Journal reading 指導醫師：陳嘉玲醫師 Present by R1 ：吳致寬. Company Logo Evidence-Based Review of Bone Strength in Children and Youth With cerebral

Journal reading

指導醫師：陳嘉玲醫師Present by R1：吳致寬

www.themegallery.com Company Logo

Evidence-Based Review of Bone Strength in Children and Youth

With cerebral Palsy

Michal Cohen, MD, Eli Lahat, MD, Tzvy Bistritzer, MD, Amir Livne, MD, Eli Heyman, MD, and Marianna Rachmiel, MD 2009


Cerebral palsy is the most common form of chronic physical disability in childhood

prevalence is 2~4 /1000.Motor involvement being a shared

characteristic. Accumulating evidence demonstrating

children and youth with cerebral palsy suffer low or suboptimal bone strength


Bone strength depends on

1.bone mass the peak bone mass reached 60%~80% : genetic factors 20%~40% : hormonal, extrinsic factors, such as diet, lifestyle, medicationsthe rate of bone loss,2.density 3.structural properties of bone.


Osteopenia and osteoporosis ? ‘‘low bone mass’’ z score that is ≦ 2.0 adjusted for age, gender, and body size.

2007 Official Positions of the International Society for Clinical Densitometry requires

1.Clinically significant fracture history 2.Low bone mineral content or a bone mineral density Osteoporosis : reduced bone mass and abnormal microarchitecture demonstrated by bone biopsy, which is rarely performed in children.


Rickets ?

Fragility fractures and decreased bone mineral density

rickets v.s. osteoporosis. Rickets decreased mineralization of the growing bone deficiencies of calcium, vitamin D, or phosphorus and less commonly the existence of mineralization inhibitors. Dx : serum minerals↓, typical radiological parameters. In this report, refer to low bone mass that is not caused by rickets. adequate calcium and vitamin D requirements are the first assessment and consideration in children with cerebral palsy


Problem

Review of bone health in children with cerebral palsy. We aimed to answer a number of questions:1. Is bone strength impaired in children with cerebral palsy and if so, what are the risk factors for such impairment?

2. Are children with cerebral palsy at increased risk for bone fractures, what are the risk factors, and is it related to bone mineral density?

3. Which methods should be used for bone-health assessment in children with cerebral palsy?

4. How can bone strength be improved in children with cerebral palsy?


Methods

A systematic literature search of PubMed and Cochrane databases between the years 1995 and 2008

Discussion


Question no. 1a:

Is Bone Strength Impaired in Cerebral Palsy?


Bone mineral density and bone mineral content of children with cerebral palsy are lower than age-matched normal values (level III) and (level IIa)

Dual-energy x-ray absorptiometry Follow-up of these children bone mineral density to increase by 2.5% per year not a sufficient increment during childhood Adult osteoporosis bone mineral loss Childhood decreased bone mass insufficient bone mineralization


Tibial peripheral quantitative CT lower cortical bone mineral content, area and

thickness, polar strength-strain index and periosteal circumference in CP patients (level III).

decreased bone strength due to smaller and thinner bones.

High resolution magnetic resonance imaging distal femur trabecular bone micro-architecture markedly underdeveloped in children with CP (level IIa).


Conclusion no. 1a

There are sufficient data in the current pediatric literature to support that there may be significantly decreased bone mass in children with cerebral palsy.


Question no. 1b:

What are the Risk Factors for Impaired Bone Mineral Density in Children With Cerebral Palsy?

Text

CP

Text

Fx

BMD


Risk factor

Best correlate with the degree of bone mineral density (level III)

1.Feeding difficulties with low nutritional status 2.Low weight z scores 3.Child’s motor functional ability lack of weight bearing and impaired muscle function Physical activity most significant modifiable factors in healthy

children.

4.Prolonged immobilization due to orthopedic and other surgery


Risk factor

Antiepileptic drug usage 35% of children with CP Induce the cytochrome P450 enzyme, (such as phenytoin, phenobarbital, and

carbamazepine) impair bone mineralization (level III) & (level IV) Also evidence of reduced bone mineral density valproate, oxcarbazepine, or lamotrigine (level III)


Risk factor

Growth hormone, insulin-like growth factor,1 thyroid stimulating hormone, and sex steroids

found little data dealing directly with the relations between the hormonal status of children with cerebral palsy and their bone density.

Disordered puberty and growth retardation were described in children with cerebral palsy (level III) might cause bone mineral density to be lower

than expected for age


Conclusion no. 1b

Children with cerebral palsy that low body mass index have feeding difficulties, low motor functional ability Delayed puberty and growth Use antiepileptic drugs are at increased risk for low bone mass.


Question no. 2a:

Are Children With Cerebral Palsy at Increased Risk for Bone Fractures?

Text

CP

Text

Fx

BMD


CP Fracture

Fracture risk in the general pediatric population 1.33~3.6 /100 children/ years most common site radius/ulna attributed to trauma during physical activities. Moderate to severe cerebral palsy 15.5% (level III) Following proximal femoral osteotomy surgery 20%(level III). Fracture incidence in children with cerebral palsy 2.98~4.8 fractures /100 children/ years


CP Fracture

Most common sites in children with cerebral palsy lower limbs, femur and tibia (level III) Institutionalized, non-ambulatory children and young adults 6 to 29 years old, with cerebral palsy and rickets dominance of upper extremity fractures was found (level III). The cause for fractures in children with cerebral palsy was often unknown or attributed to minimal trauma and diagnosis was frequently delayed (level III).


CP Fracture

Several risk factors reported: (level III). 1.a history of a previous fracture 2.a feeding gastrostomy tube 3.higher body fat 4.older age 5.rickets 6.antiepileptic drug treatment, 7.seizures not related to the antiepileptic drug treatment 8.hip spica casting, 9.a mixed muscle tone disorder, 10.usage of standing equipment in physical therapy


Conclusion no. 2a

Comparison of fracture rates between the cerebral palsy and healthy children might be inappropriate.

However, given the unique characteristics of their fractures, lifestyle, and risk factors, we suggest children with cerebral palsy who demonstrate one or more of those risk factors should be monitored frequently for symptoms of restlessness, limb deformity, and signs of pathological fractures.


Question no. 2b:

What is the Relation Between Bone Mineral Density and Fractures in Cerebral Palsy?

Text

CP

Text

Fx

BMD


BMD Fracture

Possible relationships between fracture risk and decreased bone mass in the general pediatric population are still debatable

Children and adults with spastic cerebral palsy With history of fractures significantly lower lumbar spine mineral density dual-energy x-ray absorptiometry z scores (level III). King et al


BMD Fracture

Henderson et al reported different results : Lumbar and femoral bone mineral density dual-energy x-ray absorptiometry z scores not significantly related to a history of previous fractures in children with spastic cerebral palsy (level III)


BMD Fracture

North American Growth in Cerebral Palsy project, fracture history related to distal femur bone mineral density z scores but not to spine z scores (level III).

A possible relation between BMD and fractures might be masked by the undiagnosed fractures


Conclusion no. 2b

We believe that even though there is no conclusive evidence regarding the relation between bone mineral density and fractures in these children, a causal association is possible.

Thus, in a child with cerebral palsy and the suggested risk factors a high index of suspicion concerning fractures should be kept.


Question no. 3a:

What Methods are Available for Assessing Bone Health in Children With Cerebral Palsy?


Dual-energy x-ray absorptiometry(DEXA) Currently the method of choice analyzes the attenuation of x-rays of 2 energies transversing through bone to estimate its density and mass.


Dual-energy x-ray absorptiometry(DEXA)

1.Bone mineral content in grams2.Bone mineral density in grams per cm2, bone mineral content / bone area, 3.Volumetric bone mineral density in grams

per cm3 considering thickness as well4.Bone mineral density z score below -2 is considered low bone mass.



Rapid, easy to use, accurate, and reproducible

Limitations in children: 1. 2-dimensional technique, does not measure a true volumetric density results are influenced by bone size and shape. In growing children, bone dimensions of different regions change consistentlybone mineral density z scores consider average height and weight during youth. inaccuracy of bone mineral density assessment



2.DEXA assumes homogeneity in the composition of soft tissues near the bone unknown and variations 3.In lumber spine assessments, posterior vertebral elements might increase bone mineral density estimations.4.Reaching the machine is a limiting factor Severely disabled children and positioning 5.Surgery, osteotomy, or metallic fixation devices might impair interpretation.6.Radiation exposure less appealing as a tool for screening or follow-up.7. Bone density at different sites is not equally



Whole-body DEXA bone mineral content Includes all skeletal regions Including trabecular and cortical regions Adjustments for height variability low radiation, though a longer scanning time


Quantitative computed tomography.

3-dimensional technique, true volumetric measurements (volumetric bone mineral density) assess bone size and shape and differentiate between cortical and trabecular bone.

Limitations 1. lack of complete normative pediatric database2. the high radiation involved 3. a significant cost-accessibility difficulty4. possible interference by movement and metallic devices


Quantitative computed tomography.

Peripheral quantitative computed tomographyholds the advantages of quantitative computed

tomographywith less radiation involved


Quantitative ultrasound.

Ultrasound transducers quantitate the transmission velocity through the bone evaluated as well as the signal attenuation.

Normal values according to age and gender exist. Not involving ionizing irradiationSimplicity of use, short test timeLower costSmall and portable device


Quantitative ultrasound

Limitations of this method are 1. technical problems due to very thick soft tissue or severe agitation2. the limited experience in children 3. measurements might be affected by temperature 4. quantitative ultrasound has been evaluated in comparison to bone mineral density measurements in both healthy children and children with various chronic illnesses, there is lack of reproducibility.


Magnetic resonance imaging

Uses the principles of magnetism to create 3-D images. negative image of bone matrix positive image of interstitial space between trabeculae

The advantage of MRI not exposing subjects to irradiation provide various cross sections without moving patient good reproducibility in children with cerebral palsy

(level IIa).


Magnetic resonance imaging

Limitations are 1. Age limitation: magnetic resonance imaging is

optimal when cancellous bone is surrounded by fatty marrow and thus less optimal in children

2. Cannot be used for children with metallic devices, as many cerebral palsy children are operated

3. long scan durations4. subject motion can interrupt imaging.


Biochemical turnover markers.

Specific markers of bone formation Serum bone specific alkaline phosphataseosteocalcincarboxyl (C)-terminal extension of procollagen type Iamino (N)-terminal extension of procollagen type III


Biochemical turnover markers.

Markers of bone resorptionUrinary hydroxyprolineHydroxylysineN-telopeptidePyridinolineDeoxypyridinolineCarboxyterminal telopeptide of type 1 collagenBone specific hydroxypyridinium collagen cross links


Question no. 3b:

Which is the Most Applicable Assessment Method in Children With Cerebral Palsy?


Conclusion no. 3b

Dual-energy x-ray absorptiometry most widely used most data presented are based on this method. best combination of cost, ability to adjust for body size, and availability suggest whole body is preferable. Quantitative CT and peripheral quantitative

CT accurate however less accessible High-resolution MRI reproducibility was very good (level IIa) MRI and quantitative CT do not seem feasible to us in daily life context.


Conclusion no. 3b

Blood and urine bone and specific markers evaluate bone turnover pathophysiology of reduced bone strength not yet applicable as a monitoring or survey method More reference data should be gathered from quantitative ultrasound, peripheral quantitative CT, and distal femur DEXA prior to using them regularly.


Question no. 4:

How Can Bone Strength Be Improved in Children With Cerebral Palsy?


Physical activity and load bearing

Possible benefit from physical activity & load bearing suggested by small randomized controlled studies

(level Ib).

Load bearing physical activity for eight months nine children with spastic CP femoral bone mineral content↑ 9.6% ~ 11.5% femoral volumetric bone mineral density↑5.6% compared with a -6.3% change in the control group.



A randomised controlled trial of standingprogramme on bone mineral density in non-ambulant children with cerebral palsy

Increase duration or frequency

QCT

140.6 %

80.5 %

9 month



Prolonging standing duration in children with CP vertebral vBMD density increase 8.16mg/cm3 (6%) (95% CI 1.93 to 14.39; p=0.01). tibial volumetric bone mineral density -0.85 mg/cm3 (95% CI 216.83 to 15.13; p=0.92)



Low magnitude mechanical loading is osteogenic in children with disabling conditions Children with disabling conditions(CP & MD) Interventionvertical ground-based vibration small plate oscillating at 90 Hz(0.3G) displacement < 100 μm 10 min/day, 5 days/week for 6 months


Outcome: vTBMD of Proximal Tibia & spine (L2)

↑6.27 mg/ml (↑ 6.3%)

↓9.45 mg/ml (↓11.9%)

SPINE

Mean change = 6.72 mg/ml (p=0.14),( 4.7% difference, p=0.31)

+7.29 mg/ml (5.5% increase over baseline)

+0.56 mg/ml (0.3% increase from baseline)

v.s

TIBIA


compliance was low (44%)


Vitamin D and calcium supplementation

Two studies 1.Vitamin D decreasing fracture rate in children with severe CP and rickets (level III) 2.Vitamin D and calcium to children with severe CP and epilepsy treated with various AED

increase bone mineral density (level IIa)


Bisphosphonates.

Bisphosphonates improve bone status reduce fracture risk in children with CP Intravenous pamidronate in children with severe CP reduced bone density (level IIb), In quadriplegic CP (femoral z score –4 vs –1.8) (level Ib) CP + history of fractures and low bone mineral density (spinal z score -4.1 vs -2.5) (level III). Fracture rate : 0.34 0.04 per person years (level III). During post-treatment follow-up ( 2 to 3 years ) average metaphyseal distal femur bone mineral density z score -1.7 -3.6, fracture rate↓ (level III).


Growth hormone

Insulin-like growth factor 1 Insulin-like growth factor–binding protein 3 decreased in children with cerebral palsy (level III ) support the hypothesis that the growth hormone-

insulin-like growth factor axis is impaired

Five children with cerebral palsy and decreased spinal bone mineral density were treated with recombinant growth hormone for 18 months (level Ib). bone mineral density z score increased 1.17 SDs


Vitamin K

Vitamin K promoting bone formation factor. Vitamin D + vitamin K2 (15 months of treatment) institutionalized bedridden prepubertal children, treated with AED, serum osteocalcin↑ bone formation/resorption markers↑ z score of cortical bone mineral density of 2nd metacarpal bone ↑ (level III).


Conclusion no. 4

Physical activity, especially biomechanical loading the only suggested modality (without any hx of pathological fractures or spinal compression fractures) asymptomatic low bone mass Bisphosphonate treatment should be considered in children with CP history of fractures abnormally low bone mineral density.


Conclusion

In this review, we addressed the short-term aspects of bone health in cerebral palsy.

Most data are derived from nonrandomized descriptive studies, not based on large populations; we found only a few level II studies.


Conclusion

Currently, the best method to detect low bone dual-energy x-ray absorptiometry

Whole-body dual-energy x-ray absorptiometry Data are lacking regarding the reliability and efficacy

of distal femur dual-energy x-ray absorptiometry, peripheral quantitative CT, quantitative ultrasound, and bone markers,


Conclusion

Load-bearing physical activity cannot be overemphasized as primary and secondary prevention Alertness for detection of pathological fractures and

spine compression fractures should be kept fracture is detected in face appropriate roentgenographic characteristics diagnosis of osteoporosis should be raised Therapy with bisphosphonates may be considered.


Reference

A randomized controlled trial of standing programme on bone mineral density in non-ambulant children with cerebral palsy. Arch Dis Child. Caulton JM, Ward KA, Alsop CW, Dunn G, Adams JE, Mughal MZ. 2004;89:131-135.

Low magnitude mechanical loading is osteogenic in children with disabling conditions. J Bone Miner Res. Ward K, Alsop C, Caulton J, Rubin C, Adams J, Mughal Z. 2004;19:360-369.

The effect of weight-bearing physical activity program on bone mineral content and estimated volumetric density in children with spastic cerebral palsy. J Pediatr. Chad KE, Bailey DA, McKay HA, Zello GA, Snyder RE. 1999;135:115-117.


Z-score

Z-scores use an application of statistical theory to describe how far a child's weight is from the

average (for the NCHS/WHO values) weight of a child of the same height in the reference data.

It is expressed in multiples of the standard deviation and is derived as follows:

weight-for-height z-score =observed weight – median weight

standard deviation

▼

Documents

Journal reading 指導醫師：陳嘉玲醫師 Present by R1 ：吳致寬. Company Logo Evidence-Based Review of Bone Strength in Children and Youth With cerebral