Dear Editor,
We read with interest the paper by Tanaka and colleaguesCitation1. The authors evaluated the efficacy of bone turnover markers (BTM) and bone mineral density (BMD) in predicting vertebral fracture risk reduction in patients treated with once weekly teriparatide for 72 weeks. A variable response of bone formation markers was noted: a reduction in bone-specific alkaline phosphatase during the first 24 weeks with stabilization thereafter, an increase in osteocalcin concentrations, remaining high until the end of the study, and a biphasic fluctuation in procollagen type 1 amino-terminal propeptide (P1NP) concentrations, that is, an initial increase until 4 weeks, followed by a decrease to lower than baseline concentrations at 12 weeks. Regarding bone resorption, urinary concentrations of N-terminal telopeptide (NTX) were stable during the study, whereas serum NTX concentrations showed an increase after 24 weeks. The authors concluded that vertebral fracture risk reduction is mainly explained by increased BMD rather than by BTM (83% and 66% of the treatment effect, respectively) as estimated by two separate methods.
A few comments may be of interest. Once weekly teriparatide appears to be effective in vertebral fracture risk reduction, as the same group showed previously, demonstrating an 80% reduction in vertebral fracture risk after 72 weeks of treatment, although there was no significant reduction in non-vertebral fracturesCitation2.
Teriparatide increases BMD and bone turnover by initially stimulating bone formation before bone resorption, an effect known as the ‘anabolic window’Citation3. After this period, bone formation is reduced and bone resorption is increased, but the active balance leads to an increase in BMD after 18 monthsCitation4. The reduction in vertebral fracture risk demonstrated by once weekly teriparatide was surprisingly higher than previously been reported with a once daily formulationCitation1.
It is surprising that a 6.7% increase in BMD accounts for a 66–83% reduction in fracture risk and the authors should provide a more plausible explanation, taking into account that the contribution of BMD response to treatment with bisphosphonates in fracture risk reduction is much lower (12–18%)Citation5,Citation6. Moreover, a recent meta-analysis showed that teriparatide-mediated increases in spine BMD accounted for 25–32% of vertebral fracture risk reductionCitation7. The non-significant effect on non-vertebral fracture risk is also another issue that should be discussed. The study included only Japanese patients, but previous studies did not report any difference regarding BMD responses to teriparatide according to ethnicityCitation7.
We suggest that an improvement in bone quality by teriparatide may also account for this high anti-fracture capacity. BMD, as measured by dual X-ray absorptiometry (DXA), cannot reflect the exact changes in bone micro-architecture, which influence fracture riskCitation3. Bone biopsies have shown that teriparatide improves bone geometry and trabecular connectivity, effects that cannot be seen with DXACitation3. Once weekly teriparatide has also been efficacious in increasing cortical thickness and improving biomechanical properties at the femoral neck and shaftCitation4.
Finally, BTM may not be useless in evaluating anti-fracture efficacy. Bone formation and resorption markers increase dramatically during the first 6–12 months of teriparatide once daily and, although there is uncertainty regarding the optimal BTM response to treatment, recent guidelines consider that decreasing bone resorption markers with anti-resorptive agents and increasing bone formation markers with anabolic drugs indicates a good response to treatmentCitation8. Finally, a recent consensus on the definition of failure of therapies to reduce fracture risk recommends that a significant response to treatment must be considered when 25% decline from baseline concentrations for bone resorption markers (mainly, serum C-telopeptide of type 1 collagen) with anti-resorptive treatments, and 25% increase in P1NP with anabolic agents after 6 months is observedCitation9.
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This letter was not funded.
Declaration of financial/other relationships
This letter was written independently. The authors did not receive financial or professional help with the preparation of the manuscript.
References
- Tanaka S, Kuroda T, Sugimoto T, et al. Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide. Curr Med Res Opin 2014;30:931-6
- Nakamura T, Sugimoto T, Nakano T, et al. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 2012;97:3097-106
- Girotra M, Rubin MR, Bilezikian JP. The use of parathyroid hormone in the treatment of osteoporosis. Rev Endocr Metab Disord 2006;7:113-21
- Ito M, Oishi R, Fukunaga M, et al. The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT. Osteoporos Int 2014;25:1163-72
- Watts NB, Geusens P, Barton IP, et al. Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res 2005;20:2097-104
- Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004;7:255-61
- Nakamura T, Tsujimoto M, Hamaya E, et al. Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide: a meta-analysis. J Bone Miner Metab 2012;30:321-5
- Watts NB, Adler RA, Bilezikian JP, et al.; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:1802-22
- Diez-Perez A, Adachi JD, Agnusdei D, et al.; IOF CSA Inadequate Responders Working Group. treatment failure in osteoporosis. Osteoporos Int 2012;23:2769-74