Women's Health: Menopause and perimenopause AND Osteoporosis (Case 3)

nonhormonal treatment options for menopause

ANTIDEPRESSANTS ANTICONVULSANTS CLONIDINE (alpha adrenergic agonist) NHPS VAGINAL LUBRICANTS LIFESTYLE MODIFICATIONS

what is the link between hypertension and hormonal therapy

Consider topical/transdermal estrogen if ↑CVD risk/smoking/HTN/DM/gallstones.

Estradiol (TOPICAL) Premarin (vaginal cream) >>> conjugated equine estrogen (CEE) (EXCEPTION) Estring (vaginal ring) Vagifem (Vaginal tablet)

MOA for Estradiol :In studies for vulvar and vaginal atrophy in postmenopausal women, local estrogens have been shown to reduce vaginal pH levels and mature the vaginal and urethral mucosa after 12 weeks of therapy, thereby improving vaginal dryness and mucosal atrophy. MOA for CEE: Conjugated estrogens contain a mixture of estrone sulfate, equilin sulfate, 17 alpha-dihydroequilin, 17 alpha-estradiol and 17 beta-dihydroequilin. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in postmenopausal women. INDICATION: Vulvar and vaginal atrophy associated with menopause: vaginal therapy directly acts on the vaginal tissues and alleviates symptoms of atrophy; it may be used for the treatment of urogenital aging.... vaginal estrogen is preferred when urogenital SXs are the only concern.. these concerns include atrophy, dryness, stress incontinence) ***the vaginal delivery is ok even in breast cancer history IFFFF failed non-hormonal treatment Premarin Dosing: 0.5-2g pv HS (Cyclic 3w/1wk) after initial, short-term tx ~1-2 wk, often taper down to lowest effective dose (eg. 1-3Xper wk) Patient Counselling: Gently insert applicator filled with vaginal cream deeply into vagina. Cleanse applicator after use with warm water and mild soap (do not boil or use hot water). ESTRING Dosing: -diffusion controlled membrane drug release system made of polysiloxane materials (more rigid than the nuvaring) -release rate is zero order and can be controlled by the thickness of the membrane and the nature of the membrane material 2 mg intravaginally following insertion the ring should remain in place for 90 days *may avoid major systemic actions by its novel formualtion which gives sustained delivery of low dose of estradiol. Estring consists of an intra-vaginal silastic ring which releases a very small dose of estradiol (8 microgram/day) over a protected period of time (84 days) -the initial burst of E2 levels lasts only for a few hrs (<2%). the reminder of the drug is released over 90 days Patient Counseling: Vaginal ring: Insert as deeply as possible into the upper one-third of the vagina; exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, ring should be gently pushed further into vagina. Straining at defecation may make the ring move down in the lower part of the vagina; if this occurs, push up ring with finger. If ring is expelled prior to 90 days, it may be rinsed in lukewarm water and reinserted. If vaginal infection, ulceration, erosion, or adherence to vaginal wall develops, remove ring and reinsert only after healing is complete. VAGIFEM: Dosing: Initial: Insert 1 tablet (10 mcg) once daily for 2 weeks; Maintenance: Insert 1 tablet twice weekly Patient counseling: Insert tablet with supplied applicator at the same time each day. Once inserted, press plunger until fully depressed, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead (if the tablet has fallen out of applicator but still remains in the package, it can be reinserted in the applicator for use). Local abrasion caused by the vaginal applicator has been reported in women with severely atrophic vaginal mucosa. CONTRAINDICATIONS TO ALL: history of breast cancer, CHD, stroke/TIA, VTE, liver diseasendometrial cancer, unexplained vaginal bleeding. Raynaud's may be caused/worsened by unopposed estrogen. AE: Breast tenderness, headache, mood changes. Tapering useful when discontinuing to ↓AE.54 Serious & rare: DVT, pulmonary embolism, stroke, ?dementia. Timing hypothesis (critical window or critical timing): A woman's age and time since menopause onset influence her outcomes and should be considered in her risk/ benefit ratio when considering initiating hormone therapy ↑ CV harm in those started late (10+ yrs post menopause) vs within 6 yrs. DI: 3A4 substrate (↑ estrogen level by 3A4 inhibitors; ↓ level by 3A4 inducers); weak 1A2 inhibitor

Treatment of Vasomotor SXs associated with menopause

NHPs Hormone Therapy

compare the 3 dosage forms (pk,metabolism, DI) for post-menopausal hormonal therapy

When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health -TREND towards bio-identical Hormones (Health Canada has approved "NOT custom-compunded" products Estrogen: the pharmacological, physiological and metabolic actions of estrogens vary not only with the form of estrogen given but also by the route of administration ORAL -subject to high first pass metabolism in the intestinal mucosa and liver (decreased bioavailability) -when estrogens are taken orally they are readily absorbed but there is extensive pre-systemic metabolism, first by the intestinal mucosa and then by the liver. -decreased concentration of estradiol but increased concentration of estrone -cigarette smoking would increase hepatic metabolism of oral estrogens -INCREASED liver synthesis of sex hormone-binding globulin (SHBG) and corticosteroid-binding protein angiotensinogens, thyroxine- binding globulin -use short term on lowest effective dose TRANSDERMAL -does not result in wide swings in plasma estrogen concentrations seen after oral or topical dosing, but rather in constant, sustained levels. -the drugs are absorbed directly from implant site or across the skin into the systemic circulation and do not suffer extensive metabolism seen after oral dosing. -limited evidence for benefits/harms vs oral route -"metabolically friendly": avoids first pass metabolism so no significant ↑ in triglycerides, C-reactive protein, SHBG, or blood pressure consider use in women: •At high risk of: VTE; CVD•With: malabsorption syndromes, diabetes; hypertension •With spontaneous or estrogen-induced hypertriglyceridemia •Who: are obese; smoke; have gallstones >>>Overall: trend toward transdermal being considered safer than oral VAGINAL RINGS -alone (if vaginal symptoms only) or added to systemic therapy for vaginal symptoms -Estring was designed to give sustained delivery of estradiol to the vaginal mucosa. there is no evidence that the small incerase in the palsma estradiol concnetration has any sustained systemic action -in the vagina the silastic ring relaeses estradiol at a rate of 8 micrograms/day. it is improabbale that such a small amount woudl cause local irritation -since the ring is located in the upper third of the vaginal vault, the mucus will carry the drug down the vagina, bathing the mucosa thus producing relatively high concnetrations of estradiol locally in the vagina. at the same time estradiol will be absorbed by the vaginal epithelium from where it will be absorbed into the systemic circulation.... as there is no systemic absorption (barely) for the drug to have na effect on the uterus it would have to be transported from the absorption site in the upper vault of the vagina into the uterus >>there are 4 possible modes of transport of released estradiol from the vagina to the uterus: -diffusin through tissue -transport by blood -transport by lymph -transport by mucus THUS, THE EFFECT ON THE ENDOMETRIUM AND UTERUS IS EXPECTED TO BE MINIMAL BECAUSE OF DIFFUSION BARRIERS AND SYSTEMIC ABSORPTION for both the vaginal and transdermal routes: increased concentrations of estradiol but decreased concentrations of estrone -cigarrete smoking has relatively little effect on clearance of estrogen administered by these routes -liver protein synthesis is not less affected by these routes CREAM the intravaginal use of creams containing CEE, estrone, estradiol or estriol also result in a marked systemic absorption of estrogens elevating circulating plasma estrogen concentrations. Progestins: ORAL Androgens: ORAL TOPICAL

premature ovarian failure

cessation of menses prior to age 40

streoid induced osteoporosis

highest rate of bone loss occurs in first 3-6 months of therapy and cumulative doses increase the risk of fracture (specially vertebral) -intermittent course of steroids may also increase the risk -ICS and bone loss??

change in management approach of osteoporosis

old approach: decision was based on BMD test results new approach: decision is based on risk of future fracture

ANTIDEPRESSANTS

*Reduce vasomotor symptoms by 25-69% (may also help with mood symptoms) *low dose is often effective (start low and titrate up if necessary to minimize AE. >>ALLOW 2-4 weeks for effect SSRI -paroxetine (most well studied) -citalopram -escitalopram (fluoxetine and sertraline are alos studied but they ahve less consistent results associated) SNRI -venlafaxine -desvenlafaxine AE: GI, headache, insomnia, jitteriness, sexual dysfunction, tremor, agitation, weight gain, withdrawal effects. DI: concerning drug interactions!!

Progestogen use in menopause *oral only... BUT may use Levonorgestrel IUD (MIRENA) if oral TX is not tolerated Oral meds: Provera, g - Medroxyprogesterone (MPA) Prometrium, g - Micronized progesterone

*Required if intact uterus and on estrogen therapy (in order to prevent endometrial cancer) *cyclic regimen increase bleeding, bloating compared to continuous regimen Different types of progestogens are available. Oral micronized progesterone (Prometrium) does not blunt the positive effects of estrogen on HDL-cholesterol, whereas both medroxyprogesterone and norethindrone can blunt estrogen's positive effect. -Progestogens term encompasses all forms of progestogens divided into 1)natural or endogenous (micronized progestogens) and 2) synthetic progestins (MPA, drospirenone or norethindrone acetate) Provera, g Dosing: 2.5 mg po daily 5-10 mg po x 10-14 days per month (14 day TX q 3 months an option but use is limited.....) Prometrium,g Dosing: 100-200 mg po HS 200-300mg x 10-14 days per month PK UNIQUE FORMULATION FEATURES -micronized progesterone mixed with penut oil and formulated in a gelatin capsule (original formulation) -F increases as the particle size decreases (inc surface area)... this is attributed to increased rate of dissolution as a result of particle size reduction (inc surface area) -penut oi (and linolenic acid) has high degree of unsaturation which promotes chylomicron formation, and absorption of oleoginous substances via the lymphatic system (partially escaping the livers first pass effect) >> the lymphatic system represents an accessory route by which fluids can flow from the interstitial spaces into the blood. this system carry proteins and large particulate matter away from the tissue spaces, neither of which can be removed by absorption directly into blood capillary. they are present ubiquitosly in the body with the exception of the CNS and the BONES -HOWEVER, Prometrium is now formulated in a blend of sunflower oil and soya lecithin (Oil). sunflower oil is a monounsaturated/polyunsaturated mixture of mostly oleic acid (omega 9) and linoleic acid (omeg-6) group of oils....... THE GENERIC progesterone is still formulated in peanut oil (Teva-Progesterone) -the absorption of prometrium follows a dissolution rate limited absorption AE: -less breakthrough bleeding -due to sedating effect give at night

postmenopausal long term implications

- cardiovascular disease -cancer -osteoporosis associated fractures -diabetes -thyroid disease *most rapid bone loss occurs in the first 15 years following menopause after which bone loss continues at a much lower rate.

Goals of therapy of osteoporosis

- prevent fractures by addressing clinical risk factors that increase fracture risk -prevent development or progression of osteoporosis by maximizing or maintaining existing BMD -minimize risk of falls

Goals of therapy for menopause

- relieve undesirable vasomotor or urogenital SXs of perimenopause and menopause -prevent or minimize menopause-related bone loss -help the woman maintain the highest possible quality of life

Psychological Sxs: MANAGEMENT

-SXs may be difficualt to differentiate from the manifestations of a depressive disorder -relaxing and stress reduction techniques -lifestyle modifications -estrogen(alone or in combo with antidepressive sxs) -prescription antidepressants -psychotherapy -st.Johns wort

menstrual cycle changes

-abnormal ueterine bleeding is cased by orarian dysfunction -heavier blleding than normal -prolonged bleeding -menses occuring more than every 3 weeks -spotting between menses -bleeding after sex -amenorrhea MANAGEMENT: -most irregular bleeding during perimenopause is normal -if significant change in bleeding, patient should be referred for further evaluation

clinical presentation of Menopause Signs + Symptoms

-absense of menses for 12 consecutive months -blood tests to measure FSH and estradiol levels -signs and sX of hypoestrogenism>> unknown if these Sxs are a result of decreased hormone concentrations or secondary to vasomotor and urogenital symptoms. perimenopausal: -decreased libido -dyspareunia -reduced vaginal lubrication -valvovaginal itchig and irritation Menopausal: -sexual difficulties -urinary tract infections -incontinence MOST PREVELANT -hot flashes -night sweats -disrupted sleep (associated factors: Vasomotor symptoms, hormone dynamics, primary sleep disorders, mental health symptoms, medical problems, lifestyle factors, psychosocial factors) -vaginal dryness -loss intrest in sex -loss of energy (worsening pms, loss of concentration, poor memory) -mood swings -loss of skin tone -urinary leaking -headaches -mastalgia -muscle pain -dry itchy skin -weight gain

Nonpharm therapy for osteoporosis

-adequate intake of dietary calcium, vitamin D and proteins >dietary sources of calcium include: broccoli, cheese, milk, salmon -regualr exercise and lifestyle chnages (minimizing caffeine to no more than 3 servings daily and alcohol to no more than 2 drinks per day) -smoking cessation -minimize falls for those who have osteoporosis>>home safety assessment

Sleep disturbances: MANAGEMENT

-alleviation of vasomotor symptoms -improved sleep hygiene (regualr schedule, cool dark room, avoid caffeine and spicy foods before bed) -prescription therapy (HT in form of low dose E or P) -micronized progesterone (ADR of sedation ma be beneficial when dosed at bedtime

Androgens (Testosterone) ORAL TOPICAL

-for symptoms of androgen deficiency post bilateral oophorectomy and post-menopause. Testosterone gel: ANDROGEL 1% Dosing: 2.5-5g daily

Combination Hormone therapy

-offers convenience of progestin and estrogen in a single dosage form. -continuous progestin regimen prevents withdrawal bleeding (benefits/risks are controversial) -SOGC or NAMS do not recommend a specific regimen -HOWEVER, SOGC does state: cyclic regimen may be preferred in perimenopausal or recently postmenopausal women: >have a higher risk of abnormal bleeding with a continuous combined regimen..... after 1-2 years women may switch to continous >>>EH=Estradiol Hemihydrate >>>E2=Estradiol-17Beita COMBINATION TAB -Activelle: EH 1mg + norethindrone 0.5mg tab -Activelle LD: EH 0.5mg + norethindrone 0.1mg tab -Angeliq: E2 1mg + drospirenone 1mg tab Dosing: take 1 tab po daily COMBINATION PATCH Estalis: E2 50mcg/d + norethindrone 140mcg or 250mcg Dosing: apply one patch twice / week

Safety issues concerned with Bioidentical hormonal therapy

1) endometrial cancer Unopposed BH estrogen has been shown to cause endometrial hyperplasia and there have been case reports published of endometrial cancer associated with compounded BH.Estriol (lower affinity for and shorter binding time to E receptors in endometrium and breast tissue -thought this may lead to decreased risk of endometrial and breast problems). However, increase in endometrial cancer reported with ORAL use in some, but not all studies. One expert (L'Hermite) recommends against using estriol in ORAL compounded productsCompounded progesterone cream is often recommended with BH estrogen. However, concerns have been expressed that progesterone from the cream may not always be adequately absorbed resulting in a false sense of protectionDavis et al recommends micronized oral progesterone if endometrial protection needed 2)Breast Cancer conventional HT:Estriol: weak estrogenic activity -lower risk (no studies to support claim)Progesterone: prospective cohort study showed lower risk as compared to synthetic progestogen regimens -synthetic progestogens may exert estrogenic activity (insufficient evidence to support progesterone safer than synthetic)

GQ 3)are the bisphosphonates readily absorbed after oral dose? describe the unique property of bisphosphonates (alendronate) compared to other small molecular weight drugs in general. should bisphosphonates be used for long term management of osteoporosis?

4 generations of bisphosphonates have been developed for the treatment of osteoporosis. -Absorption of these agents from the gut is quite poor (F<2%) because of their polar nature, and as a therapeutic class, they have limited cellular penetration. Bisphosphonates can be given iv or taken by mouth. When taken orally, they must be taken after a prolonged fast (usually first thing in the morning), with water only, followed by 30-60 min with nothing else by mouth to allow for adequate absorption. Under ideal conditions, less than 1% of an orally administered dose is absorbed; After absorption, about 40 to 60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the pharmacokinetics of subsequent doses. delayed relase can be taken with food (ACTONEL DR) taking a bisphosphonate with food or anything containing divalent cations will completely block its absorption. There is no systemic metabolism. The half-life in plasma is short. Fifty percent of the absorbed dose binds to bone surfaces, mostly avidly at sites of active remodeling. The skeletal capacity is large and the binding sites are virtually unsaturable. The 50% or so that does not bind to bone is excreted rapidly by the kidneys. up to 50% of the actual absorbed dose is taken up specifically by the bone within 4-6 hours and the rest is excreted by the kidney. -bisphosphonates have a short circulating half life and very limited exposure to non-target tissues. because the bisphosphonates are only released from the bone whne the bone is resorbed, thye have a tissue half life of 1-10 years; however, these agents remian pharamcologically active only when they are exposed on bone resorption surfaces. they are excreted in urine mainly as unmetabolized drug These agents are not recommended in patients with renal impairment (serum creatinine, <2.5 mg/dL), a history of esophageal disease, gastritis, or peptic ulcer (5) LONG TERM USE: Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5-10 yr of bisphosphonate treatment. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. For patients without recent fracture and with fem neck BMD > -2.5 after the initial course of Rx, consider a "drug holiday" Higher risk patients should be treated continuously (benefits would out-weight the costs) **why is zoedronic acid given as an IV ?????? potency depends on the R2 group

Osteoporosis risk factors: indications for BMD measurement

ADULTS (< 50 YO) -fragility fracture -certain meds: glucocorticoid use (prednisone-equivalent dose ≥7.5 mg/day for at least 3 months (cumulative) in the previous year) AND use of other high-risk medications, e.g., aromatase inhibitors, androgen deprivation therapy -hypogonadism or premature menopause (<45 yo) -malabsorption syndrome -primary hyperparathyrodism -other disorders??? ADULTS (50-64 years old) - age more than or equal to 65 yo (men and women) >clinical risk factors for fractures ( men 50-64 years and menopausal women) -fragility fracture after age 40 -certain meds: glucocorticoid use (prednisone-equivalent dose ≥7.5 mg/day for at least 3 months (cumulative) in the previous year) AND use of other high-risk medications, e.g., aromatase inhibitors, androgen deprivation therapy -vertebral compression fracture -parent with hip fracture -osteopenia or vertebral fracture identified on X-ray -current smoking -high alcohol intake -low body weight (<60 kg) or major weight loss (>10% of weight at age 25) -RA -other disorders??? AGE (> or equal to 65) -all women and men ** if any of the age groups were suspected of a risk factor initiate BMD testing ** followed by the BMD testing assessment of fracture risk (CAROC) places an individual in LOW(10 yr fracture risk is <10%), MODERATE (10 yr fracture risk is 10-20%), HIGH (10 yr fracture risk is >20%) risk category. >>for adults over the age of 50 recommend calcium nd vitamin D supplementation followed by weight bearing exercises and fall prevention strategies

Clonidine

Antihypertensive (alpha 2 adrenergic agonist) indicated for vasomotor symptoms associated with menopause 0.1 mg daily or 0.05 mg BID *likely less effective than antidepressants or gabapentin AE: hypotension, headache, dry mouth, dizziness, sedation.

Menopause Physiology

At the time of menopause, the ovary has no follicles left that respond to the stimulation of follicle-stimulating hormone (FSH). The lack of follicular stimulation and development signals the end of the regular menstrual cycle and the monthly fluctuations of both estradiol and progesterone concentrations. Without follicular development and the designation of a graafian (dominant) follicle, estradiol concentrations remain low and ovulation does not occur; therefore, progesterone concentrations remain low as well. As a result, endometrial proliferation occurs rarely and there are no secretory changes. The pituitary gland increases the production and release of both FSH and luteinizing hormone (LH) in an attempt to entice the ovary to initiate follicular development. The ovary cannot respond; therefore, FSH and LH concentrations remain elevated while estradiol and progesterone concentrations remain low. The postmenopausal female continues to produce estrogen in the adipose tissue as a result of the conversion of androstenedione (from the adrenal gland) to estrone.[2] The amount of estrone produced depends on the amount of adipose tissue present. Estrone has a weaker effect on the endometrium than estradiol; therefore, proliferation of endometrial tissue is rare, except in women who are obese. During perimenopause, cessation of menses, along with the increase in FSH and LH and decrease in estradiol and progesterone, occurs gradually over several months to years.[2] The ovary becomes slow to respond to FSH and LH. Therefore, it can take longer for follicular development and endometrial proliferation to occur; however, unlike in menopause, the follicles in the ovary are still able to respond and ovulation does still occur.

zoledronic acid

BISPHOSPHONATE INJECTION Zole- dronic acid (ZA) is the most potent of the clinically available bisphosphonates. In addition to its antiresorptive activity, there has been increasing evidence to suggest that it also has anticancer properties. INJECTION OVER ORALL ROUTE: Bisphosphonates are generally administered orally for the treatment of benign osteoporosis, but because of poor oral bioavailability and the potential to cause intermittent gastro- intestinal toxicity, the intravenous administration is the preferred route in cancer patients with bone metastases. Before intravenous bisphosphonates are used, the patient's serum calcium level must be normal. Once-yearly administration of zoledronic acid should be infused over at least 15 minutes. Aceta- minophen or ibuprofen can be given to decrease adverse effects. IV may be given in predeference to increase the bioavailability

Bioidentical hormones

Bioidnetical hormones are chemical substances that are identical in molecular structure to human hormones SOGC definition: custom-mixed recipes that are not regulated or approved, and thus there is no scientific evidence of the effect they may have on the body bioidentical estrogens: Estradiol >>> estrone/estriol Nonbioientical estrogens: Equilin sodium sulfate , ethynyl estradiol

Osteoporosis Pharmacological therapy

CALCIUM AND VITAMIN D >> Antiresorptive BIPHOSPHONATES (alendronate, etidronate, risedronate, zoledronic acid)>> Antiresorptive DENOSUMAB (PROLIA) - human monoclonal antibody igG2 RANK >>> Antiresorptive SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) (Raloxifene (Evista)) >> antiresorptive CALCITONIN >> antiresorptive and may decrease pain form vertebral fractures > removed from the canadian market HORMONE THERAPY (Estrogen +/- progestogen) >>antiresorptive _______________________________________________ TERIPARATIDE -parathyroid hormone aids bone formation *anabolic*

medical conditions and drugs commonly associated with an increased risk of osteoporosis

CONDITIONS Anorexia IBD CKD Diabetes (type I) Liver disease menopause prior to 45 Gastrectomy Cushing's syndorme Hyperthyroidism (untreated) Hypeyparathyroidism, primary Hypergonadism (untreated) DRUGS Antiepileptic drugs (phenytoin) Antiretrovirals Chemoterapeutic agents Corticosterods Cyclosporine Loop diuretics levothyroxine PPIs SSRIs Vitamin A Heparin Thiazolidinediones

Calcitonin

Calcitonin is released from the thyroid gland when serum calcium is elevated. Calcitonin demonstrated a moderate increase in BMD and decrease in vertebral fractures Calcitonin is FDA indicated for osteoporosis treatment for women who are at least 5 years past menopause EFFICACY?? Only vertebral fractures have been documented to decrease with intranasal calcitonin therapy Calcitonin does not consistently affect hip BMD and does not decrease hip fracture risk. Because efficacy is less robust than the other antiresorptive therapies, calcitonin is reserved as third-line treatment. If used, calcitonin should be prescribed for short-term (4 weeks) treatment and should not be used in place of other more effective and less expensive analgesics nor should it preclude the use of more appropriate osteoporosis therapy.

NHP's used in Osteoporosis

Dietary Soy Isoflavone phytoestrogens are plant-derived com- pounds that possess weak estrogenic agonist and antagonist effects. The most common source for isoflavone is dietary soy products. Isoflavones such as genistein and daidzein are structurally similar to estrogens and thus can bind to estrogen receptors to produce weak estrogenic activity. Genistein is the most abundant and biologically active isoflavone in soybeans. The evidence supporting a positive bone benefit from soy protein (isoflavone) intake is conflicting, with some positive data with larger isoflavone intakes (76 mg daily) A 2006 systematic review concluded that evidence for the use of phytoestrogens in women with osteoporosis was equivocal, with some trials demonstrating a positive effect on BMD and others showing no effect

Diagnosis of osteoporosis

Dual energy X-ray absorptiometry (DEXA) -measure BMD as a measure of bone strength -reported as a t-score traditionally low BMD was the primary trigger for initiation of therapy BUT, most fragility fractures occur in those with a BMD in the non-osteoporotic range (T-score higher than -2.5)

Custom compounding : combination of estrogens

Estriol : Estradiol (1:1) or (8:2) Triest>>> (estriol 80%, estradiol 10%, estrone 10%) BHs can be custom compounded for an individual but there are also Health Canada approved, manufactured products ** the rationale is that estriol has weak estrogenic activity (giving the combinations would mimic the natural levels in the body more closely) -claims to have a lower risk of breast cancer (not supported by large RCTs) **some argue that the effect of these products is due to the higher receptor affinity and activity of estradiol Rationale for costume compounding: -individualized therapy: individualized formulations -some claim less AE -follow compounding regulations Rationale against costume compounding: -does not have to undergo rigorous quality assurance testing (purity, dose, accuracy, mandatory reporting of ADRs) -false safety claims can be misleading (Eg: all natural) -no uniform packaging and labeling for patients regarding black box warnings -not all pharmacists are equiped SOGC: Consumers and prescribersshould be aware that the content of custom-compounded HT in Canada is unregulated and its safety unknown

ANTICONVULSANTS

Gabapentin Pregabalin *generally less effective than HT for vasomotor Sxs (helpful with insomnia) -initiate at a low dose (eg: gabapentin 300 mg HS or pregabalin 50 mg HS) AE:dizziness, somnolence, ataxia, headache, edema, weight gain, rash. Rare: euphoria.

Indications for therapy: Traditional HT vs. Bioidentical HT

Hormone therapy (traditional): -vasomotor SXs -Urogenital Sxs -Osteoporosis Bioidentical hormone therapy: -vasomotor sxs -urogenital sxs -osteoporosis -diminished libido -cognition -sleep and fatigue -well being and quality of life

Goals of therapy: Traditional HT vs. Bioidentical HT

Hormone therapy (traditional): alleviation of symptoms -progesterone added for women with uterus to prevent estrogen induced endometrial hyperplasia Bioidentical Hormone therpy: -replacement of hormones to restore the levels in premenopausal range -progestogen is often included even in those without a uterus

Hormone therapy for menopause

Hormone therapy: E alone, P alone, E and P combos, conjugated estrogen and bezadoxifene E plus or minus p plus or minus testosterone? gold standard for treating Sxs of menopause is *Estrogen* -Estrogen term encompasses all forms of estrogens.... In products used for menopause: conjugated estrogens, conjugated equine estrogens, 17Beta-estradiol, estradiol, estrone) -administered orally, transdermally or vaginally - Progestogens are combined with estrogen to reduce the risk of endometrial cancer. -CHC may be an open to provide supplemental estrogen - Alternatives to estrogen for the treatment of vasomotor symptoms include progestogen therapy alone, clonidine, SSRIs (e.g., paroxetine, fluoxetine, sertraline, citalopram or escitalopram), SNRIs (e.g., venlafaxine or desvenlafaxine) and gabapentin. Evidence supporting efficacy of these agents varies from well-controlled trials to case reports and adverse effects may be significant.

Genitourinary symptoms: MANAGEMENT

Lower urinary tract symptoms -proper hygiene -(compared to placebo): dryness, dyspareunia (caused by vulvovaginalatrophy), urinary frequency, stress urinary incontinency (SUI) and urgency urinary incontinence (UUI)urge incontinence. -Local estrogen: recurrent UTI -Antibiotic thrapey: UTIs -Anti-muscarinic therapy: incontinence

Bisphosphonates GQ 2) the bisphosphonates share a common structural backbone. what endogenous constituent is this class of drugs trying to mimic? what are the SAR requirements for bisphosphoantes? refer to written notes for SAR

MOA: bisphosphonates are designed to mimic pyrophosphate (P-O-P) where the oxygen is replaced with a C to create a nonhydrolyzable backbone. because pyrophosphate is a normal constituent of bone these analogues selectively bind to the hydroxyapatite portion of the bone. bisphosphonates effectively inhibit osteoclast proliferation, decrease osteoclast activity, reduce osteoclast life span and as a result reduce the number of sites along the bone surface where resorption occurs. (LIMIT bone turnover.. and allow osteoblasts to form well-mineralized bone without opposition Antiresorptive or anabolic pharmacologic therapy is recommended if the 10-year absolute fracture risk is greater than 20% (high risk). In those with a moderate risk, management decisions should be individualized Large RCTs have demonstrated that alendronate and risedronate and zoledronic acid decrease the risk of vertebral and hip fractures Etidronate may reduce the risk of vertebral fractures? MISSING DOSE: If a patient misses a weekly dose, they can take it the next day. If more than 1 day has lapsed, that dose is skipped until the next scheduled ingestion. They can be administered orally (daily, weekly, or monthly) or iv (quarterly or yearly). SIDE EFFECTS: GI effects such as abdominal pain, dyspepsia and nausea. Rarely may cause esophagitis or esophageal ulceration when used long term atypical fractures of the femur were reported RARE RISKS: >>ONJ (osteonecrosis of the jaw) (more commonly in patients with cancer and/or those who have received high doses of iv bisphosphonates, poor dental hygiene or infection)>> inform the dentist if taking bisphosphonate, suggets the patient to get dental checkups and emphasize good dental hygiene.>>>> if ONJ occured treat infectin and the symptoms that follow >>Atypical fractures -unusual fracture of the femur with no or minimal trauma -associated with long term bisphosphonate use -monitor for prodrome of thigh/groin pain (subtrochanteric fracture observed with this atypical fracture) - MOA for the fractures unknown but could be due to severely suppressed bone turnover with long term BP therapy. leading to frozen bone which becomes fragile and brittle. (not known if this is due to therapy or underlying osteoporosis) IF thigh/pain or groin pain this is an urgent bilateral investigation >>esophageal cancer) -no RCTs (conflicting results) -ensure proper administration of BPs (take with water and don't lie down 30minutes after) >>For most patients with osteoporosis, the benefits of treatment outweigh the risks

Natural health products for menopause

Many of the studies evaluating the efficacy of natural health products for the treatment of menopausal symptoms have limitations such as small size, lack of control group or other poor design factors. Additionally, lack of standardization of natural health product composition (roots, extracts, herb mixtures) and variability in doses used make comparisons between trials difficult EVENING PRIMROSE OIL (gamma lineloic acid may be active ingredient??) -4-6g/day -likely no better than placebo for vasomotor symptoms -AE: generally safe, headache, indigestion, nausea, soft stools. ?may ↓ seizure threshold DI: increase the effect of anticoagulants and anti-platelets CHASTEBERRY (vitex angus-castus) -although possibly effective (20-40mg/day) for PMS, insufficient evidence to support use in postmenopausal women. -Phytoestrogen, ?may effect FSH, LH, dopamine PHYTOESTROGEN SUPPLEMENTS >>> contain isoflavones which may have some estrogenic activity. **RED CLOVER (isoflavone source) -likely no better than placebo for vasomotor symptoms. -may increase HDL (insufficient evidence) -may incerase BMD -AE: rash, ?avoid in hormone sensitive conditions -DI: decrease the effect of estrogen!!!! and OCs. incerase the effect of anticoagulants, antiplatelets **SOY (active ingredient is unclear ... maybe isoflavone) -conflicting results wether better or worse than placebo for vasomotor symptoms -not efective in breats cancer survivors -Phytoestrogen with estrogenic effects; may block thyroid hormone production -AE:constipation, bloating, mood, nausea, ?avoid in hormone sensitive conditions -DI: antibiotics may decrease effect they may decerase the effect of estrogen tamoxifen and warfarin >>>>>>>>SOY may also be used in osteoporosis: (REFER TO NHPS for osteoporosis card) ** BLACK COHOSH (Actaea Racemosa) -20mg po BID...onset 2-4 weeks -likely no better than placebo and worse than HT for vasomotor symptoms -estrogenic effects -seretonergic effects????? -AE:headache, dizziness, GI upset, weight gain, heaviness in legs, cramping, seizures, -safe if history of breast cancer rare: liver toxicity (avoid concurrent use of other hepatotoxic drugs) DI: increase the effect of tamoxifen and antihypertensives, decerase the absorption of iron Wild yam (Dioscorea Villosa) -insufficient evidence to support use for libido and vaginal dryness - Progesterone precursor; since conversion to progesterone does not occur in the human body, prescribed progesterone may be more useful. DONG QUAI (Angelica Sinensis) -no better than placebo for vasomotor symptoms -estrogenic effects -AE: generally well tolerated VALERIAN -conflicting evidence if effective for insomnia -onset: several days to one month -AE: withdrawal symptoms, hypothermia, restlessnes

Physiochemical factors affecting drug absorption

Molecular Size - Absorption decreases as molecular size increases. the effect is membrane specific (intestinal vs transdermal) Lipophilicity - measured by partition coefficient between oil and water. absorption increases for more lipophilic drugs Partition coefficient is a measure of a drug's distribution in a lipophilic/ hydrophilic phase system, and is indicative of its ability to penetrate biologic multiphase systems. Charge -Absorption decreases for ionic species

osteoporosis treatment algorithm: NOT GLUCOCORTICOID INDUCED: in men GQ 6

NOT GLUCOCORTICOID INDUCED: fragility fracture or DXA T-score < or equal to -2.5 1st line: bisphosphonates PLUS Ca and Vit D (ADJUNCT zoledronic acid) **testosterone is not recommended for the treatment of osteoporosis in men unless they have a deficiency** fragility fracture or DXA T-score < or equal to -2.5 AND LOW TESTOSTERONE 1st line: testosterone added to oral bisphosphonates PLUS Ca and Vit D if bisphosphonates and testosterone are not tolerated/Contraindicated: 1st line: denosumab or teriparatide PLUS Ca and Vit D GLUCCOCORTICOID INDUCED: 1st line: bisphosphonates PLUS Ca and Vit D

Management of patients based on their Risk-Factor assessment

Patients who are categorized as being at low risk of fracture after their assessment should undertake, as appropriate, the lifestyle measures previously mentioned (Reassess in 5 years) Management strategies for patients at moderate risk should be individualized (consider additional tests and risk assessments, may consider pharmacotherapy!) Pharmacologic therapy is recommended for those at high risk of fracture. for all levels of risk consider NON PHARM measures (diet, exercsie, lifestyle changes)

Estradiol (ORAL) Premarin - conjugated equine estrogen (CEE) Estrace, g -Micronized estradiol - 17 Beita

Premarin: Dosing: 0.625 mg po daily Estrace, g: Dosing: 1 mg po dialy

is Bioidentical hormonal therapy really safer? what is the evidence?

Progesterone: Headache, vaginal spotting and bleeding, rash, depression, dizziness, dry mouth, insomnia, breast pain, drowsiness **Micronized progesterone may be better tolerated and less likely to cause negative affects on lipoproteins as compared to medroxyprogesterone acetate(RCT evidence-PEPI trial) Estradiol: headache, abdominal pain, URTI, endometrial hyperplasia, nausea, peripheral edema, application site reaction (with topical products), leukorrhea, weight gain, arthralgia, infection ** Estriol: Endometrial hyperplasia Testosterone: Acne,hirsutism

Saliva testing and costum compounding BHT

Rationale for use: -provide individualized therapy based on their salivary hormone levels; also helps to monitor therapy so the dose can be adjusted in response to hormone levels Rationale against: -salivary levels of hormones do not accurately reflect serum levels, salivary levels fluctuate based on time of the day, diet

RALOXIFENE (EVISTA) -breast cancer prevention and increased risk of stroke?

SERM a second- generation mixed estrogen agonist/antagonist (EAA) approved for prevention and treatment of postmenopausal osteoporosis, is an estrogen agonist on bone but an antagonist on the breast and uterus efficacy- Raloxifene decreases vertebral fractures and increases spine and hip BMD, but to a lesser extent than bisphosphonates After raloxifene discontinuation, the medication effect is lost, with bone loss returning to age- or disease-related rates. For women with severe osteoporosis, particularly when hip fracture risk reduc- tion is desired, a bisphosphonate is likely a better choice. *EVISTA has no intrinsic estrogen agonist activity in mammary tissue. The long- term effectiveness of raloxifene in reducing the risk of breast cancer has not been fully established.* *The incidence of stroke, myocardial infarction, hospitalized acute coronary syndrome, cardiovascular mortality, or overall mortality (all causes combined) was comparable for EVISTA and placebo.* ADRS: leg cramps, hot flashes, TE risk

GQ 5) are there significant differences in the PK of SERMS?

SERMS are very highly bound to plasma proteins (lipophilic agents) Currently, there are two main chemical classes of SERMs: the triphenylethylene derivatives (tamoxifen and toremifene) and the benzothiophene derivatives (raloxifene) Tamoxifen and toremifene are ER agonists in bone, the cardiovascular system and the endometrium, but act as ER antagonists in breast tissue.[4,5] Raloxifene is an ER agonist in bone and the cardiovascular system, but acts as an ER antagonist in breast tissue and the endometrium the pharmacokinetic-pharmacodynamic goal in novel SERM development is to design a drug with an adequate half-life, such that it will reach the ER at sufficient steady-state concentrations to achieve the desired effect, i.e. to activate or inhibit ER activity. tamoxifene and toremifene both minimally go through first-pass metabolism (F=100%) Raloxifene undergoes extensive first pass metabolism to form glucoronide conjugates, resulting in an absolute bioavailability of just 2%. Raloxifene is not metabolized by the cyp enzyme system the terminal elimination half life of these drugs range from 25 hours to 7 days SUMMERTY OF PK: Clinically used SERMs are administered orally and absorbed from the gastrointestinal tract. With the exception of raloxifene, SERMs have very high bioavailability. SERMs are lipophilic compounds highly bound to plasma proteins, especially albumin. They are all metabolised in the liver; tamoxifen and toremifene are metabolised by the CYP enzyme system, and raloxifene is metabolised by glucuronyltransferases into glucuronide conjugates. All SERMs are eliminated in the bile and excreted in the faeces. Very little drug is eliminated in the urine.

TERIPARATIDE

SYNTHETIC recombinant polypeptide hormone which stimulates osteoblasts to form new bone. the role of PTH is to reserve calcium as much as possible (inc its abs from GI, efflux of calcium from bone and decreased loss of calcium from urine) short term exposure to PTH stimulates new bone formation by preferentially stimulating osteoblasts over osteoclasts... continuous admin of PTH leads to preferential stimulation of osteoclasts!! used in those with severe osteoporosis or those at high risk of glucocorticoid induced osteoporosis Teriparatide, a parathyroid hormone (PTH) analogue, is an anabolic agent that causes a steady gain in bone density and reduces the risk of vertebral and nonvertebral (but not hip) fractures. It may also decrease the pain of vertebral fractures. ADRS: -injection site reactions, headaches, dizziness and leg cramps CIs: -pre-existing hypercalcemia -severe renal impairment -pregnancy **Maximum lifetime exposure for an individual limited to 24 months due to rat studies showing increase risk of osteosarcoma

patch used for menopause (type, dose?)

Transdermal therapy should be preferentially offered to women at high risk of venous thromboembolism, women with malabsorption, women with spontaneous or estrogen-induced hypertriglyceridemia, and obese women with metabolic syndrome) PATIENT EDUCATION: **rotate the site of application with the patch (abdomen/tigh/buttocks) **do not rotate site of application with the gel (arm/abdomen/thigh) Diffrent types used: -Estradiol-17 beita patch (ESTRADOT) 50 mcg twice/wk

Moisturizers/lubricants

Use for urogenital symptoms (vaginal dryness and dyspareunia) -may decrease sperm motility -apply at bedtime 3 times per weekalleviate the dryness and discomfort of vaginal atrophy KY jelly: used prior to intercourse to provide lubrication BIOADHESIVE VAGINAL MOISTURIZERS: polycarbophil gels (e.g., Replens) and hyaluronic acid gels (e.g., Gynatrof), are used continuously to increase vaginal moisture

Non-pharm therapy for menopause

Women with mild symptoms may try nonpharmacologic approaches and women experiencing only mild vaginal symptoms may try vaginal lubricants or moisturizers. Women with more debilitating symptoms should be informed regarding the risk and benefits of hormone therapy (HT) and nonhormonal therapies. EXERCISE - decreases hot flashes (HT much more effective for improvement of vasomotor SXs) - evidence is insufficient to demonstrate benefit on vasomotor Sxs, BUT... exercise is good for overall health anyway. THUS, women aged 18-64 are advised to accumulate at least 150 minutes of moderate to vigorous aerobic physical activity per week in bouts of 10 minutes or more and to perform muscle- and bone-strengthening activities using major muscle groups at least 2 days per week SEXUAL ACTIVITY -Increasing blood flow to the pelvic region may relieve vaginal dryness and pain on intercourse. This is usually done through sexual stimulation. -Therefore, in women who are experiencing vaginal dryness, increasing sexual activity, rather than avoiding it due to discomfort, may be beneficial. PELVIC FLOOR EXERCISES -kegel exercises may be beneficial for women who are experiencing incontinence LIFESTYLE AND DIETARY MEASURES -smoking cessation to decrease vasomotor Sxs -incerasing fat intake, fruit, vegis, whole grains -weight loss (decrease by 9 kg led to 2-3 less hot flashes per day) -intake of spicy foods, caffeine or alcohol can exacerbate vasomotor Sxs -PHYTOESTROGENS (plant based substances that may have weak estrogenic or antiestrogenic activity) TEMPRATURE CONTROL -warm environemnts may exacerbate SXs (keep the room cool) PSYCHOEDUCATIONAL INTERVENTIONS -education, counselling, cognitive-behavioural strategies and mindfulness-based stress reduction and all showed improvements in vasomotor symptoms ACUPUNCTURE conflicting evidence

Fragility fracture

a fracture occurring spontaneously or following minor trauma such as a fall from standing height or less

osteoporosis epidemiology

affects 1 in 4 women and 1 in 8 men in canada over 50 years of age CONSEQUENCES: osteoporosis may lead to chronic disabling pain and loss of height from vertebral fractures. In severe cases, kyphosis (curvature of the spine or hunching) can cause shortness of breath and dysphagia. In individuals who have sustained a hip fracture, mortality in the first year has been reported to be as high as 28% in women and 37% in men

postmenopause

all years following final menstrual period

Breast cancer controversy and HT

based on WHI, an increased risk of breast cancer was observed in postmenopausal women using conjugated estrogens in combination with medroxyprogesterone acetate (MPA) he risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics

pain management with osteoporosis

bedrest, analgesics, opioids -calcitonin -PTH (with vertebral fracture pain??) -nonpharms: physical support (back braces) -heat/ice applications -massage therapy -fall voidance -exercise

Bone anatomy

bones have a solid outer surface called compact bone. the inner bone is called spongy bone(as it is less dense than compact bone). bones contain cells called osteoclasts which break down bone tissue other cells called osteoblasts make new bone tissue using minerals such as calcium and phosphate from the blood. hormones like estrogen, growth hormone and testosterone help keep the number of osteoblasts more than osteoclasts so that more bone is made than removed. physical exercise also help keep bones to grow stronger. peak bone mass is reached around the age of 30 (strongest bones in lifetime of the individual). after this age, osteoclasts gradually remove more bone than the bone made by osteoblasts

Monitoring therapy of menopause

both nonpharm and pharm tehapies may require several weeks t months of use before efficacy can be established Vasomotor symptoms resolve within 5 years of menopause for the majority of women; it is therefore reasonable to continue therapy for up to 5 years. Urogenital atrophy may continue to be problematic indefinitely.

Recommendations for use of HT

clearly identified indications: VMS, symptoms associated with genitourinary syndrome of menopause; osteoporosis (SOGC does not support use of HT if only indication is prevention of chronic disease -women's age, time since the onset of symptoms of menopause, health and quality of life priorities -women's medical history (identify CI or risk factors for VTE, coronary heart disease, stroke, breast cancer) who should be considered for HT? -premature ovarian failure or early menopause (VMS may be severe) >>>>>>> start terapy and continue until average age of 51-52 of menopause; reassess -otherwise heathy symptomatic VMS early postmenopausal women -postmenopausal women experiencing urogenital symptoms including vaginal atrophy ONSET of effectiveness of HT: vasomotor SXs: 4 weeks or longer... vaginal SXs: reversal of atrophic changes and relief of Sxs in 3-6 months. faster relief with vaginal as compared to systemic therapy. DURATION OF THERAPY? -shortest time possible!!!! -3-6 years to control the vasomotor sxs -for vaginal symptoms (may need to be and can be) continued indefinitely.

Perimenopuase

climacteric time leading to menopause, typically cahracterized by missed menses or W/O symptoms of hypoestrogenism -perimenopause has an average duration of 4 years with a range of 2-8 years

Osteoporosis

condition leading to compromised bone strength, resulting in a fragile skeleton venerable to fractures. BONE strength is determined by both bone quantity, measure by BMD and quality (architecture, turnover, damage accumulation, mineralization) Osteoporosis is defined as a BMD of 2.5 standard deviations (SD) or more below the average for young, healthy women (T-score of ≤ −2.5 SD). A BMD between −1 and −2.5 signifies osteopenia there are 2 types of osteoporosis: >primary osteoporosis (older age and reduced amount of estrogen in women) TYPE I (postmenopausal) -Increase bone resorption with no change in formation -Bone loss occurs during the first 3-6 years after menopause -Fractures (vertebral, hip, distal radius) in women approx 15-years post menopause -Due primarily to hormone deficiency >>>>> -after menopause womens ovaries stop making the hromone estrogen. with the drop in the level of this hormone, bone removing cells called osteocalsts become more active than the bone making cells called osteoblasts. THUS this would lead to the breaking of the bones as they become unable to whitstand the pressure from normal activitties. TYPE II (senile or age related) - occurs in both men and women over age of 70 -geratest risk of fractures (hip, pelvic and vertebral) -trabecular = cortisol >secondary osteoporosis TYPE III (affects both children and adults relating to conditions like cancer, hormone problems or use of certain medications)

Contraceptives (low dose)

during perimenopause, this is an option for symptomatic, healthy, nonsmkers (reevaluate at age 50)

DINOSUMAB (PROLIA) GQ 4) describe the PK and PD of denosumab (prolia) why is it giveterm-52n by injection? why does it have to be kept in the fridge but not frozen?

first line for the treatment of osteoporosis Prolia is a human monoclonal antibody (IgG2) that binds to receptor activator of nuclear factor-kappa B (RANK) ligand and inhibits osteoclast formation, function and survival. indication: Treatment of osteoporosis in men or in postmenopausal women: SubQ: 60 mg as a single dose, once every 6 months MOA: Denosumab is a promising new antiresorptive agent with a unique mechanism of action. It is a fully human monoclonal antibody (immunoglobulin G2) that binds to RANKL, blocking its ability to bind to its receptor activator of nuclear factor kappa B on the surface of osteoclast precursor cells and mature osteoclasts. Thus denosumab inhibits osteoclastogenesis and increases osteoclast apop- tosis Produced from "xenomouse" technology that uses an altered mouse strain to produce human antibodies instead of mouse antibodies. The pharmacokinetic profile of denosumab is typical of monoclonal antibody. It follows nonlinear, dose-dependent pharmacokinetics. After rapid and prolonged absorption from subcutaneous injection, serum concentrations are detectable in approximately 1 hour, and Cmax occurs 5-21 days after injection, t1/2 is approximately 32 days. Supplied as solution for single dose injection. Should be kept in the fridge between 2 - 8oC, but must not be frozen (it dentures the proteins)... has a narrow window thus must be kept in a specific temeprature. -comes in a solution form (be careful with storage) PK: the pk of denosumab is based on its chemistry as a monoclonal antibody. -follows non-linear, dose-depenedent pk. after rapid and prolonged absorption from a subcutaneous site the serum concentrations are detectable in approximately an hour. -concentrations may remain detectable for up to 9 months or longer (however, denosumab is not incorporated into bone) -half life is 32 days AE: The most common adverse effects in patients with osteoporosis were arthralgia, nasopharyngitis, back pain, and headache. CI immunosuppressed impaired renal function pregnancy

dosing regimens of HT for menopausal symptoms Is there a tapering regimen that should be recommended? why? when?

for dosing, start on a low dose to decrease SE (uterine bleeding, tender breasts, and increased cancer risk. (may need higher doses in young women like those with early menopause) -tapering may be useful sometimes when decreasing the dose to decrease SE Dose of the hormones: ESTROGEN CEE: 0.3-0.45 mg -Oral micronized 17 β-estradiol: 0.5mg -Transdermal 17 β-estradiol patch:0.014 -0.0375mg PROGESTOGEN - dose needed to protect vs. endometrial hyperplasia -MPA: 5-10mg/d (cyclic regimen); 2.5-5mg/d (continuous regimen) -Micronized progesterone: 200-300mg HS (cyclic regimen); 100-200mg HS (continuous regimen) CONTINUOUS VS SEQUENTIAL VS COMBINED -If last menstrual period < 1yr prior, a sequential combined regimen recommended (e.g. continuous estrogen with 12-14 days progestogen/month) - If last menstrual period > 1yr prior, female who wish to avoid monthly withdrawal bleed, may start continuous combined regimen - If breakthrough bleeding occurs following switch to continuous combined & does not settle within 3-6months, consider switch back to sequential for 1 or more years - If bleeding is heavy or erratic on sequential regimen, consider increasing the dose of progestagen (e.g. double) - Persistent bleeding beyond 6 months warrants referral/investigation - 90% of female persisting with regimens will eventually be bleed free - If AEs secondary to progestagen (mood swings, PMS like effects, androgenic effects), may decrease dose by 1⁄2 &/or decrease duration to 7 -10 days

RISK with HRT

is the risk with HRT small???? It all depends! The risk of breast cancer expressed as 8 extra cases per 10,000 women per year seems small to most people. However the risk of any adverse event (breast cancer, coronary heart disease, stroke, blood clots) over 5.2 years was ≅ 1.5% or one extra adverse event for every 66 women. This number is not so small, and shows how perceived risk can vary depending on duration of therapy, and addition of multiple risks. The individual risk would vary depending on a patient's age and baseline risk factors. Individual assessment must weigh potential benefits with potential risks. this is perfect from LEXICOMP: When used for the relief of menopausal symptoms, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Criticisms & limitations of the WH study for Combination hormonal therapy (Estrogen and progestin): : 1) data from WHI included age 50-79 but mean age at start was 63 -potential for decreased risk in young feamles age 50-59; 2) most data from oral MPA+CEE, thus, potential for better outcomes with endo-genous/transdermal formulations. 3) attrition & adherence concerns. *If HRT chosen for menopausal symptom management, consider lowest effective dose for shortest time* For combination HT: harm>benefits over 5 years many possible benefits have been called into question following large scale RCTs. (there is controversy regarding this) -the risk was observed to be less in young (<50-59 year old females) IN SUMMARY: in WHI the older age of the participants was a limitation. For all age groups, risk (cardiovascular & breast cancer) exceeded benefit (colorectal cancer & fracture); however, since baseline risk is lower for younger women, the number needed to harm (NNH) would be correspondingly higher. Criticisms & limitations of the WH study for estrogen only treatment: -Overall estrogen only therapy 6.8yr from WHI n=10,739; appears safer than combination but populations studied were different [WHI E-only trial: higher baseline CV risk (higher BMI, CV hx, higher BP, diabetes) but ↓breast ca risk]. -Similar criticisms & limitations as above. (mean age 63), most data with CEE.

magnesium and osteoporosis

magnesium stops calcium induced constipation There is preliminary evidence that suggests taking magnesium orally might reduce bone loss and bone turnover in postmenopausal osteoporosis (9104,60928). In another study of postmenopausal women who were also taking estrogen, magnesium 600 mg plus calcium 500 mg and a multivitamin supplement daily increased bone mass better than estrogen alone (12506). What effect magnesium has with this combination is speculative. Some epidemiological research suggests that magnesium intake is related to increased bone mineral density the calcium magnesium ratio is important for bone health from dynamed: higher magnesium intake associated with higher BMD in men and women of white race (but not black race)

Fractures and osteoporosis

major symptom of osteoporosis... other symptoms occur as a result of bone loss common fracture locations in people with osteoporosis include: wrist, spine, hips **fracture of the femoral neck **fracture of trochanter vertebral fractures : kyphosis and Lordosis

Assessment of fracture risk FRAX VS CAROC

patient assessment for osteoporosis should include patients risk factors, fracture and falls *Decision to treat based on risk of fracture from CAROC (but fracture rates are from FRAX)* 2 sources are available for assessing patient's risk of fractures: -WHO FRAX risk assessment tool: algorithm developed to predict an individuals 10 year fracture risk. It incorporates assessment of clinical risk factors (sex, age, body mass index, prior fracture, parental hip fracture, prolonged glucocorticoid use, rheumatoid arthritis, current smoking, alcohol intake) and (optionally) the femoral neck BMD. This tool is appropriate to use for both men and women and is specific for use in Canadians. - Canadian Association of Radiologists and Osteoporosis Canada (CAROC) risk assessment tool: assign an initial risk category based on sex, age and femoral neck BMD. Certain risk factors, i.e., a prior fragility fracture or glucocorticoid use, raise the initial risk category to the next level; having both of these risk factors places the individual in the highest risk category he 10-year fracture risk is classified as low (<10%), moderate (10-20%) or high (>20%); An individual's risk can vary over time, and should be re-evaluated every 5-10 years in those with low risk, and every 1-5 years in those with moderate risk.

Menopause definition

point in time cessation of menses for at-least 12 consecutive months (retroactive determination) -natural menopause occurs around 52 years of age (before age 40, considered premature menopause and after 55 eyars considered late menopause) early to middle menopausal transition: -menses are more frequent (shorter cycles 2-7 days) -increased blood flow -premenstrual spotting Late menopausal transition: -menses skipped > cycles lengthened -menses are often more than 2 months apart

Osteoporosis treatment algorithm : not glucocorticoid induced in women

post menopuasal with fragility fracture or DXA T-scare < or equal to -2.5 1st line: bisphosphonates PLUS calcium and vitamin D suuplementation 2nd line: raloxifene or dinosumab PLUS ca and vit D 3rd line: calcitonin PLUS ca and vit D if bisphosphonates, raloxifene and calcitonin are not tolerated 1st line: teriparatide PLUS ca and vit D 2nd line: HRT or denosumab PLUS ca and vit D GLUCCOCORTICOID INDUCED: 1st line: bisphosphonates PLUS Ca and Vit D

Screening for osteoporosis

screening assessment recommendations: WHO? men and women over 50 yo WHATT? risk factors for OP and fractures and falls WHY? identify those at high risk of fractures HOW? history and physical exam

Duavive >>> SERM

selective estrogen receptor modulator (SERM): estrogen agonist/antagonist; ↓breast cancer risk. >Bazedoxifene and Estrogen (CONJUGATED) Dosing for vasomotor symptoms: 20/0.45mg po OD

Thermoneutral zone and menopause

small core body temperature elevations acting within a reduced thermoneutral zone trigger hot flashes in symptomatic postmenopausal women (decreased estradiol leads to CNS/vasomotor instability which leads to decreased seretonin and increased norepinephrine. these fluctuations lead to a a narrow thermoregulatory setpoint in the hypothalamus. (leading to hot flshaes)

Menopausal transition

time period from menstrual cycle irregularity to final menstrual period

Hormone Therapy for osteoporosis

used traditionally for both prevention and treatment. estrogen reduces bone resorption and slows postmenopausal bone loss -benefits disappear once therapy is stoped reduces fracture risks in postmenopausal women but....... Due to associated adverse effects only recommended for short-term treatment <5 years of menopausal symptoms The Women's Health Initiative study demonstrated that HT (conjugated equine estrogens with or without a progestogen) decreased clinical fractures at the hip, vertebrae and non vertebrae fractures in postmenopausal women.

Calcium supplementation

vitamin D and Calcium prevent progressive bone loss Most of the body's calcium is stored in bone. Calcium is essential for functions such as muscle contraction and nerve conduction. With insufficient calcium intake, parathyroid hormone (PTH) is released, leading to reduced excretion of calcium from the kidney, increased calcium resorption from bone and vitamin D activation by the kidneys. An increase in vitamin D activation results in increased calcium absorption from the GI tract. This feedback normally helps maintain an adequate serum calcium level. Deficiency in vitamin D can result in secondary hyperparathyroidism and increased calcium resorption from bone VitD (800-1000 IU/d) & calcium (1200mg/d) ↓ risk of hip and nonvertebralfractures in elderly people residing in institutions. RECOMMENDATIONS: calcium : men and women under 50: 1000 mg/d men and women over 50: 1200 mg/day vit D: men and women under 50: 400-1000 IU/day men and women over 50: 800-2000 IU/day -try to obtain calcium from diet first Calcium carbonate - 40% E Ca (most commonly used) Calcium Citrate - 21% E Ca (individuals on acid suppressors as abs is not affected by reduced acidity) Calcium gluconate - 9% E Ca Calsium lactate - 13% E Ca DRUG INTERACTION: Calcium supplements may decrease absorption of bisphosphonates (separate administartion by 2 hours) Does calcium increase the risk of CVD? -conflicting results -calcium may cause vascular calcification, supplements (but not dietary Ca) may cause spike in serum calcium concentrations that adversely affect blood coagulability or flow.