1. Osteoporosis Review

2. Osteoporosis “Silent disease” until complicated by fractures
Most common bone disease in humans
Characterized by:
Low bone mass
Microarchitectural deterioration
Compromised bone strength
Increased risk for fracture
Want to treat before manifests symptoms
Bone mass only part of the picture—other factors into play

3. Failure To Diagnose and Treat
Studies show failure to diagnosis and treat osteoporosis in older patients who have suffered a fracture
In 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 medications
US Department of Health and Human Services: Bone Health and Osteoporosis: A Report of the Surgeon General, Office of the Surgeon General, 2004.

4. Risk Factors Major Additional History of fracture as an adult
Fragility fracture in first degree relative
Caucasian/Asian postmenopausal woman
Low body weight (< 127 lb)
Current smoking
Use of oral corticosteroids > 3 mo.
Additional
Impaired vision
Estrogen deficiency at early age (< 45 YO)
Dementia
Poor health/frailty
Recent falls
Low calcium intake (lifelong)
Low physical activity
> 2 alcoholic drinks per day
Many of these are nonmodifiable. Already working against you.

5. Factors Associated with Bone Loss in Men
Genetics
Smoking/alcohol
Calcium intake
Physical activity/strength
Testosterone production
Estrogen production
Hypogonadism is best-characterized risk factor for osteoporosis and osteoporotic fractures in men. Other risk factors same as women.

6. Medical Conditions Associated with Increased Risk of Osteoporosis
COPD
Cushing’s syndrome
Eating disorders
Hyperparathyroidism
Hypophosphatasia
IBS
RA, other autoimmune connective tissue disorders
Insulin dependent diabetes
Multiple sclerosis
Multiple myeloma
Stroke (CVA)
Thyrotoxicosis
Vitamin D deficiency
Liver diseases
50,000 IU weekly for six weeks
Higher-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

7. Drugs Associated with Reduced Bone Mass
Aluminum
Anticonvulsants
Cytotoxic drugs
Glucocorticosteroids (oral/high dose inhaled)
Immunosuppresants
Gonadotropin-releasing hormone (e.g. Lupron)
Lithium
Heparin (chronic use)
Supraphysiologic thyroxine doses
Aromatase inhibitors
Depo-Provera
Anticonvulsants—inhibit vitD metabolism
Thyroxine- keep towards upper end of normal
Not an inclusive list

8. Risk Assessment/Diagnosis
After menopause, all women should be evaluated clinically for osteoporosis risk to determine need for BMD testing
50-60% of men with osteoporosis have disorders known to reduce bone loss, such as hyperparathyroidism, intestinal disorders, malignancies, conditions resulting in immobilization
BMD recommended in men with known risk factors and who have lost > 1.5 inches in height
Diagnosis can be established in patients who have never had a fragility fracture by BMD measurement

9. World 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 sex
BMD = Bone mineral density SD = Standard deviation
*Measured at the hip, spine, or wrist
OP 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 fractures
Z-score: compares your score to age, sex, race-matched people. If don’t look like peers, look into secondary cause.

10. Who Should be Tested?
Decision to test based on individual risk profile, never indicated unless results influence treatment decision
BMD 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 OP
Individuals w/vertebral abnormalities
Individuals receiving or planning to receive long-term steroid therapy
Individuals w/primary hyperparathyroidism
Individuals being monitored to assess response or efficacy of an approved OP drug therapy
Recommendations and focus will be on women—will cover men towards end of the talk.
*Medicare permits repeat BMD testing every 2 years.

11. NOF – 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 older
Dramatically alters approach to assessing fracture risk and treatment
Will help identify people at high risk for developing osteoporosis/fractures and ensure appropriate treatment
Uses absolute fracture risk methodology to enhance treatment decisions to individualize plan for each patient

12. NOF’s Clinician’s Guide
Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHO
Also called 10-year fracture risk model and 10-year fracture probability
Estimates the likelihood of a person to break a bone due to low bone mass over a period of 10 years
Most useful to determine if treatment needed for those with low bone mass or osteopenia

13. Universal Recommendations
Adequate intake of calcium, vitamin D
Weight-bearing and muscle-strengthening exercises to reduce risk of falls/fracture
Provide strategies for fall prevention
Avoidance of tobacco use/excessive alcohol use
Talk to your provider about bone health
Have a bone density test and take medication when appropriate
Several interventions to reduce fracture risk can be recommended to the general population.

14. Adequate Intake of Calcium/Vitamin D
Adequate intakes of dietary calcium and vitamin D, including supplements if necessary
Elemental calcium per day (> 50 YOA) = at least mg
Vitamin D3 per day (> 50 YOA) = international units (IU)
Vitamin D3 (cholecalciferol) plays major role in Ca absorption
Controlled clinical trials have demonstrated the combination reduces fracture risk
Inexpensive, well-tolerated
Safe upper limits of Ca/day = 2500 mg
D = 2000 IU

15. Calcium/D Product Selection
Product (% elemental Ca)
Elemental Calcium (mg)
Vitamin D (units)
Comments
Calcium carbonate (40)
-Tums Ultra
-Caltrate 600 Plus
-Oscal Plus D
-Viactiv Chews
400
600
500
200
125
100
Requires 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 VitD
315
Take without regard to meals. Serving size usually equals 2 capsules so label can be misleading to patients.
Vitamin D
-Multivitamin (D3)
-Vitamin D
Some products also come in chewable, liquid, dissolvable tablet.

16. Vitamin D and Fall Risk
In addition to its effect on BMD, may contribute to reduction in fracture risk
Improved muscle function
Reduction in risk for falls
Meta-analyses of 5 clinical trials (> 60 YOA) showed significant reduction in risk for falling in those taking vitamin D plus calcium versus those taking placebo
Vitamin D deficiency prevalent in older adult population
Inadequate sun exposure, use of sunscreen
Homebound, institutionalized
Northern latitudes
Maintain 25-hydroxyvitamin D3 at least > 40 ng/mL
Treatment: 50,000 IU vitD weekly x 6-8 weeks, then assess need for chronic monthly therapy
A 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

17. Regular Weight-Bearing Exercise
Defined as those in which bones and muscles work against gravity as feet and legs bear the body’s weight
Include walking, jogging, Tai-Chi, stair climbing, dancing, tennis, yoga
Improve agility, strength, balance
May increase bone density modestly, reduce fall risk, enhance muscle strength, improve balance

18. Avoidance of Tobacco and Alcohol
Tobacco products detrimental to skeleton, overall health
NOF strongly encourages tobacco cessation programs as osteoporosis intervention
Excessive alcohol intake also detrimental to bone health and requires treatment
Negative estrogen effects

19. Who 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 spine
Prior vertebral or hip fracture
Low 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 algorithm
Lost 1 ½ inches of height

20. FDA-Approved Drugs for Osteoporosis
Bisphosphonates
Alendronate, 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)

21. Bisphosphonates – Antiresorptive Agents
Agents FDA-approved for:
Prevention and treatment of osteoporosis in postmenopausal women
Treatment to increase bone mass in men with osteoporosis
Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids
Treatment of Paget’s disease of bone in men and women
Mechanism: inhibits bone resorption by attaching to bony surfaces undergoing active resorption and inhibiting action of osteoclasts
Leads to increases in bone density and reduced fracture risk
Treatment 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 women
The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not
receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily.
Paget’s disease of bone in men and women
The recommended treatment regimen is 40 mg once a day for six months.

22. Bisphosphonates – 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 period
Ibandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year period
Alendronate appears to be well tolerated and effective for at least ten years
Alendronate 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 [29]. 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) [30]. 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).

23. Bisphosphonates – Dosing
Alendronate*
Prevention
5 mg PO daily
35 mg PO weekly
Treatment
10 mg PO daily
70 mg PO weekly
70 mg/2,800 IU vitamin D PO weekly
Risedronate
Prevention/Treatment
Ibandronate
Prevention/Treatment
2.5 mg PO daily
150 mg PO monthly
Treatment
3 mg IV every 3 months
*Alendronate also available in oral solution.

24. Bisphosphonates – 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 day
Tablet 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

25. Bisphosphonates – Adverse Effects
Hypocalcemia (18%)
Hypophosphatemia (10%)
Musculoskeletal pain, cramps – recent FDA warning
Gastrointestinal
Abdominal pain
Acid reflux
Dypepsia
Esophageal ulcer
Gastritis
Osteonecrosis of the jaw (IV bisphosphonates)
Visual disturbances (rare)
First two transient, mild
GI 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.

26. Bisphosphonates Contraindications/Precautions
Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia
Inability to stand or sit upright for at least 30 minutes
Patients at increased risk of aspiration
Hypocalcemia
Should be corrected prior to initiating therapy
Renal insufficiency (Not recommended if CrCl < ml/min)
Achalasia=Failure of muscle bands to relax
GERD not an absolute contraindication. Weigh pros/cons.

27. Bisphosphonates – Missed Dose
Once weekly alendronate, risedronate
Take on morning after remembering, then resume once weekly on regularly chosen day
Once monthly ibandronate
If next dose > 7 days away, take dose the morning following the date remembered
Then return to original schedule
If next dose < 7 days away, wait until next scheduled dose
Must not take two 150 mg tablets within the same week

28. Zolendronic Acid (Reclast®)
Approved for treatment of osteoporosis in postmenopausal women in August 2007
Single 5 mg infusion given IV over > 15 minutes, once yearly
Should still supplement with calcium/vitamin D
May be ideal for those with GI contraindications to the oral formulations

29. Price Comparison Drug Price Alendronate (Fosamax®) 10 mg once daily
70 mg once weekly
70 mg/2800 IU weekly
30 day supply: $72.99
30 day supply: $32.99 (generic)
30 day supply: $79.70
Risedronate (Actonel®)
5 mg once daily
35 mg once weekly
30 day supply: $65.99
30 day supply: $63.99
Ibandronate (Boniva®)
2.5 mg once daily
150 mg once monthly
30 day supply: $75.99
Check formulary

30. Bisphosphonates
Very well tolerated in patients who adhere to proper administration techniques
Proper patient counseling for correct administration is KEY to reduce risk of adverse effects and increase tolerability
Place in Therapy: should be considered first-line for prevention/treatment of osteoporosis in patients with no contraindications

31. SERMs – Raloxifene FDA-approved for:
Prevention and treatment of osteoporosis in postmenopausal women
Mechanism: tissue-selective activity, acts as an estrogen agonist on bone
Estrogen antagonist on breast, uterus
decreases total and LDL-cholesterol but does not raise triglycerides
Osteoporosis — 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 [42], 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)

32. Raloxifene – Clinical Efficacy
Reduces risk of vertebral fracture by 30% in patients with previous spinal fracture, 55% in patients without prior spinal fracture over 3 years
Increases BMD at all skeletal sites and reduces total and LDL cholesterol
Less potent antiresorptive agent than bisphosphonates, although direct comparison studies lacking
Role in heart disease, breast cancer under investigation
decreased 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

33. Raloxifene – Dosing/Administration
For prevention and treatment
60 mg PO once daily
Can be taken any time of day without regard to meals
Should supplement with calcium/vitamin D if dietary intake inadequate

34. Raloxifene – Adverse Effects
Frequency > 10%
Hot flashes
Arthralgias
Sinusitis
Frequency 1-10%
Chest pain
Insomnia
Migraines
Peripheral edema
Diaphoresis
**Has been associated with increased risk of thromboembolism (DVT, PE) and superficial thrombophlebitis; risk is similar to reported risk of HRT

35. Raloxifene Contraindications/Precautions
History of DVT/PE or at high risk
Cardiovascular disease
History of uterine/cervical carcinoma
Discontinue at least 72 hours prior to and during prolonged immobilization
Price
30-day supply = $86.99
No generic available

36. Raloxifene
Place in Therapy: considered first-line in women who cannot tolerate bisphosphonates and have no contraindications to therapy
Combination therapy (usually a bisphosphonate with a non-bisphosphonate) can provide additional small increases in BMD when compared to monotherapy
Impact of combination therapy on fracture rate unknown

37. Estrogen/Hormone Therapy (ET/HT)
FDA approved for:
Prevent osteoporosis
Treatment of moderate/severe vasomotor symptoms of menopause
Treatment of moderate/severe symptoms of vulvar and vaginal atrophy associated with menopause
Consider topical preparations to treat vaginal symptoms rather than oral ET/HT

38. FDA Recommendations – ET/HT
When prescribing medications for osteoporosis, physicians should consider all non-estrogen therapies first
When prescribing ET/HT, use smallest dose for shortest amount of time to achieve treatment goals
Prescribe ET/HT products only when benefits believed to outweigh risks for a specific patient

39. Calcitonin FDA-approved for: Mechanism:
Treatment of osteoporosis in women who are > 5 years postmenopausal
Treatment of Paget’s disease of bone
Adjunctive therapy for hypercalcemia
Mechanism:
Peptide composed of 32 amino acids which binds to osteoclasts and inhibits bone resorption
Promotes the renal excretion of calcium, phosphate, sodium, magnesium and potassium by decreasing tubular reabsorption
Calcitonins 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.

40. Calcitonin – Clinical Efficacy
Has been shown to increase spinal bone mass and may decrease risk of vertebral fracture
Conflicting data on efficacy of calcitonin at sites other than the spine
Less effective than bisphosphonates in treatment of osteoporosis
Beneficial, 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

41. Calcitonin – Dosing/Administration
Intranasal
200 units (1 spray) alternating nares daily
Store unopened bottles in refrigerator, protect from freezing
Can store open bottles at room temperature for up to 35 days
Activate pump of new bottles until full spray produced (allow to reach room temperature before priming)
Each bottle contains at least 30 doses
IM/SQ
100 units/every other day (minimum effective dose not well-defined)
Should perform skin test prior to initiating therapy
Should supplement with calcium/vitamin D if dietary intake inadequate
intramuscular 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

42. Calcitonin – Adverse Effects
Most common:
Nasal spray: rhinitis (12%), irritation of nasal mucosa (9%), epistaxis (3.5%), sinusitis (2.3%), back pain, arthralgia, headache
Injection: nausea (10%), flushing (2-5%)
Temporarily withdraw use of nasal spray if ulceration of nasal mucosa occurs
Periodic nasal examinations recommended
Demonstrated with long-term use of calcitonin in Paget's disease, is the development of antibodies and resistance to calcitonin [1]. 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.

43. Calcitonin Contraindications Precautions Drug interactions
Clinical allergy to calcitonin-salmon
Precautions
Nasal ulcerations
Tachyphylaxis (parenteral dosage forms)
Drug interactions
No formal studies designed to evaluate DI
Price per month
200 units/mL (2): $42.08
200 units/ACT (3.7): $81.59

44. Calcitonin
Valid option for treatment of established osteoporosis, especially when accompanied by fracture pain
Place 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 therapy
Place in therapy:
Use for vertebral fracture pain if needed, other analgesics may be acceptable alternatives
Not recommended for prev/treatment, in general
May be synergistic with agents that inhibit bone resorption. May be used in combo.

45. Parathyroid Hormone [PTH (1-34)] Anabolic agent
FDA-approved for:
Treatment of osteoporosis in postmenopausal women at high risk for fracture
previous osteoporotic fracture, multiple risk factors for fracture, extremely low BMD (< -2.5), or failed/intolerant to previous treatment
Treatment of primary or hypogonadal osteoporosis in men at high risk of fracture
Mechanism: recombinant formulation of endogenous parathyroid hormone (PTH)
stimulates osteoblast function, increases gastrointestinal calcium absorption, increases renal tubular reabsorption of calcium
Enhances bone turnover by initiating greater bone formation
Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and
phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of
bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium
absorption. The biological actions of PTH and teriparatide are mediated through binding to
specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of
PTH bind to these receptors with the same affinity and have the same physiological actions on
bone 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.

46. PTH (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 months
Increases lumbar spine BMD as well as at the femoral neck, total hip, and total body
Safety, efficacy of PTH (1-34) has not been demonstrated beyond 2 years of treatment
All 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.

47. PTH (1-34) – Dosing/Administration
20 µg SQ once daily for treatment of osteoporosis
Thigh or abdominal wall
Forteo® prefilled pen contains 28 daily doses
Important to read Medication Guide and User Manual before starting and each time medication refilled
Should be administered initially under circumstances where the patient can immediately sit or lie down, in the event of orthostasis (dizziness, palpitations are transient)

48. PTH (1-34) – Adverse Effects
Most common
Dizziness, rash, nausea, headache, leg cramps, arthralgia, rhinitis, transient hypercalcemia
S/s of hypercalcemia: nausea, vomiting, constipation, low energy, or muscle weakness
Most adverse effects in the clinical trials were mild and generally did not lead to the discontinuation of the drug
Osteosarcoma risk in animals
Lead to black box warning by FDA
None 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 [38]. 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.

49. PTH (1-34) – Warnings/Precautions
Increased risk of osteosarcoma (rats) – clinical relevance unknown (no excess reports in humans)
Avoid in:
Paget’s disease of bone
Prior radiation therapy to skeleton
Bone metastases
Hypercalcemia
History of skeletal malignancy
Pregnant/nursing

50. PTH (1-34) – Price One-month supply $539.99
Lilly offers Forteo® Patient Assistance Program for Medicare-eligible (LillyMedicareAnswers) and non-Medicare eligible patients
LillyMedicareAnswers intended for patients who are enrolled in any Medicare Part D prescription drug plan and who meet certain eligibility requirements
Expected to start early 2007
For non-Medicare patients, application process includes paper application and income restrictions
Call or visit for more details
For 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.

51. PTH (1-34)
Due to safety concerns, PTH treatment should be limited to those most severely affected and for a maximum of two years
Combination therapy with a bisphosphonate not recommended as effects do not appear additive
Cost, daily SQ injection may be prohibitive for some patients
It 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

52. PTH (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 therapy
In patients considered to be bisphosphonate "failures," PTH may be started approximately 3 months after bisphosphonates are discontinued
Antiresorptive 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

53. Approaches to Monitoring Therapy
Always important to ask patients about adherence, encourage continuation of therapies to reduce fracture risk
Monitoring of therapy should be considered, as up to 1/6 of women taking effective therapies continue to lose bone, especially if they smoke
May measure bone mineral density at a single site after one year of therapy, but results may be misleading; usually done every 2 years
Drugs may decrease a patient’s risk for fracture even when there is no apparent increase in BMD
Biochemical 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.

54. Glucocorticoid-Induced Osteoporosis – Recommendations
ACR recommends the following interventions in patients taking prednisone doses of 5 mg/day or higher for more than 3 months
Calcium/vitamin D (1500mg/day, 800 IU/day)
Weekly formulations of bisphosphonate therapy
Replacement of gonadal steroids in men, if deficient
Calcitonin therapy, if bisphosphonates contraindicated or not tolerated
Follow BMD to assess if bone loss continues

55. How 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 disorders
Recognize risk factors that warrant osteoporosis screening
Assess diet/lifestyle for effect on bone health
Advise patients to take active steps to ensure bone health
Be familiar with treatment of osteoporosis/low bone mass
Actively look for other bone disease that can lead to bone loss/fractures

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57. References JAMA 2004;291(16):1999 J Clin Densitom 2004;7(1):1-6
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