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case_images: Patient 1. (A-C) Osteoporotic vertebral fractures in a young girl with GC-treated systemic juvenile idiopathic arthritis who underwent complete vertebral body reshaping with GC weaning, well-controlled underlying disease, and significant residual growth potential. (A) highlights growth deceleration while on GC therapy, and an increase in height velocity during and following her GC wean. The increase in height velocity provided an early sign of her potential to undergo spontaneous (medication-unassisted) vertebral body reshaping, informing the decision to withhold osteoporosis-targeted therapy. (B) shows lack of significant impact of GC therapy on the LS aBMD Z-score trajectory. This observation highlights the importance of vertebral fracture identification independent of a given LS aBMD Z-score threshold in the pGIO setting (for further discussion see text). (C) demonstrates this patient's reclamation of near-normal vertebral dimensions following Grade 2, GC-induced vertebral fractures at T12 and L1. She also demonstrated intervertebral disk herniation at the superior endplates of the affected vertebrae (similar to the appearance of Schmorl's nodes). Her young age, significant residual growth potential and resolution of osteoporosis risk factors were the main factors in her improved vertebral body structure.. Abbreviations: a, areal; BMD, bone mineral density; GC, glucocorticoid; pGIO, pediatric glucocorticoid-induced osteoporosis; L, lumbar; LS, lumbar spine; MPH, midparental height; T, thoracic.
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case_images: Her growth chart was consistent with chronic GC exposure, including linear growth deceleration and excess weight for height (Fig. 1A). Her lumbar spine (LS) areal bone mineral density (aBMD) Z-score was +0.2, which was within the "normal range" and robust for her height Z-score of -3.6 (Fig. 1B). A routine lateral spine radiograph showed Genant Grade 2 (moderate) vertebral fractures at T12 and L1 (Spinal Deformity Index [SDI] = 4, Fig. 1C), with an exaggerated thoracolumbar kyphosis and loss of lumbar lordosis. Given her young age, planned GC wean, and early signs of linear growth recovery from GC excess (Fig. 1A), the decision was made to monitor her skeletal health trajectory optimistically instead of initiating bone protection therapy. During the follow-up visits, she showed marked improvement in her height velocity (Fig. 1A), a persistently normal LS aBMD Z-score trajectory (Fig. 1B), and early signs of vertebral body reshaping but with superior endplate depression at T12 and L1 (Fig. 1C). T12 and L1 vertebral heights in the absence of bone protection (bisphosphonate) therapy, but persistent irregularity and depression of the T12 and L1 superior endplates. This finding was consistent with residual fracture healing plus intervertebral disk herniation (similar to the appearance of Schmorl's nodes) (Fig. 1C).
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case_images: Patient 2. (A-D) The skeletal health of a girl with GC-treated juvenile dermatomyositis who received 2 courses of daily, supraphysiological GC therapy for the treatment of her rheumatic condition; the second course was associated with vertebral fractures and an ongoing need for GC treatment, prompting IV bisphosphonate therapy. (A) Weight loss during the first GC wean, growth deceleration with the second GC course, and attainment of a normal adult height in the years following her GC wean. These observations were consistent with absence of a permanent GC effect on height plus well-controlled underlying disease during the critical growing years. (B) The patient's vertebral fracture trajectory, including vertebral body reshaping plus densification of the vertebral endplates on pamidronate and ongoing vertebral body reshaping post-GC and postpamidronate discontinuation. The thoracic spine is shown at the top (where available) and lumbar spine at the bottom. Her vertebral fracture evolution on these spine x-rays was as follows: normal L1 vertebral body at 7 years of age (thoracic and lumbar SDI = 0). At 9 years of age, she developed an incident (new) Genant Grade 2 vertebral fracture at L1 (SDI = 2); at 11 and 12 years, she demonstrated L1 partial reshaping (SDI = 1) followed by complete vertebral body re-shaping at 15 years of age (SDI = 0). (C) The patient's multisite BMD parameters by DXA, highlighting the supra-physiological aBMD Z-score trajectories at all 3 sites (LS, total hip, and TBLH) on IV pamidronate, while also receiving GC therapy. The uniform decline in BMD parameters postpamidronate cessation was expected (with values remaining well within the normal range), as the patient returned to her normal "endogenous" BMD set-point following bisphosphonate discontinuation. (D) The patient's transiliac bone sample taken for bone histomorphometry prepamidronate and 2 years postpamidronate, highlighting the main effects of IV bisphosphonate therapy on bone tissue in children, increases in cortical width and in trabecular number (both growth mediated). This outcome is caused by the antiresorptive effect of bisphosphonate therapy on the endocortical surface combined with the uncoupled, innate periosteal apposition that occurs during growth on the periosteal surface. The observed bone tissue effects on IV pamidronate underscore the importance of treating osteoporosis during the growing years, a period that is exquisitely sensitive to the bone density- and structure-enhancing effects of bisphosphonate therapy.. Abbreviations: a, areal; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; GC, glucocorticoid (s); IV, intravenous; JDM, juvenile dermatomyositis; L, lumbar; LS, lumbar spine; MPH, midparental height; SDI, Spinal Deformity Index; TBLH, total body less head.
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case_images: Unlike in patient 2 (Fig. 2D), the dystrophinopathy plus GC-induced growth impairment in patient 3 prevented the typical growth-mediated increase in cortical thickness and trabecular number on potent antiresorptive therapy.
case_images: PMC11747689_03
case_images: Patient 2. (A-D) The skeletal health of a girl with GC-treated juvenile dermatomyositis who received 2 courses of daily, supraphysiological GC therapy for the treatment of her rheumatic condition; the second course was associated with vertebral fractures and an ongoing need for GC treatment, prompting IV bisphosphonate therapy. (A) Weight loss during the first GC wean, growth deceleration with the second GC course, and attainment of a normal adult height in the years following her GC wean. These observations were consistent with absence of a permanent GC effect on height plus well-controlled underlying disease during the critical growing years. (B) The patient's vertebral fracture trajectory, including vertebral body reshaping plus densification of the vertebral endplates on pamidronate and ongoing vertebral body reshaping post-GC and postpamidronate discontinuation. The thoracic spine is shown at the top (where available) and lumbar spine at the bottom. Her vertebral fracture evolution on these spine x-rays was as follows: normal L1 vertebral body at 7 years of age (thoracic and lumbar SDI = 0). At 9 years of age, she developed an incident (new) Genant Grade 2 vertebral fracture at L1 (SDI = 2); at 11 and 12 years, she demonstrated L1 partial reshaping (SDI = 1) followed by complete vertebral body re-shaping at 15 years of age (SDI = 0). (C) The patient's multisite BMD parameters by DXA, highlighting the supra-physiological aBMD Z-score trajectories at all 3 sites (LS, total hip, and TBLH) on IV pamidronate, while also receiving GC therapy. The uniform decline in BMD parameters postpamidronate cessation was expected (with values remaining well within the normal range), as the patient returned to her normal "endogenous" BMD set-point following bisphosphonate discontinuation. (D) The patient's transiliac bone sample taken for bone histomorphometry prepamidronate and 2 years postpamidronate, highlighting the main effects of IV bisphosphonate therapy on bone tissue in children, increases in cortical width and in trabecular number (both growth mediated). This outcome is caused by the antiresorptive effect of bisphosphonate therapy on the endocortical surface combined with the uncoupled, innate periosteal apposition that occurs during growth on the periosteal surface. The observed bone tissue effects on IV pamidronate underscore the importance of treating osteoporosis during the growing years, a period that is exquisitely sensitive to the bone density- and structure-enhancing effects of bisphosphonate therapy.. Abbreviations: a, areal; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; GC, glucocorticoid (s); IV, intravenous; JDM, juvenile dermatomyositis; L, lumbar; LS, lumbar spine; MPH, midparental height; SDI, Spinal Deformity Index; TBLH, total body less head.
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case_images: Unlike in patient 2 (Fig. 2D), the dystrophinopathy plus GC-induced growth impairment in patient 3 prevented the typical growth-mediated increase in cortical thickness and trabecular number on potent antiresorptive therapy.
case_images: Patient 3. (A-E) The skeletal health trajectory of a boy with DMD who started daily, supraphysiological GC therapy at 5.9 years of age and IV pamidronate at 8 years for early signs of vertebral collapse. In contrast to patients 1 and 2, this patient had persistent and permanent threats to bone health, including long-term GC therapy plus a progressive myopathy. These "disease context" features have led to guidelines that support initiating bone protection therapy at early, rather than late, signs of bone fragility in individuals with DMD. (A) describes the profound growth arrest of GC-treated DMD, including lack of response to rhGH. The slight improvement in linear growth after 14 years of age was attributed to progression through endogenous puberty. Spontaneous puberty in the daily GC-treated DMD setting is unusual; the need for pubertal induction is more typical. (B and C) The patient's vertebral fracture trajectories. (B) Thoracic spine. Demonstrates minimal anterior wedging at T11 that did not quite meet fracture criteria at 8 and 11 years of age (defined as >20% loss of vertebral height ratio); however, given the natural history of progressive vertebral collapse in GC-treated DMD combined with a significant decline in total hip aBMD Z-score, bone protection therapy (IV ZA) was initiated at 8 years of age. At 12 years of age, he demonstrated an incident (new) Genant Grade 1 vertebral fracture at T7. At 14, 16, and 17 years of age, the Grade 1 vertebral fracture at T7 was stable, with evidence for a global decrease in height at T8 that did not quite meet fracture criteria. (C) Lumbar spine. Shows normal lumbar vertebrae at 8 and 11 years of age, followed by a mild decrease in height at L3 (at 12 years of age) that did not meet the fracture criteria. At 16 years of age, there was a new Genant Grade 2 vertebral fracture at L5 with buckling of the anterior cortex at the superior endplate (diagonal arrow) and a new Genant Grade 1 vertebral fracture at L4. There was also a Grade 1 monoconcave fracture at L2 with loss of endplate parallelism. At 17 years of age, his spine x-ray was stable relative to the previous. At 17 years of age, his vertebral deformities remained stable (while continuing IV bisphosphonate therapy as he transitioned to adult care). (D) The multisite aBMD Z-score trajectories on IV ZA therapy, showing favorable evolution at the spine, progressive decline despite bisphosphonate therapy at the hip, and stabilization for the TBLH measurement. (E) The bone structure on transiliac bone biopsy in GC-treated DMD treated with IV bisphosphonate therapy. Unlike in patient 2 (Fig. 2D), the dystrophinopathy plus GC-induced growth impairment in patient 3 prevented the typical growth-mediated increase in cortical thickness and trabecular number on potent antiresorptive therapy. Nevertheless, it was anticipated that the degree of osteoporosis on transiliac bone biopsy would have been more severe in the absence of treatment.. Abbreviations: a, areal; BMD, bone mineral density; DMD, Duchenne muscular dystrophy; GC, glucocorticoid; GH, growth hormone; IV, intravenous; rhGH, recombinant human growth hormone; L, lumbar; MPH, midparental height; SDI, Spinal Deformity Index; T, thoracic; TBLH, total body less head; ZA, zoledronic acid.
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case_images: He did not develop significant weight gain on deflazacort, but he did have a decline in his linear height velocity (Fig. 3A) with mild Cushingoid features. Lateral spine x-ray showed minimal anterior wedging at T11 that did not quite meet fracture criteria but that was also not consistent with anterior physiological rounding (SDI = 0) (Fig. 3B and 3C) and LS aBMD Z-score declined to -2.3 (Delta -0.5 from baseline at 6.7 years of age, Fig. 3D). Given minimal changes at T11 on his lateral spine x-ray (accompanied by declines in LS aBMD Z-scores) in the context of persistent risk factors and a disease setting known to be at high risk for fragility fractures, he was started on IV zoledronic acid (ZA) at 8.5 years of age (annual dose 0.1 mg/kg/year divided 6 monthly), following a transiliac bone biopsy (Fig. 3E). He started recombinant human growth hormone (rhGH) at 13 years of age (0.03 mg/kg/dose, 6 days per week); this was tolerated uneventfully but was ultimately discontinued at the patient's request after 1.5 years due to lack of significant improvement in height velocity despite prescription adherence (Fig. 3A). His TBLH aBMD Z-score was stable, and his height Z-score remained low at -4.4 (Fig. 3A and 3D). Fig. 3B and 3C). Figure 3E shows the patient's response to bisphosphonate therapy on transiliac bone biopsy.
case_images: (A) The deleterious effect of GC therapy on bone and growth plate metabolism in childhood. (B) The most important functional consequences of GC-induced bone and growth plate toxicity.. Abbreviations: GC, glucocorticoid; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa-Beta ligand.
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case_images: In addition to disease-related factors, GCs have both direct and indirect adverse effects on the growth plate and developing skeleton, as recently reviewed in detail, and outlined in Fig. 4A. As shown in Fig. 4B, GCs wreak havoc on the mechanostat model of bone strength development by interfering at virtually every stage of the cascade; therefore, it is not surprising that GCs are potent disruptors of bone strength.
case_images: An overall, thematic approach when considering the management of skeletal health in GC-treated children. The approach to GIO management in children is intimately linked to the known fracture risk in various disease contexts and whether risk factors are transient, variable or persistent. These profiles, in turn, determine whether a child is able to recover spontaneously from bone health threats (without osteoporosis therapy), or require bone protection (ie, bisphosphonate therapy).. Abbreviations: DMD, Duchenne muscular dystrophy; GC, glucocorticoid; GIO, glucocorticoid-induced osteoporosis.
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case_images: To unravel the myriad GC effects on the developing skeleton from a practical perspective, natural history studies have taught us to categorize GC-treated children into 3 overarching groups (Fig. 5): those with aggressive but more limited GC exposure (eg, children with leukemia), those with variable GC exposure (eg, children with GC-treated inflammatory disorders and nephrotic syndrome), and those with aggressive and long-term (even permanent) GC exposure (eg, GC-treated DMD).