Pediatric Osteoporosis

There are several commonly used definitions for osteoporosis. At the National Institutes of Health (NIH) Consensus Conference, osteoporosis was defined as a skeletal disorder characterized by compromised bone strength that predisposes to an increased risk of fracture.[3] The World Health Organization (WHO) defines osteoporosis in adults as a bone mineral density (BMD) at least 2.5 standard deviations (SD) below peak (defined as the BMD achieved by healthy young adults of the same race and gender aged 18-30 years). For adults, BMD is commonly expressed in T-scores, defined by SD from the mean peak BMD, with T-scores at the lumbar spine or hip of < -2.5 defining osteoporosis.

Although this definition is functionally valid for adults, it is not appropriate for children because they have not yet attained peak bone mass. Because the T-score is a measure of BMD compared with early adulthood, its use in children whose BMD and bone mineral content (BMC, in grams) have not yet reached peak will generally yield a low value. Instead, Z-scores are used in children because they reflect SD scores from the mean in comparison to BMD and BMC of healthy children of the same age, gender, and body size. Some but not all Z-score measures also incorporate race.

It is also important to note that BMD is derived from an areal measure, defined as the BMC in grams per selected bone area measured in centimeters squared. It therefore is not a true volumetric density. Unlike adult patients in whom the bone volume does not change over time, a child’s bones grow and model over time, with the growth of individual bones not happening uniformly in 3 dimensions. Sufficient population-based data correlating BMD measures with fracture rates in healthy children are also not available. For all these reasons, the official WHO definition of osteoporosis cannot pertain to children.

At the first Pediatric Consensus Development Conference (sponsored by the International Society for Clinical Densitometry [ISCD]) an official position on the use and interpretation of densitometric studies in children based on expert opinion was released; it was subsequently updated several times.[1, 4, 5]  The following are the most recent pediatric osteoporosis definitions and fracture risk positions in children[1] :

• “The diagnosis of osteoporosis in children and adolescents should not be made on the basis of densitometric criteria alone.”

• “The finding of one or more vertebral compression (crush) fractures is indicative of osteoporosis, in the absence of local disease or high-energy trauma. In such children and adolescents, measuring BMD (bone mineral density) adds to the overall assessment of bone health.”

• “In the absence of vertebral compression (crush) fractures, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and BMD Z-score ≤ -2.0. A clinically significant fracture history is one or more of the following: 1) two or more long bone fractures by age 10 years; 2) three or more long bone fractures at any age up to age 19 years.”

• “A BMC/BMD Z-score > -2.0 does not preclude the possibility of skeletal fragility and increased fracture risk.”

The ISCD guidelines additionally stipulate that dual-energy x-ray absorptiometry (DXA) is the preferred method for assessing BMC and areal BMD (aBMD) in children and adolescents.[1]   Although population-based data on the relationship between BMD and fracture are still limited, population-based reference curves for DXA assessments of BMC and aBMD for total body less head (TBLH), lumbar spine, hip, femoral neck, and distal one-third radius for black and nonblack children in the United States are available from the Bone Mineral Density in Childhood Study (BMDCS).[6]

Unlike in adults, in whom osteopenia is defined as a T-score between -1 and -2.5, use of the word “osteopenia” is not appropriate when referring to pediatric BMC/BMD values. Instead, low BMCs or aBMDs are defined by Z-scores of -2.0 or less adjusted for age, sex and body size (height z-score). "Low bone mineral mass or bone mineral density" is the phrase that is recommended for low BMC or aBMD in the absence of a fracture history suggestive of osteoporosis.[5, 1]

See Osteoporosis for information on non-pediatric osteoporosis.

Low BMD in adults is generally due to net bone loss after peak accrual. In children low BMD can result from loss of bone or, more commonly, failure to accrue adequate bone mineral for the bone size. Some causes of low BMD are also due to inherited conditions, particularly ones that affect collagen amount or function (such as osteogenesis imperfecta).

DXA provides aBMD measures, which are 2-dimensional measurements derived by dividing BMC measured in grams in a specified bone region (eg, lumbar spine) by the bone area (BA) in cm2.  Since it does not account for the depth of the bone, it gives “density” as a reading in g/cm2. This method of assessing BMD is limited because changes in bone volume are not accounted for. This can result in inaccurate estimations of the degree of bone loss or the skeletal response to treatment. 

Low BMD in children results when there is an imbalance between the rates of bone formation and resorption. Low-turnover conditions, characterized by low bone formation, include chronic liver disease, burn injuries, and conditions that affect the bone marrow (eg, leukemias) or their treatments. High-turnover states, such as hyperparathyroidism or hyperthyroidism, can result in an increase in bone resorption.

Bone will not accrue normally when there are deficits of calcium, phosphate, and/or vitamin D or when bone is not exposed to normal physical/mechanical stresses and strains. One population particularly at risk for failure to accrue bone are infants born prematurely. Because most calcium is transmitted from mother to fetus during the third trimester, premature infants do not receive in utero all the calcium their bodies need to normally mineralize. With rapid postnatal increases in bone turnover, fewer opportunities are available for the bones to mineralize.[7]

Furthermore, most of these children receive parenteral nutrition (first as intravenous [IV] fluids and then later as total parenteral nutrition [TPN]) for the first several weeks of life. Calcium and phosphorus requirements are generally not able to be met by TPN in any age group, and infants, especially the very premature infant, can present with poor bone mass and metabolic bone disease.

Other populations of children experience secondary bone loss from adaptations to trauma and infection or threat of infection. These include bone loss due to immobilization as well as loss due to the stress response, in which endogenous glucocorticoids act in the same manner as exogenously administered steroids. These compounds cause an initial increase in osteoblast production of the receptor activator of nuclear transcription factor kappa B ligand (RANKL), which stimulates marrow to produce osteoclastic cells, increasing bone resorption. However, steroids also promote osteoblast apoptosis and reduce marrow cell osteoblast differentiation, eventually leading to a low-turnover bone loss or adynamic bone.

Another mechanism linked to bone loss is the inflammatory response. This involves the production of the cytokines interleukin (IL)–1 beta and IL-6, as well as tumor necrosis factor (TNF) alpha. These can increase bone resorption via stimulation of osteoblast production of RANKL.

Bone mass and, for children, the ultimate achievement of young adult peak bone mass are predominately determined by genetics. Adequate dietary intake and absorption of calcium, phosphorus, and vitamin D are also critical for normal bone accrual.

Phosphorus is relatively plentiful in most Western diets, and therefore dietary phosphorus deficiency that is significant enough to cause bone disease is very rare. Calcium intake is much more likely to be deficient in children, particularly young adolescent girls. The NIH Consensus Conference on Osteoporosis recommended that preadolescent and young adolescent girls have a calcium intake that is 50% more than the intake recommended for younger children and older adults.[8] Dietary calcium supplementation in the preadolescent years may be a key factor in optimizing peak bone mass. However, when dietary calcium supplementation is stopped, data suggest that the increase in bone mass is not maintained.

Another critical factor for optimal bone accrual is exercise. Results from the Bone Mineral Density in Childhood Study showed that self-reported weight-bearing physical activity contributed to significantly greater BMC accrual after adjustment for age, height velocity, Tanner stage, prior visit BMC, and calcium intake in both sexes and both racial subgroups (defined as blacks and non-blacks in this study).[9]

Conditions that adversely affect bone mineralization and strength can result in pediatric osteoporosis. Primary osteoporosis occurs because of an intrinsic skeletal defect of genetic or idiopathic origin. Osteogenesis imperfecta (OI) is the most common of the genetic conditions. Secondary osteoporosis stems from chronic systemic illnesses in children due to either the effects of the disease process on the skeleton or their treatment. Causes of secondary osteoporosis include immobility, leukemia, inflammatory conditions, glucocorticoid therapy, hypogonadism and poor nutrition.[10]

The following table lists some of the most frequent conditions that result in reduced bone mass in children.[11]

Table 1. Conditions Associated with Reduced Bone Mass in Children and Adolescents (Open Table in a new window)

Table from: Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics. 2014 Oct. 134 (4):e1229-43.

OI, a rare genetic disorder of type 1 collagen, is perhaps the most studied form of primary osteoporosis. Individuals with OI present with varying degrees of fracture, blue sclerae, dentinogenesis imperfecta, ligament laxity, and hearing impairment.[12] Bone biopsy shows decreased cortical and cancellous bone mass.[13] Dominant mutations in COL1A1 and COL1A2 account for 95% of OI cases.[14]

See Osteogenesis Imperfecta (OI) for more information.

Idiopathic juvenile osteoporosis (IJO) is another rare form of primary osteoporosis and is a diagnosis of exclusion. IJO typically presents before puberty and spontaneously remits after puberty. Its characteristic features are bone pain, difficulties in walking, and metaphyseal and vertebral fractures.[15]

Secondary forms of pediatric osteoporosis can be the result both of the primary disease and of the treatments for that disease or concomitant features. Sarcopenia, malnutrition, malabsorption, proinflammatory cytokines, sunlight avoidance, immobilization, endocrine dysfunction, and chronic glucocorticoid exposure are among the factors that contribute to the deleterious effects on bone.  

Medications, such as tenofovir, corticosteroids, cyclosporine, and other cytotoxic agents, may contribute to bone loss. Long-term glucocorticoid use decreases bone formation and increases resorption. A study indicated that the risk of bone loss secondary to oral corticosteroid use is higher in boys than in girls, whereas cumulative inhaled corticosteroid use did not increase the risk of bone loss in either boys or girls.[16] However, more recent studies have shown that children with asthma receiving budesonide and beclomethasone dipropionate have decreased linear growth, and that children who receive long-term inhaled corticosteroid therapy for asthma have height deficits 1-2 years after treatment initiation that persist into adulthood.[17]

Thus, long-term therapy with inhaled corticosteroids is safer than frequent bursts of oral corticosteroids on bone mineral accretion.[17] However, an attempt to minimize any adverse effects with use of the lowest effective dose is recommended.

Highly powered studies do not exist for pediatric osteoporosis; thus, the data on the prevalence of pediatric osteoporosis are inadequate. For example, through 1991, the rare condition of idiopathic juvenile osteoporosis had been reported in only 60 cases. However, numerous observational studies have shown that survivors of pediatric and adolescent cancers are at risk for low bone mass after completion of therapy. Other studies have shown secondary bone fragility occurs early in the disease process, with 16% of children with acute lymphoblastic leukemia and 7% of children with a rheumatologic condition having evidence of vertebral compression fractures within 30 days of diagnosis.[18, 19]

Prognosis depends on the underlying cause and the severity of the bone disease. While osteoporosis in children is not linked to increased mortality as in adults, it may have serious effects on a child’s quality of life, including pain, poor school performance, loss of function, and other long-term consequences. In extreme cases, including idiopathic juvenile osteoporosis and low BMD for age in immobile children with severe developmental delay, crippling bony deformities may lead to cardiopulmonary compromise.

Genetic conditions that lead to increased bone resorption may have a satisfactory prognosis if antiresorptive agents can eliminate further bone loss. (See Treatment.)

In the case of trauma-induced or burn-induced low BMD for age in which bone formation is primarily affected, prognosis depends on the patient’s genetically determined peak bone mass and the efficacy of clinically experimental therapies, such as anabolic steroids and pamidronate, along with correction of progressive vitamin D deficiency that is a consequence of the skin’s failure to make adequate vitamin D with ultraviolet light exposure, similar to what is seen in elderly persons. (See Treatment.)

Although theories suggest that early-onset bone loss may be overcome as new healthy bone replaces compromised bone, a long-term outcome study in 144 young adults with very low birth weight who were studied around the time of peak bone mass have significantly lower BMD at the lumbar spine and femoral neck compared with term-born peers.[20]  Studies have evaluated the impact of bone-involving diseases during childhood (anorexia nervosa, malignancy, and juvenile rheumatoid arthritis) on BMD and fracture risk in adult age.[21, 22, 23] These trials have demonstrated that even after resolution of some childhood diseases, permanent bone damage (in terms of reduced BMD and increased fracture risk) can be seen in adulthood.

Use education as a means of prevention and treatment. As early as possible, inform patients of any age with low BMD for age or osteoporosis why bone loss has occurred and how to keep bone loss under control. Also inform patients with low BMD for age or osteoporosis of the consequences of bone loss. Instruct children, adolescents, and their families that the roots of adult-onset osteoporosis may begin in childhood.

The American Academy of Pediatrics (AAP) recommends that pediatricians assess children’s calcium and vitamin D consumption at ages 3 and 9 and then yearly in the preteen and teen years. Most children can get the recommended amount of calcium by eating 3 servings a day of low-fat dairy products (4 servings for adolescents). Infants less than 1 year old should receive 400 IU of vitamin D daily. Children older than age 1 year and adolescents should receive 600 IU of vitamin D daily through diet or supplements. The AAP also encourages physical activity, primarily weight-bearing exercise, as an important part of keeping bones healthy.[11]

For patient education resources, see the Osteoporosis Health Center and What Is Juvenile Osteoporosis?, as well as the slideshow A Visual Guide to Osteoporosis.

Patients with low bone mineral density for age may be asymptomatic or may present with bone pain. Many have had fractures or imaging studies (usually radiographs or dual-energy x-ray absorptiometry [DXA] studies) suggestive of demineralization or failure to accrue normal bone. Some have a history that suggests an underlying genetic or other condition. Peripubertal children with idiopathic juvenile osteoporosis often experience a gradual onset of pain, primarily in the lower body (eg, hips, ankles, knees, feet), manifested by discomfort when walking.

Fractures are common in healthy youth. By 16 years of age, nearly one-half of boys and one-third of girls have sustained a fracture. The clinical challenge remains in identifying those children with skeletal pathology associated with their fracture. The first step in ascertaining this is questioning about the mechanism and site of the fracture. In pediatrics, hip, femur, and vertebral fractures are rare and fractures that take place after minimal trauma may be concerning. Taken together, a history of axial skeletal fractures or multiple fractures from low biomechanical force may be indicators of skeletal fragility and should raise concern for osteoporosis.[24]

Often the results of a general examination of a child with osteoporosis can be normal. Some children have joint hypermobility or hypomobility. Children with spine disease may present with spinal deformities (eg, kyphosis, kyphoscoliosis), with short stature and/or a shortened upper to lower segment ratio. Pectus deformities (both carinatum and excavatum) can also be present.  More severe forms of metabolic bone disease can present with long bone deformities. Limping or splinting due to pain may also be observed.

In genetic forms of primary osteoporosis, such as osteogenesis imperfecta, additional examination findings can include characteristic facial features, blue sclerae, dentinogenesis imperfecta, and hypermobility.

The workup of children with suspected osteoporosis often includes laboratory studies and dual-energy x-ray absorptiometry (DXA) assessments. Rarely, quantitative computed tomography (CT) scans may be employed (primarily for research purposes) and/or bone biopsy for bone histology.

A basic laboratory panel to assess calcium status and bone turnover is often warranted. This panel includes serum calcium (total or ionized), phosphorus, creatinine (to ascertain that renal function is normal), and parathyroid hormone concentrations (PTH).  Spot measurements of urine calcium and creatinine (ideally collected as second morning voids) can be helpful to assess the adequacy of calcium intake and the possibility of hypercalciuria.

Alkaline phosphatase (total or bone-specific) and osteocalcin can be measured to assess bone formation rates. Serum and urine cross-links of type I collagen (deoxypyridinoline), N-telopeptide of type I collagen (NTx) or C-telopeptide of type I collagen (CTx), and urine creatinine can assess bone resorption rates, although normative data for these measures may be limited. These tests help define whether the bone loss is resulting from a high- or low-turnover condition.

Magnesium levels provide an index of total body magnesium status. Low serum magnesium can inhibit PTH secretion and function.

Children with osteoporosis of unclear etiology should also be screened for celiac disease and inflammatory bowel disease.

Sometimes laboratory findings can be suggestive of a diagnosis. High or normal serum calcium levels with normal or low phosphorus levels and high PTH concentrations suggest secondary hyperparathyroidism. Low serum calcium levels with high or normal phosphorus levels suggest hypoparathyroidism (when PTH is low) and pseudohypoparathyroidism (if PTH is high or normal).

Pediatric reference ranges for many of these measures based on age and gender can be found on the Mayo Clinic Laboratories website.

Prediction of bone loss with biochemical bone markers. Adapted from Ross PD, Knowlton W. Rapid bone loss is associated with increased levels of biochemical markers. (DPD stands for deoxypyridinoline.) J Bone Miner Res 1998 Feb; 13(2): 297-302.

The amount of calcium in bone (both absolute amounts and the amount for bone size) can be quantified in several ways. In pediatrics, bone densitometry based on dual-energy x-ray absorptiometry (DXA) is the most widely used method. This method yields 2-dimensional imaging (quantified as grams per centimeter squared) of the total body (usually reported as total body less head in children) or of regions of bone, such as the lumbar spine, hip, or radius.

The International Society for Clinical Densitometry (ISCD) updated its position on DXA assessment in children and adolescents.[1]  According to the ISCD, DXA measurement is the preferred method for assessing bone mineral content (BMC) and areal bone mineral density (BMD) in patients at increased risk for fracture. In patients with primary bone disease, or at risk for a secondary bone disease, DXA should be performed when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture, and the DXA results will influence that management. DXA should not be performed if safe and appropriate positioning of the child cannot be assured.

In children and adolescents, posterior-anterior (PA) spine and total body less head (TBLH) are the preferred skeletal sites for performing BMC and areal BMD measurements in most pediatric subjects. Other sites may be useful depending on the clinical need. Soft tissue measures in conjunction with whole body scans may be helpful in evaluating patients with chronic conditions associated with malnutrition or with muscle and skeletal deficits. The hip is not a preferred measurement site in growing children because of variability in skeletal development.

Proximal femur DXA measurements can be used, if reference data are available, for assessing children with reduced weight bearing and mechanical loading of the lower extremities or in children at risk for bone fragility who would benefit from the continuity of DXA measurements through the transition into adulthood. DXA measurements at the 33% radius (also called 1/3 radius) may be used in ambulatory children who cannot be scanned at other skeletal sites, provided adequate reference data are available. Lateral distal femur DXA measurements, if reference data are available, correlate well with increased lower extremity fragility fracture risk in non-ambulatory children.

If a follow-up DXA scan is indicated, the minimum interval between scans is 6-12 months.

In children with short stature or growth delay, spine and TBLH BMC and areal BMD results should be adjusted. For the spine, adjust using either bone mineral apparent density (BMAD) or the height Z-score. For TBLH, adjust using the height Z-score.

An appropriate reference data set must include a sample of healthy representatives of the general population sufficiently large to capture variability in bone measures that takes into consideration gender, age, and race/ethnicity. When upgrading densitometer instrumentation or software, it is essential to use reference data valid for the hardware and software technological update.

Serial DXA reports should include the same information as for baseline testing. Additionally, indications for follow-up scan; technical comparability of studies; changes in height and weight; and change in BMC and areal BMD Z-scores should be reported.

The American Academy of Pediatrics (AAP) issued a clinical report on bone densitometry in children and adolescents.[2]  According to the report, DXA is recommended for children with the following conditions:

• Primary bone disorders such as idiopathic juvenile osteoporosis and osteogenesis imperfecta

• Secondary conditions known to increase fracture risk (eg, chronic inflammatory diseases, immobilization for long periods, endocrine or hematologic diseases, cancer and associated treatments that adversely affect bone)

• A history of clinically significant fracture

DXA may also be indicated based on risk factors including patient’s age at fracture, severity of underlying conditions, exposures to radiation or drugs detrimental to bone, and family history. Testing should be performed on initial evaluation and before treatment begins.[2]

DXA provides an assessment bone calcium content, which is measured in grams; the bone area is measured in cm2; and the 2-dimensional BMD is measured in g/cm2. Pediatric reference ranges are taken from large studies using DXA and are incorporated into the software that provides the printout; thus, actual individual BMD and its comparison to age-related normal values (Z-score) is printed out as part of the report.

The main drawback of DXA is that it is an areal rather than true volumetric density, and therefore tends to overestimate BMD in larger patients and underestimate it in smaller patients. In addition, it does not provide data on bone strength. Criteria for pediatric DXA reporting are now available on the website of the International Society for Clinical Densitometry.

Bone demineralization on DXA does not always indicate osteoporosis. If a workup for reduced BMD is not initiated, many potentially severe and disabling causes of bone loss, such as Paget disease or bone loss secondary to an underlying disease, may be missed.

See Imaging of Osteoporosis for more information on this topic.

Other methods under investigation include calcaneal and phalangeal ultrasonography and quantitative CT (qCT), which involves the most radiation of any of the tests. Reference range values for phalangeal ultrasonography results are now available.

Peripheral qCT (pQCT), which usually involves a foot or a lower limb and much less radiation than the qCT scan, can also provide an indirect assessment of bone density. However, DXA is by far the most commonly used technique. Criteria for performing and reporting pQCT imaging are also found on the website of the International Society for Clinical Densitometry.

See Imaging of Osteoporosis for more information on this topic.

Because of the availability of blood and urine biochemical markers of bone turnover, the use of bone histology obtained by iliac crest bone biopsy is no longer routine. When done, histology for bone biopsies is generally carried out using quantitative histomorphometry.

For patients older than 10 years, tetracycline or one of its analogs is administered 14 days before biopsy and then 2 days prior to biopsy. Using one of several specialized orthopedic needles, a biopsy sample is obtained consisting of a 6-mm core of trabecular bone tissue. When processed, the amounts of mineralized bone, unmineralized bone, and bone surface can be quantitated. In addition, the tetracycline binds to newly calcified bone at the mineralization front, which is the boundary between mineralized bone and unmineralized matrix where new bone forms.

Each time a dose of tetracycline is administered, it forms a band at the mineralization front that can be detected under a fluorescent microscope. The distance between the 2 fluorescent bands can be quantitated. When divided by the time interval between doses and multiplied by the length of bone surface taking up the tetracycline yields, the rate of new bone formation is achieved. The eroded or resorbed bone surface also can be quantitated, and all can be compared to reference values for age.

Perform these studies if analysis of bone markers and other biochemical determinations are inconclusive regarding the nature of the activity of the bone in a particular condition. These studies also form the basis for validating the biochemical bone marker analyses. See Bone Markers in Osteoporosis for more information on this topic.

Management is primarily medical, depending on the underlying condition. If the underlying condition is optimally managed and low bone density for age persists, then management depends on bone dynamics. See Osteoporosis and Nonoperative Treatment of Osteoporotic Compression Fractures for more information on these topics.

The primary goals of the management of osteoporosis are prevention of fractures, including vertebral fractures, and scoliosis and improvement in function, mobility, and pain.[10]

When bone resorption exceeds bone formation, an antiresorptive agent such as a bisphosphonate may be used. A review has been developed for educational purposes by the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society regarding bisphosphonates in the treatment of pediatric osteoporosis. The following information is from the executive summary.[34]

Bisphosphonates are chemical analogs of pyrophosphate, in which the oxygen atom is replaced by a carbon atom (P-C-P instead of P-O-P). By adhering to the bone surface, bisphosphonates come into close contact with osteoclasts, where they exert their therapeutic actions.

Bisphosphonates have the potential to bring about sizeable changes in bone density and the reshaping of vertebral bodies in children. A greater response to bisphosphonates in bone mineral density (BMD) and content is seen in children compared with adults, since the cortical surfaces of bone thicken as the bisphosphonate interferes with modeling, while skeletal resorption is blunted along endocortical surfaces.

Bisphosphonate administration, particularly intravenous, in children with moderate and severe forms of osteogenesis imperfecta (OI) has been adopted as part of routine clinical care. However, in children with mild forms of OI or osteoporosis caused by chronic illness, the evidence suggests that bisphosphonate therapy should be relegated to well-designed clinical trials or used on compassionate grounds for such children who, in addition, show clinical evidence of bone fragility associated with low bone mass or density. There are insufficient data on the use of bisphosphonates as preventative agents to recommend their administration to children with asymptomatic reductions in bone mass or density alone.

Bisphosphonates have been widely used in children with OI. Reported therapeutic effects include improvement in bone density, grip strength, vertebral height, cortical thickness, trabecular number, quality of life and mobility, decreased bone pain, and bone turnover and fracture rate.

The first step in treating children with osteoporosis caused by systemic illness is to identify and manage modifiable risk factors by quelling the underlying disease, restoring the normal hormonal milieu (eg, growth hormone and sex steroid status), correcting vitamin D deficiency, and rectifying underweight or overweight status and physical deconditioning. However, if these measures are insufficient, consideration of treatment with a bisphosphonate is warranted for those with low BMD or bone mineral content and bone fragility.

In neuromuscular diseases, most of the clinical studies examining the use of bisphosphonates have been carried out in children with bone fragility or low BMD that is secondary to cerebral palsy. Both randomized clinical trials and small, uncontrolled studies have tested the efficacy of intravenous pamidronate in increasing BMD among nonambulatory children with cerebral palsy and have noted skeletal gains at the spine, femoral neck, and/or total body and the absence of serious adverse effects.

There is a lack of consensus regarding the use of bisphosphonates in idiopathic juvenile osteoporosis. Complicating the issue is the fact that many of the reports of bisphosphonate use for idiopathic juvenile osteoporosis include data from heterogeneous case series that include patients with osteoporosis of varying etiologies.

Short-term safety issues with bisphosphonates include transient hypocalcemia; a brief acute-phase reaction, including influenza-like symptoms such as low-grade fever, headache, nausea, vomiting, rash, tachycardia, myalgia, and bone pain; and esophageal irritation. Uncommon short-term safety issues are nephrotoxicity, anterior uveitis and atrial fibrillation.

Potential long-term adverse effects include radiographic metaphyseal bands, iatrogenic osteopetrosis, fractures after bisphosphonate discontinuation in growing children, delayed healing at osteotomy sites, esophageal cancer, and osteonecrosis of the jaw. It is noteworthy that no cases of some of these adverse effects (eg, esophageal cancer and osteonecrosis of the jaw) have been seen in children.

The current generation of oral bisphosphonates includes alendronate and risedronate. The primary parenterally administered bisphosphonate is pamidronate.

To date, there is no consensus on the optimal agent, dosage, or duration of therapy. In the absence of numerous randomized, controlled trials comparing different agents, doses, and durations in various bone disorders, it is impossible to state whether one treatment protocol is more efficacious than another. However, the response to intravenous therapy seems to be more consistently positive than the response to oral agents.[34] A Cochrane Database Systemic Review confirmed that bisphosphonates increase bone density in children and adolescents with OI.[35]

Preliminary data suggest that zoledronic acid (ZA) is as effective as pamidronate in preventing bone loss.[36] Acute adverse events related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks as well as benefits of ZA therapy in the pediatric population.[37]

Denosumab, the monoclonal antibody to receptor activator of nuclear transcription factor kappa B ligand (RANKL), can successfully prevent bone loss in adults with osteoporosis; however, data on its safety and efficacy in children are limited.[38]

Anabolic steroids (eg, testosterone, oxandrolone) may be helpful in forming new bone; however, consider the risks of premature closure of the epiphyses, short stature, and hirsutism. Also consider the potentially increased risk of tumor development. However, when oxandrolone was given for 1 year to a group of children following burn injury, no epiphyseal closure was demonstrated, and only 2 cases of clitoral hypertrophy were observed (both were reversed after cessation of the drug).[39]

Recombinant human growth hormone is a useful anabolic agent for children with growth hormone deficiency; its benefits for others with low bone density for age have not been extensively studied. It does improve bone mineral content (BMC) in children with burn injury if given for a year, but the need for repeated injections and the cost limit its use.[40]

The absence of a safe and effective anabolic agent makes bone loss secondary to low bone formation more difficult to manage than bone loss secondary to high bone resorption. Parathyroid hormone (PTH), which is potentially very promising when given intermittently to osteoporotic adults, is not approved for use in children because of the detection of osteogenic sarcoma in mice that were given very high test doses.[41]

Unless a resectable tumor can be identified as the cause of low bone density for age or osteoporosis, surgery is unlikely to play a role in treatment. In most cases, the cause is systemic and results in widespread disease. Surgeries may be necessary for rod placement or for stabilization of fracture.

Calcium and vitamin D are the most important dietary nutrients to help prevent adult osteoporosis, although a study suggests that calcium supplementation does not promote a significant accumulation in the appendicular skeleton in children.[42] A diet rich in dairy products is recommended to help provide the calcium and vitamin D required.[43]

The American Academy of Pediatrics (AAP) endorses recommended dietary allowances for calcium and vitamin D as shown in the following table. The AAP also supports testing for vitamin D deficiency in children and adolescents with conditions associated with increased bone fragility.[44] The Global Consensus Recommendations on Prevention and Management of Nutritional Rickets released similar information including universal supplementation of all infants with vitamin D from birth to 12 months of age, independent of their mode of feeding.[45]

Table 2. Calcium and Vitamin D Dietary Reference Intakes ^[11] (Open Table in a new window)

↵a Upper limit (UL) indicates level above which there is risk of adverse events. The UL is not intended as a target intake (no consistent evidence of greater benefit at intake levels above the recommended dietary allowance [RDA]).

↵b Reflects adequate intake reference value rather than RDA. RDAs have not been established for infants.

Table from: Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics. 2014 Oct. 134 (4):e1229-43.

The following tables show dietary sources of both calcium and vitamin D.[11]

Table 3. Dietary Sources of Calcium (Open Table in a new window)

↵a Not all soy beverages are fortified to this level.

Table from: Dietary Guidelines for Americans, 2010. Available at: https://www.fns.usda.gov/dietary-guidelines-2010.

Table 4. Sources of Vitamin D (Open Table in a new window)

↵a The activity of 40 IU of vitamin D is equivalent to 1 µg.

↵b Not all brands of orange juice, yogurt, and cheese are fortified with vitamin D.

Activity plays a role in the prevention of osteoporotic fractures. Several studies in the United States and in Europe have established that regular weight-bearing exercise, such as jumping, in school-aged children improves bone mass.[46, 9] Encouraging such exercises as walking, running, tennis, volleyball, hiking, hockey, dancing, skiing, basketball, gymnastics, soccer, aerobics, jumping rope, and lifting weights can help with contribution to BMC in children and adolescents.

Lack of locomotion, due to either recurrent fractures in children with OI or chronic illnesses, reduces mobility, muscle force, and subsequently bone strength. 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.[10]

Experts in pediatric osteoporosis may come from several subspecialties. Traditionally, osteoporosis is often the province of the pediatric endocrinologist, but experts may be found in pediatric nephrology, gastroenterology, genetics, or orthopedic surgery as well.

Generally, children with osteoporosis do not require hospitalization unless they have a complication such as a hip fracture. This is a very uncommon occurrence in children; however, following a fracture, anticipatory intervention is needed to minimize future hospital stays and to identify individuals at risk for repeated fracture.

The aim of outpatient care is to closely monitor bone mineral density to determine if ongoing bone loss occurs or if the process has reached a plateau. The AAP recommendation for repeating bone densitometry testing is that, although 6 months should normally elapse between measurements, it might be appropriate in some cases to wait at least 1 year.[47]  In situations of ongoing bone loss, measurements of biochemical markers of calcium metabolism, vitamin D status, and bone formation and resorption can help guide management.

Transferring a patient is not necessary unless pediatric subspecialty care is unavailable at the institution.

Therapy includes antiresorptive agents such as bisphosphonates (eg, alendronate, risedronate, pamidronate, zoledronic acid) as well as calcium and vitamin D supplementation. Hormone replacement therapy (eg, estrogen, estrogen analogs) does not have a role in pediatric therapy unless the low bone mass is attributable to hypogonadism.

Preferred treatment of vitamin D deficiency is listed in the table below[11] :

Table 5. Treatment of Vitamin D Deficiency (Open Table in a new window)

Vitamin D2, ergocalciferol; vitamin D3, cholecalciferol.

↵a Vitamin D3 may be more potent than vitamin D2.

Table from: Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics. 2014 Oct. 134 (4):e1229-43.

Class Summary

These agents decrease bone resorption and prevent bone loss from diminishing bone mass on an ongoing basis. They are available in parenteral and oral dosage forms for acute and chronic treatment, respectively.

Pamidronate (Aredia)

Pamidronate inhibits both normal and abnormal bone resorption. It appears to inhibit bone resorption without as much impact on bone formation and mineralization. It is administered intravenously (IV), using a variety of regimens. Pamidronate is approved for use in hypercalcemia of malignancy and Paget disease. It has also been used in children with osteopenic bone disease.

Alendronate (Fosamax)

Alendronate is an orally administered bisphosphonate that is approved as an antiresorptive agent to treat Paget disease and postmenopausal osteoporosis.  Although a large trial of low dose alendronate did not show benefits for children with OI, the studies with higher doses have showed greater efficacy.

Risedronate (Actonel)

Risedronate is an aminobisphosphonate. It inhibits bone resorption via actions on osteoclasts or osteoclast precursors. It is indicated for the prevention and treatment of osteoporosis.  It has been demonstrated to have efficacy in children with mild/moderate OI.

Calcium

For optimal bone health, dietary sources of required daily calcium should be recommended in preference to calcium supplements, not only because of the improved bioavailability of dietary sources of calcium, but also to encourage lifelong healthy dietary habits for children and adolescents. The most commonly consumed dietary sources of calcium are milk, other dairy-containing products, and calcium-fortified juices.  Oral calcium either as dietary intake or supplement should be routinely used in conjunction with vitamin D in the treatment of Vitamin D deficiency regardless of age or weight. The dose of a supplement can be selected based primarily on the content of elemental calcium. The most widely available calcium supplements are calcium carbonate and calcium citrate.

Vitamin D

Although routine 25OHD screening is not recommended for healthy children, children at risk of osteoporosis or vitamin D deficiency (with factors/conditions that reduce vitamin D synthesis or intake) should have their vitamin D status ascertained by measurement of a serum 25OHD concentration. Deficiency is defined as a concentration < 30 nmol/L and insufficiency a concentration 30–50 nmol/L, Deficiency, <30 nmol/L). 

For treatment of nutritional rickets per the most recent Global Consensus Recommendations, the minimal recommended dose of vitamin D is 2000 IU/d (50 μg) for a minimum of 3 months. Oral treatment is preferred to intramuscular therapy.  For daily treatment, both D2 and D3 are equally effective. When single large doses are used, D3 appears to be preferable compared to D2 because the former has a longer half-life. Vitamin D treatment is recommended for a minimum of 12 weeks, recognizing that some children may require longer treatment duration.