Journal of Pediatric Rehabilitation Medicine: An Interdisciplinary Approach 7 (2014) 125–132 DOI 10.3233/PRM-140281 IOS Press
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Bisphosphonate use in children with pediatric osteoporosis and other bone conditions Elizabeth A. Szalay UNM Carrie Tingley Bone Health Center, University of New Mexico School of Medicine, Carrie Tingley Hospital, 1127 University Blvd. NE, Albuquerque, NM 87102, USA Tel.: +1 505 272 5214; Fax: +1 505 272 6500; E-mail: [email protected]
Accepted 24 March 2014
Abstract. Bisphosphonates (BPs) are used most commonly in children with osteogenesis imperfecta, resulting in increased trabeculae and cortical thickness, increased bone density as measured by DXA (Dual Energy X-ray Absorptiometry), and improved vertebral morphology. Less well documented in controlled trials are decrease in long bone fractures, improved strength and motor function, and decreased pain [1]. Outside of children with osteogenesis imperfecta, use of bisphosphonates in children is increasing, all of which is off-label. This is seen in children with other chronic conditions resulting in pediatric osteoporosis and insufficiency fractures. Additional indications include steroid dependency with progressive loss of bone density, avascular necrosis of bone, and chronic regional pain syndrome. This review highlights the potential benefits and risks of the use of bisphosphonates in these unique children at risk for fracture or bone collapse. Keywords: DXA, bisphosphonates, pediatric osteoporosis
1. Introduction Pediatric osteoporosis and low bone density are seen commonly in children with chronic illness. Conditions associated with low bone density include cerebral palsy, inflammatory arthritis, cystic fibrosis, childhood cancer, gastrointestinal disorders, idiopathic juvenile osteoporosis, and any condition requiring longterm steroid treatment [2]. Non- steroid medications implicated in low bone density in children including seizure medicines, stomach acid blockers, and depo Medrol [2]. Some children exhibit hereditary low bone density, manifested throughout life and familial, that is not readily classified as osteogenesis imperfecta. Establishing a diagnosis of pediatric osteoporosis or low bone density for age is the first step in developing a treatment plan [3]. Bone strength is determined by multiple factors including the microarchitecture of bone, the collagen substrate, and mineralization. As all of these factors are difficult to measure, bone mineral density (BMD) as measured by dual energy x-ray ab-
sorptiometry (DXA) scanning is commonly used as a proxy for bone strength [4]. DXA is the gold standard for the diagnosis of low bone density in children, but its interpretation in complicated and fraught with potential error. In pediatric densitometry, only the BMD Z-score is considered for diagnostic purposes, which compares the child to an age-and-sex-matched mean. Chronically ill children may have growth retardation or a delayed bone age, and while there are many recommendations for adjusting for growth retardation, such as correcting for height Z-score or height age (interpreting the DXA results using the age at which the child’s height falls on the 50th percentile) [3]. Many other factors (body weight, activity level, degree of sexual maturity, etc.) influence fracture risk, such that the DXA Z-score alone should not be used as an indication for bisphosphonate treatment [2,5]. Children with a BMD Z-score two standard deviations (SD) below the mean are said to have “low bone density for age;” the term “osteopenia” is not densit-
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Fig. 1. Supracondylar fracture in child with cerebral palsy.
ometrically defined and should not be used for children [5]. The clinical definition of “osteoporosis” is bone fragility such that fractures occur with minimal trauma. A densitometric definition of osteoporosis has been established in adults, defined as a T-score (comparing the individual to a young adult ideal mean) of less than 2.5 SD below the mean. In children, no densitometric definition of “osteoporosis” has been established. The diagnosis of “osteoporosis” in pediatrics requires both low bone density and a “clinically significant fracture history,” defined as a long bone fracture of the lower extremities, a vertebral compression fracture, or two or more long-bone fractures of the upper extremities [5].
2. Pharmacologic treatment for “pediatric osteoporosis” Insufficiency fractures, those occurring as a result of minimal trauma, such as fractures of the proximal tibia or distal femur seen in children with spastic quadriplegia (Fig. 1), may occur during routine care, such as dressing the child or donning orthotics. Fractures are painful, and the immobilization required both impedes
Fig. 2. Lateral radiograph of spine demonstrating compression fractures, platyspondyly, and kyphosis.
activity of daily living and promotes further bone loss. This sets up a cycle for ongoing risk of fracture. Children with leukemia, steroid dependency, or “idiopathic juvenile osteoporosis” may present with painful compression fractures of the spine, which can lead to platyspondyly, kyphosis, or scoliosis (Fig. 2). Faced with painful fractures and the likelihood that the child’s risk of further fractures is significant, parents and patients alike are anxious to intervene. Unfortunately, there are few treatment options available beyond nutritional and exercise interventions. None of the medications approved for adult osteoporosis (bisphosphonates, parathyroid hormone (PTH), denosumab) is approved for use in children by the United States Food and Drug Administration (FDA). Parathyroid analogues in particular have a “black box” warning against the use in children due to the risk of cancer in laboratory animals.
3. Bisphosphonates Bisphosphonates (BPs) are a class of drug that disrupts osteoclast function and survival. The nitrogencontaining BPs pamidronate, alendronate, ibandronate,
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risendronate, and zoledronate are particularly potent at inhibiting bone resorption [6]. They have been well studied in adults, but no large-scale randomized trials have been performed in children without osteogenesis imperfecta. This is partly because the pediatric osteoporosis population is small, and it is difficult to randomize children to a non-pharmacologic arm after they have suffered a disabling insufficiency fracture. Despite the fact that BP use is off-label in children, these agents have been used for younger patients for many years [7,8]. The primary experience is with children with osteogenesis imperfecta, for which BPs have become a mainstay of treatment [9]. Extrapolation from this experience has led to BP treatment of a variety of other pediatric conditions, such as cerebral palsy, muscular dystrophy, and steroid-associated bone fragility. Side effects of these medications are minor and transitory: many patients experience fever, myalgias, and other flu-like symptoms, especially with the first infusion of an IV BP. Hypocalcemia is rare absent hypovitaminosis D or impaired renal function [10]. The oral BPs are associated with esophageal erosion, which has decreased in incidence since the dosing has been optionally changed to once weekly. Serious side effects include osteonecrosis of the jaw, typically seen in cancer patients on both high dose IV BPs and chemotherapy, and atypical fractures of the femur, reported in adults, usually on BP therapy > 5 years [11]. Neither of these complications has been reported in children, although atypical femur fractures in adults with osteogenesis imperfecta have been reported [12]. Children, unlike adults with postmenopausal osteoporosis, have reproductive potential: no large studies on BP treatment prior to reproduction have been performed. Animal studies using BP doses far in excess than those used in humans have demonstrated retardation of bone growth and fetal underdevelopment [13]. Howerver, small studies of women having children following BP therapy have reported a few detrimental effects, such as transient abnormalities of serum calcium levels [14] and lower birth rate compared to controls [15]. Intravenous pamidronate has the best “track record” in children, usually in doses of 4–9 mg/kg/year given every 3–4 months via 1–3 day infusion. This success comes with the potential inconvenience of a trip to the hospital or infusion center for IV access and a several hour infusion, which may disrupt school and other activities of daily living. Accordingly, many parents prefer a trial of oral BPs such as oral alendronate. This may be given at home once weekly, but the exact
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dosing requirements (given on an empty stomach first thing in the morning with at least 8 oz. of plain water, remaining upright with delay in taking other food, drink, or medications) are likely not always followed, resulting in poor absorption of the drug and the possibility of esophagitis. Pharmacy instructions commonly advise a delay of 30 minutes before eating, but this protocol decreases absorption by as much as 40% as compared to waiting one to two full hours [16]. No pediatric dosing protocols for alendronate have been established. This center empirically extrapolated from the adult dose of 70 mg/week to 1 mg/kg/week. Other published studies have described oral alendronate doses as high as 1 mg/kg/d [17]. Zoledronate is a bisphosphonate of significantly greater potency, which translates to shorter infusion time and less frequent dosing regimen [8]. Pediatric experience with zoledronate has been reported in small series [18], but there are few large comparative series. Interest in the longer acting IV bisphosphonates such as zoledronate is increasing. The optimal dose of zoledronic acid that does not result in hypocalcemia, hypophosphatemia, hypomagnesemia, or overly suppressed bone turnover remains to be determined. An additional potential disadvantage is the significantly prolonged half-life of the drug, which has not been extensively examined in children with future reproductive potential. While no studies have examined the duration of excretion in children treated with zolendronate, pamidronate, a drug with a shorter half-life, has been detected in urine up to 8 years following treatment [19]. Regardless of the BP chosen, treatment of pediatric osteoporosis with BPs must be accompanied by monitoring Vitamin D status (with serum 25 OH Vitamin D levels between 20 and 40 ng/ml (50–100 nmoles/L)) and adequate calcium intake (250 mg/day for infant to 1300 mg/day for teen). Clinical response – e.g. fractures – is the ideal outcome to monitor treatment, but given that fracture, even in susceptible patients, is a rare event, monitoring of BMD is a surrogate outcome [4]. Patients must be monitored by sequential DXA scanning. A study from our center of alendronate-treated patients showed that, while some children exhibited a marked improvement in bone density, others showed no response at all, in fact, there was no statistical difference in the change of BMD between the alendronate treated group and historical controls with similar diagnoses [20]. This suggests that during BP treatment, failure to see improved BMD on sequential DXA scans demands reassessment of treat-
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ment and/or switching to an alternative treatment such as IV BP. Despite the fact that fracture is the ultimate endpoint to be addressed, studies that use fracture or fracture rate as an endpoint requires very large numbers of subjects, a population that simply does not exist in pediatric osteoporosis. Accordingly, most studies of bisphosphonate treatment in children use the surrogate endpoint of change in BMD [2]. A study of 25 children with quadriplegic cerebral palsy demonstrated a lower fracture rate following 1 year treatment with pamidronate [21], but there are no large scale studies in children that correlate percent improvement of BMD or Z-score with a corresponding decrease in fracture risk, especially in chronically ill or relatively immobile children. There is no consensus regarding duration of therapy in children and adolescents with secondary osteoporosis: ideal would be treatment until the BMD Z-score is within the normal range (greater than −2 SD) and no fractures are occurring, but in many chronically ill children this is an unattainable goal. A Cochrane review suggests a “short-term (3 years or less) BP use appears to be well tolerated [22].” The fact that prolonged BP treatment decreases osteoclastic bone remodeling and has been associated with atypical femur fractures in adults has led many practitioners to advocate a “drug holiday” after 3–5 years of BP treatment [23]. Studies suggest that while gains from BP therapy plateau after 2–4 years, discontinuance of the drug in the growing child leads to decreasing BMD Zscores with growth [7]. 3.1. Treatment of “low bone density for age” While low BMD suggests an increased fracture risk, the correlation of bone density and fracture is not as well defined in children like in adults. Large population studies on fracture risk in children primarily looked at healthy children [24], which may not be applicable to chronically ill or wheelchair ambulatory children. Smaller studies looking at fracture risk in children with cerebral palsy or muscular dystrophy demonstrated a strong correlation of fracture history with BMD Z-score of the distal femur [25,26]. Because of the lack of clarity between BMD and fracture risk in chronically ill children, bisphosphonate treatment for “low bone density for age” cannot be recommended in the absence of a significant fracture history, even in children with chronic disease such as cerebral palsy. Rather, initial management involves a thorough
workup for treatable etiologies (such as Vitamin D deficiency, leukemia, endocrinopathy or gluten intolerance), maximization of Vitamin D status, calcium and protein intake, and emphasis on weight bearing exercise. 3.2. Treatment of fragility fractures in children with cerebral palsy Children with cerebral palsy, especially those who are nonambulatory, often have growth inhibition and low bone density for age, and are at greater risk for fracture [24,25]. An event such as orthopaedic surgery, concurrent illness, or immobilization can result in a dramatic loss of bone density [27] and an increased risk of fragility fracture, most commonly seen in the distal femur or proximal tibia. Low bone density alone should not be an indication for bisphosphonate therapy, but once fragility fracture has occurred, most families are anxious for treatment to prevent further fracture. Intravenous bisphosphonate for one year in a small randomized study produced an average 89% improvement of bone density [8], while a study from this center looking at alendronate in children and adolescents showed a more modest gain, averaging 10% [20]. This suggests that IV therapy is likely more effective: given the option, many parents nonetheless prefer a trial of oral therapy because it avoids the need for painful IV access and a visit to the hospital or infusion center. Regardless of BP chosen, children should be monitored for response using DXA scan: lack of improvement in BMD and/or ongoing fractures suggests change in the therapeutic plan. The only report of BP use in a prophylactic fashion suggests that limited dosing of IV pamidronate at the time of orthopaedic surgical intervention could mitigate the post-operative bone loss experienced by children with low bone density to begin with, thus possibly decreasing the risk of post-operative fragility fracture [28]. Twenty four children 4–18 years old with known low bone density or conditions associated with low bone density were randomized to receive a single dose of pamidronate vs. placebo following orthopaedic surgery: the treated children demonstrated a trend towards less post-operative bone density loss. 3.3. Treatment of low bone density in steroid-treated children Glucocorticoid treatment in children is associated with increased bone resorption, impaired bone forma-
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A
B
Fig. 3. AP and lateral radiographs of collapse of avascular body of talus 1 year following diagnosis: family declined bisphosphonate treatment.
tion, alterations in calcium absorption and loss, and changes in sex steroid and growth hormone. This results in reduction of both bone size and bone mass. Children prescribed more than 3 courses of systemic steroids yearly may exhibit a 20% increase in ageadjusted fracture rates. Unlike adults, rapid recovery was seen after discontinuation of steroids, usually by 1 year after treatment [7]. Because of these factors, there are insufficient data to support the prophylactic use of BPs in glucocorticoid-treated children. Children treated with steroids for conditions such as leukemia may experience painful or even asymptomatic compression fractures of the spine: the existence of spinal compression fractures, multiple long bone fractures, or documented insufficiency fractures would be an indication for BP treatment, especially if a continuing steroid requirement is anticipated. A study from Korea evaluated 24 patients with acute lymphoblastic leukemia and non-Hodgkin lymphoma with IV pamidronate, compared to a control of 10 untreated patients, demonstrating increases in BMD Zscores and relief of reported bone pain [29]. 3.4. Treatment of children with duchenne muscular dystrophy on steroid treatments A subset of steroid dependent children is children with Duchenne muscular dystrophy (DMD). Steroid therapy for children with DMD is currently accepted as offering benefits of improved strength, slowing progression of weakness, and delaying the loss of ambulation and the development of scoliosis [30]. The steroid therapy often causes obesity, and the children eventually become non-ambulatory, both of which contribute to increased fracture risk in the face of low BMD. With no end in sight for the steroid requirement, some clinicians choose to treat preemptively with bis-
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phosphonates, but there are few studies to recommend this treatment. Gordon et al. described offering (bisphosphonate) therapy when there was evidence of progressive osteopenia, rather than specifically upon occurrence of insufficiency fracture. The patients were routinely prescribed supplemental calcium and Vitamin D. A surprising finding in their study of 16 patients on bisphosphonates compared to 28 boys who did not receive bisphosphonate was “significantly improved survival (p = 0.005, log-rank test) compared with treatment of steroids alone.” They found a “possible therapy-duration effect for bisphosphonate use” (p = 0.007, log-rank test) [31]. The use of BP in children with DMD remains controversial: the 2010 Lancet review recommends IV BPS for vertebral fracture, holding as controversial “prophylactic treatment using oral BPs” [32]. 3.5. Fractures in children with spina bifida Children with spina bifida often present with lower extremity fractures that may go unnoticed for days due to insensate limbs. Given the delay in diagnosis, these fractures are occasionally confused with infection, as the child exhibits warmth, swelling, mild fever, and increased sedimentation rate. Children with spina bifida occasionally paradoxically demonstrate bone density well above the mean at peripheral DXA sites such as the distal femur, but those who are nonambulatory are at risk for low bone density for age [33]. This, coupled with a high incidence of obesity, increasing the stress applied to bone, may result in lower extremity fractures. However, insensitivity to pain plays a large role in fractures – the individual does not experience pain when overloading the bone, which may lead to fracture – so clearly all fractures in children with spina bifida are not insufficiency fractures. Consideration of bisphosphonate therapy must take into account bone density Z-scores as well as a careful history of fracture mechanism.
4. Use of bisphosphonates in pediatric conditions other than fracture 4.1. Pediatric osteonecrosis Osteonecrosis of bone in children occurs in Legg Perthes disorder of the hip, unstable slipped capital femoral epiphysis, sickle cell disease, as a sequel of trauma; especially following fractures of the talus and
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B
Fig. 4. One year following diagnosis of AVN of talus: family chose to use oral alendronate.
femoral neck, in severe osteomyelitis, and in children treated with long term and/or high dose steroid therapy, such as for childhood cancers. The natural history of pediatric osteonecrosis is variable – some children heal the lesion with minimal deformity, while others proceed to disintegration of the affected bone, with resultant marked joint incongruity and progressive joint debility (Fig. 3A and 3B). Published literature on treatment options is rare: a 2013 study of twenty zoledronate- treated children with post-chemotherapy osteonecrosis at various sites, with mixed results – 25% were pain free with minimal joint destruction while 50% reported ongoing pain with activity [34]. A study in 395 adult hips with osteonecrosis of the femoral head compared oral alendronate treatment to control, and demonstrated, with a mean follow-up of 4 years, significantly less collapse of the affected bone in the treated patients [35]. (Fig. 4A and 4B) There is limited literature supporting the use of BP in childhood avascular necrosis, especially in cases of Legg Perthes disorder [36,37]. In rodent models, femoral head structure can be almost completely preserved with alendronate or zolendronate treatment [38]. The issue of availability of a parenteral drug in an avascular area has spurred investigations of other modes of administration, such as intraosseous injection of BP and bone morphogenetic protein [39]. Other than Legg Perthes disorder, avascular necrosis of bone in children is a relatively rare entity that makes large comparative and randomized trials difficult if not impossible. The author’s unpublished experience in children with dead bone as a result of devastating musculoskeletal infection suggests that bisphosphonate use improves pain and function, often delaying the need for salvage surgery such as hip arthrodesis or hip arthroplasty. Especially in a child who has had infections, the longer the delay before a definitive procedure is done, the less likely for recurrence of infections. These children often do not wish to discontinue
Fig. 5. Pelvis radiograph demonstrating severe bone avascular necrosis and destruction Right hip secondary to septic hip and osteomyelitis: alendronate treatment improved pain and functional capacity.
the medication, as they note an increase in pain when they do so (Fig. 5). In BP treated children who do not have primary low bone density, continual monitoring of bone density is needed to insure that an osteopetrosis situation is not created, but the improvement in bone density is often greatest in the area affected by injury or infection. It has not been established at what Z-score above the norm (normal is considered a Z-score up to +2 SD above the mean) an increase in fracture risk might be observed. 4.2. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is a rare, but disabling neurological condition in children that usually follows trauma. Pain is out of proportion to the physical findings, and regionalized osteopenia can be severe. In adult patients with CRPS, bisphosphonate therapy has been demonstrated to be useful to mitigate pain [40,41]. Tran et al. in 2010 state “in terms of pharmacological treatment, oral and intravenous bisphosphonates. . . have been proven to reliably decrease pain and swelling as well as increase range of motion in patients with CRPS [42].” The pediatric experience of BP in CRPS is more limited. A published case study of an 11 year old with CRPS who was treated with a total of 11 infusions of pamidronate over 24 months, reported reduction in pain, improvement in function, and normalization of bone density and strength; as reflected by peripheral quantitative computerized tomography and DXA scans comparing the affected to nonaffected lower extremity.
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It remains unclear whether the pain relief from BP relates to improved bone density in the affected region, decreased osteoclastic resorption, or other undefined mechanism.
5. Conclusions Any use of bisphosphonates in the United States is off-label, as none of the bisphosphonates is FDA approved for use in children. For this reason, the use of BPs should be limited to children who have demonstrated a significant fracture history, or, such as the case of children with Duchenne muscular dystrophy on steroid treatment, have decreasing Z-scores and a perceived significant increase in fracture risk. Parents and patients must be advised of the off-label status for children: in particular, that long-term, large, randomized studies of children treated with BPs to treat increased fracture risk not associated with osteogenesis imperfecta do not exist, as they are advised of the risks and benefits of therapy. For those patients who are considered appropriate for therapy given the individual risk/benefit ratio, serum Vitamin D levels should be monitored, as well as calcium intake, and treatment response should be followed with serial DXA scans. Failure of improvement of BMD and/or BMD Z-score, bone pain, and/or frequency of fracture should occasion reevaluation of the treatment plan.
Conflict of interest The author reports no conflict of interest.
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Bisphosphonate use in children with pediatric osteoporosis and other bone conditions Elizabeth A. Szalay UNM Carrie Tingley Bone Health Center, University of New Mexico School of Medicine, Carrie Tingley Hospital, 1127 University Blvd. NE, Albuquerque, NM 87102, USA Tel.: +1 505 272 5214; Fax: +1 505 272 6500; E-mail: [email protected]
Accepted 24 March 2014
Abstract. Bisphosphonates (BPs) are used most commonly in children with osteogenesis imperfecta, resulting in increased trabeculae and cortical thickness, increased bone density as measured by DXA (Dual Energy X-ray Absorptiometry), and improved vertebral morphology. Less well documented in controlled trials are decrease in long bone fractures, improved strength and motor function, and decreased pain [1]. Outside of children with osteogenesis imperfecta, use of bisphosphonates in children is increasing, all of which is off-label. This is seen in children with other chronic conditions resulting in pediatric osteoporosis and insufficiency fractures. Additional indications include steroid dependency with progressive loss of bone density, avascular necrosis of bone, and chronic regional pain syndrome. This review highlights the potential benefits and risks of the use of bisphosphonates in these unique children at risk for fracture or bone collapse. Keywords: DXA, bisphosphonates, pediatric osteoporosis
1. Introduction Pediatric osteoporosis and low bone density are seen commonly in children with chronic illness. Conditions associated with low bone density include cerebral palsy, inflammatory arthritis, cystic fibrosis, childhood cancer, gastrointestinal disorders, idiopathic juvenile osteoporosis, and any condition requiring longterm steroid treatment [2]. Non- steroid medications implicated in low bone density in children including seizure medicines, stomach acid blockers, and depo Medrol [2]. Some children exhibit hereditary low bone density, manifested throughout life and familial, that is not readily classified as osteogenesis imperfecta. Establishing a diagnosis of pediatric osteoporosis or low bone density for age is the first step in developing a treatment plan [3]. Bone strength is determined by multiple factors including the microarchitecture of bone, the collagen substrate, and mineralization. As all of these factors are difficult to measure, bone mineral density (BMD) as measured by dual energy x-ray ab-
sorptiometry (DXA) scanning is commonly used as a proxy for bone strength [4]. DXA is the gold standard for the diagnosis of low bone density in children, but its interpretation in complicated and fraught with potential error. In pediatric densitometry, only the BMD Z-score is considered for diagnostic purposes, which compares the child to an age-and-sex-matched mean. Chronically ill children may have growth retardation or a delayed bone age, and while there are many recommendations for adjusting for growth retardation, such as correcting for height Z-score or height age (interpreting the DXA results using the age at which the child’s height falls on the 50th percentile) [3]. Many other factors (body weight, activity level, degree of sexual maturity, etc.) influence fracture risk, such that the DXA Z-score alone should not be used as an indication for bisphosphonate treatment [2,5]. Children with a BMD Z-score two standard deviations (SD) below the mean are said to have “low bone density for age;” the term “osteopenia” is not densit-
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Fig. 1. Supracondylar fracture in child with cerebral palsy.
ometrically defined and should not be used for children [5]. The clinical definition of “osteoporosis” is bone fragility such that fractures occur with minimal trauma. A densitometric definition of osteoporosis has been established in adults, defined as a T-score (comparing the individual to a young adult ideal mean) of less than 2.5 SD below the mean. In children, no densitometric definition of “osteoporosis” has been established. The diagnosis of “osteoporosis” in pediatrics requires both low bone density and a “clinically significant fracture history,” defined as a long bone fracture of the lower extremities, a vertebral compression fracture, or two or more long-bone fractures of the upper extremities [5].
2. Pharmacologic treatment for “pediatric osteoporosis” Insufficiency fractures, those occurring as a result of minimal trauma, such as fractures of the proximal tibia or distal femur seen in children with spastic quadriplegia (Fig. 1), may occur during routine care, such as dressing the child or donning orthotics. Fractures are painful, and the immobilization required both impedes
Fig. 2. Lateral radiograph of spine demonstrating compression fractures, platyspondyly, and kyphosis.
activity of daily living and promotes further bone loss. This sets up a cycle for ongoing risk of fracture. Children with leukemia, steroid dependency, or “idiopathic juvenile osteoporosis” may present with painful compression fractures of the spine, which can lead to platyspondyly, kyphosis, or scoliosis (Fig. 2). Faced with painful fractures and the likelihood that the child’s risk of further fractures is significant, parents and patients alike are anxious to intervene. Unfortunately, there are few treatment options available beyond nutritional and exercise interventions. None of the medications approved for adult osteoporosis (bisphosphonates, parathyroid hormone (PTH), denosumab) is approved for use in children by the United States Food and Drug Administration (FDA). Parathyroid analogues in particular have a “black box” warning against the use in children due to the risk of cancer in laboratory animals.
3. Bisphosphonates Bisphosphonates (BPs) are a class of drug that disrupts osteoclast function and survival. The nitrogencontaining BPs pamidronate, alendronate, ibandronate,
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risendronate, and zoledronate are particularly potent at inhibiting bone resorption [6]. They have been well studied in adults, but no large-scale randomized trials have been performed in children without osteogenesis imperfecta. This is partly because the pediatric osteoporosis population is small, and it is difficult to randomize children to a non-pharmacologic arm after they have suffered a disabling insufficiency fracture. Despite the fact that BP use is off-label in children, these agents have been used for younger patients for many years [7,8]. The primary experience is with children with osteogenesis imperfecta, for which BPs have become a mainstay of treatment [9]. Extrapolation from this experience has led to BP treatment of a variety of other pediatric conditions, such as cerebral palsy, muscular dystrophy, and steroid-associated bone fragility. Side effects of these medications are minor and transitory: many patients experience fever, myalgias, and other flu-like symptoms, especially with the first infusion of an IV BP. Hypocalcemia is rare absent hypovitaminosis D or impaired renal function [10]. The oral BPs are associated with esophageal erosion, which has decreased in incidence since the dosing has been optionally changed to once weekly. Serious side effects include osteonecrosis of the jaw, typically seen in cancer patients on both high dose IV BPs and chemotherapy, and atypical fractures of the femur, reported in adults, usually on BP therapy > 5 years [11]. Neither of these complications has been reported in children, although atypical femur fractures in adults with osteogenesis imperfecta have been reported [12]. Children, unlike adults with postmenopausal osteoporosis, have reproductive potential: no large studies on BP treatment prior to reproduction have been performed. Animal studies using BP doses far in excess than those used in humans have demonstrated retardation of bone growth and fetal underdevelopment [13]. Howerver, small studies of women having children following BP therapy have reported a few detrimental effects, such as transient abnormalities of serum calcium levels [14] and lower birth rate compared to controls [15]. Intravenous pamidronate has the best “track record” in children, usually in doses of 4–9 mg/kg/year given every 3–4 months via 1–3 day infusion. This success comes with the potential inconvenience of a trip to the hospital or infusion center for IV access and a several hour infusion, which may disrupt school and other activities of daily living. Accordingly, many parents prefer a trial of oral BPs such as oral alendronate. This may be given at home once weekly, but the exact
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dosing requirements (given on an empty stomach first thing in the morning with at least 8 oz. of plain water, remaining upright with delay in taking other food, drink, or medications) are likely not always followed, resulting in poor absorption of the drug and the possibility of esophagitis. Pharmacy instructions commonly advise a delay of 30 minutes before eating, but this protocol decreases absorption by as much as 40% as compared to waiting one to two full hours [16]. No pediatric dosing protocols for alendronate have been established. This center empirically extrapolated from the adult dose of 70 mg/week to 1 mg/kg/week. Other published studies have described oral alendronate doses as high as 1 mg/kg/d [17]. Zoledronate is a bisphosphonate of significantly greater potency, which translates to shorter infusion time and less frequent dosing regimen [8]. Pediatric experience with zoledronate has been reported in small series [18], but there are few large comparative series. Interest in the longer acting IV bisphosphonates such as zoledronate is increasing. The optimal dose of zoledronic acid that does not result in hypocalcemia, hypophosphatemia, hypomagnesemia, or overly suppressed bone turnover remains to be determined. An additional potential disadvantage is the significantly prolonged half-life of the drug, which has not been extensively examined in children with future reproductive potential. While no studies have examined the duration of excretion in children treated with zolendronate, pamidronate, a drug with a shorter half-life, has been detected in urine up to 8 years following treatment [19]. Regardless of the BP chosen, treatment of pediatric osteoporosis with BPs must be accompanied by monitoring Vitamin D status (with serum 25 OH Vitamin D levels between 20 and 40 ng/ml (50–100 nmoles/L)) and adequate calcium intake (250 mg/day for infant to 1300 mg/day for teen). Clinical response – e.g. fractures – is the ideal outcome to monitor treatment, but given that fracture, even in susceptible patients, is a rare event, monitoring of BMD is a surrogate outcome [4]. Patients must be monitored by sequential DXA scanning. A study from our center of alendronate-treated patients showed that, while some children exhibited a marked improvement in bone density, others showed no response at all, in fact, there was no statistical difference in the change of BMD between the alendronate treated group and historical controls with similar diagnoses [20]. This suggests that during BP treatment, failure to see improved BMD on sequential DXA scans demands reassessment of treat-
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ment and/or switching to an alternative treatment such as IV BP. Despite the fact that fracture is the ultimate endpoint to be addressed, studies that use fracture or fracture rate as an endpoint requires very large numbers of subjects, a population that simply does not exist in pediatric osteoporosis. Accordingly, most studies of bisphosphonate treatment in children use the surrogate endpoint of change in BMD [2]. A study of 25 children with quadriplegic cerebral palsy demonstrated a lower fracture rate following 1 year treatment with pamidronate [21], but there are no large scale studies in children that correlate percent improvement of BMD or Z-score with a corresponding decrease in fracture risk, especially in chronically ill or relatively immobile children. There is no consensus regarding duration of therapy in children and adolescents with secondary osteoporosis: ideal would be treatment until the BMD Z-score is within the normal range (greater than −2 SD) and no fractures are occurring, but in many chronically ill children this is an unattainable goal. A Cochrane review suggests a “short-term (3 years or less) BP use appears to be well tolerated [22].” The fact that prolonged BP treatment decreases osteoclastic bone remodeling and has been associated with atypical femur fractures in adults has led many practitioners to advocate a “drug holiday” after 3–5 years of BP treatment [23]. Studies suggest that while gains from BP therapy plateau after 2–4 years, discontinuance of the drug in the growing child leads to decreasing BMD Zscores with growth [7]. 3.1. Treatment of “low bone density for age” While low BMD suggests an increased fracture risk, the correlation of bone density and fracture is not as well defined in children like in adults. Large population studies on fracture risk in children primarily looked at healthy children [24], which may not be applicable to chronically ill or wheelchair ambulatory children. Smaller studies looking at fracture risk in children with cerebral palsy or muscular dystrophy demonstrated a strong correlation of fracture history with BMD Z-score of the distal femur [25,26]. Because of the lack of clarity between BMD and fracture risk in chronically ill children, bisphosphonate treatment for “low bone density for age” cannot be recommended in the absence of a significant fracture history, even in children with chronic disease such as cerebral palsy. Rather, initial management involves a thorough
workup for treatable etiologies (such as Vitamin D deficiency, leukemia, endocrinopathy or gluten intolerance), maximization of Vitamin D status, calcium and protein intake, and emphasis on weight bearing exercise. 3.2. Treatment of fragility fractures in children with cerebral palsy Children with cerebral palsy, especially those who are nonambulatory, often have growth inhibition and low bone density for age, and are at greater risk for fracture [24,25]. An event such as orthopaedic surgery, concurrent illness, or immobilization can result in a dramatic loss of bone density [27] and an increased risk of fragility fracture, most commonly seen in the distal femur or proximal tibia. Low bone density alone should not be an indication for bisphosphonate therapy, but once fragility fracture has occurred, most families are anxious for treatment to prevent further fracture. Intravenous bisphosphonate for one year in a small randomized study produced an average 89% improvement of bone density [8], while a study from this center looking at alendronate in children and adolescents showed a more modest gain, averaging 10% [20]. This suggests that IV therapy is likely more effective: given the option, many parents nonetheless prefer a trial of oral therapy because it avoids the need for painful IV access and a visit to the hospital or infusion center. Regardless of BP chosen, children should be monitored for response using DXA scan: lack of improvement in BMD and/or ongoing fractures suggests change in the therapeutic plan. The only report of BP use in a prophylactic fashion suggests that limited dosing of IV pamidronate at the time of orthopaedic surgical intervention could mitigate the post-operative bone loss experienced by children with low bone density to begin with, thus possibly decreasing the risk of post-operative fragility fracture [28]. Twenty four children 4–18 years old with known low bone density or conditions associated with low bone density were randomized to receive a single dose of pamidronate vs. placebo following orthopaedic surgery: the treated children demonstrated a trend towards less post-operative bone density loss. 3.3. Treatment of low bone density in steroid-treated children Glucocorticoid treatment in children is associated with increased bone resorption, impaired bone forma-
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A
B
Fig. 3. AP and lateral radiographs of collapse of avascular body of talus 1 year following diagnosis: family declined bisphosphonate treatment.
tion, alterations in calcium absorption and loss, and changes in sex steroid and growth hormone. This results in reduction of both bone size and bone mass. Children prescribed more than 3 courses of systemic steroids yearly may exhibit a 20% increase in ageadjusted fracture rates. Unlike adults, rapid recovery was seen after discontinuation of steroids, usually by 1 year after treatment [7]. Because of these factors, there are insufficient data to support the prophylactic use of BPs in glucocorticoid-treated children. Children treated with steroids for conditions such as leukemia may experience painful or even asymptomatic compression fractures of the spine: the existence of spinal compression fractures, multiple long bone fractures, or documented insufficiency fractures would be an indication for BP treatment, especially if a continuing steroid requirement is anticipated. A study from Korea evaluated 24 patients with acute lymphoblastic leukemia and non-Hodgkin lymphoma with IV pamidronate, compared to a control of 10 untreated patients, demonstrating increases in BMD Zscores and relief of reported bone pain [29]. 3.4. Treatment of children with duchenne muscular dystrophy on steroid treatments A subset of steroid dependent children is children with Duchenne muscular dystrophy (DMD). Steroid therapy for children with DMD is currently accepted as offering benefits of improved strength, slowing progression of weakness, and delaying the loss of ambulation and the development of scoliosis [30]. The steroid therapy often causes obesity, and the children eventually become non-ambulatory, both of which contribute to increased fracture risk in the face of low BMD. With no end in sight for the steroid requirement, some clinicians choose to treat preemptively with bis-
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phosphonates, but there are few studies to recommend this treatment. Gordon et al. described offering (bisphosphonate) therapy when there was evidence of progressive osteopenia, rather than specifically upon occurrence of insufficiency fracture. The patients were routinely prescribed supplemental calcium and Vitamin D. A surprising finding in their study of 16 patients on bisphosphonates compared to 28 boys who did not receive bisphosphonate was “significantly improved survival (p = 0.005, log-rank test) compared with treatment of steroids alone.” They found a “possible therapy-duration effect for bisphosphonate use” (p = 0.007, log-rank test) [31]. The use of BP in children with DMD remains controversial: the 2010 Lancet review recommends IV BPS for vertebral fracture, holding as controversial “prophylactic treatment using oral BPs” [32]. 3.5. Fractures in children with spina bifida Children with spina bifida often present with lower extremity fractures that may go unnoticed for days due to insensate limbs. Given the delay in diagnosis, these fractures are occasionally confused with infection, as the child exhibits warmth, swelling, mild fever, and increased sedimentation rate. Children with spina bifida occasionally paradoxically demonstrate bone density well above the mean at peripheral DXA sites such as the distal femur, but those who are nonambulatory are at risk for low bone density for age [33]. This, coupled with a high incidence of obesity, increasing the stress applied to bone, may result in lower extremity fractures. However, insensitivity to pain plays a large role in fractures – the individual does not experience pain when overloading the bone, which may lead to fracture – so clearly all fractures in children with spina bifida are not insufficiency fractures. Consideration of bisphosphonate therapy must take into account bone density Z-scores as well as a careful history of fracture mechanism.
4. Use of bisphosphonates in pediatric conditions other than fracture 4.1. Pediatric osteonecrosis Osteonecrosis of bone in children occurs in Legg Perthes disorder of the hip, unstable slipped capital femoral epiphysis, sickle cell disease, as a sequel of trauma; especially following fractures of the talus and
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B
Fig. 4. One year following diagnosis of AVN of talus: family chose to use oral alendronate.
femoral neck, in severe osteomyelitis, and in children treated with long term and/or high dose steroid therapy, such as for childhood cancers. The natural history of pediatric osteonecrosis is variable – some children heal the lesion with minimal deformity, while others proceed to disintegration of the affected bone, with resultant marked joint incongruity and progressive joint debility (Fig. 3A and 3B). Published literature on treatment options is rare: a 2013 study of twenty zoledronate- treated children with post-chemotherapy osteonecrosis at various sites, with mixed results – 25% were pain free with minimal joint destruction while 50% reported ongoing pain with activity [34]. A study in 395 adult hips with osteonecrosis of the femoral head compared oral alendronate treatment to control, and demonstrated, with a mean follow-up of 4 years, significantly less collapse of the affected bone in the treated patients [35]. (Fig. 4A and 4B) There is limited literature supporting the use of BP in childhood avascular necrosis, especially in cases of Legg Perthes disorder [36,37]. In rodent models, femoral head structure can be almost completely preserved with alendronate or zolendronate treatment [38]. The issue of availability of a parenteral drug in an avascular area has spurred investigations of other modes of administration, such as intraosseous injection of BP and bone morphogenetic protein [39]. Other than Legg Perthes disorder, avascular necrosis of bone in children is a relatively rare entity that makes large comparative and randomized trials difficult if not impossible. The author’s unpublished experience in children with dead bone as a result of devastating musculoskeletal infection suggests that bisphosphonate use improves pain and function, often delaying the need for salvage surgery such as hip arthrodesis or hip arthroplasty. Especially in a child who has had infections, the longer the delay before a definitive procedure is done, the less likely for recurrence of infections. These children often do not wish to discontinue
Fig. 5. Pelvis radiograph demonstrating severe bone avascular necrosis and destruction Right hip secondary to septic hip and osteomyelitis: alendronate treatment improved pain and functional capacity.
the medication, as they note an increase in pain when they do so (Fig. 5). In BP treated children who do not have primary low bone density, continual monitoring of bone density is needed to insure that an osteopetrosis situation is not created, but the improvement in bone density is often greatest in the area affected by injury or infection. It has not been established at what Z-score above the norm (normal is considered a Z-score up to +2 SD above the mean) an increase in fracture risk might be observed. 4.2. Complex regional pain syndrome Complex regional pain syndrome (CRPS) is a rare, but disabling neurological condition in children that usually follows trauma. Pain is out of proportion to the physical findings, and regionalized osteopenia can be severe. In adult patients with CRPS, bisphosphonate therapy has been demonstrated to be useful to mitigate pain [40,41]. Tran et al. in 2010 state “in terms of pharmacological treatment, oral and intravenous bisphosphonates. . . have been proven to reliably decrease pain and swelling as well as increase range of motion in patients with CRPS [42].” The pediatric experience of BP in CRPS is more limited. A published case study of an 11 year old with CRPS who was treated with a total of 11 infusions of pamidronate over 24 months, reported reduction in pain, improvement in function, and normalization of bone density and strength; as reflected by peripheral quantitative computerized tomography and DXA scans comparing the affected to nonaffected lower extremity.
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It remains unclear whether the pain relief from BP relates to improved bone density in the affected region, decreased osteoclastic resorption, or other undefined mechanism.
5. Conclusions Any use of bisphosphonates in the United States is off-label, as none of the bisphosphonates is FDA approved for use in children. For this reason, the use of BPs should be limited to children who have demonstrated a significant fracture history, or, such as the case of children with Duchenne muscular dystrophy on steroid treatment, have decreasing Z-scores and a perceived significant increase in fracture risk. Parents and patients must be advised of the off-label status for children: in particular, that long-term, large, randomized studies of children treated with BPs to treat increased fracture risk not associated with osteogenesis imperfecta do not exist, as they are advised of the risks and benefits of therapy. For those patients who are considered appropriate for therapy given the individual risk/benefit ratio, serum Vitamin D levels should be monitored, as well as calcium intake, and treatment response should be followed with serial DXA scans. Failure of improvement of BMD and/or BMD Z-score, bone pain, and/or frequency of fracture should occasion reevaluation of the treatment plan.
Conflict of interest The author reports no conflict of interest.
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