Endocrine-2 Flashcards
no med chem of male reproductive
Naturally occurring estrogens
17β-estradiol > estrone > estriol
Estrogen is synthesized from what two things
androstenedione or testosterone
Anterior Pituitary Gonadotropins
- Luteinizing Hormone (LH)
- Follicle Stimulating Hormone (FSH)
Trophoblast gonadotrophin
Human chorionic gonadotropin (hCG)
Gonadotropin Receptors
FSHR: FSH
LHR: LH, hCG
Growth/maturation _________ follicle of ovary
Graafian
Corpus Luteum hormones
Progesterone, Estrogen
Endometrium:
endothelial lining, stroma
myometrium
smooth muscle
Perimetrium
outer serous coat
Follicular phase
estrogen builds endometrium
* Cell proliferation, increased thickness
* Induction of progesterone receptor
Luteal phase
progesterone prepares for implantation
* Ends estrogen effects on growth
* Stimulates endothelial secretions
* Blood vessel growth
Post-implantation
Stimulates LHR in corpus luteum to maintain
estrogen, progesterone synthesis
What does the ERalpha and ERbeta estrogen receptors do
ERα: female reproductive tract, mammillary gland, hypothalamus, endothelial cells, vascular smooth muscle
ERβ: Prostate, ovaries, lung, brain, bone, vasculature
Osteoblasts
↑ synthesis, type I collagen, osteocalcin, osteopontin
Estrogens plasma bound: _______________________ (SHBG) albumin
sex-hormone binging globulin
Single PR gene; two main isoforms: PR-A and PR-B which is inhibitory and which is excitatory
PR-A - inhibitory
PR-B - excitatory
Ligand-binding: dimerization, binding to what
progesterone response element (PRE)
What are Anti-progestins and Progestin Modulators used for
Early pregnancy termination
Ulipristal acetate (ELLA)
progesterone receptor modulator/partial PR agonist
inhibits ovulation
emergency contraception
Anti-Estrogens: “Pure” Estrogen Antagonists
Clomiphene and Fulvestrant
Estrogen Modulators/Anti-estrogens
Tamoxifen, Raloxifene, Clomiphene, Fluvestrant
Aromatase Inhibitors: steridal and non-steridal
Steroidal: formestane, exemestane (AROMASIN)
* irreversible
Non-steroidal: anastrozole (ARIMIDEX), letrozole (FEMERA), vorozole
* Reversible
Effects of estrogen
-Maturation of the female reproductive organs
-Maintains skin & blood vessels / & thickness of the vaginal lining
-↓ the resorption (breakdown) of the bone by osteoclasts
-↑ the coagulability of the blood
-Normal development of the endometrial (uterine) lining
-Can increase various hormone binding globulin
Progesterone during pregnancy and menstrual cycle regulation
During pregnancy – it maintains the endometrial lining
Menstrual cycle regulation – cyclical development & shedding of the endometrial lining
Androgens
Androstenedione is a weak androgen; it is converted to testosterone in the periphery
Testosterone & dihydrotestosterone (DHT) have significant androgen activity
_____ has a greater affinity for the androgen receptor and is the more potent androgen
DHT
Available LARC methods
copper IUD
levonorgestrel IUD
etonogestrel SUBDERMAL IMPLANT
copper IUD MOA
Primary – continual release of Cu++ into the uterine cavity Copper ions toxic to sperm; ↓ viability, ↓ motility
levonorgestrel IUD MOA
Primary – LOCAL effect; continual local release of progestin into uterine cavity
-Thickens the cervical mucus (sperm traveling up to the uterus is difficult)
-Over time causes changes to and thinning of the uterine lining
etonogestrel subdermal implant MOA
Primary – controlled release of progestin; suppresses ovulation
Thickens cervical mucus & produces a thinner endometrium
LACR return to fertility
1-2 cycles
Estrogen component actions
Helps prevent ovulation (estrogen will inhibit FSH production)
Regulates proliferation of the endometrial (uterine) lining; provides cycle control
Prevents the adverse effects of estrogen deficiency on various things
Elimination of estrogen
extensive 1st pass hepatic metabolism primarily by CYP450 3A4 enzymes
ethinyl estradiol
the synthetic estrogen used in almost all CHC products Available in oral doses containing
(usually 20mcg as starting dose)
Progestin component actions
-Suppression of LH - ↓ response of the ovary to FSH; LH surge is inhibited
-Thickens cervical mucus
-Slows ovum transport through Fallopian tubes
-Continuous use produces an atrophic endometrial lining
____________ an analog of spironolactone; has anti-mineralocorticoid activity
drospirenone
Risk of Estrogen: venous thromboembolism
[deep vein thrombosis (DVT), pulmonary embolism (PE)]
Risk of estrogen: CV disease
↑ risk occurs in women > 35yrs; especially if a heavy smoker
-contraindicated in smokers over 35 yo
-contraindicated with any ASCVD event
Risk of estrogen: Hypertension
Systolic BP ≥160 or Diastolic BP ≥100 is a contraindication to CHC
Systolic BP ≥140-159 or Diastolic BP ≥90-99 – generally should not use CHC, R>B
Risk of estrogen: breast cancer
several large population-based studies have NOT found a significant association btw the use of CHCs and breast cancer; do not use with a personal history of breast cancer
Risk of estrogen: headaches w/ focal neurological deficits what is contraindicated
Use of CHC
Risk of estrogen: breastfeeding concerns
Estrogen decreases breastmilk production
CHC are approved if breast milk is well established
Do not start until > 6 weeks postpartum
Traditional “21/7” cycles
mainly monobasic (same dose of E/P)
-the progesterone ingredient has more effect on the side effects not the phases
-the standard recommendation is to start on a monobasic
Who benefits from a entended or continuous cycle birth control
severe menstrual cramps
excessive bleeding
endometrial pain
-increased breakthrough bleeding
What is the day 1 start
initial pack started on 1st day of bleeding
no backup needed
What is a sunday start
initial pack started on 1st Sunday after period started
back needed for 1st week
no period on the weekend
What to do if 2 or more pills are missed
use a non-hormone backup method until active hormone tabs have been taken for 7 days
Side effects of too much estrogen
nausea/vomiting/bloating (take at night)
HTN
headache
darkened pigmentation
Side effects of too little estrogen
amenorrgea
vaginal dryness
BTB
Side effects of too much progesin
fatigue
mood changes
headache
Side effects of too little progestin
BTB
Side effects of too much androgen activity
acne
decreased libido
increased appetite
weight gain
Recommendations for adverse effects of birth control
an adequate trail for any pill should be 3 months
most side effects disappear by 4th cycle
Birth control serious ACHES
abdominal pain
chest pain
headaches
eye problems
severe leg pain
Transdermal Patch for non-daily contraceptive
3 wk on / 1 wk off
if women is >90 kg its a decreased efficacy
increases risk of VTE
Vaginal ring for non-daily contraceptive
3 wk on / 1 wk off (use new ring)
<3 hr then efficacy not affected
no douching
Progestin-only contraceptives: norethindrone MOA
increase thickness of cervical mucus (harder for sperm to move)
no placebo days
late by 3 hrs is a missed pill
Why are POPs the preferred oral contraceptive pill during breast feeding
they do not effect milk production and no clotting risk
can start right after pregnancy
What is the OTC progestin only pill
norgestrel (Opill)
Depo-injection
suppress FSH/LH
endometrial thinning
-cause weight gain
-BTB
-decreased bone mineral density (BMD)
takes 6-12 months for fertility to return
Copper IUD emergency contraception
if placed w/in 5 days of intercourse it is the most effective method
increased BMI does not decrease effectiveness
Ulipristal Acetate emergency contraception
SPRM (block progesterone from binding to receptor)
Inhibits or delays ovulation from occuring
give w/in 5 days
High dose progestin-only tablet for emergency contraception
inhibit or delay LH surge
levonorgestrel (PlanB)
take w/in 3 days
Yuzpe Method of emergency contraception
uses combo w/ high dose of progestin
causes nausea and vomiting
Comparative effectiveness of EC (highest to lowest)
copper IUD
ulipristal acetate
OTC levonorgestrel
Yuzpe
Indications for using topical corticosteroids
relieve dermatitis
eczema
ano-genital itching
external vaginal itching
MOA of corticosteroids
anti-inflammatory decrease production of mediators
immunosuppressive
anti-proliferative
Potency of topical corticosteroids
chemical structure modification
vasoconstrictor assay
potency classification
vehicle formulation
As a general rule ointments and gels are more or less potent than creams and lotions
more
Enhanced absorption effects of topical corticosteroids
skin hydration
occlusive dressings
Age of patient in relation to topical corticosteroids
-younger and older tolerate lower potency
-infants use the mildest topical in the diaper area
-elderly should only use high potency in short bursts
-very high potency should be avoided in children
Location of application in relation to topical corticosteroids
thinner the skin, the lower potency it should be
medium-high to very high are needed for chronic, hyperkeratotic lesions and areas involving palms and soles
Indication/type of lesion in relation to topical corticosteroids
lower potency are best for inflammation
medium to high good for chronic lesions in thicker areas
super-potent reserved for short term use
Local adverse effects of topical corticosteroids
atrophy (occur where absorption is high, cause thinning)
telangiectasia
striae
purpura
steroid acne
hypersensitivity rxns
Systemic adverse effects of topical corticosteroids
glucocorticoid excess (cushing, hyperglycemia, growth suppression)
HPA axis suppression
Cataracts and glaucoma
How much to apply “fingertip method”
tip of finger to first index
Occlusive technique increases skin penetration up to 10x when giving topical corticosteroids when should you use these
only used under the direction of a physician
What does the wolffian duct system consist of
epididymis, vas deferens, seminal vesicles
What do androgens cause in adulthood for males
male pattern baldness
prostatic hyperplasia
What do androgens cause in senescence for males
decreased energy, muscle mass, bone density
insulin resistance, truncal obesity, increase serum levels
Testosterone is secreted by ______ cells of testes
leydig
Androstenedione and dehydroepiandrosterone are what kind of androgens
weak androgens
-they are then converted to testosterone peripherally
Androgen synthesis levels of 5 alpha reductase / aromatase _______ across tissues
differ
In androgen synthesis, liver metabolizes T to what two inactive metabolites
androsterone
etiocholanolone
The active metabolites of androgens are 5 alpha reductase - dihydrotestosterone (DHT) which has a high affinity for ___ and aromatase which is _________ (ET)
AR
estradiol
AR mutations what is androgen insensitivity syndrome
loss of function mutations
CAG repeat extension (Kennedy’s disease)
What are heptanoate and cyclopentyl propionate T esters
esters inhibit metabolism; low bioavailability; given IM; hydrolyzed to T
What is undecanoate T ester
oral, absorbed into lymphatic circulation, bypasses hepatic catabolism
Androgen Receptor Antagonists Flutamide MOA
AR blockage alone insufficient
-LH compensates
-given with GNRH analog
What is the common 5 alpha reductase inhibitor
Finasteride
Androgen Receptor Antagonists Spironolactone MOA
fluid retention, HTN
gynecomastia; given with MR antagonist
Definition of menopause
absence of a menstrual period for 12 months
Characteristics of menopause
dysfunctional uterine bleeding/irregular menstrual cycles
unpredictable fertility
increasing FSH levels
Systemic symptoms of menopause
hot flashes
insomnia / sleep disturbances
psychological symptoms
Local symptoms of menopause
Atrophic vaginitis
-vaginal dryness, burning, irritation
-lack of lubrication, dyspareunia
Urogenital atrophy
-lower urinary tract symptoms
-recurrent urinary tract infections
-urge and stress incontinence
Diagnosis and assessment of menopause
Going to have bleeding changes
symptoms consistent with menopause
increase FSH levels
women <40 they check FSH levels
Surgical menopause
removal of both ovaries before natural menopause occurs
increased vasomotor symptoms
receive E/P hormone replacement therapy
Women with h/o hysterectomy
no uterus, no periods, might experience symptoms, FSH levels could be measured if needed
Women using levonorgestrel IUD
eventually develop amenorrhea; no periods to monitor FSH levels could be measured
Non-drug / lifestyle recommendations for management of vasomotor symptoms
dress in layers of clothes
identify and decrease triggers: spicy foods, hot beverages, caffeine, alcohol
Drug therapy for perimenopause symptoms
CHC
-lower dose pill
-vaginal ring
Drug therapy for menopause symptoms
need both therapies
consider tissue-targeted therapy
OTC vaginal moisturizers
Vaginally inserted estrogen for more moderate to severe symptoms
Vaginal estrogen products
estrogen cream
estrogen vaginal tablet
estrogen vaginal ring
Key points of vaginal estrogen products
local effect
low dose estrogen
does not stimulate uterine lining
progestin is not needed
no time limit
Who should not receive systemic therapy in hormone therapy or hormone replacement therapy
women w/ h/o CHD
women w/ h/o breast cancer
women >60 yo or >10 yrs from menopause
Who should receive systemic therapy in hormone therapy or hormone replacement therapy
women w/ severe symptoms
if <60 yo w/in 10 yrs of menopause
use lowest dose
short-term and taper off in 3-5 yrs
transdermal therapy have lower risk of VTE and stroke than oral therapy
Example estrogens and progestin
estrogens: conjugated equine estrogens, estradiol
progestin: medroxxyprogesterone (MPA), levonorgestrel (IUD)
Menopause treatment for women with a uterus
must use combo of estrogen and progestin to decrease risk of endometrial cancer (use every day)
could use continuous E and cyclic P therapy (take P only 12-14 days)
Menopause treatment for women w/o a uterus
estrogen therapy alone every day
What is the progestin drug that is used to induce withdrawal of bleeding
Provera
-help diagnose workup for amenorrhea
-may be used to treat women w/ dysfunctional bleeding
What are the two major components of the testes and what are their functions
Leydig cells – testosterone is the major hormone secreted (LH)
Seminiferous tubules (lined with Sertoli cells) – sperm production (FSH)
What are the 4 functions of testosterone
Development of the male reproductive structures
Male secondary sex characteristics at puberty
Maintenance of libido (sex drive) and erectile function
Required for the maturation of sperm
Primary hypogonadism in male reproductive
(Presents with low to normal testosterone levels, poor or no sperm…elevated FSH & LH)
-Absence of testes
-Lack of testosterone production
-Lack of functional sperm
Secondary hypogonadism in male reproductive
(Presents with LOW gonadotropins (FSH/LH)…low testosterone levels, no sperm)
-Pituitary adenomas
-Hyperprolactinemia
-Hypothyroidism
Drug therapy for primary male hypogonadism
testosterone replacement therapy
-Restores virilization / masculinization
-Restores libido and sexual performance and energy
-Increase quality of life
Monitoring for primary male hypogonadism
Symptom improvement
Testosterone levels – in the ~mid-normal range
ADRs for primary male hypogonadism
↑BP, major CV events, VTE, ↑ risk of prostate cancer, ↑BPH symptoms
Why is testosterone not given orally
1st pass metabolism causes many hepatotoxicity reactions
What is the intranasal gel, transdermal patch, and transdermal gel for primary male hypogonadism
Intranasal-Natesto
Transdermal patch-Androderm
Transdermal gel-Androgel
How to treat secondary hypogonadism if the man does not want children
Testosterone levels achieved in the blood do not ↑ testosterone levels in the testes that are high enough to cause the production of sperm
How to treat secondary hypogonadism if the man wants children
Give “Gonadotropins” to restore virilization and spermatogenesis
The drugs are given by IM injection 3 times per week
What are the two steps in fixing secondary hypogonadism if the man wants children
-Give Human Chorionic Gonadotropin (hCG) - stimulates Leydig cells to make testosterone
-Give a source of FSH - monitor sperm count; mix of FSH and LF
What is Benign prostatic hyperplasia (BPH)
a benign enlargement of the prostate gland that occurs as men age
What are the two prostate growth periods
Puberty through age 25-30yrs. Reaches normal size ~5-20gm
Starts again at ~40yrs through 80yrs.
Prostate tissue: Glandular epithelial tissue composes 20-30% of BPH tissue
-Growth is stimulated by the androgen hormone dihydrotestosterone (DHT)
-Men with large prostates (>40-50gm) may have more epithelial tissue
-This tissue responds to 5-alpha reductase inhibitors (↓ DHT production)
-5a-reducatase inhibitors can reduce the size of the gland
Prostate tissue: Smooth muscle tissue composes 70-80% of BPH tissue
-Smooth muscle tissue is less sensitive to androgen hormones
-Smooth muscle tissue growth is stimulated by other mechanisms (i.e., estrogen)
-Muscular tissue is under alpha-adrenergic tone
-This tissue responds to alpha adrenergic blocker therapy
What is LUTS (lower urinary tract symptoms)
Symptoms are caused by many factors; both static (enlargement) and dynamic (muscle tone)
What are the obstructive symptoms of LUTS
Hesitancy
Weak urine stream
Intermittency
Dribbling
Bladder fullness
What are the irritative symptoms of LUTS
Frequency
Urgency
Urinary incontinence
Nocturia
What are the 4 complications of BPH
-Urinary retention
-Recurrent urinary tract infection (UTI)
-Irreversible impairment of bladder function
-Chronic renal failure
Assessment of BPH
-Medical history
-Duration and description of LUTS
-Sexual function
-Overall health / other medical conditions
*Current medications (antihistamines, decongestants, anticholinergic drugs etc.)
BPH: Objective / Recommended initial tests for a basic evaluation (of any man w/ LUTS)
Urinalysis
Physical exam with Digital Rectal Exam (DRE)
PSA level
Frequency/volume charts
What should the PSA levels be in men over 60 and then in men under 60
If ≥60yoPSAshouldbe<4mg/ml
If < 60yo PSA should be < 2.5 mg/ml
What is the key point when determining LUTS
Serum creatinine is NOT recommended for the initial evaluation for LUTS
Treatment of BPH non pharm “Watchful Waiting” strategy
patient is monitored but takes no active therapy
follow-up with patient ~12months
Appropriate for
-Mild symptoms (AUA < 8)
-Moderate symptoms (AUA 8-19) & patient is NOT bothered by them.
Treatment of BPH non pharm lifestyle modifications to reduce symptoms
Fluid restriction / Fluid restriction in the evening
Decrease caffeine and alcohol consumption
Avoid drugs known to worsen symptoms
Drug therapy for patients with BPH
Alpha-1 receptor antagonists (relax smooth muscle, urinary flow increased)
monitor 2-4 wks
What are the two non-selective alpha blockers used in BPH
terazosin
doxazosin
What are the three selective alpha blockers used in BPH
tamsulosin
silodosin
alfuzosin
What are the non-selective alpha 1 receptor antagonists associated with
first dose syncope
5 alpha-reductase inhibitors MOA
↓ conversion of testosterone to dihydrotestosterone (DHT)
(reduces prostate size by 25%)
What are the use of 5 alpha-reductase inhibitors appropriate for
Men with enlarged prostates as evidenced by either:
-Estimated size of at least 40gm
-PSA level ≥ 1.5
Monitoring and follow-up for 5 alpha-reductase inhibitors
3 months
takes 6-12 months to see new effect
Options – similar clinical effectiveness for 5 alpha-reductase inhibitors in BPH
finasteride (Type II 5a-reductase inhibitor)
dutasteride (Non-selective 5a-reductase inhibitor)
Sexual side effects of 5a-reductase inhibitor
↓ Libido; ejaculatory dysfunction (3-15%); erectile dysfunction (3-5%)
Clinical monitoring concerns of 5a-reductase inhibitor
-Patients need a baseline PSA level before starting therapy
-5a-reductase inhibitors decrease PSA levels by 50%
-A delay in prostate cancer diagnosis has been observed if this is not remembered
When to use surgical interventions in BPH
Patients with malignant or complicated disease
Patients with moderate to severe disease unresponsive to pharmacologic therapy
Types of Sexual Dysfunction in Men
Decreased libido
Increased libido
Delayed ejaculation
Premature ejaculation
Retrograde ejaculation
Infertility
Erectile dysfunction
Erectile dysfunction: hormonal classification
hypogonadism, hyperprolactinemia, hyper/hypothyroidism, adrenal disease
Erectile dysfunction: neurologic classification
cerebral disease, stroke, spinal disease, peripheral neuropathy (diabetes)
Erectile dysfunction: vascular classification
atherosclerosis, CAD, PVD, HTN, hyperlipidemia; diabetes
Pathophysiology of ED
-With increasing age – collagen and elastic fibers in the penile structure decrease
-Decrease of smooth muscle content in men over 65yrs
-Decrease in sensitivity, metabolic imbalance of contractile and relaxing factors “Endothelial dysfunction”
Physiology of penile erection
Erection begins with stimulation
the release of nitric oxide
↑cGMP
development of an erection
What enzyme metabolizes cGMP
Phosphodiesterase (PDE)
Oral PDE-5 Inhibitors MOA
Inhibition of PDE5 prevents the metabolism of cGMP
↑ cGMP levels…helps to initiate & maintain an erection
What are the Oral Available products for PDE-5 Inhibitors
avanafil: 15 min before sex
sildenafil: 60 min before sex
vardenafil: 60 min before sex
TADALAFIL: 30 min before sex
(no more than 1 dose per 24 hrs)
Oral PDE-5 Inhibitors effectiveness
consider a trial of 7-8 doses
If one drug does not work try another one
assess how they are using it (are they engaging in foreplay)
Adverse effects of Oral PDE-5 Inhibitors
Headache, flushing, nasal congestion, heartburn
Cyanopsia
Hypotensive effects
Contraindications of Oral PDE-5 Inhibitors
Contraindicated with any organic nitrate due to severe hypotension that may result
Examples: nitroglycerin, isosorbide dinitrate
Priapism Precautions in Oral PDE-5 Inhibitors
-Is an erection lasting > 4hrs
-Is a medical emergency; immediate medical attention should be sought
-Penile tissue damage and permanent loss of erectile function may result
Other treatments for erectile dysfunction
Alprostadil
VED- Vacuum erection device
Penile prostheses
Hypopituitarism for male reproductive
-Can be due to primary pituitary disease or secondary hypothalamic disease
-Can be partial
-Can be complete “panhypopituitarism” - historically refers to loss of all anterior pituitary
hormones
Etiology of Hypopituitarism for male reproductive
Tumors - pituitary tumors are the #1 cause
(Microadenoma < 10mm Macroadenoma >10mm)
Infarction of the vasculature of the gland
Trauma / Whiplash type injuries
Neurosurgery or Radiation
Autoimmune disease, Infection/Inflammation, Idiopathic
Symptoms of Hypopituitarism for male reproductive
You only need about 30% of the pituitary gland to function Symptoms usually appear when ~70-80% of the gland is destroyed
Hypopituitarism for male reproductive causes a hormone deficit of
GH (short stature in children, weight gain, metabolic disturbance, and fatigue in adults)
FSH/LH (hypogonadism and infertility)
TSH
ACTH
Prolactin
Diagnosis of Hypopituitarism for male reproductive
History & physical
Imaging studies
Laboratory analysis
Stimulation testing
Treatment of Hypopituitarism for male reproductive if there is an ATCH deficit
Give a glucocorticoid to prevent adrenal insufficiency Increase dose during states of stress, e.g., infection, surgery
Treatment of Hypopituitarism for male reproductive if there is TSH deficit
levothyroxine
Treatment of Hypopituitarism for male reproductive if there is FSH/LH deficit
Males: Testosterone
Females: CHC
For Fertility: Gonadotropins (Menotropins), Synthetic hCG
Treatment of Hypopituitarism for male reproductive if there is growth hormone
the use of synthetic growth hormone is AGE dependent
What are the two components of the bone
Minerals: provide tensile strength
Organic: proteins, bone cells
What are the the sources of calcium
Absorption of Ca++ from the GI tract
Bones
The regulation of calcium homeostasis involves what 5 things
Parathyroid Hormone (PTH)
1,25(OH)2 D = calcitriol
Bones
GI tract
Kidneys
What are the two functions of the parathyroid hormone
-to control ionized Ca levels in a very tight range
-to do this it produces and secretes parathyroid hormone (PTH)
The result of increased PTH causes and increase in what levels
Calcium
What are three things that stimulate the increase of PTH secretion
The main trigger = Low Ionized Calcium Levels
Low vitamin D levels
High phosphorus levels*
Disorders of PTH: Primary Hypoparathyroidism
Due to loss of function or removal of PTH gland(s)
-Will cause signs and symptoms due to hypocalcemia
-Is managed with the administration of Calcium and Vit D supplements
Disorders of PTH: Primary Hyperparathyroidism
due to hyperplasia or increased activity of PTH gland
-cause signs and symptoms due to hypercalcemia
-managed with surgery
Disorders of PTH: Secondary Hypoparathyroidism
Occurs when there is a primary disorder that is causing hypercalcemia
Disorders of PTH: Secondary Hyperparathyroidism
-Triggered by hypocalcemia
-Triggered by low vitamin D levels (vitamin D insufficiency / deficiency)
-Triggered by hyperphosphatemia* (CKD is the most common cause)
Vitamin D2 (ergocalciferol)
Diet - soy, yeast…
Fortified foods – milk, OJ, some cereals
OTC Dietary supplements
Rx products
Vitamin D3 (cholecalciferol)
Diet – cod liver oil, sardines, salmon
Fortified foods – milk, OJ, some cereals
OTC Dietary supplements
Rx products
Synthesized in the skin from UVB exposure
The first hydroxylation takes place in the LIVER Vit D2/D3 is metabolized to calcidiol (25(OH) D) what are the important points of this
storage form
indicates Vit D status
used to monitor therapy
physiologically inactive
The second hydroxylation takes place in the KIDNEY 25(OH) D is converted into calcitriol (1,25(OH)2 D) what are the important points of this
-Calcitriol is the physiologically ACTIVE form of vitamin D
-Blood levels are kept very low and are tightly regulated
-PTH stimulates the conversion
Primary effects of active 1,25 (OH)2 D (calcitriol) in calcium homeostasis
Increases absorption of Ca from the GI tract
Increases calcium and phosphate reabsorption by the kidney
Calcitonin is secreted by the __________ cells of the thyroid gland
parafollicular
What is the primary function of calcitonin
inhibit bone resorption by inhibiting osteoclasts
Calcitonin salmon products MOA
potent inhibitor of osteoclasts
Therapeutic uses of calcitonin salmon injections
Adjunct treatment in hypercalcemic crisis
Paget’s disease of the bone
Therapeutic uses of calcitonin salmon nasal spray
Postmenopausal osteoporosis (only in women who are > 5yrs postmenopausal)
Etiology of Vit D deficiency
-Nutritional deficiency/malnourishment
-GI procedures
-malabsorption
-lack of sun
-CKD
Clinical Presentations of Vit D deficiency
Fractures
Bone pain
Muscle weakness
Classic bone disorders associated with severe Vitamin D deficiency
Osteomalacia (“soft bones”) – in adults
Rickets – in children
(bones are under mineralized, most caused severe deficiency for long periods of time)
Vit D insufficiency results in hypocalcemia which causes secondary hyperparathyroidism resulting in what
an increase in bone resorption to increase calcium levels in the blood
an increase in the excretion of phosphorus in the urine
At risk populations for Vit D insufficienct
Elderly
Dark skinned racial groups
Living above latitude 35oN
In Vitamin D replacement therapy 1 mcg = how many units
40 units
Vitamin D replacement therapy: Drisdol
50,000 IU/cap
VitD2 (ergocalciferol)
Requires activation by the liver & the kidney
Vitamin D replacement therapy: Rocaltrol
0.25, 0.5 mcg capsules, 1mcg/ml liquid, 1mcg/ml injection
Calcitriol 1,25(OH)2D
the active form of vitamin D
Too little free calcium causes what and too high free calcium causes what
- Too low = neuronal hyper-excitability
- Too high = neuronal depression
What are the three control points for calcium regulation
Absorption – intestines
Excretion – kidneys
Storage – bones
What does Parathyroid Hormone (PTH) do to serum calcium and serum phosphate
increase calcium
decrease phosphate
(produced by chief cells)
Osteoblast vs Osteoclast
Osteoblast: promotes bone formation
Osteoclast: promotes bone resorption
(PTH promotes precursor differentiation, PTH stimulates signaling)
Calcium feedback regulation of Parathyroid Gland: PTH ↑ Serum Calcium
↓ Calcium Excretion
↑ Active Vitamin D Metabolites
↑ Bone Calcium Resorption
Calcitonin are produced in C-cells of thyroid gland: ↓ serum calcium
↓ bone resorption
↑ renal excretion
What are the three pharmacological effects of Calcitonin
-Attenuates absorptive ability of osteoclasts
-Inhibits formation of new osteoclasts
-Has weak effect in kidney and intestine
What is converted to 25-Hydroxycholecalciferol as a precursor in the liver
Vitamin D3
What is converted to 1,25-Dihydroxycholecalciferol to active form in the kidney
Vitamin D3
Adverse effects of bisphosphonates
erosion of esophagus
What are the Bisphosphonates drugs that : inhibit osteoclast-mediated resorption
-pamidronate, zeldronate IV
-alternative form raloxifene which is a selective estrogen receptor modulator
What is cortical bone
it is dense and stiff, a major component of the long bones of the legs, arms
What is trabecular bone
more flexible; provides shock absorption
Defn of osteoporosis
a skeletal disorder of compromised bone strength which predisposes a person to ↑ fracture risk
Establishment of optimal peak bone mass in osteoporosis
Genetics
Physical activity
Ca & Vit D intake
Proper endocrine function (GH, thyroid , sex hormones)
Contributions to bone loss as we get older
Decreased osteoblast function
Decreased calcium intake and absorption from the gut
Decreased sun exposure ↓vitamin D production
In women…postmenopausal loss of estrogen (and in older men, loss of testosterone)
Risk factors for low bone mass / osteoporosis
Genetic
Lifestyle: smoking, inactivity
Nutrition: lactose intolerance
Medical disorders / Drug therapy
How is BMD measured? (bone mineral density)
DXA scan (Dual-energy X-ray Absorptiometry)
-has the best correlation with fracture risk; the gold standard test
Where is BMD measured?
“Central bones” (lumbar spine or hip/femoral neck) – give the best predictor of risk
“Peripheral bones” (forearm, heel, fingers)
Less predictive of risk than central measurement; for screening purposes only
What is T score
Compares patient’s BMD with the mean BMD of a healthy young person of the same gender
-represents the # of standard deviations from the mean BMD
What is a normal t-score
scores > -1.0
What is the t-score of low bone mass
T-score between –1.0 and –2.5
What is the t-score in patients that have osteoporosis
T-score ≤ –2.5
Recommendations for BMD measurement / monitoring: Initial Screening
-To identify those at risk for OP fractures – no consensus exists
-Women > 65yrs
-Men > 70yrs
(postmenopausal >50 yrs who have age-related fracture)
Follow up and monitoring for BMD measurement
If T-score is normal…recheck in 5yrs
If T-score indicates Low Bone Mass, recheck in ≥ 2yrs
If T-score indicates osteoporosis, drug therapy is recommended to treat osteoporosis
If drug therapy started, recheck in 2-5yrs depending on the treatment chosen
Dorsal kyphosis / “Dowager’s hump”
Loss of height
Back pain
Loss of mobility / function
Fragility fracture defn
a fracture that occurs in the absence of a major trauma
Common sites of fragility fractures
spine, ribs, hip, pelvis, wrist, forearm
Common causes of fragility fractures
fall from standing height
bending, lifting, or twisting
coughing, sneezing
Risk factors for falling
Poor health
Loss of balance
Use of sedating medications
Environmental…rugs, no bath rails, obstacles…
Risk PREDICTORS for clinical bone FRACTURES are:
Low BMD
Age >65yrs
Personal history of adult fragility fracture
Family history of fragility fracture due to OP
Current cigarette smoking
Current glucocorticoid steroid use
Low BMI (underweight)
Excessive alcohol use
What is the FRAX risk assessment tool
Calculates a person’s 10year risk for hip or other major OP fracture
What are the complications of osteoporosis
fracture
fracture pain
loss of mobility
nursing home placement
depression
death
Primary Osteoporosis defn
is due to the aging process; is not due to some other cause
“Postmenopausal osteoporosis”
After the peak BMD in 20-30s, bone loss begins…it accelerates at menopause
10-25% of bone is lost in the decade after menopause; up to 15% in the first 5years
mainly loss of trabecular bone
What can slow down postmenopausal osteoporosis
having enough calcium and vitamin D
Secondary osteoporosis defn
is caused by or is exacerbated by other diseases or drugs
What is the most common cause of secondary osteoporosis
Chronic glucocorticoid therapy
Secondary osteoporosis should be suspected if a fracture/fragility fracture occurs
In pre-menopausal women
In men < 70yrs
In someone with no risk factors
Patients with multiple low trauma fractures
What is Z score
-Compares patient’s BMD with the mean BMD of a control group matched for age & sex
-If the Z-score is less than –2 secondary osteoporosis should be suspected
Strategies for prevention of osteoporosis
Achieve the highest peak bone mass as possible while younger
Reduce bone loss
Prevent falls
Adequate Calcium and Vit D intake
UL of calcium
2,000 mg per day, increase risk for kidney stones
Frequency of dosing practical issues related to calcium
as dose increases, the % of calcium absorbed decreases
single dose should not be more than 500-600 mg
typically given in divided doses, one dose at bedtime if possible
What are the two calcium salts to use
calcium carbonate (Tums, needs stomach acid for absorption)
Calcium Citrate (citracal)
Calcium drug interactions
tetracyclines, fluoroquinolones, bisphosphonates, levothyroxine
(need to separate the drug dose from the calcium; take 1hr before or 4hrs p Ca++)
UL of vitamin D
4000 units
(should have around 800 units per day)
Lifestyle changes to prevent osteoporosis
stop smoking
increase physical activity
fall prevention
When to use bisphosphonate drugs for prevention of osteoporosis
T score of 1 to -2.5 AND frax >3% hip or >20% major osteoporotic
Non drug therapy for primary osteoporosis
Lifestyle modifications
Adequate Calcium + Vitamin D intake
Diagnosis of Osteoporosis
-T-score ≤ –2.5
-History of a fragility fracture (regardless of bone mineral density)
-Incidentally found (asymptomatic) vertebral compression fracture
Bisphosphonates MOA
inhibits osteoclast activity; ↓ resorption of bone
What are the bisphosphonates drugs that are used to treat primary osteoporosis
Alendronate
Risedronate
Zoledronic Acid
Oral administration counseling points for bisphosphonates
at least 30 min before eating or drinking
take only with water
must be separated from other meds
Adverse effects of bisphosphonates
GI, nausea, ab pain, heartburn (stay upright 30 min after taking)
Jaw
Atpyical femoral fractures
What is the duration of ORAL bisphosphonate treatment
5 years
What is Denosumab (Prolia®) is used for primary osteoporosis, what is its MOA
Denosumab is a monoclonal antibody with affinity for RANKL
-blocks the interaction between RANKL and
RANK
When to use Denosumab (Prolia®)
Treatment of osteoporosis
Prevention of bone loss in certain patients
Treatment/prevention of of glucocorticoid-induced osteoporosis
Effects of Denosumab
Increase BMD
decrease vertebral, non-vertebral and hip fractures
Adverse effects of denosumab
generally, well tolerated
(atypical femoral fractures have been reported)
What is the duration of denosumab treatment
5-10 years
What is the second line therapy drugs for osteoporosis
Raloxifene
PTH
Raloxifene MOA
it is a SERM
Agonist: Mimics effects of estrogen on bones and lipids
Antagonist: Blocks effects of estrogen in the breast & uterus
Effects of raloxifene
Increase BMD spine and hip
decrease spinal fractures
effects on the bone stop when the drug is stopped
Adverse effects of raloxifene
hot flashes
blood clots
When are the parathyroid hormone drugs teriparatide and abaloparatide used
moderate to severe osteoporosis in postmenopausal women
men and women w/ GIOP w/ high risk of fracture (only teriparatide)
OP in men w/ hypogonadal disorders and increase risk of fracture (teriparatide)
MOA of teriparatide and abaloparatide
Has anabolic activity if given once a day
Helps to build bone; increases bone density
Effects on the bone stop when the drug is stopped
Adverse effects of teriparatide and abaloparatide
osteosarcoma
Do not use in pts with prior skeletal irradiation therapy
Do not use with unexplained increase in alkaline phosphatase or Paget’s disease
Use of PTH drugs for osteoporosis are limited to ___ years
2
What is the last line therapy for osteoporosis
Calcitonin salmon Nasal Spray
-used for treatment of OP in women who are 5 years postmenopausal
-reduce spine fractures
Glucocorticoid Induced Osteoporosis (GIOP) background
The greatest bone loss is during the first 6-12 months of therapy
Pathogenesis of Chronic Glucocorticoid exposure
Decreases osteoblast function by affecting the activity of IGF-1 (resulting in decreased bone formation)
Promotes hypocalcemia (increases bone resorption)
Prevention and Treatment of Glucocorticoid Induced Osteoporosis (GIOP)
Use the lowest dose of steroid
Adequate Calcium + Vitamin D intake
(Elemental Calcium 1500mg and vitamin D 800 -1000 IU per day)
Drug therapy use in Glucocorticoid Induced Osteoporosis (GIOP)
Bisphosphonate therapy for any patient starting prednisone >5mg daily if duration of therapy is expected to last > 3 months
Denosumab treatment for glucocorticoids at a daily dose equivalent to ≥7.5 mg of prednisone for an anticipated duration of at least 6 months
Obtain a BMD in any patient that has already received GC therapy > 6 months
How often to repeat BMD if the patient has already received GC therapy >6 months and when should you start a bisphosphonate drug in this case
BMD yearly
Start bisphosphonate drug if the T-score is < -1
