EAST 501 Lecture Notes - Lecture 16: Mitochondrial Permeability Transition Pore, Bone Density, Bone Resorption
21 Jun 2018
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L16 – Trasler Apr 6
Osteoporosis
1
- Osteoporosis affects 75M in Japan, US and Europe à fractures are the biggest problem in patients with
osteoporosis
- a third to half of all women who have osteoporosis will have a fracture in their lifetime and 15-30% of men
- osteoporosis accounts for more hospital days than diabetes, cardiovascular disease and breast cancer
- exercise is really important for bone health and it probably works by the mechanosensory stressors (Ocytes)
that influence all of the bone modulators – this can be added to all the drug therapies
- bone remodeling units à 1M of them can be active at any given time in a healthy adult
- HRT only used for a lot of menopause symptoms (ie. hot flashes) à only used for a short time
- Raloxifene (agonist + antagonist), but it is not as good as E2 was à not as effective (as E2 as an agonist) and
therefore we have other agents
BISPHOSPHONATES
- Current drug class of choice for prevention and treatment of primary osteoporosis
- used for >30 years
- many different drugs in the category
- bind to bone undergoing remodeling, particularly OC
- they can stay in bone for years (can stay in bone for 10year – the amount of time that it takes the bone to turn
over)
- they can actually weaken bone over time
- know: ALENDRONATE
SELECTIVITY OF BPs IS CONFERRED BY HIGH AFFINITY BINDING OT HYDROXYAPATITE IN BONE
- bind with high affinity to hydroxyapatite – the inorganic phase of bone (Ca and phosphorus in the bone)
- Poor absorption of BPs by GI tract (~1%)
- 50% of absorbed BPs eliminated unaltered via kidneys
- 50% binds bone (can remain for ~10 years)
- During resorption they are taken up into the OCsà affect OC activity à released in the resorption phase à stay
in bone
SIMPLE BISPHOSPHONATES (1st gen): MECHANISM OF ACTION
- Clodronate, Etidronate à act differently than the second generation
- Endocytosed by OCs
- Metabolized into methylene-containing (non-hydrolysable) ATP analogs à analogues inhibit ATP-dependent
enzymes à leads to OC apoptosis à inhibition of bone resorption
- Inhibit ATP-dependent enzymes (eg. adenine nucleotide translocase, a component of the mitochondrial
permeability transition pore, leading to caspase activation)
- Causes OC apoptosis (inhibiting bone resorption)
NITROGEN-CONTAINING BISPHOSPHONATES (N-BPs): MECHANISM OF ACTION
- pamidronate, ALENDRONATE, ibandronate, risedronate, zolendronate
- have N in the structure
- they are more potent than the initial group (1st gen)
- N-BPs more potent than simple BPs
- endocytosed by OCs
- not metabolized to toxic ATP analogues
- inhibit farnesyl pyrophosphate synthase (FPPS) à inhibit protein prenylation or GTPases that are needed for
normal OC proliferation à losing the prenylated proteins = losing the function of the OC = compromising OC
function
o cytoskeletal rearrangement, membrane ruffling, vesicular trafficking
L16 – Trasler Apr 6
Osteoporosis
2
RELATIVE EFFECTS OF ALENDRONATE (FOSAMAX) AND RALOXIFENE ON BONE MINERAL DENSITY (BMD)
- Bisphosphonates more effective than SERM in increasing BMD
- 1400 post-menopausal women
- did a back to back comparison and looked at changes in bone mineral density over the time of the trial
- Raloxifene gives an increase of ~2% in BMD
o adding Alendronate doubles the effect
o true for the lumbar spine and the femoral neck (important bone sites)
o Alendronate was better than Raloxifene at increasing the BMD
SERIOUS SIDE EFFECTS: DO BISPHOSPHONATES CAUSE OSTEONECROSIS OF THE JAW (ONJ)?
- ONJ: Accumulation of dead exposed bone in oral cavity
o most often when you have patients that had head/neck irradiation or were on chemotherapy or agents
that may affect bone anyways like corticosteroids or local infection (would affect the bone)
o more common with the high dose IV treatment
- Associated with:
o Tissue damage (following head and neck irradiation (in cancer patients)
o Underlying malignancy
o Chemotherapy
o Corticosteroids
o Local infection (that would affect the bone)
- Most common with high dose, intravenous BP treatment (cancer patients)
- <1 case per 100,000 person-years of exposure in osteoporosis patients (low dose drugs, such as Alendronate) à
has lead to a decrease in the usage of the drug
o some dentists if their patients are on the drugs they will not do surgery in the mouths of the patients
SERIOUS SIDE EFFECTS: DO BISPHOSPHONATES CAUSE SUBTROCHANTERIC OR DIAPHYSEAL FEMUS FRACTURES
- very low incidence
- thought that it is because of the repression of bone resorption
- these drugs decrease OC function à with time = killing off OCs à no more OB and OC connections and the bone
formation goes down with time
o just having this compound in the bone for so long might be a problem
- you have regular bone remodeling to fix the wear and tear (you need the regular turn over) and you get LESS
turn over with taking BPs
CALCITONIN – not very often used
- 32 amino acid peptide, product of CALCA gene
- produced by parafollicular cells of thyroid (C-cells)
- Secreted in response to elevated serum Ca2+
- Anti-resorptive effects via direct action on OCs (via calcitonin receptor)
- Approved for use in treatment of Paget’s disease (excess breakdown and formation of bone = disorganized bone
remodeling), osteoporosis and hypercalcemia of malignancy
o Osteoporosis: women >5 year since menopause, unable to take other meds; men with mild bone loss
- Salmon calcitonin (sCT) delivered SC or intranasally
- Oral sCT in Phase III clinical trials
- Less effective than other anti-resorptives
o Used in patients unwilling or unable to take other anti-resorptives
- can be used in women who are unable to take the other drug classes
Document Summary
Bone remodeling units 1m of them can be active at any given time in a healthy adult. Hrt only used for a lot of menopause symptoms (ie. hot flashes) only used for a short time. Raloxifene (agonist + antagonist), but it is not as good as e2 was not as effective (as e2 as an agonist) and therefore we have other agents. Current drug class of choice for prevention and treatment of primary osteoporosis. Selectivity of bps is conferred by high affinity binding ot hydroxyapatite in bone. Bind with high affinity to hydroxyapatite the inorganic phase of bone (ca and phosphorus in the bone) During resorption they are taken up into the ocs affect oc activity released in the resorption phase stay. Poor absorption of bps by gi tract (~1%) 50% of absorbed bps eliminated unaltered via kidneys. 50% binds bone (can remain for ~10 years) in bone. Clodronate, etidronate act differently than the second generation.
