Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 https://doi.org/10.1186/s12969-020-0411-9 RESEARCH ARTICLE Open Access Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children Rocío Galindo-Zavala1* , Rosa Bou-Torrent2, Berta Magallares-López3, Concepción Mir-Perelló4, Natalia Palmou-Fontana5, Belén Sevilla-Pérez6, Marta Medrano-San Ildefonso7, Mª. Isabel González-Fernández8, Almudena Román-Pascual9, Paula Alcañiz-Rodríguez10, Juan Carlos Nieto-Gonzalez11, Mireia López-Corbeto12 and Jenaro Graña-Gil13,14 Abstract Background: Osteoporosis incidence in children is increasing due to the increased survival rate of patients suffering from chronic diseases and the increased use of drugs that can damage bones. Recent changes made to the definition of childhood osteoporosis, along with the lack of guidelines or national consensuses regarding its diagnosis and treatment, have resulted in a wide variability in the approaches used to treat this disease. For these reasons, the Osteogenesis Imperfecta and Childhood Osteoporosis Working Group of the Spanish Society of Pediatric Rheumatology has sounded the need for developing guidelines to standardize clinical practice with regard to this pathology. Methods: An expert panel comprised of 6 pediatricians and 5 rheumatologists carried out a qualitative literature review and provided recommendations based on evidence, when that was available, or on their own experience. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A Delphi survey was conducted for those recommendations with an evidence level of IV or V. This survey was sent to all members of the SERPE. All recommendations that had a level of agreement higher or equal to 70% were included. Results: Fifty-one recommendations, categorized into eight sections, were obtained. Twenty-four of them presented an evidence level 4 or 5, and therefore a Delphi survey was conducted. This was submitted electronically and received a response rate of 40%. All recommendations submitted to the Delphi round obtained a level of agreement of 70% or higher and were therefore accepted. Conclusion: In summary, we present herein guidelines for the prevention, diagnosis and treatment of secondary childhood osteoporosis based on the available evidence and expert clinical experience. We believe it can serve as a useful tool that will contribute to the standardization of clinical practice for this pathology. Prophylactic measures, early diagnosis and a proper therapeutic approach are essential to improving bone health, not only in children and adolescents, but also in the adults they will become in the future. Keywords: Secondary osteoporosis, Children, Low bone mineral density * Correspondence: rociogalin@hotmail.com 1 UGC Pediatría. Sección Reumatología Pediátrica, Hospital Regional Universitario de Málaga, Málaga, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 2 of 14 Background Methods Osteoporosis is a disorder characterized by bone mass Design reduction and alterations in the micro-architecture of A qualitative synthesis of scientific evidence and consen- the bone tissue resulting in bone fragility and, conse- sus based on clinical experience and existing scientific quently, an elevated risk of fractures [1]. At present, evidence was used to formulate the study design. osteoporosis is a public health problem in industrialized countries affecting about 30% of women and 8% of men Development stages older than 50 in Europe [2]. Although it has typically been Preparation began with the establishment of an expert considered an adult disorder, it is becoming increasingly panel comprised of 11 physicians, 6 pediatricians and 5 clear that osteoporosis might be rooted in childhood and rheumatologists. All are members of the SERPE and adolescence [3]. Bone matrix mineralization takes place have experience in the diagnosis and treatment of sec- during these stages of life, and therefore subjects reach peak ondary osteoporosis in children. bone mass at the end of this growth phase. If this peak is Study coordination was undertaken by one of the not optimal, it will facilitate the development of osteopor- physicians. osis in adulthood [3]. This panel of experts reached a consensus on the es- Furthermore, the incidence of childhood osteoporosis is sential contents to include in the document, consisting increasing due to, among other factors, the increased sur- of the following eight sections: vival rate of patients suffering from chronic diseases and the increased use of drugs that can damage bones [4]. 1. When osteoporosis should be suspected In its Official Positions published in 2013, the Inter- 2. How to prevent it national Society for Clinical Densitometry considered 3. Laboratory tests used in screening two possible conditions regarding the diagnosis of child- 4. Imaging tests used in screening hood osteoporosis [5]: 5. Treatment: calcium and vitamin D supplementation 6. Treatment: bisphosphonates (BPs) – Presence of one or more vertebral fractures (VF) 7. Follow-up in the absence of local disease or high-energy 8. Glucocorticoid-induced osteoporosis (GIOP) trauma. – Z-score of bone mineral density (BMD) or bone One or two experts were appointed to be responsible mineral content (BMC) ≤ − 2 (adjusted for size in for a literature review of each section, which was con- cases of children measuring below the 3rd ducted with the assistance of a rheumatologist and an percentile) and a history of clinically significant expert in methodology. fractures; specifically: Following the revision, each of the experts responsible  two or more long bone fractures occurring by age for the literature review provided recommendations re- 10 years; or garding each section based on evidence, when that was  three or more long bone fractures at any age up available, or on their own experience. to age 19 years. Afterwards, the panelists held a meeting to discuss and draft the recommendations. The level of evidence was de- Moreover, their guidelines state that a Z-score higher termined for each section using the Oxford Centre for than -2 does not preclude the possibility of bone fragil- Evidence-based Medicine (CEBM) system. For this pur- ity, especially in those patients suffering from disorders pose, both a rheumatologist and an expert in methodology that favor secondary osteoporosis. provided guidance. A Delphi survey was conducted for At present, in pediatrics there is growing interest those recommendations with an evidence level of IV or V. in this pathology. However, recent changes made to This survey was sent to all members of the SERPE. All the definition of childhood osteoporosis [5, 6], along recommendations that had a level of agreement higher or with the lack of guidelines or national consensuses equal to 70% were included. regarding its diagnosis and treatment, have resulted in a wide variability in the approaches used to treat Results this disease [7]. A total of 51 recommendations, categorized into eight sec- For these reasons, the Working Group of Osteogenesis tions, were obtained (Table 1). Twenty-four of them pre- Imperfecta and Childhood Osteoporosis of the Spanish sented an evidence level 4 or 5, and therefore a Delphi Society of Pediatric Rheumatology (SERPE, by its Span- survey was conducted. This was submitted electronically ish acronym) has sounded the need for developing and received a response rate of 40%. All recommendations guidelines to standardize clinical practice with regard to submitted to the Delphi round obtained a level of agree- this pathology. ment of 70% or higher and were therefore accepted. Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 3 of 14 Table 1 Recommendations, levels of evidence, grade of recommendation according to the Oxford CEBM and level of agreement in Delphi round* Recommendation LE GR LADR General recommendations 1 There is a need to monitor BMD in patients with chronic diseases, especially those of endocrinologic, nutritional, 4 D 95% rheumatological, renal, metabolic, hematological, neurological and gastrointestinal origin. There is no universal consensus regarding when and how to carry out such an assessment for all the pathologies involved. Following the existing guidelines for each pathology is therefore recommended [8–22]. 2 Special attention must be paid to patients with chronic diseases who receive treatments that contribute to osteoporosis 2b B development; e.g., GCs, chemotherapy treatments or antiepileptic drugs [17, 19, 20, 23–28]. Lifestyle and dietary habits 3 It is important to identify those children at risk for osteoporosis due to causes related to lifestyle, long-term immobilization 2a B or problems of anorexia or malnutrition [19, 29–34]. 4 Healthy dietary habits must be established by means of a balanced diet that meets specific calcium and vitamin D 2a B requirements for each age and allowing for adequate nutritional intake [35, 36]. 5 Tobacco, caffeine and alcohol use must be avoided in children and adolescents [35, 37, 38] [39–41]. 2a B 6 High impact and low frequency exercise - e.g., running or jumping - must be recommended for healthy children and 1a A adolescents [31, 42–46]. 7 This kind of sport must also be recommended for children with low BMD [23, 47, 48]. 3a C 8 It is important to recommend exposure to sunlight on the hands, face and arms between six to eight minutes/day in the 4 D 90% summer (avoiding the hottest part of the day between 10 a.m. and 3 p.m.) and 30 min/day during the coldest months of the year [15, 49, 50]. Complementary test 9 Children with chronic diseases are at greater risk of vitamin D deficiency than the general 2a B population. Therefore, it would be advisable to monitor them, mostly during the end of winter [49–51]. 10 Regarding all children and adolescents who are suspected of suffering from secondary osteoporosis, the following lab work 5 D 83% for the initial study is recommended: blood and urine chemistry, urine screening and bone turnover markers (Table 6) [52]. 11 The role of bone turnover makers in pediatric populations with bone fragility is insufficiently defined, but they can be useful 5 D 80% in treatment follow-up and evaluation. For this reason, they are included in the initial study of these patients [23, 52–56]. 12 Measurements of bone turnover makers in urine are not recommended for all patients since the collection of the sample 5 D 90% may be not correctly carried out due to the patient’s age or concomitant disease [57]. 13 Specific complementary tests detailed in Table 7 can be carried out for some children and adolescents depending on the 5 D 90% suspected underlying condition [15, 23, 58]. 14 Interpretation of analytical values must be done taking into consideration the factors that modify them. These factors are 2b B biological (age, sex, pubertal stage, ethnicity) and other controllable variables (circadian rhythm, diet, season of the year) [53, 55–61]. 15 Since low bone mass has been associated with increased fracture risk, DXA is the most recommended method for pediatric 2a B populations in order to assess bone health. However, it does not allow for a prediction of fracture risk [34, 48, 62, 63]. 16 DXA of the lumbar spine and total body less head (TBLH) is the chosen method to measure BMD in pediatric populations, 2a B since they are the most accurate and reproducible areas of the skeletal system for this measurement [6, 64, 65]. 17 Data analyses must be carried out using pediatric software (software for adults overestimates BMD) [66, 67]. 2b B 18 Vertebrae DXA measurement is recommended for children under the age of five due to its higher reproducibility and 2a B shorter time necessary for conducting this test [5, 6, 64, 66, 67]. 19 For children under the age of three, total body BMD is not recommended on a routine basis due to its lack of 3a C reproducibility in such young children; rather BMC should be used [5, 6, 64]. 20 Regarding children of short stature (< p3) or with a growth retardation problem, it is recommended to adjust their results 2a B by means of a size Z-score [6, 23, 64, 68, 69]. 21 For children suffering from joint contracture or with mobility problems - e.g., with cerebral palsy - distal femur 2a B measurement can be an alternative [68]. 22 For children with suspected secondary osteoporosis, it is recommended to extend the study with a plain lateral thoracic 2b B and lumbar X-ray to assess vertebral compression fractures, particularly if they are receiving GCs [23, 70–73]. 23 In the event of low bone mass or risk factor persistence, a second plain lateral thoracic and lumbar X-ray should be taken 3b C after one year [70, 71] . 24 The minimum time interval to wait before repeating a bone density measurement is six months, a period of one year being 3b C advisable, apart from exceptional cases [6, 64, 66, 74, 75]. Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 4 of 14 Table 1 Recommendations, levels of evidence, grade of recommendation according to the Oxford CEBM and level of agreement in Delphi round* (Continued) Recommendation LE GR LADR 25 DXA can be used to assess treatment response after six months in the event of high doses of corticosteroids, 3b C chemotherapy, or in situations of malnutrition or active treatment [6, 64, 66, 74]. 26 In cases of children who initially present normal densitometry results, but in whom risk factor(s) persist, the periodicity of 5 D 95% the densitometry must be individualized according to the risk factor associated and an interval of one or two years is advised until peak bone mass is reached [6, 64, 66, 74, 75]. Prevention 27 Oral calcium supplementation could improve BMD in healthy children with a low-calcium diet. Nevertheless, increasing cal- 5 D 90% cium intake by means of calcium-rich foods is preferable to supplementation [36–38, 76]. 28 With respect to children with chronic diseases, adequate treatment of the disease is the most important step to be taken 2b B regarding osteoporosis prevention and treatment [23, 77–79]. Treatment 29 Vitamin D supplementation must be prescribed for all those patients with chronic pathologies presenting levels lower than 4 D 90% 20 ng/mL and for those with levels between 20-30 ng/mL who present Z-score ≤ − 2 or any data showing bone fragility [51, 80, 81]. 30 For children and adolescents with a low BMD or osteoporosis, calcium supplementation is recommended, particularly for 2b B-C those patients with a low-calcium diet, as well as supplementation of the proper amount of vitamin D3 in order to keep plasmatic levels of 25-hydroxyvitamin D3 higher than 30 ng/dL [82, 83]. 31 The required amount of calcium and vitamin D supply needed in children with pathologies that can jeopardize intestinal 5 D 90% absorption or modify their body’s use of these nutrients is unknown. For this reason, in the event that such patients present osteoporosis or low BMD according to chronological age, it is advisable to initially prescribe the dose required to ensure a recommended daily intake of healthy children. Treatment can be modified according to plasmatic 25-hydroxyvitamin D3, iPTH and calciuria levels, which must be monitored every six to twelve months [49–51, 82, 83]. 32 Treatment with BP should be administered to those pediatric patients with osteoporosis (Z-score ≤ − 2 + pathological 1b A fracture or VF regardless of Z-score) [9, 84–88]. 33 Treatment with BP can be considered for patients without osteoporosis, but a low BMD in early puberty (Tanner 2): 5 D 78% - When active risk factors are present: patients with Z ≤ − 2. 5 SD (with a declining trajectory confirmed at least on two separate occasions with one year apart). - When patients no longer present active risk factors: patients with Z ≤ -3DS (with a declining trajectory confirmed on at least on two separate occasions with one year apart) [9, 84–87]. 34 Intravenous BPs should be used whenever there are VF, if there is some contraindication to the use of oral BPs, or 3a B-C according to the patient’s preferences [88–91]. 35 Oral BPs can be used in the absence of contraindications and VF, or during the de-escalation phase [9, 84–87]. 5 D 70% 36 The BP dosage should be discontinued or progressively reduced in those patients not presenting fractures during the 5 D 90% preceding year and having reached a Z-score higher than -2 [9, 84–87]. Follow-up 37 A follow-up is recommended for patients at risk for osteoporosis while other risk factors persist and during treatment with 4 D 95% calcium and/or vitamin D3, BPs or other osteoporosis treatments [49, 51, 74]. 38 Calcium and phosphorus metabolism (serum levels of calcium, phosphorus, alkaline phosphatase, iPTH and 25- 4 D 90% hydroxyvitamin D3) should be evaluated on an annual basis [49, 51]. 39 During treatment with vitamin D, it is recommended to monitor serum levels of 25-hydroxyvitamin D3 every 6 to 12 5 D 88% months, unless the dosage is changed. In such cases, patients should be monitored at 3–6 months [49, 51]. 40 During supplementation with calcium and/or vitamin D3, calcium/creatinine levels in urine should be monitored at least 5 D 83% once a year. Renal ultrasounds should be conducted to rule out nephrocalcinosis in the event of calciuria increase, or when it is not possible to determine calciuria due to the patient’s age or pathology [49–51, 82, 83]. 41 DXA is recommended one year after the baseline DXA, and then subsequently every 1 or 2 years depending on the 4 D 93% trajectory observed. The minimum interval should be 6–12 months [74]. 42 It is recommended to perform simple lateral thoracic and lumbar X-rays to assess VF every 6 months to 2 years (with 1 year 5 D 73% being the average), according to the risk factor magnitude and the functional status of the child [51, 71, 74]. 43 For pediatric patients with reduced mobility due to cerebral palsy and congenital myopathies, a spine X-ray is recom- 5 D 88% mended at 6–8 years of age, or earlier in the event of back pain, and then periodically until the end of growth [23]. 44 During treatment with intravenous BPs, assessments of laboratory parameters are recommended before each 5 D 83% administration. For oral BPs, checks every six months are recommended [9, 84–86, 88–92]. 45 During treatment with BPs, annual DXA is recommended [9, 84–86, 88–92]. 5 D 85% Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 5 of 14 Table 1 Recommendations, levels of evidence, grade of recommendation according to the Oxford CEBM and level of agreement in Delphi round* (Continued) Recommendation LE GR LADR Corticosteroid-induced osteoporosis 46 Lateral spine x-ray is recommended in order to detect VF at the beginning of treatment 2a B with GCs and after one year [70, 71, 93]. 47 It is recommended to carry out lumbar spine or TBLH DXA within the first six months after the beginning of treatment with 4 D 85% GCs, and then every 9 to 12 months if treatment continues [94]. 48 It is recommended to start simultaneous treatment and/ or optimize calcium intake (500–1000 mg/day) and vitamin D 400 2b B IU/day for those patients who are scheduled to receive systemic GCs for three months or more [95]. 49 Treatment with calcium and vitamin D must be maintained for three months after discontinuation of GCs [95]. 5 D 88% 50 For children and adolescents receiving GCs chronically and presenting low BMD (Z-score ≤ − 2) and pathological fractures, it 1b A is recommended to use BPs associated with calcium and vitamin D [87, 95, 96]. 51 Lateral spine x-rays or BMD checks with DXA are not recommended on a routine basis for those children and adolescents 1b A being treated with inhaled GCs at dosages under 800 mcg/day, unless they present other risk factors [97–99]. LE level of evidence, GR grade of recommendation, LADR Level of agreement in Delphi round, GCs glucocorticoids, BMD bone mineral density, BMC bone mineral content, DXA dual-energy x-ray absorptiometry, iPTH intact parathyroid hormone, BPs bisphosphonates, VF vertebral fractures Discussion drugs that alter intestinal absorption may need higher When osteoporosis should be suspected intakes of calcium and vitamin D [23, 35, 49, 104]. Factors that contribute to osteoporosis in children and Calcium-rich foods are preferable to supplements for adolescents can be both genetic and lifestyle associated. attaining optimal calcium intake, not only because they In children suffering from chronic diseases or receiv- have a higher bioavailability [23] and are easier to digest, ing bone harmful treatments for a prolonged period of but also because their consumption avoids possible sec- time, several factors that increase bone resorption and ondary cardiovascular effects common in adults [105] decrease bone formation converge and result in in- and favors positive nutritional habits from childhood creased bone fragility [100] [63]. For this reason, bone [23]. Thus, systematic supplementation with calcium in health must be assessed during follow-up, adopting ad- the absence of osteoporosis or low BMD is not recom- equate preventive measures. mended [106]. It should only be considered for those pa- Table 2 shows some of the pathologies responsible for tients with calcium-poor diets [42]. secondary osteoporosis. Vitamin D is an important hormone for the absorp- There is no universal consensus regarding when and tion and use of calcium [103]. There is some dispute how to assess bone health for all of the pathologies in- regarding the optimal levels of vitamin D, although in volved. However, there are some clinical guidelines for general terms, serum levels of 25-hydroxyvitamin different pediatric disorders (Table 3). D3 ≥ 50 nmol/L (20 ng/mL) are considered normal. BMD in patients with chronic diseases should be moni- Those between 30-50 nmol/L (12-20 ng/mL) are regarded as tored based on the existing guidelines for each disorder. insufficient, and those < 30 nmol/L (12 ng/mL) deficient [49]. In addition, special attention must be paid to patients suf- In order to maintain appropriate levels, the intake of fering from chronic diseases and receiving treatment that food enriched in vitamin D is important, as well as daily may favor the development of osteoporosis; e.g., glucocor- exposure to sunlight on the hands, face and arms for 6 ticoids (GCs), chemotherapy or antiepileptic drugs. to 8 min in the summer months (avoiding the hottest part of the day) and 30 min in the coldest months of the year. However, there is no exposure to ultraviolet B How to prevent osteoporosis (UVB) rays that is safe in terms of skin cancer [49]. There are numerous factors that impact bone health in Children suffering from chronic diseases have an in- children. Many of these are modifiable, at least in part creased risk of vitamin D deficiency. Therefore, monitor- (Table 4) [35]. ing vitamin D serum levels would be advisable in these Nutritional factors with higher evidence of conferring patients, especially in late winter [104]. a positive effect on bone health are calcium, phosphorus In addition, a large number of other nutrients play a and vitamin D [23]. Table 5 shows the daily nutrient re- significant role in bone metabolism, such as proteins, quirements for a healthy child [103], although children potassium, magnesium, copper, iron, phosphate, zinc suffering from chronic diseases or under treatment with and vitamin A, C and K [23, 104]. Thus, it is important Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 6 of 14 Table 2 Causes of secondary osteoporosis 43, 104]. Nevertheless, physical activity with excessive Neuromuscular disorders Cerebral palsy impact increases fracture risk [44]. Duchenne muscular dystrophy There are other factors such as tobacco, caffeine and Rett syndrome Myopathies alcohol consumption that are associated with decreased Diseases resulting in long-term BMD and increased fracture risk [35, 37, 38, 104]. This immobilization is one reason, among others, to avoid their consumption Hematological diseases Leukemias in children and adolescents. Hemophilia It is also essential to maintain an adequate nutritional Thalassemia state because both, extreme thinness and adiposity, are Systemic autoimmune Juvenile systemic lupus erythematosus diseases Juvenile dermatomyositis associated with lower BMD and increased fracture risk Systemic juvenile idiopathic arthritis [29, 30, 35]. Systemic sclerosis Furthermore, the optimal control of the primary dis- Lung diseases Cystic fibrosis ease is the most effective way to prevent and treat sec- Gastrointestinal diseases Celiac disease ondary osteoporosis [23, 35]. Inflammatory bowel disease Chronic liver disease Diagnosis Cow’s milk protein allergy Laboratory tests Renal diseases Nephrotic Syndrome Chronic renal failure The diagnosis of secondary osteoporosis is usually made after the diagnosis of the underlying disease that causes Psychiatric illnesses Anorexia nervosa it. However, in some cases, it may be the first manifest- Infectious diseases HIV infection ation of the underlying disease. Although most of the Immunodeficiencies disorders included in the differential diagnosis can be in- Endocrine diseases Delayed puberty ferred by means of a thorough medical history review Hypogonadism Turner syndrome and physical examination, some pathologies - e.g., phos- Klinefelter Syndrome phocalcic metabolism alterations, hypothyroidism or Growth hormone deficiency some types of leukemia- can be paucisymptomatic and Acromegaly Hyperthyroidism require complementary tests for accurate diagnosis Diabetes [100]. For this reason, it is recommended to perform the Hyperprolactinemia analytical parameters listed in Table 6 when assessing a Cushing syndrome Adrenal insufficiency child with suspected or established diagnosis of secondary Hyperparathyroidism osteoporosis. Regarding the parameters shown in Table 7, Vitamin D metabolism disorders they are only justified in the event of clinical suspicion. Inborn errors of metabolism Glycogen storage disease These biochemical parameters must be interpreted Galactosemia Gaucher disease based on factors such as age, sex, growth rate, nutri- tional status and pubertal stage, among others [52, 59]. Skin conditions Epidermolysis bullosa Bone turnover markers are certain substances released Iatrogenesis Systemic glucocorticoids Cyclosporine into the bloodstream during bone formation or resorp- Methotrexate tion that reflect bone metabolic activity at a given time. Heparin Though numerous, amino-terminal propeptides from Anticonvulsants Radiation therapy type 1 procollagen (P1NP) and carboxy-terminal telo- peptides (CTx) should be used as reference markers to evaluate formation and resorption, respectively [107, 108]. These can be measured in the blood and urine to recommend a varied diet, including fruits and vegeta- [109], although for children it is preferable to determine bles, to ensure an adequate intake of key nutrients in them in plasma [53, 110, 111]. In adults, they have been order to maintain good bone health in children and ado- shown to be useful for monitoring treatment in patients lescents [23, 35, 104]. with osteoporosis [112]. In children, however, such inter- Moreover, exercise and regular physical activity are pretation is much more complex [54, 110, 113], although considered among the most effective strategies for maxi- they can help in monitoring antiresorptive therapy com- mizing peak bone mass during childhood [23, 35, 42, pliance and measuring its effectiveness [100]. 104]. High impact and low frequency exercise - e.g., jumping, running or resistance training - favor BMD in- Imaging tests crease in children and are more suitable than others The diagnosis of childhood osteoporosis is essentially such as swimming or biking in terms of bone health [35, based on the presence of fragility fractures. However, a Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 7 of 14 Table 3 Assessment of BMD for certain diseases or chronic treatments involved in childhood secondary osteoporosis Disease / Treatment BMD assessment Celiac disease DXA if: -no adequate dietary adherence -irregular menstruation -anemia -other risk factors for fractures [74] Cerebral palsy Difficult lumbar spine X-ray interpretation in cases of severe scoliosis. Total-body or distal femur DXA (area with higher fracture risk), only if there are fragility fractures [8]. Duchenne muscular Baseline DXA and annual monitoring. dystrophy Lateral spine x-ray: Baseline - On GCs treatment: Repeat every 1–2 years. - Not on GCs treatment: Repeat every 2–3 years. - If back pain or ≥ 0, 5 SD decline in spine BMD Z score on serial measurements over 12-month period: Repeat. Refer to osteoporosis specialist following the first fracture [11]. Rett syndrome Baseline DXA, and serial controls according to individual risk [15]. Epilepsy Consider DXA for epileptic patients receiving anti-epileptic drugs for a prolonged period [13] Thalassemia DXA every 2 years from adolescence [12] Inflammatory/ systemic Consider DXA for patients receiving high doses of GCs [74]. disease Juvenile idiopathic < 6 years: DXA in the presence of fragility fractures. arthritis (JIA) > 6 years: DXA if not presenting rapid remission of JIA or in need of high doses of GCs [18]. Neoplasms Baseline DXA two years after completing chemotherapy with osteotoxic drugs; e.g., MTX, GCs or hematopoietic cells transplantation; or secondary effects that favor osteoporosis development (growth hormone deficiency, hypogonadism, etc.) DXA follow-up based on the results of baseline DXA and persistent risk factors [17] Cystic fibrosis DXA in children ≥ age 8 if: - weight < 90% ideal weight - FEV1 < 50% - Delayed puberty - High dosis of GCs > 90 days per year At 18, all of them [101]. Diabetes mellitus DXA if: - low BMD specific risk factors - increased daily insulin dosis - impaired renal function - fracture history [74] Anorexia nervosa DXA in patients with amenorrhea for more than 6 months [13]. Systemic lupus DXA evaluation in patients with prolonged systemic GCs exposure exceeding ≥0.15 mg/kg daily for ≥ 3 months. Repeat erythematosus on an annual basis if Z-score ≤ − 2 [102]. DXA dual-energy x-ray absorptiometry, BMD bone mineral density, GCs glucocorticoids, MTX methotrexate, FR risk factors dual-energy x-ray absorptiometry (DXA) is recommended asymptomatic, should always be assessed by means of a to ensure a complete assessment of bone health [5]. simple lateral full spine x-ray or by DXA vertebral frac- Despite numerous limitations [100], DXA is the ture assessment, if feasible [39, 114]. chosen method for determining bone health in children. Lumbar spine and total-body less head are the preferred skeletal sites for performing DXA as they are the most Treatment accurate and reproducible areas in children. In addition, Calcium and vitamin D supplementation Z-score should be adjusted according to the height in Calcium and vitamin D supplementation have not children with a size below the 3rd percentile [5]. shown any clinically significant effect on BMD in studies Other techniques for assessing bone quality in pediatrics performed in healthy children [106]. In contrast, some are peripheral quantitative computed tomography and studies have reported a favorable effect in patients with ultrasound. However, although superior to DXA in certain chronic diseases that favor osteoporosis such as cerebral aspects, there are insufficient studies of pediatric popula- palsy [8]. On the other hand, no side effects have been tions to recommend their use on a routine basis [100]. reported [8, 40]. Thus, although there are no studies that Furthermore, in a patient with suspected or confirmed assess the effect of supplementation on the incidence of bone fragility, the presence of VF, which are frequently fractures, calcium supplementation is considered Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 8 of 14 Table 4 Risk factors of osteoporosis in childhood Bisphosphonates Modifiable Nutritional • Caloric intake BPs are synthetic analogs of pyrophosphate that inhibit • Protein intake bone resorption. They selectively concentrate and in- • Calcium intake • Phosphorus intake crease BMD in high remodeling rates skeleton areas • Vitamin D [115]. They are hydrophilic drugs with low intestinal ab- • Others (vitamins K, group B, Mg, K sorption (< 1%) and high distribution volumes that are …) excreted in urine. Thus, dosages must be adjusted ac- Lifestyle • Solar exposure cording to glomerular filtrate. Moreover, they are char- • Physical exercise • Tobacco acterized by a very slow elimination from bone tissue, • Alcohol and remain in the body for years after treatment [115]. Partly High risk • Prematurity Knowledge on the mid- and long-term safety of these modifiable diseases • Pregnancy and nursing in drugs is constantly increasing [100]. Thus, some authors adolescents • Intestinal malabsorption recommend their use as long as osteoporotic criteria are • Cystic fibrosis met, particularly in those patients with long bones and VF • Celiac disease and who exhibit poor potential for spontaneous recovery • Inflammatory bowel disease • Food allergies (age at puberty, risk factor persistence, etc.) [116]. • Chronic lactose intolerance To date, BPs have only been prescribed as a secondary • Chronic liver disease prevention measure. In other words, once the first frac- • Chronic kidney disease • Cerebral palsy ture occurs. Their use is intended to prevent the appear- • Chronic rheumatic diseases … ance of new fragility fractures. It is currently known that Hormonal • Treatment with glucocorticoids they confer a positive effect on BMD [9, 84–87], and • Hyperparathyroidism there is increasing knowledge regarding their long-term • Hypogonadism safety [100]. On the other hand, if the peak bone mass Non- Genetics reached at the end of the growth stage is not optimal, modifiable osteoporosis is more likely to develop during the later Sex Ethnicity stages of life [3]. On the basis of the above data, our working group recommends that clinicians consider treatment with BPs for those patients without osteopor- advisable in children and adolescents with low BMD or osis, but low BMD in early puberty, with low Z-scores osteoporosis, especially those patients with a low and decreasing trajectories. dietary intake. In any case, BPs are used off label in childhood osteo- Likewise, ensuring proper vitamin D3 intake is recom- porosis, so informed consent must be obtained when mended in order to maintain plasmatic levels of 25- they are prescribed. hydroxyvitamin D3 higher than 50 nmol/l (20 ng/dL). Second and third generation BPs are the most com- Table 6 shows the recommended daily intake of calcium monly used BPs in children. Some of them are intraven- and vitamin D for healthy children [103]. The optimal in- ously administered and others orally [100]. Oral BPs are take for children with disorders that may interfere with in- widely used in adulthood osteoporosis, and some studies testinal absorption or modify calcium metabolism remains have demonstrated that they increase BMD and decrease unknown [41]. Thus, initially, supplementation should be fracture risk in patients with Osteogenesis Imperfecta. prescribed with respect to these recommendations and Nevertheless, in contrast to intravenous BPs, they subsequently be modified according to plasmatic 25- lack sufficient potency to induce remodeling after VF hydroxyvitamin D3, intact paratohormone (iPTH) and cal- [117] and are contraindicated in patients with ciuria, which must be monitored every 6–12 months. esophagitis risk factor; e.g., gastroesophageal reflux or hiatal hernia. Intravenous BPs are preferred for pediatric osteoporosis, and oral BPs are only used Table 5 Daily calcium and vitamin D requirements according to for patients with mild forms of osteoporosis, without age VF, when intravenous administration is contraindi- Age Calcium (mg) Vitamin D (IU) cated for any reason, or during the treatment main- 0–6 months 200 400 tenance phase [100]. 6–12 months 260 400 Table 8 shows doses and dosing intervals for the most 1–3 years 700 600 commonly used BPs in pediatrics [100]. 4–8 years 1000 600 The optimal treatment duration is not clearly defined and is currently based on expert recommendations 9-18 years 1300 600 [116]. We propose discontinuing or progressively Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 9 of 14 Table 6 Basic Diagnostic Studies frequency be individualized according to the patient’s Laboratory test Variables to analyze risk factors, with a minimum period of 6 months and a Blood count maximum period of 2 years. Blood chemistry Calcium, ionized calcium, phosphorus, In addition, no studies or guidelines have established magnesium, total proteins, creatinine, urea, the optimal periodicity for assessing phosphocalcic me- glucose, 25-hydroxyvitamin D3, PTH, TSH, free T4 tabolism. Our recommendation is to make an analytical 24-hour urine Calcium, phosphorus, creatinine, tubular determination on an annual basis. chemistry phosphorus reabsorption, sodium In regard to patients receiving calcium and vitamin D Urine screening Ca/Creatininea supplementation, since the optimal intake for children Bone turnover Total alkaline phosphatase and adolescents suffering from chronic diseases is un- makers known [41], doses should be modified according to cal- a Sample from a single urination, preferably first one in the morning ciuria and plasmatic levels of 25-hydroxyvitamin D3 and iPTH. The optimal frequency for monitoring these param- decreasing BPs dosing for those patients who have not eters is unknown [49], although some authors advocate presented fractures during the preceding year and who that determinations should be made every 3–12 months have attained a Z-score higher than -2. [49, 51]. Our working group recommends that levels of 25-hydroxyvitamin D3 should be determined every 6–12 Follow-up months, or after 3–6 months after a dose change. Further- The aim of follow-up in patients with osteoporosis risk more, an annual determination of calciuria is recom- factors is to identify those candidates who need to start or mended. A renal ultrasound should be conducted to rule maintain specific treatments. For such patients and those out nephrocalcinosis in the event of calciuria increase, or with an established osteoporosis diagnosis, follow-up when urine collection is not possible. should be continued as long as risk factors persist or while Regarding children being treated with BPs, there are no treatment is maintained with calcium and/or vitamin D3, studies that have determined an optimal frequency for BPs or other medications for osteoporosis [49, 51, 74]. analytical checks. Our group recommends monitorization Clinical, radiological and analytical parameters should prior to each infusion for patients receiving intravenous be monitored. Assessing the number of fragility fractures BPs, and every 6 months for patients taking BPs orally. and pain episodes is important. In terms of densitom- etry, variations in Z-scores are relevant. The optimal fre- quency for DXA performance is insufficiently defined Corticosteroid-induced osteoporosis [74]. Our recommendation is to repeat DXA after one GCs are widely used with a proven effectiveness in nu- year, and then every 1–2 year thereafter according to the merous pediatric diseases. However, they carry multiple patient’s trajectory, with a minimum interval between side effects, and are associated with decreased BMD and checks of 6–12 months. bone fragility fractures [118]. It is also crucial to perform a radiological assessment Patients treated with systemic GCs lose bone mass of VF, since they are frequently asymptomatic and can more markedly during the first 3–6 months of treat- appear even in patients with Z-scores higher than -2 ment, mainly trabecular bone [118]. This loss depends [23]. Moreover, their evolution can lead to changes in on the dose and treatment duration [119, 120]. Although treatment [116]. There are no studies that have defini- lower doses are less harmful than higher doses, there ap- tively determined how often VF should be monitored, al- pears to be no unequivocally safe dose since fracture risk though some authors propose lateral spine x-rays on an have been reported to persist with prednisone (or annual or biannual basis [23]. We propose their equivalent) doses of 2. 5 a 7. 5 mg/ day [118]. Thus, as in other patients with osteoporosis risk fac- Table 7 Analytical determinations to make based on suspicion tors, monitoring BMD and VF occurrence is advisable. Studies In the absence of clear data on the optimal time for a 1 Immunoglobulins DXA in this group, we recommend performing a DXA 2 Anti-transglutaminase IgA antibodies during the first 6 months of treatment, and repeating it 3 Cortisol every 9-12 months if treatment continues. 4 Prolactin Regarding VF screening, some studies reported an in- cidence rate of around 10% during the first year, with 5 FSH, LH, testosterone nearly 50% of such cases being asymptomatic [70, 71]. 6 Homocysteine For this reason, it is advisable to assess these patients 7 Genetic studies (genes related to osteogenesis imperfecta using imaging technique at the beginning of treatment, and disorders characterized by bone fragility) and thereafter annually while GCs are maintained. Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 10 of 14 Table 8 Doses and dosing intervals for the most commonly used BPs in pediatrics Drug Administration Dose Pamidronate Intravenous (dilute in 100-250 ml physiological saline solution, < 1 year: 0. 5 mg/kg every 2 months (2nd generation) in 3–4 hours) 1–2 years: 0. 25-0. 5 mg/kg/day 3 days every 3 months 2–3 years: 0.375–0.75 mg/kg/day 3 days every 3 months > 3 years: 0. 5–1 mg/kg/day 3 days every 4 months Maximum dose: 60 mg/dose and 11. 5 mg/kg/year Neridronate Intravenous (dilute in 200–250 ml physiological saline solution, 1–2 mg/kg/day every 3–4 months (3rd generation) in 3 hours) Zolendronate Intravenous (dilute in 50 ml physiological saline solution, 0.0125–0.05 mg/kg every 6–12 months (maximum dose 4 mg) (3rd generation) in 30-45 min) Alendronate Oral 1–2 mg/kg/week (2nd generation) < 40 kg: 5 mg/day or 35 mg/week > 40 kg: 10 mg/day or 70 mg/week Maximum dose: 70 mg/week Risendronate Oral 15 mg/week (< 40 kg); 30 mg/week (> 40 kg) (3rd generation) Maximum dose: 30 mg/week The Spanish Rheumatology Society Consensus [121] Furthermore, the role of calcium and vitamin D supple- holds that the prevention of GIOP must begin as early mentation in patients prescribed inhaled GCs has not as possible for all patients receiving doses higher than 5 yet been established, although some groups recommend mg/day of prednisone (or equivalent) for more than supplementation for higher risk populations [93]. three months. Preventive actions include prescribing the lowest possible dose of GCs to control the underlying Conclusion disease, as well as encouraging physical exercise, avoid- In summary, we present herein guidelines for the pre- ing toxic products, such as tobacco and alcohol, and en- vention, diagnosis and treatment of secondary childhood suring a balanced diet with the required intake of osteoporosis based on the available evidence and expert calcium and vitamin D [121]. In fact, a recent systemic clinical experience. We believe it can serve as a useful review concluded that calcium and vitamin D supple- tool that will contribute to the standardization of clinical mentation should be started with the same dose recom- practice for this pathology. Prophylactic measures, early mended for healthy children in all children on GCs, diagnosis and a proper therapeutic approach are essen- particularly when treatment is expected to last more tial to improving bone health, not only in children and than 3 months, as a preventive action against GIOP de- adolescents, but also in the adults they will become in velopment [95]. In addition, our group recommends the future. maintaining this supplementation for three months after Abbreviations discontinuation of GCs treatment since its effect on BMC: Body mass content; BMD: Body mass density; BPs: Bisphosphonates; bone continues even after treatment has been halted. CEBM: Centre for Evidence-based Medicine; CTx: Carboxy-terminal Nevertheless, no studies have determined an optimal telopeptides; DXA: Dual-energy x-ray absorptiometry; GCs: Glucocorticoids; GIOP: Glucocorticoid-induced osteoporosis; iPTH: Intact paratohormone; period of supplementation. This same review recom- P1NP: Amino-terminal propeptides from type 1 procollagen; SERPE: Pediatric mends the use of BPs for preventive purposes [95], Rheumathology Spanish Society; UVB: Ultraviolet B; VF: Vertebral fractures despite the lack of any comprehensive data. Our own Acknowledgements working group does not consider its systematic use in We thank the Spanish Pediatric Rheumatology Society, Laboratorios Rubió the absence of fragility fractures. Nevertheless, its ef- and Alexion Pharma for granting. fectiveness is proven when GIOP has been estab- We thank Dra. Estíbaliz Loza, InMusc Medical Director for her assistance in conducting the literature review, in determining the recommendations level lished; i.e., when pathological fractures are clearly of evidence and in setting up the Delphi survey. evident [87, 95, 96]. Thanks also to the Spanish Rheumatology Society for the original manuscript Most studies suggest that an inhaled GCs dose lower translation. than the equivalent of 800 mcg/day of budesonide has Authors’ contributions only a minimum effect on fracture risk, while higher RGZ coordinated the project, conducted a literature review about calcium doses are associated with an accelerated decrease in and vitamin D supplementation in secondary osteoporosis in children, provided recommendations based on evidence, was a major contributor in BMD and a higher risk of fractures. In these patients, al- writing the manuscript, read and approved the final manuscript. RBT though non-pharmacological preventive actions are jus- conducted a literature review about bisphosphonates in secondary tified [97, 98, 122], it is not advisable to routinely carry osteoporosis in children, provided recommendations based on evidence, was a major contributor in writing the manuscript, read and approved the out such procedures as lateral spine x-rays or DXAs, final manuscript. BML conducted a literature review about imaging tests unless these patients have other risk factors [97–99]. used in secondary osteoporosis screening in children, provided Galindo-Zavala et al. Pediatric Rheumatology (2020) 18:20 Page 11 of 14 recommendations based on evidence, read and approved the final Received: 2 October 2019 Accepted: 3 February 2020 manuscript. CMP conducted a literature review about when secondary osteoporosis in children should be suspected, provided recommendations based on evidence, read and approved the final manuscript. 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