1. Osteoporosis Part 3 of 3: Treatment
Hello, my name is Clare Kennedy. I am a physician assistant with academic and clinical training in Geriatrics and osteoporosis management. I’d like to welcome you to Osteoporosis module three in our study of geriatrics. This series has been divided into three modules. If you have not completed Module 1 and 2 , please close out of this module and do Module 1 and 2 at this time then return and do Module 3. Our process will be for you to complete these modules in sequence. We hope you will enjoy these modules.
Ellen Davis-Hall, PhD, PA-C
Professor
Clare J. Kennedy, MPAS, PA-C
Assistant Professor, PA Program
SAHP , COM
UNMC
Omaha, NE.
office:

2. PROCESS Series of modules and questions
Step #1: Power point module with voice overlay
Step #2: Case-based question and answer
Step # 3: Proceed to additional modules or take a break
Our process will be to review the topic with PowerPoint modules with voice overlay. This will be followed by a case based questions with answers to explain the right and wrong answers. Then you will need to complete the evaluation to receive credit for the unit. The learner is recommended to complete a module before disengaging. When the module and questions are completed click on “Mark Reviewed” on the main page of the minifellowship to indicate your completion.

3. Objectives
Part 1: Identify risk factors for osteoporosis with an emphasis on modifiable risk factors
Part 2: Describe the most current methods of, and standards for, diagnosis and monitoring of treatment
Part 3: Describe the available treatment modalities for osteoporosis and their effectiveness
The objectives for this topic are to Identify risk factors for osteoporosis with an emphasis on modifiable risk factors; describe the most current methods of, and standards for, the diagnosis of osteoporosis and monitoring its treatment; and to describe the available treatment modalities for osteoporosis and their effectiveness. The third part of this presentation will address this final objective.

4. Drug Therapy Options for Osteoporosis
Antiresorptive agents
Anabolic agents
Once the diagnosis of osteoporosis is made, a plan of treatment needs to be decided upon. We have already talked about the importance of vitamin D, calcium, exercise and life style modification.
There are two types of drug therapy for osteoporosis: antiresorptive agents and anabolic agents
Let’s look at antiresorptive agents first.

5. Antiresorptive Agents
Bisphosphonates
Estrogen
Selective estrogen receptor modulators (SERMs)
Calcitonin
There are four classes of antiresorptive therapies: bisphosphonates, estrogen, selective estrogen receptor modulators (SERMS), and calcitonin. All of these types of drugs decrease bone loss by decreasing the activity of osteoclasts (the cells responsible for resorption or breakdown); stabilize the microarchitecture of the bone, decrease bone turnover….all these things result in fracture reduction. BMD is increased because the resorption spaces in bone get filed in with new bone, and the amount of mineral in the bone increases. This therapy should be considered for all patients with osteoporosis. Now lets look at each of these drugs in more detail….

6. Bisphosphonates- Non-hormone Compounds
Alendronate (Fosamax)
Risendronate (Actonel)
Ibandronate (Boniva)
Three bisphosphonates are currently available for treatment in the US. We will discuss only the first two in detail, since the newest addition has minimal data at this time. These drugs bind to the bone and are taken up by osteoclasts. They block the pathway that leads to production of certain essential lipid compounds inside the osteoclasts…..leading to an early death of these cells and a decreased ability for osteoclasts to cause bone loss.

7. Alendronate (Fosamax) Research
Spinal BMD increases of 6-8%, and hip increases of
3-6% over three years. (Black, et al 1996)
50% reduction in fracture risk for spine, hip and wrist (Cranney et al 2002a)
Benefits seen as early as 1 year for spinal fractures and 18 months for hip fractures (Black et all 2000)
95% of women who take alendronate maintain or increase bone mass (Black et al, 2000)
Benefits seem to continue even 2 years after med is stopped (Tonino et al, 2000)
Also approved for treatment of male osteoporosis and prevention of steroid induced osteoporosis
This drug has been used for 10 years and seems to be safe and effective for that period of use.
It has been shown to increase BMD by 6-8% at the spine and 3-6% at the hip over a three year period in post menopausal women with osteoporosis. These increases in BMD are associated with 50% reduction in fracture risk for spine, hip and wrist. Benefits can be seen as early as 1 year for spinal fractures and 18 months for hip fractures. Black has demonstrated that 95% of women who take alendronate maintain or increase bone mass. Benefits seem to continue even 2 years after the medication is stopped and we now think even longer. It is also approved for treatment of male osteoporosis and prevention of steroid induced osteoporosis. The dosage for prevention is 5 mg/day or 35 mg/week; and for osteoporosis treatment, it is 10 mg/day or 70 mg/week.

8. Risedronate (Actonel) Research
Increases BMD and reduce fracture risk significantly
Increases spine BMD by approximately 5% and hip BMD by 2-3% (Harris et al, 1999)
41% reduction in spine fractures; 39% reduction in non-spine fractures; and 30% reduction in hip fractures (Harris et a, 1999; McClung et al, 2001)
Reductions in spine fractures can be seen after one year of therapy (Harris et al, 1999)
Approved for treatment of osteoporosis, osteopenic post-menopausal women, and prevention and treatment of steroid induced osteoporosis
Studies of this drug have been conducted for 5 years and it seems to be safe and effective. Risedronate has been shown to Increase spine BMD by approximately 5% and hip BMD by 2-3% over 3 years in post-menopausal women with osteoporosis. Treatment is associated with a 41% reduction in spine fractures and a 39% reduction in non-spine fractures, and a 30% reduction in hip fractures. Reductions in spine fractures can be seen after just one year of therapy. It is approved to treat osteoporosis and prevent bone loss in osteopenic post- menopausal women, as well as to prevent and treat steroid induced osteoporosis. The approved dose is 5 mg./day or 35 mg/week

9. Ibandronate (Boniva) Research
Chesnut (2004)
Daily oral dose of 2.5 mg compared with “intermittent administration”
“Intermittent administration” consisted of 20 mg every other day for 12 doses given every three months
No difference was noted from placebo in regard to GI side effects
Vertebral fracture risk was reduced by 62% with daily dosing
Vertebral fracture risk was reduced by 50% with intermittent dosing
May hold promise as an effective and convenient alternative to current bisphosphonate therapies
Noting that there have been some patient difficulties with compliance when using bisphosphonates, the maker of this new drug has made an early effort to examine the effectiveness of intermittent versus daily dosing. Chesnut et al published their research in 2004 on this drug.

10. Clinical Advice for Bisphosphonate Use
Morning dosing, empty stomach, full glass of water
No food or other liquids other than water for 30 minutes
Should not lie down during this period
Proceed cautiously when prescribing to patients with:
known history of esophageal narrowing or ulcers of the esophagus
long term problems with stomach ulcer
heartburn that requires medication
Because all of these drugs are poorly absorbed, they should be taken first thing in the morning on an empty stomach with a full glass of water.
Food or liquids other than water should not be eaten for 30 minutes and patients should not lie down during this period. Providers should proceed cautiously when prescribing to patients with a known history of narrowing or ulcers of the esophagus, stomach ulcers and heartburn.

11. Hormone Therapy
In 1942 conjugated equine estrogen (CEE) was approved for the relief of menopausal symptoms
In 1972 use extended to postmenopausal osteoporosis
Early 1970s observation that estrogen was associated with an increased risk of endometrial cancer
PEPI (Postmenopausal Estrogen/Progestin Interventions, 1996) and HOPE (Women’s Health, Osteoporosis, Progestin, Estrogen, 2002) studies demonstrated that postmenopausal hormone therapy had a favorable effect on BMD at all sites
spine (3.5 to 7%)
hip (2 to 4%)
forearm (3 to 4.5%)
Increases apparent after 1 year use
No differences in estrogen formulations
Now we will proceed to the second class in our group of antiresorptive agents, hormones or more specifically, estrogen therapy. Estrogen is important throughout life to bone development and maintenance in both men and women. Unlike bisphosphonates, however, estrogen also acts on many reproductive and non-reproductive tissues throughout the body. Consideration must be given to these effects as well as possible risks.
Let’s discuss what we know about estrogen. First, let’s look historically…..In 1942 estrogen (Conjugated equine estrogen) was approved for the relief of menopausal symptoms. By 1972, estrogen use extended to postmenopausal osteoporosis. In the early 1970s it was observed that estrogen alone (without progestin) was associated with an increased risk of endometrial cancer. Generally use continued and the PEPI (Postmenopausal Estrogen/Progestin Interventions) trial and the HOPE (Women’s Health, Osteoporosis, Progestin, Estrogen) study demonstrated that postmenopausaqol hormone therapy has a consistent and favorable effect on BMD at all sites, including increases a the spine (3.5 to 7%), hip (2 to 4%), and forearem (3 to 4.5%) These increase become apparent after 1 year use and no significant differences found in effects of different estrogen formulations.

12. Estrogen and Fracture Risk
Research mostly observational studies
Meta-analyses suggest
Estrogen reduces the risk of non-spine fractures by 27%
Estrogen reduces the risk of spinal fractures by 33% (Torgerson and Bell-Syer, 2001)
Research on estrogen and fracture risk/prevention is more limited. Although fewer fractures are demonstrated, these have largely been observational studies and subject to biases. Meta-analyses by Torgerson and Bell-Syer, however, suggested that estrogen does reduce the risk of non-spine and spinal fractures significantly.

13. Women’s Health Initiative (WHI)
1990s: Trials designed to answer questions about hormones
Two separate trials:
women with an intact uterus
women post-hysterectomy
Treatment:
Intact uterus group treated with CEE and medroxyprogesterone (MPA)
Post-hysterectomy group treated with CEE alone
Hip and spine fractures were reduced by one-third in both groups
Other results:
increased risk of stroke, cognitive impairment, and deep vein thrombosis in the women taking HT
No clear cardiovascular benefit was found
Breast cancer risk was increased
(Cauley, et al, 2003)
Then the Women’s Health Initiative (WHI) hormone trials were designed in the 1990s to try to answer some of the existing questions.
There were two separate trials; one are for women with an intact uterus, and another for women post-hysterectomy. Intact uterus group was treated with conjugated equine estrogen ( CEE) and medroxyprogesterone (MPA) while the post-hysterectomy group treated with CEE alone. The positive effect on fracture reduction was dramatic; but other trial results tempered the benefit to bones. These findings noted an increased risk of stroke, cognitive impairment, and deep vein thrombosis in the women taking Hormone Therapy (HT) . No clear cardiovascular benefit was found and breast cancer risk was increased in women taking the combined therapy, causing that research arm to be discontinued. When these results were announced, it changed practice significantly.

14. Decision Factors in Hormone Use
Weigh known benefits against known risks
Hormone therapy still appropriate for women with osteoporosis who cannot tolerate other medications
Perimenopausal women currently advised to take lowest dose possible for as short a time as necessary to achieve treatment goals
Even low doses of hormones are effective at preserving bone density
No long term benefit exists once discontinued
Goal of hormone therapy: Capture positive effects without incurring deleterious effects
We now have several recommended decision factors in hormone use, all revolving around weighing known benefits against known risks. It may still be a necessary drug to treat osteoporosis in women who cannot tolerate other treatments. It is also still useful in perimenopausal management. We now know that there are positive benefits for bone even with small doses of hormones. Unfortunatley, unlike the bisphosphonates, there doesn’t appear to be any lastling benefits in regard to bone. Bone loss begins again when hormone therapy is withdrawn. Our goal for hormone therapy is to capture the positive effects of estrogen on bone without incurring any of the deleterious effects on other tissues.

15. Selective Estrogen Receptor Modulators (SERMs)
Called “designer estrogens”
Interact with estrogen receptors located throughout the body.
Provide benefits of estrogen without some of the negative effects (Ettinger et al, 1999)
Perhaps we are moving closer to this goal as we examine our next antiresorptive therapy, the SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS), These are the so-called “designer estrogens” that interact with estrogen receptors located throughout the body. They have been shown to provide some of the benefits of estrogen (improvement of BMD and cholesterol) without some of the negative side effects (such as breast tenderness and menstrual bleeding or spotting.

16. Raloxifen (Evista) Research
Spine BMD increased 2-3% and hip BMD by 2.5% after three years. (Ettinger et al, 1999)
Spine fractures reduced by 50%, but no effect was noted on hip or other non-spine fractures
(Ettinger et al, 1999, Cranney et al 2002)
Spine fracture reduction achieved at one year
(Maricic et al, 2002)
No long term fracture benefit once discontinued
Other potential benefits
decrease in total cholesterol and LDL
possible decreased incidence of breast Cancer
Raloxifene is the only FDA approved SERM for the treatment of osteoporosis. It has been shown to increase spine BMD by 2-3% and hip BMD by approximately 2.5% after three years. Spine fractures were reduced significantly, but interestingly enough, no effect was noted on hip or other non-spine fractures. Spine fracture reduction, however, is evident at one year. Like estrogen, the benefit only is derived while taking the drug.
Still there are other potential benefits which include decreases in total cholesterol and LDL, and a possible decreased incidence of breast Cancer There are ongoing studies in both of these areas.

17. Raloxifen Use
Approved for prevention and treatment of postmenopausal osteoporosis at a dose of 60 mg/day
Side effects:
a possible return or exacerbation of hot flashes
blood clots in the legs, and/or lungs.
Drug should be discontinued if the patient is immobilized for long periods of time
Raloxifene is FDA approved for prevention and treatment of postmenopausal osteoporosis at a dose of 60 mg/day. It is not without side effects which may be troubling such as a return or exacerbation of hot flashes and more dangerous….blood clots in the legs and lungs. Because of this potential danger, this drug should be discontinued if the patient is immobilized for long periods of time such as on bedrest. There is another SERM. Tamoxifen, which is used for prevention of breast cancer. It is not approved for the prevention or treatment of osteoporosis. Although it has been observed to improve BMD in postmenopausal women, it actually may cause bone loss in premenopausal women.

18. Calcitonin (Miacalcin)
Inhibits bone resorption by directly inhibiting osteoclasts
In 1970s and 1980s calcitonin was administered by subcutaneous injection
Calcitonin now available as a nasal spray
Prevent Recurrence of Osteoporotic Fractures (PROOF) trial found a decline of spinal fracture of 33%
No significant differences for non-spine fractures
Calcitonin has a unique pain-relief benefit for acute spinal fractures
Dose: 200 IU/day ( 1 spray, alternate nostrils)
Side effects: nasal stuffiness, nausea, dry mouth
(Chesnut et al, 2000)
Naturally occuring, this is a hormone secreted by the parafollicular (non-thyroid cells) found within the thyroid gland. It inhibits bone resorption by acting directly on the osteoclasts, inhibiting their activity. It was actually one of the first drugs available to treat osteoporosis. In 1970s and 1980s it was administered by subcutaneous injection. Now the nasal calcitonin is the preferred product. Its use has declined, however, with the development of newer (oral) treatments for osteoporosis. The Prevent Recurrence of Osteoporotic Fractures (PROOF) trial reported a decline of spine fracture by 33% for individuals taking 200 IU/day. But no significant differences were found for non-spine fractures. Flaws have been cited in this study’s methodology so this data might not be valid. Calcitonin has a unique benefit of providing pain relief particularly for women who have just sustained a spinal fracture. It is currently approved to treat osteoporosis at a dose of 200 IU/day in women who have been postmenopausal for at least 5 years. Its side effects are few but include nasal stuffiness, nausea, dry mouth. It is usually recommend to alternate nostrils.

19. Antiresorptive Summary
Bisphosphonates (caution in those with esophageal problems)
Hormones (weigh benefits against risks)
SERM (may increase hot flashes)
Calcitonin (decreases spinal fractures, and provides some pain relief of these fractures)
In summary, we have four drug classed in this group as noted on the slide. Each have their benefits and drawbacks. Before we leave this discussion of antiresorptive therapy, I want to note some present and future concerns with the bisphosphonates.

20. Recent Concerns with Bisphosphonates
Severe bone, joint and/or muscle pain have been reported. (Wysowski and Chang, 2005)
Osteonecrosis of the jaw recently reported (Ruggiero, et al 2004; Carter and Goss, 2003; Starck and Epker, 1995)
Ocular inflammation has been reported
(Fraunfelder and Fraunfelder, 2003)
Long term bone strength has been called into question (Odvina et al, 2005).
It has been suggested that bisphosphonate therapy be discontinued after 5 years
(Medical Letter, 2005)
Severe bone, joint and/or muscle pain have been reported. Pain started an average of 3 month after beginning therapy. This pain remitted in 66% of the patients after the drug was discontinued. Pain was sometimes diffuse and disabling in Medical Letter.
Osteonecrosis of the jaw recently reported in cancer patients, and in women without cancer after tooth extraction while on a bisphosphonate, failure of a dental implant reported in one woman
Ocular inflammation with abnormal or blurred vision, ocular pain, conjunctivitis, uveitis and scleritis have been reported
LONG TERM BONE STRENGTH-the half life of alendronate in bone can be as long as 10 years. Whether long term bone mineralization could weaken bone rather than strengthening it is unknown. In one report, 9 patients with non vertebral fractures who had taken alendronate for 3-8 years showed evidence of severe suppression of bone formation on bone biopsy These drugs theoretically might weaken bone in the longer term by inhibiting normal repair of bone “microdamage” that occurs in daily life. Because of this, it has been suggested that bisphosphonate therapy be discontinued after 5 years. More research is needed.

21. Anabolic Agents Parathyroid hormone Fluoride Growth hormone Statins
Insulin-like growth factor (IGF-1)
The other type of drug therapy we have not yet discussed are the anabolic agents. Only the first two of these will be reviewed here. The last three are still in the research stage.

22. Anabolic Agents: Parathyroid Hormone (PTH)
Teriparatide (Forteo) Eli Lilly and Company recombinant human PTH (1-34)
Stimulates new bone formation
Increases bone mass
Increases trabecular connectivity
Increases mechanical strength
20 micrograms given once daily subcutaneously for up to 2 years-with sustained effect thereafter
Increases vertebral, femoral, and total-body mineral density and is well tolerated
(Neer, et al, 2001)
Although this drug is currently available in the US, it is not considered a first line agent. It is usually utilized by endocrinologists. It does show generalized improvement in bone mineral density, and decreases the risk of vertebral and non-vertebral fractures. The 40 microgram doses used in this research increased BMD slightly, but did not change fracture risk, and had more side effects. So the recommended dose seems to be 20 micrograms. The difficulty, is the subcutaneous route. The good news is that it has a sustained effect even after injections stop.

23. Anabolic Agents-Fluoride
One of the first treatments for osteoporosis
Increases spine bone density but does not necessarily reduce fracture risk
Builds bone, but bone is more “brittle”
May even cause increased appendicular fractures
Research is conflicting and controversial
May prove useful in combination with a bisphosphonate, but further research is needed
Historically fluoride was one of our early treatments for osteoporosis. Unfortunately, although it does increase bone mass, the quality of that bone seems to be poor.

24. Summary of Part 3: Treatment
Antiresorptive therapies are our primary treatment for osteoporosis, most notably the bisphosphonates
Recent data is calling into question the quality of the bone resultant from bisphosphonate therapy
Consideration might be given to discontinue this drug after 5 years of therapy
Research is ongoing for newer pharmacological agents
In summary of the antiresorptive section, bisphosphonates are our primary tool for treatment. Recent concerns have been raised, however, about the quality of the bone, and it has been recommended to consider discontinuing the bisphosphonate after 5 years. Research in this area is being carefully watched for further clinical direction.

25. The End of Module Three on Osteoporosis
References
Black et al, Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996, Dec 7;348(9041):
Black et al, Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial Research Group. J Clin Endocrinol Metab 2000 Nov;85(11):
Brett, A. Is long term bisphsphonate therapy safe? Medical Letter, 2005 May 1;25(9)
Carter et al, Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 2003;48:268
Cauley et al, Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women’s Health Initiative Randomized Trial. JAMA 2003 Oct 1:290(13):
Chesnut et al, A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The Preventive Recurrence of Osteoporotic Fractures study. PROOF Study Group. Am J Med 2000, Sep;109(4):267-76
This completes our third module on Osteoporosis. To complete the question for credit for this module, please close out this module, and advance to the question in 3 in Blackboard, then answer the question and review the answer. Then also complete the evaluation of these modules to assist us with improvement and for you to attain credit for the module. We thank you for the persistence in completing this educational effort on this important subject.

26. References
Chesnut et al, Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J of Bone and Min Res 2004, March; 19(8):
Cranney et al, Osteoporosis methodology group and the osteoporosis research advisory group. Meta-analyses of therapies for postmenopausal osteoporosis. II Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002, Aug;23(4):508-16
Ettinger et al, Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators. JAMA 1999 Aug 18;282(7):637-45
Fraunfelder & Fraunfelder, Bisphosphonates and ocular inflammation. N Engl J Med 2003; 348:1187
Harris et al, Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group, JAMA 1999 Oct 13;282(14):

27. References
Lindsay et al. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002 May 22-29;287(20);
Maricic et al, Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002 May 27;162(10):1140-3
McClung et al, Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001 Feb 1;344(5):333-40
Neer, et al, Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal woman with osteoporosis. NEJM 2001, 344:
Odvina et al, Severely suppressed bone turnover: A potential complication of alendronate therapy. J Clin Endocrinol Metab 2004 Dec 14
Ruggiero, et al Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527

28. References
Starck & Epker, Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: A case report. Int J Oral Maxillofac Implants1995;10:74
Tonino et al Skeletal benefits of alendronate: 7 year treatment of postmenopausal osteoporotic women. Phase III osteoporosis Treatment Study Group. J Clin Endocrinol Metab 2000 Sep;85(9):
Torgerson et al, Hormone replacement therapy and prevention of nonvertebral fractures: A meta-analysis of randomized trials. JAMA 2001 Jun 13;285(22):2891-7
Torgerson et al, Hormone replacement therapy and prevention of vertebral fractures: A meta-analysis of randomized trials. BMC Musculoskelet Disord 2001;2(1):7-10
Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: Results from the Postmenopausal estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996 Nov 6;276(17):
Wysowski & Chang, Alendronate and risedronate: Reports of severe bone, joint and muscle pain. Arch Intern Med 2005; 165:527

29. Post-test
A 67 year old woman presents to your office with a DEXA score of She has been told by her family doctor that she "should take a medication for her bones." She is currently being treated for mild hypertension with HCTZ and has a history of GERD under treatment with omeprazole. Family history is positive for breast cancer in her mother. The best drug treatment for this patient's osteoporosis is:
Alendronate
CEE/MPA
Raloxifene
Calcitonin

30. Correct Answer: Raloxifene