Denosumab: An Emerging Therapy in Pediatric Bone Disorders

Abstract

Purpose of Review

Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), and has emerged as an important novel therapy for skeletal disorders. This article examines the use of denosumab in children.

Recent findings

Considerable safety and efficacy data exists for denosumab treatment of adults with osteoporosis, bone metastases, and giant cell tumors. Pediatric data is limited; however, evidence suggests denosumab may be beneficial in decreasing bone turnover, increasing bone density, and preventing growth of certain skeletal neoplasms in children. Denosumab’s effect on bone turnover is rapidly reversible after drug discontinuation, representing a key difference from bisphosphonates. Rebound increased bone turnover has led to severe hypercalcemia in several pediatric patients.

Summary

Denosumab is a promising therapy for pediatric skeletal disorders. At present, safety concerns related to rebounding bone turnover and mineral homeostasis impact use of denosumab in children. Research is needed to determine if and how these effects can be mitigated.

Introduction

Despite recent advances in understanding of the pathogeneses of skeletal disorders in children, clinical management remains challenging, in large part because of the paucity of bone-altering therapies available for pediatric use. Denosumab is a new class of anti-resorptive medication and inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), which has emerged as an important novel therapy for osteoporosis, malignancies, and other skeletal disorders. The scope of this article is to describe the mechanism of action of denosumab, to review existing safety and efficacy data in adults and children, and to discuss the potential benefits and critical knowledge gaps in the application of this therapy to children.

The Role of RANKL in Bone Modeling and Remodeling

The skeleton is continuously renewed through bone remodeling; a lifelong process in which mature bone is broken down by osteoclasts and new bone is formed by osteoblasts. This process is tightly coupled in order to maintain calcium homeostasis and to repair skeletal microdamage that accumulates over time [1]. In children, linear growth occurs through strictly regulated, site-specific uncoupling of bone formation and resorption, termed bone modeling. Bone formation on the outer periosteal surface increases bone size, while resorption expands the marrow cavity and sculpts the outer surface of the bone [2]. The net result of bone modeling is an increase in bone size and mass.

Many skeletal disorders are characterized by disruption of the bone remodeling cycle. A relative increase in resorption and/or decrease in formation lead to a net loss in bone mass, changes in bone microarchitecture, and increased risk of fracture. These are common processes in children with chronic illnesses, who have multiple risk factors related to mobility, nutrition, and exposure to bone-toxic therapies [3]. In addition, osteolytic disorders such as primary tumors and metastases result in bone destruction through localized activation of osteoclasts [4]. Therapeutic strategies to treat these disorders include targeting the bone remodeling cycle through anti-resorptive medications that inhibit osteoclasts, and/or anabolic therapies that promote osteoblast activity.

A primary regulator of bone resorption is Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL), a transmembrane protein from the superfamily of the tumor necrosis factor receptors which is highly expressed by osteoblasts [5]. After binding to the Receptor Activator of Nuclear factor Kappa-B (RANK) on the surface of osteoclasts and pre-osteoclasts, RANKL promotes osteoclast differentiation and activity, leading to increased bone resorption [6] (Figure 1). Osteoprotegerin (OPG) is a soluble, non-signaling glycoprotein produced by osteoblasts that acts as a “decoy receptor”, preventing the binding of RANKL to its receptor and blocking its catabolic effects [7]. The balance between RANKL and OPG is thus an important determinate of skeletal homeostasis, and discrepancy between these factors has been implicated in multiple disease processes, including post-menopausal osteoporosis, inflammatory disorders, and cancer-related bone loss [8].

Figure 1. Regulation of osteoclast-mediated bone resorption.

RANKL is expressed by osteoblasts and binds to RANK on the surface of osteoclast precursors and mature osteoclasts. This binding stimulates osteoclast differentiation, activity, and survival, leading to bone resorption and release of calcium and phosphorus into the serum. OPG is a non-signaling decoy receptor which binds RANKL and prevents its interaction with RANK. The balance between RANKL and OPG is thus an important determinant of bone resorption and mineral homeostasis. Denosumab is a fully human monoclonal antibody to RANKL, which similar to OPG binds to RANKL and inhibits its effect on osteoclast activity. RANKL = receptor activator of nuclear kappa-B ligand; RANK = receptor activator of nuclear kappa-B, OPG = osteoprotegerin.

Denosumab

Denosumab is a fully human monoclonal antibody of the IgG2 immunoglobulin isotype to RANKL. It binds with high affinity and specificity to RANKL, mimicking the inhibitory effects of OPG and resulting in rapid suppression of bone resorption. The pharmacokinetics of denosumab have been studied extensively in adults, and are similar to other fully human monoclonal antibodies, exhibiting dose-dependent, non-linear elimination [9 10]. In adults given 60 mg subcutaneously, serum concentrations decline after 4–5 months with a half-life of approximately 30 days. Repeated doses of 60 mg every 6 months result in minimal drug accumulation, with an increase in bone turnover markers towards baseline values at the end of each dosing interval. Doses above 60 mg result in dose-dependent increases in exposure, and at 120 mg monthly reaches steady-state after 4–5 doses, with continuous suppression of bone turnover throughout dosing intervals. These data inform the 2 commercially available formulations of denosumab: Prolia, administered as 60 mg subcutaneously every 6 months, and Xgeva, administered as 120 mg subcutaneously once monthly after 3 weekly loading doses (Amgen, Inc).

The pharmacokinetics and pharmacodynamics of denosumab in children are unknown; however, they are likely to be impacted by pediatric-specific factors. Monoclonal antibody dosing in children is typically scaled down to account for decreased body weight and surface area [11]. Because denosumab elimination is non-linear due to its interaction with RANKL, dosing must also take into account relative levels of RANK/RANKL/OPG activity. The increased skeletal metabolism related to bone modeling and growth in children is therefore likely to impact both pediatric dosage and dosing intervals.

Current Indications

Osteoporosis

Denosumab was initially marketed as Prolia for treatment of post-menopausal osteoporosis. Four phase 3 trials have been conducted in this population, including the pivotal FREEDOM study, which was the first randomized, placebo-controlled trial of denosumab to demonstrate a decrease in vertebral and non-vertebral fractures [12]. Similar findings were reported in subsequent trials that included both post-menopausal women and men with osteoporosis [13 14]. Additional studies comparing the efficacy of denosumab and alendronate showed higher gains in bone mineral density (BMD) and greater reductions in bone turnover in denosumab-treated subjects [15–17]. An ongoing, open-label FREEDOM extension arm has reported continued gains in BMD and reductions in bone-turnover with up to 8-years of treatment [18].

Sex steroid deprivation is a common treatment strategy for hormone responsive cancers, and denosumab has been studied in two phase 3 trials for cancer treatment-induced bone loss. The Prolia formulation was found to increase BMD and prevent new vertebral fractures in a phase 3 study of men receiving androgen-deprivation therapy for prostate cancer [19]. Similar findings were reported in a phase 3 study of women receiving adjuvant aromatase inhibitors for breast cancer, where denosumab was found to improve BMD [20]. Together these data led to denosumab’s approval for treatment of both postmenopausal osteoporosis and bone loss associated with sex steroid deprivation therapy [21]. Denosumab was overall well-tolerated in adult osteoporosis trials, with no significant increase in adverse events in comparison to placebo or alendronate.

Bone Metastases

Skeletal events in cancer patients include fracture, pain, and spinal cord compression, carrying a high risk of morbidity and mortality. The monthly Xgeva formulation has been investigated for prevention of skeletal-related events in patients with bone metastases in three simultaneously conducted phase 3 trials. These included patients with breast [22], prostate [23], and advanced cancer or multiple myeloma [24], and each reported similar results, demonstrating delayed time to first on-study event in comparison to zoledronate. Overall survival and disease progression were similar in denosumab and zoledronate-treated patients, however an ad hoc subanalysis in patients with multiple myeloma favored zoledronate [24]. These results led to approval for prevention of skeletal-related events in adults with bone metastases from solid tumors; however, this indication does not extend to multiple myeloma [25].

Denosumab was generally well-tolerated in phase 3 cancer studies. The most common treatment-associated adverse event was hypocalcemia, which occurred more frequently in denosumab-treated patients (12.4 versus 5.3 percent in the zoledronate group)[26]. Time to first occurrence of hypocalcemia was also shorter in the denosumab group (median 3.8 versus 6.5 months), likely reflecting denosumab’s more potent effects on bone turnover.

Hypercalcemia

Anti-resorptives are frequently utilized for treatment of hypercalcemia due to their ability to inhibit osteoclast-mediated release of calcium into the serum. A phase 2 study in hypercalcemia of malignancy found that high dose monthly denosumab was highly effective at reducing serum calcium levels, with a median response time of 9 days and median duration greater than 3 months [27]. Additional support was provided by an ad hoc analysis of two large phase 3 trials of denosumab versus zoledronate treatment for patients with solid tumors, which found that denosumab significantly delayed time to development of first on-study hypercalcemia [28]. Based on these results, denosumab received approval for treatment of hypercalcemia of malignancy refractory to bisphosphonates [25].

Hypercalcemia is a frequent complication of hematopoietic stem cell transplantation in patients with osteopetrosis, a disorder of high bone mass which may result from defects in RANK/RANKL signaling. Shroff et al report two children (age 3 and 12 years) with loss-of-function mutations in the TNFRSF11A gene encoding RANK, who underwent hematopoietic stem cell transplantation resulting in robust activation of osteoclasts and refractory hypercalcemia. In both patients denosumab resulted in prompt normalization of serum calcium levels [29] (Table 1). Given its targeted activity against RANKL signaling, denosumab is an intuitive treatment choice for this indication.

Table 1.

Published reports of denosumab treatment in children and adolescents

Indication & Reference	Patients &Reference	Dose	Duration	Response	On-Treatment Adverse Effects	Post-Treatment Adverse Effects
Osteopetrosis & hypercalcemia
29	12 &3 yo girls	0.13–0.27 mg/kg every 4–7 weeks	14 months	Normalization of serum calcium	None	Unknown
Giant cell tumor
32, 33	10 children ≥ 12 yo	120 mg monthly	ongoing	Decreased tumor size, improved pain	None	Unknown
34, 35	10 yo girl	120 mg monthly	24 months	Decreased tumor size, improved pain	Mild hypocalcemia & hypophosphatemia	Severe hypercalcemia
36, 37	10 yo boy	120 mg monthly	14 months	Decreased tumor size, improved pain	None	Severe hypercalcemia
Osteogenesis imperfecta
41, 42	4 boys age 5–18y (type 6)	1 mg/kg every 8–12 weeks	24 months	Increased BMD, improved pain	Mild hypocalcemia (1 patient)	Unknown
43	23 mo boy (type 6)	1 mg/kg every 4–12 weeks	12 months	Increased BMD, improved mobility1	Severe hypercalcemia2	None
44	10 children age 5–11 (types 1, 3 &4)	1 mg/kg every 12 weeks	12 months	Increased BMD	Mild hypocalcemia (1 patient)	Mild hypercalcemia
Juvenile Paget’s disease
46	7 yo girl	0.5 mg/kg × 2 doses	6 weeks	Improved pain & mobility	Severe hypocalcemia & hypophosphatemia	Severe hypercalcemia
Fibrous dysplasia
47, 48	9 yo boy	1–1.5 mg/kg monthly	7 months	Decreased tumor expansion & pain	Mild hypophosphatemia	Severe hypercalcemia
Central giant cell granuloma
49	9 yo girl	120 mg monthly	18 months	Decreased tumor size & tooth mobility, improved radiodensity	None	Unknown
Aneurysmal bone cyst
50	8 & 11 yo boys	70 mg/m2 monthly	ongoing	Cyst partial regression, improved pain	Mild hypocalcemia (1 patient)	Unknown
51	5 yo boy	1.2–1.6 mg/kg monthly	12 months	Cyst regression, healed fracture, improved pain	None	Unknown
Cerebral palsy
71	10 children age 5–17	10 mg	one-time dose	n/a	None	Unknown

& = and, yo = years old, mo = months old, mg = milligrams, kg = kilograms, m² = meters squared, BMD = bone mineral density, n/a = not applicable

¹Clinical improvement occurred in the setting of concomitant denosumab treatment and 4 limb rodding surgery.

²Developed 2 months following 2 monthly doses (personal communication, Leanne Ward).

Giant Cell Tumors

Giant cell tumor of bone is an uncommon, locally aggressive neoplasm which may rarely metastasize. Tumors are composed of distinctive, multinucleated osteoclast-like giant cells and proliferative stromal cells. These abnormal stromal cells highly express RANKL, leading to the hypothesis that RANKL is responsible for giant cell recruitment and ultimately bone destruction and tumor expansion [30]. Management typically involves surgical resection, with systemic therapy reserved for patients with tumors that cannot be fully removed [31]. Denosumab has been studied in a large open label phase 2 trial, with a study population that included ten adolescents confirmed to have closed epiphyses on radiographs [32 33](Table 1). Denosumab prevented tumor progression in 163/169 patients with unresectable disease, and prevented or decreased surgical morbidity in the majority of patients with resectable tumors. Common adverse events included hypophosphatemia (affecting 3% of patients), back, and extremity pain. Denosumab was subsequently approved for treatment of giant cell tumors in adults and skeletally mature adolescents, and is the only medication currently labeled for this indication [25].

Additional reports in two children support the efficacy of denosumab, with both cases demonstrating improvement in giant cell tumor expansion and bone pain [34–37](Table 1). Within several months of denosumab discontinuation both children developed an acute rebound in bone turnover, which was accompanied by severe and life-threatening hypercalcemia necessitating hospitalization and bisphosphonate treatment. This phenomenon, discussed in detail in a later section, has been observed in other children treated with denosumab, and is an important safety concern which appears to be principally associated with pediatric use.

Additional Pediatric-Relevant Conditions

Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is the most frequent form of primary osteoporosis in children. Common types result from autosomal dominant COL1A1/1A2 mutations leading to defects in type 1 collagen, while rarer forms result from autosomal recessive mutations in genes responsible for collagen processing or osteoblast function [38]. Bisphosphonates improve bone density, pain, and mobility in OI, and are frequently prescribed for patients with moderate to severe forms [39]. Type 6 OI, due to SERPINF1 mutations, is autosomal recessive with distinct histologic features including prominent unmineralized osteoid, and a typically poor response to bisphosphonates [40]. Semler and Hoyer-Kuhn et al reported 4 boys with type 6 OI treated with a 2-year course of denosumab [41 42]. Patients were initially given 1 mg/kg every 12 weeks, which resulted in a rapid decline in bone turnover markers with each dose, and return to pre-treatment levels after 6–8 weeks. Based on this observation, the dosing interval was shortened to maintain continuous suppression of bone resorption. Children showed a modest increase in BMD, and appeared to tolerate therapy with the development of mild, asymptomatic hypocalcemia in only one patient.

A 23-month old boy with type 6 OI was treated by another group using a similar regimen, however this child had a persistent decline in BMD and continued to fracture over a 12-month treatment period [43], After undergoing four limb rodding surgery to correct severe deformity he developed a significant increase in BMD and improved mobility while on denosumab. Rebound hypercalcemia was observed 2 months following two-monthly denosumab doses; anti-denosumab antibodies were found to be negative. Denosumab was discontinued and pamidronate was given to treat the hypercalcemia, which resolved after a single dose (personal communication, Leanne Ward). Interestingly, a post-treatment biopsy 3 months after the final dose showed persistent unmineralized osteoid and an increased number of osteoclasts compared to pre-treatment.

Hoyer-Kuhn et al reported an open-label study of 10 children with various types of classical OI treated with denosumab for 12 months [44]. Patients were given 1 mg/kg every 3 months, and showed a modest increase in lumbar spine BMD and no improvement in pain or mobility over the treatment period. Effects on mineral metabolism were detectable but mild, including asymptomatic hypocalcemia while on-treatment in one child. Interestingly, mild asymptomatic hypercalcemia was noted in several patients during the trial period just prior to the fourth dose of denosumab. Taken together, these results support that further studies of denosumab in children with OI are warranted, in particular to determine the optimal dose and frequency necessary to maintain consistent osteoclast inhibition.

Juvenile Paget’s Disease

Juvenile Paget’s disease (JPD) is a rare disorder resulting from inactivating mutations in TNFRSF11B, which encodes OPG [45]. Unopposed activation of RANK signaling results in increased osteoclast activity, leading to fractures, deformities, and bone pain. Management includes anti-resorptives, and denosumab is an intuitive treatment given its selective inhibition of the RANK pathway. Grasemann et al report an 8-year-old girl with JPD refractory to bisphosphonates, who was given denosumab 0.5 mg with rapid and dramatic improvement in bone turnover, pain, and mobility [46]. Denosumab was associated with severe and life-threatening disturbances in mineral metabolism, including hypocalcemia requiring hospitalization and intravenous calcium, as well as rebound hypercalcemia seven weeks after denosumab discontinuation. Despite her dramatic therapeutic response, denosumab was discontinued due to safety concerns. While the potential for denosumab as a targeted therapy for JPD is promising, further research into its effects on mineral homeostasis is needed to determine if and how these safety issues can be mitigated. In the interim, denosumab should be used with extreme caution in children with JPD.

Other Benign Osseous Lesions

Based in part on its efficacy in giant cell tumors, denosumab has been investigated as a potential treatment for other benign fibro-osseous lesions affecting children and adolescents, including fibrous dysplasia [47 48], central giant cell granuloma [49], and spinal aneurysmal bone cysts [50 51]. The pediatric literature is currently limited to case reports and small series, all of which report beneficial effects on lesion growth and associated bone pain. Patients received monthly high dose treatment adapted from the Xgeva regimen, which resulted in frequent abnormalities in mineral metabolism. These included mild to moderate hypocalcemia in several patients, and severe rebound hypercalcemia in the fibrous dysplasia patient. Similar to studies in giant cell tumors, these reports highlight denosumab’s potential therapeutic use for skeletal neoplasms, as well as the need to better understand its metabolic effects, in particular for children receiving frequent, high dose therapy.

Safety and Tolerability of Denosumab in Adults and Children

Effects on Bone Turnover, Modeling, and Remodeling

Denosumab has powerful inhibitory effects on bone turnover. In phase 3 trials, bone turnover markers of denosumab-treated subjects were consistently lower than placebo- and bisphosphonate-treated subjects [12 13 15 16 19 20 22–24]. Histomorphometry studies likewise showed potent, sustained inhibition of bone turnover, while maintaining normal bone microarchitecture and without adverse effects on mineralization [16]. Bone turnover suppression may have unique consequences for the growing skeleton, which relies on bone modeling to maintain shape and linear growth. Anti-resorptive treatment with bisphosphonates does not appear to impair growth with typical use [52–54], although subtle modeling defects of uncertain consequence may persist after treatment discontinuation [55]. Although these findings are reassuring, they should not be generalized to denosumab, which is a far more potent inhibitor of bone resorption. Pre-clinical studies of denosumab treatment in rodents and primates demonstrated significant inhibitory effects on linear growth and tooth eruption [21 25 56]. While clinical data is limited, several series have reported continued linear growth during denosumab treatment [34 36 37 42 44 48 57]. Histologic evaluation in a child with fibrous dysplasia demonstrated continued epiphyseal activity both during and after denosumab treatment, providing further evidence that denosumab does not appear to adversely affect growth in the clinical setting [48].

Osteonecrosis of the jaw is a rare complication of denosumab and other anti-resorptives, particularly in patients receiving long-term therapy with chronic suppression of bone turnover. A recent metanalysis of patients receiving anti-resorptives for cancer treatment showed a 1.7% risk of osteonecrosis of the jaw associated with monthly denosumab treatment, which was slightly higher than that 1.1% risk associated with intravenous bisphosphonates [58]. Osteonecrosis of the jaw is even rarer in the setting of osteoporosis treatment [59]. To date there have been no reported cases of osteonecrosis of the jaw in children.

Osteoclasts have important roles in microdamage repair and bone healing. Atypical femoral fractures are a rare complication of anti-resorptives and have been reported in a small number of patients receiving denosumab [60]; however ongoing surveillance is needed to determine a clear association. Denosumab does not appear to impair fracture healing in animal models [61]. While there is little clinical data available, denosumab demonstrated no negative effects on fracture healing in the FREEDOM trial, regardless of the timing of administration [12]. No negative effects on healing have been reported in pediatric patients for whom fracture data is available [47 51].

Bone Turnover Rebound and Post-Discontinuation Effects

Unlike bisphosphonates, which incorporate into hydroxyapatite and have long terminal half-lives, the therapeutic effects of denosumab are rapidly reversed after treatment. In post-menopausal women, denosumab discontinuation resulted in a rebound of both markers of bone resorption (C-telopeptide) and formation (procollagen-1 propeptide) to levels 60 and 40% above pre-treatment levels, respectively, and remained elevated for approximately two years [62]. A similar phenomenon of bone turnover rebound has been observed in pediatric patients, and while information is limited given the small patient numbers, key differences from adults are emerging. Bone turnover rebound in children appears to be more vigorous, of shorter duration, and more commonly associated with hypercalcemia. For example, in the child treated for fibrous dysplasia, serum C-telopeptide rebounded to 250% above the pre-denosumab baseline, necessitating bisphosphonate treatment for hypercalcemia; C-telopeptide then returned to baseline after 5 months. While hypercalcemia post-discontinuation of denosumab is described in one published report of an adult treated with long-term denosumab therapy [63], 5 cases have been reported in the much more limited pediatric literature (Table 1). This may be related to the higher baseline bone turnover in children, which could result in a proportionately greater rebound post-discontinuation. Rebound may also be especially affected by the presence of high bone turnover disorders, which disproportionately affect the population of children who have been treated with denosumab in reports to date.

Differential action of anti-resorptives on the growing skeleton may also contribute to the prodigious bone turnover rebound in children. Because the characteristic uncoupling of the bone modeling cycle allows for selective inhibition of resorption with relative sparing of bone formation, anti-resorptives are expected to have more potent effects in growing children compared to adults [55 64]. In children bisphosphonates lead to temporary inhibition of epiphyseal activity with each dose, resulting in the formation of sclerotic metaphyseal bands on radiographs, likely related to retained calcified cartilage [65 66]. A similar phenomenon occurs in children treated with denosumab, with dense sclerotic bands that ultimately fade after denosumab discontinuation [37 48 57](Fig 2). Release of mineral from these bands following completion of therapy is a potential contributor to post-discontinuation hypercalcemia.

Figure 2. Sclerotic metaphyseal bands associated with denosumab treatment.

Radiographs from a child with fibrous dysplasia treated with 6 doses of monthly denosumab show the development of sclerotic bands (white arrows) at the wrist (panel A) and knee (panel C). After discontinuing treatment time the bands have become less dense in appearance over time (panel B, 4-years post-treatment and panel D, one-year post-treatment), and have migrated proximally with linear growth.

Bone turnover reversibility after denosumab discontinuation also results in rapid loss of its therapeutic effects. Adult patients who discontinued denosumab during the FREEDOM trial lost the bone density gained during treatment over a one-year period [67]. This BMD loss did not appear to be associated with an increased fracture risk; however, in the post-marketing period reports have emerged of spontaneous single or multiple vertebral fractures arising during the discontinuation period in post-menopausal [68–70] and breast cancer patients [71]. For this reason, some have proposed that patients receiving denosumab should be given pre- and/or post-treatment with bisphosphonates to mitigate these effects [71]. The rapid reversibility of denosumab effects should also be considered in clinical decision-making. Patients with a history of non-adherence may rapidly lose therapeutic effects if doses are missed or given late, and may not be optimal candidates for denosumab [72]. Conversely, reversibility may be an attractive feature in treatment of children with acquired skeletal disorders that carry the potential for full recovery.

Loss of denosumab effects post-discontinuation also has implications for treatment of giant cell tumors and other osseous lesions. While little has been published about tumor recurrence post-treatment, there are case reports of increased lesion growth after denosumab discontinuation in patients with giant cell tumor [73] and fibrous dysplasia [48]. This suggests the action of denosumab in osseous lesions may be cytostatic rather than cytotoxic, and long-term therapy may be required to maintain therapeutic efficacy.

Other Safety Issues

Denosumab has been studied in adults with chronic kidney disease in a phase 1 study of a single 60 mg injection [74]. Renal impairment did not appear to affect the pharmacokinetics or pharmacodynamics of denosumab, however hypocalcemia was seen in 30% of patients with severe renal failure and those receiving dialysis, suggesting denosumab should be used cautiously with judicious monitoring of calcium in this population.

In addition to its role in bone metabolism, RANKL is expressed by immune cells including activated T lymphocytes, B cells, and dendritic cells [56]. RANKL and RANK-deficient mice show immune abnormalities, including absent lymph nodes and thymic changes [56]. In the FREEDOM study the overall incidence of infections was low and similar between denosumab and placebo-treated groups, however there was a slightly higher incidence of skin infections in denosumab-treated subjects [12]. These findings were not replicated in subsequent trials, and ad hoc sub analyses showed heterogeneous etiologies for these events with no clear clinical pattern [75]. While these data are reassuring, further investigation is warranted to determine denosumab effect on immune function, particularly in immunocompromised children.

RANKL is also highly expressed in mammary tissue. In RANKL and RANK-deficient mice, mammary glands appear to develop normally during sexual maturation; however, lobuloalveolar structures fail to form during pregnancy due to apoptosis and impaired proliferation of mammary epithelium [76]. It is unknown if denosumab treatment in pre-pubertal and pubertal girls will impact breast development, however this endpoint should be monitored in future pediatric studies.

Conclusions

Denosumab is a promising anti-resorptive that offers the potential for targeted intervention in children with disorders affecting the RANKL pathway. The reversibility of denosumab effects represents a key difference from bisphosphonates, and is an important consideration in clinical decision-making. Important safety concerns related to bone turnover rebound and mineral homeostasis impact use of denosumab in children, and research is needed to determine if and how these effects can be mitigated. At present, denosumab in children use should be limited to clinical trials and for compassionate use in patients with significantly impaired quality of life.