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At the same time, the bone health assessment of a child on chronic GC therapy needs to be extended beyond BMD in order to identify risk factors as well as early manifestations of osteoporosis. As such, bone health monitoring in pediatric chronic GC users includes an evaluation of calcium and vitamin D intake, back pain, physical activity, and disease-related risk factors for attenuated bone mineral accrual and bone loss such as chronic inflammation and disuse.

Because early diagnosis and appropriate intervention can prevent or delay the progression of osteonecrosis and the need for joint replacement, patients using high-dose GC therapy or those treated with GCs for prolonged periods should be evaluated for joint pain and decreased range of motion at each visit [ 58 ].

Magnetic resonance imaging should be considered in adult or pediatric patients presenting with these signs or symptoms [ 16 ]. Health care providers must be aware of the risk of AS in patients who have received supraphysiological GC doses. However, as is seen following longer courses of GC treatment, AS may result from multiple short courses of high-dose therapy.

If AS is suspected, biochemical testing of the HPA axis should be considered after GC treatment has been reduced to a physiologic dose. Given the ease and practicality of a first morning cortisol measurement, it should be considered for the initial screening of patients at risk for AS. Therefore, a normal cortisol value does not rule out the presence of AS. If a patient has signs or symptoms of AS and requires further testing, then referral to an endocrinologist should be considered. Clinicians must be aware that exogenous estrogen therapy, which affects cortisol-binding globulin levels, increases serum cortisol; therefore, the same thresholds for diagnosing AS do not apply in the setting of estrogen use.

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The insulin tolerance test ITT is the definitive test for evaluation of the HPA axis, but performing this test is complicated and risky for patients since insulin is administered to achieve hypoglycemia. The ITT is contraindicated in children secondary to the risks of hypoglycemia on the pediatric brain. Therefore, in the setting of a normal morning cortisol result and the presence of AS symptoms, the low-dose adrenocorticotropic hormone ACTH stimulation test should be performed to confirm the diagnosis since it is a sensitive and specific test for AS [ — ]. It is also important to rule out malnutrition as a cause of poor growth [ 9 , ].

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There are currently no evidence-based guidelines for the monitoring of dyslipidemia and CV risk in patients using corticosteroid therapy. All patients should be educated about the classic signs and symptoms of hyperglycemia polyuria, polydipsia, unexplained weight loss so that they are screened for steroid-induced diabetes if symptoms arise. If blood glucose or A1C is abnormal at baseline, then home blood glucose monitoring is also recommended. Glucose investigations should be repeated after starting GC therapy. In the absence of screening guidelines for GC-induced diabetes in children, the authors recommend that physicians be aware of the risk of hyperglycemia in children receiving long-term supraphysiological GC doses and, at a minimum, screen for classic symptoms [ 98 ].

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An annual FPG should also be considered. In children presenting with symptoms suggestive of diabetes, FPG should be performed. The diagnostic criteria for diabetes in children are the same as for adults [ 38 ]. More frequent screening of glucose parameters should be considered in children who are at potentially higher risk of developing hyperglycemia or diabetes, such as transplant recipients, obese patients, or those with conditions such as ALL or nephrotic syndrome. An earlier examination is required in patients with symptoms of cataracts namely blurred vision , however, this is generally not considered an ocular emergency that requires urgent treatment.

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Early referral for monitoring of intra-ocular pressure glaucoma is recommended in patients at higher risk of developing steroid-induced glaucoma, such as those with a personal or family history of open angle glaucoma, diabetes mellitus, high myopia, or connective tissue disease especially rheumatoid arthritis.

Any pre-existing comorbid conditions that may increase the risk of GC-induced AEs should be treated prior to corticosteroid initiation, and patients should be instructed to avoid contact with persons that have infections, such as shingles, chickenpox or measles. Patients should also be advised to carry a steroid treatment card and wear a medical identification tag, and to adopt lifestyle habits that may help minimize the risk of excessive weight gain with GC use, such as participation in regular physical activity and following a healthy, low-calorie diet.

Finally, whenever possible, GC-sparing agents should be considered. In patients with severe asthma, for example, use of the anti-immunoglobulin E IgE monoclonal antibody, omalizumab, has been shown to reduce the occurrence of asthma exacerbations requiring systemic corticosteroid therapy and to improve symptoms and asthma-related quality of life [ ].

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At present, omalizumab is reserved for patients with difficult to control asthma who have documented allergies and whose asthma symptoms remain uncontrolled despite ICS therapy [ ]. A number of published guidelines have addressed the prevention and treatment of GC-induced osteoporosis in adults [ — , — ]. Most guidelines and evidence support the use of bisphosphonates and teriparatide as first-line therapy for GC-induced osteoporosis in adults. A number of studies have demonstrated that the bisphosphonates alendronate, risedronate and zoledronic acid are effective for the prevention and treatment of GC-induced bone loss [ — ], although their long-term efficacy on fractures is not well established [ ].

Teriparatide has been shown to be effective in improving BMD and reducing vertebral fractures in patients with GC-induced osteoporosis [ — ]. Although other therapies such as calcitonin, raloxifene and denosumab may also play a role in the management of GC-induced osteoporosis in adults, they are not currently recommended as first-line therapy. Calcitonin has been found to prevent lumbar spine bone loss in the setting of GC use, but the same protection has not been observed at the femoral neck or with respect to fracture risk [ ].

The European Medicines Agency EMA recently completed a review of the benefits and risks of calcitonin-containing medicines and concluded that there is evidence of a small, increased risk of cancer 0. Therefore, given this risk as well as its lack of efficacy in reducing fracture risk, calcitonin is not recommended as first-line therapy for GC-induced osteoporosis.

However, it may be considered when bisphosphonates are contraindicated or in those patients who are intolerant to oral or IV bisphosphonates. Due to its analgesic effect, calcitonin can also be considered in patients who have sustained an acute fracture. However, the generalizability of these findings are limited since the study cohort was predominantly Asian and did not include patients on high-dose GC therapy. Furthermore, as a selective estrogen receptor modulator, raloxifene use for osteoporosis prevention and treatment is limited to the postmenopausal female population.

In animal models, denosumab has been shown to prevent steroid-induced bone loss and improve bone strength [ ]. A phase 2 trial also found that denosumab improved lumbar spine BMD in patients with rheumatoid arthritis treated with corticosteroids and bisphosphonates [ ]. The phase 3 FREEDOM trial found denosumab to be associated with a slightly increased risk of cellulitis [ ], although the 2-year extension trial found no increased risk with longer term treatment [ ].

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In addition to pharmacologic therapy, current guidelines for GC-induced osteoporosis in adults recommend preventive measures such as smoking cessation, reduced alcohol consumption, participation in weight-bearing and strength-building exercises, falls risk assessment, and calcium and vitamin D supplementation [ — , — ]. Cochrane investigators reviewed the available data on calcium and vitamin D use in GC-treated patients and found that supplementation prevented bone loss at the lumbar spine and forearm, but had no effect on femoral neck BMD or fracture incidence [ ].

There are currently no evidence-based guidelines for the prevention and treatment of GC-induced osteoporosis in children. Most of the studies examining bisphosphonate use in GC-treated children have been observational in nature and have utilized the intravenous IV preparation, pamidronate [ ]. Some evidence suggests that bisphosphonate therapy increases BMD, promotes reshaping and relieves back pain from previously fractured vertebral bodies, and is safe and well-tolerated in children with secondary osteoporosis [ — ], although long-term safety and efficacy data is still required.

Currently, experts recommend consideration of bisphosphonate therapy in children with evident bone fragility associated with reductions in BMD parameters, particularly if there is a persistence of risk factors and, thereby, less likelihood of spontaneous BMD restitution and growth-mediated reshaping of vertebral bodies [ ].

Initial treatment for osteonecrosis includes bed rest and non-steroidal or other analgesics to relieve pain. For patients with early stage or less advanced osteonecrosis, joint-preserving strategies, such as reducing weight-bearing activities and core decompression with or without marrow transplantation , have been utilized with varying levels of success. For more advanced disease, femoral head or total hip replacement surgery is usually required [ 16 ].

Since these replacements generally have a year lifespan, strategies that delay the need for surgery are desired. Some evidence suggests that treatment with alendronate may reduce the risk of bone collapse and delay the need for surgery [ , ]. However, a recent randomized, controlled trial found no benefit of alendronate vs.

In children with osteonecrosis in the leukemia setting, IV pamidronate has been associated with significant improvements in pain and mobility [ , ]. When possible, referral to a multidisciplinary diabetes team should be considered. Initial management involves appropriate lifestyle modification strategies; if targets are not met with these modifications, pharmacotherapy is recommended, and the same spectrum of glucose-lowering medications is used for GC-induced diabetes as is used for pre-existing type 2 diabetes.

If a sulfonylurea is selected, it is important to consider both the dosing frequency of the GC as well as the duration of action of the insulin secretagogue. Sulfonylureas with shorter half-lives i. Agents with longer half-lives e. A reasonable starting dose for insulin is 0. With once-daily morning administration of prednisone, fasting glucose may be unaffected, but blood glucose will be higher later in the day. If this occurs, then an intermediate-acting insulin such as N or NPH or a premixed combination of intermediate- and fast-acting insulin can be initiated in the morning.

If blood glucose is elevated in the morning as well, then an evening insulin dose may also be required. If shorter-acting GCs are administered more than once per day, or if dexamethasone is used, then both fasting and non-fasting glucose levels are likely to be affected.

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In this case, twice-daily intermediate-acting insulin or long-acting insulin, such as detemir or glargine, are recommended; fast-acting insulin may also be required at mealtimes. In order to prevent hypoglycemia, it is important to remember to adjust diabetes medications if GC doses are reduced. The treatment of GC-induced diabetes in children is best accomplished through the combined efforts of a multidisciplinary pediatric diabetes healthcare team [ 98 ]. As with adults, lifestyle interventions should be initiated; if glycemic targets are not met with these modifications, insulin must be considered.

Many of the other glucose-lowering agents used in adult patients with type 2 diabetes have not been licensed for use in the pediatric population and may be contraindicated in children with complex medical issues [ 98 ]. Until the safety and efficacy of these medications in children are established, they cannot be recommended for routine clinical use in this population. The lowest effective dose should be utilized for treatment of the underlying condition and the dose should be re-evaluated regularly to determine if further reductions can be instituted. If possible, the GC should be administered once-daily in the morning.

Currently, evidence-based recommendations are lacking for withdrawal of high-dose GC treatment and management of individuals with biochemical evidence of AS. If high-dose GC therapy is no longer required, then GC doses can be reduced relatively quickly from pharmacologic to physiologic doses. These tables present modest, but safe, approaches to GC withdrawal and assume that the clinician has access to testing. However, in the absence of evidence-based guidelines, some physicians may choose to withdraw GC therapy gradually without testing. Regardless of the withdrawal regimen chosen, clinicians need to be aware of the symptoms of AS and to slow the withdrawal regimen should these symptoms arise.

Screening tests should be considered to assess adrenal function as GC therapy is being withdrawn. This treatment model replicates the physiological response of the healthy adrenal gland in order to prevent an adrenal crisis. To our knowledge, there is no evidence to support or refute this practice. The safest approach would be to treat asymptomatic patients with biochemical evidence of AS no differently than those with symptomatic AS.

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Consideration should be made to educate patients about the risk of AS if they have been treated with GC therapy within the last year, but have not had testing to rule out AS. In the event of severe illness or surgery, stress dose steroids should be considered to prevent adrenal crisis. The potency of dexamethasone and betamethasone in suppressing growth has been shown to be nearly 18 times higher than that of prednisolone [ ].

Therefore, to reduce the risk of growth suppression in children, lower potency agents, such as prednisolone, should be used whenever possible. There has been some evidence of short-term benefits on growth velocity with rhGH therapy [ ], however further study, including evaluation of final adult height, is required.