AUTHOR INFORMATION

Section 1 of 11

Authored by Gordon L Klein, MD, MPH, Professor, Departments of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Texas Medical Branch

Gordon L Klein, MD, MPH, is a member of the following medical societies: American Academy of Pediatrics, American Gastroenterological Association, American Pediatric Society, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, American Society for Nutritional Sciences, North American Society for Pediatric Gastroenterology and Nutrition, Sigma Xi, and Society for Pediatric Research

Edited by Steven M Schwarz, MD, FAAP, FACN, Chair, Department of Pediatrics, Long Island College Hospital; Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Jatinder Bhatia, MD, Professor of Pediatrics, Chief, Section of Neonatology, Vice Chairman for Clinical Research, Department of Pediatrics, Medical College of Georgia; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and Jatinder Bhatia, MD, Professor of Pediatrics, Chief, Section of Neonatology, Vice Chairman for Clinical Research, Department of Pediatrics, Medical College of Georgia

Author's Email:	Gordon L Klein, MD, MPH
Editor's Email:	Steven M Schwarz, MD, FAAP, FACN

eMedicine Journal, May 4 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

Background: The World Health Organization (WHO) defines osteoporosis as a bone density (or bone mass) that is at least 2.5 standard deviations below peak bone mass (defined as the bone mass achieved by healthy adults aged 18-30 years). Standard deviation from the mean peak bone mass is termed the T score. Thus, a T score of the lumbar spine or hip at least 2.5 standard deviations below the norm defines a condition of osteoporosis.

Although functionally valid for adults, this definition creates difficulty when evaluating pediatric patients. Children have not attained peak bone mass, and sufficient data correlating bone density with fractures are not available. Although preliminary studies have examined the role of lumbar spine bone density and the risk of fracturing in children with burn injuries, more extensive population-based studies have not been conducted. Therefore, the official definition of osteoporosis does not pertain to children at the present time. However, at an NIH Consensus Conference in 2000, osteoporosis was defined as a skeletal disorder characterized by compromised bone strength that predisposes to an increased risk of fracture. Adult-onset osteoporosis also involves loss of bone trabecular structure; however, no evidence indicates that this occurs in children. Therefore, children exhibiting low bone mass are defined as osteopenic, not osteoporotic. With the rapid advances in technology for quantitation of bone mass, the definitions of osteoporosis, osteopenia, and even osteomalacia may have to be revised in the future.

Pathophysiology: Low bone density in children involves the net loss of bone. Bone density is currently a 2-dimensional measurement. It is the quotient of the bone mineral content (BMC) measured in grams by absorptiometry in a specified bone region (eg, hip, lumbar spine), divided by the bone area (BA) in cm² to give a reading in g/cm². This 2-dimensional method of assessing bone density is limited because changes in bone volume, and therefore bone strength, cannot be detected. This leads to an inaccurate estimation of the severity of bone loss or the skeletal response to treatment. Pathways to decreased bone density all lead to an imbalance between the rate of bone formation and the rate of bone resorption. Thus, low-turnover conditions, such as hypoparathyroidism, burn injuries, or conditions that affect bone marrow (eg, malignancies) or their treatments, may result in a reduction of bone formation.

Other high-turnover states, such as Paget disease or hyperparathyroidism, can result in an increase in bone resorption. Interestingly, almost all preterm infants fall into this group. Since the majority of calcium is transmitted from mother to fetus during the third trimester, infants born prematurely do not receive all the calcium their body needs to mineralize normally. With rapid postnatal increase in bone turnover, there are fewer opportunities for the bones to mineralize, as recently shown by Naylor et al. Furthermore, the majority of these children receive total parenteral nutrition (TPN) for at least the first 3 weeks of life. TPN solutions are contaminated with aluminum; therefore, these infants remain at risk for bone aluminum accumulation and consequent decreased mineralization. In addition, calcium and phosphorus requirements cannot be met by TPN, and the infant, especially the very premature infant, presents with hypophosphatemic metabolic bone disease.

Frequency:

• In the US: Data indicating the frequency of osteopenia in children are inadequate. The rare condition of idiopathic juvenile osteoporosis has been reported in 60 cases through 1991. By contrast, vertebral fracture prevalence attributed to osteoporosis in elderly women in the United States and Western Europe may be as high as 25%. As many as 54% of American postmenopausal women are estimated to have osteopenia as defined by a T score of 1.0 and 2.5, and an additional 30% are estimated to be osteoporotic.

• Internationally: The prevalence of osteoporosis worldwide (outside the United States and western Europe) is variable. For example, the incidence of hip fracture in Koreans has increased from 3.3 per 10,000 to 13.3 per 10,000 between 1991 and 2001. In a 2005 study in Tehran, women aged 60-69 years had a 32.4% prevalence of spinal osteoporosis and a 5.9% prevalence of femoral osteoporosis, in contrast to a prevalence in similarly aged men of 9.4% and 3.1%, respectively. In Taiwan, the prevalence was 11.35% for women and 1.35% for men older than 50 years, based on bone density determinations.

Mortality/Morbidity:

• Contributing factors to mortality and morbidity, especially in the elderly, primarily are related to trauma. These factors include falls with resultant hip fractures necessitating immobilization.

• In extreme cases, including idiopathic juvenile osteoporosis and osteopenia in immobile children with severe developmental delay, crippling bony deformities may lead to cardiopulmonary compromise.

Race:

• Caucasians are at the greatest risk for fractures, while blacks and Asians appear to be at the lowest risk.

Sex:

• Osteoporosis mainly affects postmenopausal women and the elderly of both sexes. The protective effects of estrogens on bone are well known. During menopause, women lose their estrogen-producing capacity and develop a greater risk for significant osteoporosis.

Age:

• Classic osteoporosis is a disease of adulthood.

• Children present with many forms of osteopenia from a variety of causes. The roots of adult disease are believed to begin in childhood, but this concept is being challenged by the argument that osteoporotic bone from whatever origin is replaced by newer intact bone as bone grows.

CLINICAL

Section 3 of 11

History:

• Patients with osteopenia or osteoporosis may be asymptomatic or may present with severe bone pain.



• In the elderly, severe back pain and limitation of motion may signify a vertebral compression fracture, though patients may be asymptomatic as well. Pain often is worse when standing and is relieved by walking. Loss of height is observed following vertebral fracture.



• In the peripubertal child with idiopathic juvenile osteoporosis, a gradual onset of pain occurs, primarily in the lower body (eg, hips, ankles, knees, feet), manifested by discomfort when walking.

Physical:

• Children may present with spinal deformities (eg, kyphosis, kyphoscoliosis).



• Pigeon breast deformity, a crown-pubis/pubis-heel ratio less than 1, short stature, long bone deformities, and limping are other findings that may be observed.



• In adults, loss of height and progressive kyphosis are the most prominent findings with thoracic vertebral compression fractures; lordosis or scoliosis are observed with lumbar-vertebral compression fractures.



• Hip fractures often are observed following falls, especially in individuals who are elderly; women are more likely than men to fall on their hips.

Causes:

• The most likely risk factor for idiopathic juvenile osteoporosis is genetic. Genetic factors also may play a role in some of the secondary causes of osteopenia (eg, inflammatory bowel disease, rheumatoid arthritis).



• Children present with many forms of osteopenia from a variety of causes. The roots of adult disease are believed to begin in childhood. While a genetic determinant of peak bone mass is likely, there is a significant relationship between the amount of calcium intake and peak bone mass in preadolescent and young adolescent girls. From the work of Slemenda, the National Institutes of Health Consensus Conference on Osteoporosis recommends that preadolescent and young adolescent girls have a calcium intake that is 50% more than the intake recommended for younger children and older adults. Dietary calcium intake in the preadolescent years may be a key factor in the development of peak bone mass. However, when dietary calcium supplementation is stopped, the increase in bone mass is not maintained.



• Trauma is a risk factor for osteopenia following burn injury; the osteopenia is complicated by immobilization and high endogenous glucocorticoid production that rapidly accelerate bone loss.



• Medications, such as corticosteroids, cyclosporin, and other cytotoxic agents, may contribute to osteopenia secondary to other conditions. Chronic long-term steroid use contributes to osteopenia.

DIFFERENTIALS

Section 4 of 11

Other Problems to be Considered:

In children, osteopenic conditions can develop because of low bone formation (low bone turnover) or high bone resorption (high bone turnover).

The following conditions elicit low bone formation:

• Medication-induced osteopenia (prominently corticosteroids and cyclosporin)
  
  
• Immobilization or prolonged bed rest
  
  
• Burn injury
  
  
• Hypoparathyroidism that results in hypercalciuria
  
  
• Hepatic osteodystrophy with chronic cholestasis (all causative syndromes and conditions)
  
  
• Aluminum toxicity in association with TPN or renal osteodystrophy
  
  
• Prolonged TPN
  
  
• Corticosteroid-induced osteopenia

• Corticosteroid-induced osteopenia
  
  
• Immobilization or bed rest
  
  
• Paget disease
  
  
• Primary and secondary hyperparathyroidism
  
  
• Rickets due to vitamin D deficiency or calcium deficiency
  
  
• Idiopathic juvenile osteoporosis
  

WORKUP

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Lab Studies:

• Serum calcium, phosphorus, magnesium, creatinine levels


• • High serum calcium levels and normal or low phosphorus levels suggest hyperparathyroidism.
  
  
  
  • Low serum calcium levels and high or normal phosphorus levels suggest hypoparathyroidism.
  
  
  
  • Creatinine levels provide an indication of renal disease.
  
  
  
  • Magnesium levels provide an index of total body magnesium status.
  
  
  
• Serum parathyroid hormone (PTH) levels



• High PTH levels confirm hyperparathyroidism.



• Low PTH levels confirm hypoparathyroidism.



• Serum or urinary cross-links of type I collagen (deoxypyridinoline), N-telopeptide of type I collagen (NTx) or C-telopeptide of type I collagen (CTx), urine creatinine


• • Deoxypyridinoline, an index of bone resorption, is high in the urine of children who have rapid bone turnover.
  
  
  
  • Obtain biochemical markers of bone resorption (NTx) and formation (osteocalcin) to clarify the nature of what is occurring in the bone.
  
  
  
• Serum osteocalcin or bone-specific alkaline phosphatase: Values may vary between assays. No expected results exist. Osteopenia can develop from either high-turnover or low-turnover conditions. These tests help define which condition may be active.


• • Pediatric reference ranges for osteocalcin
    ( <12 y: 10-25 ng/mL; >13 y: 2-8 ng/mL)
  
  
  
  • Pediatric reference ranges for bone specific alkaline phosphatase
    (preadolescents: 50-150 IU/L; adolescents: 10-50 IU/L)
  
  
  

Imaging Studies:

• Dual energy x-ray absorptiometry scan


• • The amount of calcium in bone can be quantified in several ways. Bone densitometry based on dual energy x-ray absorptiometry (DEXA) is the most widely used method. DEXA provides 2-dimensional imaging of a region of bone, such as the lumbar spine, hip, or radius.
  
  
  
  • DEXA provides a computerized printout of bone calcium content, measured in grams; the bone area, measured in cm²; and the 2-dimensional bone density, measured in g/cm².
  
  
  
  • Pediatric reference ranges are taken from large studies using DEXA and are incorporated into the software that provides the printout, so that actual individual bone density and its comparison to age-related normal values (Z score) is printed out as part of the report. The main drawback is that DEXA does not measure changes in bone volume and, therefore, in bone strength.
  
  
  
• Investigational methods


• • Other methods being investigated include the calcaneal and phalangeal ultrasound and quantitative computerized tomography (qCT), which involves the most radiation of any of the tests. Reference range values for phalangeal ultrasound results have just been published online.
  
  
  
  • Peripheral quantitative computerized tomography (pqCT), which usually involves a foot or a lower limb and much less radiation than the qCT scan, also can provide an indirect assessment of bone density. However, DEXA is by far the most commonly used technique at the present time.
  
  
  

When processed, the amounts of mineralized bone, unmineralized bone, and bone surface can be quantitated. In addition, the tetracycline binds to newly calcified bone at the mineralization front, which is the boundary between mineralized bone and unmineralized matrix where new bone forms. Each time a dose of tetracycline is administered, it forms a band at the mineralization front that can be detected under a fluorescent microscope. The distance between the 2 fluorescent bands can be quantitated. When divided by the time interval between doses and multiplied by the length of bone surface taking up the tetracycline yields, the rate of new bone formation is achieved. The eroded or resorbed bone surface also can be quantitated, and all can be compared to reference values for age.

Perform these studies if analysis of bone markers and other biochemical determinations are inconclusive regarding the nature of the activity of the bone in a particular condition. These studies also form the basis for validating the biochemical bone marker analyses.

TREATMENT

Section 6 of 11

Medical Care:

• Management is primarily medical depending on the underlying condition. If the underlying condition is optimally managed and osteopenia persists, then management depends on bone dynamics.



• When bone resorption exceeds bone formation, try an antiresorptive agent (eg, bisphosphonate). The most current generation of oral bisphosphonates includes alendronate and risedronate. The primary parenterally administered bisphosphonate is pamidronate. Safe and effective pediatric doses have not been established; however, current clinical trials are investigating the use of alendronate in children with osteogenesis imperfecta, and preliminary results indicate that the drug is safe.



• Pamidronate is currently under study in children with burn injuries. The dose of pamidronate is 1.5 mg/kg weekly for 2 weeks with a maximum dose at any one time of 90 mg, which is the adult upper limit of normal. Hopefully, in the near future, more ambitious studies using bisphosphonates in children will be performed, and the value of these drugs in therapy of high-turnover bone loss will be fully appreciated. Data obtained from clinical studies in adults are very promising. However, caution in the overuse of these drugs is warranted because the drugs remain in bone for a long time and an osteopetrosislike condition has been reported.



• Osteopenia secondary to low bone formation is more difficult to manage because of the absence of a safe and effective anabolic agent. Parathyroid hormone, which is potentially very promising when given intermittently to osteoporotic adults, is not approved for use in children because of the detection of osteogenic sarcoma in rats that were given very high test doses.



• Recombinant human growth hormone is a useful anabolic agent for children with growth hormone deficiency; its benefits for others with osteopenia have not been extensively studied. It does improve bone mineral content in burned children if given for a year, but the need for repeated injections and the cost are limiting.



• Anabolic steroids (eg, testosterone, oxandrolone) may be of help in forming new bone; however, consider the risks of premature closure of the epiphyses, short stature, and hirsutism. Also consider the potentially increased risk for tumor development. However, in a 2004 study, oxandrolone was given for 1 year to a group of children following burn injury. No epiphyseal closure was demonstrated, and only 2 cases of clitoral hypertrophy were observed (both were reversed after cessation of the drug).

Surgical Care:

• Unless a resectable tumor can be identified as the cause of osteopenia or osteoporosis, surgery is unlikely to play a role in treatment. In most cases, the cause is systemic and results in widespread disease.

Consultations:

• Consult an endocrinologist to assist in the management of any patient with bone loss.

Diet:

• Calcium and vitamin D are the most important dietary nutrients to help prevent adult osteoporosis. The National Institutes of Health Consensus Conference on Osteoporosis recommended a calcium intake of 800 mg/d until age 10 years, 1200 mg/d during adolescence, and 1000 mg/d after adolescence. Calcium intake should be increased for women who are pregnant, for women who are lactating (1200 mg/d), and for individuals older than 65 years (1500 mg/d). An intake of 400-800 international U/d is also recommended.

Activity:

• Activity plays a role in the prevention of osteoporotic fractures. Several recent studies both in the United States and in Europe have established that regular weight-bearing exercise, such as jumping, in school-age children improves bone mass. However, once the exercises are stopped, the gains are lost.

MEDICATION

Section 7 of 11

Therapy includes antiresorptive agents such as bisphosphonates (eg, alendronate, risedronate, pamidronate). Hormone replacement therapy (eg, estrogen, estrogen analogs) does not have a role in pediatric therapy.

Drug Category: Bisphosphonate bone-resorption inhibitors -- Prevents bone loss from diminishing bone mass on an ongoing basis. Available in parenteral and oral dosage forms for acute and chronic treatment respectively.

Drug Name	Pamidronate (Aredia) -- Inhibits normal and abnormal bone resorption. Appears to inhibit bone resorption without inhibiting bone formation and mineralization. Administered intravenously, usually 2 doses with a 1-wk interval. Approved for use in hypercalcemia of malignancy and Paget disease. Also has been used in children suffering from osteopenic bone disease.
Adult Dose	60-90 mg/dose IV administered over 8-24 h; dilute in dextrose and water solutions Dose based on serum calcium measurements
Pediatric Dose	Not established; experimental studies use 1.5 mg/kg/dose IV; not to exceed 90 mg/dose (published results are promising)
Contraindications	Documented hypersensitivity; hypocalcemia, cardiac failure, and renal impairment
Interactions	Calcium or vitamin D may antagonize the antihypercalcemic effects of the drug
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Carcinogenicity and mutagenicity are not observed; decreased fertility and increased mortality observed in rats when administered PO; no known effects on breastfeeding Monitor hypercalcemia-related parameters, such as serum levels of calcium, phosphate, magnesium, and potassium once treatment begins; adequate intake of calcium and vitamin D is necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in patients with active upper GI problems

Drug Name	Alendronate (Fosamax) -- An oral bisphosphonate approved as an antiresorptive agent to treat Paget disease and postmenopausal osteoporosis.
Adult Dose	Paget disease: 40 mg PO qam 30 min before first food or beverage; continue treatment for 6 mo Postmenopausal osteoporosis treatment: 10 mg PO qam 30 min before first food or beverage; alternatively, 70 mg PO qwk Administer dose with 6-8 oz of plain water
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; limited data in small open-labeled studies have been published
Interactions	Dietary supplements, food, and medicines may interfere with absorption; medications (eg, antacids) interfere with absorption; histamine receptor antagonists (eg, ranitidine, cimetidine) can interfere with absorption; nonsteroidal anti-inflammatory agents can exacerbate inflammatory effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	GI conditions (eg, duodenitis, gastritis, gastroesophageal reflux disease, ulcers) may worsen; renal functional impairment may reduce excretion of the drug; tumors increased in rats with larger than recommended doses for 2 y; mutagenicity has not been observed; no effect on fertility; effects on pregnancy and reproduction not known; hypocalcemia can occur in pregnancy following exposure; unknown whether alendronate enters human breast milk

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Generally, individuals suffering from osteoporosis or osteopenia do not require hospitalization unless they have a complication such as a hip fracture. This is a very uncommon occurrence in children; however, following a fracture, anticipatory intervention is needed to minimize future hospital stays and to identify individuals at risk for repeated fractures.

Further Outpatient Care:

• The aim of further outpatient care is to closely monitor bone density to determine if ongoing bone loss occurs or if the process has reached a plateau. In these situations, measurements of biochemical markers of bone formation and resorption can help guide therapy choices and duration.

In/Out Patient Meds:

• Currently, antiresorptives are the only consistently reliable medications.

Transfer:

• Transferring a patient is not necessary unless pediatric subspecialty care is unavailable at the institution.

Deterrence/Prevention:

• Prevention includes patient education and early recognition of the symptoms and signs of hypercalcemia and hypercalciuria.

Complications:

• The main complication is fractures, including a nondisplaced fracture in the vertebral column.

Prognosis:

• Prognosis depends on the underlying cause.



• A genetic condition leading to increased bone resorption may have a satisfactory prognosis if the antiresorptive agents can eliminate further bone loss.



• For postmenopausal or senile osteoporosis in which bone formation is reduced, prognosis is improved because of the advent of parathyroid hormone administration to adults for 1 year followed by a bisphosphonate for 1 year. This results in bone gain.



• In the case of trauma- or burn-induced osteopenia in which bone formation is primarily affected, prognosis depends on the patient's genetically determined peak bone mass and efficacy of clinically experimental therapies, such as anabolic steroids and pamidronate along with correction of progressive vitamin D deficiency that is a consequence of the skin’s failure to make adequate vitamin D with ultraviolet light exposure, similar to what is seen elderly persons.

Patient Education:

• Use education as a means of prevention and treatment. Instruct children, adolescents, and their families that the roots of adult-onset osteoporosis begin in childhood; therefore, ensure adequate calcium intake and weight-bearing exercises to maximize genetically determined peak bone mass.



• As early as possible, inform patients of any age with osteopenia or osteoporosis why bone loss has occurred and how to keep bone loss under control. Also inform patients with osteopenia or osteoporosis of the consequences of bone loss.



• For excellent patient education resources, visit eMedicine's Bone Health Center. Also, see eMedicine's patient education articles Osteoporosis and Understanding Osteoporosis Medications.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Bone demineralization on x-ray does not always indicate osteoporosis. If a workup for osteopenia is not initiated, it is possible to miss many potentially severe and disabling causes of osteopenia, such as Paget disease or bone loss secondary to an underlying disease.

Special Concerns:

• Given the currently accepted WHO definition of osteoporosis, children appear to be an exception to the disease and, by present definition, do not develop this condition, even secondary to another chronic illness. However, given the more recent NIH definition of osteoporosis, the pediatrician may interpret this condition with sufficient latitude as to increase awareness of bone-weakening diseases and medications.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following complicates the diagnosis of osteoporosis in the pediatric patient?

A: Lack of dual energy x-ray absorptiometry to measure bone density in small patients
B: Lack of standard bone mass measurement data
C: Inability of dual energy x-ray absorptiometry to measure changes in bone volume
D: Inability to perform quantitative histomorphometry on pediatric bone biopsies
E: Insufficient data to define the relationship between bone density and fracture incidence in pediatric patients

The correct answer is E: The World Health Organization has data for adults and can define the disease in that context; however, data have not been adequately collected in pediatric patients.

CME Question 2: Which of the following is the chief cause of osteopenia in pediatric patients?

A: Genetic causes
B: Adverse effects of medications (eg, corticosteroids)
C: Inability to synthesize estrogens
D: Imbalance between bone formation and bone resorption (favoring resorption)
E: Imbalance between bone formation and bone resorption (favoring formation)

The correct answer is D: Only a predominance of bone resorption results in bone loss or osteopenia, regardless of etiology.

Pearl Question 1 (T/F): All of the following drugs can cause low bone density if administered chronically: corticosteroids, anticonvulsants, cyclosporin, methotrexate, and heparin.

The correct answer is True: All of these drugs can cause low bone density when administered chronically.

Pearl Question 2 (T/F): The most common presentation of a child with osteopenic bone disease is bone pain.

The correct answer is False: Chronic underlying disease is the most common presentation. While the majority of patients have no symptoms referable to the skeleton, there is no reason to suspect osteopenia unless chronic disease is present.

Pearl Question 3 (T/F): Bed rest can cause osteopenia.

The correct answer is True: Bed rest can reduce bone formation within 1 week in healthy young adult volunteers.

Pearl Question 4 (T/F): Juvenile osteopenia and adult-onset osteoporosis have the destruction of trabecular architecture in common.

The correct answer is False: Progressive destruction of trabecular architecture occurring in pediatric patients has not been reported.

BIBLIOGRAPHY

Section 11 of 11

• Baroncelli GI, Federico G, Vignolo M, et al: Cross-sectional reference data for phalangeal quantitative ultrasound from early childhood to young-adulthood according to gender, age, skeletal growth, and pubertal development. Bone 2006 Feb 10;[Medline].
• Cooper C: Epidemiology of osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2003; 5th ed: 307-13.
• Eyre D: Biochemical markers of bone turnover. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3rd ed. 1996: 114-119.
• Finkelstein JS, Hayes A, Hunzelman JL, et al: The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003 Sep 25; 349(13): 1216-26[Medline][Full Text].
• Fleming R, Patrick K: Osteoporosis prevention: pediatricians' knowledge, attitudes, and counseling practices. Prev Med 2002 Apr; 34(4): 411-21[Medline].
• Fleming R, Patrick K: Osteoporosis prevention: pediatricians' knowledge, attitudes, and counseling practices. Prev Med 2002 Apr; 34(4): 411-21[Medline].
• Greenspan SL, Luckey M: Evaluation of post-menopausal osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2003; 5th ed: 355-59.
• Hart DW, Herndon DN, Klein G, et al: Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001 Jun; 233(6): 827-34[Medline][Full Text].
• Johnston CC, Miller JZ, Slemenda CW: Calcium supplementation and increases in bone mineral density in children. N Engl J Med 1992 Jul 9; 327(2): 82-7[Medline].
• Khosla S, Kleerekoper M: Biochemical markers of bone turnover. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2003; 5th ed: 166-72.
• Klein GL, Herndon DN, Langman CB: Long-term reduction in bone mass after severe burn injury in children. J Pediatr 1995 Feb; 126(2): 252-6[Medline].
• Klein GL, Herndon DN, Goodman WG: Histomorphometric and biochemical characterization of bone following acute severe burns in children. Bone 1995 Nov; 17(5): 455-60[Medline].
• Klein GL, Nicolai M, Langman CB: Dysregulation of calcium homeostasis after severe burn injury in children: possible role of magnesium depletion. J Pediatr 1997 Aug; 131(2): 246-51[Medline].
• Klein GL, Fitzpatrick LA, Langman CB, et al: The state of pediatric bone: summary of the ASBMR pediatric bone initiative. J Bone Miner Res 2005 Dec; 20(12): 2075-81[Medline].
• Klein GL, Chen TC, Holick MF, et al: Synthesis of vitamin D in skin after burns. Lancet 2004 Jan 24; 363(9405): 291-2[Medline].
• Leonard MB, Shore RM: Radiological evaluation of bone mineral in children. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 2003; 5th ed: 173-88.
• MacKelvie KJ, Petit MA, Khan KM, et al: Bone mass and structure are enhanced following a 2-year randomized controlled trial of exercise in prepubertal boys. Bone 2004 Apr; 34(4): 755-64[Medline].
• National Institutes of Health: Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000 Mar 27-29; 17(1): 1-45[Medline].
• Naylor KE, Eastell R, Shattuck KE: Bone turnover in preterm infants. Pediatr Res 1999 Mar; 45(3): 363-6[Medline].
• Norman ME: Juvenile osteoporosis. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 3rd ed. 1996: 275-278.
• Whyte MP, Wenkert D, Clements KL, et al: Bisphosphonate-induced osteopetrosis. N Engl J Med 2003 Jul 31; 349(5): 457-63[Medline].

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