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 Strategies
SCREEN AND INTERVENE Evidence-Basis for Patient Screening
and Risk Stratification: Principles for Approaching a Broad Population of Patients at Risk for Osteoporosis

2. Program Contents Definitions Epidemiology Pathophysiology
Clinical Features
Diagnosis
Therapy

3. Definition
Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture1
Current NIH definition: Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk for fracture1
These 3-D micro-CT bone scans of lumbar spine biopsies illustrate the microscopic changes in bone architecture that are characteristic of osteoporosis2
Normal trabecular bone of a 52-year-old female, shown on the left, appears as a dense network of thick trabeculae with small open spaces2
Osteoporotic 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 struts2
References
NIH 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 rapid
prototyping 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 menopause
Low bone mass coupled with micro-architectural deterioration leading to enhanced bone fragility and ultimately fracture

5. Risk Factors You Can’t Change

6. Contents
Epidemiology
Prevalence
Incidence
Sites
Cost
Status of care

7. Prevalence 44 million Americans have or are at risk of osteoporosis
55% of all people ages 50 years
10 million have osteoporosis
34 million more have low bone mass
50% of women aged 50 years will experience a fracture in their lifetime
Prevalence is expected to increase with the growth of the elderly population

8. Prevalence of Osteoporosis Will Increase With an Increasing Aging Population20
1900
1950 15 %
1985
Projected
2020
Population 10
>65 Years
With an expanding elderly population, osteoporosis and the subsequent risk for fracture are expected to increase dramatically
Bone 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.4
Over 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.5,7 5
Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994: US Census Bureau

9. Osteoporotic Fracture Incidence Is High
1,600,000
1,400,000
1,200,000
1,000,000
Cases/Year
800,000
600,000
400,000
200,000
Breast
Heart
Osteoporotic
Cancer
Disease
Fractures
Women’s Health Facts and Figures. Washington, DC: ACOG; 2000.

10. Distribution of Fractures
Vertebral
46%
(700,000)
Wrist
16%
(250,000)
Hip
19%
(300,000)
Other
NIH/ORBD National Resource Center. October 2000.

11. Estimated $13.8 billion/year
High Economic Burden
Estimated $13.8 billion/year
Hospitalization ($8.6)
Outpatient ($1.3)
Nursing
Home
($3.9)
Ray NF et al. J Bone Miner Res. 1997;12:24-35.

12. Current Status of Care
3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated
3% of wrist fracture patients receive BMD testing
Only 12% of vertebral fractures are diagnosed and 2% are treated
Freedman 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. Content
Pathophysiology
Bone Remodeling
Types of Osteoporosis

14. The Bone Remodeling Cycle
Osteoclast
Osteoblast
Osteoblast
Recruitment
Resorption
Mineralization
Parathyroid 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:
Osteoid
Deposition
Courtesy: Dr. Mone Zaidi

15. Disordered Bone Remodeling as the Cause of Osteoporosis
High Remodeling
Hypogonadal (including post-menopausal)
Hyperparathyroidism
Hyperthyroidism
Others
Low Remodeling
Involutional (Aging)
Glucocorticoids (high dose)
HIV

16. Pathogenesis of Osteoporoses Resorption Must Exceed Formation
Normal Remodeling
Osteoclast Overactivity
Hypogonadal States
Parathyroid and Thyroid
Parathyroid 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 Dysfunction
Involutional (Aging)
Glucocorticoids
HIV
Courtesy: 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 unrecognized
Associated with
Deformity, height loss, back pain
Morbidity and mortality
Predict future vertebral and non-vertebral fractures
Vertebral fractures remain undetected in clinical practice and are a major cause of mortality and morbidity
Almost 20% of patients with a prevalent vertebral fracture experience an additional fracture within a year
Early detection is critical
Vertebral 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 involved
Wrist
Ankle
Pelvis
Humerus
Rib
Others
Associated with significant disability
Fractures 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 activities
According 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.8
Like 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 independence
50% do not regain previous mobility
Mortality is high
1 in 5 patients die within 1 year
Patients not treated for osteoporosis
Hip fracture is the most devastating consequence of osteoporosis, with a high rate of morbidity and mortality
Although hip fracture is easily detected, less than 5% of patients are actually referred for medical evaluation and treatment
Hip 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.3
NIH Consensus Development Panel. JAMA. 2001;285:

21. Risk of Fracture All postmenopausal women with the following: Low BMD
Fracture after 50 years
Age 65 years
Maternal history of fracture after 50 years
Low body weight (125 lb)
Smoking
Corticosteroid use
Other secondary causes
Postmenopausal women with low BMD and an existing fracture after age 50 are the most at risk for fracture
Identification of all other risk factors is critical for early diagnosis
A 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.19
The 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.21
Other secondary causes of osteoporosis include hypogonadism, anorexia nervosa, type 1 diabetes, pregnancy, hyperparathyroidism, acromegaly, chronic liver disease, alcoholism, and rheumatoid arthritis.1
Black DM et al. Osteoporosis Int. 2001;12:

22. A Fracture Begets a Future Fracture Future Fractures (Fold Increase)
Existing Fracture
Wrist
3.3
1.4 -
Vertebral
1.7
4.4
2.5
Hip
1.9
2.3
Wrist
Vertebral
Hip
History of prior fracture at multiple sites has been associated, in the literature, with an increased risk of subsequent fractures
In 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 fracture
They 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)
Reference
Klotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk of
future 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 factors
Low BMD
Presence of a fracture after 50 years
Risk for fracture increases
With number of risk factors
With each subsequent fracture

24. Content Diagnosis Clinical Assessment Diagnostic Criteria
Bone Densitometry

25. Clinical Evaluation History Physical Tests Risk factor assessment
Medical history
Family history
Social history (smoking, alcohol)
Evaluation of fall risk
Physical
Height loss >1.5 inches
Kyphosis
Tests
BMD
X-ray of thoracic/lumbar spine
Bone turnover markers
Laboratory tests as necessary
Extensive clinical evaluation for fracture risk is essential for all postmenopausal women
Evaluation comprises patient history assessment (risk factors, medical and social history), physical exam, and x-ray/BMD scan
All 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.1
AACE Guidelines. Endocr Pract. 2001;7:

26. Kyphotic vs. Non-Kyphotic
The Kyphotic Woman
The Non-Kyphotic Woman
Likely has osteoporosis and vertebral fractures
Confirmatory spinal x-ray for diagnosis
Baseline BMD
Spinal x-ray or DXA if height loss >1.5 inches
Atraumatic vertebral fractures = osteoporosis a
Kyphosis (convexity of the spine) may be indicative of osteoporosis
Diagnosis 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.

27. Diagnosis BMD Criteria: Low T-Score
Non-BMD Criteria: Fragility Fracture

28. WHO Diagnostic Criteria
The WHO Study Group. Geneva, 1994
T-Score* Classification
> Normal
-1.0 to -2.5 Osteopenia
< -2.5 or lower Osteoporosis
< fracture Severe osteoporosis
The World Health Organization (WHO) defines a T-score of -2.5 or lower as indicative of osteoporosis
The 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 standard
WHO criteria applied
Risk Assessment/ Research
Peripheral DXA (pDXA)
Ultrasound
Quantitative computed
tomography (QCT)
Central DXA is the “gold standard” for diagnosis of osteoporosis
Peripheral devices are less sensitive and restricted to fracture risk assessment
Central 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.10
Quantitative 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.10
Ultrasound 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.15
National Osteoporosis Foundation. Washington, DC; 1999.

30. Central vs Peripheral DXA
Central DXA
Establish or confirm diagnosis
Assess fracture risk
Follow up
Enhance patient compliance
Peripheral DXA
Different from WHO T-score criteria
Fracture risk assessment in elderly with low T-scores
Central DXA is a major diagnostic tool
Other applications include assessment of fracture risk, serial BMD changes, and increased patient compliance
In 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.1,10
Second, 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.1
Lastly, 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

31. Content Therapeutic Considerations Mode of Action
Anti-resorptive Agents
Anabolic Agents
Bisphosphonate Failure
Efficacy Testing

32. Goals for Therapy Fracture prevention Stabilize or increase bone mass
Provide tolerability and long-term safety
Ensure compliance and adherence
Rapid and sustained prevention of fracture is the major goal of osteoporosis treatment
Because 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.9
In 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.43,44
The 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 intake
Diet and/or supplementation: 1200 mg/day
Vitamin D supplementation
Diagnose and treat deficiency/insufficiency
Supplement: IU/day
Regular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low)
Fall prevention advice
Home safety evaluation
Dietary and lifestyle changes are useful approaches to prevent osteoporotic fractures
Patient 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.48,49
Other 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.28
Fractures 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
Yes No
Yes No
Calcitonin (Miacalcin®)
Yes
Raloxifene (Evista®)
Yes
Alendronate (Fosamax®)
Risedronate (Actonel®)
Yes
Yes
Of the currently available therapies, risedronate, alendronate, and raloxifene are the only agents approved for prevention and treatment of osteoporosis
This program will review the clinical evidence on fracture reduction for available osteoporosis therapies in randomized, controlled, preplanned studies
Five 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.28,29
The 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.
Yes
Ibandronate (Boniva®)
Yes
Ibandronate Injection
(Boniva®)
Yes *
Parathyroid hormone
(Forteo®)
*Not considered.

35. Osteoporosis Therapeutics
Decrease Resorption
Enhance Formation
Parathyroid Hormone
Bisphosphonates
Estrogen
Raloxifene
Calcitonin

36. Anti-Resorptive Versus Anabolic
High Turnover Bone Loss
Low Turnover Bone Loss
Parathyroid 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 - Anabolic
Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

37. PTH Mode of Delivery = Bone Activity Intermittent versus Continuous =
Osteoblastic versus Osteoclastic
Formation versus Resorption
Bone Gain versus Bone Loss
Tam 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 Action
Receptor Binding and
Signal Transduction
Increased Osteoblast
Survival
Enhanced Osteoblast
Differentiation
Although 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 and
Activity of Bone-Forming
Osteoblasts

39. Calcitonin
Courtesy: 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 marrow
Does not inhibit the activity of mature resorbing osteoclasts
Osteoclast birth increases exponentially to a peak within the first few years of the menopausal transition
Maximum bio-efficacy in early menopause and declines with age and disease severity/fractures
Zaidi, M., et. al. (2001) Journal of Bone and Mineral Research.

42. Structure of BisphosphonatesOH R1 OH OH OH
O = P – C – P = O
O = P – O – P = O OH R2 OH OH OH
Bisphosphonate
Polyphosphate

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 ADHERENCE
Disruption to daily routine?
(less frequent dosing)
Concern about side effects?

45. Adherence With Osteoporosis Medications Is Poor30 25 20 15 10 5
26%
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 Fracture
12.6% 14 * 12
9.4% 10 8 6 4 2 †
Compliant
Noncompliant
(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 Weekly
P<0.001 vs daily therapy 10 20 30 40 50 60 70 80 90
100
Oct 2002
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct 2003
Patients 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-Sodium 7
30-minute postdose fast
60-minute postdose fast 6 5 4
Mean % Change in BMD (95% Cl) 3 2 1
Spine (L1-L4)
Trochanter
Total Hip
Femoral Neck
Although 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 trials
Heterogenous group of bones, with different proportions of cortical and cancellous bone
Differences 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 sexes
Accelerated following menopause, disease and drugs
Early detection and intervention is mandatory
Fracture stratification allows identification beyond BMD
Bisphosphonates are the mainstay of therapy
Ensuring 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 risk
T-score alone does not provide a complete assessment of fracture risk
Combination 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 obtainable
Amenable to intended treatment
Intuitive
Adapted from Kanis JA et al. Osteoporos Int. 2005;16:

54. Clinical Risk Factors Femoral neck T-score + Age
Previous low trauma fracture
Current cigarette smoking
Rheumatoid arthritis
High alcohol intake (> 2 units/day)
Parental history of hip fracture
Prior or current glucocorticoid use
Adapted 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 agents
Based on statistical modeling using many medical, social, and economic assumptions