years, but only when taking the drug. No effect was seen on hip or non-spine fractures. Raloxifene is FDA approved at a dose of 60mg for the prevention and treatment of osteoporosis. As with estrogens, however, there are potential side effects such as blood clots in the leg or lungs, especially in individuals who are immobile or inactive for long periods of time. This may limit their use in females with severe spastic quadriplegia.

Parathyroid Hormone

PTH is known to have an anabolic effect when bone is exposed to it intermittently and a catabolic effect if exposure is persistent. Forteo (teriparatide) is a synthetic form of PTH-34. In clinical trials it has been shown to increase BMD and decrease the risk of vertebral and non-vertebral fractures in postmenopausal females. It also increases BMD in men with hypogonadal osteoporosis. It is not indicated for treatment of osteoporosis in children and young adults who still have open growth plates. It is not approved for use in other forms of secondary osteoporosis, unless there is a documented increased fracture rate, and therefore has not been well studied in adults with CP.

Growth hormone

The growth hormone-IGF1 axis is a key regulator of bone cell function.55 It is well-known that growth hormone–deficient children experience poor longitudinal bone growth and that growth hormone–deficient adults experience improvement in BMD after growth hormone treatment. Ali et al.55 demonstrated an improvement in the spinal BMD changes in 10 children, age 5 to 15 years, with CP (six with a Gross Motor Function Classification System (GMFCS) GMFC score I–III and four with GMFC score IV–V) who were treated for 18 months with 50mcg/day of growth hormone. In those treated with growth hormone, the average height z score increased by +0.67 compared to −0.01 (p=0.01) in the placebo group. The spinal BMD z score (for height) increased by +1.169 SD 0.614 in the treated versus +0.24 SD 0.25 (p=0.03) in the placebo group. Osteocalcin, IGF-1, and IGF binding protein 3 levels also increased with growth hormone.

There are limited studies examining the effectiveness and side effects of growth hormone treatment in children with CP, let alone in adults. It would not be rational to extrapolate these data to the adult with CP. Although not genetically distinct, the skeletons of adults with CP have experienced a very different physiological and pathological milieu, before and after puberty, compared to that of patients without the challenge of neuromuscular disease. They may not have experienced the same pubertal effects on the bone, for example, because of the likelihood of aberrant pubertal development in children with CP. Exposure to nutritional stresses, anti-seizure medications, and the skeletal stress of multiple orthopedic procedures are some of the factors that would affect the metabolic response of bone to growth hormone.

In all the treatment areas examined thus far, there are many more studies in the abled adult with osteoporosis than in the abled child. The opposite holds for those with CP, where there are many more studies in children than in adults. This clearly highlights the need for further directed investigations into treatment options and safety in the adult with CP. Specifically, a heightened awareness of secondary causes of osteoporosis and their evaluation in the adults with disabilities is needed.

Future directions

Bone health is essential to well-being and quality of life in the aging adult. A debilitating condition such as cerebral palsy compromises bone health.

Surprisingly little is known about the true fracture prevalence, the risk factors for fractures, the optimal technology for measuring or assessing bone mass and strength, or the effect of nutrition, physical activity, and various drug modulators in the adult with CP. Clinical research studies are lacking and are difficult to do. A number of barriers, such as the heterogeneity of the individual’s neuromuscular disability, restricted mobility and accessibility to clinical research centers, dispersion of care among many clinical centers specializing in the care of CP, and cognitive or communication factors, restrict these studies. Informed consent is another important aspect of clinical research that may be difficult to address in the more seriously cognitively impaired. The need for these studies is great as this population survives into old age. The following recommendations for future research are presented, in the order in which information has been presented in this paper.

Epidemiology

More epidemiological studies are needed to better understand the incidence and prevalence of fractures or poor bone healing, e.g. from orthopedic procedures, in adults. The few studies from which fracture data in CP can be gleaned date from the middle of the last century. These studies may not be relevant to today’s adult. For example, in children, such improvements as the ability to survive previously high-risk surgeries and fatal infections have changed the nature of the disability in the modern adult with CP. This may, in turn, influence fracture susceptibility. These considerations underscore the need for updated epidemiological studies of fracture rate and fracture type in the adult with CP.

Health care for adults with CP is now spread among many institutions, large and small. Many small, independent epidemiological or research studies are difficult to financially justify and therefore fund. Resources are wasted with duplication of research at different sites. Moreover, if the study design, methodologies used, and assessment modalities are not in some way standardized, the results from these studies may not be comparable. Clinical centers may need to combine their patients, as well as their resources, to arrive at more-relevant conclusions. Cross-sectional and longitudinal multi-center studies need continued support and development.

The following may help address these concerns: (1) Create a registry for CP participants.

If osteoporosis in the adult with cerebral palsy is supported financially as a health care priority, then creating a large database would be feasible. This could be similar to cancer registries. Such a registry would allow the accumulation of a sufficiently large population base with agreed-upon definitions of clinical parameters. This would be available for multiple research studies, epidemiological or otherwise. Privacy would be an important issue, and initially participation in such a registry would be sporadic. (2) Create a consortium of clinical research centers.

The consortium would function as an oversight group, vetting research proposals from member centers as well as other clinical sites. This could be a way to prevent duplication of research efforts while facilitating multi-center studies. Financial resources could then be better allocated.

Risk factors

A combined database from multiple clinical centers would also facilitate additional epidemiological research such as assessing risk factors for fractures. Research in the field of genetics and molecular biology continues to uncover genetic risk factors for osteoporosis. A better understanding of the genetic factors that lead to fracture risk in all adults, including those with cerebral palsy, is now possible, given the contributions from the Human Genome Project and similar efforts.

Potential areas for future research in the assessment of risk factors for osteoporosis in the adult with CP include the following: (1) Genetic research in the development of CP

CP, a somewhat heterogeneous mix of neurological and neuromuscular insults, was previously thought to be an acquired condition. More and more genetic disorders, however, are being described as comorbidities or even causes of the brain disorder. A theoretical question, based on the close interdependence suggested by the muscle-bone unit concept, is whether an understanding of the genetic influences leading to the perinatal neurological insult would affect the dysfunctional bone in cerebral palsy. These genetic studies would more directly relate to muscle biology. (2) Genetic research in the development of osteoporosis

As we learn more about the genetics and molecular biology of osteoporosis, we are able to define the genetic makeup most prone to fracture. A genetic-risk assessment of those adults with CP who fracture more readily would greatly help focus bone care. For example, individuals with genetic markers for abnormal bone mass could be selected for earlier assessment and more-aggressive interventions to help prevent fracture-related morbidities, and thus a worsening disability. These genetic studies would more directly relate to bone biology. (3) Development of guidelines for screening secondary causes of osteoporosis

A better and more timely assessment of other clinical contributors to poor bone health would slow the decline in bone health associated with aging. Screening guidelines for these conditions should recognize the greater likelihood of their occurrence in the adult with CP while avoiding unnecessary investigations. Such conditions as premature hypogonadism (e.g. menopause or andropause), growth hormone deficiency, or other types of pituitary failure should be screened periodically. This requires the development of better health-care algorithms.

Measurement

Bone mass or BMD is much more difficult to measure in the disabled adult than in the abled population. An important area for clinical research is the development of novel sites or technologies to circumvent these difficulties.

BMD testing is the most common technology used to assess bone mass. Measurement of BMD in adults with CP has been hindered by surgical and other artifacts, as well as by positioning difficulties involved in scanning the participant. Development of new technologies or modifications of existing ones is needed to overcome these issues and better assess bone microarchitecture.

The use of QUS in CP is an example of such technology. This would require better reference standards for its use in the adult with CP. Peripheral QCT may also be more useful in the CP adult who cannot tolerate certain positions or endure the scanning time needed for some techniques. More portable technologies and better reference standards await future investigations.

DXA still has the advantages of widespread use, minimal radiation exposure, precision, and use in many previous clinical studies. It is imperative to exploit this technology as much as possible in the CP population. Faster scanning times would diminish the motion artifact typically seen in DXA scans of individuals with CP. Alternate peripheral regions of interest for scanning would help avoid skeletal sites most prone to surgical intervention and therefore hardware artifacts. Precedents have already been established in children with CP in the exploitation of the distal femur as a site that meets some of these criteria. The participant can be more easily positioned for scanning this region and there are fewer DXA-dependent artifacts. More studies are needed in the application of this site to adults with CP. Reference standards for the distal femur in both the disabled and abled populations are necessary.

Research is needed in assessing body composition, as is more reliable and reproducible anthropometry in the adult with CP. These are vital to a better understanding of the nutritional impact on bone health.

Treatment

Information obtained from studies examining the effects of nutritional intake and physical activity on bone health that have been performed in abled adults may not have relevance to the adult with CP. Clinical adult research using precise classifications of the severity of CP is needed to confirm, e.g. the effect of calcium and vitamin D supplementation on fracture rate as well to define the minimal intake needed for these benefits. The same holds for other vitamins and micronutrients that influence bone health. Multiple or integrative effects of various nutrients and physical activity may be different in persons with CP.

Pharmacological interventions in those who have established osteoporosis (i.e. treatment) or in those who are at risk for osteoporosis (i.e. prevention) have been extensively studied in the abled population. These studies have been extrapolated to the adult with disabilities. However, the type of fragile bone leading to osteoporosis in the adult with CP may be different from that seen in most adults with primary or senile osteoporosis. Basic bone-biology research is yielding an in-depth understanding of the regulation and function of the two most important cells in the bone: the osteoblast and the osteoclast. As we learn more about the roles these cells play in different types of osteoporosis, treatment modalities become more rational and selective.

A better understanding of the unique aspects of cellular dysregulation in the adult with CP is also a necessary prelude to the development of treatment strategies unique to the neuromuscular character of the muscle-bone unit in CP.

Another practical area of research would be investigation into the development of a more regional anatomic approach to treating fragile bones. For example, the adult with diplegia may be at greater risk of lower-extremity fractures than of fractures of the wrist or spine; or a hemiplegic adult could be at a greater risk of fracturing either the more- or the less-involved side. Current treatments for osteoporosis affect bone throughout the skeleton, even in sites where fracture is unlikely. This extensive whole-body exposure may be unnecessary and may even be harmful in certain cases. Much more research is needed to explore the feasibility and methodology of localizing treatment with these pharmacological agents. Use of the bisphosphonates with localized infusions awaits better methods of vascular access for the extremity of interest. These issues are especially pertinent to the adult with CP.

The bisphosphonates are the most prescribed treatments for osteoporosis. Although there are some studies in the use of, for example, pamidronate in children, less is known about its use in adults with CP. There is a need for randomized, placebo-controlled, multi-center trials looking at the benefits as well as the risks in the adult with CP. For example, the side effects of the oral bisphosphonates on gastric or gastroesophageal irritation are more relevant to the adult with a long history of gastroesophageal reflux disease. The results from studies in children may not be easily extrapolated to adults. Additionally, the newer bisphosphonates, such as ibandronate and zoledronic acid, may be more useful in this group, given their infrequent dosing and intravenous route. One drawback in all of these studies is the number of patients needed to see a true clinical effect on fracture rate.

In summary, future basic and clinical research in osteoporosis in adults with CP need to be multi-centered and centrally funded if possible. This research needs to be focused on the aspects of bone biology, clinical risk factors, techniques of measuring bone mass or strength, nutritional needs, physical activity interventions or their surrogates, unusual pharmacology, and specialized pharmacological treatment modalities that are unique to adults with CP.

Ancillary