Address Options for Prevention and Treatment of Osteoporosis
Key Points:
- Lifestyle adjustments are universally recommended for bone health
- Bisphosphonates have the strongest data showing risk reductions in both vertebral and non-vertebral fractures.
- Adequate calcium and vitamin D intake and regular physical exercise are important for the prevention of osteoporosis, and they play an important role in its treatment.
- 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 (also see Annotation #4, "Discuss Primary Prevention of Fractures")
Estrogen has traditionally been considered first-line therapy in women over 50 years of age for prevention of osteoporosis and in prematurely menopausal women under the age of 50. If the only reason hormone therapy has been prescribed is for osteoporosis prevention, other options 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.
Post-transplantation Bone Loss
Antiresorptive therapy and calcitriol may be effective at preventing bone density loss after transplantation [A]. Considering the rates of bone loss after transplantation described in Annotation #3, "Patient on Chronic Glucocorticoid Therapy of Transplant Recipient," 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 are 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 [A].
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.
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 [A].
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 [C], [D].
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, risedronate, and ibandronate. [Conclusion Grade I: See Conclusion Grading Worksheet B -- Annotation #13 (Bisphosphonates for Primary Osteoporosis) in the original guideline document]. (See Appendix B, "Recommended Pharmacologic Agents" in the original guideline document.)
Refer to the original guideline document for more information.
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 [A].
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 #13 (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 [A].
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 [A].
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 #13 (Bisphosphonates for Glucocorticoid-Induced Bone Loss) in the original guideline document].
In patients with high risk of fracture secondary to long-term glucocorticoid therapy, teriparatide may be considered a therapeutic option [A].
Teriparatide is only approved for duration of two years. A gradual decrease in bone mass has been noted after discontinuation of teriparatide therapy; however, following therapy with a bisphosphonate has been shown to preserve the benefits [M], [R].
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 [A] and zoledronate [A] may prevent bone loss after organ transplantation. A few small studies have evaluated oral bisphosphonate therapy in post-transplant patients [A], [B], [R].
Bisphosphonates and the Risk of Osteonecrosis of the Jaw
The risk of development of osteonecrosis of the jaw (ONJ) in postmenopausal osteoporotic patients treated with oral or intravenous bisphosphonates appears to be very low, as only a small number of cases have been reported, most associated with alendronate therapy. Based on review of the published literature and unpublished data, the current risk estimate for ONJ in patients with postmenopausal osteoporosis is between 1 in 10,000 and less than 1 in 100,000 patient-treatment years [M]. The pathophysiology of this condition is not known, but it may be associated with excessive suppression of bone turnover, decreased angiogenesis, or dental infection or trauma.
In summary, bisphosphonate-associated ONJ appears to occur most commonly in patients with multiple myeloma or breast or prostate cancer metastatic to the skeleton who receive frequent intravenous infusions of potent nitrogen-containing bisphosphonates. This disorder appears to be rare in postmenopausal women or men treated with oral bisphosphonates for osteoporosis. Jaw osteonecrosis may occur during treatment with intravenous or oral bisphosphonates, but 94% of cases in the largest series to date [M] occurred with intravenous zoledronic acid or pamidronate in cancer patients. Risk factors include cancer, frequent infusions of intravenous nitrogen-containing bisphosphonates, and dentoalveolar trauma or infection. Before beginning therapy with oral or intravenous bisphosphonates, patients should be referred for dental care to address dental issues. Bisphosphonate therapy should not be started until dental issues have been resolved. Treatment with systemic antibiotics and oral antibiotic rinses may help with pain and eventually lead to healing. Stopping bisphosphonate therapy may be prudent, as anecdotal evidence suggests that this may help in some cases. Aggressive dental surgery should generally be avoided.
Bisphosphonates and Risk of Atrial Fibrillation
Recent publications have suggested that at least some postmenopausal women taking oral or intravenous bisphosphonates for osteoporosis may be at increased risk of atrial fibrillation. The HORIZON Trial [A] demonstrated an unexpected mildly increased risk of serious atrial fibrillation. This was not seen in a subsequent trial of postmenopausal women following hip fracture that showed that zoledronic acid reduced fractures and mortality but did not show an increased incidence of atrial fibrillation in this older population at higher risk of atrial fibrillation [A]. Reanalysis of the Fracture Intervention Trial with alendronate and a retrospective review of risedronate data did not show an increased risk of atrial fibrillation [A], [NA]. Conflicting data is reported from two separate population-based case control studies [C]. In light of the conflicting results from these studies, it is premature to stop oral or intravenous bisphosphonates in patients with postmenopausal osteoporosis due to concerns about atrial fibrillation. Patients who are currently on bisphosphonates are advised to continue their medication as prescribed and to direct any questions they have about their medication to their health care provider.
Selective Estrogen Receptor Modulator (SERM)
The only SERM approved for the prevention and treatment of osteoporosis is raloxifene.
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) [A].
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 [A].
In the STAR trial [A], raloxifene was found comparable to tamoxifen for the prevention of invasive breast cancer. Thus, raloxifene appears to be the drug of choice for women with osteoporosis if the main risk is of spinal fracture and there is an elevated risk of breast cancer.
Calcitonin
Treatment of Osteoporosis in Postmenopausal Women
Nasal salmon-calcitonin 200 international units 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 [A].
Post-transplantation
Several studies have shown that nasal spray calcitonin has little effect on prevention of bone loss after organ or bone marrow transplantation [A].
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 complementary agents (phytoestrogens, ipriflavone, natural progesterone, magnesium, vitamin K, eicosapentaenoic and gamma-linolenic acid supplementation, and kampo formulae).
Alternative and Complementary Agents
Adherence to Medications for Bone Loss
Adherence (compliance + persistence) is a major problem with medications for bone loss. The literature suggests that 45% to 50% of patients on one of these agents have stopped them within one year [B]. Adherence to therapy was associated with significantly fewer fractures at 24 months [B]. The use of follow-up bone densitometry and bone markers has not been shown to improve adherence. Follow-up phone calls or visits have shown improvement in adherence [R]. Although not studied, a close relationship with a primary care provider who thoroughly discusses the rationale, risks and benefits of treatment most likely improves adherence significantly, especially if followed up by a phone call or visit. Several studies support weekly bisphosphonate dosing versus daily, and/or monthly dosing versus weekly to improve compliance [A], [B].