Osteoporosis refers to decreased bone density and altered bone microarchitecture, which can contribute to pathologic fractures in (CYSHCN). Osteopenia is decreased bone density that is not to the degree of osteoporosis.

Historically, pediatric osteoporosis was defined as a significantly decreased bone mineral density (BMD) ≤ -2 or 2.5 SD on dual-energy X-ray absorptiometry (DXA); osteopenia was defined as a less decreased BMD of -1 to -2.5 SD. Experts now realize the complexity of ascertaining norms, particularly in different groups of CYSHCN, and that DXA results alone are not appropriate for defining pediatric osteopenia or osteoporosis. As a result, the term osteopenia has mostly fallen out of use among pediatric metabolic bone health experts, whereas the definition of osteoporosis has been broadened to include certain types of fractures, not just DXA scores. (see Diagnosis, below).

Pathologic fractures occur with low force because of weakened bone due to an underlying disease or medical condition. Pathologic fractures include, but are not limited to, fragility fractures, which specifically refer to fractures that occur during routine activities. Many groups of CYSHCN suffer from frequent pathologic fractures. For example, these types of fractures are seen in 4-12% of children with cerebral palsy and in 25-50% of boys with Duchenne muscular dystrophy. [Grover: 2017]

CYSHCN may have osteopenia or osteoporosis leading to pathologic fractures. While some children are born with primary bone conditions, such as osteogenesis imperfecta, many CYSHCN are at increased risk for pathological fractures due to decreased mobility, decreased calcium and/or vitamin D intake, inadequate dietary protein, sex steroid or growth hormone disruptions, decreased absorption of nutrients, increased inflammatory cytokines, and medications. These can reduce bone formation and, in some cases, also increase bone resorption.

This resource explains some of the current thinking about screening, diagnosis, prevention, and treatment of osteopenia and osteoporosis among CYSHCN.

Osteoporosis [Vierucci: 2017]

• Chronic bone pain
• Loss of height
• Skeletal deformity
• Long bone fractures
• Premature loss of ambulation

Pathologic fractures (many children are asymptomatic)

• New skeletal deformities or changes in positioning
• Painful bony areas, swelling, or bruising
• Behavior changes
• Sleep changes

Fragility fractures can occur with daily care (e.g., during dressing), during positioning for X-rays, during physical therapy, or from a seizure. Sometimes a fracture is recognized without any recollection of a traumatic event, and up to half of vertebral fractures in chronically ill children may be painless. [Vierucci: 2017]

Assess Risk Factors

Testing

Pathologic fractures of the long bones or vertebrae signal that the child should be evaluated for osteopenia and osteoporosis, as the diagnosis is important to determine treatment options. Recurrent fractures of the small bones (like the fingers) are not currently considered in the diagnosis of osteoporosis.

Diagnosis of pediatric osteoporosis is complicated and currently defined as at least 1 of the following 2 options: [Vierucci: 2017]

• Vertebral compression fracture not associated with high-impact trauma or local disease is diagnostic of osteoporosis, OR
• Clinically significant, recurrent long-bone fracture history, defined as 2 or more by age 10 -- or 3 or more at any age up to 19 years, AND
• Documented reduced bone mass (bone mineral content or bone mineral density) of at least 2 standard deviations below the norm. DXA scan results are considered the preferred method of obtaining this information in the pediatric population, although there is some use of peripheral quantitative CT. DXA scans in children can be difficult to interpret in light of the historical lack of adequate information about norms in healthy children and because children's bones are in a state of change throughout childhood as they put on more bone mass as part of normal growth.

Note: In contrast to adults, BMD or BMC <= -2.0 SD are not considered diagnostic of osteoporosis without also having a relevant fracture history, and BMC/BMD score > -2.0 SD does not preclude the possibility of skeletal fragility and increased fracture risk. [Bianchi: 2010]

See [Ward: 2016] (requires purchase) for an algorithm of the diagnosis and treatment of primary and secondary pediatric osteoporosis based on the 2013 International Society for Clinical Densitometry’s guidelines for pediatric use. [Bishop: 2014]

Differential diagnosis includes rickets. Children found to have bone fragility rickets should be treated with appropriate replenishment of vitamin D, calcium, and phosphorus prior to further evaluation of bone density. [Vierucci: 2017] Other conditions that can result in look-alike fractures include trauma (accidental and child abuse), osteomalacia (but the bones are soft, not brittle), metabolic disorders that soften bones, tumor and metastases, and infection.

Medical conditions associated with osteoporosis (links lead to Portal modules with diagnosis and management information for the condition):

• Neuromuscular conditions including cerebral palsy, Rett syndrome, muscular dystrophy, spinal muscular atrophy, spina bifida, and others associated with limited mobility
  • Cerebral Palsy
  • Rett Syndrome
  • Duchenne & Becker Muscular Dystrophies
  • Myotonic Muscular Dystrophy Type 1
  • Spinal Muscular Atrophy
• Genetic conditions including primary bone disorders (such as osteogenesis imperfecta) as well as Turner syndrome, Prader-Willi, XXY/Klinefelter syndrome, Cornelia de Lange syndrome, and Down syndrome
  • Turner Syndrome
  • Prader-Willi Syndrome
  • XXY (Klinefelter) Syndrome
  • Cornelia de Lange Syndrome
  • Down Syndrome
• Metabolic conditions including galactosemia, homocystinuria, and Fabry disease
  • Galactosemia
  • Homocystinuria (Classic)
  • Fabry Disease
• Endocrine conditions including hyper- or hypoparathyroidism, growth hormone deficiency, delayed puberty or hypogonadism, type 1 diabetes, and others
• Rheumatologic conditions, such as juvenile idiopathic arthritis and systemic lupus erythematosus
• Renal disease
• Cholestatic liver disease
• Celiac disease, inflammatory bowel disease, cystic fibrosis, and other conditions associated with malabsorption of nutrients
  • Celiac Disease
• Malignancy and patients who have undergone transplantation
• Conditions significantly affecting skin, such as dermatomyositis and epidermolysis bullosa
• Cyanotic congenital heart disease
• Thalassemia
• Prematurity
  • Premature Infant Follow-Up

Medications associated with osteoporosis may include:

• Classic antiepileptics (anticonvulsants), including phenobarbital, carbamazepine, phenytoin, benzodiazepines, and valproate. Since children who start on antiepileptic medications in childhood will be on those medications for many years, the fracture risk by adulthood is substantial. The impacts of newer antiepileptic drugs, such as levetiracetam, oxcarbazepine, lamotrigine, topiramate, gabapentin, and vigabatrin, on bone health are unclear and controversial. [Fan: 2016] [Vierucci: 2017]
• Steroids including progesterone-only contraceptives such as medroxyprogesterone/Depo-Provera or Implanon (unclear data for Nexplanon) and glucocorticoids used for inflammatory conditions [Pongsatha: 2010]
• Methotrexate
• Cyclosporine
• Growth hormone agonists
• Heparin

Mechanisms:

• Valproic acid is thought to directly act on the bone, increasing activity of the osteoclasts (the cells responsible for bone breakdown in the dynamic process of remodeling). [Valsamis: 2006]
• CYP450 hepatic enzyme induction by certain anticonvulsant medications appears to contribute to increased metabolism of 25-hydroxyvitamin D to inactive metabolites, which results in metabolic bone disease. [Fan: 2016]

All children should receive the recommended daily allowance of Calcium and Vitamin D in their diet. Protective measures for bone health include nutrition, weight-bearing exercise, treatment of the underlying disease, and avoidance of medications that contribute to reduced bone density when possible. If a child's diet is at risk, supplements may be necessary to achieve recommended daily allowance; however, it is preferable for the micronutrients to come from the diet when possible. Patients on medications that can reduce bone density, such as anticonvulsants or steroids, could benefit from a higher daily intake of vitamin D than standard recommended daily allowance (in combination with monitoring levels). Some experts recommend up to 2,000 units daily of vitamin D3 for children taking longer-term courses of glucocorticoids. [Fan: 2016]

Exercise should be encouraged for all children. For children with limited mobility, identifying adaptive forms of exercise that optimize participation is important. Children who have limited ambulation should be prescribed appropriate equipment, such as bracing and walkers, to promote mobility. Children who are not able to stand independently should spend an hour or more, if possible, in a stander daily.

Since bone density drops during casting, minimize the duration of casting when possible. Special care must be taken in handling right after coming out of a cast to avoid trauma or undue forces that might cause a fracture in the same area. Aquatic therapy (e.g., exercise in a pool) during this time might provide the safest environment to remobilize and strengthen the affected extremity. Protective splinting should be individualized to the particular clinical scenario.

If pathologic fractures have already occurred, the first step is to:

• Review the child’s prevention program and ensure adequate nutrition, including calories, protein, vitamin D, and calcium intake.
• Reduce exposure to medications that increase the child’s risk (e.g., change to a different anticonvulsant).
• Manage any additional factors that might be contributing (renal or liver conditions, celiac disease, or other conditions causing malabsorption of nutrients and hormone imbalances).
• Provide opportunities for regular exercise. (See Prevention, above).

If these factors have been addressed and pathologic fractures continue and are at a low likelihood of spontaneous recovery, medical treatment of osteoporosis may be considered. Currently, bisphosphonates, which prevent bone resorption, are the main medical treatment for pediatric osteoporosis. Bisphosphonates are employed to reduce risk of recurrent fractures and improve quality of life; however, data supporting these outcomes as well as long-term safety in various CYSHCN are limited.

Bisphosphonate Therapy
The strongest evidence for improvements with bisphosphonate use is in children with osteogenesis imperfecta, glucocorticoid-related osteoporosis, and cerebral palsy. [Vierucci: 2017] Because of the complexity and lack of expert consensus on pediatric osteoporosis, therapeutic decisions regarding bisphosphonates are rarely made based exclusively upon the bone density scores but rather upon the clinical picture in terms of fracture history. Due to evolving information and guidelines, primary care clinicians should consult with a pediatric endocrinologist or other specialist trained in managing bone health in CYSHCN to determine if bisphosphonate therapy is appropriate and to create an individualized plan for the child (Pediatric Endocrinology (see NW providers [1])).

Generally, before starting therapy with bisphosphonates, baseline labs are obtained to ensure adequate vitamin D level, exclude other contributing causes to low bone density, ensure no contraindication (e.g., low-serum calcium), and confirm normal liver/renal function and blood counts since use of these medications could impact these. "Untreated hypocalcemia, hypophosphatemia, vitamin D deficiency, and rickets/osteomalacia are contraindications to bisphosphonate therapy." [Ward: 2016] Experts also consider poor renal function to be a contraindication. [Ward: 2016]

Intravenous bisphosphonate therapy is considered more effective than oral therapies, at least in preventing recurrent vertebral fractures. [Grover: 2017] Most studies of intravenous bisphosphonates for pediatric therapy include pamidronate and zoledronic acid. Oral bisphosphonates, such as alendronate or risedronate, have less evidence for use in pediatrics and side effects can include esophagitis, but only rarely mucosal lesions. [Ward: 2016] Risk of short-term side effects, such as bone pain, fever, and nausea/vomiting (typical only after the first infusion) [Grover: 2017], as well as asymptomatic hypocalcemia and impact on lifestyle and well-being, must be weighed against the anticipated benefits of therapy. Uveitis, thrombocytopenia, avascular necrosis of the jaw, and atypical femur fractures are not clearly associated with bisphosphonates in the pediatric population. [Ward: 2016] [Grover: 2017]

Once therapy is initiated, labs are typically monitored yearly. Bone density is remeasured approximately 12 months after initiation of therapy. Bisphosphonate therapy is typically done for at least 2 years to stabilize the patient and then may be continued at lower doses until growth is completed if risk factors are not able to be eliminated. Therapy duration may be reduced in those with lower risk who achieve stability.

Outside of bisphosphonates, novel therapeutic agents being explored include: [Ward: 2016]

• Denosumab (monoclonal antibody which inhibits osteoclast formation)
• Antisclerostin antibody (to prevent decreases in bone formation)
• Odanacatib (to suppress bone resorption)
• Anti-TGF-beta (transforming growth factor) antibody (which may inhibit progression of certain forms of osteogenesis imperfecta)

However, pediatric outcome and safety data are currently lacking.

Measuring and interpreting bone density is challenging and is best done at a pediatric center with extensive experience in measuring bone density in children. For children with neurodevelopmental disability with positioning challenges or internal metal hardware, special views may be needed (e.g., lateral femur). For children with atypical body composition (e.g., very small stature for age, very low muscle mass for age or size), clinical interpretation can be particularly challenging. Primary care clinicians should partner with experienced pediatric centers when ordering and interpreting DXA scans.

Primary care clinicians should consult with a pediatric endocrinologist or other specialist trained in managing bone health in CYSHCN to determine if bisphosphonate therapy is appropriate and how to tailor it for the individual patient. These specialists may offer useful insight into other ways to reduce risk and manage children with primary or secondary bone disease. Other consultations to consider include specially trained dieticians and physical therapists. Primary care providers can also work with the child's existing specialists (such as a neurologist, rheumatologist, or oncologist) to discuss alternative medication and treatment options that may decrease or eliminate some risk factors for osteoporosis.

Despite the lack of avascular jaw necrosis in children taking bisphosphonates, some experts recommend a baseline evaluation with pediatric dentistry prior to starting medical therapy, coupled with routine follow up and good oral hygiene. [Ward: 2016] Needed oral procedures are recommended prior to medical treatment: however, this recommendation is not evidence-based. [Ward: 2016]

For related subspecialist:

• Pediatric Endocrinology (see NW providers [1])
• Nutrition Assessment Services (see NW providers [0])
• Physical Therapy (see NW providers [0])
• Pediatric Neurology (see NW providers [0])
• Pediatric Immunology (see NW providers [0])
• Pediatric Hematology/Oncology (see NW providers [1])
• Pediatric Hematology/Oncology (see NW providers [1])
• Bone Densitometry/DEXA (see NW providers [0])
• Pediatric Dentistry (see NW providers [2])