Using Osteoporosis Therapies in Combination
- 1.3k Downloads
Purpose of review
The objective of this review is to update evidence regarding the use of osteoporosis drugs in sequence or in combination to optimize increases in bone mass and strength.
Simultaneous use of denosumab plus teriparatide produces larger increases in BMD than does monotherapy. The use of bisphosphonates or denosumab after teriparatide results in progressive gains in BMD. When switching from bisphosphonates and especially denosumab to teriparatide, an overlap of 6-12 months may prevent the transient loss of BMD in cortical sites. Phase 3 trials document fracture risk reduction with anabolic therapy for 12-18 months followed by an anti-remodeling drug.
With the exception of adding teriparatide to ongoing denosumab therapy, there is little evidence to support the use of more than one osteoporosis drug at a time. In contrast, sequential therapy regimens of anabolic drugs followed by potent anti-remodeling agents will be the new standard for treating patients at imminent risk of fracture.
KeywordsOsteoporosis anabolic anti-remodeling combination sequential
Compliance with Ethical Guidelines
Conflict of Interest
Michael McClung reports receiving payment from Amgen, Merck, and Radius Health as a member of their scientific advisory boards and for speaking at scientific meetings.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 7.•• Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532–43. In this phase 3 fracture endpoint trial, romosozumab was administered for one year followed by denosumab for an additional 12 months. The substantial reduction in vertebral fracture risk achieved with romosozumab during your one was maintained in year two compared to the effect of placebo followed by denosumab CrossRefGoogle Scholar
- 8.•• Cosman F, Miller PD, Williams GC, Hattersley G, Hu MY, Valter I, et al. Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: results of the ACTIVExtend Trial. Mayo Clin Proc. 2017;92:200–10. This is the extension of the phase 3 fracture endpoint trial with abaloparatide in which 6 months of alendronate therapy after 18 months of abaloparatide maintained the reduction in fracture risk CrossRefGoogle Scholar
- 13.•• Seeman E, Martin TJ. Co-administration of antiresorptive and anabolic agents: a missed opportunity. J Bone Miner Res. 2015;30:753–64. This commentary reviews the physiological basis for the simultaneous use of anabolic and anti-remodeling agents, explains the limitation of areal BMD by DXA to evaluate the effectiveness of such combinations and urges more reliance on new imaging techniques to assess changes in structure and strength CrossRefGoogle Scholar
- 16.Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell NH, Downs RW, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2002;137:875–83.CrossRefGoogle Scholar
- 18.Harris ST, Eriksen EF, Davidson M, Ettinger MP, Moffett AH Jr, Baylink DJ, et al. Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2001;8:1890–7.Google Scholar
- 24.Schafer AL, Sellmeyer DE, Palermo L, Hietpas J, Eastell R, Shoback DM, et al. Six months of parathyroid hormone (1–84) administered concurrently vs sequentially with monthly ibandronate over two years: the PTH and ibandronate combination study (PICS) randomized trial. J Clin Endocrinol Metab. 2012;97:3522–9.CrossRefGoogle Scholar
- 28.Cosman F, Wermers RA, Recknor C, Mauck KF, Xie L, Glass EV, et al. Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive agent. J Clin Endocrinol Metab. 2009;94:3772–80.CrossRefGoogle Scholar
- 32.•• Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet. 2013;382(9886):50–6. This and the follow-up 2 year study (Leder, reference 33) demonstrated a BMD advantage in patients receiving combined therapy with denosumab and teriparatide compared to either therapy alone CrossRefGoogle Scholar
- 33.•• Leder BZ, Tsai JN, Uihlein AV, Burnett-Bowie SA, Zhu Y, Foley K, et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J Clin Endocrinol Metab. 2014;99:1694–700. The two-year extension of the DATA trial provides evidence that following teriparatide with denosumab is beneficial while beginning teriparatide when denosumab is discontinued, without an overlap of both drugs, should be avoided CrossRefGoogle Scholar
- 35.Tsai JN, Uihlein AV, Burnett-Bowie SA, Neer RM, Zhu Y, Derrico N, et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study. J Bone Miner Res. 2015;30:39–45.CrossRefGoogle Scholar
- 36.• Tsai JN, Uihlein AV, Burnett-Bowie SM, Neer RM, Derrico NP, Lee H, et al. Effects of two years of teriparatide, denosumab, or both on bone microarchitecture and strength (DATA-HRpQCT study). J Clin Endocrinol Metab. 2016;101:2023–30. Using high resolution QCT analysis in the day to trial, combined with therapy with denosumab plus teriparatide resulted in larger increments in trabecular and cortical bone mass and strength then did teriparatidemonotherapy, but the advantage of combined therapy over denosumab alone was small CrossRefGoogle Scholar
- 37.• Eriksen EF, Brown JP. Commentary: Concurrent administration of PTH and antiresorptives: additive effects or DXA cosmetics. Bone. 2016;86:139–42. This commentary suggests that the apparent BMD advantage of combining denosumab and teriparatide should be interpreted cautiously without more convincing evidence of a clinical advantage CrossRefGoogle Scholar
- 48.Brown JP, Roux C, Törring O, Ho PR, Beck Jensen JE, Gilchrist N, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013;28:746–52.CrossRefGoogle Scholar
- 50.Prolia Prescribing Information. http://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/prolia/prolia_pi.ashx. 2017, page 8. Accessed 26 February 2017.
- 60.Boonen S, Marin F, Obermayer-Pietsch B, Simões ME, Barker C, Glass EV, et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2008;93:852–60.CrossRefGoogle Scholar
- 61.Muschitz C, Kocijan R, Fahrleitner-Pammer A, Pavo I, Haschka J, Schima W, et al. Overlapping and continued alendronate or raloxifene administration in patients on teriparatide: effects on areal and volumetric bone mineral density--the CONFORS Study. J Bone Miner Res. 2014;29:1777–85.CrossRefGoogle Scholar