Protection from Osteoporosis for Two Years with One Shot?

The balance between collagen and mineral components that make up bone is delicate to maintain bone strength and stiffness. Imbalances in these components can impair bone quality and reduce strength, leading to osteoporosis. Increasing bone mass decreases bone fracture risk. Bone mass can be increased by modifying lifestyle factors or by medication administration.1

Zoledronic acid (Reclast®, Zometa®) is a bisphosphonate indicated by the Food and Drug Administration (FDA) for postmenopausal, male, and glucocorticoid-induced osteoporosis. Bisphosphonates decrease osteoclast maturation, number, recruitment, bone adhesion, and lifespan and indirectly increase bone mineral density. Zoledronic acid is administered intravenously (IV) and is 40% excreted, compared to 50-65% of other oral bisphosphonates. Zoledronic acid also has fewer gastrointestinal side effects and is used in patients who have intolerances to oral bisphosphonates.1

The American College of Obstetricians and Gyencologists’ guidelines for osteoporosis recommend any FDA-approved therapy be used including raloxifene, bisphosphonates, parathyroid hormone, denosumab, or calcium. No treatment algorithm or preferential treatment is suggested.2 The Medical Services Commission recognizes that bisphosphonates have the largest body of randomized controlled trial evidence of all therapies in osteoporosis. However, cost effectiveness is low with zoledronic acid and it is therefore recommended to be reserved for high-risk patients unable to tolerate oral therapy.3

According to the University of Michigan Health System guidelines, the World Health Organization’s Fracture Risk Assessment Tool (FRAX) should be used to assess the need for treatment. Medication is recommended to begin in patients with 10-year fracture risks greater than 3% at the hip or 20% total. Zoledronic acid is only recommended to reduce hip and vertebral fracture risk in post-menopausal women and glucocorticoid-induced osteoporosis.4

Title: Efficacy and Safety of Single-Dose Zoledronic Acid for Osteoporosis in Frail Elderly Women5
Design Randomized, placebo-controlled, double-blinded study; N = 181
Objective To determine the efficacy and safety of zoledronic acid to treat osteoporosis in frail elderly women in long-term care facilities
Study Groups One 5 mg dose of zoledronic acid or placebo IV
Methods All participants were older than 65 years, resided in a nursing home or assisted-living facility and had history of vertebral or hip fracture or osteoporosis. A bone mineral density (BMD) lower than −2.0 at the spine, hip, or radius was considered osteoporosis. All participants received a daily divided dose of vitamin D (800 IU per day) and 1200 mg per day of elemental calcium (supplement plus diet). Patients were randomized 1:1 to receive either zoledronic acid or placebo. Baseline blood tests and BMD values were obtained. Subsequent follow-up visits after randomization occurred at six, 12, and 24 months.
Duration December 2007 – March 2012
Primary Outcome Measure Percentage change in BMD of the total hip and spine at 12 months
Baseline Characteristics At baseline, both groups had substantial impairment: 95% of participants were categorized as frail/pre-frail, 74% were dependent in at least once basic activity of daily living (and 31% in at least 3), and 85% had a gait speed characteristic of frailty (<0.8 m/s). There were no group differences in age (p = 0.85), body mass index (p = 0.29), or calcium (p = 0.50) or vitamin D (p = 0.83) intake.
Results Mean total hip BMD increased more in the treatment group than in the placebo group, both at 12 months (2.8% vs −0.5%, p < .001) and 24 months (2.6% vs. −1.5%, p < .001).  Mean spine BMD also increased more in the treatment group than in the placebo group at 12 months (3.0% vs. 1.1%, p = .01) and 24 months (4.5% vs. 0.7%, p < .001).
Adverse Events Common Adverse Events: headache (16%), pyrexia (8%), fatigue (24%), arthralgias (11%), myalgias (8% treatment), influenza-like illness (7%), falls (5%), calcium <8.4 g/dL (2%)
Serious Adverse Events: 67% treatment vs. 60% placebo, p = 0.29

Eighteen women in the treatment group (20%) and 15 in the placebo group (16%) experienced any fracture (p = .50), six of them vertebral in the treatment group (7%) and eight vertebral in the placebo group (9%).

Percentage that Discontinued due to Adverse Events: Fourteen participants in the treatment group (16%) and 12 in the placebo group (13%) died during the study period (p = .61).
Study Author Conclusions We found that, compared with calcium and vitamin D alone, adding a single dose of intravenous zoledronic acid significantly improved BMD of the hip and spine over two years. Changes in bone turnover suggest that zoledronic acid had a continued effect for two years after a single dose. There were no significant differences in serious adverse events through 24 months, although fracture and mortality rates were descriptively higher in the zoledronic acid group. Despite the robust increase in BMD at the hip and spine, we did not observe a reduction in total or vertebral fractures.

This study is applicable to a population susceptible to osteoporosis: elderly, frail women. Because only 180 women were required to be recruited for 95% power to detect a difference in BMD of 2.4% at the spine and 86% power to detect a difference in BMD of 1.6% at the femoral neck (using a two-tailed t-test), the sample size was appropriate to meet the power requirements. However, the treatment group was significantly frailer at baseline than the placebo group, which may have affected the fracture rates. It is unknown whether such frail individuals can benefit from zoledronic acid therapy due to the compromised skeletal integrity. In less frail elderly women, a single infusion of zoledronic acid may benefit skeletal health and would be convenient for both patients and doctors. Therefore, the findings of this study are likely clinically significant.

References

1.) O’Connell M, Borchert JS.Chapter 73. Osteoporosis and Other Metabolic Bone Diseases. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L.  Pharmacotherapy: A Pathophysiologic Approach, 9eNew York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811480. Accessed June 09, 2015.

2.) American College of Obstetricians and Gynecologists (ACOG). Osteoporosis. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2012 Sep. 17 p.

3.) Medical Services Commission. Osteoporosis: diagnosis, treatment and fracture prevention. Vancouver (BC): British Columbia Medical Services Commission; 2011 May 1. 15 p.

4.) Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic Acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med. 2015;175(6):913-21.

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