Osteoporosis is a skeletal condition of compromised bone strength accompanied by an increased risk of fracture 1. Bone strength reflects both bone density and bone quality. According to the International Society for Clinical Densitometry, osteoporosis in the pediatric population is defined as the presence of both a clinically significant fracture history and a bone mineral density (BMD) Z-score ≤ -2.0. A clinically significant fracture history includes:
Two or more long bone fractures by the age of 10 years
Three or more long bone fractures by the age of 19 years 2.
Primary osteoporosis in the pediatric population occurs due to an intrinsic skeletal defect of genetic or idiopathic origin. Osteogenesis Imperfecta (OI) is the most common condition, with an incidence of 1 in 25,000 births 3.
Secondary osteoporosis in children is due to either the effects of a chronic disease process on the skeleton or its treatment. With medical advances resulting in improved survival rates and long-term outcomes, complications such as secondary osteoporosis are on the rise in children with chronic diseases 3.
Epidemiology including risk factors and primary prevention
In healthy children, 80% of fractures occur in the upper extremities. Risk factors for fractures include age, gender, previous fractures, genetic predisposition, poor nutrition, total body mass, vigorous physical activity and, equally, lack of physical activity 3.
In non-ambulatory, disabled children, 70% of fractures are in the lower extremities, with over 50% occurring at the distal femur. Prevalence of osteoporosis in children with cerebral palsy (CP) is up to 50%. CP) is the most common chronic pediatric disability associated with pediatric osteoporosis. The prevalence of osteoporosis in children with CP is up to 50%, and the annual fracture rate in patients with CP is approximately 5%, double that of a normal age-matched population 4. Osteoporosis associated with chronic disease is often secondary to limited mobility, lack of weight-bearing activity, reduced muscle strength, endocrinologic disorders, limited sunlight exposure, poor nutrition, and use of certain medications.
Several commonly prescribed medications can reduce BMD, including glucocorticoids, anticonvulsants 5, antidepressants 6,7, and Proton Pump Inhibitors (PPIs)8. In illnesses such as rheumatic disorders, nephrotic syndrome, leukemia, and Duchenne Muscular Dystrophy(DMD), which are all commonly treated with glucocorticoids, the prevalence of vertebral fractures ranges from 7-32 % and the 12-month incidence from 6-16 % 9.
Mechanical stress on bone is needed to stimulate osteoblasts to create bone; after all, bones adjust their strength in proportion to the stress placed upon them. Consequently, children with disabilities often have smaller, thinner bones with lower cortical mass due to reduced mechanical stress and weight bearing.
In addition to mechanical stress, vitamin D and calcium are essential to maintaining bone health and strength; low calcium and vitamin D levels lead to reduced bone density and sometimes excessive osteoclast activity 10,11. Children with disabilities are at increased risk for low calcium and vitamin D due to poor nutrition, oral motor feeding difficulties, gastrointestinal malabsorption, and limited sunlight exposure. Overall, the presence of malnutrition increases the likelihood of low BMD by nine-fold 12.
Finally, endocrinologic disorders, such as hypogonadism, hyperthyroidism, hyperparathyroidism, and growth hormone deficiency, which are more prevalent in children with chronic diseases, also negatively impact bone mass development by increasing bone resorption.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Increased fracture risk has been associated with several factors:
- Prior fracture
- Increased body fat
- G-tube dependence
- Impaired cognition
- Decreased or no ambulation
- Minimal sun exposure
- Selected medication use
Without intervention, BMD continues to reduce, and the risk of osteoporosis increases over time.
Specific secondary or associated conditions and complications
Fractures can lead to several complications such as deformity in growing bones, contractures, pain, and a predisposition for pressure ulcers, respiratory and gastrointestinal difficulties, and secondary fractures. Femur fracture in a still ambulatory child with Duchenne Muscular Dystrophy may be the precipitating event resulting in premature loss of ambulation.
2. ESSENTIALS OF ASSESSMENT
- Pertinent medical history
- Chronic medical disorders (e.g., CP, malabsorption syndromes, renal or liver disease)
- Endocrine disorders
- Pain in a limb or joint
- Previous fractures
- Nutrition history
- Significant weight gain or loss
- Typical daily food intake (Note that vegan and low/no milk diets are at higher risk of low calcium and vitamin D levels)
- Use of vitamins and supplements
- Medication use
- Proton pump inhibitors
- Antidepressants (SSRIs and SNRIs)
- Daily activity level
- Time per day spent weight bearing
- Daily sun exposure
- Time in a splint/cast
- Frequency of falls
Weight, length, and skinfold thickness help estimate nutritional status. Assessment of pubertal stage is valuable since children with delayed puberty may lack adequate sex steroids required for bone development. The presence of hip dysplasia, femoral anteversion, and contractures are important to note because they may affect imaging performed for BMD evaluation.
The primary functional assessment tool is gait evaluation. Namely, in children with CP, the Gross Motor Functional Classification System (GMFCS) -Expanded and Revised is used to classify motor function ranging from community ambulators (I) to dependent, non-ambulators (V). Children with GMFCS scores of IV and V have a significantly higher incidence of osteoporosis than those with scores of I to III. This pattern is similarly true when evaluating children with other types of chronic immobility 10, 13-15.
- 25-hydroxy(OH) Vitamin D level
The National Osteoporosis Foundation uses the following criteria:
- Vitamin D deficiency: < 10 ng/mL.
- Vitamin D insufficiency: 10-30 ng/mL.
- Vitamin D sufficiency: > 30 ng/mL.
- Calcium, phosphate, parathyroid hormone, and magnesium levels
- Alkaline phosphatase, osteocalcin, and N-telopeptide (markers of bone turnover)
- Urine calcium/creatinine level (to evaluate for hypercalciuria)
- Serum procollagen type I N-terminal propeptide (PINP), a marker of bone formation, and serum collagen type I cross-linked C-telopeptide (CTx), a marker of bone resorption. Recently, the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine have recommended these two markers for BMD evaluation, both of which have been studied in healthy children in order to generate reference data 9.
Dual-energy x-ray absorptiometry (DXA) scan is the most commonly used and widely available technique to measure bone mass and density in children: it is highly reproducible, inexpensive, and confers low radiation exposure 9. Baseline DXA is recommended by 18 years of age or 2 years after the end of chemotherapy for cancer survivors but earlier in pediatric patients with a history of fracture, low body weight, chronic glucocorticoid therapy, delayed puberty, or gonadal failure 16.
DXA is a 2-dimensional study not a volumetric measurement. Since there is inherent variance in this measurement secondary to size (e.g., increased height results in relatively larger bone area values), values must be compared to age- and sex-specific normative values. For children, Z-scores rather than T-scores are used. Low DXA Z-scores (≤ -2.0) are one measurement used to assess increased fracture risk and may also be used to assess need for and effectiveness of treatment. DXA scans should not be performed more than every 6 to 12 months 2. The results from machines of different manufacturers are not necessarily comparable.
Posterior-anterior (PA) spine and total body less head (TBLH) are the preferred skeletal sites to measure BMD in pediatric patients. The hip is not a preferred site in this population due to the possibility of immature skeletal development, hip dysplasia, contractures, and femoral anteversion. Vertebral measurements may be complicated by scoliosis or kyphosis. Finally, femur measurements are technically feasible in children, but there is insufficient information regarding methodology, reproducibility and reference data for this measurement site to be clinically recommended at this time 2.
Quantitative computerized tomography (QCT), a volumetric measure of BMD of the hips or spine, is primarily a research technique used for BMD assessment. Clinically, QCT may be useful for measuring BMD of the spine of individuals with scoliosis, disk space narrowing, compression fractures, or osteophytes, all of which can affect the accuracy of DXA results. According to the American College of Radiology, in these instancese the following criteria are used:
- Osteoporosis: BMD < 80 mg/cm3
- Osteopenia: BMD 80-120 mg/cm3
- Normative: BMD >120 mg/cm3
Fragility fractures for children with restricted mobility often occur during routine daily activities. Door sills, rug edges, and other obstacles can increase the risk for falls in ambulatory children. The presence of door jams, bed covers, and seat belt straps, which can catch the leg or arm of wheelchair users, may further increase the likelihood of falls and subsequent fracture.
Children with disabilities typically receive less sun exposure, which is the primary source of Vitamin D, than non-disabled children. The National Osteoporosis Foundation recommends 10 minutes of sun exposure to bare skin once or twice a day, depending on skin type, without sunscreen 17.
Professional IssuesFragility fractures are most common in a physically vulnerable population. For non-verbal children presenting with fractures and no known traumatic event, the need for investigation of potential abuse may be warranted. Previous clinical assessment documenting fracture risk may help in the acute care assessment. It is also essential to fully address pain control needs for non-verbal children, assessing this through behavioral observations.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Unfortunately, none of the medications approved for adult osteoporosis (e.g. bisphosphonates (BP), parathyroid hormone (PTH), or denosumab) is approved for use in children by the United States Food and Drug Administration (FDA). While there are still no established treatment guidelines for children with osteoporosis, supplementation of calcium and vitamin D should be standard of care for all children at risk. Use of BPs is increasing but remains controversial outside of the child with osteoporosis and fragility fractures 18,19; in general, treatment with BPs in the pediatric population is reserved for those who sustain long bone or vertebral body fractures.
Overall, optimal timing, dosing, and duration of BP in the pediatric population is still largely undetermined due to lack of large-scale, randomized controlled trials. The original pamidronate study recommended a dose of 0.5–1 mg/kg per day administered over 3 days every 3 months 20,21. One study of 25 children with quadriplegic cerebral palsy demonstrated a significantly lower fracture rate following 1 year of treatment with pamidronate 22. More recently, BPs such as zoledronate, which has the benefit of higher potency and less frequent administration, are being used. One retrospective cohort study showed that intravenous infusions of zoledronate (0.025–0.05 mg/kg per day, commonly given over 30 min as a single dose, every 6 months) are associated with improvement in BMD, reduction in bone turnover, and improved vertebral shape at 12 months 23.
While there are benefits to BP therapy, potential late effects of long-term, continuous BP treatment remain a concern. The anti-resorptive effect of BP therapy impedes bone remodeling, thus inhibiting normal bone repair, with a risk of increased bone stiffness, microcracks, and delayed healing of osteotomies in children 3. Given these concerns, more evidence is needed to assess whether ‘treatment holidays’, switching from treatment to maintenance intravenous regimens with less frequent cycles, or oral BP may be safer or beneficial to avoid these potential late effects of BP therapy in childhood.
BMD parameters are tracked as a measure of efficacy following initiation of BP therapy; however, there are no studies which have addressed which BMD increment or cut-off is associated with a clinically acceptable decrease in fracture rates post-treatment. In the absence of such data, a reasonable rule of thumb is to aim for a BMD Z-score >−2 SD 9. Typically, this equates to a minimum of 2 years of treatment, the time point at which the maximum benefit from bisphosphonate therapy has been observed in children with OI 24. Once the patient is clinically stable, a lower (half-dose or less) maintenance protocol is given until the patient attains final adult height, at which time treatment can be discontinued if the patient is stable 9.
Of note, to minimize the risk of hypocalcaemia from BP treatment, the serum vitamin D level should be >50 nmol/L prior to the first infusion, and adequate calcium intake should be maintained post-infusion 25.
At different disease stages
Current treatment centers on adequate nutrition, increased physical and weight bearing activity, and vitamin D/calcium supplementation. Correction of vitamin D deficiency may require doses that are substantially higher than the recommended dietary allowance for children.
According to the National Institute of Child Health and Human Development, to maintain optimal bone health, young children aged 2 to 5 years should play actively several times a day, while children aged 6 to 17 years should get at least 60 minutes of physical activity every day 26. High impact activity has an anabolic effect on the growing skeleton and has been shown to increase bone mass in healthy children, particularly those prepubertal and in early puberty 27. Similarly, physical therapy may help improve protective muscle strength, balance, and return to safe mobility after a fracture 13,14.
Although the impact of physical activity in children with chronic illnesses remains virtually unchartered, a pilot study in children after cancer therapy showed an increase in total body and femoral neck BMD compared to controls after 6 months of group-based aerobic and strength training exercises 28. For non-ambulatory children with CP, passive standing has been shown to decrease the risk of vertebral fractures but not lower limb fractures 29. Even more, dynamic standing has been shown to be more effective than passive standing for increasing BMD in non-ambulatory children; however, additional studies are needed to determine the optimal parameters of mechanical loading (ie, mode, frequency, intensity, and duration) 30.
Coordination of care
Treatment of osteoporosis in the pediatric population often involves a team-based approach. The team may include pediatric rehabilitation physicians, dieticians, endocrinologists, rheumatologists, and radiologists, who interpret the DXA scans; physical therapists and school personnel to ensure adequate weight-bearing activity and provide environmental guidelines for those at risk for fractures; and orthopedic surgeons to perform surgery to stabilize fragile or fractured bones and to correct bony deformities.
Patient & family education
Prevention remains the key component of osteoporosis treatment; therefore, early education of fracture risk factors and early initiation of weight-bearing activities and nutritional supplements are imperative. Safe transfers and safe means of mobility can be taught with the help of physical and occupational therapists. Children with disabilities are often handled by multiple family members, personal care workers, medical staff, and school personnel on a daily basis; thus, education of all caregivers with regard to appropriate equipment use, transfer and positioning methods, and range of motion exercises is necessary. Safety support needs for ambulatory children may be high, and it may be challenging to balance the encouragement of weight bearing activity against the risk of injury from falls.
The ultimate outcome measurement for treatment of osteoporosis is prevention and reduction of fractures. Most research has focused on improving BMD, which has not directly correlated with fracture reduction, especially in the pediatric population 13. Pain relief, reduction of deformity, return to school, and participation in family activities are also measures of successful treatment outcomes.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
More frequent and higher-impact exercise through adapted physical education in school, community recreation, and mobility aids is encouraged for partially mobile children. Research into technological solutions to facilitate bone loading for children without high-impact exercise options is needed.
Based on studies in adults, high frequency, low amplitude whole body vibration (WBV) is being developed as a non-drug therapy to increase muscle force and mobility in children 3. A randomized study in mice with OI showed improved cortical and trabecular bone with WBV 31, and an observational study in children with OI demonstrated improved ground reaction force, balance and mobility 32. However, small randomized clinical trials conducted in children with CP receiving approximately 9 min/day of WBV, five times a week, demonstrated greater walking speed but no effect on bone 33. Clearly, larger, long-term studies are needed.
Ongoing investigational therapies for osteoporosis treatment include Strontium ranelate, osteoclast inhibition with monclonal antibodies, synthetic human PTH, and cathepsin K inhibitors. In one recent study, strontium ranelate was able to effectively reduce fractures in an animal model of OI by improving bone mass and strength, thus representing a potential therapy for the treatment of pediatric OI 34.
To date, denosumab use has been reported in a few children with osteoporosis due to OI and in children with giant cell tumors, aneurysmal bone cysts, and fibrous dysplasia 9. While there is no evidence of an adverse effect on human growth plate activity, hypercalcemia post-discontinuation of denosumab has been reported in several pediatric cases (at a much higher rate than seen in the adult population) and may be a potential limitation 35. Finally, teriparatide, a synthetic version of PTH, is currently being used in adults to directly stimulate bone formation; however, it is currently contraindicated in children due to the risk of osteosarcoma reported in rodent models 36. At this time, there are no pediatric studies with cathepsin K inhibitors available.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Overall, studies of BP use in children have been small and of short duration, and optimal timing and dosing of BP in the pediatric population is still undetermined. Bone mass accrual is fastest during puberty, which may be an optimal time to maximize pharmacologic intervention. There is no data to confirm whether individuals treated with BPs as children maintain bone density into adulthood or have decreased fracture rates over subsequent decades 11,15,18,37.
Many children with disabilities cannot perform or access the type of high-impact exercise needed to build BMD. There is insufficient evidence that passive weight-bearing devices have long-term benefits; the combination of vibration plates and standing devices has had limited study. Research is needed to define the intensity and duration of weight bearing activity needed to provide sustained benefits in children with low BMD 15,18,37.
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- Shea MLO, Garfield LD, Teitelbaum S, et al. Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2013;24(5):1741-1749.
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Original Version of the Topic
Jill R. Meilahn, DO, Deb McLeish, Michael Ward, MD, Elizabeth Moberg-Wolff. Osteoporosis / osteopenia in children. 09/20/2014.
Christina Kokorelis, DO
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Melissa Trovato, MD
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