Review Article

Ewha Med J 2023;46(4):e18

[Link]
eISSN 2234-2591

Diagnosis and Management of Osteoporosis in

Children and Adolescents
Hye Young Jin , Eu Seon Noh , Il Tae Hwang
Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea

Received Sep 6, 2023 Recent advances in medicine have led to an increase in the number of children and adolescents
Accepted Oct 6, 2023
treated for various chronic diseases and cancer. Increasingly sophisticated genetic analysis techniques
have also clarified some genetic factors that contribute to bone fragility. Osteoporosis, characterized
Corresponding author
Il Tae Hwang
Department of Pediatrics, Kangdong
Sacred Heart Hospital, Hallym University
by reduced bone mass and skeletal fragility, can result from primary or secondary causes that originate
College of Medicine, 150, Seongan-ro, in childhood and adolescence, which are critical periods for bone mineral acquisition. It is essential
Gangdong-gu, Seoul 05355, Korea
Tel: 82-2-2224-2257 to identify children and adolescents at risk of fractures due to osteoporosis, and early intervention is
crucial. Conservative management strategies, such as treating underlying diseases, replacing deficient
Fax: 82-2-483-8334
E-mail: ithwang83@[Link]

Key Words
hormones, providing nutritional support to meet calcium and vitamin D requirements, and encouraging
Adolescent; Child; Osteoporosis; regular physical activity, should be prioritized. Pharmacological treatment should be initiated in a timely
Pamidronate
manner following a comprehensive bone health examination. Intravenous pamidronate therapy has
been safely and effectively administered to children and adolescents, although long-term follow-up is
necessary. Further investigation is needed regarding bone fragility fractures of unknown etiology and
the application of new medications for pediatric use.

Introduction
Osteoporosis is a disorder characterized by a decrease in bone mass and changes in bone
tissue micro-architecture, leading to skeletal fragility and an increased risk of fractures [1].
Historically, osteoporosis was considered an adult disease. However, it is now understood to have
roots in childhood and adolescence, as these are the periods when bone mass and architecture
are accumulated. The total bone mass reaches its peak a few years after the long bone epiphyses
have fused. This maximum bone mass an individual can achieve is referred to as peak bone mass
(PBM). A significant portion of PBM is determined by unmodifiable genetic factors [2]. However,
other factors such as hormones, immobility, nutrition, pubertal timing, increased cytokines,
and certain medications can also impact bone health. Therefore, chronic illnesses and specific
osteotoxic treatments during childhood and adolescence can affect PBM accrual, leading to
low bone mineral density (BMD). Low BMD during these formative years can increase the risk of
fractures in youth, potentially leading to osteoporosis and fractures in adulthood. The incidence of
fractures in children and adolescents is on the rise, with fractures resulting from a combination of
intrinsic and extrinsic factors [3]. As such, it is crucial to assess bone health and adopt preventive
measures early in children and adolescents at risk for low BMD. This article reviews the diagnosis,

© 2023 Ewha Womans University College of Medicine and Ewha Medical Research Institute
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([Link]
licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Osteoporosis in Children and Adolescents

causes, and management of osteoporosis in children and adolescents, with the aim of applying
this knowledge to the clinical field for the evaluation and treatment of pediatric osteoporosis.

Definition and Diagnosis of Osteoporosis in Children and

Adolescents
The World Health Organization defines osteopenia and osteoporosis based on T-scores,
which are used to compare a patient's BMD with the maximum BMD of young adults. This
comparison is only applicable to postmenopausal women. Some definitions categorize a
Z-score of less than −1.0 as osteopenia and less than −2.5 as osteoporosis. The International
Society for Clinical Densitometry (ISCD) recommends the term "low BMD for chronological
age" when the BMD Z-score is lower than −2.0 [4]. The diagnosis of osteoporosis in children
and adolescents should not be made solely based on bone densitometry (dual-energy X-ray
absorptiometry [DXA]) [5]. The presence of one or more vertebral compression fractures without
local disease or high-energy trauma indicates osteoporosis [6]. In the absence of a vertebral
compression fracture, osteoporosis is defined by the presence of both a clinically significant
fracture and a BMD Z-score of less than or equal to −2.0 [6]. Three or more long bone fractures
are considered clinically significant (or two or more long bone fractures if the patient is under
10 years old) [6]. The ISCD definition aims to prevent the overdiagnosis and overtreatment
of osteoporosis in young individuals who do not have skeletal fragility. However, waiting for a
second or third fracture could unnecessarily delay treatment in children and adolescents with
bone fragility, potentially leading to permanent disability [7]. In addition, a BMD Z-score>−2.0
does not preclude the possibility of skeletal fragility or increased fracture risk, as is also noted
in the ISCD guidance [6]. Therefore, children and adolescents with risk factors for low BMD
require a comprehensive bone health evaluation, which could lead to an accurate diagnosis of
osteoporosis and identify the cause of bone fragility [7]. DXA is part of a comprehensive skeletal
health examination in children and adolescents [6]. Although lumbar BMD and whole-body (total
body minus head) BMD measurements are commonly performed in children, the 2019 ISCD
guideline recommends using the proximal femur, lateral distal femur, and radius as skeletal sites
for BMD measurement in children who need additional information, or in whom spine or whole-
body DXA cannot be performed, if reference data are available [6]. Interpreting and reporting
DXA results in children and adolescents should be done with caution. Appropriate reference
data should be established, and BMD results should be adjusted in children with short stature
or growth delay. The clinical utility of these measurements may be limited in very young children
due to a lack of reference data for those under 5 years old. A few Korean pediatric reference
BMD data sets have been published. BMD increases with age, reaching a plateau at 17−20 years
in females and 20−23 years in males [8–10].
High-resolution peripheral quantitative computed tomography (pQCT) is a novel imaging
method to evaluate BMD. pQCT at the radius and tibia can provide information about bone
and muscle geometry, as well as volumetric cortical and trabecular BMD [11]. The potential
diagnostic value and clinical applicability of pQCT for evaluating pediatric bone health warrant
further investigation.
In cases of low BMD, a lateral thoracolumbar radiograph is recommended for detecting
vertebral fractures. Lateral spine radiographs should be regularly performed in children and
adolescents with persistent risk factors [12]. Asymptomatic vertebral fractures can sometimes
be detected in patients with prolonged glucocorticoid (GC) treatment, progressive myopathy,

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or immobility [12]. Specifically, children and adolescents with reduced mobility due to cerebral
palsy or myopathy should receive a lateral spine X-ray examination at 6−8 years of age [13]. The
bone condition of patients chronically treated with GCs requires careful follow-up, including a
lateral spine X-ray before the initiation of GCs and regularly during treatment. Follow-up lateral
spine X-rays are recommended according to the patient's risk factors, with a follow-up period
ranging from 6 months to 2 years [14].
Physical examination and laboratory findings can provide us with clues to distinguish between
various diseases that cause osteoporosis. The following clinical presentations may suggest
congenital bone fragility: skin laxity, blue sclerae, abnormal dentition, easy bruising, a dysmorphic
face, joint hypermobility, and wormian bones. In such instances, inheritable osteoporosis may
be identified through molecular analysis. Genetic analysis has also revealed disease-causing
variants of osteogenesis imperfecta (OI) associated genes in individuals who have a significant
history of fractures but no extraskeletal symptoms [15]. Conversely, there have been instances
of fragility fractures with unknown causes and mechanisms, despite negative genetic testing
results. This highlights the need for further research into monogenic and polygenic determinants
of skeletal strength. Hormonal studies should be conducted to diagnose or exclude hormone-
deficient states. Bone turnover markers such as type 1 procollagen, carboxy-terminal
telopeptides, alkaline phosphatase, and osteocalcin can be useful in monitoring medical therapy
[16].

Causes of Osteoporosis in Children and Adolescents

Numerous factors can influence bone mineral deposition and the formation of bone mass.
Certain genetic diseases can lead to inherent bone vulnerability and an increased risk of
fractures, a condition known as primary osteoporosis. OI, Ehlers-Danlos syndrome, Marfan
syndrome, cleidocranial dysplasia, osteoporosis-pseudoglioma syndrome, and fibrous dysplasia
are all well-documented genetic diseases associated with bone fragility. Among these, OI
is a rare inherited disorder characterized by bone fragility, which is caused by defects in the
biosynthesis of type 1 collagen [17]. The clinical manifestations of OI can range from subclinical
to lethal, and may include low bone mass, skeletal deformities, hypermobile joints, short stature,
blue sclera, dentinogenesis imperfecta, and hearing loss. Consequently, OI is classified into
several types based on these clinical features. The most common mutations associated with all
types of OI are found in the COL1A1 and COL1A2 genes [18]. Apart from these genetic diseases,
idiopathic juvenile osteoporosis can also present with symptoms such as bone pain, bone
deformities, fractures, and low bone mass, all of which stem from an unknown cause. A diagnosis
of idiopathic juvenile osteoporosis is made after other potential diseases have been ruled out.
Secondary osteoporosis develops due to chronic illness or treatments affecting bone formation,
resorption, or bone matrix mineralization. The incidence of pediatric secondary osteoporosis
is increasing as a consequence of improvements in the survival rates of chronic diseases,
including cancer. Low BMD could be caused by hormone deficiencies or excess, malnutrition,
immobilization, chronic inflammation, and medication associated with underlying diseases.
Table 1 summarizes various causes of secondary osteoporosis. Sex hormones influence
the growth and maintenance of bone, consequently impacting PBM [19]. Therefore, the risk
of fractures increases in several clinical conditions associated with hypogonadism, including
delayed puberty, premature ovarian failure, hyperprolactinemia, Turner syndrome, Klinefelter
syndrome, and hypogonadism induced by cancer treatment. Bone formation and resorption

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Table 1. Causes of secondary osteoporosis

Neuromuscular disorders Cerebral palsy
Duchenne muscular dystrophy
Progressive myopathy
Endocrine disorders Delayed puberty
Hypogonadism
Growth hormone deficiency
Hyperthyroidism
Hyperparathyroidism
Cushing disease
Vitamin D metabolism disorder
Hematologic disorders Leukemia/Lymphoma
Hemoglobinopathy
Gastrointestinal disorders Inflammatory bowel disease
Celiac disease
Malabsorption
Chronic liver disease
Milk intolerance
Renal disorders Chronic renal failure
Nephrotic syndrome
Connective tissue disorders Systemic lupus erythematosus
Juvenile idiopathic arthritis
Juvenile dermatomyositis
Inborn errors of metabolism Glycogen storage disease
Galactosemia
Gaucher disease
Others Immobilization
Anorexia nervosa
Glucocorticoids
Chemotherapeutic agents
Immune suppressants
Anticonvulsants
Anticoagulant
Radiation therapy
Adapted from Galindo-Zavala et al. [14] with CC-BY.

are also affected by growth hormone deficiency and thyroid disorders, leading to secondary
osteoporosis. Hyperparathyroidism, which can result from parathyroid adenoma, chronic renal
failure, disorders related to vitamin D metabolism, and multiple endocrine neoplasms, can
enhance bone resorption by stimulating the receptor activator of nuclear factor kappa B ligand
(RANKL) and reducing osteoprotegerin (OPG) levels due to an excess of parathyroid hormone
[20]. In addition to endocrinologic disorders, neuromuscular, gastrointestinal, and renal disorders
can also contribute to the development of secondary osteoporosis (Table 1). Childhood

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cancer survivors often have low BMD due to the cancer itself, the effects of chemotherapy
and radiotherapy, accompanying hormonal deficiencies, and poor nutritional status [21]. GC
treatment is necessary for children and adolescents with certain chronic diseases, including
cancer. Excessive GCs, whether iatrogenic or not, can directly or indirectly inhibit bone formation
while increasing bone resorption [22]. Direct effects include upregulation of PPAR-γR2,
increased sclerostin expression, and an increased RANKL/OPG ratio. Secondary hypogonadism,
reduced calcium resorption, and decreased insulin-like growth factor-1 production can indirectly
affect bone remodeling [22]. Therefore, patients receiving GC treatment for more than three
months require special attention. A higher cumulative dose and longer duration of GC treatment
are risk factors for low lumbar BMD in pediatric patients with chronic diseases [23].

Management of Osteoporosis in Children and Adolescents

It is essential to identify children or adolescents who are at risk for osteoporosis based on the
abovementioned causes. Early diagnosis and management are critical for preventing recurrent
fractures and permanent bone deformities. A developing skeleton has more potential for
recovery and reshaping because growing bones continuously elongate, widen, and strengthen.
Thus, the diagnosis of osteoporosis in children and adolescents does not automatically
necessitate pharmacologic therapy. A comprehensive bone health examination should assess
whether risk factors are transient and whether there remains growth potential. In cases of
secondary osteoporosis, treatment of the underlying disease and cessation of osteotoxic
medication are prioritized. Hormonal deficiencies should be diagnosed as early as possible and
adequately managed [24,25]. Although conservative management is preferred in children and
adolescents, pharmacological therapy should be considered in patients with recurrent lone bone
fractures or vertebral fractures [7].

1. Conservative measures
The Committee on Pediatric Bone Health of the Korean Society of Pediatric Endocrinology
has published clinical practice guidelines for optimizing bone health [26]. These guidelines
recommend calcium and vitamin D supplementation, lifestyle changes, and regular physical
activity for children and adolescents with chronic diseases to help prevent osteoporosis.
Additionally, maintaining a healthy body composition and ensuring adequate hormonal status are
also advised for optimal bone health.
Calcium and vitamin D supplementation improves BMD, particularly in children and
adolescents with a low-calcium diet or decreased vitamin D concentration [27,28]. Calcium-
rich foods are preferred over calcium tablets or powder. The recommended daily calcium
requirements range from 500 mg to 1,000 mg according to age [26]. The 25-OH-vitamin D
level should be maintained above 20 ng/mL (50 nmol/L) [29]. Vitamin D must be prescribed
for patients with chronic diseases with vitamin D levels below 20 ng/mL. In individuals with low
BMD (Z-score≤–2.0), vitamin D supplementation should be considered when vitamin D levels are
below 30 ng/mL (75 nmol/L) [14]. However, meta-analyses of vitamin D supplementation have
shown no effects on BMD or fracture risk when the baseline 25-OH-vitamin D level is >16 ng/
mL (40 nmol/L) [30]. The maintenance dose of vitamin D is 400 IU for children below 1 year old
and 600 IU for children over 1 year old. Calcium and vitamin D should be provided to all children
and adolescents taking GCs, particularly when treatment lasts over 3 months. Healthy dietary
supplements that contain appropriate calories, proteins, and vegetables or fruits containing

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vitamins and minerals are also helpful for maintaining bone health [26].
Regular physical activity may enhance bone quality and strength, as the mechanical forces
exerted on the bone aid in bone remodeling [31,32]. Weight-bearing exercises, including
running, jogging, jumping, and resistance training, can boost bone mineral acquisition in children,
especially during early puberty [31]. However, excessive exercise may also heighten the risk
of fractures, underscoring the need for careful monitoring and control of activity intensity. For
optimal bone health maintenance, a sedentary lifestyle should be avoided. Furthermore, an
extremely lean physique can impact PBM accrual in adolescents, indicating the importance of
maintaining an appropriate body weight [33].

2. Drug therapy
Bisphosphonates are the most frequently used medications for treating osteoporosis. These
are synthetic analogs of pyrophosphate that inhibit osteoclastic function and decrease bone
remodeling. Bisphosphonates are commonly prescribed to individuals with primary osteoporosis,
such as OI. Current research indicates that oral or intravenous bisphosphonates can enhance
BMD and decrease the frequency of fractures in both children and adults with OI [34,35].
Bisphosphonate therapy has proven to be effective and safe for both secondary and primary
pediatric osteoporosis [36]. Bisphosphonates can significantly improve BMD in conditions
of bone fragility related to disuse, such as cerebral palsy [37]. Intravenous bisphosphonate
therapy can alleviate back pain and improve the vertebral height ratio when used to treat painful
vertebral fractures in Duchenne muscular dystrophy [38]. Furthermore, bisphosphonates are
well tolerated in childhood cancer survivors with low BMD [21].
Several bisphosphonates exist, each with varying potency and dosage (Table 2). Oral
bisphosphonates are typically considered for mild cases or those without vertebral fractures [39].
However, the efficacy and safety of oral bisphosphonates in children have not been well studied.
If oral bisphosphonates are contraindicated or vertebral fractures are present, an intravenous
bisphosphonate should be used [14]. Intravenous pamidronate (3-amino-1-hydroxypropylidene-
bisphosphonate) is primarily used in children and adolescents, and can be administered to
children under 2 years of age. The dosage, interval, and duration of pamidronate may vary based
on the center's or clinician's experience (Table 2). Zoledronic acid (ZA), a highly potent third-
generation intravenous bisphosphonate, is increasingly being used in children and adolescents
[40]. Recent studies have shown that ZA significantly improved BMD in children and adolescents

Table 2. Bisphosphonates used in pediatric patients

Drug Administration Dose Potency
Pamidronate Intravenous (in 200–250 mL 0.5–1 mg/kg/day, 2–3 consecutive days 100
(second generation) saline in 3–4 hours) every 2–4 months
9–11.5 mg/kg/year
Maximum: 60 mg/dose
Alendronate Oral 1–2 mg/kg/week 100–1,000
(second generation) <40 kg: 5 mg/day or 35 mg/week
>40 kg: 10 mg/day or 70 mg/week
Maximum: 70 mg/week
Neridronate Intravenous (in 200–250 mL 1–2 mg/kg/day every 3–4 months 100
(third generation) saline in 3 hours) Maximum: 100 mg/dose
Zoledronate Intravenous (in 50 mL saline 0.025–0.5 mg/kg every 6–12 months >10,000
(third generation) in 30–45 minutes) Maximum: 4 mg/dose

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[38,41]. Compared to pamidronate, ZA treatment has a beneficial effect as it is generally

infused over a shorter duration (30 minutes) with a longer interval (6–12 months) [42]. During
bisphosphonate therapy, regular clinical monitoring using DXA and risk factor assessments
should be conducted to determine whether to cease, reduce, or continue the same dose of
bisphosphonate treatment [39].
Intravenous bisphosphonates may trigger acute phase reactions within 24–48 hours
following the initial administration. These reactions can include symptoms such as fever,
nausea, and malaise, which are typically self-limiting or can be managed with antipyretics. Iritis,
characterized by red or painful eyes, is a rare side effect, particularly in patients with preexisting
rheumatological conditions. Oral bisphosphonates, on the other hand, may cause esophagitis,
dysphagia, and retrosternal pain. Transient hypocalcemia is a side effect common to both
forms of bisphosphonates, necessitating the intake of calcium and vitamin D both before and
after infusion. Bisphosphonates are retained in the bone, and as such, patients on long-term
bisphosphonate therapy should be monitored due to an increased risk of atypical proximal
fractures and jaw osteonecrosis. The use of bisphosphonates is contraindicated in children and
adolescents with renal impairment, as the kidneys are responsible for the excretion of these
drugs.
Denosumab received approval for the treatment of postmenopausal osteoporosis in 2010.
Since then, it has emerged as a promising new therapy for skeletal diseases in pediatrics,
although it has not yet received approval for pediatric use [43,44]. RANKL, expressed by
osteoblasts, interacts with RANK on the surface of osteoclasts, thereby promoting osteoclast
activity. Soluble OPG, also produced by osteoblasts, inhibits the interaction between RANKL
and RANK. Denosumab, a monoclonal antibody, inhibits the binding between RANKL and
its receptor RANK, effectively mimicking the effects of OPG [45]. To date, denosumab has
been administered to a limited number of patients with various diseases such as OI, juvenile
Paget disease, fibrous dysplasia, central giant-cell granuloma, metastatic giant cell tumor, and
aneurysmal bone cyst in children. However, limited data are available regarding the dosage,
duration, and response to denosumab therapy in children and adolescents. Furthermore, its
efficacy and safety for pediatric use still need to be thoroughly investigated.

Conclusion
Personalized therapy, guided by a comprehensive risk factor assessment, is necessary
for treating osteoporosis in children and adolescents. It is crucial to identify those at risk of
osteoporotic fractures for early intervention. Conservative management can enhance BMD in
this population, given the potential for spontaneous recovery of bone health. However, it is also
essential to initiate an optimal pharmacological approach to prevent significant morbidity, such
as irreversible bone deformity. Unkown etiology and mechanism of bone fragility need to be
clarified. Additional research is needed to determine the efficacy, safety, dosage, and treatment
duration of medical interventions, including new drugs.

Acknowledgements
Not applicable.

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Conflict of Interest
No potential conflict of interest relevant to this article was reported.

ORCID iD
Hye Young Jin: [Link]
Eu Seon Noh: [Link]
Il Tae Hwang: [Link]

Author Contribution
Conceptualization: Jin HY, Hwang IT
Investigation: Jin HY, Noh ES
Writing – Original Draft: Jin HY
Writing – Review & Editing: Jin HY, Noh ES, Hwang IT

Ethics Approval and Consent to Participate

Not applicable.

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