Bone Homeostasis

The structural units of compact bone.  Blood vessels and nerves run through the Haversian canals, which run lengthwise through the bone.

Collagen I or Collagen XXIV

• 1. Estrogen and androgen (when younger)
• 2. Physical activity
• 3. Dietary calcium
• 4. Genetics

Obviously, the only ones we can regulate are 1-3. And all 1-3 are needed; no compensating.

• ~90% of the bone surface is normally inactive, thus only 3% of cortical bone is remodeled/year.
• In contrast, 25% of trabecular bone is remodeled/year.

• Derived from marrow precursor cells in response to physical/biochemical signals (i.e. CSF-1)
• Multinucleated
• Clasts "crumble" = resorb = excavate into the bone
• Expresses RANK

• Receptor for Activating NF-kB
• Required for osteoclast bone resorption

• RANK Ligand
• Binds to RANK to induce osteoclast formation
• Produced by osteoblasts (two types= membrane-bound + soluble form)

• Acts as a decoy receptor for RANKL
• Produced by osteoblasts
• Levels are based on estrogen levels: if estrogen-deprived, OPG is suppressed (osteoclast production increases)

• Activation: osteoclast's RANK binds to osteoblast's RANKL to induce osteoclast maturation
• Resorption: osteoclasts make a ring-like seal and extent villi to digest the mineral matrix (old bone).
• Reversal: end of resorption (after 3 weeks).
• Formation: osteoblasts synthesize new bone matrix
• Quiescence: osteoblasts become resting bone lining cells on the newly formed bone surface

• Demineralization: Osteoclast villi secrete carbonic acid, citric acid, and H+. 
• Proteolysis: Osteoclast villi secrete cathespin K, collagenases and other proteases. 
• This will break down the extracellular matrix and release things that were adsorbed onto the hydroxyapatite, like IGF-1 and TGF-beta

• Osteoblast Proliferation: Stimulated by the cytokines and growth factors that were adsorbed onto the hydroxyapatite.
• Inhibition of Bone Demineralization: The new osteoblasts secrete alkaline phosphatase, which hydrolyzes phosphate esters, including pyrophosphate.
• Promotion of Crystallization: Inhibition of demineralization + Liberation of P_i = crystallization of calcium phosphate salts and mineralization of bone matrix.

• Our bodies use bone as a mechanism to maintain the correct plasma Ca²⁺ level.
• Ca²⁺ is needed for neurotransmitter release, muscle contraction, and blood coagulation.

• Life Basics! Such as:
• 1. Nucleotides and ribonucleotides
• 2. Intermediary metabolism
• 3. Energy metabolism (ATP)
• 4. Activity of signaling 
• 5. Within bone it is complexed with calcium as hydroxyapatites, having the general formula Ca10(PO4)6(OH)2, as well as being present as Ca3(PO4)2

• 1. Bone: for every 800-1000 mg of calcium intake, the bone remodels 300 mg of it's calcium
• 2. Intestine: active vit-D dependent transport + facillitated diffusion
• 3. Kidney: excretion

• Facilitates absorption of phosphate and Ca²⁺ from the small intestine
• Interacts with PTH to enhance calcium and phosphate mineralization from bone (thus bone mobilizing)
• Decreases renal excretion of both calcium and phosphate
• Active form of vitamin D, requiring two hydroxylations
• Effects are mediated by Vitamin D Receptor, which translocate to the nucleus to modify gene transcription

• Increases calcium reabsorption in the distal tubule, and increases absorption from intestines
• Inhibits phosphate reabsorption from the proximal tubule, therefore increasing urinary excretion
• Enhances reabsorption of Mg²⁺ and excretion of water, aas, citrate, K⁺, bicarbonate, Na⁺, Cl^- and SO₄^2-
• Increases calcitriol production by stimulating 1a-hydroxylase activity in kidney mitochondria (proximal tubule)
• Down-regulated by an increase in Ca²⁺ levels, which are noticed by the calcium sensing receptor on parathyroid cells

• 1. PTH₁R (GPCR)- binds PTH and PTH-related protein
• 2. PTH₂R (GPCR)- binds only PTH
• 3. CPTH receptor (on osteocytes)- binds truncated amino end of PTH

The GPCRs couple with G_s (adenylate cyclase) and G_q (phospholipase C -> DAG + IP3 -> Ca²⁺)

• True form is 84 aa PTH
• Stored in secretory granules until discharged into the circulation
• If aas # 1 and 2 are removed, the protein can bind to receptor, but cannot activate cAMP or IP3-Ca+2 signaling pathways
• If the first 6 aas have been removed (i.e., PTH converted to aas 7-84), PTH action is inhibited.

• D₂ and D₃ are absorbed from the small intestine
• Circulates in the blood with a vitamin D binding protein (an alpha-globulin)

• Phosphatonin
• Increases clearance of inorganic phosphate
• Makes weird vitD metabolite w/ OH at carbon24
• Increased osteocyte expression causes low plasma phosphate, low plasma calcium, and defective mineralization

• Hypocalcemic hormone opposing action of PTH
• Most potent inhibitor of osteoclast-mediated bone resorption (by decreasing their ruffled-border surface area)
• Released in response to hypercalcemia
• Salmon calcitonin is used therapeutically
• At high doses, there is an increased excretion of Ca²⁺
• Tx: Paget's, Osteoporosis, Hypercalcinemia

• Target the GI, Kidney, and Bone
• Decrease levels of Ca²⁺ and P_i
• Demineralize bone

• Targets bone
• Increases Ca²⁺ levels
• Demineralizes bone

• Targets bone
• Decreases Ca2+ levels
• Mineralizes bone

• Primary: caused by hypersecretion of PTH
• Familial: mutations in CaSR
• Tx: Saline, Calcitonin, IV bisphosphonates (inhibit osteoclast bone resorption), Oral sodium phosphate

• Calcium deficient: Tx IV CaCl, Calcitriol
• Hypoparathyroidism: Tx Calcitriol, Ca²⁺ supplements

• Toxic due to too much calcium and phosphate absorption + too much demineralization
• Tx: stop taking vitD; administer glucocorticoids

• Reduced Ca2+ absorption, thus increased PTH, thus increased demineralization, thus weak bones
• Because the fetus acquires >85% of its calcium stores during the third trimester, premature infants are especially susceptible to rickets
• Tx: sun, calcitriol (1000-4000 units/day for a few weeks)

• Often seen in bone disease accompanying chronic renal failure
• Increased phosphate levels reduce serum [Ca+2], which activates PTH secretion and exacerbates the hyperphosphatemia.
• Tx: The calcium sensing receptor agonist, cinacalcet, may be used to suppress PTH secretion

• Calcium sensing receptor agonist
• Suppresses PTH secretion
• Tx hyperphosphatemia
• ADEs: hypocalcemia

• 1. Bisphosphates
• 2. Estrogen
• 3. Selective estrogen response modulators (SERMS)
• 4. Calcium

• The most frequently used drugs for osteoporosis
• Also used for Paget's disease and Hypercalcemia, and anti-tumor via anti-angiogenic effects
• Three year relative efficacy of therapeutic interventions of BMD of the lumbar spine
• ADEs: GI distress and Osteonecrosis of the jaw
• ADME: poorly absorbed

The outcome of the Women’s Health Initiative showed estrogen as part of HRT caused an increased risk of heart disease and breast cancer.

• i.e. Raloxifene
• Estrogenic agonist on bone, inactive on uterus, anti-estrogenic on breast
• Reduces the risk of vertebral compression fracture

• OPG mimic; RANKL sequesterer
• In Phase III clinical trials
• After 3 years, therapy showed a 68% decrease in vertebral fractures, 41% decrease in hip fractures, and a 20% decrease in non-vertebral fractures

• First Gen: minimal side chains
• Second Gen: nitro R2 side chain, 10-100x potency of 1^st
• Third Gen: ring side chain, 10,000x potency of 1^st

• Concentrate at site of active bone remodeling
• Get incorporated into bone matrix
• When released by osteoclast acidic environment, this class directly inhibits osteoclasts
• 1. First Gen gets metabolized into a nonhydrolyzable ATP analog (AppCCl2p) that accumulates within osteoclasts and induces apoptosis
• 2. Second & Third Gen directly inhibit multiple steps in the pathway from mevalonate to cholesterol and isoprenoid lipids (required proteins for osteoclast activity)

• Alendronate: increased BMD—14% increase in lumbar spine, with smaller increments for hip, femur and forearm
• Zoledronate: shown to decrease vertebral and non-vertebral fractures (used if GI distress occurs w/ other bisphosphonates)
• Etidronate: Paget's
• Pamidronate: Hypercalcemia and prevention of bone loss (breast cancer & multiple myeloma) IV-only
• Tiludronate: Paget's
• Zometa: Prevention of bone loss (prostate and breast cancer pts w/ HRT)
• Ibandronate: Prevention and Tx of postmenopausal osteoporosis

• In elderly: suppresses bone turnover and improves BMD
• In post-menopausal: reduces cortical bone loss

Reduction they cause in Ca+2 excretion constrains bone loss in patients with hypercalcuria

• Anabolic agent for osteoporosis and Paget's
• Mitogen for osteoblasts and it increases trabecular bone mass.
• ADE: accelerates cortical bone loss.
• MoA: Its use leads to hydroxyapatite being converted to fluoroapatite, which is denser and more brittle.
• Studies of its impact on fractures have been inconsistant.

• Anabolic agent for osteoporosis and Paget's
• Currently the only agent that increases new bone formation.
• Prevention: for 2 years in people at high risk for fracture
• MoA: increases trabecular bone at the lumbar spine and femoral neck (near hip-see diagram). It has less significant effects at cortical bone sites.
• Dose: 20 ug qd SC
• BBW: Osteosarcoma
• ADEs: nausea, headache, leg cramps and dizziness.

• Complex alteration in bone and mineral metabolism that occurs as a direct result of chronic kidney disease (CKD)
• Identifying patients at risk and evaluating for SHPT is imperative because early intervention may slow or arrest the progression of both bone and cardiac disease. 
• Because 40% of patients with diabetes develop nephropathy, diabetic patients alone will account for 12 million people with CKD.
• Sites for intervention: Excretion of P_i, Activation of Vit D₃, Serum Ca²⁺
• Tx: oral phosphate binders, calcitriol or its analogs, & calcimimetics

• Nonabsorbable cationic ion-exchange resin that binds dietary phosphate. It also binds bile acids leading to decreased cholesterolabsorption.
• Expensive

• Paricalcitol: reduces PTH without producing hypercalcemia or altering serum P
• Doxercalciferol: A prodrug that must be activated by hepatic C25 hydroxylation1a25-(OH)2D2 for secondary hyperpara-thyroidism