CHAPTER 42 AGENTS THAT AFFECT BONE MINERAL HOMOEOSTASIS.

PRINCPLE HORMONAL REGULATORS OF BONE MINERAL HOMEOSTASIS.

PTH (parathyroid hormone)

Single-chain peptide hormone composed of 84 amino acids. It produces at THYROID GLAND in
precursor form of 115 amino acids. Contains vit D receptor and the enzyme, CYP27B1 (produces 1,
25(OH) 2D to suppress PTH production. Metabolic clearance of intact PTH is rapid, with a half time of
disappearance measured in minutes.

BONE – PTH increases the activity and number of osteoclasts, the cells responsible for bone resorption;
however PTH act s on the osteoblast to induce membrane-bound and secreted soluble forms.
RANK LIGAND (RANKL) acts on osteoclasts and osteoclast precursor to increase both the number and
activity of osteoclasts.
This action increase bone remodeling, a specific sequence of cellular events initiated by osteoclast bone
formation.
DENOSUMAB – an antibody that inhibits the action of RANKL has been developed for the treatment of
excess bone resorption in patients with osteoporosis and certain cancer.
PTH inhibits production and secretion of sclerostin from osteocytes.
SCLEROTIN – protein that blocks osteoblast proliferation by inhibiting the wnt pathway.
VITAMINE D – found in dairy products. Both natural form (vit D3 cholecaliferol) and plant derived form (vit
D 2 ergocaliferol) are present in the diet. Is the first hydroxylated in the liver.
ERGOCALIFEROL – contains double bond, binds well than choleciferol and its metabolites to vitamin D-
binding protein. The major transport protein of these compounds in the blood and have different path of
catabolism. So their half-life is shorter.

DRUGS
Calcipotriene (calcipotiol) used to treat psoriasis.
Doxercalciferol and paricalcitol treatment for secondary hyperparathyroidism in patients with chronic
kidney disease.
Eldecalcitol phase 3 clinical trials in japan for the treatment of osteoporosis.
Fibroblast growth factor is a single chain protein with 251 amino acids, including a 24 amino acid leader
sequence. It inhibits 1, 25(OH) 2D production and phosphate reabsorption in the kidney. It requires O-
glycosylation for its secretion. FGF23 is normally in activated by cleavage at an RXXR site. Mutations in
this site lead to excess FGF23, the underlying problem in autosomal dominant hypophosphatemic
rickets.

Interaction of PTH, FGF23 and VITAMINE D

Main targets: intestine, kidney, bone
PTH in intestine increase calcium and phosphate. In kidney decrease calcium exertion, increase
phosphate excretion. In bone calcium and phosphate increase by high doses.
Vit D in intestine increase calcium and phosphate. In kidney calcium and phosphate may be decrease. In
bone increase calcium and phosphate resorption.
FGF23 in intestine decrease calcium and phosphate absorption. In kidney increase phosphate excretion,
decrease 1, 25(OH) 2D production. In bone decrease mineralization.

SECONDARY HORMONAL REGULATORS OF BONE MINERAL HOMEOSTASIS

A number of hormones modulated the actions of PTH, FGF23, and vitamin D in regulating bone mineral
homeostasis.

CALCITONIN
The principle effects of calcitonin are to lower serum calcium and phosphate by actions on bone and
kidney. Inhibits osteoclastic bone resorption.
In the kidney
Calcitonin reduces calcium and phosphate reabsorption as well as reabsorption of other ions, including
sodium, potassium and magnesium.
Calcitonin in pharmacological amounts decreases gastrin secretion and reduces gastric acid output while
increasing secretion of sodium, potassium, chloride and water in the gut. pentagastrin isa potent
stimulator of calcitonin secretion.

GLUCOCORTICOIDS
Hormones alter bone mineral homeostasis by antagonizing vitamin D stimulated intestinal calcium
transport. This hormone has proven useful in revising the hypercalcemia associated with lymphomas and
granulomatous disease.
Prolonged administration of glucocorticoids is common cause of osteoporosis in adults and can cause
stunted skeletal development in children

ESTROGEN
Can prevent accelerated bone loss during the immediate postmenopausal period and at least transiently
increase bone in postmenopausal woman. Estrogen also increases DBP production by the liver, which
increases the total concentrations of the vitamin D metabolites in circulation without necessarily
increasing the free levels.
Receptors: bone
Estrogen has direct effects on bone remodeling.

DENOSUMAB
Is a fully human monoclonal anti body that binds to and prevents the action of RANKL.
Inhibits osteoclast formation and activity. It isa an effective as the potent bisphosphonates in inhibiting
bone resorption and has been approved for treatment of postmenopausal osteoporosis and some cancer.
Administered subcutaneously every 6 months.

CALCIMIMETICS
First representative of a new class of drugs that activates the calcium sensing receptor. CASR is widely
distributed but has its greatest concentration in the parathyroid gland. Cinacalcet is approved for the
treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of
parathyroid carcinoma.

PLICAMYCIN
Is a cytotoxic antibiotic, used for two disorder the Paget disease and hypercalcemia?

THIAZIDES DIURETIC
Thiazides may increases the effectiveness of PTH in stimulating reabsorption of calcium by renal tubules
or may act on calcium reabsortption secondarily by increasing sodium reabsorption in the proximal tubule.

FLUORIDE
Effective for the prophylaxis of dental caries and has previously been investigated for the treatment of
osteoporosis.flouride in drinking water is most effective in preventing dental caries if consumed before
the eruption of the permanent teeth. Adverse effect: nausea, vomiting, gastrointestinal blood loss.

STRONTIUM RANELATE
This drug is used in Europe for treatment of osteoporosis. Appears to block differentiation of osteoclasts
while promoting their apoptosis, thus inhibiting bone resorption.

ABNORMAL SERIUM CALCIUM AND PHOSPHATE LEVELS

HYPERCALCEMIA
Causes central nervous system depression, including coma and potentially lethal. Major causes are
hyperparathyroidism and cancer.
HYPERPHOSPHATEMIA
Is a common complication of renal failure and also found in all types of hyperparathyroidism, vitamin
D intoxication and the rare syndrome of tumoral calcinosic.

HYPOPHOSPATEMIA
Acute hypophosphatemia may cause a reduction in the intracellular levels of high energy organic
phosphate. Should be avoided when using forms of therapy that can lead lead to it.

PRIMARY HYPERPARATHYROIDISM
Cinacalcet approved for secondary hyperparathyroidism.

HYPOPARATHYROIDISM
In PTH deficiency or an abnormal target tissue response to PTH, serum calcium falls and serum
phosphate rises. A number of patients with pseudohypoparathyriodism appear to have osteits fibrosa,
suggesting that the normal or high PTH levels found in such patients are capable of acting on bone not on
the kidney. The principle therapeutic goal is to restore normocaclcemia and normophospatemia. Vitamin
D and calcium is due in the past. This complication is more rapidly reversible with cessation of calcitriol
therapy than therapy with vitamin D.

NUTRITIONAL VITAMINE D DEFICIENCY OR INSUFFICIENCY

The level of vitamin D thought to be necessary for good health is being reexamined with the appreciation
that vitamin D acts on a large number of cell types beyond those responsible for bone and mineral
metabolism.

CHRONIC KIDNEY DISEASE

The major sequel of chronic kidney disease that impact bone mineral homeostasis are deficient
1,25(OH)2D production,retentionof phosphate with an associated reduction in ionized calcium levels and
the secondary hyperparathyroidism that results from the parathyroid gland response to lowered serum
ionized calcium an low 1,25(OH)2D.

In contrast to the hpocalcemia that is more often associated with chronic kidney disease, some patients
may become hypercalcemic from overzealous treatment with calcium. In the absence of kidney function,
any calcium absorbed from the intestine accumulates in the blood.

DEFEROXAMINE an agent used to chelate iron also binds aluminum and is being used to treat this
disorder.

VITAMINE D PREPERATION
Individuals with vitamin D deficiency or insufficiency should first have their 25(OH) D levels restored to
normal (20-30) with vitamin D. DOXERCALCIFEROL and PARICALCITOL treatment for secondary
hyperparathyroidism of chronic kidney disease.
INTESTINAL OSTEODYSTROPHY a number of gastrointestinal and hepatic disease cause disordered
calcium and phosphate homeostasis, which ultimately leads to bone disease. The important common
features in this group of disease appear to be malabsorption of calcium and vitamin D.

OSTEOPOROSIS defined as abnormal loss of bone predisposing to fractures. It is common in

postmenopausal in women but also occurs in men. Osteoporosis is most commonly associated with loss
of gonadal function as in menopause but may also occur as an adverse effect of long term administration
of glucocorticoids or other drugs.

ALENDRONATE, RISEDRONATE, IBANDRONATE, AND ZOLEDRONATE are approved for the

treatment of osteoporosis. The serm RALOXIFENE is approved for treatment of osteoporosis. It protects
against spine fractures. It does not prevent hot flushes and imposes the same increased risk of venous
thromboembolism as estrogen. TERIPARATIDE the recombinant form of PTH 1-34, is approved for
treatment of osteoporosis if given 20mg subcutaneously daily. CALCITONIN is approved for use in the
treatment of postmenopausal osteoporosis.

X-LINKED AND AUTOSOMAL DOMINANT HYPOPHOSPHATEMIA AND RELATED DISEASE

This disorder usually manifest in childhood as rickets and hypophostemia, although they first present in
adults.in both X-linked and autosomal dominant hypophosphatemia biologically active FGF23
accumulates leading to phosphate wasting in the urine and hypophostemia.

NEPHROTIC SYDROME
Patients with nephrotic syndrome can lose vitamin D metabolites in the urine presumably by loss of the
vitamin D binding protein. Such patients may have very low 25(OH)D levels.

IDIOPATHIC HYPERCALCIURIA individuals with idiopathic hypercalciuria, characterized by

hypercalcuria and nephrolithiasis with normal serum calcium and PTH levels. Divided into 3 groups:

1. Hyperabsorbers, patients with increased intestinal absorption of calcium, resulting in high-normal

serum calcium. low normal PTH and secondary increase in urine calcium.
2. Renal calcium leakers, patients with a primary decrease in renal reabsorption of filtered calcium
leading to low normal serum calcium and high normal serum PTH
3.renal phosphate leakers, patients with a primary decrease in renal reabsorption of phosphate, leading
to increased 1,25(OH)2D production, increased intestinal calcium absorption, increased ionized serum
calcium, low-normal PTH levels and a secondary increase in urine calcium.

ENTERIC OXALURIA
Patients with short bowel syndromes and associated fat malabsorption can present with renal stones
composed of calcium and oxalate. the reason for the development of oxaluria for some patients are
thought to be twofold: first in the intestinal lumen,calium fails in the binds oxalate and no longer prevents
its absorption; second enteric flora acting on the increased supply of nutrients reaching the colon produce
larger amounts of oxalate.

The increase intestinal calcium binds the excess oxalate and prevents its absorption. One to 2g of
calcium carbonate can be given daily in divided doses, with careful monitoring of urinary calcium and
oxalate to be certain that urinary oxalates fall without a dangerous increase in urinary calcium.