Bone Homeostasis and PTH

Purington

Where is the primary Ca reservoir in the body and why is it necessary?

BONE

provides structure, support & ambulation

What is the normal serum calcium range?

8\.8 - 10.4 mg/dL

Where is PTH released from and what is its effect in Ca homeostasis?

From parathyroid gland - chief cells

is released when Ca is low, increases resorption in kidney & mobilizes from bone & indirectly increases Ca from gut

Pick The Hell up

Where is Calcitonin secreted from and what is its effect in Ca homeostasis?

Released from thyroid - C cells and parafollicular cells

released when Ca high, decreases mobilization from bone & resorption from kidney

Convulsive Ca

What is the active form of Vitamin D and how is it converted to the active form?

1, 25 Vit D2 (calcitriol)

metabolized via liver then the kidney w/ PTH

derived from endogenous cholesterol

Why is Vit D important to take with Ca?

Increases absorption of Ca

Where does PTH have effects?

Bone - increases osteoclasts

Kidneys - increase absorption, dec phosphorus abs

Indirectly GI - inc Ca abs w/ vit D

Where does Calcitonin have effect?

Bone -increases storage via osteoblast activation

Where does Vit D have effect?

GI - increase Ca abs

Kidney - increase Ca and phosphorus reabs

PTH glands - negative feedback

What is the function of an osteoclast?

breakdown bone and release Ca

What is the function of osteoblasts?

to build bone and store Ca

How are osteoclasts and osteoblasts activated?

By a RANK-L

What are the two bone types?

1. Trabecular
2. Cortical

What % of trabecular bone if remodeled each year in adults

?

25%

What % of cortical bone is remodeled each year in adults?

3%

What are some trabecular bones?

spine, pelvis, hips - more turnover so more likely to see fxts here

What are some cortical bones?

long bones

Femur and ulna

What are some diseases of bone homeostasis?

Hyperparathyroidism

Hypoparathyroidism

Vitamin D deficiency

Paget’s Disease

Osteoporosis

What are the the 3 treatments for hyperparathyroidism?

1. Surgical removal of PTH glands
2. Inhibition of RANK-L to decrease bone loss: inhibition of osteoclasts
3. Calcimimetics

What is the downside for surgical removal of PTH glands?

loss of thyroid function

What drug inhibits RANK-L to decrease bone loss?

Denosumab - Prolia

What are some Calcimimetics?

Cinacalcet (Sensipar)

Etelcalcitide (Parsabiv)

What is Sclerostin and why is it a target for calcium homeostasis disorders?

Inhibition of sclerostin

improves osteoblast-mediated bone formation (inhibits bone loss)

What drug targets sclerostin?

Romosozumab (Evenity)

what is a CI for Evenity (Romosozumab)?

CV

stroke

What are some causes of Hypoparathyroidism?

removal of PTH or idiopathic

What is the treatment for hypoparathyroidism?

replace PTH

supplementation of Ca and Vit D

What are 3 products to replace PTH?

1. Natpara - full length 84 aa PTH
2. Forteo - 34-aa
3. Tymlos - 34 aa

What are some SE of Forteo?

osteosarcoma (helps Increase PTH)

injection site discomfort or pain

muscle or joint pain

What are genetic causes for Rickets?

* X-linked hypophosphatemic rickets (XLH): increases plasma FGF-23 (decrease phosphate levels
* Autosomal dominant hypophosphatemic rickets (ADHR): mutation expressing proteolytic-resistant FGF-23

What is Rickets?

Vitamin D deficiency

effects on cortical bones

What are some non-genetic causes of rickets?

IV administration of saccharated iron (increased FGF 23)

Phosphatonin-secreting tumor (increased FGF 23)

Oncogenic osteomalacia

Chronic dyalsis for renal insufficiency (increased FGF 23 decreased serum phosphate)

What is the treatment for Rickets?

Calcitonin (Fortical)

Vitamin D replacement

What are Paget’s disease?

age-associated localized bone remodeling

impairs bone healing, no new bone deposition

can lead to compression of bones in ear (demineralization bone loss)

What is the treatment for Paget’s disease?

Calcitonin (Fortical)

Vitamin D replacement

Bisphosphonates (+ osteoblast activation)

What is osteoporosis (OP)?

Abnormal age-related bone loss → predisposition of fractures

increase bone absorption or decrease bone formation or BOTH

What causes an acceleration of bone loss?

post-menopausal

lack of estrogen which helps increase osteoclast activity

When should someone be treated for OP?

T score of -2.5 or less at hip, spine, or neck

T score of of btwn -1 and -2.5 w/ a 10-yr probability of hip fracture >3% or major OP fracture >20%

For ever 1.0 change in T-score how much does fracture risk increase in women age 55+?

doubles

What is oteopenia?

pre-osteoporosis

T -1 to -2.5

What are some medications that can cause OP?

SSRIs

GC

Anticonvulsants

Chemo

TH excess

PPIs

What are some medical conditions that can cause OP?

CNS disorders

COPD

Endocrine/metabolic disorders

GI disorders

Hematologic disorders

HIV or AIDS

Severe liver disease

Nutrition disorders

Renal insufficiency

RA or SLE

What are non-pharmacological strategies to treat OP?

Diet

Weight-bearing exercise

Alcohol and smoking

Light therapy (conversion to Vit D in skin with UV light)

What are some anti-resportive therapies for OP?

HRT - estrogen

SERMS

Bisphosphonates

Oral phosphate binders

Biologics

How does HRT of estrogen increase bone density and when is it counterindicated?

lack of estrogen causes bone loss

increases osteoblasts lifetime and builds bones

CI: HR+ breast cancer, CV risk, ovarian cancer

How do SERMS increase bone mineral density?

Agonists in bone but antagonists in breast and endometrium

reduce risk of new vertebral fractures

decrease levels of bone turnover markers

What are 2 examples of SERMS?

1. Tamoxifen
2. Raloxifene

Why is tamoxifen different from Raloxifene and Badoxifene?

Has agonist activity in endometrium

Raloxifene/Badoxifene - are antagonists of endometrium

What bones are most affected by SERMS?

Trabecular bone

faster remodeling so will see the results first

What is the MOA of bisphosphonates?

Inhibit osteoclasts

increase osteoclast apoptosis via accumulation of geranyl pyrophosphate which is cytotoxic

(less breakdown of bone)

What does the structure of a bisphosphonate look like?

Analogues of inorganic pyrophosphate

2 phosphates and 2 R groups

What is important clinical pearl to remember about bisphosphonates?

can work too well

increased risk of cortical bone fractures → allow reset within treatment

IVs can cause acute renal failure and hepatitis

Where are bisphosphonates stored in the body?

The bone

has less off target effects

What are the three oral options for bisphosphonates?

Alendronate - Fosamax

Risendronate - Actonel

Ibandronate - Boniva

What are the 2 IV options for bisphosphonates?

Zolendronate - Reclast

Pamidronate - Aredia

What are ADRs to bisphosphonates?

GI irritation (limit in upper GI disorders)

renal disorders need reduced dose

Accumulation in skeleton w/ chronic therapy

Osteonecrosis of the jaw

How do you take oral bisphosphonates?

must take on empty stomach and with water

no Ca

What are the two oral phosphate binders that increase serum calcium?

Calcium Carbonate

Calcium citrate

What is the MOA of Ca carbonate and citrate?

bind to phosphate and inhibit absorption

* risk hypercalcemia & vascular calcification (+ ca)

What is the MOA of Sevelamer?

non-absorbable ion-exchange resin

binds to phosphate and decreases absorption

When is Sevelamer used and what other additional effect does it have?

dialysis to dec phosphate

binds to bile acids & may dec cholesterol absorption

What is superior for the treatment of OP Biologics or Oral?

Biologics - $$$