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Disease/Disorder

Definition

Osteoporosis is a skeletal condition of compromised bone strength accompanied by an increased risk of fracture.1 Bone strength reflects both bone density, size and bone quality with the latter affected by microarchitecture, bone remodeling and mineralization.2 In contrast to adults, osteoporosis in the pediatric population should not be made solely on densitometry. According to the International Society for Clinical Densitometry, pediatric osteoporosis is defined as the presence of one or more vertebral fractures not associated with either localized disease or significant trauma or 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.3

The term osteopenia, used in adults to describe densitometry T scores of between -1 and -2.5, is not recommended in children and is instead replaced with “low bone mineral mass” or “low bone mineral density” in children with low Z-scores on densitometry without fracture history as above.3

Etiology

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.4 Other causes include Idiopathic Juvenile Osteoporosis and Osteoporosis-pseudoglioma syndrome.2

Secondary osteoporosis in children is due to either the effects of a chronic disease process or it’s treatment, including immobility, on the skeleton. 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.4 Glucocorticoid use and the underlying inflammatory conditions often being treated by this medication class are among the most common contributors to secondary osteoporosis.5

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.4

In non-ambulatory, disabled children, 70% of fractures are in the lower extremities, with over 50% occurring at the distal femur. Cerebral Palsy (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.6 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,7 antidepressants,8,9 Proton Pump Inhibitors (PPIs), and histamine H2 receptor antagonists.10,11 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 %.12

Patho-anatomy/physiology

Mechanical stress on bone is needed to stimulate osteoblasts to create bone as bones adjust their strength in proportion to the stress placed upon them. Peak childhood bone mass and quality dictates adult bone strength. Consequently, children with disabilities often have smaller, thinner bones with lower cortical mass due to reduced mechanical stress and weight bearing leading to increased fracture risk across the lifespan.5,13

Cytokine and growth factors produced by skeletal muscle and known as myokines are also involved in bone metabolism. Decreased activity, medications and procedures inhibiting muscle contraction may affect myokine secretion, potentiating the effects of impaired mobility on bone structure and strength.14

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.15,16 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.17

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:

  1. Prior fracture
  2. Increased body fat
  3. G-tube dependence
  4. Impaired cognition
  5. Decreased or no ambulation
  6. Minimal sun exposure
  7. 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, 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.

Essentials of Assessment

History

  1. 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
  2. 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
  3. Medication use
    • Steroids
    • Anticonvulsants
    • Proton pump inhibitors and H2 blockers
    • Antidepressants (SSRIs and SNRIs)
    • Chemotherapy
  4. Daily activity level
    • Time per day spent weight bearing
    • Daily sun exposure
    • Time in a splint/cast
    • Frequency of falls
    • History of immobility

Physical examination

Weight, length, and skinfold thickness help estimate nutritional status. Postural and spinal exam may indicate vertebral involvement. 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.

Functional assessment

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.15,18,19,20

Laboratory studies

  1. 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.
  1. Calcium, phosphate, parathyroid hormone, and magnesium levels
  2. Alkaline phosphatase, osteocalcin, and N-telopeptide (markers of bone turnover)
  3. Urine calcium/creatinine level (to evaluate for hypercalciuria)
  4. 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.12
  5. When etiology is unclear, screening for malabsorption syndromes such as celiac disease or inflammatory bowel disease should be considered.

Imaging

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.12  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.21 In children with hematopoietic stem cell transplantation, annual bone mineral densitometry and vertebral fracture assessment is recommended.22 Vertebral fracture screening should be performed routinely in high risk patients including those with back pain, known low bone mineral density and those treated with steroids.23

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. However, osteoporosis cannot be diagnosed off of densitometry alone. 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.3

Quantitative computerized tomography (QCT), a volumetric measure of BMD of the hips or spine, is primarily a research technique used for BMD assessment and confers the highest radiation dose of any test of bone density. 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 instances the following criteria are used:

  1. Osteoporosis: BMD < 80 mg/cm3
  2. Osteopenia: BMD 80-120 mg/cm3
  3. Normative: BMD >120 mg/cm3

Environmental

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.24

Professional Issues

Fragility 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.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Goals in management of pediatric osteoporosis and low bone mineral density are centered around optimizing peak bone mass, preventing pain, fractures and scoliosis, and improving function, and mobility.

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,25,26,27 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.28,29 One study of 25 children with quadriplegic cerebral palsy demonstrated a significantly lower fracture rate of almost 70% following 1 year of treatment with pamidronate, in spite of return to pre-treatment BMD levels.30 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.31 While BP treatment does increase BMD in pediatric CP patients, randomized controlled trial evidence is limited with even less data on the role of BP on fracture reduction rates. Overall, BP treatment is probably efficacious in increasing BMD and possibly in reducing fracture rates.32

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.4 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.12  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.33 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.12

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.34

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.35 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.36 Similarly, physical therapy may help improve protective muscle strength, balance, and return to safe mobility after a fracture.18,19

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.37  For non-ambulatory children with CP, passive standing has been shown to decrease the risk of vertebral fractures but not lower limb fractures.38 Another small study found programmed standing trending towards being an effective treatment to improve BMD in pediatric CP, though the results did not achieve statistical significance.39 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 (i.e. mode, frequency, intensity, and duration).40

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.

Emerging/unique interventions

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.18 Pain relief, reduction of deformity, return to school, and participation in family activities are also measures of successful treatment outcomes.

Cutting Edge/Emerging and Unique 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 and other solutions to facilitate bone loading for children unable to perform high-impact exercise options is needed.41

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.4 A randomized study in mice with OI showed improved cortical and trabecular bone with WBV,42 and an observational study in children with OI demonstrated improved ground reaction force, balance and mobility.43 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.44 Clearly, larger, long-term studies are needed. This will be difficult as there are many variables to consider including side-alternating vs vertical vibration, frequency of vibration intervention, duration and dosage.

Ongoing investigational therapies for osteoporosis treatment include Strontium ranelate, osteoclast inhibition with monoclonal 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.45 A more recent article showed comparable efficacy in improving BMD, strength and reducing fractures of strontium ranelate in a mouse model of OI when compared to alendronate, the standard of care.46

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.12 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.47  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.48 At this time, there are no pediatric studies with cathepsin K inhibitors available.

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.16,20,25,49

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.20,25,49

Botulinum toxin, a frequently used management tool for abnormal muscle tone in children with cerebral palsy and other conditions, may affect BMD through decreased mechanic stress from muscles contraction as well as by alterations in myokines. Human studies in temporomandibular joint dysfunction treated with multiple masticatory botulinum toxin injections showed cone-beam computed tomography changes consistent with osteopenia.50,51 Changes in bone structure and strength have also been demonstrated in animal models treated with botulinum toxin.52 Further research is needed to better understand what effect botulinum toxin may have on bone health in pediatric patients as well as what factors may prevent deleterious changes such as injection dosage, toxin type and treatment interval.

References

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  48. Vahle, J., Long, G., Sandusky, G. W., Ma, Y., & Santo, M. (2004). Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicologix Pathology, 426-438.
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  50. Raphael K, T. A. (2014). Osteopenic consequences of botulinum toxin injections in the masticatory muscles: a pilot study. J Oral Rehabil., 555-563.
  51. Raphael K, J. M. (2020). Effect of multiple injections of botulinum toxin into painful masticatory muscles on bone density in the temporomandibular complex. J Oral Rehabil., 1319-1329.
  52. Tang MJ, Graham HK, Davidson KE. Botulinum toxin A and osteosarcopenia in experimental animals: a scoping review. Toxins (Basel). 2021 Mar 14;13(3):213

Original Version of the Topic

Jill R. Meilahn, DO, Deb McLeish, Michael Ward, MD, Elizabeth Moberg-Wolff. Osteoporosis / osteopenia in children. 9/20/2014.

Previous Revision(s) of the Topic

Christina Kokorelis, DO and Melissa Trovato, MD. Osteoporosis / osteopenia in children. 7/3/2018.

Author Disclosure

Melissa Trovato, MD
Nothing to Disclose

Anton Dietzen, MD
Nothing to Disclose