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ABSTRACT

Childhood is a unique time during which individuals accrue bone rapidly, and peak bone mass is achieved early in the third decade of life. Several factors may adversely influence bone accrual, including primary skeletal disorders as well as secondary causes of low bone density such as specific endocrinopathies, altered weight-bearing, and certain medications. Pediatric osteoporosis is defined by both: 1) a clinically significant fracture history; and 2) a low bone mineral density (BMD). Pragmatically, the diagnosis of osteoporosis is indicated by a BMD Z-score ≤ -2.0 and a clinically significant fracture history, defined as two or more long bone fractures by age 10 years, or three or more long bone fractures at any age up to 19 years. Additionally, the finding of one or more vertebral non-traumatic compression fractures is diagnostic of osteoporosis independent of BMD. Notably, the diagnosis of pediatric osteoporosis should not be made based on densitometric criteria (i.e., DXA) alone. As childhood osteoporosis has several potential underlying etiologies, evaluation requires a careful assessment by a clinician with expertise in the possible mechanisms that may be contributing to the increased skeletal fragility. Both non-pharmacologic therapies as well as bone-active medications, such as bisphosphonates, increase bone mass and may lower the risk of fracture. The development of novel therapies that may restore physiologic anabolic bone activity in children with insufficient bone accrual from various causes has the potential to improve care for pediatric patients with osteoporosis. Prospective data acquisition to inform treatment strategies for primary prevention of fracture in children with osteoporosis, as is done in adult populations, is urgently needed to prevent the significant morbidity of fracture in this vulnerable population. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text,WWW.ENDOTEXT.ORG.

INTRODUCTION

Childhood and adolescence are unique time periods during which individuals accrue bone rapidly, and peak bone mass is only achieved early in the third decade of life. Several congenital or acquired factors may adversely influence bone accrual, including primary skeletal disorders, or secondary causes of low bone density such as delayed puberty, endocrinopathies, altered weight-bearing, and certain medications.

Pediatric osteoporosis is defined by both: 1) a clinically significant fracture history; and 2) a low bone mineral density (BMD). Pragmatically, the diagnosis of osteoporosis is indicated by a BMD Z-score ≤ -2.0 and a clinically significant fracture history, defined as two or more long bone fractures by age 10 years, or three or more long bone fractures at any age up to 19 years. Additionally, the finding of one or more non-traumatic vertebral compression fractures is diagnostic of osteoporosis independent of BMD. Notably, the diagnosis of pediatric osteoporosis should not be made based only on densitometric criteria (i.e., DXA) (1).

ETIOLOGIES

Secondary Causes of Low Bone Density or Osteoporosis

NUTRITIONAL AND MALBSORPTIVE

Deficient Intake of Calcium and Vitamin D:

Insufficient intake of calcium and/or vitamin D can result in suboptimal bone mineralization, and the associated secondary hyperparathyroidism has the potential to cause deleterious effects on bone. However, data are conflicting regarding the impact of calcium or vitamin D deficiency and their replacement on bone mineral content (BMC) and BMD. One systematic review of dairy intake or calcium supplementation in children and adults 1-25 years old concluded that these measures provide no beneficial effect on bone mineralization or fracture risk (23). A meta-analysis of 21 randomized controlled trials (RCTs) found no significant change in total body BMC in those randomized to supplemental dairy or calcium alone regardless of baseline intake; however, the study did find an increase in whole body BMC in children with low baseline calcium intake who received high doses of dietary calcium supplements or dairy products with or without vitamin D supplementation (24). Another meta-analysis of 19 RCTs reported a small favorable effect on total body BMC and upper limb BMD with calcium supplementation, but no effect at the lumbar spine or femoral neck (25). A more recent meta-analysis of 15 RCTs and three non-randomized studies did find a positive impact of calcium supplementation on femoral neck BMD in children (26). Calcium supplementation has also been reported to have a beneficial effect on bone strength estimates in prepubertal and early pubertal children (27). Of note, maternal calcium supplementation during pregnancy has not been demonstrated to benefit offspring BMD even when baseline intake was low (28). Overall, data suggest a possible small effect of dietary calcium or dairy supplementation on bone outcomes when baseline intake is low, with greatest effects at the whole body and femoral neck.

Similarly, data for the effects of vitamin D deficiency and supplementation are mixed, but overall suggest some effect on bone outcomes. One study reported that baseline 25-hydroxyvitamin D (25OHD) levels predict prospective changes in lumbar spine BMD over the next three years in peripubertal Finnish girls (29), and a case control study of 150 African American children 5-9 years old reported that those with forearm fractures were more likely to be vitamin D deficient (30). In Chinese adolescents, 25OHD levels 20-37 nmol/L (8-15 ng/mL) in girls and 33-39 nmol/L (13-16 ng/mL) in boys are reported to have positive effects on bone outcomes (31). The impact of race is interesting, with dark skinned children typically having lower 25OHD levels than light skinned children, but higher BMD measures. Further, data suggest that vitamin D supplementation in dark skinned (but not light skinned) children living in northern latitudes positively impact femoral neck BMC (32). Some data (but not all) suggest that maternal vitamin D status may predict offspring BMD, with low maternal 25OHD levels being concerning for low peak bone mass in their children (33). However, a meta-analysis of vitamin D supplementation during pregnancy and infancy reported no impact on subsequent bone health (34).

Conditions of Low Energy Availability or Energy Deficit

Conditions such as anorexia nervosa and the female athlete triad (Triad)/relative energy deficiency in sports (RED-S) are known to be associated with low BMD, reduced bone strength, and increased prevalence of fractures (35,36), even in adolescents. Anorexia nervosa in both male and female adolescents is associated with low BMD (35,37-39), and reduced bone accrual in adolescent girls with anorexia nervosa (40) raises significant concerns regarding peak bone mass acquisition. Young oligo-amenorrheic athletes have lower BMD than eumenorrheic athletes at the femoral neck and hip and lower strength estimates at the distal tibia; they also have lower spine BMD and lower strength estimates at the radius than non-athletes (41-43). Factors contributing to impaired bone outcomes include lower lean mass, lower BMI, hypogonadism, low levels of insulin like growth factor-1 (IGF-1), relatively high cortisol levels, and alterations in levels of appetite regulating hormones that also have an impact on bone health, (such as insulin, leptin, peptide YY and oxytocin) (37,44).

Conditions of Malabsorption

Conditions such as celiac disease, inflammatory bowel disease, cystic fibrosis, and biliary atresia are associated with malabsorption of essential nutrients, including vitamin D, that are important for optimizing bone health.

Celiac disease is associated with low BMD (45) and an increase in fracture risk (46). One meta-analysis reported that a lifetime history of bone fractures was twice as common in those with celiac disease versus controls, and that a baseline history of celiac disease is associated with a 30% increase in any fracture and 69% increase in spine fracture (46). The impact of celiac disease on bone health is related to a decrease in BMI and lean mass (in those who have poor weight gain or a decrease in body weight following diagnosis), malabsorption with reduced bioavailability of calcium and vitamin D, secondary hyperparathyroidism, an increase in intestinal production of inflammatory cytokines (IL-1β, IL-6 and TNF-α), and because of antibodies that may bind to bone tissue transglutaminase (47,48). The institution of and adherence to a gluten free diet mitigates most of these factors.

Inflammatory bowel disease results in low bone mass in 30-50% of patients, who also demonstrate reduced rates of bone accrual during the adolescent years, resulting in compromised peak bone mass (49). Data for fractures are conflicting, with studies in children reporting modest to no increase in long bone fractures while studies in adults report a 32-40% increase in fracture risk (50-52); asymptomatic vertebral fractures are often missed in retrospective studies based on self-report. Some studies (but not all) report a higher risk of impaired bone health in children with Crohn’s disease (53,54) compared to those with ulcerative colitis, likely because the former more commonly affects areas of the intestine responsible for absorption of vital nutrients and is more likely to be associated with use of glucocorticoids, but data are conflicting in this regard (55-57). In general, children with Crohn’s disease are most likely to present with growth and puberty delay. There are also conflicting data regarding whether or not bone compromise is more likely in boys (vs. girls) with inflammatory bowel disease (55,57,58).

In addition to malabsorption of vital nutrients, factors that contribute to low bone density and impaired bone accrual in inflammatory bowel disease include low BMI and reduced lean mass, associated pubertal delay and hypogonadism, poor nutritional intake, reduced physical activity, active inflammation (cytokine secretion by activated T-cells, and increased IFN-γ and TNF-α, which may inhibit osteoblastic activity and active osteoclasts both directly and via RANK ligand), and chronic use of glucocorticoids, which have anti-inflammatory effects (which helps with the condition) but affect bone metabolism at multiple steps (52-55,59,60). In general, the severity of disease correlates with the extent of bone compromise.

Cystic fibrosis results in low bone density in 30-60% of individuals with the condition, associated with increased fracture risk in adults (61,62). A 100-fold increase in vertebral fractures and a 10-fold increase in rib fractures has been reported in adults with cystic fibrosis (61), and this can be problematic, as poor bone health can result in non-eligibility for a lung transplant in certain centers (63). Many factors contribute to low bone density including reduced BMI and lean mass when associated with low body weight, low levels of IGF-1, pubertal delay and hypogonadism, malabsorption of fat-soluble vitamins (including vitamins D and K), insufficient protein intake in diet, fecal calcium losses, secondary hyperparathyroidism, physical inactivity, increased secretion of inflammatory cytokines (IL-1β, IL-6 and TNF-α), chronic use of glucocorticoids, and direct effects of chloride channel defects (64-66).

Biliary atresia is also associated with malabsorption of fat-soluble vitamins, including vitamin D, and therefore, the condition can result in low bone density, which correlates with the severity of liver disease and jaundice (67,68).

CONDITIONS OF REDUCED MECHANICAL BONE LOADING (INCLUDING DISUSE OR IMMOBILIZATION

Mechanical loading leads to a reduction in sclerostin secretion from osteocytes, the mechanosensors of bone, and increased signaling along the canonical Wnt pathway with an increase in bone formation (69). There are data to suggest that an optimal nutritional status and estrogen levels are permissive for these effects of mechanical loading on bone (70). Meta-analyses have demonstrated beneficial effects of bone loading activity on bone in children, particularly in the pre- and early pubertal years (71,72). Therefore, conditions of reduced mechanical loading are associated with impaired bone accrual and low BMD. Similarly, the pull of muscle on bone is known to have bone anabolic effects. During periods of muscle disuse and prolonged immobilization, in addition to reduced osteoblastic activity (from increased production of sclerostin), there is an activation of osteoclastic bone resorption. Thus, conditions associated with hypotonia, spinal cord injury, spina bifida, muscular dystrophy, spinal muscular atrophy (SMA), and severe burns are associated with impaired bone accrual and low BMD in children and adolescents.

Patients with cerebral palsy (particularly those with limited ambulation) have low bone density and increased fracture risk associated with reduced mechanical loading of the skeleton, muscle wasting, suboptimal nutrition, and also vitamin D deficiency or impaired metabolism from concomitant use of certain anti-epileptic drugs (73-75). Studies have demonstrated that the severity of cerebral palsy predicts the severity of low BMD Z-scores in this condition (76,77).

Duchenne and other muscular dystrophies are associated with reduced muscle mass, muscle strength, and muscle function resulting in low bone density and increased fracture risk (75,78-82). Concomitant glucocorticoid therapy also impacts bone deleteriously, although amelioration of the underlying condition through glucocorticoid use may mitigate these effects to some extent (83). In one study, 53% of patients with Duchenne muscular dystrophy treated with deflazacort had vertebral fractures over a nine-year period (84). Another study has reported a 16-fold increased risk of fracture in patients taking daily deflazacort (85). Vamorolone, a dissociative steroidal anti-inflammatory drug, holds promise for use in this condition without significant bone effects (86). Studies have also reported impaired calcium metabolism and vitamin D status as well as high IL-6 levels in Duchenne muscular dystrophy, which could also contribute to impaired bone health (75,79,80,87). Similarly, spinal muscular atrophy (SMA) is associated with low bone density and increased fracture risk (88-91). Low bone density in patients recovering from burns (92) is consequent to immobilization, muscle wasting, increased release of inflammatory cytokines that active osteoclastic activity and increase bone turnover, and low 25OHD levels (93). In one study, 27% of children with severe burns had low bone density Z-scores (92).

ENDOCRINE CONDITIONS

Many hormones have a direct impact on osteoblast and osteoclast activity (Figure 1); thus, a disruption in these hormone systems can have deleterious effects on bone.

Figure 1.

Regulation of Bone Formation and Resorption. Osteoblasts are the primary bone-forming cells. Osteoblast anabolic activity is stimulated by testosterone and growth hormone and inhibited by cortisol and hyperglycemia. Osteoclasts mediate bone resorption. Thyroid hormone, parathyroid hormone, and inflammatory cytokines increase bone resorption, while estradiol inhibits osteoclast function. Osteocytes embedded within the bone matrix secrete sclerostin which inhibits osteoblast function; mechanical loading decreases sclerostin production thereby “releasing the brake” on osteoblast activity. Calcium deficiency, often as a result of vitamin D deficiency, leads to poorly mineralized bone matrix as well as secondary hyperparathyroidism.

Hypogonadism

Conditions of hypogonadism (Table 1) are associated with low bone density and impaired bone accrual given the critical role of the gonadal hormones on bone (70). Estradiol has anti-resorptive effects through its effects on the RANK-RANK-ligand-osteoprotegerin system. Estradiol also inhibits secretion of sclerostin, which otherwise inhibits the canonical Wnt signaling pathway and therefore osteoblast action, and also inhibits osteoclastic action (94). Testosterone has both direct bone anabolic and anti-resorptive effects, and also affects bone through its aromatization to estradiol. It increases periosteal bone apposition, while decreasing endosteal bone resorption, which collectively accounts for the larger size and thicker cortices of the male adult skeleton (70). During puberty, the rising levels of estradiol and testosterone are critical for adolescent bone accrual (95), and hypogonadism is therefore associated with reduced bone accrual, low bone density, and an increased risk of fracture (96,97).

Hypercortisolemia

Chronic administration of glucocorticoids for underlying inflammatory or other conditions (such as inflammatory bowel disorders, chronic arthritis, Duchenne muscular dystrophy, renal conditions including post-transplant patients, and connective tissue disorders), and endogenous hypersecretion of cortisol (ACTH dependent or independent) can cause low bone density and increase the risk for fracture (98). Excessive exposure to glucocorticoids has multiple deleterious effects on bone. It inhibits osteoblastic activity (through direct effect on osteoblast precursors and stimulation of apoptosis of mature osteoblasts and osteocytes), reduces mechanosensing ability through its osteotoxic effects, increases osteoclast activity by decreasing osteoprotegerin and increasing RANK-ligand secretion from osteoblasts, impairs calcium absorption from the gut, impairs the renal handling of calcium, has an inhibitory effect on the growth hormone (GH)-IGF-1 axis, and leads to reduced muscle mass, impaired collagen formation, and suppression of the HPG axis (98,99).

Importantly, hypercortisolemia is associated with increased fracture risk (particularly of the spine) independent of low BMD, related to the dose and duration of therapy (99). Low bone density can become evident within 3-6 months of therapy and improves in the first year after stopping glucocorticoids (particularly after the first six months). One study in children receiving glucocorticoids for three years for rheumatic disease reported an unadjusted vertebral fracture incidence rate of 4.4 per 100 person-years, and a 3-year incidence proportion of 12.4% (100). The highest annual incidence was in the first year, and every 0.5 mg/kg increase in glucocorticoid dose was associated with a doubling of fracture risk. Of concern, 50% of the fractures were asymptomatic and would have been missed without a lateral spine x-ray (100). Importantly, recovery of vertebral shape and height appears possible in children affected in the pre- or early pubertal years and is unlikely in those who are mid to late pubertal (99,101).

Chronic, Untreated Hyperthyroidism

Chronically high thyroid hormone levels, including at initial diagnosis of Graves’ disease, can lead to increased bone resorption and low BMD, particularly at cortical sites (102-104). An increase in IL-6 levels has been associated with this condition and contributes to increased bone resorption (105). Subclinical hyperthyroidism, as seen in survivors of pediatric differentiated thyroid carcinoma receiving levothyroxine at doses that suppress TSH (but with thyroid hormones levels still in the normal range), does not appear to have major negative effects on bone (106), indicating that high levels of thyroid hormones, but not suppressed TSH, account for the deleterious effects on bone in patients with hyperthyroidism.

Hyperparathyroidism

Primary hyperparathyroidism is rare in children and adolescents (and mostly associated with conditions such as MEN1 and MEN2), but secondary hyperparathyroidism occurs in conditions of hypocalcemia and vitamin D deficiency, and both secondary and tertiary hyperparathyroidism may be associated with chronic renal disease. The latter is discussed in a later section of this chapter. Chronic hyperparathyroidism causes increased bone resorption and results in low BMD, and the forearms (and primarily cortical sites) are involved to a greater extent that other parts of the body in this condition, with relative sparing of the spine (107).

Growth Hormone Deficiency and Resistance

Both GH and IGF-1 have multiple effects on bone. GH increases levels of osteoprotegerin, stabilizes the canonical Wnt signaling pathway, increases muscle mass and bone growth, while also stimulating local and hepatic IGF-1 secretion. The latter also stabilizes the canonical Wnt signaling pathway to activate osteoblasts, stimulate bone growth and an increase in muscle mass, increases 1-α hydroxylase activity, thus increasing intestinal absorption of calcium and phosphorus, increases tubular reabsorption of phosphorus, and increases RANK ligand activity. Thus, conditions of GH deficiency and resistance are at risk for low BMD. Adults with GH deficiency in the KIMS database had a 2.7 times higher fracture risk than the general population (108), and other studies have also reported an increased fracture risk in this population (109). However, a higher risk of fractures has not been observed in children with GH deficiency who received GH replacement therapy (110). Further, areal BMD in children with GH deficiency is often no longer low after adjusting for body size (111). Quantitative computed tomography studies have reported normal volumetric BMD, lower cortical thickness, and no differences for trabecular structure in children with GH deficiency vs. controls (112). In conditions of undernutrition, an acquired state of GH resistance and low levels of IGF-1 contribute to low rates of bone accrual and low BMD (113).

Poorly Controlled Diabetes

While studies are still in the process of examining the effects of diabetes on bone in children, data seem quite clear that poorly controlled diabetes is associated with low BMD (114-117). This has been linked to low IGF-1 levels secondary to hypoinsulinemia resulting from poor diabetes control, increased markers of oxidative stress, and increased secretion of inflammatory cytokines (118).

CHRONIC MEDICAL CONDITIONS

Chronic inflammatory states such as inflammatory bowel disorders, connective tissue disorders, chronic arthritis and other inflammatory states are associated with low BMD for multiple reasons, including increased release of proinflammatory cytokines, which activate osteoclastic activity, chronic use of glucocorticoids and possibly some degree of undernutrition. Many of these conditions have been covered in previous sections.

Systemic Mastocytosis

Systemic mastocytosis is associated with low bone density in adults (119,120), and BMD in these patients correlates with tryptase levels, mast cell proportion in bone marrow biopsies, and duration since diagnosis (119). Data are lacking in children.

Leukemia and Other Malignancies

Infiltrative conditions such as leukemia and other malignancies is associated with low bone density. Low bone density in patients with malignancy is a consequence of poor nutrition, malabsorption and diarrhea, vitamin D deficiency and associated hyperparathyroidism, release of inflammatory cytokines, chronic use of glucocorticoids, the effects of chemotherapy (gonadal failure, a direct suppressive effect of alkylating agents on bone marrow, and bone toxicity of high-dose methotrexate), as well as a direct effect of radiation therapy on osteoblasts. Pediatric acute lymphoblastic leukemia (ALL) is a known cause of low bone density and osteoporotic fractures (121-123). One study reported a cumulative fracture incidence of 32.5% for vertebral fractures and 23% for non-vertebral fractures in children with ALL over a six-year period, with 39% of children with vertebral fractures being asymptomatic (123). Vertebral reshaping occurred in younger children, but persistent vertebral deformity was noted in about 25%, particularly in older children and those with more severe vertebral collapse.

Beta-Thalassemia and Sickle Cell Disease

A large proportion of children with beta-thalassemia are reported to have low bone mass or bone density with reduced bone accrual compared to controls, regardless of transfusion and chelation regimens (124-126). One study reported BMC Z-scores of ≤ -2 in 61% of adolescents with beta-thalassemia (124). Another study reported that 82% and 52% of children and adolescents with transfusion dependent beta-thalassemia had low BMD Z-scores at the spine and the hip, respectively (125). Other studies, however, have reported much lower rates of low BMD in these children. Overall, nutritional status is a major determinant of bone outcomes in this condition. Similarly, sickle cell disease in children and young adults has been associated with low bone density (127,128), even after height adjustment (129), related to puberty, hip osteonecrosis, chronic pain, and hemoglobin values (129). Many of these children also have low calcium intake and low serum concentrations of 25OHD (127). Other predictors of low BMD include a low BMI, male sex, delayed puberty, and low serum zinc concentrations (128,130).

Chronic Kidney Disease

Chronic kidney disease is a major risk factor for low BMD and fractures because of the associated secondary or tertiary hyperparathyroidism, hyperphosphatemia, reduced mineralization (reduced 1-α hydroxylase), increased cytokines such as TNF-α, and chronic use of glucocorticoids (131-133).

IATROGENIC CAUSES

Certain medications can also contribute to low bone density in children and adolescents. Antiepileptic medications such as phenytoin, primidone, phenobarbital, and carbamazepine impair vitamin D metabolism by stimulating hepatic microsomal cytochrome P450 enzymes, causing vitamin D deficiency, secondary hyperparathyroidism, and low BMD (134). Data also suggest that antiepileptic drugs may inhibit the cellular response to parathyroid hormone (PTH). Further, use of valproic acid has been associated with increased osteoclast activity and low BMD in some studies. In contrast, newer antiepileptic medications such as lamotrigine and topiramate have not been associated with impaired vitamin D metabolism or low bone density.

As already discussed, chronic glucocorticoid use has several deleterious effects on calcium absorption, retention, and osteoblast and osteoclast function. Methotrexate and certain antiviral drugs have also been demonstrated to contribute to impaired bone health. Further, medications that suppress the hypothalamic-pituitary-gonadal axis such as GnRH analogs and depo medroxyprogesterone acetate are associated with low BMD. Lastly, radiation therapy is known to have direct deleterious effects on osteoblasts.

LIFESTYLE FACTORS

Cigarette smoking is believed to be a risk factor for low bone density (135), although it is difficult to sort out the effects of smoking on bone versus the contribution of risk factors common among smokers, which include a low BMI, greater intake of alcohol, lower levels of physical activity, and poor diet. The longer the duration of smoking and the greater the number of cigarettes consumed, the greater the risk of fracture. Further, healing following a fracture is slower in smokers than non-smokers, and complications during the healing process are more common in smokers. Even exposure to secondhand smoke has been related to suboptimal bone outcomes. Women who smoke often produce less estrogen and tend to enter menopause earlier, which would also contribute to increased bone loss. Further, levels of cortisol and free radicals are higher in smokers, which may also contribute, and nicotine and free radicals are toxic to osteoblasts. Importantly, quitting smoking does reduce the risk of low bone density and fractures. However, it may take several years to lower a former smoker’s risk.

Additionally, alcohol is deleterious to bone when consumed in excess (136); more than two alcoholic drinks per day are associated with low bone density, and may be related to decreased absorption of calcium, increased concentrations of cortisol and PTH, lower levels of estrogen, and alcoholper se is toxic to osteoblasts. Reduced bone density and impaired bone quality contribute to increased fracture risk (137).

Table 1.

Causes of Low Bone Density or Osteoporosis

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PRIMARY CAUSES OF LOW BONE DENSITY OR OSTEOPOROSIS

Osteogenesis imperfecta (COL1A1, COL1A2, IFITMF5, SERPINF1, CRTAP, LEPRE1 and other genes) Marfan syndrome (FBN1) Ehlers Danlos syndrome (COL5A, COL3A, non-monogenic forms) Homocystinuria (CBS, MTHFR, MTR, MTRR, and MMADHC genes) Lysinuric protein intolerance (SLC7A7) Osteoporosis pseudoglioma syndrome (LRP5) Idiopathic juvenile osteoporosis Hypophosphatasia (ALPL) Others

Other Primary Conditions Associated with Fragility Fractures but Without Low Bone Density Polyostotic fibrous dysplasia (GNAS1) Osteopetrosis (LRP5, CLCN6, CA2, others) Pycnodysostosis (CTSK)

SECONDARY CAUSES OF LOW BONE DENSITY OR OSTEOPOROSIS

Nutritional and Malabsorptive Conditions • Deficient intake of calcium and vitamin D • Conditions of low energy availability or energy deficit (e.g., anorexia nervosa, Female Athlete Triad/Relative Energy Deficiency in Sports (RED-S)) • Conditions of malabsorption (e.g., celiac disease, inflammatory bowel disease, cystic fibrosis, biliary atresia)

Conditions of Reduced Mechanical Bone Loading (Including Disuse or Immobilization) • Cerebral palsy • Spinal cord injury • Spina bifida • Muscular dystrophy • Spinal muscular atrophy • Severe burns • Conditions of prolonged immobilization

Endocrine Conditions • Hypergonadotropic hypogonadism: O Primary ovarian insufficiency O Primary testicular insufficiency • Hypogonadotropic hypogonadism: O Isolated or combined pituitary hormone deficiencies (genetic and acquired causes) O Hyperprolactinemia O Functional hypothalamic amenorrhea (conditions of energy deficit, chronic stress) O Medications (e.g., depot medroxyprogesterone acetate, GnRH analog therapy) • Hypercortisolemia: O Iatrogenic from prolonged use of glucocorticoids for underlying chronic conditions* O Endogenous: adrenal, pituitary and ectopic tumors • Hyperthyroidism (chronic untreated) • Hyperparathyroidism • Growth hormone deficiency and resistance • Diabetes (particularly when poorly controlled)

Chronic Medical Conditions • Chronic inflammatory states** • Mastocytosis • Infiltrative conditions (e.g., leukemia and other malignancies) • Thalassemia and sickle cell disease • Chronic kidney disease

Iatrogenic • Antiepileptic medications • Glucocorticoids • Methotrexate • Antiretroviral drugs • Depot medroxyprogesterone acetate • GnRH analogs • Radiation therapy

Lifestyle factors smoking and chronic alcohol use

*

Examples: Duchenne muscular dystrophy, inflammatory bowel disorders, chronic arthritis, renal conditions including post-transplant patients, connective tissue disorders, leukemia and other malignancies

**

Examples: Inflammatory bowel disease, chronic arthritis, connective tissue disorders, nephrotic syndrome

EVALUATION

TREATMENT

CONCLUSIONS

Childhood osteoporosis has several potential underlying etiologies, requiring a careful assessment by clinicians with expertise in the numerous mechanisms which can contribute to skeletal fragility. Both non-pharmacologic therapies as well as bone-active medications such as bisphosphonates increase bone mass and may lower the risk of fracture. The development of novel therapies that can restore physiologic anabolic bone activity in children with insufficient bone accrual of various causes has the potential to improve care for pediatric patients with osteoporosis. Prospective data acquisition to inform treatment strategies for primary prevention of fracture in children with osteoporosis, as is done in adult populations, is urgently needed to prevent the significant morbidity of fracture in this vulnerable population.

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