Regulation of Calcium and Phosphate Homeostasis II Flashcards
E2 and the anabolic androgens (testosterone and dihydrotestosterone) stimulate bone growth and increase and/or maintain
Bone density
Exerts a number of effects that collectively affect Ca2+ and PO4 homeostasis to maintain bone density
Estrogen
Stimulates the expression of VDR in the duodenum and may also directly increase Ca2+ absorption
E2
What is the predominant ER receptor in humans?
ER-alpha
Estrogen receptors are expressed by
Growth plate chondrocytes
Acts in a biphasic manner to first stimulate longitudinal bone growth, but then over time induces epiphyseal closure, thus terminating longitudinal growth
ER
In osteocytes, E2 blocks apoptosis and stimulates the secretion of
TGFB
Blocks osteoclast differentiation
TGFB
Impairs osteoclast differentiation and RANKL synthesis
Estrogen
Which three things does estrogen promote in bones?
- ) Osteoclast apoptosis
- ) Osteoblast proliferation
- ) Osteoprotegerin production
Collectively, these actions support the maintenance of bone density by thwarting
Osteoclast-mediated reabsorption
Is by and large sequestered to the epiphyseal chondrocytes, growth plate cartilage, osteocytes, and osteoblasts
Androgen Receptor (AR) expression
Men with total E2 deficiency due to mutations in either ERa or CYP19 exhibit severe
-Despite normal testosterone levels
Osteopenia
Thus, we may not receive a direct effect on bone growth from
AR expression
Aromatase, i.e. the enzyme which aromatizes testosterone into E2
CYP19
We can treat these men with osteopenia in order to induce epiphyseal closure and longitudinal bone growth by giving them
Exogenous Estrogen
Since the predominant circulating anabolic androgen, testosterone, can be aromatized into E2 by a variety of tissues, the anabolic effects of androgens in bone are possibly due to
E2
The best indicator of fracture risk in aging men
E2
21-carbon steroids produced by the adrenal cortex
-produced in zona fasciculata and zona reticularis
Glucocorticoids
In the context of bone, function to enhance reabsorption
Glucocorticoids
Thus, prolonged glucocorticoid excess can result in
Glucocorticoid-induced osteoporosis
Glucocorticoid-induced osteoporosis can lead to the development of
Osteonecrosis
The rapid focal deterioration of bone, often occuring within the femoral head
Osteonecrosis
Has complex effects in bone, involving both direct (via effects within osteoblasts, osteoclasts, and osteocytes), as well as indirect mechanisms within the kidneys and the small intestine where Ca2+ reabsorption and absorption, respectively, are impaired
Glucocorticoids
Impede skeletal muscle function by increasing catabolism
Glucocorticoids
Muscle wasting and the deleterious effects within bone can be exacerbated by the inhibitory effect of glucocorticoids on
Gonadal estrogen and androgen production
Osteoblasts, osteoclasts, and osteocytes all express
Glucocorticoid receptors
Within osteoblasts and osteocytes, glucocorticoids upregulate
Apoptosis
Actually extend the life of osteoclasts
Glucocorticoids
The production of RANKL is promoted by
Glucocorticoids
The production of RANKL is promoted by glucocorticoids, thereby increasing the ratio of
RANKL:osteoprotegerin; a mechanism that promotes
Osteoclast-mediated bone reabsorption
Predominantly synthesized by the liver in response to GH
IGF-I
However, it has been shown that IGF-I is also synthesized in
Osteocytes and chondrocytes
Postnatally and through adolescence, GH and IGF-1 together stimulate
Longitudinal bone growth
In long bones, exerts mitogenic effects in chondrocytes within the epiphyseal cartilages (epiphyseal lengthening) concomitant with stimulating local IGF-1 expression
GH
Due to their anabolic effects, GH and IGF-I can also regulate modeling and remodeling of
Trabecular and cortical bone
Note that the anabolic effects of GH depend on
IGF-I
Osteoblast activity is upregulated by
GH
GH promotes osteoblasts to express
IGF-I
The expression of IGF-I in osteoblasts is also stimulated by
PTH and E2
IGF-I expression is reduced by
Glucocorticoids
In children, hypothyroidism is associated with
Blunted growth
Has been shown to increase the activity of both osteoblasts and osteoclasts
Thyroid Hormone
In adult hyperthyroidism, an upregulation in bone mineralization is in fact linked with increased
Reabsorption
A wasting of the bone matrix that is associated with the age dependent drop in E2, and perhaps androgen, production that occurs in older men and women
Osteoporosis
In women, the loss of ovarian function that defines menopause results in a profound decline in bioavailable
E2
The hallmark sign of osteoporosis is the demineralization of bone leading to decreased bone density in the
Spine, hip, pelvis, and/or wrist
Serum Ca2+, PO4, and PTH generally remain normal in
Osteoporosis
Increases bone mineral density and thus exerts anti-osteoporotic effects in properly nourished post menopausal women
Estrogen Replacement Therapy (ERT)
Commonly prescribed for osteoporosis
Bisphosphonates
Act to prevent bone absorption by impairing osteoclast activity and accelerating osteoclast apoptosis
Bisphosphonates
Another treatment treatment for osteoporosis is
Selective Estrogen Receptor Modulators (SERM)
A SERM which functions as an E2 agonist in bone, while antagonizing E2 in breast and uterine tissue
Raloxiphene
A human monoclonal antibody against RANKL that is used to treat osteoporosis
Denosumab
The third most common endocrine disorder
Primary hyperparathyroidism
Approximately 75-80% of the time, results from a single parathyroid adenoma causing hypersecretion of PTH from parathyroid glands
Primary hyperparathyroidism
Elevated PTH results in
Hypercalcemia
In severe cases of hyperparathyroidism, we see loss of cortical bone and deposition of
Trabecular bone
The chief complaint in symptomatic hyperparathyroid patients is usually bone pain and
Arthralgias
More frequent in those over 50 years of age and is 3x more common in women
Hyperparathyroidism
If present, symptoms from pathologic hypercalcemia only appear at serum levels greater than
12 mg/dL
In an electrocardiogram, hypercalcemia will show as a
Shortened QT
During phase 2 depolarization (i.e. the plateau phase; of the cardiac myocyte action potential, calcium slowly enters the cell. The duration of phase 2 is directly correlated with the duration of the
ST segment
When the extracellular Ca2+ levels are elevated, the Type L channels become
-activate and inactivate more frequently
Irritated
Although rare with hypercalcemia, disruption of cardiac electrical activity can lead to serious
Arrythmias
With regard to skeletal muscle, experimental evidence has shown that excess extracellular Ca2+ raises the membrane potential necessary to open the motor neuron voltage-gated Na+ channels, thus inducing
Hypoexciteability
Patients with hypercalcemia due to primary hyperparathyroidism have increased renal excretion of
Ca2+ and PO4
The hypercalciuria predisposes the formation of
Kidney stones
Also, the abnormal increase in Ca2+ concentration within the forming urine can induce aberrant CaSR activity which can lead to a form of
Ca2+ Dependent nephrogenic diabetes insipidus
The most common cause of true hypocalcemia is the loss of calcitriol synthesis that results from the advanced stages of
Chronic kidney disease
Signs and symptoms of this condition are associated with the increase in nerve and muscle excitability that accompanies
Hypocalcemia
It appears that extracellular Ca2+ aids in somehow stabilizing membrane Na+ channels within
Skeletal muscle and neurons
With low extracellular Ca2+, membrane permeability to Na+ is increased and the result is
Hyperexciteability
If severe enough, hypocalcemia can impair ventricular conductivity and ventricular myocyte contractility and is shown on an ECG as
Prolonged QT interval
Skeletal muscle cramping and/or tetany, and perioral and distal extremity paresthesias can occur with
Hypocalcemia
There are two signs that can be used in the diagnosis of hypocalcemia. The first is
Trousseau’s sign
Shows as a carpal spasm due to the loss in brachial artery circulation that occurs upon inflation of a BP cuff above systolic BP
Trousseau’s sign
Approximately what percent of patients with hypocalcemia will show Trousseau’s sign?
94%
The second test for hypocalcemia is known as
Chvostek’s sign
This is observed as ipsilateral facial muscle contraction when the facial nerve is tapped anterior to the ear
Chvostek’s sign
Which test has a higher specificity, Trousseau’s or Chvostek’s?
Trousseau’s
Hyperphosphatemia is indicated by serum PO4 above
5mg/dL
Most often due to acute and chronic renal failure, when GFR falls under 30 mL/min
Hyperphosphatemia
Abnormally elevated PO4 tends to precipitate
Ca2+
Tends to precipitate Ca2+, impairs calcitriol synthesis, and impedes PTH mediated bone resorption
Abnormally elevated PO4
Thus, the signs and symptoms of hyperphosphatemia are actually attributed to the ensuing
Hypocalcemia
If prolonged, hyperphosphatemia and the associated Ca2+ imbalances can progress to the formation of metastatic calcifications which tend to develop within the vascular walls, ventricular myocardium, as well as
Atrial and mitral valves
The most common etiology of hypophosphatemia is due to an increase in PO4 excretion that accompanies
Hyperparathyroidism
During severe hypophosphatemia (≤1 mg/dl), the affinity of hemoglobin for O2 is increased due to a decrease in
2,3 DPG
Since O2 cannot be effectively offloaded to tissues,
skeletal muscle cell weakness and sometimes skeletal muscle necrosis can occur. This necrosis is also known as
Rhabdomyolysis
A condition of childhood calcitriol deficiency or resistance prior to epiphyseal plate closure
Rickets
The adult form of Rickets is called
Osteomalacia
The calcitriol deficiency induces increased PTH-dependent elimination of PO4 in the urine, and the inability to absorb
Dietary Ca2+
SIgns and symptoms of Rickets/osteomalacia would then include bone pain and tenderness, diminished bone density/mineralization, as well as
Hypophosphatemia, hypocalcemia, and hypocalciuria
If this condition is not corrected, we can see severe bone weakening and
Tetanic respiratory failure
