Medication Update.

ESTROGEN

There are, at present, no large-scale, prospective, double-blind, placebo-controlled, randomized clinical trials to determine the efficacy of estrogen in reducing the fracture risk of patients with osteoporosis. Most of the available data on the efficacy of estrogen in reducing fractures are derived from retrospective, observational, or small prospective studies. These studies suggest that any protective effect of estrogen is dose-related and effective only when the patient is taking estrogen.

The PEPI study was a 3-year prospective study conducted on 875 postmenopausal women randomly allocated to placebo or conjugated equine estrogen with or without progesterone. The results revealed that estrogen, with or without progesterone, significantly increased the bone mineral density of the lumbar vertebrae and the proximal femur, but did not significantly alter the risk of fractures. The HERS study included 2,763 postmenopausal women with evidence of coronary heart disease. The main aim of this 5-year, prospective, placebo-controlled, randomized clinical trial was to determine the efficacy of estrogen in the secondary prevention of coronary heart disease. The study was aborted 4.1 years after its initiation. During this period, there was no significant difference in the fracture rate between the subjects receiving estrogen and progesterone and those on placebo.

A few years ago the National Institutes of Health launched a major prospective, double-blind, placebo-controlled, randomized clinical trial--the Women's. Health Initiative--to determine the effects of estrogen replacement on a variety of parameters including bone mass and fracture risk reduction. The results will not be available for another few years.

ALENDRONATE (FOSAMAX)

MODE OF ACTION:

Inhibits bone resorption by binding to the hydroxyapatite crystals and inhibiting the intracellular enzymes of the osteoclasts.

EFFECTS ON FRACTURES (COMPARED WITH PLACEBO):

Lumbar vertebrae:

* 47% reduction in new single vertebral fractures over a 3-year period.

* 55% reduction in clinical vertebral fractures over a 3-year period.

* 90% reduction in multiple vertebral fractures over a 3-year period. FIT Study (Black et al 1996; 2,027 postmenopausal women, age range 55-81 years, entry t-score -2.1 or lower).

* 59% reduction in symptomatic vertebral fractures at 12 months. FIT Combined analysis (Black et al, 2000; 3,658 postmenopausal women, age range 55-80 years, entry t-score -2.5 or lower).

Proximal femur:

* 51% reduction in hip fractures over a 3-year period. FIT Study (Black et al 1996; 2,027 postmenopausal women, age range 55-81 years, entry t-score -2.1 or lower).

* 56% reduction at year 4. FIT Study (Cummings et al 1998; 4,432 postmenopausal women, age range: 55-81 years, entry t-score -2.5 or lower).

* 63% reduction at 18 months. FIT Combined analysis (Black et al 2000; 3,658 postmenopausal women, age range 55-80 years, entry t-score -2.5 or lower).

Others:

* 47% reduction in non-vertebral fractures over a 1-year period. FOSIT Study (Pols et al 1999; 1,908 postmenopausal women, mean 63 years, entry t-score -2.0 or lower).

* 20% reduction in hospitalization, over a 3-year period.

* 52% reduction in bed days due to back pain, over a 3-year period.

CONTRAINDICATIONS:

Esophageal stricture, achalasia, or other problems associated with delayed esophageal emptying.

Inability to stand up or sit up for 30 minutes.

Hypersensitivity to alendronate.

Pregnancy category C.

ADVERSE EFFECTS:

Abdominal pain and upper GI upset (especially if not taken as directed).

Musculoskeletal pain, headache, nausea, dyspepsia, flatulence, constipation, and diarrhea.

DRUG-DRUG INTERACTIONS:

Patients should not take any other medications for at least 30 minutes after taking alendronate.

DRUG-FOOD INTERACTIONS:

Should be taken on a fasting stomach.

Patients should not eat or drink any fluid other than plain water for 30 minutes after taking alendronate.

RECOMMENDED DOSE:

Treatment:

10 mg once a day.

70 mg once a week is as effective as a daily dose of 10 mg.

May be initiated at 5 mg daily or 35 mg weekly if patient experiences upper GI adverse effects. The dose may be titrated as patient tolerates medication.

Prevention: 5 mg once a day, or 35 mg once a week.

Patients should take dose with a 6 to 8 oz. glass of water. Patients should not lie down, bend, stoop or get involved in any activity that may increase the risk of gastroesophageal reflux for at least 30 minutes after taking alendronate.

DOSAGE FORMS AVAILABLE:

Available in 5 mg, 10 mg, 35 mg and 70 mg tablets.

For patients with Paget's disease, 40 mg tablets are available.

MANUFACTURER:

Merck

OTHER POINTS OF INTEREST:

Effective in corticosteroid-induced osteoporosis.

Effective in osteoporosis in men.

May be combined with estrogen or raloxifene.

Should not be combined with calcitonin.

CALCITONIN NASAL SPRAY (MIACALCIN)

MODE OF ACTION:

Inhibits bone resorption by interfering with osteoclast activity.

EFFECTS ON FRACTURES (COMPARED TO PLACEBO):

Lumbar vertebrae:

* 36% reduction in vertebral fractures over a 5-year period. PROOF Study (Chestnut et al, 2000; 1,255 postmenopausal women, mean age 68 years, entry criteria one or more vertebral compression fractures and lumbar vertebrae t-score -2.0 or lower).

Proximal femur:

* No statistically significant reduction. PROOF Study (Chestnut et al, 2000; 1,255 postmenopausal women, mean age 68 years, entry criteria one or more vertebral compression fractures and lumbar vertebrae t-score -2.0 or lower).

Others:

* No statistically significant reduction. PROOF Study (Chestnut et al, 2000; 1,255 postmenopausal women, mean age 68 years, entry criteria one or more vertebral compression fractures and lumbar vertebrae t-score -2.0 or lower).

CONTRAINDICATIONS:

Allergy to calcitonin.

Pregnancy category C.

ADVERSE EFFECTS:

Rhinitis and back pain.

DRUG-DRUG INTERACTIONS:

None

DRUG-FOOD INTERACTIONS:

RECOMMENDED DOSE:

None

DOSAGE FORMS AVAILABLE:

Patients should use 200 IU (one puff) in one nostril every day, alternating nostrils every other day.

MANUFACTURER:

Available as a 2,200 IU/mL solution in a 2 mL glass bottle with a spray adapter that delivers 200 IU/0.9 mL per actuation.

OTHER POINTS OF INTEREST:

Novartis

Patients should also be taking calcium supplements with vitamin D for maximum benefit.

Calcitonin nasal spray should be refrigerated.

Calcitonin has a centrally mediated analgesic effect in some patients.

Antibodies may develop as calcitonin is antigenic, being based on the same sequence of amino acids as salmon calcitonin.

RALOXIFENE (EVISTA)

MODE OF ACTION:

Estrogen agonist on bone and lipids: Increases bone mineral density by decreasing bone resorption by reducing the number and activity of osteoclasts.

Selective Estrogen Receptor Modulator (SERM):

Decreases total and low-density lipoprotein plasma cholesterol. Does not affect triglycerides or high density lipoprotein cholesterol.

Decreases fibrinogen plasma level.

Estrogen antagonist on uterus and breast: No increase in risk of uterine or breast cancer or endometrial bleeding.

No increase in endometrial mucosal thickness or breast pain.

EFFECTS ON FRACTURES (COMPARED WITH PLACEBO):

Lumbar vertebrae:

* 30% to 55% reduction in vertebral fractures over a 3-year period.

MORE Study (JAMA 1999; 7,705 postmenopausal women, mean age 67 years, entry t-score -2.5 or lower).

Proximal femur:

* No statistically significant reduction. MORE Study (JAMA 1999; 7,705 postmenopausal women, mean age 67 years, entry t-score -2.5 or lower).

Others:

* No statistically significant reduction. MORE Study (JAMA 1999; 7,705 postmenopausal women, mean age 67 years, entry t-score -2.5 or lower).

Pregnancy, or if there is a possibility that the patient may become pregnant (pregnancy category X).

CONTRAINDICATIONS:

Venous thromboembolic disease (active or history of venous thromboembolic disease).

Known hypersensitivity to raloxifene.

Venous thromboembolic events, especially during the first four months of therapy. The incidence is similar to hormone replacement therapy. Patients should stop taking raloxifene at least 72 hours prior to periods of prolonged immobilization.

ADVERSE EFFECTS:

Hot flashes and leg cramps are the most common adverse effects.

Patients should not take cholestyramine (Questran) at the same time as raloxifene. Their administration times should be spaced as far apart as possible.

DRUG-DRUG INTERACTIONS:

Patients taking warfarin (Coumadin) should be monitored for a decrease in their International Normalized Ratio.

Raloxifene may be taken with or without food.

DRUG-FOOD INTERACTIONS:

Patients should take 60 mg once a day.

RECOMMENDED DOSE:

DOSAGE FORMS AVAILABLE:

MANUFACTURER:

Available in 60 mg tablets.

OTHER POINTS OF INTEREST:

Eli Lilly

RISEDRONATE (ACTONEL)

Patients should still be encouraged to take calcium supplements with vitamin D.

MODE OF ACTION:

Inhibits bone resorption by binding to the hydroxyapatite crystals and inhibiting the intracellular enzymes of the osteoclasts.

EFFECTS ON FRACTURES:

Lumbar vertebrae:

* 41% reduction over a 3-year period, 65% reduction after first year. VERT (North American) Study (Harris et al, JAMA 1999, 2,458 postmenopausal women, mean age 69 years, entry criteria: t-score -2.0 or lower and 1 radiographic vertebral fracture or at least 2 vertebral fractures).

49% reduction over a 3-year period, 61% reduction after first year. VERT (International) Study (Reginster et al, Osteoporos Int 2000; 1,226 postmenopausal women, mean age 71 years, entry criteria: at least 2 radiographic vertebral compression fractures, mean t-score lumbar vertebrae: -2.77 placebo group, -2.69 risedronate 2.5 mg group, and -2.84 risedronate 5.0 mg group).

Proximal Femur:

* 39% to 58% reduction over a 3-year period. HIP Study (McClung, et al 2001, subgroup of 5,445 postmenopausal women, age range 70-79 years, entry femoral neck t-score -4.0 and lower in the absence of risk factors for hip fracture or -3.0 and lower in the presence of risk factors).

* No statistically significant reductions over a 3-year period in hip fractures in HIP Study (McClung, et al 2001, subgroup of 3,886 postmenopausal women aged 80 years and older. BMD was not measured in all participants).

Others:

* 39% reduction over a 3-year period. VERT (North American) Study (Harris et al, JAMA 1999, 2,458 postmenopausal women, mean age 69 years, entry criteria: t-score -2.0 or lower and 1 radiographic vertebral fracture or at least 2 vertebral fractures).

* 33% reduction over a 3-year period. VERT (International) Study (Reginster et al, Osteoporos Int 2000; 1,226 postmenopausal women, mean age 71 years, entry criteria: at least 2 radiographic vertebral compression fractures, mean t-score lumbar vertebrae: -2.77 placebo group, -2.69 risedronate 2.5 mg group, and -2.84 risedronate 5.0 mg group).

CONTRAINDICATIONS:

Hypersensitivity to risedronate.

Hypocalcemia.

Pregnancy category C.

ADVERSE EFFECTS:

Abdominal pain, back pain, arthralgia.

DRUG-DRUG INTERACTIONS:

Calcium supplements and antacids may decrease the absorption of risedronate.

DRUG-FOOD INTERACTIONS:

Should be taken on a fasting stomach. Patient should not eat or drink any fluid other than plain water for 30 minutes after taking alendronate.

RECOMMENDED DOSE:

5 mg once a day.

Patients should take dose with a 6 to 8 oz. glass of water. Patients should not lie down, bend or stoop for at least 30 minutes after taking alendronate.

DOSAGE FORMS AVAILABLE:

Available in 5 mg.

For patients with Paget's disease, 30 mg tablets are available.

MANUFACTURER:

Procter & Gamble

OTHER POINTS OF INTEREST:

Effective in corticosteroid-induced osteoporosis.

References

Black DM, et al: Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348:1535-1541

Black D, et al: The early antifracture efficacy of alendronate in women with osteoporosis: results from FIT. Osteoporos Int 2000, S173

Black EB, 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; 282(7):637-645

Chavassieux PM, et al: Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies. J Bone Miner Res 2000; 15:754-762

Chestnut CH, et al: A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 2000; 109:267-276

Cohen S, et al: Risedronate therapy prevents corticosteroid-induced bone loss. Arthritis Rheum 1999; 11:2309-2318

Cummings SR, et al: Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998; 280:2077-2082

Delmas PD, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337:1641-1647

Downs RW, et al: Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. J Clin Endocrinol Metab 2000; 85:1783-1788

Harris ST, et al: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999; 282:1344-1352

Hebel SK, Katstrup EK (Eds): Drug Facts and Comparisons. St. Louis, MO, 2001

Hutchison TA, Shahan DR, Anderson ML (Eds): DRUGDEX System. MICROMEDEX, Inc., Englewood, Colo, 2000

Khovidhunkit W, Shoback D: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med 1999; 130:431-439

Lieberman UA, et al: Effect of oral alendronate on bone mineral density and incidence of fractures in postmenopausal women. N Engl J Med 1995; 333:1437-1443

McClung MR, et al: Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344:333-340

Orwoll E, et al: Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000; 343:604-610

Pols HA, et al: FOSIT (Fosamax International Trial). Osteoporos Int 1999; 9:461-468

Reginster J-Y, et al: Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11:83-91

Rossini M, et al: Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001; 16:113-119

Tonino R, et al: Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. J Clin Endocrinol Metab 2000; 85:3109-3115

Therefore, it was decided to try estrin therapy on patients with menopausal osteoporosis. Estrin has a very marked ability to put patients with postmenopausal osteoporosis into a positive calcium and phosphorus balance. Whether the effect of estrin is sufficient to make its administration of practical value is yet too soon to say.

Fuller Albright Transaction of the Association of American Physicians, 1940