Letter to the Editor: “Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline”

We read with great interest the clinical guidelines concerning the pharmacological management of osteoporosis in postmenopausal women, by Eastell et al (1). The authors recommend denosumab as an alternative, initial treatment of osteoporosis (recommendation 3.1). The immediate implementation of this recommendation could have worrisome consequences for a large number of women as a result of the uncertainties on denosumab discontinuation (DD) management.

DD is associated with a severe rebound effect for 2 years, combining an increase in bone turnover markers (BTMs) and a complete loss of the gained bone mineral density (BMD) (2). In the absence of a potent bisphosphonate prescription at DD, 1% to 10% of women develop spontaneous multiple vertebral fractures (MVFs) (3, 4). Authors suggest that this is likely secondary to the absence of drug protection (return-to-baseline risk), rather than to a rebound phenomenon (increased risk beyond baseline), based on the results of the post hoc analysis of the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months Trial (3). However, this vertebral fracture (VF) annualized risk of 7.1% (60.7% multiple) is clearly underestimated, as (i) follow-up was too short: only 9 (n = 674) or 12 (n = 372) months from the last denosumab injection, and (ii) 14.5% took osteoporosis treatment (including denosumab). Moreover, the severity of the observed cases is not clearly depicted. In a series of 70 women with VF after DD, the median number of VF was five (minimum one, maximum 11) within 7 to 20 months (median 11) after the last denosumab injection (4). Thus, in most cases, MVFs have a detrimental effect on quality of life.

In the absence of randomized studies, uncertainties remain about strategies to control the rebound effect. As authors illustrate, some case series showed that the prescription of a bisphosphonate after DD reduces BMD loss. However, those case series [i.e., Horne et al. (5)] and a phase II study (6) also suggested that more potent bisphosphonates (zoledronic acid and alendronate, respectively) may be more efficacious than less potent ones, such as risedronate (5). Moreover, cases of MVF have been reported with raloxifene, ibandronate, or alendronate after DD but none after zoledronic acid. In those cases, BTM rebound was not sufficiently controlled. Thus we think that in accordance with the precautionary principle, the authors’ recommendation 3.3—to give any antiresorptive treatment, including hormone therapy, selective estrogen receptor modulators or “other therapy” after denosumab—is insufficient. Although the optimal bisphosphonate and its timing and duration of administration are unclear, a potent bisphosphonate should be recommended with a strict clinical and biological monitoring of BTM for 2 years. Based on the follow-up of >170 patients after DD (personal data), we suggest that the adjustment of the dose and frequency of bisphosphonate administration to maintain BTM in the premenopausal range would limit BMD loss and avoid VF (4). Another strategy to limit the rebound effect would be to give a potent bisphosphonate before the start-up of denosumab (4).

Pending validation studies of these strategies, contrary to recommendation 3.1, we propose denosumab as a second-line treatment limited to specific indications. A first-line prescription should be exceptional and imperatively left to the responsibility of a specialist in bone pathologies.

Acknowledgments

Disclosure Summary: The authors have nothing to disclose.

Abbreviations:

Abbreviations:
 
• BMD

  bone mineral density

 
• BTM

  bone turnover marker

 
• DD

  denosumab discontinuation

 
• MVF

  multiple vertebral fracture

 
• VF

  vertebral fracture

References and Notes