Agents Affecting Mineral Ion

Homeostasis and Bone Turnover

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 Calcium
Adult men 1300 g, women 1000 g of calcium
99% is in bone and teeth.
Normal serum calcium ranges from 8.5 to 10.4 mg/dL (4.25–5.2 mEq/L, 2.1–
2.6 mM)
three components:
ionized (~50%), exerts biological effects and this fraction is tightly
regulated
protein-bound (~40%, predominantly to albumin
complexed to anions such as phosphate and citrate (~10%)
CALCIUM STORES

Skeletal calcium largely is in a crystalline form that resembles

the mineral hydroxyapatite with other ions in the crystal lattice.

The steady-state content of calcium in bone reflects the net

effect of bone resorption and bone formation
CALCIUM ABSORPTION AND EXCRETION

In the U.S., ∼75% of dietary calcium is obtained from milk and dairy
products.

The recommended adequate daily intake value for calcium is 1300 mg in

adolescents, 1000 mg in adults, and 1250–1500 mg in postmenopausal
women; typical intake is only ∼50% of these values.

Calcium enters the body only through the intestine (∼300 mg/day), both by
facilitated diffusion throughout the small intestine and by active transport in
the proximal duodenum.

The former accounts for the majority of total calcium uptake, whereas
active transport is the process that is regulated by vitamin D.
CALCIUM ABSORPTION AND EXCRETION

The efficiency of intestinal calcium absorption is inversely related to total

calcium intake.

Certain drugs such as glucocorticoids or phenytoin depress intestinal calcium

transport.

Opposed to uptake is an obligatory calcium loss of 150 mg/d due to mucosal

and biliary secretions and sloughing of intestinal cells; diseases associated
with chronic diarrhea or malabsorption promote fecal calcium loss.
CALCIUM ABSORPTION AND EXCRETION

Calcium excretion in the kidney also is highly regulated.

About 9 g of Ca2+ is filtered in the glomeruli, of which >98% is

reabsorbed in the tubules.

The efficiency of tubular reabsorption is tightly regulated by

parathyroid hormone (PTH) but also is influenced by filtered Na+,
the presence of non–reabsorbed anions, and diuretics.
 Phosphate

Phosphate is present in plasma, extracellular fluid, cell membrane phospholipids,

intracellular fluid, collagen, and bone.

More than 80% of total body phosphate is found in bone and ∼15% in soft tissues.

Phosphorus (P) in the body exists in both organic and inorganic forms.

Organic forms include phospholipids and various organic esters.

In extracellular fluid, the bulk of phosphorus exists as inorganic phosphate (Pi) in

the form of NaH2PO4 and Na2HPO4.

Within bone, phosphate is complexed with calcium as hydroxyapatite and calcium

phosphate.
ABSORPTION, DISTRIBUTION, AND EXCRETION

Phosphate is a component of many foods;

Intestinal uptake of phosphate primarily is passive, although an active

component is stimulated by several factors, including vitamin D.

In adults, about two-thirds of ingested phosphate is absorbed, almost all

of which is excreted into the urine.

In children, phosphate balance is positive and the plasma concentration

of phosphate is higher than in adults.
ABSORPTION, DISTRIBUTION, AND EXCRETION

Phosphate excretion by the kidney also is highly regulated.

More than 90% of plasma phosphate is filtered at the glomeruli, >80%

of which is reabsorbed in the tubules.

Renal phosphate reabsorption is regulated by a variety of factors,

including PTH and dietary phosphate.

Vitamin D has minimal effects on renal phosphate excretion.

BISPHOSPHONATES

Bisphosphonates are pyrophosphate analogs; they contain 2

phosphonate groups attached to a germinal (central) carbon that replaces the oxygen
in pyrophosphate.

They have a strong affinity for bone, especially areas undergoing remodeling.

They are used extensively in conditions characterized by osteoclast-mediated bone

resorption, including osteoporosis, steroid- induced osteoporosis, Paget’s disease,
tumor-associated osteolysis, breast and prostate cancer, and hypercalcemia.
Available Bisphosphonates

Etidronate (DIDRONEL) is used for the treatment of Paget’s disease but largely
has been supplanted by pamidronate and zoledronate for hypercalcemia.
Pamidronate (AREDIA) is approved in the U.S. for parenteral treatment of
hyper- calcemia (60–90 mg infused over 4 hours), and also is used for Paget’s
disease.

Several bisphosphonates are approved for the treatment of Paget’s disease,

including tiludronate (SKELID), alendronate (FOSAMAX), and risedronate
(ACTONEL), typically at higher doses than those employed in osteoporosis.

Zoledronate (ZOMETA) also appears to be quite effective as a single infusion

of 4 mg.
ABSORPTION, FATE, AND EXCRETION

All oral bisphosphonates have very limited bioavailability.

They should be administered with a full glass of water following an

overnight fast and at least 30 minutes before breakfast.

They are excreted primarily by the kidneys and are not

recommended for patients with a creatinine clearance of less than
30 mL/min.
ADVERSE EFFECTS
Generally well tolerated; patients will experience symptoms of esophagitis.

Symptoms often abate with fastidious adherence to recommendations for taking

these drugs.
If symptoms persist, a proton pump inhibitor at bedtime may be helpful.

The oral drugs may be better tolerated when taken once weekly or monthly, with
no reduction in efficacy.

Patients with active upper GI disease should not be given oral bisphosphonates.

Mild fever and aches may accompany the first infusion of pamidronate.
These symptoms are short-lived and generally do not recur.

Zoledronate has been associated with deterioration of renal function.

Thus, zoledronate should be given over at least 15 minutes at a maximum dose of
4 mg. and renal function should be assessed periodically.
Therapeutic Uses

HYPERCALCEMIA

Pamidronate is used parenterally in the management of malignancy- associated hypercalcemia.

Zoledronate is also FDA-approved for this indication and appears to be more effective than
pamidronate, at least as safe, and can be infused over 15 minutes rather than 4 hours.

POSTMENOPAUSAL OSTEOPOROSIS

CANCER

Second- and third-generation bisphosphonates also may act as anticancer drugs by inhibiting the
activation of cancer-associated proteins, such as Ras, through suppression of ger-
anylgeranylation and farnesylation.
Based on their side chains, the bisphosphonates are grouped into first-, second-, and
third- generation drugs.

First-generation drugs (e.g., medronate, clodronate, and etidronate) contain minimally

modified side-chains or a chlorophenyl group (e.g., tiludronate) and are the least potent
agents.

Second-generation aminobisphosphonates (e.g., pamidronate, alendronate, and

ibandronate) contain an N-atom in the side chain and are 10–100 times more potent than
the first-generation drugs.

Third-generation drugs (e.g., risedronate and zoledronate) contain an N-atom within a

hete- rocyclic ring and are up to 10,000 times more potent than first-generation drugs.

Bisphosphonates concentrate at sites of active remodeling and are incorporated into the
bone matrix.

When the bone is remodeled, they are released in the acid environment of the resorption
lacunae and induce apoptosis in the osteoclasts.
 Parathyroid Hormone

PTH is a polypeptide hormone that regulates plasma Ca2+ by affecting bone

formation/resorption, renal Ca2+ excretion/reabsorption, and calcitriol synthesis (thereby
indirectly regulating GI calcium absorption).

PHYSIOLOGICAL FUNCTIONS

The primary function of PTH is to maintain a constant concentration of Ca2+ in the

extracellular fluid.

The principal processes regulated are renal Ca2+ reabsorption and mobilization of bone Ca2+.
Regulation of Secretion

Plasma Ca2+ is the major regulator of PTH secretion; hypocalcemia

stimulates and hypercalcemia inhibits PTH secretion.

Sustained hypocalcemia also induces parathyroid hypertrophy and

hyperplasia.

The active vitamin D metabolite calcitriol directly suppresses PTH gene

expression.
Effects on Bone

PTH increases bone resorption and thereby increases Ca2+ delivery to

the extracellular fluid.

The apparent cellular target for PTH is the osteoblast.

PTH also recruits osteoclast precursors to form new bone remodeling

units
Effects on Kidney

In the kidney, PTH enhances the efficiency of Ca2+ reabsorption, inhibits

tubular reabsorption of phosphate, and stimulates conversion of 25-OHD to
calcitriol.

As a result, filtered Ca2+ is avidly retained and its plasma concentration

increases, whereas phosphate is excreted and its plasma concentration falls.

Newly synthesized calcitriol interacts with specific high-affinity vitamin D

receptors (VDRs) in the intestine to increase the effi- ciency of calcium
absorption, thereby also increasing the plasma Ca2+ concentration.
INTEGRATED REGULATION OF EXTRACELLULAR Ca2+
CONCENTRATION BY PTH

Even modest reductions of serum Ca2+ stimulate PTH secretion.

Acutely, the regulation of tubular Ca2+ reabsorption by PTH suffices to

maintain plasma Ca2+ homeostasis.

With more prolonged hypocalcemia, renal 1alpha-hydroxylase is stimulated;

this enhances the synthesis and release of calcitriol, which directly stimulates
intestinal calcium absorption.

PTH and the resulting increase in calcitriol also stimulate Ca2+ release from
bone.
INTEGRATED REGULATION OF EXTRACELLULAR Ca2+
CONCENTRATION BY PTH

When plasma Ca2+ rises, PTH secretion is suppressed and tubular Ca2+ reabsorption
decreases.

The reduced PTH promotes renal phosphate conservation, and both the decreased
PTH and the increased phosphate reduce calcitriol production and thereby decrease
intestinal Ca2+ absorption.

Finally, bone remodeling is suppressed. These physiological events provide an

integrated response to positive or negative excursions of plasma Ca2+ concentration.
PARATHYROID HORMONE

Continuous administration of PTH or high circulating PTH levels

achieved in primary hyperthyroidism causes bone demineralization
and osteopenia.

Paradoxically, intermittent PTH administration promotes bone

growth.

The FDA has approved human recombinant PTH (1-34) for treating
severe osteoporosis, and full-length PTH is also undergoing clinical
trials.
ABSORPTION, FATE, AND EXCRETION

Pharmacokinetics and systemic actions of PTH (1-34) (teriparatide, FORTEO)

are identical to those for endogenous PTH.

Teriparatide is administered by once-daily subcutaneous injection of 20 ug into

the thigh or abdomen.

With this regimen, serum PTH levels peak at 30 minutes after theinjection and
decline to undetectable levels within 3 hours.

Teriparatide is eliminated by non- specific enzymatic mechanisms in the liver and

kidney.
CLINICAL EFFECTS

In postmenopausal women with osteoporosis, teriparatide increases bone

mineral density and reduces the risk of vertebral and nonvertebral fractures.

The precise role of this agent relative to other agents used for osteoporosis,
alone or in combination, remains to be determined.

Candidates for teriparatide therapy at this time are women with a history of
an osteoporotic fracture who have multiple risk factors for fracture and who
are intolerant or have failed other therapies.

The drug is also approved to increase bone mass in men with idiopathic or
hypogonadal osteoporosis who are at high risk for fracture.
ADVERSE EFFECTS

In rats, teriparatide increased the incidence of bone tumors, including

osteogenic sarcoma.

The clinical relevance of this is unclear, especially since higher PTH levels in
patients with primary hyperparathyroidism are not associated with an
increased tumor risk.

Nevertheless, teriparatide use should be limited to 24 months, and the drug

should not be used in patients at increased risk for osteosarcoma (e.g., those
with Paget’s disease, unexplained elevations of alkaline phos- phatase, open
epiphyses, or prior radiation therapy involving the skeleton).
Vitamin D

Vitamin D traditionally was viewed as a permissive factor in calcium

metabolism, facilitating efficient absorption of dietary calcium and
allowing full expression of PTH action. Vitamin D is a hormone, rather
than a vitamin, and plays an active role in calcium homeostasis.
Vitamin D

CHEMISTRY AND OCCURRENCE

Ultraviolet irradiation of several animal and plant sterols converts them to

compounds possessing vitamin D activity.

In animals, the principal precursor sterol is 7-dehydrocholesterol, which is

synthesized in the skin; exposure to ultraviolet light in sunlight converts 7-
dehydrocholesterol to cholecalciferol (vitamin D3).

Ergosterol, which is present only in plants, is the precursor to vitamin D2

(ergocalciferol) and its derivatives.

Derivatives of vitamin D2 and vitamin D3 are both biologically active—although

some data suggest that the D3 hormones may be more potent in certain settings—
and are widely available in a variety of commercial vitamin preparations.
HUMAN REQUIREMENTS AND UNITS

The recommended daily dose of vitamin D is 400 IU, or 10 ug.

Vitamin D intake in many individuals (e.g., premature infants, the elderly, and African
Americans) may be inadequate; contributory factors include decreased intake of dairy
products, decreased sun exposure and increased use of sunscreen, and increased
prevalence and duration of exclusive breast-feeding.
ABSORPTION, FATE, AND EXCRETION
Both vitamins D2 and D3 are absorbed from the small intestine and transported as
chylomicrons in the lymphatics.

Bile salts are essential for adequate absorption.

The primary route of vitamin D excretion also is the bile.

Severe shortening or inflammation of the small bowel or hepatic or biliary

dysfunction may cause overt vitamin D deficiency.

In the blood, vitamin D circulates bound to vitamin D-binding protein.

Its plasma t1/2 is ∼24 hours, but it is stored in fat for prolonged periods.
METABOLIC ACTIVATION
Whether endogenously synthesized or acquired from diet, vitamin D requires
modification to become biologically active.
The primary active metabolite of vitamin D is calcitriol,

The initial 25-hydroxylation occurs in the liver to form 25-OH-cholecalciferol or

25-OH- ergocalciferol (collectively termed 25-OHD).

After production in the liver, 25-OHD enters the circulation, largely bound by
vitamin D-binding protein.

Final activation occurs predominantly in the kidney, where 1alpha-hydroxylase

in the proximal tubule converts 25-OHD to calcitriol.

PHYSIOLOGICAL FUNCTIONS AND MECHANISM OF ACTION

Calcitriol augments absorption and retention of Ca2+ and phosphate.
 Therapeutic use of Vit D

SPECIFIC FORMS OF VITAMIN D

Calcitriol (1,25-dihydroxycholecalciferol; CALCIJEX, ROCALTROL) is
available for oral and parenteral use.
Doxercalciferol (1alpha-hydroxyvitamin D2, HECTORAL), a prodrug that must
be activated by hepatic 25-hydroxylation, is approved for treating secondary
hyperparathyroidism.

Dihydrotachysterol (DHT, ROXANE) is a reduced form of vitamin D2 that is

converted in the liver to its active form, 25-hydroxydihydrotachysterol. It is
active at high doses in mobilizing bone Ca2+ and therefore can be used to
maintain plasma Ca2+ in hypoparathyroidism.
 Therapeutic use of Vit D

1alpha- hydroxycholecalciferol (1-OHD3, alphacalcidol; ONE-ALPHA) is a

synthetic vitamin D3 analog that is already hydroxylated in the 1alpha position
and is rapidly converted by 25-hydroxylase to 1,25- (OH)2D3. Because it does
not require renal activation, it has been used to treat renal osteodys- trophy.

Ergocalciferol (CALCIFEROL, DRISDOL) is vitamin D2; it is available for

oral, intramuscular, or intravenous administration. It is indicated for the
prevention and treatment of vitamin D deficiency and for the treatment of
hypoparathyroidism and the genetic disorders of vitamin D synthesis or action
described above.
NUTRITIONAL RICKETS
Nutritional rickets results from inadequate exposure to sunlight or deficiency
of dietary vitamin D.

Breast-fed infants should receive 400 U of vitamin D daily as a supplement.

Since the fetus acquires more than 85% of its calcium stores during the third
trimester, premature infants are especially susceptible to rickets and may
also require supplemental vitamin D.

Treatment of fully developed rickets requires a larger dose of vitamin D.

Although 1000 U/day probably is sufficient, daily doses of 3000–4000 U/day

are frequently used to promote more rapid healing.

Vitamin D may be given prophylactically in conditions that impair its

absorption (e.g., diarrhea, steatorrhea, and biliary obstruction), sometimes
by the parenteral route.
• OSTEOMALACIA AND RENAL OSTEODYSTROPHY
• Osteomalacia, distinguished by undermineralization of the bone matrix, occurs
commonly during sustained phosphate depletion.

• Patients with chronic renal disease are at risk for developing osteomalacia, but also
may develop the complex bone disease called renal osteodystrophy.
• In this setting, bone metabolism is stimulated by an increase in PTH and by a delay in
bone mineralization due to decreased renal synthesis of calcitriol.

• Either a high turnover state reminiscent of primary hyperparathyroidism or a state of

adynamic bone may result.
• The former is treated with dietary phosphate restriction and phosphate binders such
as sevelamer (RENAGEL) and lanthanum carbonate (FOSRENOL).
• Renal osteodystrophy associated with adynamic bone disease may be due to overly
aggressive suppression of PTH with calcitriol or other vitamin D analogs.
• Vitamin D therapy should be discontinued if the 25-OHD and serum calcium levels
are elevated.
HYPOPARATHYROIDISM
Vitamin D and its analogs are the mainstay of the therapy of
hypoparathyroidism.

Dihydrotachysterol has a faster onset, shorter duration of

action than 25-OHD, and traditionally has been the
preferred agent.

Calcitriol also is effective and often is used acutely while

awaiting effects of slower-acting forms of vitamin D.
Calcitonin
Calcitonin is produced by the C cells of the thyroid gland; its actions generally
oppose those of PTH.

Salmon calcitonin, which differs from the human sequence at approximately half
of the residues, is used therapeutically because it is more potent and is cleared
more slowly from the circulation.

REGULATION OF SECRETION
Calcitonin secretion increases with hypercalcemia and decreases when plasma
Ca2+ is low; the hormone in circulation has a t1/2 of 10 minutes.
Circulating concentrations are normally low (<15 pg/mL in males and 10 pg/mL
in females) but can be markedly elevated with C cell hyperplasia or medullary
thyroid cancer.

MECHANISM OF ACTION
The hypocalcemic and hypophosphatemic effects of calcitonin result primarily
from direct inhibition of osteoclast bone resorption.
• CALCITONIN
• Measurement of serum calcitonin is used diagnostically to detect
medullary thyroid cancer, especially in the setting of multiple endocrine
neoplasia, type 2.

• Therapeutically, it is used in the acute management of hypercalcemia.

• It also is approved for Paget’s disease, generally by subcutaneous injection

because of limited bioavailability of the intranasal form, and for the
therapy of osteoporosis.

• After initial therapy at 100 units/day, the dose typically is reduced to 50

units three times a week.

• Side effects include allergic reactions, nausea, hand swelling, urticaria,

and rarely intestinal cramping.
• CALCIUM SENSOR MIMETICS: CINACALCET
• Calcimimetics mimic the action of calcium via the CaSR to inhibit PTH secretion by
the parathyroid glands.
• Because of this enhanced sensitivity, they decrease PTH secretion for any given level
of Ca2+.
• The calcimimetic cinacalcet (SENSIPAR) is FDA-approved for the treatment of
secondary hyperparathyroidism due to chronic renal disease and for patients with
hypercalcemia associated with parathyroid carcinoma (Figure 61–9).

• In clinical trials, cinacalcet also effectively reduced PTH levels in patients with
primary hyperparathyroidism and normalized serum calcium without altering bone
mineral density for up to 2 years.

• Cinacalcet given orally achieves peak serum levels at 2–6 hours, with maximum
biological action (suppression of PTH) at 2–4 hours after administration. After
absorption, the drug is eliminated, primarily by the kidney, with a t1/2 of 30–40 hours.
The drug is also metabolized by multiple hepatic CYPs.
The principal adverse effect of cinacalcet is hypocalcemia.

The drug should not be used if the initial serum calcium is <8.4
mg/dL; serum calcium and phosphate concentrations should be
measured within one week and PTH should be measured within 4
weeks of therapy initiation.

Adynamic bone disease may develop in patients with secondary

hyperparathyroidism, so the drug should be discontinued or the
dose decreased if the PTH level falls below 150 pg/mL.
 Treatment of osteoporosis

• Bisphosphonates
• Bisphosphonates have emerged as the most effective drugs for treatment
and prevention of osteoporosis.

• Second- and third-generation oral agents (e.g., alendronate, risedronate,

ibandronate) have sufficient potency to suppress bone resorption at doses
that generally do not inhibit mineralization.

• They generally are well tolerated (especially when given weekly or

monthly).

• For patients in whom the oral drugs cause severe esophageal distress
despite counter- measures, ibandronate (BONIVA, 3 mg every 3 months)
can be given intravenously for skeletal protection.
• A formulation of alendronate in combination with vitamin D (FOSAMAX
PLUS D) is approved for treatment of osteoporosis.
• Calcium
• The utility of supplemental calcium to protect bone has been the subject of
considerable debate.
• While the impact of supplementation in adolescents, young adults, or early
postmenopausal women is argued, some studies do suggest that supplemental
calcium in the elderly, typically in combination with vitamin D, suppresses
bone turnover, improves bone mineral density, and decreases the incidence of
fractures.
• Typical dosing has been in the range of 1000 mg/day in adolescents and young
adults and 1500 mg/day in the elderly.
• Calcium supplements are most often taken with meals to improve absorption.

• Vitamin D and Its Analogs

• The role for oral supplementation with vitamin D also has been controversial;
at least one prospective trial found that neither vitamin D nor calcium had a
major impact on prevention of osteoporotic fractures in women.
• Nonetheless, supplemental vitamin D may be of value in patients whose intake
appears inadequate based on dietary assessment.
• Estrogen
• Postmenopausal status or estrogen deficiency at any age significantly increases
the risk for osteoporosis.
• Likewise, overwhelming evidence supports the positive impact of
postmenopausal estrogen replacement on bone conservation and protection
against osteoporotic frac- tures.
• The apparently increased risk of adverse cardiovascular events in prospective
studies has led to the recommendation that hormone replacement therapy
should not be first-line therapy for prevention or treatment of osteoporosis.
• Selective Estrogen Receptor Modulators
• Raloxifene (EVISTA) acts as an estrogen agonist on bone and liver, is inactive
on the uterus, and acts as an estrogen antagonist on the breast.
• In post- menopausal women, raloxifene modestly increases bone mineral
density and has been shown to reduce the risk of vertebral compression
fractures; in this setting, it is approved for both the prevention and treatment of
osteoporosis.
• The major adverse effect is worsened vasomotor symptoms; the drug also
increases the incidence of deep venous thrombosis.
Calcitonin

Calcitonin modestly increases bone mass in patients with osteoporosis,

particularly those with high bone turnover and is approved for the treatment
of established osteoporosis in postmenopausal women.