2Osteoporosis “Silent disease” until complicated by fractures Most common bone disease in humansCharacterized by:Low bone massMicroarchitectural deteriorationCompromised bone strengthIncreased risk for fractureWant to treat before manifests symptomsBone mass only part of the picture—other factors into play
3Failure To Diagnose and Treat Studies show failure to diagnosis and treat osteoporosis in older patients who have suffered a fractureIn study of 4 Midwestern health systems:1/8 – 1/4 of hip fracture pts received BMD testing< ¼ were given calcium/D supplements< 1/10 treated with antiresorptive medicationsUS Department of Health and Human Services: Bone Health and Osteoporosis: A Report of the Surgeon General, Office of the Surgeon General, 2004.
4Risk Factors Major Additional History of fracture as an adult Fragility fracture in first degree relativeCaucasian/Asian postmenopausal womanLow body weight (< 127 lb)Current smokingUse of oral corticosteroids > 3 mo.AdditionalImpaired visionEstrogen deficiency at early age (< 45 YO)DementiaPoor health/frailtyRecent fallsLow calcium intake (lifelong)Low physical activity> 2 alcoholic drinks per dayMany of these are nonmodifiable. Already working against you.
5Factors Associated with Bone Loss in Men GeneticsSmoking/alcoholCalcium intakePhysical activity/strengthTestosterone productionEstrogen productionHypogonadism is best-characterized risk factor for osteoporosis and osteoporotic fractures in men. Other risk factors same as women.
6Medical Conditions Associated with Increased Risk of Osteoporosis COPDCushing’s syndromeEating disordersHyperparathyroidismHypophosphatasiaIBSRA, other autoimmune connective tissue disordersInsulin dependent diabetesMultiple sclerosisMultiple myelomaStroke (CVA)ThyrotoxicosisVitamin D deficiencyLiver diseases50,000 IU weekly for six weeksHigher-dose vitamin D ( IU) reduced the relative risk of both hip and nonvertebral fracture (RR 0.74, 95% CI and RR 0.77, 95% CI , respectively).Not an inclusive list
7Drugs Associated with Reduced Bone Mass AluminumAnticonvulsantsCytotoxic drugsGlucocorticosteroids (oral/high dose inhaled)ImmunosuppresantsGonadotropin-releasing hormone (e.g. Lupron)LithiumHeparin (chronic use)Supraphysiologic thyroxine dosesAromatase inhibitorsDepo-ProveraAnticonvulsants—inhibit vitD metabolismThyroxine- keep towards upper end of normalNot an inclusive list
8Risk Assessment/Diagnosis After menopause, all women should be evaluated clinically for osteoporosis risk to determine need for BMD testing50-60% of men with osteoporosis have disorders known to reduce bone loss, such as hyperparathyroidism, intestinal disorders, malignancies, conditions resulting in immobilizationBMD recommended in men with known risk factors and who have lost > 1.5 inches in heightDiagnosis can be established in patients who have never had a fragility fracture by BMD measurement
9World Health Organization Diagnostic Criteria DIAGNOSIS BMD CRITERIA *Normal within 1 SD of a “young normal” adult (T-score at -1.0 and above)Osteopenia between 1 and 2.5 SD below that of a “young normal” adult(T-score between -1 and -2.5)Osteoporosis SD or more below that of a “young normal” adult (T-score at or below -2.5)Severe Osteoporosis 2.5 SD or more below that of a “young normal” adult and fracture(s)T-score is the number of SDs above or below the average BMD value for young, normal adults of the same sexBMD = Bone mineral density SD = Standard deviation*Measured at the hip, spine, or wristOP is a continuum. With arbitrary lines put on bell-shaped curve as populations studied. Goal is to prevent seeing these T-scores.BMD expressed as relationship to two norms: the expected BMD for patient’s age and sex (Z-score) or for “young normal” adults of same sex (T-score). Difference between pt’s score and norm is expressed in SD above or below the mean.Women who have lost 1 ½ inches of height, women presenting with fracturesZ-score: compares your score to age, sex, race-matched people. If don’t look like peers, look into secondary cause.
10Who Should be Tested?Decision to test based on individual risk profile, never indicated unless results influence treatment decisionBMD testing should be performed on:All women 65 YOA and older regardless of risk factors*Younger postmenopausal women with one or more risk factors (other than being white, postmenopausal and female)Postmenopausal women who present with fractures (confirm diagnosis, determine disease severity)Medicare covers BMD testing for the following individuals aged 65 and older:Estrogen deficient women at clinical risk for OPIndividuals w/vertebral abnormalitiesIndividuals receiving or planning to receive long-term steroid therapyIndividuals w/primary hyperparathyroidismIndividuals being monitored to assess response or efficacy of an approved OP drug therapyRecommendations and focus will be on women—will cover men towards end of the talk.*Medicare permits repeat BMD testing every 2 years.
11NOF – Clinician’s Guide to Prevention and Treatment of Osteoporosis www.nof.org Released 2/21/08 (previous update in 2003)Guidelines expanded to include African-American, Asian, Latina and other postmenopausal women, also addresses men 50 years and olderDramatically alters approach to assessing fracture risk and treatmentWill help identify people at high risk for developing osteoporosis/fractures and ensure appropriate treatmentUses absolute fracture risk methodology to enhance treatment decisions to individualize plan for each patient
12NOF’s Clinician’s Guide Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHOAlso called 10-year fracture risk model and 10-year fracture probabilityEstimates the likelihood of a person to break a bone due to low bone mass over a period of 10 yearsMost useful to determine if treatment needed for those with low bone mass or osteopenia
13Universal Recommendations Adequate intake of calcium, vitamin DWeight-bearing and muscle-strengthening exercises to reduce risk of falls/fractureProvide strategies for fall preventionAvoidance of tobacco use/excessive alcohol useTalk to your provider about bone healthHave a bone density test and take medication when appropriateSeveral interventions to reduce fracture risk can be recommended to the general population.
14Adequate Intake of Calcium/Vitamin D Adequate intakes of dietary calcium and vitamin D, including supplements if necessaryElemental calcium per day (> 50 YOA) = at least mgVitamin D3 per day (> 50 YOA) = international units (IU)Vitamin D3 (cholecalciferol) plays major role in Ca absorptionControlled clinical trials have demonstrated the combination reduces fracture riskInexpensive, well-toleratedSafe upper limits of Ca/day = 2500 mgD = 2000 IU
15Calcium/D Product Selection Product (% elemental Ca)Elemental Calcium (mg)Vitamin D (units)CommentsCalcium carbonate (40)-Tums Ultra-Caltrate 600 Plus-Oscal Plus D-Viactiv Chews400600500200125100Requires acidic environment for dissolution and disintegration. Best to take with meals. Greater risk for constipation with carbonate form.Calcium citrate (24)-Citracal Plus D- Citracal Petites with VitD315Take without regard to meals. Serving size usually equals 2 capsules so label can be misleading to patients.Vitamin D-Multivitamin (D3)-Vitamin DSome products also come in chewable, liquid, dissolvable tablet.
16Vitamin D and Fall RiskIn addition to its effect on BMD, may contribute to reduction in fracture riskImproved muscle functionReduction in risk for fallsMeta-analyses of 5 clinical trials (> 60 YOA) showed significant reduction in risk for falling in those taking vitamin D plus calcium versus those taking placeboVitamin D deficiency prevalent in older adult populationInadequate sun exposure, use of sunscreenHomebound, institutionalizedNorthern latitudesMaintain 25-hydroxyvitamin D3 at least > 40 ng/mLTreatment: 50,000 IU vitD weekly x 6-8 weeks, then assess need for chronic monthly therapyA conservative approach to vitamin D replacement would be to give 800 IU daily with a target serum 25-hydroxyvitamin D concentration >30 ng/mL. A more aggressive approach would be to maintain serum levels >30 ng/mL, recognizing that some patients need more than 800 IU daily.Treatment dose: 50,000 IU qweek x six weeks
17Regular Weight-Bearing Exercise Defined as those in which bones and muscles work against gravity as feet and legs bear the body’s weightInclude walking, jogging, Tai-Chi, stair climbing, dancing, tennis, yogaImprove agility, strength, balanceMay increase bone density modestly, reduce fall risk, enhance muscle strength, improve balance
18Avoidance of Tobacco and Alcohol Tobacco products detrimental to skeleton, overall healthNOF strongly encourages tobacco cessation programs as osteoporosis interventionExcessive alcohol intake also detrimental to bone health and requires treatmentNegative estrogen effects
19Who Should Be Treated? NOF Recommendations – 2008 Initiate therapy to reduce fractures in postmenopausal women/men > 50 with:BMD T-scores < -2.5 at hip or spinePrior vertebral or hip fractureLow bone mass (T-scores -1.0 to -2.5 at hip or spine) when:10-year probability of hip fracture is > 3%10-year probability of major osteoporosis-related fracture is > 20%Based on US-adapted WHO algorithmLost 1 ½ inches of height
20FDA-Approved Drugs for Osteoporosis BisphosphonatesAlendronate, Alendronate plus D (Fosamax®, Fosamax Plus D®)Risedronate, Risedronate with Calcium (Actonel®)Ibandronate (Boniva®)Selective Estrogen Receptor Modulators (SERMs)Raloxifene (Evista®)Calcitonin (Miacalcin®, Fortical®, Calcimar®)Parathyroid Hormone [PTH (1-34), teriparatide]Forteo®Estrogen/Hormone Therapy (ET/HT)Premarin®, Estrace®, Prempro®Risedronate w/ calcium (500 mg as carbonate)
21Bisphosphonates – Antiresorptive Agents Agents FDA-approved for:Prevention and treatment of osteoporosis in postmenopausal womenTreatment to increase bone mass in men with osteoporosisTreatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoidsTreatment of Paget’s disease of bone in men and womenMechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclastsLeads to increases in bone density and reduced fracture riskTreatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density.Treatment of glucocorticoid-induced osteoporosis in men and womenThe recommended dosage is one 5 mg tablet once daily, except for postmenopausal women notreceiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily.Paget’s disease of bone in men and womenThe recommended treatment regimen is 40 mg once a day for six months.
22Bisphosphonates – Clinical Efficacy Controlled clinical trials indicate over 3-4 year period, alendronate ↑ bone mass and ↓ incidence of vertebral, hip, and all non-vertebral fractures by 50%Controlled clinical trials indicate risedronate ↑ bone mass and ↓ risk of vertebral fractures by 40% and non-vertebral fractures by 30% over 3-year periodIbandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year periodAlendronate appears to be well tolerated and effective for at least ten yearsAlendronate is well tolerated and effective for at least ten years. In an extension study of 247 postmenopausal women with osteoporosis, alendronate (5 or 10 mg/day) resulted in continued increases in bone mineral density over a ten-year period . The total ten-year increase in lumbar spine density was 13.7 and 9.3 percent for the 10 and 5 mg/day groups, respectively. Increases in bone mineral density were greatest in the initial five years of the study (10 and 6.8 percent for the 10 and 5 mg/day groups, respectively). Fracture benefit appeared to be maintained throughout the study. In patients assigned to discontinue alendronate after year five, a gradual loss of effect was seen (as measured by markers of bone turnover and bone density). The safety and tolerability of alendronate were similar to those of placebo.Similar ten-year results were seen in the extension study of the Fracture Intervention Trial (FIT) . During years 6 to 10 of follow-up, there were no significant differences in bone mineral density at most sites in patients receiving either 5 or 10 mg of daily alendronate, suggesting that after five years of alendronate therapy (10 mg daily or 70 mg weekly), it may be reasonable to decrease to a maintenance dose (5 mg daily or 35 mg weekly).
23Bisphosphonates – Dosing Alendronate*Prevention5 mg PO daily35 mg PO weeklyTreatment10 mg PO daily70 mg PO weekly70 mg/2,800 IU vitamin D PO weeklyRisedronatePrevention/TreatmentIbandronatePrevention/Treatment2.5 mg PO daily150 mg PO monthlyTreatment3 mg IV every 3 months*Alendronate also available in oral solution.
24Bisphosphonates – Administration Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (1 hour prior for monthly ibandronate)Should only be taken upon arising for the dayTablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at least 30 minutes (60 minutes for monthly ibandronate)Should supplement with calcium/vitamin D if dietary intake inadequate
25Bisphosphonates – Adverse Effects Hypocalcemia (18%)Hypophosphatemia (10%)Musculoskeletal pain, cramps – recent FDA warningGastrointestinalAbdominal painAcid refluxDypepsiaEsophageal ulcerGastritisOsteonecrosis of the jaw (IV bisphosphonates)Visual disturbances (rare)First two transient, mildGI more common, less severe (ranging from 1-4%)Osteonecrosis: “dead bone.” Researchers say cases are rare, and seem most common among patients receiving intravenous bisphosphonates such as Zometa or Aredia in conjunction with chemotherapy or radiation for breast cancer and multiple myelomas. Incidents also appear more likely to follow serious dental surgery, such as a tooth extraction. Recommend routine dental care.The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring.Visual disturbances: Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported with most bisphosphonates. However, these complications appear to be rare.
26Bisphosphonates Contraindications/Precautions Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasiaInability to stand or sit upright for at least 30 minutesPatients at increased risk of aspirationHypocalcemiaShould be corrected prior to initiating therapyRenal insufficiency (Not recommended if CrCl < ml/min)Achalasia=Failure of muscle bands to relaxGERD not an absolute contraindication. Weigh pros/cons.
27Bisphosphonates – Missed Dose Once weekly alendronate, risedronateTake on morning after remembering, then resume once weekly on regularly chosen dayOnce monthly ibandronateIf next dose > 7 days away, take dose the morning following the date rememberedThen return to original scheduleIf next dose < 7 days away, wait until next scheduled doseMust not take two 150 mg tablets within the same week
28Zolendronic Acid (Reclast®) Approved for treatment of osteoporosis in postmenopausal women in August 2007Single 5 mg infusion given IV over > 15 minutes, once yearlyShould still supplement with calcium/vitamin DMay be ideal for those with GI contraindications to the oral formulations
29Price Comparison Drug Price Alendronate (Fosamax®) 10 mg once daily 70 mg once weekly70 mg/2800 IU weekly30 day supply: $72.9930 day supply: $32.99 (generic)30 day supply: $79.70Risedronate (Actonel®)5 mg once daily35 mg once weekly30 day supply: $65.9930 day supply: $63.99Ibandronate (Boniva®)2.5 mg once daily150 mg once monthly30 day supply: $75.99Check formulary
30BisphosphonatesVery well tolerated in patients who adhere to proper administration techniquesProper patient counseling for correct administration is KEY to reduce risk of adverse effects and increase tolerabilityPlace in Therapy: should be considered first-line for prevention/treatment of osteoporosis in patients with no contraindications
31SERMs – Raloxifene FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal womenMechanism: tissue-selective activity, acts as an estrogen agonist on boneEstrogen antagonist on breast, uterusdecreases total and LDL-cholesterol but does not raise triglyceridesOsteoporosis — Tamoxifen provides some protection against postmenopausal bone loss due presumably to its partial agonist activity (show figure 3) [41-44]. However, the increase in bone density with tamoxifen (about 1.2 percent in the lumbar spine at two years) is substantially less than that with estrogen or a bisphosphonate such as alendronate (5 to 7 percent at two years). Bone loss has been reported in some studies, in which tamoxifen was administered to premenopausal women , although the effect is not universal. Not FDA approved.The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Trial is the only prospective study of tamoxifen in which fracture risk was examined. In this study, 13,328 women were randomly assigned to tamoxifen (20 mg/day) or placebo, with the primary objective to determine whether tamoxifen reduced the incidence of invasive breast cancer in high-risk women. In the latest report with seven years follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 versus 116 in the placebo group, RR 0.68, 95 percent CI 0.51 to 0.92)
32Raloxifene – Clinical Efficacy Reduces risk of vertebral fracture by 30% in patients with previous spinal fracture, 55% in patients without prior spinal fracture over 3 yearsIncreases BMD at all skeletal sites and reduces total and LDL cholesterolLess potent antiresorptive agent than bisphosphonates, although direct comparison studies lackingRole in heart disease, breast cancer under investigationdecreased serum total and LDL cholesterol by 5% to 6% and 8% to 10%, respectively, compared to placebo.STAR study: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs
33Raloxifene – Dosing/Administration For prevention and treatment60 mg PO once dailyCan be taken any time of day without regard to mealsShould supplement with calcium/vitamin D if dietary intake inadequate
34Raloxifene – Adverse Effects Frequency > 10%Hot flashesArthralgiasSinusitisFrequency 1-10%Chest painInsomniaMigrainesPeripheral edemaDiaphoresis**Has been associated with increased risk of thromboembolism (DVT, PE) and superficial thrombophlebitis; risk is similar to reported risk of HRT
35Raloxifene Contraindications/Precautions History of DVT/PE or at high riskCardiovascular diseaseHistory of uterine/cervical carcinomaDiscontinue at least 72 hours prior to and during prolonged immobilizationPrice30-day supply = $86.99No generic available
36RaloxifenePlace in Therapy: considered first-line in women who cannot tolerate bisphosphonates and have no contraindications to therapyCombination therapy (usually a bisphosphonate with a non-bisphosphonate) can provide additional small increases in BMD when compared to monotherapyImpact of combination therapy on fracture rate unknown
37Estrogen/Hormone Therapy (ET/HT) FDA approved for:Prevent osteoporosisTreatment of moderate/severe vasomotor symptoms of menopauseTreatment of moderate/severe symptoms of vulvar and vaginal atrophy associated with menopauseConsider topical preparations to treat vaginal symptoms rather than oral ET/HT
38FDA Recommendations – ET/HT When prescribing medications for osteoporosis, physicians should consider all non-estrogen therapies firstWhen prescribing ET/HT, use smallest dose for shortest amount of time to achieve treatment goalsPrescribe ET/HT products only when benefits believed to outweigh risks for a specific patient
39Calcitonin FDA-approved for: Mechanism: Treatment of osteoporosis in women who are > 5 years postmenopausalTreatment of Paget’s disease of boneAdjunctive therapy for hypercalcemiaMechanism:Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorptionPromotes the renal excretion of calcium, phosphate, sodium, magnesium and potassium by decreasing tubular reabsorptionCalcitonins from many species are effective in humans, but salmon calcitonin is the one most widely used. It is highly potent in humans because of its high affinity (forty times that of human calcitonin) for the human calcitonin receptor and its slow rate of clearance.
40Calcitonin – Clinical Efficacy Has been shown to increase spinal bone mass and may decrease risk of vertebral fractureConflicting data on efficacy of calcitonin at sites other than the spineLess effective than bisphosphonates in treatment of osteoporosisBeneficial, short-term effect on acute bone pain after osteoporotic fracture (vertebral)Why pain relief occurs is not well understood; one possibility is a rise in endorphin levels induced by calcitonin.Effect of nasal calcitonin on fracture risk NOT stated in the PI.PROOF: The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo. 33% reduction in new vertebral fractures over 5-yr period. Only 511 (out of 1255) completed 5-yrs. Highest dropout groups were: “other” meaning could have changed to other therapies (fosamax, nasal spray approved), and adverse effects
41Calcitonin – Dosing/Administration Intranasal200 units (1 spray) alternating nares dailyStore unopened bottles in refrigerator, protect from freezingCan store open bottles at room temperature for up to 35 daysActivate pump of new bottles until full spray produced (allow to reach room temperature before priming)Each bottle contains at least 30 dosesIM/SQ100 units/every other day (minimum effective dose not well-defined)Should perform skin test prior to initiating therapyShould supplement with calcium/vitamin D if dietary intake inadequateintramuscular route is recommended over the subcutaneous route when the volume of calcitonin to be injected exceeds 2 mL.Patients should keep track of number of doses taken from the bottle; after 30 doses each spray may not deliver the correct amount of medication, even if bottle is not completely empty.Injectable-have EPI on hand
42Calcitonin – Adverse Effects Most common:Nasal spray: rhinitis (12%), irritation of nasal mucosa (9%), epistaxis (3.5%), sinusitis (2.3%), back pain, arthralgia, headacheInjection: nausea (10%), flushing (2-5%)Temporarily withdraw use of nasal spray if ulceration of nasal mucosa occursPeriodic nasal examinations recommendedDemonstrated with long-term use of calcitonin in Paget's disease, is the development of antibodies and resistance to calcitonin . Serum alkaline phosphatase concentrations rise when a patient with Paget's disease becomes resistant to calcitonin, which serves to warn the physician that calcitonin has lost its efficacy. Such a warning system does not exist in osteoporosis, because calcitonin has a minimal effect on biochemical markers of bone turnover.Some experts are reluctant to use calcitonin for the long-term treatment of osteoporosis because of the fear that undetected resistance will develop. However, some studies have shown that nasal calcitonin maintains efficacy in preventing perimenopausal bone loss after as long as five years of continuous use.
43Calcitonin Contraindications Precautions Drug interactions Clinical allergy to calcitonin-salmonPrecautionsNasal ulcerationsTachyphylaxis (parenteral dosage forms)Drug interactionsNo formal studies designed to evaluate DIPrice per month200 units/mL (2): $42.08200 units/ACT (3.7): $81.59
44CalcitoninValid option for treatment of established osteoporosis, especially when accompanied by fracture painPlace in therapy: because of cost, adverse effects, inconvenience of nasal administration, recommend using calcitonin until pain is no longer a problem and then switching to a bisphosphonate for long-term therapyPlace in therapy:Use for vertebral fracture pain if needed, other analgesics may be acceptable alternativesNot recommended for prev/treatment, in generalMay be synergistic with agents that inhibit bone resorption. May be used in combo.
45Parathyroid Hormone [PTH (1-34)] Anabolic agent FDA-approved for:Treatment of osteoporosis in postmenopausal women at high risk for fractureprevious osteoporotic fracture, multiple risk factors for fracture, extremely low BMD (< -2.5), or failed/intolerant to previous treatmentTreatment of primary or hypogonadal osteoporosis in men at high risk of fractureMechanism: recombinant formulation of endogenous parathyroid hormone (PTH)stimulates osteoblast function, increases gastrointestinal calcium absorption, increases renal tubular reabsorption of calciumEnhances bone turnover by initiating greater bone formationEndogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium andphosphate metabolism in bone and kidney. Physiological actions of PTH include regulation ofbone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calciumabsorption. The biological actions of PTH and teriparatide are mediated through binding tospecific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids ofPTH bind to these receptors with the same affinity and have the same physiological actions onbone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration stimulates osteoblast over osteoclast activity.
46PTH (1-34) – Clinical Efficacy Shown to decrease the risk of new vertebral fractures by 65% and nonvertebral fractures by 53% versus placebo after median exposure of 19 monthsIncreases lumbar spine BMD as well as at the femoral neck, total hip, and total bodySafety, efficacy of PTH (1-34) has not been demonstrated beyond 2 years of treatmentAll patients received 1000 mg calcium, 400 IU vitamin D daily-Most of the gains in BMD occur in the first few months, although anti-fracture efficacy is evident only after six months or more of treatment. Patients on bisphosphonates will often have incremental improvement in BMD even after 10 years of treatment; while it appears that the BMD changes with PTH begin to level off after 18 months.
47PTH (1-34) – Dosing/Administration 20 µg SQ once daily for treatment of osteoporosisThigh or abdominal wallForteo® prefilled pen contains 28 daily dosesImportant to read Medication Guide and User Manual before starting and each time medication refilledShould be administered initially under circumstances where the patient can immediately sit or lie down, in the event of orthostasis (dizziness, palpitations are transient)
48PTH (1-34) – Adverse Effects Most commonDizziness, rash, nausea, headache, leg cramps, arthralgia, rhinitis, transient hypercalcemiaS/s of hypercalcemia: nausea, vomiting, constipation, low energy, or muscle weaknessMost adverse effects in the clinical trials were mild and generally did not lead to the discontinuation of the drugOsteosarcoma risk in animalsLead to black box warning by FDANone of the AE in the trials caused d/c of the drug.Osteosarcoma concern: The most theoretically worrisome adverse event, is the development of osteosarcoma . No cases have been reported in three years of post marketing experience with teriparatide. However, a high proportion of Fischer rats administered PTH from infancy through senescence (ie, eight weeks to two years) developed osteosarcoma at doses that were in the range of 30 to 4500 mcg/day for humans. Clearly higher doses for long duration were major risks for development of osteosarcoma in rats. It should be noted there are several case reports of coexistent osteosarcoma in patients who have primary hyperparathyroidism. Although outside groups have studied the potential risk for osteosarcoma in humans, and concluded there was minimal risk, the FDA contends that PTH therapy be limited to two years, pending further post-marketing studies.
49PTH (1-34) – Warnings/Precautions Increased risk of osteosarcoma (rats) – clinical relevance unknown (no excess reports in humans)Avoid in:Paget’s disease of bonePrior radiation therapy to skeletonBone metastasesHypercalcemiaHistory of skeletal malignancyPregnant/nursing
50PTH (1-34) – Price One-month supply $539.99 Lilly offers Forteo® Patient Assistance Program for Medicare-eligible (LillyMedicareAnswers) and non-Medicare eligible patientsLillyMedicareAnswers intended for patients who are enrolled in any Medicare Part D prescription drug plan and who meet certain eligibility requirementsExpected to start early 2007For non-Medicare patients, application process includes paper application and income restrictionsCall or visit for more detailsFor current LillyAnswers patients enrolled in Medicare Part D who meet certain qualifying criteria and are prescribed either Forteo or Zyprexa, the company will continue LillyAnswers benefits until Lilly receives a favorable advisory opinion from OIG regarding theLillyMedicareAnswers program or such other date as Lilly may later determine.
51PTH (1-34)Due to safety concerns, PTH treatment should be limited to those most severely affected and for a maximum of two yearsCombination therapy with a bisphosphonate not recommended as effects do not appear additiveCost, daily SQ injection may be prohibitive for some patientsIt appears that alendronate modifies PTH action such that blunting may occur when these drugs are combined. Benefit on increased BMD was seen with combination of Forteo and HRT.Studies shown that BMD decreases after PTH d/c, therapy with antiresorptive agent helped to preserve the gains.Alternative regimens requiring less frequent administration are currently under investigation—weekly, intermittently
52PTH (1-34) Place in Therapy: Recommend PTH for women or men with severe osteoporosis (low bone mineral density [T-score < -2.5] and at least one fragility fracture) who are refractory to or unable to tolerate bisphosphonate therapyIn patients considered to be bisphosphonate "failures," PTH may be started approximately 3 months after bisphosphonates are discontinuedAntiresorptive therapy may be considered after discontinuation of PTH to maintain gains in BMD acquired with PTH alone in those at high risk for subsequent fracture
53Approaches to Monitoring Therapy Always important to ask patients about adherence, encourage continuation of therapies to reduce fracture riskMonitoring of therapy should be considered, as up to 1/6 of women taking effective therapies continue to lose bone, especially if they smokeMay measure bone mineral density at a single site after one year of therapy, but results may be misleading; usually done every 2 yearsDrugs may decrease a patient’s risk for fracture even when there is no apparent increase in BMDBiochemical markers of bone turnover can be used to monitor response to treatment. Current evidence suggests that both the decrease in turnover and increase in BMD induced by antiresorptive therapies contribute to their antifracture efficacy. Biochemical markers show considerable variability within individuals such that fairly large changes are required to indicate a treatment effect; however, with antiresorptive therapy, the changes are often substantial.
54Glucocorticoid-Induced Osteoporosis – Recommendations ACR recommends the following interventions in patients taking prednisone doses of 5 mg/day or higher for more than 3 monthsCalcium/vitamin D (1500mg/day, 800 IU/day)Weekly formulations of bisphosphonate therapyReplacement of gonadal steroids in men, if deficientCalcitonin therapy, if bisphosphonates contraindicated or not toleratedFollow BMD to assess if bone loss continues
55How Can Health Professionals Improve Bone Health? To help patients maintain strong, healthy bones, health care professionals should:Indentify and assist in recommending appropriate treatment for individuals at high risk for osteoporosis and other bone disordersRecognize risk factors that warrant osteoporosis screeningAssess diet/lifestyle for effect on bone healthAdvise patients to take active steps to ensure bone healthBe familiar with treatment of osteoporosis/low bone massActively look for other bone disease that can lead to bone loss/fractures
56References Actonel® Prescribing Information (www.actonel.com) Ann Intern Med 1990;112:352Ann Intern Med 2006;144:753Boniva® Prescribing Information (www.boniva.com)Clinical Reviews in Bone and Mineral Metabolism 2004;2(4):291Evista® Prescribing Information (www.evista.com)Forteo® Prescribing Information (www.forteo.com)Fortical® Prescribing Information (www.fortical.com)Fosamax® Prescribing Information (www.fosamax.com)
57References JAMA 2004;291(16):1999 J Clin Densitom 2004;7(1):1-6 J Am Acad Orthop Surg 2006;14:347Miacalcin® Prescribing Information (www.miacalcin.com)Reclast® Prescribing Information (www.reclast.com)National Osteoporosis Foundation (http://www.nof.org)NEJM 2003;348:1187NEJM 2004;350(12):Osteoporosis Int 1998;8:1