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The treatment options for patients with osteoporosis and osteoporotic fractures continue to broaden. This update includes results from recent clinical trials about new agents that improve bone density (BMD) and decrease fracture risk and offer a perspective on their role in fracture prevention and in the treatment of osteoporosis. The recent data on the effects of estrogen and progesterone on fracture risk and their overall risk and benefits from the Heart and Estrogen/Progestin Replacement Study follow- up (HERS II) and Women's Health Initiative (WHI) trials are also reviewed. These two studies received a great deal of media and public attention and forced clinicians and patients to reexamine the role of combined estrogen/progesterone treatment in fracture prevention and its overall impact on women's health. Finally, an important article that reviews the clinical use of bone densitometry and offers nomograms to predict 5-year fracture risk using age and BMD is discussed.

A once yearly intravenous bisphosphonate

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES

Bisphosphonates (alendronate and risedronate) have become the mainstay of osteoporosis treatment in both men and women. However, administration of these drugs, which have poor oral bioavailability and occasionally cause esophageal irritation, can be cumbersome, leading to poor compliance. In addition, some patients have been unable to take oral bisphosphonate treatment because of esophogitis, inflammatory bowel disease, or because they are at bed rest. For these patients pamidronate, an infusible bisphosphonate given every 3 months, has been a treatment alternative, but is not Food and Durg Administration (FDA) appr′oved for this indication. A new and more potent aminobisphosphonate, zoledronic acid, significantly improves BMD when infused only once a year.

Intravenous zoledronic acid in postmenopausal women with low bone density. (N Engl J Med, 2002) (1).

This was a randomized, placebo-controlled, dose-ranging trial comparing 4 regimens of zoledronic acid (0.25 mg or 0.5 mg or 1 mg intravenous every 3 months, 2 mg twice a year, or 4 mg intravenous once a year) in 351 postmenopausal women with low bone mass. At 12 months, the combined zoledronic acid groups had a 5% and 2.5 % increase in lumbar spine and femoral neck BMD, respectively, and there was no significant difference in the effect of the 3 month versus once a year regimen. This study was not powered to examine fracture prevention and was not long enough to address that issue. Adverse events were more common in the treatment groups (45–67% versus 27% in the placebo group) and consisted of musculoskeletal pain, nausea, and fever. The authors state that most of the toxicity occurred with the first dose, the number of side effects over the year was not different in the different dose groups, and that withdrawals for toxicity were not different by dose. The authors do not state whether the toxicity with the first infusion was dose dependent.

Zoledronic acid is currently available for the adjuvant treatment of metastatic bone disease and is in clinical trials now addressing fracture prevention. If zoledronic acid is found to significantly decrease the risk of fractures when infused once a year, it will be an alternative treatment for patients who need an intravenous bisphosphonate and for patients who are unable to comply with oral bisphosphonate treatment. This may be a particularly appealing treatment for hospitalized fracture patients to prevent further bone loss during immobilization and rehabilitation, and for hospitalized patients about to initiate long-term, high-dose glucocorticoid therapy who might have difficulty complying with oral bisphosphonate regimens.

Availability of an agent to stimulate bone formation

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES

Until recently, all the FDA-approved treatments available to prevent osteoporotic fractures were antiresorptive agents that had limited ability to increase bone density. Teriparatide (PTH) is the first agent that stimulates bone formation and has been shown to decrease fracture risk.

Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women (N Engl J Med, 2001) (2).

In an 18-month placebo-controlled trial, 1,637 postmenopausal women with a prior vertebral fracture were randomly assigned to treatment with 20 or 40 μg/ml of parathyroid hormone (teriparatide) by daily subcutaneous injection. New nonvertebral fractures occurred in 6% of placebo patients and 3% of those in the parathyroid hormone group (relative risk [RR] = 0.47). The difference in BMD between the treated and placebo patients was 9% and 13% in the lumbar spine, and 3% and 6% in the femoral neck in the 20 μg/ml and 40 μg/ml groups respectively. Total body BMD increased 2% and 4%, respectively. One vertebral fracture was prevented for every 12 years of treatment with the 20 μg/ml dose (FDA-approved dose) at a cost of $96,000 per fracture avoided. New or worsening back pain was reported in 23% of the placebo group and 17% of the 20 μg/ml group. The study was not powered to assess a difference in femoral fracture rates. Nausea, headache, dizziness, leg cramps, and increased urinary calcium were more common in the PTH group. Mild hypercalcemia occurred in 2% of women in the placebo group and 11% of those in the 20 μg/ml group. The study was stopped prematurely by the sponsor because bone tumors developed in Fischer 344 rats during a long-term toxicology study. Teriparatide should not be given to those with a higher risk of osteosarcoma such as those with Paget's disease, history of skeletal radiation, or children with open epiphysis. The effects of tereparatide on bone density after 18 months are unknown.

Two studies found that adding alendronate to teriparatide does not have greater effects on bone density than treatment with teriparatide alone (3, 4). A study in 437 osteoporotic men demonstrated an increase of 5.9% and 1.5% in lumbar spine and femoral neck bone density over 11 months (5).

Studies are ongoing to determine the effects of teriparatide on BMD after treatment is discontinued and whether use of an antiresorptive agent after termination of teriparatide treatment helps to sustain its effects on BMD. The place of teriparatide in the treatment of osteoporosis and osteoporotic fractures is still unclear. Given the high cost ($516 per month [6]), daily subcutaneous administration, and unknown long-term effects, it will most likely be used to treat patients who have severe osteoporosis or continue to experience fractures despite treatment with bisphosphonates or those patients with contraindications to or toxicity from bisphosphonates.

Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES

For years, the use of hormone replacement therapy (HRT) was justified on the basis of epidemiologic data that demonstrated a lower rate of heart disease in HRT users and prospective studies that showed beneficial effects on lipid profiles. In addition, HRT use is associated with higher BMD and lower fracture rates. The assumed cardiovascular benefits outweighed the smaller increased risk of breast cancer and thrombosis. However, the prospective HERS II and WHI trials showed no cardiovascular benefits of conjugated equine estrogen (CEE) with medroxyprogesterone (MPA) and led to a reexamination of the role of estrogens in the prevention and treatment of osteoporosis.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the WHI randomized controlled trial. (JAMA, 2002) (7).

This component of the WHI was a randomized, placebo-controlled trial of 0.625 mg/day of CEE and 2.5 mg/day of MPA versus placebo on incidence of coronary heart disease (CHD) and invasive breast cancer in 16,608 healthy postmenopausal women over a period of 5 years. The relative risks of cardiovascular disease, stroke, and breast cancer were increased (1.29, 1.44, and 1.26 respectively) but the relative risk of hip fracture and colorectal cancer was decreased to 0.66 and 0.63, respectively. The overall relative risk of cancer was 1.03 and the risk of mortality was 0.98. This study confirmed an increased risk of breast cancer and the protective effects of estrogen on fractures.

Absolute risks per 10,000 person years of exposure were 7 more CHD events, 8 more strokes, 8 more pulmonary embolisms (PEs), 8 more breast cancers, 5 fewer hip fractures, and 6 fewer colorectal cancers. The time trend analyses showed that the protective effects from colorectal cancer occurred after 3 years of treatment, and was seen uniformly through the 5 years for hip fracture. An increased risk of stroke emerged after one year, but the increased risk for CHD and PE was seen soon after randomization. The absolute increase in risk of breast cancer went from 0.2% per year in non-HRT users to 0.3% per year in HRT users.

Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow up (HERS II). (JAMA, 2002) (8).

HERS I was a 4.1-year randomized, double-blind, placebo-controlled study of the effects of 0.625 mg of CEE and 2.5 mg of MPA on cardiovascular events in postmenopausal women with coronary artery disease. HERS II was the 2.7- year open label extension study of the HERS I study and 2,321 of the 2,763 women who participated in HERS I went on to participate in HERS II. The decision to continue or start HRT was left up to the physician and patient, and 81% of those patients originally assigned to HRT continued that treatment at the end of year 1 and 45% at the end of year 6. After a total of 6.8 years of study, HRT did not decrease the risk of cardiovascular events in this high-risk group of women.

Noncardiac disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow up (HERS II). (JAMA, 2002) (9).

This article addressed noncardiovascular events in the HERS study and found no difference in the risk of any fracture (RR = 1.04, 95% confidence interval [95% CI] 0.87–1.25) in the hormone replacement versus the placebo group. The RR for any cancer was not significantly increased (RR = 1.19, 95% CI 0.95–1.50), the relative risk of biliary disease and thromoboembolic disease was increased to 1.48 (95% CI 1.12–1.95) and 1.40 (95% CI 0.64–3.05), respectively.

The WHI and HERS study found no protective effect of combination HRT against cardiovascular disease or recurrent cardiovascular events in postmenopausal women. The WHI study showed that HRT decreased hip fracture risk but this was not demonstrated in the HERS II trial. However, the WHI included over 16,000 women while HERS II included only 2,321 women and was not powered to assess hip fracture differences. The total risks and benefits of HRT versus no HRT are very close in terms of overall cancer risk and mortality in the WHI study. Although no overall health advantage was seen from treatment with this dose of conjugated estrogen and progesterone, the role of lower dose estrogen or the same dose of estrogen without progesterone is still under study. The arm of the WHI study addressing risks and benefits of estrogen without progesterone is ongoing. The following article addresses the possible benefits of lower doses of estrogen on bone density.

Effects of lower doses of conjugated equine estrogen with and without medroxyprogesterone acetate on bone in early postmenopausal women. (JAMA, 2002) (10).

In this study, 822 healthy postmenopausal women within 4 years of their last period (early menopause) were randomized to receive various doses of estrogen (CEE) (0.625, 0.45, 0.3 mg/day) with or without progesterone (MPA) for two years. In this study, a dose effect was shown, the 0.625 md dose of CEE had greater effects on spine BMD than the 0.3 mg/day dose. The effects of MPA on improvements in BMD were only seen in lumbar spine BMD and were only significant at the higher dose of estrogen (0.625 mg). The 0.3-mg dose of CEE was associated with stable BMD in the lumbar spine.

This study found that lower doses of estrogen, which are often adequate to control vasomotor symptoms and have less detrimental effects on coagulation factors and endometrial hyperplasia, may also have beneficial effects on preserving lumbar spine BMD. This work confirms a study by Recker et al (11) that low-dose (0.3 mg) continuous estrogen and progesterone therapy with calcium and vitamin D preserved bone density in elderly women.

Predicting life time fracture risk: the role of bone density and risk factors.

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES

Clinical use of bone densitometry. (Ann Intern Med, 2002) (12).

This article reviews methodology for bone density testing and guidelines for its use in screening for osteoporosis. Risk factors for hip fracture that are independent of BMD include previous vertebral fracture (RR = 4), age, maternal history of hip fracture (not kyphosis), conditions that increase risk of falling, and serum estradiol levels. BMD data (using the QDR-1000 densitometer [Hologic, Inc., Bedford, MA]) from the Study of Osteoporotic Fractures trial were used to create nomograms giving the 5-year risk of vertebral and hip fractures for white women using femoral neck BMD and age. The 5-year fracture risks for women below the age of 65 were extrapolated. The authors argue that although risk factors (sex, weight, and race) correlate with BMD, it is impossible to predict BMD with accuracy given these risk factors.

Many experts believe that information given to patients about bone density should include information about 5-year fracture risk as well as the t score. The t score is difficult for patients to understand, while estimated fracture risk is more tangible and aids in clinical decision making. This article provides nomograms that estimate 5-year fracture risk based on age and hip BMD that are useful in clinical practice.

Summary

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES

New treatment options for osteoporosis are now available and others are in development. They allow us to achieve greater improvements in bone mass, more convenient medication dosing regimens, and more predictable fracture reduction. New data have helped us to reassess the role of estrogen in the treatment and prevention of osteoporosis and fractures and to balance the risks and benefits to women's overall health. Our understanding of how to use bone density to more accurately assess bone mass and predict fracture risk is improving. All of these advances will lead to significant improvements in fracture prevention and quality of life, both now and in the future.

REFERENCES

  1. Top of page
  2. A once yearly intravenous bisphosphonate
  3. Availability of an agent to stimulate bone formation
  4. Update on the role of estrogen in the treatment of osteoporosis: the risks and benefits of estrogen replacement from the Heart and Estrogen/Progestrin Replacement Study (HERS) and Women's Health Initiative (WHI) studies
  5. Predicting life time fracture risk: the role of bone density and risk factors.
  6. Summary
  7. REFERENCES