Menopause Live - IMS Updates

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.


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].


Martin Birkhaeuser

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


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  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

  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

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  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

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  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

  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

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