Metabolic Bone Diseases Notes PDF

**METABOLIC BONE DISEASES** Dr Ademola Adelekan Department of Chemical Pathology, College of Medicine & Health Sciences, Afe Babalola University, Ado-Ekiti/Federal Teaching Hospital, Ido-Ekiti **Introduction** Bone is a rigid connective tissue composed of collagen and salts, including calcium...

**METABOLIC BONE DISEASES** Dr Ademola Adelekan Department of Chemical Pathology, College of Medicine & Health Sciences, Afe Babalola University, Ado-Ekiti/Federal Teaching Hospital, Ido-Ekiti **Introduction** Bone is a rigid connective tissue composed of collagen and salts, including calcium phosphate. The adult human body contains 206 bones whereas 270 are found in infants. Bone is a dynamic substance that is constantly being resorbed and new deposits are being laid down. The deposition and resorption are regulated by three synergistic substances; serum mineral levels, parathyroid hormone (PTH) and 1,25(OH)~2~ VitD. Metabolic bone disease occurs when there is disruption of the synchrony of bone metabolism and mineral metabolism. They often present with characteristic biochemical patterns e.g., osteomalacia, Paget\'s disease, and metastatic malignancy. Osteoporosis, on the other hand, usually presents with normal biochemical parameters but the urinary excretion of various analytes may be increased. **Review of Mineral & Bone metabolism** a. **Regulation of mineral metabolism** a. **Renal handling of Ca & P** b. **Intestinal Absorption of Ca & P** **Figure 1** The metabolism of calcium is linked intimately with that of phosphate (See Figure above). The homeostatic mechanisms are directed principally toward the maintenance of normal extracellular calcium and phosphate concentrations, which sustain the extracellular and intracellular processes and provide substrate for skeletal mineralization. The parathyroid gland responds to a decrease in free calcium concentration within seconds with the increase in serum PTH rapidly altering both renal and skeletal metabolism with an indirect action on the intestines. **Renal Handling of Calcium and Phosphate:** Of the about 10 g or approximately 250 mmol of calcium filtered by the kidneys each day, 65% is reabsorbed in the proximal tubule. Approximately 10 to 20% of calcium is reclaimed in the thick ascending loop of Henle, and 5 to 10% in the distal convoluted tubule. PTH enhances calcium reabsorption. In contrast to the calcium-conserving effect of PTH on the kidneys, PTH increases renal phosphate excretion at the proximal tubule by directly lowering the renal phosphate threshold. Normally, 85 to 90% of phosphate is filtered by the kidneys each day is reabsorbed by the renal tubules (proximal and distal convoluted tubule). **Intestinal Absorption of Calcium and Phosphate:** PTH increases intestinal calcium absorption by increasing 1,25(OH)~2~ VitD. Calcium is absorbed by passive diffusion and by an active transport system. Passive diffusion accounts for absorption of about 10% of ingested calcium per day. Active calcium absorption in the duodenum is under the control of 1,25(OH)~2~ VitD. Approximately 60 to 70% of dietary phosphate intake is absorbed. As with calcium, both passive and active transport systems exist; 1,25(OH)~2~ VitD is the principal regulator of the active transport of phosphate. PTH-stimulated synthesis of 1,25(OH)~2~ VitD thus offsets the phosphaturic effect of PTH. Phosphate depletion or hypophosphatemia stimulates formation of 1,25(OH)~2~ VitD by the kidneys. **Effect on Bone:** PTH has an acute effect on the skeleton. Acutely, PTH decreases collagen synthesis in osteoblasts, but osteoclastic bone resorption is increased, with a net increase in mineral (calcium and phosphate) release from bone into the extracellular fluid. b. **Bone Metabolism** **Bone structure:** Bone is a special connective tissue hardened by mineralization with calcium phosphate in the form of hydroxyapatite \[Ca~5~(PO~4~)~3~(OH)~2~\]. It is composed of approximately 70% inorganic matter (minerals) and 30% organic matter (osteoid). Peak bone mass is attained by 30 years and begins to decrease slowly by 40 years. Bone has 4 important functions 1. Structural support (provides rigidity and shape, protection and support for body structures, and aids locomotion) 2. Houses haematopoetic bone marrow. 3. Metabolic regulation of calcium and phosphate. 4. Buffer system (release of phosphate buffer in chronic metabolic acidosis). Bone tissue is a dynamic structure undergoing constant remodeling. The bone turnover allows the bone tissue to repair itself and to adapt to forces placed on it. During childhood, bone turnover is very high and formation outweighs resorption. In young adulthood, formation and resorption are in equilibrium. But after age 35-40, there is a net loss. The bone's overall mechanical properties are a combination of the rate of bone turnover, collagen matrix, structure, size, geometry, and the bone density. In order for the strength of the bone to be maintained, the bone turnover must be carefully regulated. The human skeleton is made up of long bones (e.g., humerus, tibia and femur) and flat bones (e.g., skull, ileum and scapula). There are 2 main histological types of mature bone: 1. The cortical or compact bone, which comprises up to 85% of the bone mass has a dense ordered structure. Cortical bone is found mainly in the shaft of long bones and the surfaces of flat bones. It is composed of bone laid down concentrically around central canals (Haversian systems). The canals contain blood vessels, lymph vessels, nerves and connective tissue. A concentric layer of rings or lamellae of bone matrix surround each Haversian canal. Tiny spaces (lacunae) containing osteocytes are within the lamellae. 2. The trabecular or cancellous bone is lighter than the cortical bone and has an irregular structure. Trabecular bone forms the ends of long bones and the inner parts of flat bones. It contains interconnecting plates and bars called trabeculae, with intervening marrow lending it a honeycomb appearance. The trabeculae are aligned along lines of stress; this connectivity adds considerably to its strength. The collagen fibres are parallel to one another arranged. In general, each bone has an outer layer of cortical bone overlying trabecular bone and the medullary cavity. The cortical bone has an outer membrane called the periosteum. The periosteum has two layers: 1. The outer fibrous layer 2. The inner cell layer with osteogenic potential which lays down new bone allowing the bone to enlarge, a process known as periosteal apposition. The inner surface of the cortex has another lining called the endosteum. Bone tends to undergo resorption from the endosteal surface. Both the periosteum and the endosteum contain the multicellular unit of bone which comprises osteocytes, osteoblasts and osteoclasts and their precursors. Osteoblasts and osteoclasts function in a coordinated manner, by their respective bone forming and resorbing activities, to carryout remodeling, growth and repair. **Bone turnover (remodeling):** Bone turnover is a dynamic process, which constantly renews the bone and maintains its mechanical competence. Each year, 5--10 % of the bone of the skeletal system is renewed in cycles. The term modeling is restricted to the period of skeletal growth, when the size and shape of the bone is determined. The process of bone turnover in adults is known as remodeling. Bone remodeling is part of the body's way to manage mineral (i.e., calcium and phosphate) homeostasis, and a mechanism for repair and adaption. The basic multi-cellular unit (Bone Remodeling Unit, or BRU) of remodeling, comprises the osteocytes, osteoblasts, and osteoclasts. The activity of the BRUs is regulated by mechanical forces, bone cell turnover, hormones (e.g., parathyroid hormone, growth hormone, calcitonin) and local factors. The remodeling is partially initiated by the osteocytes ([Fig. 1 -- Sequence of bone remodeling](https://www.clinical-laboratory-diagnostics-2020.com/k06.html#_idTextAnchor2746)), which detect mechanical stress and respond to biochemical stimuli. Activation results in the lining cells of the endosteal surface being retracted, and digestion by matrix metalloproteinases of the endosteal membrane. Osteoclasts are then recruited, followed by fusion of activated osteoclasts to become multi-nucleated osteoclasts. The activated osteoclasts cause resorption of the underlying bone forming a resorption cavity. The activation and resorption process takes 10--15 days. In the next step osteoblasts are recruited to the cavity, lay down new osteoid which becomes calcified. The entire process is completed after 3--6 months. The rate of bone turnover is dependent on the type of bone, being highest in sites where trabecular bone predominates (vertebrae) and lowest in cortical bone (hip).  **Figure 2**- Sequence of bone remodeling 1. Resting bone with lining cells that contain osteocytes. 2. The lining cells recede and the underlying membrane is removed by metalloproteinase. 3. Osteoclasts are recruited and activated followed by fusion to become multi nucleated osteoclasts. 4. Osteoclasts digest the underlying bone forming a resorption cavity. 5. Osteoblasts are recruited to the cavity. 6. Osteoblasts lay down new osteoid, which is then calcified. **Regulation of bone metabolism** Bone metabolism is regulated via central mechanisms (hormones) and the local control of the osteoblasts, osteocytes and osteoclasts. **Osteoblast:** derived from mesenchymal cells. It differentiates to osteocytes & synthesize and deposits the bone matrix. **Osteocyte:** Osteoblasts, encased by the matrix that they themselves synthesize become osteocytes, (terminally differentiated cells). Osteocytes have less matrix forming activity, and their alkaline phosphatase activity is reduced. The cells occupy small lacunae within the bone matrix and constitute more than 90% of the bone cells. Osteocytes, isolated by bone matrix from each other communicate through protoplasmic extensions via lacuno-canaliculi with neighboring cells. These processes may have the potential to stimulate bone resorption. Osteocytes act as mechanosensory cells and are responsible for the maintenance of bone structure and mass. By far the most abundant matrix protein in the osteocyte environment is type-1 collagen. **Osteoclast:** Osteoclasts are large end-differentiated multi nucleated cells derived from bone marrow macrophages of the hematopoietic lineage. The unique function is resorbing bone matrix. The osteoclastic bone resorption is important for modeling and remodeling the bone and for the calcium homeostasis. Normal bone physiology depends on the interaction of osteoblasts and osteoclasts. There are, however, diseases in which this interaction is disrupted, such as osteoporosis, Paget's disease and bone metastases. **Bone matrix:** The organic bone matrix produced by the osteoblastic cells contains: a. 90% collagen type 1 b. 5% proteoglycans (chondroitin sulfate, glucuronic acid, heparan sulfate, decorin, biglycan, versican), cell adhesion molecules (fibronectin, thrombospondin, vitronectin, osteopontin, bone sialoprotein), γ-carboxylated proteins (1% osteocalcin, matrix Gla protein, protein S) c. 3% growth factors and d. 2% osteonectin. **Mineralization of the organic bone matrix:** Active osteoblasts synthesize the bone matrix which is composed of organic (osteoid) and inorganic (mineral) components. The osteoid consists predominantly of type-1 collagen, with small amounts of proteoglycan, lipids and several non-collagenous proteins (osteocalcin, fibronectin, osteonectin and β-carboxyglutamic acid containing protein). The osteoid comprises about one third of the total skeleton weight. The inorganic mineral component consists of crystals of hydroxyapatite. Hydroxyapatite is a mineral composed of calcium, phosphate, and water and gives the bone its hardness and weight. The resorptive cavity created by the osteoclast is often the site of subsequent osteoblastic activity which fills the cavity with new bone. **Hormonal modulation of bone metabolism** During adulthood, bone is remodeled in order to adapt acute changes in calcium homeostasis, bio mechanical demands and to renew and repair old bone substance and osseous micro fractures. Hormones that systemically affect the bone metabolism are primarily parathyroid hormone and calcitriol (1,25(OH)~2~ VitD). Others include growth hormone/IGF-1, estrogens and testosterone, glucocorticoids, thyroid hormones, and calcitonin. *(See Fig 1 above)* The proliferation of osteoblasts is stimulated by some growth factors eg transforming growth factor-β (TGF-β), IGF-1. In contrast, PTH and some cytokines arrest osteoblast proliferation and indirectly stimulate bone resorption. The activity of osteoclasts is inhibited by calcitonin. **Markers of bone metabolism** In metabolic bone diseases (Paget's disease, rickets and osteomalacia, primary and secondary hyperparathyroidism) and osteoporosis, biomarkers of bone metabolism and bone turnover are important clinical tools in patient management. The biomarkers are supplementary to imaging procedures, bone mineral density measurements, and possible histomorphological examinations of bone aspirates. *Routine investigations and bone markers for the diagnosis and monitoring of bone disorders are shown in Table of summary. (See end of note)* Bone turnover markers reflect whole body rates of bone resorption and bone formation. The markers provide a dynamic assessment of the skeleton and can provide real-time assessment of bone remodeling. They consist of bone formation markers and bone resorption markers. The formation markers include enzymes and peptides released by the osteoblast at the time of bone formation, whereas the resorption markers are typically a measure of the breakdown products of type 1 collagen. **Bone formation markers**: In the serum, the markers that are preferably measured are those which show greater activation of the osteoblasts than the osteoclasts: - Bone Alkaline phosphatase (BALP) - Osteocalcin (OC) - Procollagen type 1 N-terminal propeptide (P1NP) - Procollagen type 1 C-terminal propeptide (P1CP) These markers are important, especially the bone ALP in combination with the PTH assay, if adynamic bone disease is suspected in dialysis patients. **Bone resorption markers**: The markers that are preferably measured are those which show greater activation of the osteoclasts than of the osteoblasts: - Hydroxyproline - Pyridinoline (PYD) and deoxypyridinoline (DPD) in the morning urine. - Collagen cross-linked telopeptides e.g., N- telopeptide (NTX), C-telopeptide (CTX), C-telopeptide of Type 1 collagen (ICTP) in urine (or blood). - Tartrate Resistant acid phosphatase (TRACP5a) The most important indication for bone resorption markers such as CTX, PYD and DPD is monitoring the course and assessment of the progress in treatment of osteoporosis. The markers give information: - Whether a high turnover bone metabolism exists. - How high the extent of the bone resorption is? - Whether there is a response to treatment. Within the scope of monitoring osteoporosis, the optimal points in time of the response to treatment with bisphosphonates is 1 month after the start of the treatment and 6 months for estradiol substitution. Bone resorption markers are also indicated: - For osteomalacia/rickets - For monitoring of Paget's disease - For estimating the bone participation in hyperparathyroidism. **Definition of Metabolic Bone Diseases** A group of diseases united by a common feature of an **abnormal bone chemical milieu** characterized by an **imbalance between bone formation & resorption** with **abnormalities of minerals (e.g., Ca, P) & hormones** (e.g., Vit D, PTH) leading to **defective skeleton & bone abnormalities.** They are often detected and monitored using bone markers and most are clinically reversible once the underlying defect has been rectified. **Types** There are many MBDs but our focus is on common ones with characteristic biochemical findings. 1. Osteoporosis (& Osteopenia) 2. Rickets & Osteomalacia 3. Chronic kidney disease metabolic bone disease, CK-MBD (Renal Osteodystrophy) 4. Paget's disease 5. Bone metastases The most prevalent MBDs are osteoporosis, osteomalacia and rickets, and renal osteodystrophy. These three diseases affect the skeleton in general. Two diseases characterized by localized bone involvement are Paget's disease and bone metastases. MBDs may also be due to disorders of PTH metabolism (Hyperparathyroidism, Hypoparathyroidism, Pseudohypoparathyroidism) and rare types include Osteogenesis imperfecta, component of Fanconi's Syndrome (a renal tubular disease associated with RTA type 1, hypokalemia, glycosuria, phosphaturia (& hypophosphataemia) and non-selective aminoaciduria, fibrous dysplasias, etc. Various other conditions, often rare, may produce generalised bone disease, with or without biochemical changes. **Common Types of Metabolic Bone Diseases** **1) OSTEOPOROSIS & Osteopenia** Osteoporosis is a MBD characterized by a progressive reduction in bone mineral density with abnormal micro-architecture giving rise to weak, fracture-prone bone. It is the most common metabolic bone disease in Western society (prevalence \~ 5%). However, prevalence in developing countries \> developed countries. Common in the elderly, especially postmenopausal women. M:F ratio = 1:4 **OSTEOPENIA:** This is also known as (''too little'' bone). It is a descriptive term for a loss of bone density observed radiologically. It may be local (as in disuse atrophy of an immobilized limb) or generalized osteopenia. Generalized osteopenia can be caused by osteoporosis unrelated to other diseases, endocrinopathies (hypercortisolism, hypogonadism, hyperparathyroidism, hyperthyroidism), deficiency states (rickets/osteomalacia, scurvy, malnutrition), neoplastic diseases (multiple myeloma, metastatic carcinoma, leukemia), chronic diseases (malabsorption syndrome, chronic renal failure), drugs (heparin, glucocorticoids, alcohol), and hereditary diseases (homocystonuria, osteogenesis imperfecta). Pathogenesis: The rate of formation is usually normal but the rate of resorption is increased. Increased osteoclast activity relative to osteoblast activity and there is greater loss of trabecular bone than compact bone. In women, the decrease in sex steroids at menopause accelerates bone loss to about 2% per year from 0.5% per year. There is equal loss of osteoid and mineral resulting in decreased bone mass. Aetiology: PRIMARY OSTEOPOROSIS: Type I osteoporosis occurs as a result of oestrogen deficiency, mostly affects trabecular bone and often gives rise to vertebral body collapse. (Postmenopausal osteoporosis) Type II occurs as a result of the natural loss of bone with age and affects trabecular and cortical bone, often associated with femoral neck fractures. (Senile osteoporosis) SECONDARY OSTEOPOROSIS: Endocrine causes: Thyrotoxicosis, Cushing's syndrome, hypogonadism, diabetes mellitus Drugs: heparin, corticosteroids, chronic alcoholism (number one cause in men) Other: immobilization, weightlessness (as in astronauts) Presentation: In the early stage it is asymptomatic but as the disease progresses bone pain (e.g., severe backache), spontaneous fractures and collapse of vertebrae, and fractures of the ribs and hips with minimal trauma occur. Fragility fractures of the spine, hip, forearm, humerus and pelvis are diagnostic of osteoporosis. Vertebral compression fracture, the most common osteoporotic fractures are frequently painful. **Investigation:** The diagnosis is often only made once patients present with fractures. The serum biochemistry is usually unhelpful in diagnosis because the levels of calcium, phosphate, and PTH are generally normal. Other biochemical tests may, however, be of use in detecting the [underlying causes] of secondary osteoporosis. The diagnosis depends on the clinical picture and radiological examination. The diagnosis of osteoporosis is determined by the bone mineral density, which is measured by dual-energy X-ray absorptiometry. The diagnosis of osteoporosis is established when the bone mineral density is less than or equal to 2.5 standard deviations below the reference range of a young adult population. Also, it is the best way to estimate the severity of the disease. Serum PINP has been found to reflect histomorphometric measures of bone formation and has been identified as the most promising marker of bone formation and designated the reference marker of bone formation in osteoporosis by the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine. Bone markers are principally used to assess the bone turnover state prior to commencement of therapy and to monitor therapeutic response. Markers of bone resorption should decrease with antiresorptive therapy whereas markers of formation would increase with PTH therapy. The plasma ALP activity may rise after a fracture. Urinary hydroxyproline excretion may be increased if there is rapid bone loss, but is often within reference interval. Urinary excretion of pyridinium crosslinks is increased in patients with osteoporosis but also in other conditions associated with increased bone resorption. Serum concentrations of CTX may be twice the upper limit of reference interval. Rx: Prevention is the primary goal. Patients at risk of developing osteoporosis should be counselled to avoid known risk factors, for example excessive alcohol intake. Adequate dietary intake of calcium, vitamin D, and regular exercise are also. Hormonal replacement therapy may be of value in preventing primary osteoporosis after menopause in women but this may have side effects. Raloxifene has been used and is a selective estrogen receptor modulator (SERM). Treatment with bisphosphonates (drugs which suppress bone resorption) may be beneficial. They increase BMD and inhibit bone resorption, probably by inhibiting osteoclast activity. Strontium ranelate is a dual action bone agent (DABA) that stimulates osteoblasts and inhibits osteoclasts. Calcitonin inhibits osteoclast reabsorption and recombinant PTH analogues such as Teriparatide stimulate osteoblasts. **2) OSTEOMALACIA AND RICKETS** Osteomalacia refers to the softening of bones due to a defective mineralization of the bone matrix or cartilage, or both resulting in the accumulation of excess osteoid. It is called ***Rickets*** in children. Aetiopathogenesis: The basic cause is calcium, phosphate deficiency or both. Calcium deficiency is usually due to the vitamin D deficiency syndromes. i. Decreased absorption (malnutrition, malabsorption syndromes) ii. Decreased production (lack of UV light, liver disease, kidney disease, anti-epileptics, α-1-hydroxylase mutations) iii. Resistance to vitamin D Phosphaturic rickets (phosphate deficiency) is most commonly due to due to chronic renal losses (defective tubular phosphate reabsorption) e.g., familial X-linked hypophosphataemia, Fanconi syndrome-RTA type 2) and phosphate malabsorption due to gut-binding by aluminium hydroxide antacids. In renal tubular acidosis type I (distal) there is significant loss of calcium and phosphate in the urine as the bone is mobilized to buffer the metabolic acidosis. The clinical feature of rickets in children are bone pain, fracture, and skeletal deformities such as enlarged costochondrial joints (rachitic rosary), bow legs (genu varum), knock-knees (genu valgus), and cranial defects such as frontal bossing, and posterior skull flattening (craniotabes). Also, growth retardation and muscle weakness. The feature of osteomalacia in adults are non-specific and include bone pain, muscular weakness, and fractures associated with minimal trauma. Typical X-ray changes include generalized decalcification (crushed glass appearance), widening of epiphyses (wineglass appearance), pseudo-fractures and subperiosteal erosions. The characteristic biochemical features are: hypocalcaemia, hypophosphataemia, elevated ALP and elevated serum PTH levels (secondary hyperparathyroidism). Calcium levels are however usually low/normal due to secondary hyperparathyroidism as the parathyroids try and mobilize calcium. Phosphate is often low due to the action of PTH and alkaline phosphatase levels are characteristically high as osteoblasts attempt to lay down new bone. In the vitamin D deficient syndromes there will be decreased serum vitamin D and its metabolites (normal in familial hypophosphataemia). Serum concentrations of CTx may be twice the upper limit of normal in patients with osteomalacia. Treatment: Identify the causal factors and then aim to treat the underlying cause wherever possible. Therapy involves Vitamin D or its hydroxylated derivatives together with calcium and phosphate supplements. (Osteomalacia in phosphaturic rickets and in renal osteodystrophy is \"resistant\" to vitamin D.) **3) CHRONIC KIDNEY DISEASE METABOLIC BONE DISEASE** **(CKD-MBD) or RENAL OSTEODYSTROPHY** *(see Wikipedia for difference btw Renal osteodystrophy & CKD-MBD)* This is a type of MBD which occurs in chronic renal failure (or CKD) in which there is osteitis fibrosa (fibrosing-osteitis), osteomalacia, secondary hyperparathyroidism and osteosclerosis. Also known as "Renal rickets". **Pathogenesis:** Inability to excrete phosphate is the initiating event in renal osteodystrophy i. High phosphate suppression of alpha-1 hydroxylase activity together with overall loss of alpha-1-hydroxylase due to decreased renal mass results in 1,25(OH)~2~ VitD deficiency and osteomalacia with hypocalcaemia ii. Chronic acidosis promotes bone demineralization (*osteomalacia*) to buffer hydrogen ions. iii. Hyperparathyroidism due to hypocalcaemia triggers increased bone resorption to try and raise serum calcium levels; PTH induced bone disease is called osteitis fibrosa *cystica*. iv. Hyperphosphataemia due to renal inability to excrete it can trigger metastatic calcification if the solubility product of Ca and P is exceeded. This is called osteosclerosis in bone. Bone pain is the most common complaint of patients with renal osteodystrophy. The weight-bearing bones are the site of greatest discomfort, with leg and hip pain and back pain being common. If the patient is a growing child, skeletal deformities may result, with bowing of the extremities, kyphoscoliosis, and slipped femoral epiphyses. Biochemically these patients have a low or low/normal calcium with secondary very high PTH and hyperphosphataemia. 1,25(OH)~2~ VitD is decreased. Serum ALP is increased in patients with hyperparathyroidism or osteomalacia. Treatment: Early management of renal failure calls for dietary restriction of phosphate and administration of phosphate-binding agents. Calcium supplements added to the diet to prevent secondary hyperparathyroidism may also serve as phosphate binders. Administration of 1,25(OH)~2~ VitD or other active forms of vitamin D enhances intestinal calcium absorption and may act directly on the parathyroid gland to reduce PTH secretion. Ultimately, dialysis or renal transplantation may be necessary. *Parathyroidectomy (especially if tertiary hyperparathyroidism has developed)* **4) PAGET'S DISEASE OF BONE (Osteitis Deformans)** A metabolic bone disease characterized by excessive osteoclastic bone resorption followed by formation of new bone of abnormal structure (dense trabecular bone) that is laid down in a disorganized manner resulting in deformed bones. There is increased bone turnover and remodelling due to increased osteoclastic and osteoblastic function. It is often seen in the elderly. The disorder may affect a single bone (monostotic) or many bones (polyostotic). The monostotic disorder may be asymptomatic and only come to light when the patient is investigated for some other problem. The prevalence is difficult to estimate because many subjects with the disorder are asymptomatic but surveys have indicated that 3-4% of subjects over 40 years and up to 10% over the age of 70 years have the disorder. It is often asymptomatic; the common presenting features are bone pain, bone deformities (bowed tibia/ sabre tibia, kyphosis, increasing skull size/osteoporosis circumscripta), and pathologic fractures. Sometimes, deafness due to auditory nerve compression by bone and high-output cardiac failure due to increased vascularity within the bone. The characteristic biochemical findings are: Normal serum calcium and phosphate levels (immobilisation of patients with widespread disease can result in hypercalcaemia and hypercalciuria). Moderate to markedly elevated serum alkaline phosphatase levels (values in excess of 1000 U/L are not unusual and values in excess of 2000 U/L have been recorded). Normal serum PTH levels. There is increased urinary excretion of hydroxyproline during active disease. Serial measurements of serum ALP and urinary hydroxyproline may be used when monitoring treatment of Paget's disease. Concentrations of serum CTX are 2--4 times the upper reference limit. The diagnosis is made on the basis of the clinical and/or biochemical picture and confirmed by radiology. The differential diagnosis is secondary malignancy, particularly prostatic carcinoma, which can present with a similar biochemical and radiological picture. The aim of managing Paget's disease is to give relief from bone pain and to prevent disease progression. Analgesics may be used to give relief from the pain. In severe cases, bisphosphonates may be used to reduce osteoclastic activity. Patients with bone deformity may require supports such as heel lifts or specialized footwear. Corrective surgery may be required where joints are damaged, for fractures, or severely deformed bones, or where nerves are being compressed by enlarged bones. **5) BONE METASTASES** Bone metastases are the most common skeletal complication of malignancy. Aetiopathogenesis: They occur in up 70% of patients with advanced breast or prostate cancer, and in 15% to 30% of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid gland, or kidney. Metastases can have a markedly osteolytic or osteoblastic character, but often they are mixed. Most patients with breast cancer have predominantly osteolytic lesions, but about 15% to 20% of metastases have a predominantly osteoblastic nature. Metastases of prostate cancer are generally regarded as osteoblastic. In most carcinoma metastases, however, both bone degradation and formation take place to some extent, and so both biochemical markers of bone formation and resorption can be of value in assessing the presence of bone metastasis. The lesions of multiple myeloma are purely osteolytic; the tumor cells secrete factors that suppress bone formation; generalized osteoporosis is also a feature of the disease*.* Biochemical findings: they may be silent (esp primary bone malignancies) or associated with hypercalcaemia, or hyperphosphatasaemia, or both. Haematological malignancies such as multiple myeloma and leukaemia can also present with similar biochemical features. *The main differential diagnosis is Paget\'s disease.* Many biochemical bone markers, reflecting bone formation or bone resorption, have been investigated for their potential for early detection or treatment monitoring of both bone metastases and myeloma. In addition to localized malignant lesions, generalized osteoporosis can complicate the interpretation of most resorption markers, with the possible exception of ICTP. In multiple myeloma, serum ICTP and urinary NTX are the most sensitive tools for estimating increased bone breakdown and may be clinically useful for identifying patients with increased risk for progression of bone disease. Resorption markers (e.g., deoxypyridinoline \[DPD\]) respond promptly to antiresorptive therapy (e.g., with bisphosphonates) for multiple myeloma, whereas serum ICTP has been reported to predict the overall clinical outcome. TRACP5b activity is increased in various carcinomas with bone involvement, but evidence for its clinical value is still quite limited. In carcinomas with predominantly or partially osteoblastic metastases, bone formation markers such as P1NP can help in early detection of skeletal involvement. **DIAGNOSIS OF METABOLIC BONE DISEASES** The diagnosis of metabolic bone diseases requires a careful history and physical examination. Other tests that can be performed for diagnosis of MBD may be invasive or non-invasive. The specific radiographic examination is usually non-invasive. Bone biopsy may be indicated in some cases (an invasive test). The ilium is the standard biopsy site for the evaluation of metabolic bone diseases. The preparation of undecalcified bone sections permits a distinction to be made between osteoid and mineralized bone and thus the histological identification of disorders of bone mineralization. Appropriate laboratory tests which may be invasive (serum) or non-invasive (urine) can also be done. Depending on whether the bone pathology is a formative or resorptive the following analytes can be biochemically assayed: **[Bone Formation]** - Procollagen type 1 N-terminal propeptide (P1NP) - Procollagen type 1 C-terminal propeptide (PINCP) - Bone Alkaline Phosphatase (BAP) - Osteocalcin (OC) **[Bone Resorption]** - Hydroxyproline - Pyridinium cross links e.g., Deoxypyridinoline (DPD), Pyridinoline (PYD) - Collagen cross linked telopeptides e.g., N -- telopeptide (NTX), C -- telopeptide (CTX), C-telopeptide of Type 1 collagen (ICTP) - Tartrate Resistant acid phosphatase (TRACP5a) **Summary of Routine Biochemical findings in Metabolic Bone Diseases** **Condition** **Ca** **Phosphate** **ALP** **PTH** **Vit D** **Remarks** -------------------------------- -------- --------------- --------- --------- ----------- --------------------------------------------- OSTEOPENIA N N N N N/Lo Low BMD (1-2.5 SD) OSTEOPOROSIS N N N N N/Lo Very Low BMD (\< 1 SD) RICKETS & OSTEOMALACIA Lo Lo Hi Hi Lo Low BMD PAGET'S DISEASE N N Hi N N Elevated P1NP, P1CP, CTX RENAL OSTEODYSTROPHY (CKD-MBD) Lo Hi Hi Hi Lo BONY METASTASES Hi Hi/N Hi Hi N Markers of both bone formation & resorption **Condition** **Ca** **P** **ALP** ---------------------- -------- ------- --------- OSTEOPOROSIS RICKETS PAGET'S DISEASE RENAL OSTEODYSTROPHY