Diagnosis of osteoporosis in children

Laboratory diagnostics of osteoporosis in children

The following research methods exist for biochemical assessment of bone mineral density:

• characteristics of phosphorus-calcium metabolism;
• determination of biochemical markers of bone remodeling.

When assessing biochemical parameters, routine research methods are mandatory - determination of the calcium content (ionized fraction) and phosphorus in the blood, daily excretion of calcium and phosphorus in the urine, as well as excretion of calcium in the urine on an empty stomach in relation to the concentration of creatinine in the same portion of urine.

A large number of studies devoted to osteoporosis in childhood prove that most often routine biochemical parameters of phosphorus-calcium metabolism are not changed or change insignificantly and briefly, even in cases of severe osteoporosis with a fracture.

Highly specific, sensitive methods for diagnosing osteoporosis include determining the level of parathyroid hormone, calcitonin, and active metabolites of vitamin D in the blood. These methods have strict indications for their use and have not yet become widespread in practical medicine. Parathyroid hormone is determined when hyperparathyroidism (primary or secondary) is suspected as the cause of osteoporosis; active metabolites of vitamin D are used to diagnose genetic osteomalacia and vitamin D-dependent rickets.

To determine the state of bone remodeling, highly sensitive biochemical markers of bone metabolism are studied in the blood and urine. In a pathological situation, they reflect the prevalence of impaired bone formation or bone resorption. Bone formation markers include total alkaline phosphatase (mainly its bone isoenzyme), propeptide of human collagen type I, osteocalcin. The latter indicator is considered the most informative. Bone resorption markers are tartrate-resistant acid phosphatase in the blood, oxyproline, collagen cross-links : pyridinoline and deoxypyridinoline in fasting urine; H-terminal telopeptide of urine. The most accurate and important markers of bone resorption are pyridinoline and deoxypyridinoline in urine.

Biochemical markers of bone remodeling

Bone formation activity indicators	Indicators of bone resorption activity
Alkaline phosphatase activity (blood): total alkaline phosphatase bone alkaline phosphatase	Oxyproline (urine)
	Collagen cross-links: pyridinoline (urine); deoxypyridinoline (urine)
Osteocalcin (blood)	H-terminal telopeptide (urine)
	Tartrate-resistant
Human collagen type I propeptide (blood)	Acid phosphatase (blood)

Determination of biochemical markers of bone metabolism is important not only for characterizing bone metabolism, but also for choosing a drug that increases bone mineral density, monitoring the effectiveness of therapy, and optimal prevention of osteoporosis.

Instrumental diagnostics of osteoporosis in children

The most accessible method of instrumental diagnostics of osteoporosis is a visual assessment of bone radiographs (in case of glucocorticoid osteoporosis - the bones of the spine).

Characteristic radiographic signs of decreased bone mineral density:

• increased “transparency”, change in trabecular pattern (disappearance of transverse trabeculae, coarse vertical trabecular striation);
• thinning and increased contrast of the endplates;
• decrease in the height of the vertebral bodies, their deformation according to the wedge-shaped or “fish-shaped” type (in severe forms of osteoporosis).

However, when analyzing X-ray images with the naked eye, it is almost impossible to quantitatively assess the mineral density of bone tissue. Bone demineralization can be detected by X-ray if the density decreases by at least 30%. X-ray studies are of great importance in assessing deformations and compression changes in the vertebrae.

More accurate are quantitative methods of assessing bone mass (densitometry, from the English word density ). Densitometry allows identifying bone loss at early stages with an accuracy of 2-5%. There are ultrasound, as well as X-ray and isotope methods (mono- and dual-energy densitometry, mono- and dual-photon absorptiometry, quantitative CT).

X-ray methods of bone densitometry are based on the transmission of X-rays from an external source through the bone to a detector. A narrow beam of X-rays is directed at the area of the bone being measured. The intensity of the beam passed through the bone is recorded by a detector system.

The main indicators that determine the mineral density of bone tissue:

• bone mineral content, expressed as grams of mineral in the area examined;
• bone mineral density, which is calculated based on the bone diameter and expressed in g/ ^cm2;
• Z-criterion expressed as a percentage of the age-sex norm and in standard deviation values from the average theoretical norm (SD, or sigma).

The first 2 criteria are absolute indicators of bone density of the examined area, the Z-criterion is a relative value. In children and adolescents, only this relative indicator of densitometry is used.

In adult patients, in addition to the Z-criterion, the T-criterion is calculated, which is expressed as a percentage of the peak bone mass in individuals of the corresponding sex and race at the age of 40 years (when the mineral composition of the bone is considered optimal), as well as in standard deviation values. This indicator is the main one for assessing the degree of bone demineralization according to the WHO criteria in adults.

Both criteria (Z- and T-) are expressed in numbers with signs (+) or (-). The value of sigma from -1 to -2.5 is interpreted as osteopenia, which requires mandatory preventive treatment and monitoring, since there is a real risk of fractures.

When bone density decreases to values exceeding the standard deviation by more than 2.5, the risk of fractures increases - the condition is interpreted as osteoporosis. In the presence of a fracture (fractures) and a change in the Z-criterion exceeding the standard deviation by more than 2.5 (for example, -2.6; -3.1, etc.), severe osteoporosis is diagnosed.

Diagnostic "instrumental" categories of bone mineral density reduction

T-score or T-criterion	Diagnosis	Risk of fractures
From +2.0 to -0.9	Normal BMD	Short
From -1.0 to -2.49	Osteopenia	Moderate
From -2.5 or less without fractures	Osteoporosis	High
From -2.5 or less with fractures	Severe osteoporosis	Very tall

All devices calculate Z- and T-criteria as percentages and standard deviation values from the standard sigma values.

According to more recent studies of BMD in children (2003), other densitometric criteria for assessing bone density were proposed. It is necessary to state “low bone density according to age” or “below expected values for the age group” if the Z-score is less than -2.0 SD (e.g. -2.1; -2.6 SD, etc.).

Monophoton and monoenergetic densitometers are convenient for screening studies, treatment control, but they can determine bone mineral density only in the peripheral parts of the skeleton (for example, in the radius). Using this method, it is impossible to assess bone mass in the proximal femur, vertebrae. The capabilities of two-photon and dual-energy bone densitometers are much wider.

Mono- and dual-energy (X-ray) densitometers have an advantage over photon ones, since they do not require replacement of the isotope source, have a high resolution, and have a lower radiation load.

Quantitative CT allows to determine and measure the cortical and spongy layers of bone, to represent the true bone density. The accuracy of the method is high, however, the radiation load significantly exceeds that of the above-described methods.

Ultrasound bone densitometry is based on measuring the speed of ultrasound wave propagation in bone. It is mainly used as a screening method.

Which bone area should a pediatrician select for the most informative densitometric examination? There are no strict recommendations. The choice of measurement area depends on a number of factors. Bone loss occurs in all areas of the skeleton, but unevenly. It is advisable to examine those bones that have a higher risk of fracture. X-ray densitometry is most often performed in the area of the proximal femurs and lumbar spine. This is due to the fact that bone loss is heterogeneous and there are differences between the 2 determination points, requiring 2 studies to be performed simultaneously.

Since glucocorticosteroid therapy has a greater effect on the BMD of the spine than of the femur or forearm, it is advisable to use dual-energy X-ray densitometry of the lumbar vertebrae for early diagnosis of osteoporosis and assessment of the effectiveness of its treatment. Despite its use in clinical practice, densitometry of the forearm bones is not considered a generally accepted method, the data of which are sufficient for a definitive diagnosis of osteoporosis.

Densitometry reveals the most reliable risk factor for fractures - reduced BMD. That is why its determination should be included in the list of instrumental studies when osteoporosis is suspected, and it is preferable to use dual-energy densitometry of the spine bones.

According to international recommendations, BMD (spine, proximal femur) determination using bone densitometry methods should be performed in all adult patients who are planned to be treated with GC at a dose of more than 7.5 mg/day for more than 6 months. Patients who are not receiving osteoporosis therapy should have densitometry repeated every 6 months, and those receiving this treatment - at least once a year. These recommendations can be transferred to the pediatric contingent with some changes.

As research material on osteoporosis accumulated, it became clear that there may be situations when, as a result of osteoporosis treatment, BMD increases, but the fracture rate remains just as high. Or, conversely, BMD does not increase despite specific therapy, while the fracture rate significantly decreases. It is assumed that this may be due to changes in the quality (microarchitecture) of the bone, which cannot be tested using modern methods. This is why some authors call densitometry a "surrogate" method for determining the risk factor for fractures, despite the specificity and high sensitivity of this study.

Nevertheless, bone densitometry remains the most valuable instrumental method for diagnosing osteoporosis and preventing fractures. The most common classification of osteoporosis is the WHO, based on the assessment of the densitometric T-criterion (for children - the Z-criterion).

The software of bone densitometers includes standard indicators of bone density of various skeletal areas depending on gender, age, race, calculated on the basis of large population studies. In Russia, densitometric programs are designed for examining children from 5 years of age. It is impossible to conduct densitometry on a child under 5 years of age, and from 5 years of age it is permissible only on a device that has this age program.

In a number of pediatric studies, special attention was paid to the analysis of BMD indices taking into account bone age and puberty stage according to Tanner. When the examination results were subsequently recalculated taking into account the above indices, significant differences were obtained. This is due to the frequent discrepancy between the biological and passport age of a child with osteoporosis.

There are no unified recommendations regarding densitometric studies in children.

Indications for dual-energy X-ray absorption densitometry in childhood may be:

• fracture(s) resulting from a fall from standing height without acceleration;
• therapy with glucocorticosteroids for more than 2 months;
• the presence of risk factors for the development of osteoporosis;
• monitoring of osteoporosis therapy (not earlier than 1 year from the start of treatment).

Differential diagnosis of osteoporosis in children

Differential diagnostics of osteoporosis in children does not present any great difficulties. In the presence of clinical symptoms (see above), instrumental examination methods (densitometry, in extreme cases - X-ray of the spine bones) are necessary to confirm osteoporosis, otherwise the diagnosis cannot be confirmed. With instrumental detection of reduced BMD, the diagnosis of osteoporosis is obvious, it is only necessary to decide whether osteoporosis is a syndrome or an underlying disease.

In young children, osteoporosis must be differentiated from osteomalacia, which is characterized only by demineralization and softening of the bones without a pronounced change in protein synthesis in the matrix. The basis of osteomalacia is an increased amount of non-mineralized osteoid tissue.

A classic example of osteomalacia is damage to the bone system in mineral-deficiency rickets (at its peak), much less often in a disease from the group of genetic osteomalacia. In rickets, clinical manifestations include, depending on age, changes in the shape of the skull (craniotabes, flattening of the skull bones, the presence of frontal and parietal tubercles), O-shaped curvature of the legs, muscle hypotonia. Routine laboratory tests reveal a decrease in the level of phosphorus (less often calcium), an increase in the level of alkaline phosphatase in the blood. Such biochemical changes are not characteristic of osteoporosis.

In case of significant decrease in bone mineral density of unclear origin, bone tissue biopsy, histological and histomorphometric studies are of great importance in differential diagnostics. However, the use of this method is limited (especially in children in Russia) both because of its invasiveness and traumatic nature, and because of the insufficient number of pathomorphological laboratories with special equipment for histomorphometry.

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