Search:
Menopause Live - IMS Updates
InFocus

Date of release: 15 January, 2018

Duration and management of osteoporosis drug treatment after discontinuation

The Swiss Association against Osteoporosis has published a position statement on the duration and the management of osteoporosis drug treatment after discontinuation, focusing on the long-term management of osteoporosis therapy in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density (BMD) [1]. Most patients start with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (estrogens, selective estrogen receptor modulators, bisphosphonates, denosumab). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation.



A patient is considered to remain at high risk of fracture if any of the following conditions is present: (1) hip, spine or multiple osteoporotic fractures within 5 years before and/or during therapy; (2) high fracture risk score at baseline according to FRAX and/or continuously high fracture risk based on clinical judgment or co-morbidities (e.g. continuous use of aromatase inhibitors for breast cancer, diabetes, frailty); (3) persistent low BMD. Those with a T-score persistently lower than ˗2.5 SD at the femoral neck or <˗2.0 SD in older patients and/or frequent fallers) benefit the most from continuing therapy [1]. Regular reassessment of fracture risk for decision of treatment duration is essential.

Comment

Based on the Swiss position statement and other recent publications, the following rules for osteoporosis drug treatment can be formulated:

(1) The effect of menopausal hormone therapy (MHT) on bone metabolism ends with the cessation of estrogen administration. However, the effect of MHT on trabecular bone score (TBS) and BMD persists at least 2 years after withdrawal [2]. In the WHI trial, through 5 years after discontinuation, there is no evidence for increased fracture risk, either sustained or transient, for former MHT users compared with former placebo users after stopping MHT [3]. A long-lasting decrease in fracture risk has been found for all major fractures up to 16 years after discontinuation of hormone therapy (number needed to treat = 7) [4]. Prevention of fragility fractures is an independent indication for MHT. There is no reason to place mandatory limits on the duration of MHT [5, 6].

(2) For postmenopausal women who have been on treatment with SERMs for 3–5 years and are considered at high fracture risk (see above), switching treatment to bisphosphonates or denosumab should be considered [1].

(3) For postmenopausal women who have been on oral or intravenous (i.v.) bisphosphonate therapy for 3 years (i.v.) to 5 years (oral), reassessment of individual fracture risk is mandatory. Discontinuation of bisphosphonates may be considered in patients with normal risk who have been treated for more than 5 years with alendronate, risedronate or zoledronic acid. In patients with low-to-moderate fracture risk, a drug holiday has been suggested with clinical, biochemical and densitometric reassessment every 2–3 years [1, 8-10]. However, a recent study showed that women who took a drug holiday of more than 2 years showed the highest rate of hip fractures and were associated with a significantly increased risk for hip fracture of up to 39% compared to continued bisphosphonates use [11] so that regular reassessment of fracture risk is mandatory. In view of the limited evidence, no robust recommendations can be made for ibandronate and denosumab [12]. In women at high risk (see above), treatment should preferentially be switched to denosumab, as comparison studies have shown superiority of denosumab over bisphosphonates in treatment-related changes in BMD [1, 7]. For women on bisphosphonate therapy with an incident vertebral fracture, bone-anabolic treatment with teriparatide for 24 months is advised [1]. Alternatively, continuation of treatment for up to 10 years (oral bisphosphonates) or 6 years (intravenous bisphosphonates) may be considered [1], depending on the risk (increased risk of osteonecrosis of the jaw and atypical femoral fractures) and the benefit (fracture risk reduction).

(4) For postmenopausal women who have been on denosumab therapy for at least 3–5 years, reassessment of individual fracture risk is suggested. In women at high risk (see above), continuation of treatment for up to 10 years should be considered, especially in women on an aromatase inhibitor. In the case of incident new vertebral fractures during denosumab therapy, combination therapy, with teriparatide for 24 months followed by antiresorptive therapy, should be considered on the basis of the favorable effects of combination therapy on BMD, although evidence for fracture risk reduction is lacking [1, 13, 14]. In women with a favorable treatment response to denosumab in which therapy discontinuation is considered (low fracture risk, BMD increase into age-adjusted range, cessation of aromatase inhibition), sequential treatment with non-reversible antiresorptives (bisphosphonates, or SERMs in cases of bisphosphonate intolerance) is mandatory, particularly in older women with prevalent vertebral fractures and in women without previous long-term therapy with one of the more potent bisphosphonates (alendronate, zoledronate). Sequential therapy may be guided by the rebound in bone turnover markers, particularly in patients with prior bisphosphonate therapy [14, 15]. Treatment with non-reversible antiresorptives may be needed for up to 12–24 months. Within 1–2 years of denosumab treatment cessation, BMD decreases to baseline levels regardless of the duration of previous therapy [16]. After a few clinical cases of vertebral fractures were reported upon cessation of denosumab therapy [17, 18], data from the FREEDOM study and its extension confirmed that vertebral fracture incidence increased nearly four-fold within a year after denosumab was stopped [19]. The incidence of multiple new vertebral fractures tended to be higher in women who discontinued denosumab than in subjects who discontinued placebo. Prescribers should be warned against the sudden interruption of denosumab and the need to consolidate therapy with at least 1 year of a non-reversible antiresorptive drug. In patients suffering vertebral fractures after discontinuation of denosumab, percutaneous vertebral cement augmentation should be used with caution as vertebroplasty has been associated with a high number of new vertebral fractures in these circumstances [17]. Instead, pharmacological treatment should be restarted, either with denosumab (eventually in combination with teriparatide) or zoledronate.

(5) The anabolic effects of teriparatide on bone are transient and limited to the time of exposure. Sequential therapy with antiresorptive drugs (bisphosphonates, denosumab) is mandatory to maintain bone mass and improve secondary mineralization [1].

(6) When considering the duration of and options for osteoporosis treatment, the potential contributions of poor compliance or adherence to therapy, inadequate vitamin D status, high fall risk, or new risk factors should be considered [1].

(7) Current guidelines recommend that treatment of any osteoporotic drug should always be supplemented with vitamin D at a dose of 800 IU per day to ensure a replete vitamin D status. Advice on an adequate calcium intake of 1000 mg per day from nutritional sources is considered a basic strategy in combination with osteoporotic drug treatment. If calcium intake to a target range of 1000 mg cannot be achieved through nutritional sources alone, a calcium supplement of 300–500 mg/day is recommended [1].

Comentario

Martin Birkhaeuser


Professor Emeritus for Gynaecological Endocrinology and Reproductive Medicine, University of Berne, Switzerland



    References

  1. Meier C, Uebelhart B, Aubry-Rozier B, et al. Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the Swiss Association against Osteoporosis (SVGO/ASCO). Swiss Med Wkly 2017;147:w14484


    https://doi.org/10.4414/smw.2017.14484

  2. Papadakis G, Hans D, Gonzalez-Rodriguez E, et al. The benefit of menopausal hormone therapy on bone density and microarchitecture persists after its withdrawal. J Clin Endocrinol Metab 2016;101:5004–11


    http://www.ncbi.nlm.nih.gov/pubmed/27854548

  3. Watts NB, Cauley JA, Jackson RD, et al. No increase in fractures after stopping hormone therapy: results from the Women’s Health Initiative. J Clin Endocrinol Metab 2017;102:302–8


    http://www.ncbi.nlm.nih.gov/pubmed/27820659

  4. Bagger YZ, Tank LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004;34:728–35


    http://www.ncbi.nlm.nih.gov/pubmed/15050905

  5. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353–68


    http://www.ncbi.nlm.nih.gov/pubmed/24084921

  6. Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19:109–50


    http://www.ncbi.nlm.nih.gov/pubmed/26872610

  7. Beaudoin C, Jean S, Bessette L, Ste-Marie LG, Moore L, Brown JP. Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis. Osteoporos Int 2016;27:2835–44


    http://www.ncbi.nlm.nih.gov/pubmed/27120345

  8. Black DM, Schwartz AV, Ensrud KE, et al.; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Longterm Extension (FLEX): a randomized trial. JAMA 2006;296:2927–38


    http://www.ncbi.nlm.nih.gov/pubmed/17190893

  9. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012;27(2):243–54


    http://www.ncbi.nlm.nih.gov/pubmed/22161728

  10. Adler RA, El-Hajj Fuleihan G, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016;31:16–35


    http://www.n cbi.nlm.nih.gov/pubmed/27759931

  11. Curtis J, et al. Women who discontinue bisphosphonates for two years or more have higher hip fracture risk. Presented at the 2017 ACR/ARHP Annual Meeting in San Diego




  12. Anagnostis P, Paschou SA, Mintziori G, et al. Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement. Maturitas 2017;101:23–30


    http://www.ncbi.nlm.nih.gov/pubmed/28539165

  13. Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382:50–6


    http://www.ncbi.nlm.nih.gov/pubmed/23683600

  14. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 2015;386:1147–55


    http://www.ncbi.nlm.nih.gov/pubmed/26144908

  15. Uebelhart B, Rizzoli R, Ferrari S. Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates.. Osteoporos Int 2017;28:2701–5


    http://www.ncbi.nlm.nih.gov/pubmed/28540505

  16. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 2011;96:972–80


    http://www.ncbi.nlm.nih.gov/pubmed/21289258

  17. Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after denosumab discontinuation: nine clinical cases report. J Clin Endocrinol Metab 2017;102:354–8


    http://www.ncbi.nlm.nih.gov/pubmed/27732330

  18. Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res 2017;32:1291-6


    http://www.ncbi.nlm.nih.gov/pubmed/28240371

  19. Brown JP, et al. Discontinuation of denosumab and associated vertebral fracture incidence: analysis from FREEDOM and its extension. In Proceedings of the Annual Meeting of Bone and Mineral Research, ASBMR, 2016. Atlanta, Sept 16–19