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IMS Menopause Live

Treatment failure in osteoporosis

29 August, 2012:

The treatment goal in osteoporosis is to reduce fracture risk. But how do we estimate if this has been achieved in an individual patient? In other words, how do we know that a certain therapy is effective or not? A very respectable working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) was convened to define outcome variables that may assist clinicians in decision-making [1]. In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodeling markers are not suppressed by antiresorptive therapy, and where bone mineral density continues to decrease. The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.


What is treatment failure in osteoporosis? For most of us, it would be a decrease in bone density despite therapy; for others, a new fracture means failure. But is it so simple and clear? First, we must ensure that our patient was compliant, because adherence to therapy has a direct association with fracture risk reduction and increase in bone mineral density (BMD) [2]. Second, how can we determine that a certain fracture was osteoporosis-related? The IOF document states that 'Fractures of the hand, skull, digits, feet and ankle are not considered as fragility fractures' [1]. Healthy bones will break if the trauma is forceful enough. Contrarily, hip and vertebral fractures that occur with minimal or no trauma, especially in the elderly population, are usually categorized as related to osteoporosis. Third, we have to be sure that the reason for our patient's non-response to therapy is not the result of suffering from secondary osteoporosis that needs an assessment of potential endocrinological, gastroenterological or many other conditions that may cause some derangements of bone metabolism.

On average, one should expect a reduction of around 40–60% in fracture risk for the spine and hip/femur areas in a cohort that uses an effective treatment. Thus, the mere occurrence of a fracture during the course of treatment cannot be taken automatically as proof of treatment failure. We must also remember that bone strength is determined by many factors. No therapy so far can guarantee complete prevention of future fractures.


In view of the above, the IOF document suggests that health-care providers should use pre- compared to during-therapy values of BMD and bone markers to evaluate the outcome of treatment [1]. Treatment failure is defined as 'An overall decline in BMD in the order of 5% or more in at least two serial BMD measurements at the lumbar spine or 4% at the proximal femur. Sequential measurement of markers of bone turnover should use the same assay. A significant response is a decline of 25% from baseline levels for antiresorptive treatments, and 25% increase for anabolic agents (PTH) after 6 months. For antiresorptive treatments, if baseline levels are not known, a positive response is a decrease below the average value of young healthy adults. It is assumed that the response is similar between men and women.' A recent 13-year study of 5000 women > 40 years of age concluded that the annualized percentage change in total hip BMD was no greater in fracture compared to non-fracture women [3]. The IOF document does not specify how often a repeat bone density should be done. There is a debate in the literature about the optimal interval between two consecutive BMD measurements. A recent New England Journal of Medicine paper [4] suggested that, in postmenopausal women, screening intervals should be set at approximately 15 years for women with normal bone density or mild osteopenia (T-score, greater than 1.50) at the initial assessment, 5 years for women with moderate osteopenia (T-score, 1.50–1.99), and 1 year for women with advanced osteopenia (T-score, 2.00–2.49). In my country, the Health Basket allows a free follow-up densitometry only once in 2 years in treated patients. Bone markers are not reimbursed unless ordered by a bone specialist.

Despite so many obstacles related to trying to find an easy, practical definition for treatment failure, the IOF document presents its version on that matter: '(1) two or more incident fragility fractures; (2) one incident fracture and elevated serum CTX (serum C telopeptide of type I collagen), or PINP (serum procollagen I N-propeptide) at baseline with no significant reduction during treatment, a significant decrease in BMD, or both; and (3) both no significant decrease in serum CTX or PINP and a significant decrease in BMD.' Whether or not these definitions are really helpful once a practitioner faces a decision in regard to treatment failure, I cannot say.

Amos Pines

Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel


1. Diez-Perez A, Adachi JD, Agnusdei D, et al. Treatment failure in osteoporosis. Osteoporos Int 2012 Jul 27. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/22836278 

2. Sampalis JS, Adachi JD, Rampakakis E, et al. Long-term impact of adherence to oral bisphosphonates on osteoporotic fracture incidence. J Bone Miner Res 2011 Oct 4. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/21976304 

3. Leslie WD, Morin SN, Lix LM; Manitoba Bone Density Program. Rate of bone density change does not enhance fracture prediction in routine clinical practice. J Clin Endocrinol Metab 2012;97:1211-18. http://www.ncbi.nlm.nih.gov/pubmed/22278427 

4. Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med 2012;366:225-33. http://www.ncbi.nlm.nih.gov/pubmed/22256806 

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