Physiology, structure and formation of bone

Bone is subdivided into cortical and cancellous bone. In an adult long bone, cortical bone forms the diaphyseal shaft within which is the medullary cavity containing bone marrow. Cancellous bone consists of a network of interconnecting trabecular plates and rods, and is found within the medullary cavity at the epiphyses. Bone remodelling takes place at four bone surfaces: the periosteum, the Haversian systems, at the endosteum of cortical bone and the cancellous bone surface, which is continuous with the endosteal surface. In normal adult bones, 80% of surfaces are quiescent. The rest are remodelled by a coupling process, resorption by osteoclasts being followed in sequence by bone matrix synthesis and mineralization by osteoblasts. This process takes 4 months with no net change in bone mass. Bone metabolism and mineralization is thus dependent on:
• Collagen synthesis
• Absorption and availability of calcium, affected by vitamin D
• Bone resorption and deposition, largely under hormonal control with local factors affecting bone resorption and remodelling.


Calcium absorption and distribution

Normal Western adult calcium consumption is approximately (20-25 mmol Ca2+) (800-1000 mg) daily, though it is much lower in some less affluent countries. Calcium deficiency does not appear to be a significant cause of bone disease, probably because calcium absorption increases in states of dietary calcium deficiency. Absorption is, however, sometimes reduced by generalized malabsorption.
Calcium fluxes between gut, plasma, bone and kidney are shown in Fig. 8.24. The circulating pool of calcium (about 12 mmol in total) is tiny compared with the bOD\” reservoir and small compared with the daily fluxes. Regulation

Vitamin D metabolism

The metabolism and actions of vitamin D are shown . Vitamin D is produced in the skin as cholecalciferol (vitamin D3) by photoactivation of 7-dehydrocholesterol. This, rather than dietary vitamin D, is the chi – source of vitamin D metabolites in humans and poor nutrition is of only small importance in producing vitamin D deficiency. These metabolites are transported in the circulation bound to vitamin D-binding protein.
the liver cholecalciferol is hydroxylated to 25-hydroxycholecalciferol (25(OH)D3) and the measurement of this in the blood is a good indicator of vitamin D bioavailability. The next step in the metabolism occurs in the kidn where, in the tubules, the enzyme l o-hydroxylase is CODcentrated and the highly biologically active 1,25-dihydroxycholecalciferol (l,25(OH)2D3) is produced. The kidneyalso produces a second metabolite, 24,25(OH)2D3′ well as 1,25(OH)2D3 if vitamin D supplies are adequate.. The production of 1,25(OH)2D3 is strictly regulated parathyroid hormone (PTH), phosphate and by a feedback inhibition by 1,25(OH2)D3 itself. Hypocalcae also stimulates 1,25(OH2)D3 production probably \ PTH.
Extra-renal sources of 1,25(OH)2D3 production are small under normal conditions but it can be produced – lymphomatous and sarcoid tissue. The mode of action is similar to that of other stero hormones, i.e. interaction with a specific receptor in target cell (Fig. 8.26): 1,25(OH)2D3 attaches non-coxently to an intracellular receptor protein; this complex is transported through the nuclear membrane into the nucleus, where it interacts with 0 A to initiate or suppress the synthesis of RNA-encoding proteins. The control of this is regulated by several factors; for example, interleukin, interferons and C-MYC down-regulate, and prolactin and fibronectin up-regulate. The biological potencies of the D3 metabolites influence their ligand affinities for the receptor proteins. Bone, gut, kidney and the parathyroid gland are the prime target organs, but many other tissues respond to 1,25(OH)2D3′ e.g. the skin, activated lymphocytes and cancer cells. This suggests a much wider role, e.g. immunoregulation and cellular differentiation, for vitamin D.

Calcium exchange in the normal human. The fluxes are shown in mmols per day.
Calcium exchange in the normal human. The fluxes are shown in mmols per day.
The metabolism and actions of vitamin 0. PTH, parathyroid hormone.
The metabolism and actions of vitamin 0. PTH, parathyroid hormone.

Parathyroid hormone

PTH levels rise as plasma calcium falls. The effects of PTH, secreted by the four parathyroid glands, are several, all serving to raise plasma calcium:

• Increased tubular reabsorption of calcium
• Increased excretion of phosphate
• Increased osteoclastic resorption of bone
• Increased intestinal absorption of calcium
• Increased synthesis of 1,25(OH)2D3
The effects are mediated at membrane receptors on the target cells, with resultant increased adenyl cyclase activity.
While the parathyroids are usually situated posterior to the upper and lower lobes of the thyroid, additional local ones are sometimes seen and they may also occasionally be found elsewhere in the neck or in the mediastinum.

Suggested mode of action of l,25(OH),D. (DO) on target cells (see text).
Suggested mode of action of l,25(OH),D. (DO) on
target cells (see text).

Other regulatory factors

CALCITONIN. This 32 amino acid polypeptide is produced by thyroid C-cells. Its physiological importance in man as a hypocalcaemic hormone remains uncertain. Plasma levels rise with increasing plasma calcium, and it is known to inhibit osteoclastic bone resorption and increased renal excretion of calcium and phosphate. However, total thyroidectomy (absent calcitonin) and medullary carcinoma (excess calcitonin) have few skeletal or other noticeable clinical effects. It is, however, used in the treatment of Paget’s disease and, rarely, in hypercalcaemia.

GLUCOCORTICOIDS. Steroids have complex actions on bone, essentially leading to excessive bone resorption and osteoporosis.
SEX HORMONES. Androgens and/or oestrogens have several effects on the skeleton:
• In puberty they induce the growth spurt and subsequent epiphyseal closure
• Both influence skeletal calcium content, especially postmenopausal oestrogen deficiency, which leads to progressive bone loss
GROWTH HORMONE. Acting via IGF-1 (insulin-like growth factor-I or somatomedin C, see p. 797) growth hormone stimulates growth of cartilage.
THYROID HORMONES. Excess thyroxine (T.) and triiodothyronine (T3) cause increased bone turnover, while hypothyroidism leads to growth delay.
THE ROLE OF MAGNESIUM. Total body magnesium is about 25 g. Plasma magnesium ranges between 0.7 and 1.1 mmol litre “, and generally follows plasma calcium. Magnesium deficiency prevents the release of PTH; the level should be measured when there are signs and symptoms of hypocalcaemia unresponsive to calcium administration.
THE ROLE OF PHOSPHATE. Phosphate forms an essential part of most biochemical systems from nucleic acids downwards. About 80% of all body phosphorus is within bone, plasma phosphate normally ranging from 0.80 to 1.40 mmollitre-I. Phosphate reabsorption from the kidney is decreased by PTH, thus hyperparathyroidism is associated with low plasma levels of phosphate. High levels are found in hypoparathyroidism and in renal failure when normal excretion does not occur.

Measurement of plasma calcium, phosphate and PTH

Total plasma calcium is normally 2.2-2.6 mmollitre-I (8.5-10.5 mg dl””). Usually only 40% of total plasma calcium is ionized and physiologically relevant; the remainder is protein bound or complexed and thus unavailable to the tissues. Ionized calcium is difficult to measure, but is very dependent upon protein, in particular albumin, concentration. An approximate correction for plasma calcium is to add or subtract 0.02 mmol litre ” for every gram per Litre by which the simultaneous albumin lies below or above a standard figure (normally 40 or 47 g litre-I). Thus, a total calcium of 2.22 mmollitre-I with an albumin of 35 g litre-I will become 2.32 mmollitre-I (corrected to 40 g litre-I).
For critical measurements, samples should be taken in the fasting state without use of a cuff, as this affects protein concentration.
Improved two-site immunoradiometric assays for PTH are now available that only measure the intact molecule and not fragments; interpretation requires simultaneous plasma calcium and phosphate measurements.

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