Address Options for Prevention and Treatment of Osteoporosis
Key Points:
- Lifestyle adjustments are traditionally first-line therapy for osteoporosis prevention and treatment.
- Bisphosphonates have the strongest data showing risk reductions in both vertebral and non-vertebral fractures.
- Estrogen is considered first-line therapy for the prevention of osteoporosis in prematurely menopausal women under the age of 50.
- Anabolic therapy with parathyroid hormone is indicated for patients with particularly high-risk for future fracture, and data shows reduction in vertebral and non-vertebral fracture.
- Nasal calcitonin is not considered a first-line treatment for osteoporosis, but may be useful in some populations.
- Selective estrogen receptor modulator (SERM) treatment with raloxifene has shown vertebral fracture risk reduction in postmenopausal osteoporosis.
Please see the medication tables in Appendix B, "Recommended Pharmacologic Agents" of the original guideline document for specific information on pharmacologic agents for treatment and prevention of osteoporosis.
Osteoporosis Prevention
Estrogen has traditionally been considered first-line therapy for prevention of osteoporosis in prematurely menopausal women under the age of 50. If the only reason hormone therapy has been prescribed is for osteoporosis prevention, other therapies should be considered. If the decision is made to discontinue estrogen, a BMD should be obtained to determine if other bone loss prevention therapies are needed. Other medications for prevention include bisphosphonates and raloxifene.
Osteoporosis Treatment
Bisphosphonates have the strongest data showing risk reductions in both vertebral, hip, and other nonvertebral fractures. Other treatments include raloxifene (see SERM in this annotation) and calcitonin.
Parathyroid hormone 1-34 (teriparatide) (PTH) is used for patients at highest risk for fracture. It could be first-line therapy for those patients.
Post-transplantation Bone Loss
Antiresorptive therapy and calcitriol may be effective at preventing bone density loss after transplantation. Considering the rates of bone loss after transplantation described in Annotation #3, bone mineral density testing should be performed every 6 months to one year until bone mineral density is shown to be stable or improving on therapies for osteoporosis. Studies demonstrate that standard calcium and vitamin D supplementation, with or without calcitonin, are not able to prevent bone loss after transplantation. Other studies indicate that pharmacologic vitamin D preparations or intravenous bisphosphonates, such as pamidronate, or zoledronic acid, or oral bisphosphonates, such as alendronate or risedronate are more likely to prevent bone loss after transplantation.
Alternative and Complementary Agents for Prevention and Treatment of Osteoporosis
There is conflicting data on a number of non-Food and Drug Administration (FDA) approved substances for possible use in prevention and treatment of osteoporosis. These include phytoestrogens, synthetic isoflavones such as ipriflavone, natural progesterone cream, magnesium, vitamin K and eicosapentaenoic acid. There is very limited data from randomized controlled trials of these agents for prevention or treatment of osteoporosis. A recently reported, multicenter randomized trial of ipriflavone showed no significant effect on bone density or risk of vertebral fractures.
Evidence supporting this recommendation is of classes: A, B, C, D, M, R
In addition to calcium, vitamin D, physical therapy, surgical repair, and radiologic intervention as appropriate, the therapies listed below may be used. Clinicians should be aware that patient compliance with adherence to osteoporosis therapy has been historically poor.
Gonadal Hormone Therapy
Female Gonadal Hormone Therapy
The use of supplemental estrogen in the immediate postmenopause has been well accepted in preventing the rapid loss of bone that occurs in this interval.
Supplemental estrogen not only retards accelerated bone loss, but has also been shown to create a gain in bone density. In the PEPI trial after 3 years, the women receiving hormone replacement therapy had a mean 5% gain in bone density in the spine and 2% in the hip compared to a 2% loss in the placebo group. Preliminary evidence suggests that the gain in bone mass may persist beyond the first few years. In one study, women on estrogen-progestin therapy showed a persistent increase in density over 10 years, reaching 13% over baseline.
It is generally believed that estrogen therapy is most effective when started immediately after menopause. But estrogen therapy has also been shown to have a positive effect on bone mass long after menopause, creating gains of bone mass of 5 to 10% over baseline over 1 to 3 years.
The protective effects of estrogen on bone density are lost quickly after estrogen is discontinued.
Dose response effectiveness of hormone therapy on bone mass has recently undergone considerable scrutiny.
Ultra-low estrogen supplementation has been shown to be effective in severely hypoestrogenic women in improving bone mass. Fracture data is pending.
Refer to the original guideline document for more information on female gonadal hormone therapy.
Male Gonadal Hormone Therapy
The bone loss associated with male hypogonadism is reversed by testosterone therapy at least partly via aromatization to estrogen. Testosterone therapy, although not FDA-approved for osteoporosis, seems a reasonable first therapeutic intervention in men symptomatic with hypogonadism who do not have contraindications to the use of testosterone therapy.
Evidence supporting this recommendation is of classes: A, B, C, D, M
Bisphosphonates
Treatment and Prevention of Osteoporosis in Postmenopausal Women
Alendronate has been shown to increase bone mineral density and reduce the incidence of vertebral, hip, and non-vertebral fractures in postmenopausal women having existing vertebral fractures, and those with low bone mineral density (approximately 2.1 SD below peak) compared to placebo (calcium and vitamin D).
Excellent clinical trial data based on BMD and bio-markers supports the use of oral bisphosphonates for preventing fractures in patients diagnosed with postmenopausal low bone density (osteopenia) or osteoporosis. The best clinical trials have been done with alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®). [Conclusion Grade I: See Conclusion Grading Worksheet B -- Annotation #15 (Bisphosphonates for Primary Osteoporosis) in the original guideline document]. (See Appendix B, "Recommended Pharmacologic Agents" in the original guideline document.)
Note: there are case reports of bisphosphonate-associated osteonecrosis of the jaw most often following dental extraction with exposed jaw bone in cancer patients undergoing intravenous bisphosphonate therapy. The prevalence is estimated to be approximately one in one million for patients without cancer taking oral bisphosphonates.
Treatment of Osteoporosis in Men
Alendronate has been shown to increase bone mineral density at the spine, hip, and total body and prevents vertebral fractures and decreases in height for men with osteoporosis.
Good clinical trial data support the use of alendronate for preventing bone loss in men diagnosed with osteoporosis. [Conclusion Grade I: See Conclusion Grading Worksheet B -- Annotation #15 (Bisphosphonates for Primary Osteoporosis) in the original guideline document].
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis
Alendronate increases lumbar spine, femoral neck, trochanter, and total body bone mineral density in patients who require long-term (at least one year) glucocorticoid therapy at dosages of at least 7.5 mg daily.
Risedronate has also been shown to increase bone mineral density in patients receiving glucocorticoid therapy. Treatment with risedronate 5 mg a day did have a trend of reduced fracture incidence.
Clinical trial data supports the use of oral bisphosphonates for reducing bone loss in men and women diagnosed with glucocorticoid-induced bone loss. The best clinical trials have been done with alendronate (Fosamax®) and risedronate (Actonel®). [Conclusion Grade II: See Conclusion Grading Worksheet C -- Annotation # 15 (Bisphosphonates for Glucocorticoid-induced Bone Loss) in the original guideline document].
Clinical trial data suggests that oral bisphosphonates may reduce fracture risk in men and women diagnosed with glucocorticoid-induced bone loss. [Conclusion Grade III: See Conclusion Grading Worksheet C -- Annotation #15 (Bisphosphonates for Glucocorticoid-induced Bone Loss) in the original guideline document].
Post-transplantation
Solid organ transplantation of all types and allogeneic bone marrow transplantation are associated with rapid bone loss after transplantation. In addition, many patients develop significant bone loss before transplantation.
Several studies have shown that intravenous pamidronate (Aredia®) and zoledronate (Zometa®) may prevent bone loss after organ transplantation. A few small studies have evaluated oral bisphosphonate therapy in post-transplant patients.
Evidence supporting this recommendation is of classes: A, C, D, R
Selective Estrogen Receptor Modulator (SERM)
The only SERM approved for the prevention and treatment of osteoporosis is raloxifene.
Prevention and Treatment of Osteoporosis in Postmenopausal Women
The MORE trial was a large 3-year randomized placebo-controlled study in postmenopausal women with osteoporosis. Raloxifene showed an increase in BMD and reduced the risk of vertebral fractures. The risk of non-vertebral fractures did not differ between placebo and raloxifene. There was an increased risk of venous thromboembolism compared with placebo (RR 3.1, 95% CI 1.5-6.2).
The CORE 4-year trial extension of 4,011 women continuing from MORE (7,705) showed no difference in overall mortality, cardiovascular events, cancer or nonvertebral fracture rates.
Calcitonin
Treatment of Osteoporosis in Postmenopausal Women
Nasal salmon-calcitonin 200 IU daily has shown a 33% risk reduction in new vertebral fractures compared with placebo (RR 0.67, 95% CI 0.47-0.97, p = 0.03). This occurred without significant effects on BMD. BMD measurements were not blinded to investigators and 59% (744) participants withdrew from the study early. Also, a dose response was not observed with respect to risk reduction of vertebral fractures.
Post-transplantation
Several studies have shown that nasal spray calcitonin has little effect on prevention of bone loss after organ or bone marrow transplantation.
Refer to the original guideline document for information on anabolic agents, strontium, combination therapy (estrogen and bisphosphonates); comparative trials; calcitriol-1 25-OH vitamin D; and alternative and complimentary agents (phytoestrogens, ipriflavone, natural progesterone, magnesium, vitamin K, eicosapentaenoic and gamma-linolenic acid supplementation, and kampo formulae).
Evidence supporting this recommendation is of classes: A, B, C, D