A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 297

●Vitamin D 297

●Calcium 298

●Treatment of hypercalcaemia 299

●Bisphosphonates 299

●Calcitonin 300

●Strontium ranelate 300

●Teriparatide 300

●Cinacalcet 300

CHAPTER 39

39 Calcium metabolism

VITAMIN D

The term ‘vitamin D’ covers several related compounds that

share the ability to prevent or cure rickets. These include ergo-

calciferol (vitamin D 2 ), cholecalciferol (vitamin D 3 ),α-calcidol

(1-α-hydroxycholecalciferol) and calcitriol (1,25-DHCC). The

metabolic pathway of vitamin D is summarized in Figure 39.1.

Vitamin D 3 is synthesized in skin in response to ultraviolet light

or absorbed in the upper small intestine. It is fat soluble, so bile

is necessary for its absorption. Renal 1-α-hydroxylase is acti-

vated by PTH and inhibited by phosphate, which thus influ-

ence the amount of active 1,25-DHCC produced. 1,25-DHCC is,

in effect, a hormone synthesized in the kidney. It augments

intestinal calcium absorption, mobilizes calcium from bone and

stimulates calcium reabsorption in the kidney (a minor effect).

Storage of vitamin D occurs in the body, so a single large

dose may be effective for several weeks. Enzyme induction

(Chapter 5), e.g. by anti-epileptic drugs, increases metabolic

inactivation of vitamin D and can lead to osteomalacia.

Uses

Dietary deficiency of vitamin D occurs where there is poverty

and poor diet, accentuated by lack of sunlight. Asian communi-

ties living in northern regions of the UK are at risk (chapatis and

other unleavened breads also reduce the absorption of vitamin

D), as are elderly people living alone. Pregnant and lactating

women have increased requirements. Several vitamin D prepa-

rations are available, with different potencies and uses.

INTRODUCTION

Plasma calcium is sensed by a calcium-sensitive receptor
(CaSR) in parathyroid and renal tubular cells, and maintained
within a narrow physiological range by parathyroid hormone
(PTH), vitamin D and calcitonin. The plasma calcium concen-
tration is the major factor controlling PTH secretion and a
reduction in calcium concentration stimulates PTH release.
PTH raises plasma calcium and lowers phosphate concentra-
tion. It acts on kidney and bone. PTH causes phosphaturia and
increases renal tubular reabsorption of calcium, which in asso-
ciation with mobilization of calcium from bone, increases the
plasma calcium concentration. Effects of PTH on bone include
stimulation of osteoclast activity, formation of new osteoclasts
from progenitor cells and transient depression of osteoblast
activity. PTH also plays a role in the regulation of vitamin D
metabolism, indirectly increasing gut absorption of calcium
by stimulating production of the active metabolite 1,25-
dihydroxycholecalciferol (1,25-DHCC or calcitriol, see below).
Several important metabolic diseases affect the bones,
notably hyperparathyroidism, osteomalacia and rickets,
Paget’s disease and osteoporosis. Some of these diseases (e.g.
osteomalacia) are associated with normal or low plasma cal-
cium concentrations, some (e.g. hyperparathyroidism) are
associated with hypercalcaemia and some (e.g. osteoporosis)
are associated with normal plasma calcium concentrations.
Post-menopausal osteoporosis is the most common of these
disorders; iatrogenic glucocorticoid or thyroid hormone excess
are important contributory causes. Those at risk should take
adequate dietary calcium and vitamin D (see below) and con-
tributory factors corrected if possible. Hormone replacement
therapy (HRT) with oestrogen (Chapter 41) is no longer first
line as a prophylaxis against osteoporosis in women over
50 because of an excess of thrombotic events, although it is at
least temporarily effective if started soon after menopause.
Raloxifeneis an alternative (Chapter 41). Bisphosphonates
andteriparatide(see below) are effective in treating post-
menopausal osteoporosis.

Key points

Pathophysiology of common metabolic bone disease

• Osteoporosis is characterized by reduced bone quantity
  (density).


• Paget’s disease is characterized by excessive new bone
  formation and bone resorption.


• Osteomalacia is characterized by lack of bone
  mineralization.