Physiology of Bone

Cells in Bones Longitudinal Growth: Controlled by 3

1. Osteocyte – mature bone cells; recycle hormones
Ca and PO4 1. Growth Hormone: Baby to prepuberty
2. Osteoclasts – dissolve bone by secreting 2. Sex Hormones
enzymes and acids. Release Ca to be (estrogen/testosterone)
returned to blood stream o Causes growth spurt at puberty
3. Osteoblasts – cells that produce new o Shapes your skeleton to your sex
bone cells referred to as osteogenesis 3. Thyroid Hormones (PTH &
 Osteoclasts remove matrix, osteoblasts adds
matris. Calcitonin)
 When an osteoblast’s lacunae is calcified the o Controls whether bone growth occurs
cell becomes and osteocyte. o Affects Appositional Growth – bone
growth in diameter

Bone Remodeling: Bone Homeostasis  Bone Deposit

 Osteons are formed by osteoblasts
 In healthy adults:
o Bone deposit = bone resorption
o Osteoblasts = Osteoclasts
 Bone Remodeling refers to the regular
mineral turnover that occurs in bone.
 In adults, 18 % of proteins and minerals
turns over yearly. Not uniform.
o I.e. Head of femur is remodeled more.
Why?
o Occurs where bone is injured or added
bone strength is required
o Deposits Ca+2 into bone
 Bone Resorption
o Osteoclasts break down bone
o Calcium is taken from bone and placed
into blood stream
o Lysosomes assist in the process
o Ca and PO4 are released; eventually
releasing the blood stream

Negative Feedback Loop: Bone Remodeling is controlled by 2 hormones:

 Blood Calcium is the original stimulus
 Normal Blood Ca is 9-11 mg CA/100 ml of blood
 When blood Ca ↓ (< 9 mg)  PTH is released into bloodstream  Bone resorption occurs
causing Ca to leave bone and go to the blood stream (Osteoclasts are working)
 When blood Ca ↑ (>11mg)  Calcitonin is released  Causes bone deposit to occur  Ca
from the blood is stored into bone. (Osteoblasts and Osteocytes are working.)
 Controlling Bone Remodeling
1. PTH and Calcitonin determines whether and when bone remodeling occurs.
2. Mechanical Stress determines where remodeling occurs. High stress areas grow appositionally.
 99% of all Ca is found in bone.
 Osteoclasts cause bone resorption  Controlled by PTH
 Osteoblasts cause bone deposit  Controlled by calcitonin
Factors Helping Bone Deposit
1. Vitamin D – aids in the absorption of Calcium into the bone. Part of vitamin D is converted
to the hormone calcitriol which allows Ca to pass through the S.I. (What food is Vitamin D
fortified?)
o i.e. rickets results from Vitamin D deficiency
2. Vitamin C – helps osteoblasts function
o i.e scurvy – caused from a reduction in osteoblast activity
3. Calcium tablets -
4. Diet -

Wolff’s Law: 2nd Response to Regulating Bone Remodeling

 Bone grows or remodels in response to the forces or stresses placed on it.
 Appositional growth – growth in diameter is controlled by the amount of mechanical
stress and gravity placed on the bone
 Heavy usage leads to heavy bones; nonuse leads to atrophy (bone loss)

Body’s Needs for Calcium

1. Transmit nerve impulses
2. Muscle contractions
3. Blood coagulation
4. Cell division
 If blood Ca levels are low for an extended time, bones continually lose Ca.
 Once bone density loss begins, women lose 8% of their bone mass every decade, men lose 3%
every decade
 Paget’s Disease
Definition: Paget's disease is a disorder of bone remodeling, with ↑ osteoclast-mediated
bone resorption followed by ↑ disorganized bone formation.

Etiology
A. Unknown.
B. Hereditary factors
o More often in patients’ relatives than in controls.
o A positive family history in 15-30% of patients
o High association with
 HLA DQw 1 and DR antigens.
 Sequestrosome 1 gene on chromosome 5
C. Viral Infection (slow)
o Intranuclear inclusion bodies in the osteoclasts
o Viral infection may be necessary to trigger the disease in people with the gene

Epidemiology
 Typically in mid or older age
 Men > women (3:2 in US)
 Prevalence:
o 3-3.7%, >40yrs, ↑ with age, 10% at 90 yrs
o 5% in England and north Europe. 1-3% in the US.
o Uncommon in Middle East, Africa and Asia.

Sites:
 Axial skeleton (more common)  skull + spine + pelvis
 Peripheral skeleton  proximal long bones (femur)
 Polystotic (80%)
 Monostotic (20%)  commonly tibia + iliac bones
 Overall, the most common sites (in descending order) include pelvis, lumbar spine, femur,
thoracic spine, sacrum, skull, tibia & humerus.

Stages
1. Hot or Osteoclastic: Initial phase of ↑ osteoclastic activity that affects both the cortex
and cancellous bone
2. Intermediate or Mixed: Bone destruction accompanied by new bone formation.
3. Cold phase: Disorganized new bone formation
Clinical Picture
1. Asymptomatic: Incidental finding on standard
radiograph + ↑ serum total ALP
2. Non-complicated Cases: Skeletal
manifestations: Localized pain + tenderness + ↑
warmth (due to hypervascularity)

Complications
A. Long bones C. Spine
1. Deformity e.g., Bowing of long 1. Compression neuropathy (spinal
bones nerve roots). → pain, tingling, numbness,
2. Fractures (7%), commonly in and paresis in an arm or leg or paraplegia.
femur, tibia, humerus, and forearm 2. Spinal stenosis
3. Vertebral compression and collapse
3. OA of adjacent joints (stress 4. Muscle weakness
of enlarged bones on nearby joints)
D. Bone cancer
Acetabular protrusion
4. 1. Fibrosarcomas <1%
B. Skull 2. Benign giant cell tumors
1. Head enlargement 3. Osteogenic sarcomas (0.2-1.0%)
2. Deformity: Frontal bossing E. Cardiac
1. High-output CHF (due to ↑ pagetic bone
3. Deafness (13%) or headaches and vascularity).
dizziness (auditory nerve 2. HTN
entrapment) 3. Cardiomegaly
4. Headaches 4. Angina
5. Stroke (blood vessel compression) F. Vascular: Hyperthermia
6. Vascular steal syndrome G. Metabolic
(external carotid blood flow to the 1. Hypercalcemia
skull at the expense of the brain) 2. Hypercalcuria
7. Basilar invagination 3. Nephrocalcinosis

Diagnosis
1. Imaging:
o Radiograph
o Bone Scan
o MRI, or CT scans
2. Laboratory
o ↑ ALP
o Markers of bone resorption are usually elevated
3. Histopathology: Initially there is ↑ bone resorption, followed by a compensatory ↑ in
bone formation, in disorganized fashion, producing the characteristic mosaic pattern.
Differential Diagnosis
1. Pagetic vertebrae: lymphoma & metastatic cancers, but pagetic vertebrae are usually
enlarged.
2. Paget's Disease of Bone: osteoblastic metastatic lesions.
3. In other affected bones: characteristic cortical thickening and adjacent thickened
trabeculae.
4. Focal increased uptake on scintigraphy: osteomyelitis, arthritis, metastases,
fractures.

Treatment
 Since there is no cure, the goal of the treatment is to control the disease's activity and the
complications. When there are no symptoms or ↑ALP, then treatment isn't necessary. Bone
pain can require NSAIDs. Deformity can require supports. Surgery may be necessary for
damaged joints, fractures, severely deformed bones, or when nerves are being pinched by
enlarged bone. Medications such as bisphosphonates or injectable calcitonin may be used.
 Treatment of symptomatic Paget's disease is usually directed at: suppression of the enhanced
bone resorption and skeletal turnover with calcitonin or bisphosphonates.
 Response to therapy is monitored by :
1. Reduction of symptoms
2. Maintenance of alkaline phosphatase level in a normal range
 Re treatment once values rise 25% above normal.
 Indications for Treatment of Paget's Disease of Bone
1. Pain
2. ↑Ca
3. Fractures
4. High-output cardiac failure (rare)
5. Skull involvement
6. Neurologic compromise
7. Periarticular disease
8. Prevention progression of PD

A. Medications
BISPHOSPHONATES: (oral or parentral) Treatment of choice
Etidronate: (oral)
 Similar response as calcitonin.
 Dose for Paget's disease is 5 mg/kg per day for 6 months.
 Stop for 6 months THEN reinstituted in 6-month cycles of therapy.
 Higher doses of etidronate are associated with defective mineralization of bone and
osteomalacia, with pain and fractures.
 Follow up by measuring ALP every 3-6 months.
 25% of patients may become resistant to etidronate.
However, newer, more potent bisphosphonates are very effective for the treatment of Paget's.

Pamidronate: (parentral)
 In threefold or greater ↑ALP
 An advantage of this therapy is the sustained response for a prolonged period (up
to a year or more).

Alendronate: (oral): Recommended for patients with at least a twofold ↑ALP.

Risedronate: POTENT ACTION….

CALCITONIN (MIACALCIN): injection or nasal spray

 Types: Salmon calcitonin and human calcitonin
 Mechanism of action : inhibit the function of osteoclasts.
 Indications: extensive lytic disease, severe pain, when a rapid response is desired, or when
bisphosphonates are poorly tolerated.
 Side effects: nausea, facial flushing and irritation at the injection site.
 Protocol of use :
o Salmon calcitonin is initiated at a low dose to ensure patient tolerance .
o Then ↑ to a daily dose of 100 Medical Research Council units (I.M. or S.C.)
o After 6 months of therapy, the patient may be maintained on 50 to 100 units daily.
o Approximately two thirds of patients show ↓ in ALP levels of 50% or more in 2 to 6 months.
o In case of resistance to salmon calcitonin; switch to human calcitonin.

NSAIDs: used to treat pain associated with OA.

CALCIUM (1000 mg) and VITAMIN D (800 IU) daily to prevent development of 2ry ↑ PTH

B. Physical Therapy C. Surgery

 Treat secondary
impairments e.g.
1. Gait disturbances
related to deformity
2. Spinal Stenosis.
3. Impairments resulting
from fracture
 In rare cases, you may require surgery to:
1. Help fractures heal
2. Replace joints damaged by severe arthritis
3. Realign deformed bones
4. Reduce pressure on nerves
 Excessive number of blood vessels in the affected bones
increases the risk of serious blood loss during an operation.
Therefore, disease activity must be reduced preoperatively

Prognosis
 Typically prognosis is guarded depending on the affected site
 Symptoms progress slowly and the disease doesn't spread to healthy bones like
cancer. However, there is no cure.
 Rarely, disease may progress to osteogenic sarcoma, a metastatic neoplasm
 Osteomalacia
 Osteomalacia is characterized by impaired mineralization of bone matrix .
o Calcium, phosphate, and vitamin D are necessary for the mineralization of bone.
 Vitamin D deficiency can be treated with physiologic doses of vitamin D, but higher doses
(1000 to 2000 IU/day) may hasten the healing of bone.
o In case of intestinal malabsorption  larger doses of vit D  50,000 IU 1-3 times a
week
o TREATMENT OF UNDERLYING CAUSE.
o Careful monitoring of the serum and urinary Ca and 25-OH D is necessary to prevent
vit D intoxication.
 Use of the active metabolite of 25-OH D may be necessary in resistant patients or in
those with severe liver disease who cannot achieve activation of this metabolite.
o The potential advantages of using 25-OH D are more stable bioavailability, shorter
half-life, and greater potency than the parent compound, although the cost is greater.