Presentation on theme: "SCREEN AND INTERVENE Evidence-Basis for Patient Screening"— Presentation transcript:
1 SCREEN AND INTERVENE Evidence-Basis for Patient Screening Critical Challenges in Osteoporosis— From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, Concepts, and Clinical StrategiesSCREEN AND INTERVENE Evidence-Basis for Patient Screeningand Risk Stratification: Principles for Approaching a Broad Population of Patients at Risk for Osteoporosis
2 Program Contents Definitions Epidemiology Pathophysiology Clinical FeaturesDiagnosisTherapy
3 DefinitionOsteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture1Current NIH definition: Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk for fracture1These 3-D micro-CT bone scans of lumbar spine biopsies illustrate the microscopic changes in bone architecture that are characteristic of osteoporosis2Normal trabecular bone of a 52-year-old female, shown on the left, appears as a dense network of thick trabeculae with small open spaces2Osteoporotic trabecular bone of an 84-year-old female with vertebral fracture, shown on the right, shows clear loss of bone volume, with larger spaces and perforation of the trabecular struts2ReferencesNIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy.Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: Borah B, Gross GJ,Dufresne TE, et al. Three-dimensional microimaging (MRμI and μCT), finite element modeling, and rapidprototyping provide unique insights into bone architecture in osteoporosis. Anat Rec (New Anat).2001;265:1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:
4 Key Features of Osteoporosis Bone involution in both sexes with aging and a superimposed acceleration of bone loss in women after the menopauseLow bone mass coupled with micro-architectural deterioration leading to enhanced bone fragility and ultimately fracture
6 ContentsEpidemiologyPrevalenceIncidenceSitesCostStatus of care
7 Prevalence 44 million Americans have or are at risk of osteoporosis 55% of all people ages 50 years10 million have osteoporosis34 million more have low bone mass50% of women aged 50 years will experience a fracture in their lifetimePrevalence is expected to increase with the growth of the elderly population
8 Prevalence of Osteoporosis Will Increase With an Increasing Aging Population 201900195015%1985Projected2020Population10>65 YearsWith an expanding elderly population, osteoporosis and the subsequent risk for fracture are expected to increase dramaticallyBone loss occurs in most women after menopause, with increasing prevalence thereafter. Currently between 21% and 31% of postmenopausal women in the United States have osteoporosis; 54% more have low bone density at the hip, spine, or wrist.4Over 250,000 people experience a hip fracture each year, of whom 80% are women.5 Experts estimate that because advancing age is a strong predictor for fracture risk (especially of the hip),6 the incidence of fracture will inevitably rise as the US population ages. By the year 2020, it is projected that nearly 17% of the population will be 65 years or older, a period during which the incidence of hip fracture increases at an exponential rate.5,75Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994: US Census Bureau
9 Osteoporotic Fracture Incidence Is High 1,600,0001,400,0001,200,0001,000,000Cases/Year800,000600,000400,000200,000BreastHeartOsteoporoticCancerDiseaseFracturesWomen’s Health Facts and Figures. Washington, DC: ACOG; 2000.
10 Distribution of Fractures Vertebral46%(700,000)Wrist16%(250,000)Hip19%(300,000)OtherNIH/ORBD National Resource Center. October 2000.
11 Estimated $13.8 billion/year High Economic BurdenEstimated $13.8 billion/yearHospitalization ($8.6)Outpatient ($1.3)NursingHome($3.9)Ray NF et al. J Bone Miner Res. 1997;12:24-35.
12 Current Status of Care3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated3% of wrist fracture patients receive BMD testingOnly 12% of vertebral fractures are diagnosed and 2% are treatedFreedman KB et al. J Bone Joint Surg Am. 2000;82:Gehlbach SH et al. Osteoporosis Int. 2000;11:Wiktorowicz ME. J Bone Miner Res. 1997;12:S252.
13 ContentPathophysiologyBone RemodelingTypes of Osteoporosis
14 The Bone Remodeling Cycle OsteoclastOsteoblastOsteoblastRecruitmentResorptionMineralizationParathyroid glands in man were discovered more than 120 years ago. Parathyroid hormone (PTH) was initially recognized as the major hormonal regulator of calcium homeostasis, a catabolic agent to stimulate osteoclastic bone resorption. By 1929 scientists were beginning to accumulate evidence that PTH could also have anabolic effects on the skeleton. PTH research lay relatively dormant for the next 30 years awaiting technological developments in purification and fractionation procedures that would make possible the sequencing of PTH.The intriguing question is how can a single hormone have such opposing actions, both mediated by osteoblasts? The answer is found in the method of delivery. When the skeleton is continuously exposed to exogenous PTH, the result is an increase in bone resorption. When PTH is delivered intermittently, bone formation is stimulated.At present, the agents approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis are anti-resorptive agents, that is, they reduce bone turnover and result in small but significant increases in bone mass. An agent that would increase bone mass substantially, strengthen bone mass, and restore bone architecture would have to be an anabolic agent. Some clinical research scientists suggest that parathyroid hormone may fill that role.Aurbach GD, Potts JT Jr. Parathyroid hormone. Am J Med. 1967;42:1-8.Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev. 1993;14:Whitfield JF, Morley P, Willick GE. The bone-building action of the parathyroid hormone. Implications for the treatment of osteoporosis. Drugs & Aging 1999;15:Cosman F, Lindsay R. Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue Int ;62:OsteoidDepositionCourtesy: Dr. Mone Zaidi
15 Disordered Bone Remodeling as the Cause of Osteoporosis High RemodelingHypogonadal (including post-menopausal)HyperparathyroidismHyperthyroidismOthersLow RemodelingInvolutional (Aging)Glucocorticoids (high dose)HIV
16 Pathogenesis of Osteoporoses Resorption Must Exceed Formation Normal RemodelingOsteoclast OveractivityHypogonadal StatesParathyroid and ThyroidParathyroid glands in man were discovered more than 120 years ago. Parathyroid hormone (PTH) was initially recognized as the major hormonal regulator of calcium homeostasis, a catabolic agent to stimulate osteoclastic bone resorption. By 1929 scientists were beginning to accumulate evidence that PTH could also have anabolic effects on the skeleton. PTH research lay relatively dormant for the next 30 years awaiting technological developments in purification and fractionation procedures that would make possible the sequencing of PTH.The intriguing question is how can a single hormone have such opposing actions, both mediated by osteoblasts? The answer is found in the method of delivery. When the skeleton is continuously exposed to exogenous PTH, the result is an increase in bone resorption. When PTH is delivered intermittently, bone formation is stimulated.At present, the agents approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis are anti-resorptive agents, that is, they reduce bone turnover and result in small but significant increases in bone mass. An agent that would increase bone mass substantially, strengthen bone mass, and restore bone architecture would have to be an anabolic agent. Some clinical research scientists suggest that parathyroid hormone may fill that role.Aurbach GD, Potts JT Jr. Parathyroid hormone. Am J Med. 1967;42:1-8.Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev. 1993;14:Whitfield JF, Morley P, Willick GE. The bone-building action of the parathyroid hormone. Implications for the treatment of osteoporosis. Drugs & Aging 1999;15:Cosman F, Lindsay R. Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue Int ;62:Osteoblast DysfunctionInvolutional (Aging)GlucocorticoidsHIVCourtesy: Mone Zaidi, MD Mount Sinai School of Medicine
17 Content Clinical Features Vertebral Fractures Non-Vertebral Fractures Risk Stratification
18 Vertebral Fractures Most common fractures (46%) Insidious Progressive Often unrecognizedAssociated withDeformity, height loss, back painMorbidity and mortalityPredict future vertebral and non-vertebral fracturesVertebral fractures remain undetected in clinical practice and are a major cause of mortality and morbidityAlmost 20% of patients with a prevalent vertebral fracture experience an additional fracture within a yearEarly detection is criticalVertebral fractures are frequently asymptomatic – many are only discovered by chance – and less than one third are actually diagnosed.9 Fracture of the spine may lead to crowding of internal organs and intestinal dysfunction or restrictive lung disease. Increased mortality and morbidity are associated with limited physical activity, back pain, skeletal deformity, height loss, and kyphosis. Vertebral fractures are associated with an increased risk for additional vertebral fractures and are predictive for the future development of nonvertebral fractures.9
19 NonVertebral Fractures Entire skeleton can be involvedWristAnklePelvisHumerusRibOthersAssociated with significant disabilityFractures occur at numerous sites over the entire skeleton (referred to as “nonvertebral fractures” in this presentation)Nonvertebral fractures impose significant limitations on a patient’s daily physical activitiesAccording to recent studies, undiagnosed vertebral fractures increase a patient’s risk for nonvertebral fractures, placing the entire skeleton at risk.9 Typical fracture sites include the hip, spine, wrist, and ribs, although all bones are susceptible to fracture.8Like vertebral fractures, certain nonvertebral fractures (eg, wrist fractures) are underdiagnosed and undertreated. According to a retrospective study of 1162 women 55 years of age or older, only 2.8% underwent a bone mineral density (BMD) scan, and 22.9% actually received treatment.11
20 Hip Fracture Most serious clinical event Morbidity is high 50% do not regain independence50% do not regain previous mobilityMortality is high1 in 5 patients die within 1 yearPatients not treated for osteoporosisHip fracture is the most devastating consequence of osteoporosis, with a high rate of morbidity and mortalityAlthough hip fracture is easily detected, less than 5% of patients are actually referred for medical evaluation and treatmentHip fractures are the most serious complication of osteoporosis.10 One in 5 patients dies within a year of fracture, and more than half fail to regain prefracture mobility and independence; experts estimate that almost one third of hip fracture patients require placement in a nursing home due to permanent disability.1,3 The profound effects of hip fracture are underscored by the fact that 80% of women over 75 years of age preferred death to the consequences of a hip fracture.3NIH Consensus Development Panel. JAMA. 2001;285:
21 Risk of Fracture All postmenopausal women with the following: Low BMD Fracture after 50 yearsAge 65 yearsMaternal history of fracture after 50 yearsLow body weight (125 lb)SmokingCorticosteroid useOther secondary causesPostmenopausal women with low BMD and an existing fracture after age 50 are the most at risk for fractureIdentification of all other risk factors is critical for early diagnosisA wide range of risk factors is associated with an increased risk for fracture in all postmenopausal women.10 The main question is: what are the most important risk factors? A recent study of 7782 women aged 65 years and older evaluated the predictive value of low BMD and key risk factors for bone fracture (data were obtained from the Study of Osteoporotic Fractures [SOF]).19 The FRACTURE Index assessment tool comprised a set of 7 variables – age, BMD T-score, fracture after age 50, maternal hip fracture after age 50, body weight less than or equal to 125 lb (57 kg), smoking status, and the use of arms to stand up from a chair. This index was predictive for hip, vertebral, and nonvertebral fractures, indicating that the 7 risk factors identified in the FRACTURE Index delineate the most important characteristics of women at risk for osteoporotic fractures.19 The FRACTURE Index has since been validated by the EPIDOS fracture study (a multicenter prospective study on risk factors for hip fracture performed in 7575 elderly women living at home, aged 75 to 95 years).20 The FRACTURE Index can also be used with and without BMD in older postmenopausal women to predict their 5-year risk for osteoporotic fractures.19The importance of high-dose glucocorticoid therapy as a cause of osteoporosis should not be overlooked. Glucocorticoid therapy (prednisolone at or above 7.5 mg/day or equivalent doses of other glucocorticoids) is associated with significant bone loss within 3 to 6 months and an increased fracture incidence of 15% at 1 year. Fracture rates as high as 30% to 50% have been documented in patients on long-term glucocorticoid therapy.21Other secondary causes of osteoporosis include hypogonadism, anorexia nervosa, type 1 diabetes, pregnancy, hyperparathyroidism, acromegaly, chronic liver disease, alcoholism, and rheumatoid arthritis.1Black DM et al. Osteoporosis Int. 2001;12:
22 A Fracture Begets a Future Fracture Future Fractures (Fold Increase) Existing FractureWrist3.31.4-Vertebral126.96.36.199Hip1.92.3WristVertebralHipHistory of prior fracture at multiple sites has been associated, in the literature, with an increased risk of subsequent fracturesIn a study by Klotzbuecher et al, a systematic literature review was performed to discern the relative risk of fracture by location of prior and subsequent fractureThey found that a history of wrist fracture in peri/postmenopausal women increased the risk for subsequent fracture of the wrist (relative risk 3.3) as well as for vertebral fracture (relative risk 1.7) and hip fracture (relative risk 1.9)In addition, prior vertebral fracture increased the risk for subsequent wrist fracture (relative risk 1.4), vertebral fracture (relative risk 4.4), and hip fracture (relative risk 2.3)The investigators also noted that prior hip fracture increased the risk for subsequent vertebral fracture (relative risk 2.5) and hip fracture (relative risk 2.3)ReferenceKlotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk offuture fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15:Klotzbuecher CM et al. J Bone Miner Res. 2000;15:
23 Fracture Stratification Key Points Main risk factorsLow BMDPresence of a fracture after 50 yearsRisk for fracture increasesWith number of risk factorsWith each subsequent fracture
24 Content Diagnosis Clinical Assessment Diagnostic Criteria Bone Densitometry
25 Clinical Evaluation History Physical Tests Risk factor assessment Medical historyFamily historySocial history (smoking, alcohol)Evaluation of fall riskPhysicalHeight loss >1.5 inchesKyphosisTestsBMDX-ray of thoracic/lumbar spineBone turnover markersLaboratory tests as necessaryExtensive clinical evaluation for fracture risk is essential for all postmenopausal womenEvaluation comprises patient history assessment (risk factors, medical and social history), physical exam, and x-ray/BMD scanAll postmenopausal women should undergo clinical evaluation for fracture risk. The evaluation begins with the patient’s history, which provides an overview of risk factors and may elicit signs or symptoms suggestive of the presence of fracture or comorbid conditions that may contribute to bone loss.1 The patient’s social history and circumstances should also be investigated, especially for a patient with an existing fracture (eg, Who does the patient live with? Does she have to climb stairs? Does she need help with daily living activities?). Height assessment, specifically a loss of 1.5 inches or greater, may also indicate fracture.29 Findings from the physical examination may indicate an underlying illness or condition that may be responsible for low bone mass. In turn, BMD testing may indicate the degree of low bone mass and is important for diagnosis and risk assessment; radiography may show fracture of the thoracic or lumbar spine.Certain laboratory tests are appropriate to exclude secondary causes of osteoporosis. These include a complete blood cell count, serum chemistry panel (calcium, phosphate, liver enzymes, total protein, albumin, alkaline phosphatase, creatinine, and electrolytes), and urinalysis. In women for whom other causes of bone loss are suspected, additional tests may be performed. These include measurement of thyrotropin, 24-hour urinary calcium excretion, erythrocyte sedimentation rate, parathyroid hormone concentration, and 25-hydroxyvitamin D concentration. Additional tests include dexamethasone suppression, urinary free cortisol and other tests for hyperadrenocorticism, acid-base studies, serum or urine protein electrophoresis, and bone marrow aspiration and biopsy. Undecalcified iliac bone biopsy with double tetracycline labeling may be considered in the woman with osteoporosis of no apparent cause or no response to therapy.1AACE Guidelines. Endocr Pract. 2001;7:
26 Kyphotic vs. Non-Kyphotic The Kyphotic WomanThe Non-Kyphotic WomanLikely has osteoporosis and vertebral fracturesConfirmatory spinal x-ray for diagnosisBaseline BMDSpinal x-ray or DXA if height loss >1.5 inchesAtraumatic vertebral fractures = osteoporosis aKyphosis (convexity of the spine) may be indicative of osteoporosisDiagnosis should be confirmed by spinal x-ray and dual x-ray absorptiometry (DXA)Kyphosis is a musculoskeletal condition that may not be due to osteoporosis or vertebral fractures.The relationship between kyphosis, height, and fracture incidence was recently studied in a cohort of 6349 osteoporotic women enrolled in the fracture intervention trial.30 Kyphosis was assessed using a Debreuner Kyphometer, and height loss was measured using a Harpenden stadiometer. A 15 degree increase in kyphosis was associated with height loss in excess of 4 cm (OR, 1.88; 95% CI, ) and presence of a vertebral fracture (OR, 1.57; 95% CI, ). The authors concluded that women with a significant degree of kyphosis (ie, spine curvature of 15 degrees) are likely to exhibit spinal osteoporosis, characterized by height loss, thoracic fractures, and chronic upper and middle back pain. Therefore, measurement of kyphosis may be useful in assessing the severity of spinal osteoporosis.
28 WHO Diagnostic Criteria The WHO Study Group. Geneva, 1994T-Score* Classification> Normal-1.0 to -2.5 Osteopenia< -2.5 or lower Osteoporosis< fracture Severe osteoporosisThe World Health Organization (WHO) defines a T-score of -2.5 or lower as indicative of osteoporosisThe T-score, which is expressed as the number of SDs above or below the mean for the young, healthy female population, is most frequently used for clinical decision making and standards for research purposes.1,36 According to recommendations of the WHO task force, osteoporosis is defined in women without fragility fractures as a T-score of at least -2.5 SD.37 The preferred sites of measurement are the lumbar spine and the hip, especially in the elderly, using DXA. For each SD decrease in BMD, there is an approximate doubling of fracture risk. The predictive value of low BMD for fractures is similar to the predictive value of high blood pressure for stroke.10 The WHO stresses that its T-score criteria should be used along with other factors to assist in making treatment decisions, but not as the sole determinant.37*T-score = number of standard deviations (SDs) below or above the peak bone mass in young adults.
29 Techniques Diagnosis Risk Assessment/ Research Central dual energy x-ray absorptiometry (DXA)Gold standardWHO criteria appliedRisk Assessment/ ResearchPeripheral DXA (pDXA)UltrasoundQuantitative computedtomography (QCT)Central DXA is the “gold standard” for diagnosis of osteoporosisPeripheral devices are less sensitive and restricted to fracture risk assessmentCentral DXA is the gold standard for evaluation of BMD and prediction of future fracture risk in patients with osteoporosis. According to National Osteoporosis Foundation recommendations, DXA provides assessment of BMD at the spine, hip, and wrist, the most common sites of osteoporotic fracture. DXA has the advantage over other techniques of measuring whole body bone mass. A DXA scan takes only a few minutes to complete with exposure one tenth that of a standard chest x-ray.10Quantitative computed tomography, which measures both trabecular and cortical bone density at several sites, is often used as an alternative to DXA to assess vertebral BMD. Single x-ray absorptiometry and peripheral DXA are appropriate for assessing peripheral BMD sites such as the forearm, finger, and heel.10Ultrasound densitometry (ultrasonometry) is available as a convenient portable machine for use by the primary care physician and measures BMD in other peripheral bones such as the heel, tibia, and patella. Although not as precise as DXA, ultrasound and other devices to measure peripheral BMD appear to predict short-term fracture risk.15National Osteoporosis Foundation. Washington, DC; 1999.
30 Central vs Peripheral DXA Central DXAEstablish or confirm diagnosisAssess fracture riskFollow upEnhance patient compliancePeripheral DXADifferent from WHO T-score criteriaFracture risk assessment in elderly with low T-scoresCentral DXA is a major diagnostic toolOther applications include assessment of fracture risk, serial BMD changes, and increased patient complianceIn addition to establishing a diagnosis of osteoporosis and assessing fracture risk, BMD testing is a useful tool.22 First, it is important to remember that the relationship between BMD and fracture risk is a continuous, graded, and inverse relationship.1,10Second, BMD can be used to monitor response to therapy as an indicator of intermediate outcome or progression of osteoporosis and risk status in patients not receiving treatment. Central DXA testing is preferred over other techniques since it measures BMD at central skeletal sites, which are more likely than peripheral sites to show a response to treatment; DXA is also preferred for baseline (pretreatment) and serial measures of BMD.1Lastly, in patients who fail to respond to interventions according to BMD test results, serial BMD measurements may enhance acceptance of or adherence to treatment.1
32 Goals for Therapy Fracture prevention Stabilize or increase bone mass Provide tolerability and long-term safetyEnsure compliance and adherenceRapid and sustained prevention of fracture is the major goal of osteoporosis treatmentBecause of the high rate of morbidity and mortality associated with fracture, osteoporosis treatment is aimed primarily at prevention of bone fractures.3 The importance of initiating fast-acting treatment for osteoporosis is underscored by the observation that 1 in 5 women who sustain a vertebral fracture will experience a new vertebral fracture within the same year.9In this respect, the bisphosphonates risedronate and alendronate have demonstrated the most rapid antifracture efficacy, with onset of action as early as 6 to 12 months after initiation of treatment Both agents have also demonstrated sustained antifracture efficacy for as long as 4 to 5 years of therapy.43,44The antifracture efficacy of calcitonin and the selective estrogen receptor modulator (SERM), raloxifene, is also sustained for 4 to 5 years.45,46 However, clinical studies indicate these agents do not have the rapid antifracture effects seen with bisphosphonates.
33 Nonpharmacologic Approaches Calcium intakeDiet and/or supplementation: 1200 mg/dayVitamin D supplementationDiagnose and treat deficiency/insufficiencySupplement: IU/dayRegular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low)Fall prevention adviceHome safety evaluationDietary and lifestyle changes are useful approaches to prevent osteoporotic fracturesPatient education is the foundation of several nonpharmacologic measures that can be included in the management of all postmenopausal women, regardless of their risk for osteoporotic fracture.1,28 These measures maximize and preserve bone mass and, ideally, should begin early in life. A well-informed patient who understands the importance of specific measures is more likely to make lifestyle modifications to improve overall health.It should be noted that the average American diet contains approximately 600 mg daily calcium, half the recommended daily intake. Thus, all patients should receive at least 1200 mg/day of elemental calcium (calcium citrate is preferred over calcium carbonate, especially in patients with achlorhydria or taking doses between meals).47 Similarly, adequate vitamin D intake – 400 to 800 IU/day – is essential, especially in elderly women, who may be housebound and have low vitamin D due to lack of exposure to sunlight. Supplemental calcium and vitamin D help maintain bone mass and reduce fracture risk.48,49Other nonpharmacologic measures include smoking cessation/avoidance, limiting alcohol intake, and performing regular load-bearing and muscle-strengthening exercises, as well as measures to prevent falls.1 Clinical studies have shown that load-bearing exercises effectively stimulate bone remodeling, preserve skeletal mass, and prevent falls by increasing muscle strength. However, patients should be cautioned that excessive exercise could cause amenorrhea and actually increase bone loss.28Fractures caused by falls can be minimized by identifying and treating conditions that predispose a patient to fall such as sensory defects, neurologic disease, and arthritis.1 Other helpful preventive measures include training programs designed to improve gait and balance, as well as improvement of reflexes and general coordination by adjustment of dose regimens for sedative drugs.Additional home prevention measures should be implemented for the elderly, who are the most likely to experience fracture as a result of a fall.1 These include the use of anchor (nonskid) rugs, installation of handrails and improved lighting (in bathrooms, halls, stairways), removal of loose wires and clutter, and encouragement of sturdy, low-heeled footwear.
34 Medications * FDA-Approved Prevention Treatment Hormone replacement YesNoYesNoCalcitonin (Miacalcin®)YesRaloxifene (Evista®)YesAlendronate (Fosamax®)Risedronate (Actonel®)YesYesOf the currently available therapies, risedronate, alendronate, and raloxifene are the only agents approved for prevention and treatment of osteoporosisThis program will review the clinical evidence on fracture reduction for available osteoporosis therapies in randomized, controlled, preplanned studiesFive medications are currently registered by the Food and Drug Administration (FDA) for the prevention and/or treatment of osteoporotic fracture: HRT, calcitonin, raloxifene, alendronate, and risedronate. Raloxifene, alendronate, and risedronate are approved by the FDA for prevention and treatment of osteoporosis. In contrast, HRT is approved for prevention only, and calcitonin for treatment only.28,29The FDA distinguishes between prevention and treatment of osteoporosis. In order for a drug to be indicated for prevention of osteoporotic fractures, study results must demonstrate that the drug prevents BMD loss beyond any attained with calcium plus vitamin D supplementation during the early (1 to 3 years) postmenopausal period. To be indicated for treatment, a drug must have demonstrated a significant (3-year trend/5-year rate: P<0.05) reduction in incident vertebral fracture during the later (>5 years) postmenopausal period.28,29 An FDA advisory panel recently recommended approval of parathyroid hormone (PTH), the first bone anabolic agent for the treatment of severe osteoporosis in postmenopausal women.YesIbandronate (Boniva®)YesIbandronate Injection(Boniva®)Yes*Parathyroid hormone(Forteo®)*Not considered.
36 Anti-Resorptive Versus Anabolic High Turnover Bone LossLow Turnover Bone LossParathyroid glands in man were discovered more than 120 years ago. Parathyroid hormone (PTH) was initially recognized as the major hormonal regulator of calcium homeostasis, a catabolic agent to stimulate osteoclastic bone resorption. By 1929 scientists were beginning to accumulate evidence that PTH could also have anabolic effects on the skeleton. PTH research lay relatively dormant for the next 30 years awaiting technological developments in purification and fractionation procedures that would make possible the sequencing of PTH.The intriguing question is how can a single hormone have such opposing actions, both mediated by osteoblasts? The answer is found in the method of delivery. When the skeleton is continuously exposed to exogenous PTH, the result is an increase in bone resorption. When PTH is delivered intermittently, bone formation is stimulated.At present, the agents approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis are anti-resorptive agents, that is, they reduce bone turnover and result in small but significant increases in bone mass. An agent that would increase bone mass substantially, strengthen bone mass, and restore bone architecture would have to be an anabolic agent. Some clinical research scientists suggest that parathyroid hormone may fill that role.Aurbach GD, Potts JT Jr. Parathyroid hormone. Am J Med. 1967;42:1-8.Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev. 1993;14:Whitfield JF, Morley P, Willick GE. The bone-building action of the parathyroid hormone. Implications for the treatment of osteoporosis. Drugs & Aging 1999;15:Cosman F, Lindsay R. Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue Int ;62:PTH - AnabolicCourtesy: Mone Zaidi, MD Mount Sinai School of Medicine
37 PTH Mode of Delivery = Bone Activity Intermittent versus Continuous = Osteoblastic versus OsteoclasticFormation versus ResorptionBone Gain versus Bone LossTam et al. found that daily injections of bovine or human parathyroid hormone (b/hPTH) increased bone apposition rate without an increase in bone resorption, resulting in a net increase in trabecular bone volume. Continuous administration of PTH increased both bone formation and resorption, with a net decrease in trabecular bone volume.Sprague-Dawley rats were exposed to human parathyroid hormone (1-34) [hPTH(1-34)] under the following conditions: control (vehicle), daily subcutaneous injection (sc), and intermittent via infusion of 1 hour per day, 2 hours per day, or continuous. Subcutaneous and 1 h/day infusion of hPTH(1-34) increased mineral apposition and bone formation rates, as indicated by the significant effect on osteoblast perimeter, with no increase in osteoclast perimeter.Tam CS, Heersche JNM, Murray TM and Parsons JA. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: Differential effects of intermittent and continuous administration. Endocrinology 1982;110:Dobnig H and Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
38 Net Increase in Number and Activity of Bone-Forming PTH – Anabolic ActionReceptor Binding andSignal TransductionIncreased OsteoblastSurvivalEnhanced OsteoblastDifferentiationAlthough a major action of parathyroid hormone (PTH) is to stimulate osteoclastic bone resorption, Rodan and Martin presented compelling evidence that osteogenic cells of the osteoblast lineage are a principal target of PTH.Intermittent treatment with PTH increases osteoblast number and bone formation. Dobnig and Turner proposed that the increase in osteoblast number in mature rats was due to stimulation of bone lining cells on quiescent surfaces to function as osteoblasts.Jilka et al reported that daily PTH injections in mice increased the life-span of mature osteoblasts by preventing apoptosis. This resulted in increased osteoblast number, bone formation rate, and bone mass.Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption: a hypothesis. Calcif Tissue Int 1981;33:Dobnig H and Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995;136:Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999;104:Net Increase in Number andActivity of Bone-FormingOsteoblasts
39 CalcitoninCourtesy: Mone Zaidi, MD Mount Sinai School of Medicine
40 Nasal Calcitonin: Efficacy at the Spine and Hip PROOF: Three Year Analysis
41 Estrogen and Raloxifene Reduce the birth (genesis) of new osteoclasts from bone marrowDoes not inhibit the activity of mature resorbing osteoclastsOsteoclast birth increases exponentially to a peak within the first few years of the menopausal transitionMaximum bio-efficacy in early menopause and declines with age and disease severity/fracturesZaidi, M., et. al. (2001) Journal of Bone and Mineral Research.
42 Structure of Bisphosphonates OHR1OHOHOHO = P – C – P = OO = P – O – P = OOHR2OHOHOHBisphosphonatePolyphosphate
43 Bisphosphonate Mechanism of Action Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
44 Possible Causes of Poor Adherence? Poor patient education?Lack of positive reinforcement?Complex dosing guidelines?Osteoporosis eclipsed by other chronic conditions?POOR ADHERENCEDisruption to daily routine?(less frequent dosing)Concern about side effects?
45 Adherence With Osteoporosis Medications Is Poor 3025201510526%19%19%Patients Abandoning Treatment (%)Hormone Replacement Therapy(n=334)Bisphosphonate(n=366)Selective Estrogen Receptor Modulator(n=256)Tosteson ANA, et al. Am J Med. 2003;115:
46 Long-term Compliance Reduces Fracture Risk % Patients With Fracture12.6%14*129.4%108642†CompliantNoncompliant(n=3400)(n=3425)Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.
47 Daily vs. Weekly Bisphosphonates Has Led To Increased Compliance Daily WeeklyP<0.001 vs daily therapy102030405060708090100Oct 2002NovDecJanFebMarAprMayJunJulAugSepOct 2003Patients on Therapy (%)Daily Bisphosphonates (n=33,767)Weekly Bisphosphonates (n=177,552)54.6%36.9%Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325.Data on file (Reference # ), Hoffmann-La Roche Inc., Nutley, NJ
48 Mean % Change in BMD (95% Cl) BMD Changes: 30-Minute vs 60-Minute Postdose Fast With Ibandronate-Sodium730-minute postdose fast60-minute postdose fast654Mean % Change in BMD (95% Cl)321Spine (L1-L4)TrochanterTotal HipFemoral NeckAlthough significant vs baseline, the BMD gains seen in the 30-minute postdose fast group were inferior to those seen in the 60-minute postdose group.Tankó LB, et al. Bone. 2003; 32:
49 Efficacy Testing Of Anti-osteoporosis Drugs The FDA-mandated primary outcome measures (end point) for all pivotal trials is the demonstration of efficacy in reducing vertebral fracture Non-vertebral fractures, BMD and bone remodeling markers are secondary end points Secondary end points are never statistically powered in terms of patient numbers to detect differences between placebo and drug
50 Non-Vertebral Fractures Multiple non-vertebral sites, the definition of which varies across clinical trialsHeterogenous group of bones, with different proportions of cortical and cancellous boneDifferences in non-vertebral fracture incidence and disease severity in placebo groups
51 Conclusions Characterized by a loss of bone mass and architecture Inevitable consequence of aging in both sexesAccelerated following menopause, disease and drugsEarly detection and intervention is mandatoryFracture stratification allows identification beyond BMDBisphosphonates are the mainstay of therapyEnsuring compliance through less complex dosing should lead to greater therapeutic benefit
52 Fracture Risk Reporting Since the goal of osteoporosis therapy is fracture prevention, patient selection is best based on fracture riskT-score alone does not provide a complete assessment of fracture riskCombination of clinical risk factors with BMD may provide a better way of identifying patients for treatment
53 Selection of Clinical Risk Factors Independent of BMD (if BMD is known)Validated in multiple populations (sex, ethnicity, country)Easily obtainableAmenable to intended treatmentIntuitiveAdapted from Kanis JA et al. Osteoporos Int. 2005;16:
54 Clinical Risk Factors Femoral neck T-score + Age Previous low trauma fractureCurrent cigarette smokingRheumatoid arthritisHigh alcohol intake (> 2 units/day)Parental history of hip fracturePrior or current glucocorticoid useAdapted from Kanis JA et al. Osteoporos Int. 2005;16:
55 Intervention Threshold A fracture probability above which it is cost-effective to treat with pharmacological agentsBased on statistical modeling using many medical, social, and economic assumptions