20. Clinical Evaluation of Osteoporosis

Early and correct diagnosis is essential for effective therapy. Reliable information concerning the state of bones is absolutely crucial especially if risk factors are already present. The following key questions must be accurately answered: What is the present bone mass (results of recent (and previous) measurements)? What is the present rate of bone loss (markers of remodelling in blood and urine)? Has physical damage already occurred (evidence of previous fractures on X-rays)? Are the changes (if present) reversible? The aims of clinical investigations are: To exclude a disease that can mimic osteoporosis (e.g. osteomalacia, myeloma) To elucidate the causes of osteoporosis To define the severity and topography of osteoporosis and to determine the risk of subsequent fractures To select the most appropriate form of treatment To perform the baseline measurements required for the subsequent monitoring of any treatment given. 20.1 Indicative Symptoms Back pain is one of the most frequent reasons for seeking medical advice, and every case of acute or chronic back pain must be thoroughly investigated. Since osteoporosis may be dormant and symptomless for extended periods, the onset of pain may indicate collapse or fracture of a vertebra. On the other hand, osteomalacia is characterised by widespread, early, systemic and severe bone pain – an important factor in differential diagnosis, which includes numerous other disorders: Vertebral diseases: inflammatory, degenerative, myelogenous and neoplastic Extravertebral diseases: visceral, neurological, muscular, psychosomatic and neoplastic (e.g. carcinoma of the pancreas) A detailed evaluation of back pain comprises localisation, onset, duration, continuous, intermittent, extent, type, intensity, sensory/motoric disturbances and responsiveness to various stimuli and to drugs. Possible underlying causes include: Muscular contractions and tension Vertebral collapse Protrusion of disc Ankylosing spondylitis Bone metastases Pancreatic tumours Myocardial infarction Clinical history and a careful physical examination (Table 20.1) must include the following: Table 20.1 Medical history and physical examination in osteoporosis Skeletal history Fractures, pain, deformity, reduced mobility, height loss Risk factor assessment Family history Osteoporosis, fractures, renal stones Age, ethnicity, weight Medical history Reproductive Menarche > age 15 years, oligo-/amenorrhoea, menopause Diseases Renal, GI, endocrine, rheumatic, neurologic, eating, depression Surgery Gastrectomy, organ transplant, intestinal resection or bypass Drugs Glucocorticoids, anticonvulsants, cytotoxic agents, heparin, warfarin, GnRH agonists, lithium Lifestyle and exercise Smoking, poor nutrition and exercise, alcohol Diet and supplements Frequent dieting, calcium, vitamin D, caffeine, protein Current medications Hormones, sedatives, hypertensives, diuretics, nonprescription drugs Physical examination Weight loss, diarrhoea Malabsorption, thyrotoxicosis Weight gain, hirsutism Cushing’s syndrome Muscle weakness Osteomalacia, Cushing’s syndrome Bone pain Osteomalacia, fracture, malignancy, hyperparathyroidism Tooth loss Hypophosphatasia Joint and lens dislocation Collagen disorders Skin pigmentation, stria Mastocytosis, Cushing’s syndrome Nephrolithiasis Hypercalciuria, primary hyperparathyroidism Loss of height Posture and bearing Pain on percussion of spinal processes Mobility of the vertebral column Presence of thoracic kyphosis or lumbar scoliosis Muscle tone and contractions Signs of congenital osteoporosis (e.g. blue sclerae) Acute back pain in osteoporosis is caused by sudden collapse or fracture of a vertebra. Patients often report having heard a snapping or cracking sound in the back. In contrast chronic pain in osteoporosis is due to inability of the axial skeleton to match up to the demand made on it by muscles, joints and extremities. The following questions should be answered to make the most comprehensive diagnosis of the pain syndrome: location, nature, timing, radiation and severity of the pain as well as factors that make the pain worse. Neurological features such a persistent nerve root pain or spinal cord syndromes are rare. The massive spinal shrinkage in osteoporosis (>4 cm) is mostly a consequence of the collapse of one or more of the thoracic vertebrae, but the distance from foot to hip remains constant. Other reasons for moderate decrease in height are poor posture, disc deterioration and muscle weakness. Loss of height can be approximated from the difference between the standing height and the arm span; loss of height occurs only in the spine, with hip-to-heel length remaining constant (Fig. 20.1a). When the height of the lumbar spine is reduced, the ribs may come to rest painfully on the bones of the pelvic girdle. A distinctly longer arm span indicates the degree of vertebral bone damage. Loss of height also entails characteristic folds in the skin of the back (Christmas tree phenomenon) as well as a forward bulge of the abdomen (osteoporosis tummy). Moreover the decrease in height of the vertebral bodies results in painful contact between the spinal processes (Baastrup syndrome or “kissing spine”). The body’s centre of gravity is displaced forward, so that movements during walking become slow and unsure, with small steps to avoid transmitting shocks to the vertebral column. The resulting faulty weight-bearing in turn gives rise to arthroses of the knee joints (gonarthrosis). Moreover, the unsure gait carries with it an increased risk for falls and fractures. The collapse of the thoracic vertebra produces the typical “round” back (dowager’s hump) (Fig. 20.1b). A good way to estimate the degree of “hump” is to measure the distance between the back of the head and the wall when the patient is standing straight up against it. When thoracic kyphosis is marked, the thoracic capacity may be reduced which impairs total lung volume, respiratory efficiency and exercise tolerance, and the patient’s chin may come to rest on the sternum. Fig. 20.1 (a) Changes in stature and posture due to generalised osteoporosis. (b) Typical rounding of the back (“dowager’s hump”) in a patient with osteoporosis × 20.2 Role of Conventional X-Rays in Osteoporosis Skeletal X-rays indicate bone loss only when the density has been reduced by 30–40 %; therefore, X-rays are not appropriate for early diagnosis. But they are very useful to reveal previous fractures or compressions (Fig. 20.2). The vertebral bodies exhibit various changes in shape which occur when the cancellous bone is resorbed while the cortex remains intact. Loss of trabecular bone occurs in a predictable pattern. The non-weight-bearing trabeculae are resorbed first, and therefore the vertebral bodies typically show a rarefication of the horizontal trabeculae accompanied by a relative accentuation of the vertical trabeculae (verticalisation, vertical striation) and the presence of reinforcement lines. Furthermore, the cortical rim of the vertebral bodies is accentuated, while the vertebral bodies demonstrate a picture frame, empty box, ghostlike appearance. Another useful criterion is the ballooning of the intervertebral spaces, an indication of the incipient compression of the roof and ground plates (biconcavity of the vertebrae). Schmorl’s nodes, which are caused by protrusions of the intervertebral disc into the vertebral body, are common in osteoporosis, although not pathognomonic. The criteria used to suggest the presence of osteoporosis on lateral X-rays of the spine include: Fig. 20.2 Overall outcome of vertebral fractures (Data from Cooper C, Atkinson E, O’Fallon W et al. (1992)) Incidence of clinically diagnosed vertebral fractures: a population-based study in (Rochester, Minnesota, 1985–1989. J Bone Miner Res 7:221–227) Increased radiolucency Prominence of vertical trabeculae Presence of reinforcement lines Thinning of the vertebral endplates Presence of compression fractures × Figure 20.3 shows the various types of vertebral deformities in osteoporosis Fig. 20.3 Types of vertebral deformities in osteoporosis: wedge-shaped, biconcave and compressed × For a semiquantitative evaluation of vertebral deformities, Genant has published a grading scheme, based on reductions of the anterior, middle or posterior height of vertebral bodies: Grade 0: normal Grade 1: mild deformity, 20–25 % reduction of any vertebral height Grade 2: moderate deformity, 25–40 % reduction of any vertebral height Grade 3: severe deformity, >40 % reduction of any vertebral height 20.3 Other Useful Imaging Techniques Other Parameters of the Proximal Femur The length of the femoral neck (hip axial length) correlates with the fracture risk at this site independently of the cancellous and compact bone of the proximal femur. Each cm increase in length doubles the fracture risk. The following radiological parameters are useful to calculate the fracture risk in the proximal femur: Thickness of the medial femoral shaft 3 cm below the trochanter minor Thickness of the medial cortex at the centre of the femoral neck Femoral head width Intertrochanteric region width Acetabular bone width Bone Scan 99mTc-labelled bisphosphonate is used to detect focal bone lesions and fractures. The whole skeleton can be scanned quickly by this method. Foci of increased uptake in the spine indicate fractures, degenerative, inflammatory or neoplastic lesions. Two days after a fracture, an increased uptake at the site can be expected. However, because of the limited structural details, additional imaging techniques are required for further identification. Computed Tomography (CT) This technique is particularly useful for analysis of bones and cancellous bone (Fig. 20.4). However, this can only be done with modern high-resolution instruments using sections 0.5 mm thick, together with special picture enhancing facilities, but at the cost of higher exposure to radiation. Fig. 20.4 Fractures of the pelvic girdle demonstrated in CT × Magnetic Resonance Imaging (MRI) This method involves no exposure to radiation and is especially adapted for demonstration of the bone marrow. It offers the possibility of identifying both haematopoietic and fatty bone marrow and inflammatory and neoplastic infiltrates (Figs. 20.5 and 20.6). It is the method of choice for demonstration of myeloma, lymphoma and metastases, as well as localised oedematous processes (transient osteoporosis and early stages of Sudeck’s disease). It is the ideal method to distinguish between an osteoporotic fracture and one due to spinal metastases. In addition, the diagnostic capability is greatly enhanced by application of special gradient echo sequences and by the use of contrast media. Fig. 20.5 Spondyloarthritis with bone marrow oedema syndrome of the whole spine Fig. 20.6 Nodular metastatic process in the spine in a patient with breast cancer and secondary osteoporosis × × 20.4 Bone Densitometry in Osteoporosis (DXA Method) The early diagnosis of osteoporosis, before occurrence of fractures, can only be made by means of bone density measurements (bone mineral density tests, BMD) (see Chap. 13). These measure bone density at various skeletal sites and thereby enable a prediction of risk of later fracture. A 10 % decrease in bone density doubles the fracture risk for the vertebral body and trebles it for the hip joint. If a fracture has already occurred, this test is used to confirm the diagnosis of osteoporosis, to determine its degree of severity and to establish the indication for treatment (Fig. 20.7). BMD provides the following information: Fig. 20.7 Algorithm for diagnostic investigation and treatment of osteoporosis Detects osteopenia and/or osteoporosis before occurrence of a fracture Predicts risk for later development of osteoporosis Indicates the rate of bone loss – progression – in sequential measurements Documents the efficacy or failure of therapy Increases compliance of both doctor and patient × Currently, a bone density measurement remains the best and most readily quantifiable method for assessing fracture risk and skeletal response to different treatments. Today dual energy X-ray absorptiometry (DEXA, DXA) is the most completely developed, reliable and popular bone densitometric technique in use, the “gold standard” and the “reference standard”. It is versatile and can be used to assess bone mineral content of the whole skeleton as well as of specific sites, especially those most vulnerable to fractures. Important advantages of DXA are: It is not invasive, the patient remains clothed, and it is therefore not a burden to the patient. It is very quickly carried out (5–10 min). It is cost-effective. It has a very low radiation dose (1–3 mRem equivalent to 1/10–1/100th of a normal X-ray film). It measures those skeletal areas most vulnerable to osteoporosis and to fractures – the lumbar spine and the hips. It has a documented strong gradient of risk for fracture prediction. The risk of hip fracture increases 2.6-fold for each standard deviation decrease in BMD at the femoral neck. The measurements are accurate and therefore ideal for follow-up and control investigations (accuracy error 1–10 %, precision 1 %). It is recognised by the WHO as the standard method for diagnostic definition of osteoporosis. It is recognised by the ESCEO and the IOF as the “reference standard” in the diagnosis of osteoporosis (2008). Indications for Bone Density Measurements The simplest way to determine who should have a bone density test is to decide in each case whether the results will influence a clinical decision. Any individual with risk factors should have a bone density measurement, for example, a postmenopausal woman who does not take HRT or its equivalent, a woman with early menopause or a woman with a family history of osteoporosis or men with decreased levels of androgens. According to the National Osteoporosis Foundation (NOF), a BMD measurement is recommended for: All women >65 years regardless of additional risk factors All women <65 years with one or more risk factors All postmenopausal women with fractures All women contemplating osteoporosis therapy and whose decision depends on the result of BMD All women undergoing protracted hormone therapy Additional Indications Anyone who has a disease or a condition or is taking certain drugs with the potential to induce bone loss is a candidate for a bone density measurement (DXA preferred) Age-related decrease in height Back pain of obscure origin Slim smokers Previous fractures Diseases of joints which limit movement Long-term use (>6 months) of drugs such as cortisone, warfarin, heparin or antiepileptic drugs Hyperthyroidism and hyperparathyroidism Post-transplantation, especially of the kidney, liver, heart and lungs Chronic diseases and operations which can lead to bone loss, e.g. gastric and intestinal resections Anorexia nervosa Chronic renal insufficiency Neoplasias, pre and post therapy Measurements in children are problematic for a number of reasons: There are inadequate reference data for children. There is a broad variability in developmental age at any given chronological age. DXA has inherent limitations for paediatric use because of its inability to measure the bone size in three dimensions. To ameliorate this problem, whole-body bone mineral content (BMC) is sometimes recommended for paediatric measurements. Also, the Z-score rather the T-score is the appropriate criterion for assessing the bone mineral status. BMC is preferable to BMD, because of the problems posed by changing bone size and shape during growth. Bone density measurement by DEXA is currently the only reliable method to document the effects of therapy on osteoporosis (monitoring). Decrease in the incidence of fractures is another. Moreover, annual BMD measurements increase the patient’s compliance. Clinical trials have documented significant increases in bone density under therapy with bisphosphonates after 3 months in the vertebrae and 1 year in the hips. Biannual measurements should be carried out in high-risk patients, for example, those on corticoid therapy or patients with rapid bone loss (as indicated by biochemical parameters). 20.5 Recommended Laboratory Tests The parameters usually tested in blood and urine are within normal limits in primary osteoporosis in the absence of co-morbidities. The significance of laboratory tests therefore lies mainly in recognising secondary osteoporosis (Table 20.2). Consequently the following “basic” laboratory screening tests should be carried out at diagnosis and regularly thereafter: Table 20.2 Laboratory tests for the evaluation of secondary osteoporoses Basic tests Diseases Additional tests to include Complete blood count Malabsorption PTH, vitamin D, calcium (S)PTH, vitamin D, calcium (S) Ferritin, vitamin B12 Multiple myeloma Bone marrow biopsy Protein electrophoresis (S,U) Leukaemia Blood smear Bone metastases PSA, Ca15-3, CEA Thyroid-stimulating hormone (TSH) Hyperthyroidism Thyroxine (T4), T3 Glucose (S,U) Diabetes mellitus Oral glucose tolerance test Cortisol (S) Cushing’s syndrome ACTH, dexamethasone test Addison’s disease ACTH HIV-antibody AIDS Infection diagnosis HLA B-27 Ankylosing spondylitis CRP Testosterone in men Hypogonadism SHBG, LH, FSH, prolactin Calcium (S) Hyperparathyroidism PTH Malabsorption Complete blood count Morbus Crohn PTH, vitamin D Celiac disease Alkaline phosphatase, gliadin Osteomalacia PTH, vitamin D Alkaline phosphatase Alkaline phosphatase Chronic renal failure PTH, calcium, phosphate (S) Osteomalacia PTH, vitamin D Calcium (S) Protein electrophoresis Multiple myeloma Complete blood count Bone marrow biopsy Liver enzymes Haemochromatosis Iron, ferritin (S) Alcoholic liver disease Primary biliary cirrhosis Antibodies Creatinine Chronic renal failure PTH, calcium, phosphate (S) Histamine 24 h U Mastocytosis Bone marrow biopsy Erythrocyte sedimentation rate Complete blood count Calcium and phosphate (serum) Alkaline phosphatase (serum) Glucose (serum/urine) CRP Transaminases and gamma GT (serum) Creatinine (serum), GFR And when the appropriate indications are present: T3, T4 and TSH Oestrogen and/or testosterone levels. Vitamin D metabolites. Vitamin K has recently been introduced as a new biochemical marker. Parathormone (PTH). Protein electrophoresis and immuno-electrophoresis. It is important to note that 20 % of women and up to 64 % of men with osteoporosis also suffer from diseases linked to osteoporosis (co-morbidities), hence the importance of the analyses listed above. In summary, every patient should be investigated according to the personal risk profile indicated by medical history and lifestyle factors, which determine the appropriate tests and examinations. Subsequent management will depend on the results, i.e. whether or not there is osteopenia/osteoporosis, presence of co-morbidities, current medications, etc. 20.6 Significance of Markers of Bone Turnover The measurements of collagen metabolism and bone turnover in daily practice are essential for the diagnosis and monitoring of progressive bone diseases such as skeletal metastases or Paget’s disease of bone (Table 20.3). However, bone markers cannot be used to diagnose osteoporosis, though they may help to answer some important clinical questions: Table 20.3 Biochemical markers of bone turnover Bone resorption Bone formation Blood: Blood: Tartrate-resistant acid phosphatase(TRAP) Total or bone-specific alkaline phosphatase Free pyridinoline or deoxypyridinoline Osteocalcin N- or C-telopeptide of type I collagen Procollagen I C-and N-terminal extension peptides Cross-links Osteocalcin Urine: Fasting urine calcium-to-creatinine ratio Pyridinoline and deoxypyridinoline Glycosides of hydroxylysine Pyridinoline and desoxypyridinoline N- and C-telopeptides of type I collagen Predicting the future rate of bone loss (high or low bone turnover) Predicting the risk of osteoporotic fractures Monitoring response to therapy The metabolites of bone remodelling, i.e. of resorption and formation, as well as the products of bone matrix metabolism such as collagen type 1 pass into the bloodstream and from there into the urine. These products can be identified biochemically, and their levels in blood and urine indicate “high turnover” or “low turnover” osteoporoses. It should be noted that bone markers do not replace bone density measurements for the diagnosis of osteoporosis. However, these markers do provide information about the future risk for bone loss and fragility fractures. Changes in bone formation in response to therapy are relatively slow, starting after some weeks and reaching a plateau after several months, in contrast to bone resorption which decreases rapidly a few days after initiation of antiresorptive therapy with, for example, a bisphosphonate and reaches a nadir a few weeks later. These characteristics of bone remodelling must be taken into consideration when evaluating the significance of the levels of markers of bone remodelling in blood and in urine. However, large-scale studies have shown that serial evaluation of markers of bone turnover in the serum do identify people at the highest risk of loss of bone and osteoporosis. Parameters of bone formation are bone-specific alkaline phosphatase (bone ALP), osteocalcin, and osteonectin. These are produced by osteoblasts (possibly also by endothelial cells), and their levels in the peripheral blood reflect osteoblastic activity. ALP is also produced in various tissues including the liver and kidney; but bone-specific ALP can be distinguished by immunoassays with high specificity. Osteocalcin (OC) shows a diurnal rhythm, and only about 50 % is released into the circulation, while the remaining 50 % is incorporated into hydroxyapatite. OC reflects total bone turnover, i.e. the sum of both resorption and formation. The serum concentrations of the C- and N-terminal propeptides of type I procollagen (PICP and PINC) reflect changes in synthesis of new collagen, produced by osteoblasts in bone and by fibroblasts in other connective tissues. All the PICP and PINC produced are secreted into the circulation. Parameters of bone resorption consist primarily of collagen degradation products such as “cross-links” which are released into the bloodstream and then excreted into the urine (Fig. 20.8). They appear to predict the risk of hip fracture in elderly women independently of bone density. Studies have shown that women with high levels of markers of bone resorption have about a 1.5–3-fold increased risk of hip or non-vertebral fractures. Desoxypyridinoline and cross-link telopeptides of type I collagen are the two markers of resorption most frequently investigated. Telopeptides are distinguished by their terminals: amino (NTX-OSTEOMARK) and carboxy (CTX-CROSSLAPS). Variations in diurnal rhythm and the effect of meals must be taken into account when results of these tests are evaluated. Both NTX and CTX show a significant response to antiresorptive therapy and are currently considered to be the most reliable parameters of bone resorption. However, serum NTX concentrations are elevated in chronic renal failure, and this must, of course, be taken into account, i.e. by investigation of renal function. Fig. 20.8 Molecular structure and organisation of collagen into fibrils. Note position of end terminal CTX and NTX, used as biochemical markers of collagen breakdown products in the serum × Bone sialoprotein (BSP) also appears to be a sensitive marker of bone turnover. Furthermore, BSP is thought to play an important role in attraction and growth of tumour cells in the bone marrow, e.g. in multiple myeloma, and metastases of breast cancer. Hydroxyproline should no longer be used as a marker of bone metabolism because of its lack of specificity. Its level in the urine is influenced by the breakdown of collagen in sites other than the skeleton, as well as by dietary intake of collagen. Excretion of calcium in a 24 h urinary specimen is also not an accurate reflection of bone resorption, because it depends on the renal threshold for calcium reabsorption and the dietary calcium intake. Results of bone markers before starting a treatment are not useful predictors of response to the treatment. It is also not clear if patients with high bone turnover are more likely to gain bone under therapy. Some studies have demonstrated that patients with the largest decreases in markers of bone resorption during treatment with alendronate tend to have the greatest increases in BMD. Nevertheless, changes in markers during treatment must be interpreted with caution. The results of each patient must be compared with the least significant change (LSC) (Fig. 20.9). The LSC is the minimum change that must be seen in an individual patient to be at least 95 % sure that the change is “real” and not caused by biological or laboratory variations. The LSC is about 25 % for most formation markers and 40–65 % for most resorption markers. About 65 % of patients treated with oestrogen or bisphosphonates have changes in bone resorption markers that are greater than the LSC. In contrast, raloxifene and calcitonin are associated with smaller changes in these markers. However, patients may benefit from a decrease in risk of fractures even if they do not have reductions in bone markers or improvements in bone density. In these cases with little or no change while on antiresorptive medication, it is important to check carefully: Fig. 20.9 Response of bone markers to antiresorptive agents. A decrease below the least significant change (LSC) is regarded as statistically significant If the patient is taking the medication If the patient is taking the drug as prescribed If there are secondary causes of osteoporosis × The advantage of monitoring treatment with markers is that changes in levels can be observed within weeks of starting therapy, and evidence of its efficacy is psychologically important at a time when patients are most likely to discontinue their medications (Fig. 20.10). It is necessary to emphasise that the specimens for investigation should always be taken at about the same time of day and with the patient fasting. Furthermore, indices of bone turnover may show seasonal and circadian variations. Fig. 20.10 The combination of a low hip BMD and a high serum CTX have a greater predictive value than either low hip BMD or high serum CTX alone (Modified from Garnero et al. 1996) × Recommendations for practical use of bone markers: When using bone markers, one should keep in mind that: They are not unique to bone. They may reflect both formation and resorption. They are influenced also by nonskeletal diseases. When using bone markers in the monitoring of antiresorptive therapy: Always compare the same marker. Use only markers validated for assessing bone resorption/formation. Collect the samples at the same time (8.00–10.00), if necessary after an overnight fast. Keep reasonable intervals between the controls (about 3–6 months). Use cut-off values to identify responders (−30 % for urinary DPD, −65 % for urinary NTX and CTX, −40 % for serum bone-specific AP).

Medicine Matters Rheumatology

20. Clinical Evaluation of Osteoporosis

Abstract