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Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Musculoskeletal complaints are common in the elderly population. The main concerns in geriatric orthopedics are the increased incidence of trauma, degeneration, and malignancy, commonly compounded by comorbidities and the effects of ageing. Imaging of common and important diseases of the axial and peripheral skeleton in the elderly is reviewed in this article.

Hip pain is likely to be due to a local or regional bone disease when the hip joint is painless and of normal mobility by physical examination. Targeting the right diagnosis is easy in a patient affected by bone disease (osteoporosis, Paget's disease) or when the background of the patient is suggestive (malignancy, pregnancy). However it could be more tricky in most cases: transient osteoporosis of the hip, bone fissures, Paget's coxopathy, and tumoral cell osteolysis of bones surrounding the hip are the main causes, in addition to femoral head osteonecrosis, which is detailed in another chapter.

A study was undertaken to investigate the behavior of 99mTc-Sn-pyrophosphate complex in metabolic bone disease. Of clinical importance was the generalized increased periarticular bone accumulation of the radiopharmaceutical in osteomalacia and in combined osteomalacia and osteitis fibrosa as found in patients with chronic renal failure. The pattern in primary hyperparathyroidism was variable. There was no correlation between the initial rates of accumulation of the radiophosphate complex or its bone to soft-tissue uptake ratio at 5 hr when compared with the degree of osteomalacia and osteitis fibrosa. It is postulated that the 99mTc-Sn-pyrophosphate complex has greater affinity for immature collagen than the crystal surface.

We have compared the value of MRI with conventional radiography and CT in 40 predominantly sclerotic skeletal lesions. We have found that sclerosis and other changes in the bone structure can be demonstrated by MRI in much the same way as with conventional radiography and CT. Using high resolution surface coils, it is possible to demonstrate small areas of new bone formation such as periosteal new bone or the calcification within the nidus of an osteoid osteoma. MRI is particularly appropriate if it is necessary to show soft tissue changes within an area of sclerosis, which may be responsible for the new bone formation and which may be masked on radiographs and CT by the surrounding sclerosis.

A new familial disorder, inherited as an autosomal dominant trait and characterized by dual features of neurologic degeneration and skeletal disorganization, is reported. The neurologic disease is a degenerative process of lower motor neurons and develops in middle age with progressive muscle weakness and ends in respiratory failure and premature death. Clinical examination, electromyography, and muscle biopsy with histochemical stains are diagnostic. The skeletal disorganization resembles Paget's disease of bone. It is characterized by polyostotic radiographic abnormalities, elevated serum alkaline phosphatase of bone origin, abnormal radioisotopic bone scan, elevated hydroxyprolinuria, and bone histology.

Serum proline iminopeptidase and (where possible) urinary hydroxyproline were determined in 214 subjects: normal subjects, subjects with chronic kidney disease, subjects with chronic liver disease, subjects with osteitis deformans, subjects with rheumatoid arthritis, and subjects with osteoporosis. The values of the two parameters fully corresponded. It is suggested, therefore, that proline iminopeptidase can be determined instead of hydroxyproline in cases where a primarily destructive bone disease in present.

The value of the estimation of liver and bone isoenzyme of alkaline phosphatase in a series of 500 admissions to a geriatric unit is described. A raised total alkaline phosphatase was found in 40 patients and this was due to raised levels of the bone isoenzyme in about two-thirds of these. Its value in diagnosis of treatable bone disease is emphasized.

The authors report the results they obtained by bone scintigraphy using technetium pyrophosphate. In a study of 142 patients with cancer, the authors show, as others have done, that bone scintigraphy makes it possible to find bone metastases that are radiologically undetectable and they emphasize the importance of this discovery. In 7 patients with spondylodiscitis, of whom 1 was without radiological signs at the time the scintigraphy was carried out, the authors always observed localized vertebral hyperfixation and they noted that this examination can be valuable for distinguishing spondylodiscitis from pseudo-Pott's discarthroses and from the lesions of vertebral epiphysitis, which in their experience do not result in isotopic hyperfixation. In 7 patients with epiphyseal osteonecrosis, the authors observed isotopic hyperfixation before the appearance of radiological signs. In 12 patients with osteoporosis, the authors observed hyperfixation in bone in certain compressed vertebrae, whereas other vertebrae that had probably been compressed some considerable time earlier did not fix the isotope excessively. They never observed hyperfixation in vertebrae that were not compressed. Among 5 patients with ankylosing spondylitis with radiological signs of sacro-iliac arthritis, the authors observed sacro-iliac hyperfixation in only 3 cases. Two other patients who had signs indicating ankylosing spondylarthritis, but were without radiological signs of sacro-iliac arthritis did not show sacro-iliac hyperfixation of the isotope. Among 7 patients with Paget's disease, the authors observed hyperfixation in all the bones with radiological signs of disease; in addition, in 3 patients, there was also hyperfixation in certain bones that were radiologically clear.

Supplemental hand scintigrams with abnormal features were obtained from 29% of patients (134 of 463) who were referred for routine minified bone imaging with 99mTc-Sn-polyphosphate. A wide spectrum of normal activity distribution ranging from well-defined to "wash-out" images is described in 329 cases (71%). In the abnormal images of the joints and individual bones, the changes--although not always characteristic of some particular disease--may often suggest a diagnosis and/or its pathophysiologic status. The joints with heavy uptake correlate well with the presence of active clinical findings, e.g., in the arthritides. The bone feature associated with metabolic disease, especially when full-blown, may be fairly characteristic. A potential application is in the assessment of digital circulation, particularly in obliterative vascular diseases such as scleroderma, Buerger's disease, chronic neuropathies, and possibly other collagen or vascular diseases that involve the hands. Interesting images, probably of somewhat limited usefulness, are observed in some congenital anomalies, fractures, camptodactyly, contracture deformities, unilateral lymphedema after mastectomy, etc.

Technetium-99m labeled radiopharmaceuticals are the currently accepted agents of choice for skeletal imaging. Their introduction in 1971 literally initiated a new era in clinical bone scanning. The development of techniques for reducing Tc(VII) with Sn(II) provided the means for complexing this useful radionuclide with various phosphorus-containing compounds which were already known to be avid bone seekers. Long chain polyphosphates were widely used at first, but have been superceded by pyrophosphate and its organic analogs, the diphosphonates. Pyrophosphate is characterized chemically by P--O--P bonds, and the diphosphonates by P--C--P bonds. The chemical forms of their complexes with tin and technetium are not known, but they behave in many respects as weak chelates. Labeling efficiencies for 99mTc of 95% or better are routinely obtainable with both "in house" preparations and commercial kits. Proper molar concentrations and ratios of phosphorus-compound to tin are necessary for both for good labeling and to achieve optimum tissue distribution. Unreacted TcO4- and reduced unbound 99mTc are both potential contaminants in these preparations and must be considered in radiochemical quality control. In vivo tissue distribution and kinetics of the 99mTc-Sn-phosphorus compounds differ with details of preparation, category of agent, and clinical status of the patient. Blood clearance is multi-exponential, with skeletal uptake and urinary clearance accounting for most of the activity. Scanning may be started in 2 1/2 to 4 hr, at which time skeletal activity is on the order of 40 to 50% of the injected dose. The primary indication for bone scanning remains the detection of metastases from extraskeletal malignancies, and the 99mTc labeled agents are more sensitive than either radiographs or Fluorine-18 for demonstrating active lesions. In addition, many new applications in evaluating benign bone disease have widened the clinical scope of skeletal imaging which is rapidly becoming one of the most important studies in nuclear medicine.

Increased diagnostic information may be derived with Tc-99m diphosphonate from a detailed kinetic analysis of blood disappearance, urinary excretion, and quantitative assessment of skeletal uptake. Blood and urine determinations were studied in three populations: normal volunteers, patients with negative bone scans, and patients with positive bone scans. Quantitative imaging studies were performed in normal volunteers and patients with a scintillation camera interfaced to a computer. All subjects were scanned in the lower lumbar region up to 1 hr after Tc-99m diphosphonate administration. Blood levels exhibited a triexponential clearance pattern. Significant (p less than 0.05) differences were observed for the 5-min blood and 0-1 hr urine values among the various groups. The computer-generated images showed an initial early uptake in bone, kidneys and soft tissue. Thereafter, a parallel fall-off in activity was observed in kidney and soft tissue, with a concomitant increase in bone. Skeletal uptake was different for normal and diseased bone.

In primary bone tumors the possibilities of bone scans are discussed. Exact differentiation between malignant and benign disease by this method is impossible. However, scanning provides important information about extent of the disease, metastases, multiplicity of benign lesions and influence of adjoining diseases to the bone. A special indication exists in cases of cerebral meningiomas and an absolute indication for searching osteoplastic metastases, e.g. in carcinomas of the breast and the prostate gland.

Scanning is based on the uptake of a nuclide by the crystal lattice of bone and is related to bone blood flow. Cancer cells do not take up the tracer. Normally, the scan visualizes the highly vascular bones. Scans are useful and are indicated in metastatic bone disease, primary bone tumors, hematologic malignancies and some non-neoplastic diseases. The scan is more sensitive than x-ray in the detection of malignant diseases of the skeleton.

The authors measured the degree of hypocalcaemia (delta Ca S), hypophosphataemia and the fall in urinary hydroxyproline excretion induced by an intramuscular injection of 100 MRC U of synthetic salmon calcitonin (S.C.T.) during the 24 hours following the injection. In 15 control subjects, the fall in plasma calcium was slight ( - 2.1 +/- 0.9 mg/l) but significant. In bone diseases involving hyperosteoclastosis, the degree of hypocalcaemia was much greater: 10.6 +/- 1.1 mg/l in 24 cases of Paget's disease, - 9.0 +/- 1.6 mg/l in 5 cases of diffuse malignant disease of bone, - 8.0 +/- 1.4 mg/l in 6 cases of primary hyperparathyroidism and - 3.5 +/- 0.8 mg/l in 13 cases of algodystrophy of the limbs. In the subjects studied as a whole there was a significant linear relationship between the delta Ca S and the extent of the trabecular surfaces of osteoclastic resorption, but not between delta Ca S and total 24 hour urinary hydroxyproline excretion. The S.C.T. hypocalcaemia test would appear to be a simple means for the evaluation of osteoclastic activity within the skeleton, and thus to select those bone disorders which should respond to antiosteoclastic therapy (calcitonin, diphosphonates).

The discovery of a number of phosphate complexes labelled with 99-Tc-m that localize in bone has aroused wide-spread interest in bone scanning. The physiological properties of these and other clinically useful bone-seeking radiopharmaceuticals are compared, and their physical properties assessed in relation to the characteristics and limitations of avilable detector systems. A hypothesis is put forward to explain the behaviour of the technetium-labelled agents. It is concluded that although there are differences in biochemical behaviour between these agents, strontium and fluorine, all three may, under suitable conditions, give similar clinical information. The radiation dose received by the patients is least with the usual dose of 99-Tc-m and the blood clearance of the diphosphonate and pyrophosphate preparations is faster than that of strontium, although slower than fluorine. The psi-ray energy of technetium permits a much greater efficiency of detection than of fluorine. These factors, toghether with the general availability of 99-Tc-m and its relatively low cost make the technetium diphosphonate or pyrophosphate preparations the agents of choice for most skeletal radioisotope imaging. However, there are as yet insufficient follow-up studies to be able to assess the incidence of either false-negative or false-positive findings with these agents.