Osteoporosis

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.

While functionally valid for adults, this definition creates difficulty when evaluating pediatric subjects. 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. 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 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 US 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 US and western Europe) is not known. Preliminary data suggest that its prevalence is lower in Japan than in the US.

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.

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.

• Trauma is a risk factor for osteopenia following burn injury; the osteopenia is complicated by immobilization that rapidly accelerates 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
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:

• 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.

• Investigational methods

• Other methods being investigated include the calcaneal ultrasound and quantitative computerized tomography (qCT) scan. These involve the most radiation of any of the tests.

• 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.

• 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.

• 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 commercially available and has not been tested in children.

• Recombinant human growth hormone is a useful anabolic agent for children with growth hormone deficiency, but its benefits for others with osteopenia have not been demonstrated.

• 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.

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 probably plays a role in the prevention of osteoporotic fractures; however, data to prove this conclusively are inadequate at the present time.

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.

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 more guarded because reliable anabolic agents that stimulate bone formation do not exist.

• 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 untested therapies such as resistance exercise and anabolic steroids.

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.

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. Therefore, care must be taken when applying the term osteoporosis to children.

BIBLIOGRAPHY