DISORDERS OF BONE AND

MINERAL METABOLISM
Mineral metabolism disorders

Mineral metabolism disorders are marked by abnormal
serum levels of minerals -- either too much or too little

Minerals are very important for the human body. They have
various roles in metabolism and body functions and are
essential for the proper function of cells, tissues, and
organs.

Some minerals, such as iron, make up part of many
proteins and enzymes in the body. Others, such as
potassium, help in protein synthesis from amino acids and
in carbohydrate metabolism. Minerals also play a role in
the building of muscle and bone and for normal body
growth.
MINERALS
Minerals that play a large role in the body include:
CALCIUM
PHOSPHORUS
Magnesium
Potassium
Selenium
Sodium

CALCIUM METABOLISM
Over 99% of the 12 kg of calcium present
normally in the adult human body resides in the
skeleton, where it provides mechanical stability
and serves as a reservoir sometimes needed to
maintain extracellular fluid (ECF) calcium
concentration
Skeletal calcium accretion first becomes
significant during the third trimester of fetal life,
accelerates throughout childhood and
adolescence, reaches a peak in early adulthood,
and gradually declines thereafter at rates that
rarely exceed 12% per year.
CALCIUM METABOLISM
Control of the ionized calcium concentration in the ECF
ordinarily is accomplished by adjusting the rates of calcium
movement across intestinal and renal epithelia. These
adjustments are mediated mainly via changes in blood
levels of the hormones PTH and 1,25(OH)
2
D
Intestinal absorption of ingested calcium involves both
active (transcellular) and passive (paracellular)
mechanisms.
Passive calcium absorption is nonsaturable and
approximates 5% of daily calcium intake, whereas the
active mechanism, controlled principally by 1,25(OH)
2
D,
normally ranges from 2070%.
Disorders of calcium metabolism
Nephrocalcinosis
Pseudohypoparathyroidism
Hypercalcemia
Movement - unpredictable or jerky
Kidney stones
Milk-alkali syndrome
Pagets disease
Multiple endocrine neoplasia (MEN 1)
Osteoporosis
Osteomalacia
Rickets

PHOSPHORUS METABOLISM
Although 85% of the ~600 g of body phosphorus is present
in bone mineral, phosphorus is also a major intracellular
constituent, both as the free anion(s) and as a component
of numerous organophosphate compounds including
structural proteins, enzymes, transcription factors,
carbohydrate and lipid intermediates, high-energy stores
(ATP, creatine phosphate), and nucleic acids.

Phosphate is widely available in foods and is efficiently
absorbed (65%) by the small intestine, even in the absence
of vitamin D. On the other hand, phosphate absorptive
efficiency may be further enhanced (to 8590%) via active
transport mechanisms that are stimulated by 1,25(OH)
2
D.

Disorders of phosphorus metabolism:
Hyperparathyroidism
Osteomalacia
Rickets
Rhabdomyolysis
Hypophosphatemia
Hypoparathyroidism

Metabolic bone disease
Commonly classified into three main categories:
1. Osteomalacia, and Rickets
2. Osteitis fibrosis cystica (hyperparathyroidism).
3. Osteoporosis.

The disorders listed above may result in failure of
osteoid calcification (rickets) in children because of
a disruption in the pathway of either vitamin D or
phosphate metabolism.
Defective mineralization in bone causes
osteomalacia, which can occur in both children and
adults.
Rickets, once thought defeated, is reappearing and
remains a major health problem in many developing
and developed countries.

PATHOPHYSIOLOGY
Calcification of osteoid depends on adequate levels of
ionized calcium and phosphate in the extracellular
fluid. Vitamin D influences these levels after its
dihydroxylation into calcitriol (at the 25 position in the
liver and the 1 position in the kidney).
If the enzyme that controls either of these steps is
deficient because of a mutation, vitamin D function is
less than normal.
In addition, a renal tubular defect that reduces
reabsorption may alter phosphate metabolism.
Finally, a genetic absence of the receptor for calcitriol
results in deficient calcification.
Osteomalacia
Osteomalacia is a skeletal abnormality in which
there is inadequate mineralization of bone matrix.
In children it takes the form of Rickets caused by
vitamin D deficiency. In adults osteomalacia may
be caused by abnormalities of calcium,
phosphorus and vitamin D metabolism.
The hypocalcemia and hypophosphatemia that
accompany vitamin D deficiency result in
impaired mineralization of bone matrix proteins
Osteomalacia
Osteomalacia is also a feature of long-standing
hypophosphatemia, which may be a consequence
of renal phosphate wasting or chronic use of
etidronate or phosphate-binding antacids.
This hypomineralized matrix is biomechanically
inferior to normal bone; as a result, patients with
vitamin D deficiency are prone to bowing of
weight-bearing extremities and skeletal fractures
Etiology
Vitamin D deficiency:
It causes osteomalacia because its active metabolite, 1,25-
dihydroxyvitamin D3, is essential for the absorption of
calcium and phosphate from the GIT.

Deficiency of vitamin D is now rare as the dietary allowance
of 200 400 units daily can be obtained from the dairy
products. However it may still occur.

Exposure to sunlight converts 7-dehydrocholesterol in the
skin to vitamin D3 and this is an important source of the
vitamin. Absence of sunlight may contribute to vitamin D
deficiency.
Abnormal metabolism of vitamin D

1. Liver disease: when advanced may cause
osteomalacia by interfering with the normal
hepatic conversion of vitamin D to 25-
hydroxyvitamin D3.
2. Anticonvulsant drugs: such as phenobarbital
and phenytoins, it may alter the metabolism of
vitamin D.
3. Hereditary vitamin D- dependent rickets is a
rare autosomal recessive disorder which is
caused by a defect in the renal conversion of 25-
hydroxyvitamin D3 to 1,25-hydroxyvitamin D3
which is the most active metabolite.
RENAL ABNORMALITIES
Renal osteodystrophy: may occure in chronic renal
failure of any cause which leads to:
Failure of the conversion to 1,25-dihydroxyvitamin D3.
Secondary hyperparathyroidism of renal failure.
In end-stage renal disease, renal 1-hydroxylase is
diminished or lost, and excretion of phosphate is
defective. This leads to low levels of 1,25(OH)
2
vitamin D, hypocalcemia, and failure of osteoid
calcification.
Osteodystrophy (ie, renal rickets) is the only type
of rickets with a high serum phosphate level


RENAL ABNORMALITIES
Excessive renal loss of phosphate and calcium:
Familial vitamin D-resistant Rickets (X-linked
dominant disorder) and Fanconi Syndrome (Renal
tubular defect)

Fanconi syndrome is a disorder of proximal renal
tubular transport. Phosphate, amino acids,
glucose, bicarbonate, and uric acid wasting
characterize this disorder
Gastrointestinal disorders
Any disease or surgical procedure that leads to
malabsorption may reduce the absorption of
calcium, phosphate, and Vitamin D and
osteomalacia may result.

Vitamin D deficiency leads in impaired intestinal
absorption of calcium, resulting in decreased
serum total and ionized calcium values.
Pathophysiology
The common defect in the various diseases
associated with osteomalacia is the lack of
Calcium and phosphorus for mineralization of the
bone matrix. Circulating phosphate levels are
usually low. Calcium levels may be low, but they
are often normal because of compensatory
parathyroid hyperactivity.
Rickets
In children, prior to epiphyseal fusion, vitamin D
deficiency results in growth retardation associated
with an expansion of the growth plate
caused by defective mineralization of bone before
closure of the cartilaginous growth plates.
Deformity occurs because of pressure on
weakened growth plates and on the abnormally
soft shafts of the long bones.
After closure of the growth plates, only
osteomalacia can occur, with defective
mineralization of mature lamellar bone.
clinical features
1. Pain and tenderness are common in affected
areas of the skeleton, especially the spine, ribs,
pelvis, and lower extremities.
2. Muscle weakness is common, affecting
particularly the proximal muscles of the legs.
3. Skeletal deformities and fractures occur in
severe cases:
1. The long bones may bow because of softening of the
skeleton.
2. Rickets in children is associated with widening of the
epiphyses, swelling of the wrists, knees, ankles, and
costochondral joints, bow legs and disturbances in
growth.

Laboratory findings
It depends on the cause and severity of osteomalacia.
Low serum phosphate, low or normal serum calcium,
and increased serum alkaline phosphatase levels.
X rays may show decreased bone density and
coarsening of the trabecular pattern. Loosers zones are
radiolucent bands that are perpendicular to the
periosteal surface.
Radiologic features of vitamin D deficiency in children
include a widened, expanded growth plate,
characteristic of rickets. These findings are not only
apparent in the long bones but are also present at the
costochondral junction, where the expansion of the
growth plate leads to swellings known as the "rachitic
rosary."
Laboratory findings
If vitamin D deficiency occurs after epiphyseal fusion,
the main radiologic finding is a decrease in cortical
thickness and relative radiolucency of the skeleton. A
specific radiologic feature of osteomalacia, whether
associated with phosphate wasting or vitamin D
deficiency, is pseudofractures, or Looser's zones
These are radiolucent lines that occur where large
arteries are in contact with the underlying skeletal
elements; it is thought that the arterial pulsations lead
to the radiolucencies. As a result, these
pseudofractures are usually a few millimeters wide,
several centimeters long, and are seen particularly in
the scapula, the pelvis, and the femoral neck.
Pseudofracture, Adult with
Rickets

Radiographic Images
Radiographic Images:
Rachitic Rosary enlargement of
costochondral junction

Therapy
1. Treatment of the primary disorder (e.g.
correction of a bowel disorder causing
malabsorption).
2. Vitamin D is usually the main stay of treatment.
1. In simple vitamin D deficiency, a physiologic dose of
400 units daily may be all that is needed.
2. In vitamin D resistant rickets, 50000-100000 units
daily or more may be needed. The dose is adjusted to
achieve healing of the bone lesions without inducing
hypercalcemia, which is the main complication of
excessive vitamin D administration.
Osteitis fibrosa cystica
(hyperparathyroidism)
Pathophysiology: Parathormone is important in
maintaining normal calcium homeostasis by:
Stimulating Vitamin D metabolism.
Increases renal reabsorption of Calcium.
Promotes the movement of calcium from the bones.

A parathyroid adenoma may produce excessive
PTH despite high concentrations of serum calcium
and causing the abnormalities of
hyperparathyroidism.
Clinical features
Renal symptoms: Hypercalcemia commonly lead
to hypercalciuria which can cause urinary calculi.
It may lead to deposition of calcium within the
renal parynchyma (nephrocalcinosis) with
eventual renal failure.
Gastrointestinal symptoms: Hypercalcemia will
lead to anorexia, weight loss, constipation, nausea
and vomiting with abdominal pain. Increased
incidence of peptic ulcer and pancreatitis.
Skeletal symptoms: Excess PTH increases the rate
of osteoclastic bone resorption which lead to:
Bone pain, fractures, and areas of swelling and
deformity localized to involved bones.
In severe cases there may be bone cysts.
X rays may show generalized osteopenia.

Laboratory findings
Blood chemistry:
1. Elevated serum calcium.
2. Elevated serum Alkaline phosphatse.
3. Decreased serum phosphate.
Urine chemistry:
1. Hypercalciuria.
PTH assay:
1. Elevated parathormone level measured by
radioimmuno assay.
Therapy
Surgery: When the diagnosis of primary
hyperparathyroidism is made, surgical exploration
of the neck for excision of adenoma, or excision of
3 of the parathyroid glands if there are no
adenomas.
Medical treatment: By increased fluid intake,
administration of oral phosphate (1.5 gm of
phosphorus), or estrogen therapy by decreasing
bone turnover.
Osteoporosis
a reduction in the strength of bone leading to an increased
risk of fractures. Loss of bone tissue is associated with
deterioration in skeletal microarchitecture.
The World Health Organization (WHO) operationally
defines osteoporosis as a bone density that falls 2.5
standard deviations (SD) below the mean for young
healthy adults of the same genderalso referred to as a T-
score of 2.5.
Postmenopausal women who fall at the lower end of the
young normal range (a T-score of >1 SD below the mean)
are defined as having low bone density and are also at
increased risk of osteoporosis.Is a decrease in total bone
volume..
Both increased bone resorption and decreased bone
formation have been observed.
Review the PREVIOUS lecture on Osteoporosis.
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