Metabolic, Hormonal, and Toxic Bone Disorders

8 Metabolic, Hormonal, and Toxic Bone Disorders

8.1 Osteoporosis

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility (WHO definition from 1994; see References for Chapter 8.1).

Pathology. Osteoporosis is a multifactorial disease requiring a careful diagnostic work-up. Basically, osteoporosis is due to an imbalance between bone resorption and bone formation (remodeling). A distinction is made between types of osteoporosis with increased bone turnover (high turnover) and those with reduced bone turnover (low turnover).

Whereas the bone mass of an adult consists of about 80% compact/cortical bone and only 20% cancellous (trabecular) bone, the latter is considerably more active with regard to bone metabolism. Trabecular bone is particularly susceptible to processes involving bone resorption because of its 10-fold greater surface area compared with cortical bone.

Osteoporosis involves not only a loss of bone mass but also thinning and a conversion of the originally plate-shaped trabeculae into rod-shaped trabeculae and the appearance of perforating resorptive lacunae, resulting in a loss of 3D networking ( Figs. 8.1 and 8.2). The result is loss of biomechanical competence and increased fragility; this is the reason for pathologically increased bone fragility. Trabecular microfractures indicate a failure of the bone when subjected to load-bearing. The formation of microcallus is an attempt to produce healing ( Fig. 8.3), although this process is not capable of restoring the destroyed microarchitecture.

8.1.1 Classification and Clinical Presentation of Osteoporosis

There are several classification and grading systems for osteoporosis, some of which overlap. Osteoporosis may be classified using the following criteria:

• Location and extent (e.g., disuse osteoporosis, transitory osteoporosis, complex regional pain syndrome [CRPS]).

• Age at initial onset (e.g., idiopathic juvenile osteoporosis, postmenopausal osteoporosis, senile osteoporosis).

• Bone turnover rate (high and very high turnover, low turnover).

• Severity of the osteoporosis (normal, osteopenia, preclinical osteoporosis, and clinically manifest osteoporosis; severity Grades 0–3 according to Minne).

• Bone histology.

• Etiology.

An etiological classification based on more practical features:

• Primary osteoporosis: This includes postmenopausal and senile osteoporosis as well as primary osteoporosis of the male. It is the most common form and has many causes and risk factors, although some single pathogenetic factors are known. Although it involves the entire skeleton, it primarily affects the spine and proximal extremities.

• Secondary osteoporosis: This is considerably less common (about 5% of cases), but more often leads to osteoporotic fractures. It may be related to an underlying condition or medication (e.g., glucocorticoids) or may be of a genetic origin (e.g., Turner’s syndrome, osteogenesis imperfecta). Typical disorders with an increased risk of osteoporosis include hypogonadism, hyperparathyroidism, Cushing’s disease, hyperthyroidism, chronic malabsorption syndrome, chronic inflammatory diseases, malignancies (especially multiple myeloma), and storage diseases.

Clinical presentation. Osteoporosis is a silent condition, with few exceptions. Only after the development of macrofractures, either spontaneously or after minor injury, does the disease become apparent. Typical osteoporotic fractures involve a vertebral body, the proximal femur, distal radius, proximal humerus, and sacrum. Vertebral and hip fractures, in particular, result in increased mortality of those, typically older, patients who are affected since they have an additive effect with preexisting comorbidities. Osteoporotic vertebral fractures may also cause considerable back pain that is resistant to therapy. Referred pain can occur in a pseudoradicular distribution, but neurologic deficits are not part of the typical clinical course.

Clinical screening using bone density testing to identify individuals at risk for osteoporosis are becoming increasingly important given the typical asymptomatic course of the disease. Risk factors include hereditary predisposition, steroid therapy, nutritional calcium and/or vitamin D deficiency, reduced mobility, reduced exposure to sunlight, nicotine abuse, and cachexia, as well hormonal factors such as late menarche, early menopause, amenorrhea, and hypogonadism in men.

8.1.2 Bone Density Testing

Because bone density correlates most strongly with fracture risk, noninvasive bone density testing is of great importance in the diagnostic work-up for osteoporosis. The WHO has constructed a stratification tool based on the standard deviation (SD) of the patient’s bone density from the average maximum bone density in the third decade of life (peak bone mass) of a sex- and race-matched normal population (“T-score”; Fig. 8.4). About 95% of all patients who suffer a fracture have a T-score below −2.5 SD. This value was defined as the statistical reference value for “osteoporosis.”

Fig. 8.1 Normal trabecular bone with predominantly platelike, well-connected trabecular networks. 3D CT of a bone-block specimen (4 mm × 4 mm × 4 mm) with ultra-high resolution.

Fig. 8.2 Senile osteoporosis with thin, rodlike trabeculae, reduced number of trabeculae, and decreased cross-linking. 3D CT of a bone-block specimen (4 mm × 4 mm × 4 mm) with ultra-high resolution.

Fig. 8.3 Reparative microcallus after trabecular microfracture. Enlarged view of a specimen. (Image courtesy of Dr. B. Jobke, Heidelberg, Germany.)

Fig. 8.4 Bone mineral density curve for a normal female population (by DXA [dual energy X-ray absorptiometry] of the lumbar spine). Bone density is plotted against age. A patient’s actual bone density value is compared with a reference curve with standard deviations. The measured values are stated as the deviation from the peak bone mass (T-score) and as the deviation from the age-matched mean value (Z score).

According to the WHO definition:

• T-score less than −2.5 SD: osteoporosis.

• T-score between −1.0 and −2.5 SD: osteopenia.

• T-score more than or equal to −1.0 SD: normal.

Note

This T-score–based osteoporosis stratification by the WHO is only valid for DEXA (dual energy X-ray absorptiometry) measurements.

DEXA. Dual energy X-ray absorptiometry (DEXA) is currently regarded as the method of choice for bone density analysis. Measurements are usually made in the spine and proximal femur. The patient is scanned using low dose x-rays at two different energy levels, which then allows for correction for overlying soft tissues of variable thickness by subtracting the two absorption spectra. Bone mineral density (BMD) is calculated as mass per unit surface area (g/cm²) ( Fig. 8.5a). The most important limitation of the method is that degenerative changes in the lumbar spine (osteophytes, discogenic sclerosis), aortic calcifications, and hyperostoses of the ligaments and joints are also measured and are very common, especially in patients over the age of 65 years. The presence of these types of changes must be assessed by performing an initial “scout” x-ray examination of the lumbar spine since including theses nonstructural types of calcium will result in falsely elevated BMD measurements (see Fig. 8.3).

QCT. Quantitative computed tomography (QCT) is conducted using standard clinical CT scanners with special software. Axial slices are obtained through the middle of three or four vertebrae (T12 to L4) and the bone mineral density is determined in the trabecular bone, excluding overlying structures (in g/cm³; Fig. 8.5b). Included in the image, behind the patient, is an external reference phantom of known density. The actual value is calculated by comparing the absorption coefficients in bone with the absorption coefficients in the phantom.

QUS. Quantitative ultrasound (QUS) is a more recent method for assessing the risk of fracture. Sound waves are pulsed along the bone and the attenuation of the ultrasonic amplitude as it passes through bone is used to assess bone stiffness. Measurements are typically made in the calcaneus, less commonly the tibial shaft and the phalanges. Major studies have confirmed reliable correlation between these parameters and the risk of fracture, especially with regard to the femoral neck region. However, this method has not yet been adopted for routine use.

8.1.3 Radiographic Findings in Osteoporosis

Radiography. The typical radiographic findings in osteoporosis are increased lucency, trabecular rarefaction, and thinned but sharply defined cortex ( Fig. 8.6). Conventional radiographs (thoracic and lumbar spine) are an essential part of the diagnostic work-up for osteoporosis. They allow recognition of structural changes:

• Marked lucency (evident when there has been about 30% loss of calcium; Fig. 8.7).

• Accentuation of the cortical rim of the vertebrae (“picture framing”) and increased prominence of the vertical trabeculae.

Caution

These radiographic criteria for osteoporosis are unreliable since they are dependent upon the individual subjectivity of the imager. Furthermore, they also depend upon technical factors (image parameters, physical dimensions of the patient, etc.). Radiographs allow the diagnosis of vertebral body fractures, which should be diagnosed when there is a loss of height of at least 20% relative to the expected vertebral height. The presence of vertebral fractures implies clinically relevant osteoporosis and has an immediate effect on therapeutic decisions.

Note

It is imperative to report vertebral body fractures (also on lateral chest radiographs and on chest or abdominal CT) because the presence of one vertebral body fracture increases the risk of subsequent fractures 4-fold, and two vertebral body fractures increases the risk up to 12-fold.

Fracture types typical for osteoporosis of the spine:

• Wedge fracture (most commonly found in the thoracic spine).

• Biconcave compression fracture (codfish vertebra; most common in the lumbar spine).

• High-grade compression fracture (vertebra plana, pancake vertebra; common in secondary osteoporosis).

The degree of vertebral height loss may be classified according to Genant ( Figs. 8.8 and 8.9).

For the differential diagnosis of osteoporotic fractures versus traumatic or tumor-related fractures, see also Chapter 2.2.7.

Fig. 8.5 Comparison between DXA (dual energy X-ray absorptiometry) and QCT (quantitative CT). (a) DXA is a planimetric procedure; bone density is expressed in g/cm². (b) QCT is a volumetric procedure; bone density is expressed in g/cm³.

Fig. 8.6 Generalized osteoporosis in a 92-year-old woman.

Fig. 8.7 Osteoporosis with typical “structureless” spine and increased radiolucency of the vertebrae.

Fig. 8.8 Classification of osteoporosis-related vertebral body deformities according to the degree of anterior, medial, and/or posterior loss of height.

Fig. 8.9 The course of osteoporosis. (a) Initial finding. (b) One year later: multiple osteoporotic vertebral body fractures displaying typical morphology.

CT. CT findings are the same as on radiographs, yet without being obscured by overlying structures ( Fig. 8.10). CT is important for assessing any cortical disruption and posterior wall involvement in vertebral fractures and for identifying osteolysis as a sign of a malignant (pathologic) fracture. The most specific sign of an osteoporotic vertebral fracture is an intravertebral vacuum phenomenon (due to the release of nitrogen; Chapter 2.2.7). Bandlike sclerosis and focal intravertebral calcifications are usually a sign of preexisting trabecular callus formation and suggest a subacute fracture, although they may also represent impacted trabeculae of a fresh fracture.

MRI. MRI is the best modality for identifying acute vertebral body fractures and also helps to differentiate benign from malignant fractures. An acute osteoporotic vertebral fracture produces marrow edema that is easily detected on fat-suppressed fluid-sensitive sequences as a hyperintense bone marrow signal. It is typically found in a bandlike distribution near the affected vertebral end plate ( Fig. 8.11). It may occupy the entire vertebral body, but never the whole pedicle (an important differential diagnostic criterion). A corresponding bandlike area of decreased signal intensity is evident on T1W sequences, sometimes with a hypointense fracture line as well.

Differentiation from tumor. With an osteoporotic fracture, the vertebral body rarely appears hypointense in its entirety, but there are often areas with a (bright) fat marrow signal. The detection of focal, usually round, hypointense marrow lesions on T1W sequences, not in continuity with the fracture, is not typical for osteoporotic fractures and is more in keeping with vertebral metastases.

The administration of intravenous contrast provides very little additional differential diagnostic information: osteoporotic fractures occasionally display strong, linear or bandlike areas of contrast enhancement paralleling the end plates. Diffuse vertebral enhancement is nonspecific, whereas pedicle involvement on the other hand is suspicious for malignancy. In any case, pathologic extravertebral soft tissue components that make a malignant fracture probable should be carefully looked for. See Table 2.1 for an overview of the differentiation of “osteoporotic versus malignant fractures.”

More recent special MR imaging techniques, such as DWI (diffusion weighted imaging), are supposed to make differentiation between benign and malignant vertebral body fractures easier. Refer to specialized literature for further details.

NUC MED. Fractured vertebral bodies due to neoplastic infiltration are expected to display more uptake on FDG-PET than osteoporotic vertebral body fractures. The degree of overlap is large, however, so that the positive predictive value of malignant fractures is only about 71% while the negative predictive value is approximately 91%.

DD. For the differential diagnosis of systemic osteoporosis, see Chapter 8.1.1.

Differential diagnosis of focal osteoporosis includes the following:

• Disuse osteoporosis: This affects skeletal regions less subject to load bearing such as when they are immobilized (Chapter 1.7.3).

• Para-articular demineralization secondary to an inflammatory arthritis, in which case the clinical presentation is very helpful.

• CRPS: An initiating injury is usually reported.

• Transient regional osteoporosis: see Chapter 1.5.4.

8.2 Rickets and Osteomalacia

Both of these are diseases in which vitamin D deficiency or metabolic disturbances result in insufficient mineralization of osteoid ( Fig. W8.1). In the growing skeleton the normal development of the growth plates is disrupted (rickets), while in the mature skeleton mineralization of cortical and cancellous bone is delayed (osteomalacia).

Pathology. Calcium metabolism is regulated by parathyroid hormone, calcitonin, and vitamin D, each of which can also be used therapeutically ( Fig. W8.2).

Rickets or osteomalacia develops when there is insufficient vitamin D or calcium available:

• Due to inadequate absorption of calcium related to gastrointestinal malabsorption (after gastric and small-bowel surgery, in pancreatic insufficiency, celiac disease, or gluten-sensitive enteropathy).

• From loss of phosphate in renal tubular disease (congenital, hemodialysis, transplant).

• In preterm infants who have 3 to 6 times the requirements of full-term infants.

• In liver diseases.

• In cases of inadequate exposure of the skin to sunlight, e.g., from cultural/religious restrictions (such as skin covering) or domestic causes (e.g., in nursing home residents).

Clinical presentation. The most striking findings in children are the disproportionately short stature (the growth of the extremities lags behind that of the trunk) and bony deformities.