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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Endocrinol Metab Clin North Am. 2020 Oct 13;49(4):637–650. doi: 10.1016/j.ecl.2020.07.002

Bone Health in Childhood Chronic Disease

David R Weber 1
PMCID: PMC7664841  NIHMSID: NIHMS1612501  PMID: 33153671

Introduction

The chronic diseases of childhood that are associated with impaired bone health are numerous and involve nearly all of the pediatric disciplines. These disorders are heterogeneous and the clinical aspects including treatment, course, and prognosis vary widely. Any factor that adversely affects bone mass, quality, or strength may increase the risk of fracture and should be considered a threat to bone health. Common risk factors for impaired bone health include: (1) diminished loading of bone due to immobility or muscle weakness (2) nutritional deficiency (3) exposure to bone-toxic therapeutics (4) hormonal deficiencies affecting growth and development and (5) chronic inflammation (Figure 1). Even a single fracture can dramatically alter the life-course of a medically fragile child by limiting mobility or hastening loss of ambulation. With these consequences in mind, there is growing recognition that efforts to optimize bone health in at-risk patients should be undertaken early in the disease course.

Figure 1: Risk factors for impaired bone health in childhood chronic disease.

Figure 1:

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Skeletal unloading, inadequate nutrition, exposure to bone toxic medications, hormonal disturbances, and chronic inflammation all may contribute to skeletal fragility by impairing bone accrual and/or negatively impacting bone quality.

The objectives of this review are twofold. First, to provide an overview of the chronic diseases of childhood that are most commonly associated with impaired bone health. Key aspects of these conditions relevant to the bone health provider will be summarized, and disease specific recommendations for clinical management will be discussed when available. Many of these disorders have been the subject of in-depth reviews of bone health, which will be cited. Second, to outline a general approach to the clinical evaluation and treatment of impaired bone health in children with chronic disease.

DISORDERS ASSOCIATED WITH IMPAIRED BONE HEALTH

Neurologic disorders

Cerebral palsy (CP)

CP is a non-progressive neuromuscular disorder arising from damage to the developing brain. The clinical severity varies and is commonly classified by degree of motor deficit. Comorbidities including seizures, feeding difficulties, and hypogonadism are common in severely affected individuals.1 Deficits in bone mineral density (BMD) have been noted in children with CP of all ages and have been shown to be associated with degree of motor deficit, feeding difficulty, and exposure to anti-epileptic drugs (AEDs).2 Longitudinal studies suggest that children with CP gain bone throughout childhood, albeit at a slower rate than typically developing children.3 Minimally traumatic fractures are common, especially at the distal femur.4 Children with CP who suffer a first fracture have been shown to be at high risk of further fracture,5 and should be evaluated.

The evaluation of bone health in children with CP is challenging. Commonly used tools including DXA and spine radiograph can be of limited utility in those at highest risk due to contractures, spinal deformities, and in-dwelling hardware. The optimal approach to bone health treatment remains uncertain. Mechanical loading of the skeleton can be achieved in non-ambulatory children by use of a stander, but there are minimal data relating standing regimens to bone health outcomes. Physical activity interventions and the use of low magnitude mechanical stimulation have yielded mixed results.6, 7 Both oral and intravenous bisphosphonate regimens are widely used to treat osteoporosis in patients with CP,8 and have been associated with gains in BMD and reductions in fracture rate.9 Guidelines for the management of bone health in childhood CP are available.10

Neuromuscular disorders

Duchenne muscular dystrophy (DMD) is the most common heritable neuromuscular disease in childhood. It is a progressive condition that universally results in loss of ambulation by late childhood or early adolescence. Treatment with high dose glucocorticoids initiated at an early age slows progression of the disease, but further weakens the skeleton. The combined risk factors of muscle weakness, immobility, and chronic glucocorticoid exposure contribute to a markedly elevated fracture prevalence (33-100%, depending on study).11 Glucocorticoid regimen is a factor in evaluating fracture risk, with daily deflazacort therapy being associated with the greatest risk of fracture.12

A notable feature of DMD and other conditions treated with high dose glucocorticoids is the predilection for vertebral fractures (VF), which can occur even in the absence of low BMD.13 As a result, routine screening for VF with lateral spine radiography or densitometry is essential.14 Full considerations for the evaluation and management of bone health in DMD have been extensively reviewed.15 Other childhood forms of muscular dystrophy are less common. The skeletal effects of these conditions tend to be related to the degree of muscle weakness, but have not been systematically studied.

Spinal muscular atrophy is a rare neuromuscular disease of the lower motor neurons. Clinical severity varies from profound weakness with ventilatory dependence from early infancy to mild late onset disease. Adverse skeletal effects, including scoliosis, low BMD, and atraumatic fracture are common in severely affected children.16 Treatment advances, including intrathecal injection of nusinersen, improve muscle function and may prolong survival. A small study suggested that IV bisphosphonates were safe and potentially effective in reducing fracture rate.17

Epilepsy

A primary concern for children with seizure disorders is that treatments including AEDs and the ketogenic diet may adversely affect the skeleton. The relationships between AEDs and bone mineral metabolism have been extensively reviewed.18 Many of the classic AEDs induce the CYP-450 enzyme system and thereby lower vitamin D concentration. Direct negative effects of AEDs on skeletal cells have also been reported.19 Newer generation AEDs appear to have less impact on mineral metabolism, but have not been extensively studied.20 Ketogenic diets are increasingly used to treat refractory epilepsy and may impact the skeleton via acidosis, hypercalciuria, and micronutrient deficiencies.21 Worsening of BMD deficits in longitudinal studies of children on ketogenic diets have been reported.22 Current guidelines for patients on a ketogenic diet recommend involvement of a registered dietician (RD), supplementation of calcium and vitamin D as needed, and the consideration of BMD monitoring in children on therapy for two or more years.23

Neurodevelopment disorders

Children with autism have been shown to have bones that are smaller, weaker, and less dense than typically developing peers.24 These deficits may be related to inadequate consumption of protein, calcium, and phosphorus, and less time spent in physical activity.25 Girls with Rett Syndrome are also reported to develop skeletal complications including low BMD, fragility fracture, and scoliosis.26 Guidelines for bone health management in Rett Syndrome have been published, and include a recommendation for molecular testing in all patients, as specific MECP2 genotypes appear to confer greater risk of osteoporosis.27

Chronic kidney disease (CKD)

The physiologic underpinnings of CKD metabolic bone disease (CKD-MBD) include phosphate retention, increased secretion of fibroblast growth factor 23 (FGF-23) and parathyroid hormone (PTH), impaired renal 1-α-hydroxylase activity, and hypocalcemia.28 Skeletal metabolism is affected, and can include altered bone turnover, defective mineralization, and skeletal fragility. Fracture rates in children with CKD have been found to be 2-3 times greater than the general population.29 Deficits in BMD, bone structure and muscle size have been desribed.30

Treatment is directed at controlling phosphate and maintaining normocalcemia.31 Calcitriol/vitamin D analogs are added for hypocalcemia and to treat secondary hyperparathyroidism. The negative effects of CKD-MBD persist after transplantation. Glucocorticoid sparing immunosuppression is recommended, when possible, and growth hormone should be considered in children who fail to demonstrate catch up growth.32 The use of bisphosphonates in children with CKD-MBD has not been well studied and there are concerns it could be detrimental in the setting of low bone turnover.

Inflammatory disorders

Inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), inflammatory arthritis, and systemic lupus erythematosus (SLE) can all cause skeletal damage.33 Inflammatory cytokines negatively impact bone by reducing osteoblast mediated formation and promoting osteoclast resorption.34 Glucocorticoids are frequently employed in the initial treatment of inflammatory disease and further weaken bone. Nutritional deficits are possible, especially in IBD in which absorption may be impaired. Inflammatory mediated suppression of pituitary hormone secretion is also a factor. Many of these risk factors are reversible as evidenced by findings that anti-inflammatory treatment led to recovery of growth factors, muscle and bone deficits in children with Crohn disease.35 Bisphosphonates have been shown to improve BMD in children with IBD36 and rheumatologic disorders,37 although indications for use have not been formerly defined.

Liver disease

Skeletal manifestations of severe liver disease in children include poor growth, low BMD, defects in bone mineralization (including rickets), and fracture.38 Vitamin D absorption can be profoundly impaired due to fat malabsorption, and very high doses of vitamin D supplementation may be needed. Skeletal recovery is likely after transplant, especially in younger children, as evidenced by findings that long-term survivors of childhood liver transplant had normal BMD and low fracture rate.39 There are limited data regarding bisphosphonate use in this population. Bisphosphonates should not be administered to patients with active rickets, and care should be taken in those with significant malabsorption as they may be at increased of hypocalcemia following treatment.

Cancer

Glucocorticoids are administered during induction chemotherapy in some forms of childhood cancer. Immobility and deconditioning are also common. Some children require skeletal radiation, which can further damage bone. VF are reported in 25% of children with glucocorticoid-treated acute lymphoblastic leukemia (ALL).40 The prevalence of BMD deficit, fracture, and avascular necrosis may be even higher among patients undergoing hematopoietic stem cell transplantation (HSCT).41 Many survivors of childhood cancer demonstrate skeletal recovery.42 Current recommendations suggest annual BMD and VF assessment before and after HSCT, along with attention to calcium and vitamin D repletion as needed. Bisphosphonates can be considered in children with fractures, particularly if symptomatic VF, or if there is a poor prognosis for skeletal recovery based upon age, growth potential, or more severe disease.41

Diabetes

Impaired bone health is a recognized complication of type 1 diabetes (T1D). In children with T1D, fracture risk was reported to be 14% greater in boys and 35% greater in girls, compared to healthy controls.43 Deficits in bone density and structure have been described in many,44 but not all studies.45 When present, the degree of deficit is inadequate to fully explain the fracture risk and suggests impaired bone quality. Hyperglycemia,46 the coexistence of microvascular disease,47 and abnormalities in the growth hormone axis48 have been associated with adverse skeletal outcomes. Vitamin D deficiency and inadequate calcium intake are common.49 Optimization of calcium and vitamin D intake with dietary modification and supplementation, as needed, is logical and should be incorporated into dietary counseling. Regular weight bearing physical activity should also be emphasized, noting that children with T1D tend to be less active than peers.50

Emerging data in children suggest that cardiometabolic abnormalities associated with type 2 diabetes (T2D) may adversely influence skeletal development.51 There is growing interest in the use of non-insulin pharmacotherapy to treat childhood T2D. However some of these agents (sodium-glucose cotransporter 2 inhibitors, for example)52 may alter bone metabolism and require careful study.

Cystic fibrosis (CF)

Low BMD has been described in some but not all studies of youth with CF.53 This inconsistency may be due to heterogeneity in CF severity, as studies limited to patients with severe disease have reported significant BMD deficits and fracture risk.54 Nutritional deficiency leading to low body weight and malabsorption of fat soluble vitamin D and K, as well as impaired growth and pubertal delay are all risk factors for poor bone accrual.55 Current guidelines suggest annual assessment of 25-OH vitamin D and a screening DXA scan starting at age 8 years in high risk children (underweight, poor pulmonary function).56 Oral alendronate was shown to be safe and effective in improving BMD in youth with CF.57 However, the indications for initiating bisphosphonates have not been defined.

Congenital heart disease (CHD)

Many children with CHD are critically ill during the early years of skeletal development. Children with single ventricle disease requiring Fontan palliation may be at especially high risk for bone and lean mass deficits that progress with time.58 Factors shown to impair bone health include diuretics, secondary hyperparathyroidism, and protein losing enteropathy.59, 60 There are few data describing the treatment of bone health in CHD and specific guidelines have not been published.

Metabolic

Lysosomal storage disorders can result in bony abnormalities and skeletal fragility.61 Cystinosis in particular can be associated with severe skeletal effects, including rickets, osteoporosis and CKD-MBD. The etiology is multifactorial and related to renal loss of calcium and phosphate, compounded by acidosis and CKD. Treatment is focused on managing rickets and reducing acidosis.62 Homocystinuria has also been associated with low bone density.63

Adolescent Medicine

Gender Dysphoria

The treatment of gender dysphoria in youth includes the use of gonadotropin releasing hormone (GnRH) analogues at the first signs of emotional distress with puberty. Gender affirming sex steroid therapy typically follows once persistence of gender identify has been established. Concerns about effects of long-term GnRH analog therapy on skeletal development have been raised. Small studies in adolescents found that GnRH therapy was associated with mild reductions in BMD Z-scores, but that catch up bone accrual occurred after initiation of sex steroid therapy.64 Fracture risk has not been reported in youth, but was elevated in adult trans-women.65 Recent guidelines discuss the issues of bone health in transgender people.66 A challenge to the evaluation of bone health in this population is that the interpretation of BMD and some bone biomarkers require comparison to sex-matched reference data. DXA reports should therefore include Z-scores referenced to both sex at birth and gender identity.

Eating disorders

Anorexia nervosa, bullemia, and the female athletic triad are associated with impaired bone health.67 Deficits in BMD and bone structure have been widely described and are the result of energy deficit, low body mass, and hormonal disturbances including hypogonadism.68 Low body weight is a risk factor for stress fractures in young athletes,69 and their coexistence should prompt consideration for disordered eating.

Weight restoration therapy is the cornerstone of bone health therapy. Estrogen replacement may be considered in post-menarchal females who fail to resume menses, with or without attaining weight restoration. The decision to institute estrogen replacement should be individualized and must balance skeletal risk against the loss of menses as a biomarker of health. When hormone replacement is desired, evidence supports the use of transdermal estrogen with cyclic progesterone, as this approach has been shown to improve BMD70 whereas combined oral contraceptives have not.71 Studies of bisphosphonates have largely been limited to adults and generally suggest a beneficial effect on BMD.72 Current opinion states that bisphosphonates should only be used in youth with eating disorders who have clinically significant fractures and poor prognosis for skeletal recovery.73

CLINICAL APPROACH

The goals of bone health care in children with chronic disease are to improve health and quality of life by reducing fracture frequency and to promote bone accrual during the critical years for skeletal development. Many children with chronic disease are now living long into adulthood. Maximizing peak bone mass is an important component of mitigating lifelong fracture risk. The accomplishment of these goals requires a multidisciplinary team and close communication with the specialist(s) attending to the child’s primary disorder (Figure 2).

Figure 2: Components of the bone health evaluation.

Figure 2:

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Suggested approach to the initial bone health evaluation. Frequency and extent of follow-up evaluations will depend upon initial findings and clinical course.

1Urine Ca/Cr to assess for hypercalciuria and deficient calcium absorption (see text)

2 Urine Ca/Cr falsely elevated in patients with low muscle mass. Urine Ca/Osmolality or 24-hour quantification should be used instead (see text)

3 Tubular resorption of phosphate [1-(urine phosphorus*serum creatinine) / (serum phosphorus* urine creatinine)] is helpful in determining mechanism of hypophosphatemia and significance of PTH elevations. Values <0.9 in presence of hypophosphatemia suggest significant urinary phosphate wasting.

4 Based upon clinical suspicion. Thyroid function if growth is impaired. Celiac panel if calcium/vitamin D absorption appears impaired in absence of other etiology. Sex steroids (testosterone, estradiol) may be helpful in assessing pubertal status. Bone resorption markers (beta-cross laps, urinary n-telopeptides) may be useful in assessing bisphosphonate dosing. Bone specific alkaline phosphatase if alkaline phosphatase interpretation is limited by presence of transaminitis.

5 Chronic glucocorticoid use, tenderness over vertebral bodies on exam, low spine bone density by DXA

6 Choice of site is dependent upon availability of adequate reference data for population and DXA platform. Proximal femur may be appropriate for tracking of BMD through adulthood. Lateral distal femur is used in non-ambulatory children at risk of distal femur fracture. Distal 1/3 radius may be only option in some patients with significant contractures or indwelling medical hardware.

IBD, inflammatory bowel disorder; PTH, parathyroid hormone; RDA, recommended dietary allowance; TSH, thyroid stimulating hormone

The involvement of an RD or other nutrition expert is essential. Risk factors for impaired nutrition are many and include selective eating, gastric- or jejunal-tube dependence, antacids, and malabsorption. Feeding regimens may lead to unexpected complications, as evidenced by reports of hypophosphatemic rickets caused by elemental formula74 and scurvy due to the ketogenic diet.75 A dietary history that includes assessment of calcium, phosphorus, vitamin D, as well as macro- and micronutrient intake should be performed at initial evaluation and updated periodically. Many children will require supplementation with cholecalciferol or ergocalciferol. Dosing should be individualized to maintain serum 25-OH-vitamin D levels of 20-30 ng/mL (50-75 nmol/L). Routine calcium supplementation is not advised, but should be considered if the child is unable to meet the RDA for calcium from dietary sources.

Collaboration with physical therapy (PT) and orthopedic providers is paramount. PT input is essential for the implementation of safe, tolerable weight-bearing regimens. Efforts should be made to optimize bone health prior to major elective orthopedic procedures such as scoliosis repair or osteotomies for hip dysplasia. This includes the treatment of vitamin D, calcium, and other nutritional deficiencies. In some cases, such as history of fragility fracture, the initiation of bisphosphonate therapy prior to surgery may be warranted. Deconditioning following surgery or limb immobilization can occur and lead to secondary fractures. PT, under the guidance of the orthopedic surgeon, is a critical component of post-immobilization care.

The assessment of bone health begins with a fracture history. Note should be made of fracture site, timing, and mechanism. Long bone and VF in the absence of trauma are clinically significant and support a diagnosis of osteoporosis in a child with chronic disease. In many cases, biochemical assessment is warranted. Elevations in PTH (in the absence of hypercalcemia) and/or alkaline phosphatase (in the absence of transaminitis) may be indicative of deficient calcium absorption and can be used to adjust calcium and vitamin D supplementation. Spot urine calcium/creatinine (Uca/Ucr) ratio is helpful in identifying hypercalciuria (>0.2 in children over 8 years) and deficient calcium absorption (<0.1).76 Uca/Ucr is not reliable in children with low muscle mass, and spot urine calcium/osmolality77 or quantification of 24-hour excretion should be performed instead.

Imaging

Imaging is performed to determine BMD and identify VF. DXA provides an estimate of areal BMD and is subject to size artifact including underestimation of BMD in short and overestimation of BMD in tall individuals. Techniques for adjusting BMD for size have been developed.78, 79 Size adjustment provides an estimate of the degree of BMD deficit (excess) that may be attributable to short (tall) stature. Delayed (advanced) pubertal development may also affect the assessment of BMD by DXA and should be considered in the clinical interpretation.80 Total body less head and lumbar spine are the most commonly utilized DXA sites, although the distal 1/3 radius, proximal hip, and lateral distal femur can be assessed if appropriate reference data are available. The International Society for Clinical Densitometry has sponsored a number of position development conference to define best practices for the use of DXA in children. The most recent positions, published in 2019, provide guidance on the use of DXA to assess BMD at the forearm, hip and lateral distal femur in children. The utility of vertebral fracture assessment by DXA in children was also discussed.81

Routine screening for VF should be performed in high risk patients such as those with back pain, low BMD, or treated with glucocorticoids. Lateral spine radiography or DXA can be used. The Genant semi-quantitative method, performed by a provider with pediatric expertise, is recommended for the assessment of VF.82 Using this approach, VF are graded in severity based upon loss of vertebral height as 0 (normal), 1 (mild, <25%), 2 (moderate, 25-40%), or 3 (severe, >40%). In most cases, the presence of ≥1 grade 1 or greater VF, in the absence of trauma, in a child with risk factors for impaired bone health is considered clinically significant and consistent with a diagnosis of osteoporosis. VF assessment is generally repeated annually in children with persistent risk factors and/or being treated with anti-osteoporosis agents.

Treatment

The addition of an anti-osteoporosis agent to the bone health regimen should be considered when a child with chronic disease suffers a first clinically significant fracture (vertebral, femur) or recurrent low-trauma fractures of other sites when spontaneous recovery of bone health is not anticipated.83 The decision to initiate therapy must be individualized to balance the benefits and risks. It must incorporate factors including the expected course of underlying disease (limited with possibility of recovery vs progressive), fracture frequency and mechanism (traumatic vs non-traumatic), growth and pubertal status, exposure to bone toxic medications, degree of BMD deficit, and the potential risk and severity of treatment related adverse events (hypocalcemia, acute phase reaction, renal injury, osteonecrosis of jaw).

The nitrogeneous bisphosphonates are the most widely used agents in children. Bisphosphonates increase BMD and bone strength through the inhibition of osteoclasts. Data from placebo controlled clinical trials to properly inform indication, dose, or duration of bisphosphonate therapy in children with chronic diseases are lacking. There is, however, growing clinical experience with the use of these drugs in many of the chronic diseases of childhood. Bisphosphonates have generally been shown to be effective in improving bone density, but data for fracture reduction are less conclusive.

Consensus guidelines for the use of bisphosphonates in children have been proposed84 and protocols for the use of zoledronate85 and pamidronate86 have been published. IV formulations are more potent than oral and more widely used. Zoledronate is the most potent, making it the preferred agent in many centers due to its brief infusion time (typically 30 minutes) and dosing duration (typically every 6-12 months). There are a few studies that support the efficacy of oral bisphosphonates to improve BMD in children with chronic disease.87 A potential role for bisphosphonates in children with low bone density prior to first fracture requires further study.

Conclusion

The adverse skeletal effects of childhood chronic disease are now widely recognized. Great strides have been made in defining the pathophysiology underlying impaired bone health in this population. The clinical approach continues to evolve with growing emphasis placed on incorporating bone health care into the multi-disciplinary approach to these children. There remains a need for research to more clearly define the optimal indication, dosing and duration of bisphosphonate therapy. Alternative therapies, including anti-RANKL-antibody and anti-sclerostin-antibody, are now widely used in adults and should be evaluated in children for whom bisphosphonates are contraindicated or have limited efficacy.

Key points:

  • Fisk factors for impaired bone health in children with chronic disease include immobility, nutritional deficiency, exposure to bone toxic therapies, hormonal deficiencies, and inflammation

  • Optimizing bone health in children with chronic disease requires a multidisciplinary clinical approach

  • Bisphosphonate therapy should be considered at the first sign of clinically significant skeletal fragility in a child with chronic disease and limited potential for skeletal recovery

Synopsis:

Many children with chronic disease are now surviving into adulthood. As a result, there is a growing interest in optimizing bone health early in the disease course with the dual goals of improving quality of life during childhood and reducing life-long fracture risk. Risk factors for impaired bone health in these children include immobility, nutritional deficiency, exposure to bone toxic therapies, hormonal deficiencies affecting growth and pubertal development, and chronic inflammation. This review is focused on the chronic diseases of childhood most commonly associated with impaired bone health. Recent research findings and clinical practice recommendations, when available, for specific disorders will be summarized. A general approach to the management of impaired bone health in children with chronic disease will also be provided, including a discussion of the clinical evaluations and treatments currently used.

Acknowledgments

Grant Support: National Institutes of Health, K23 DK114477

Footnotes

Financial Disclosures: The author has nothing to disclose

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