Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial

Abstract

BACKGROUND Unlike most chronic diseases, approved osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of most osteoporosis drugs remains controversial due to efficacy and safety concerns. Thus, many patients are treated with the sequential use of two or more therapies. Discontinuing teriparatide and denosumab, two of our most potent agents, results in rapidly declining bone mineral density (BMD). It is unknown if switching from one therapy to another prevents this decline or further increases BMD. METHODS This study is a pre-planned extension of the Denosumab and Teriparatide Administration study (DATA), a 24-month study in which 94 postmenopausal osteoporotic women were randomized to receive 24-months of teriparatide (20-μg-daily), denosumab (60-mg-every-6-months), or both drugs. In this extension trial, women originally assigned to 24-months of teriparatide received 24-months of denosumab whereas subjects originally randomized to 24-months of denosumab received 24-months of teriparatide. Subjects who originally received both drugs, received an additional 24-months of denosumab alone. BMD at the hip, spine and wrist were measured 6,12,18, and 24 months after the drug transitions as were biochemical markers of bone turnover. FINDINGS Transitioning from teriparatide or combination therapy to denosumab further increases BMD whereas switching from denosumab to teriparatide results in transient bone loss at the spine and hip and progressive loss at the radius shaft. After 48-months, spine BMD increased by18.3±8.5%, 14.0±6.7%, and 16.0±4.1% in the teriparatide-to-denosumab, denosumab-to-teriparatide, and combination-to-denosumab groups, respectively (P=NS for between-group comparisons). Conversely, total hip BMD increased most in the combination-to-denosumab group (8.6±3.0%), intermediately in the teriparatide-to-denosumab group (6.6±3.3%) and least in the denosumab-to-teriparatide group (2.7±3.3%), (P<0.05 for all between-group comparisons). Femoral neck BMD changes resembled those at the total hip. After 48-months, radius BMD was unchanged in the teriparatide-to-denosumab group (0.0±2.9%), decreased by −1.8±5.9% in the denosumab-toteriparatide group, and increased by 2.8±3.2% in the combination-to-denosumab group (P<0.01 combination-to-denosumab versus both other groups). INTERPRETATION In postmenopausal osteoporotic women switching from teriparatide to denosumab, BMD continued to increase whereas switching from denosumab to teriparatide results in progressive or transient bone loss. Combination denosumab/teriparatide therapy followed by denosumab alone results in the largest 4-year increases in hip and wrist BMD. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients.

Goal-Directed Treatment for Osteoporosis: A Progress Report From the ASBMR-NOF Working Group on Goal-Directed Treatment for Osteoporosis

“…(38) It is not clear that switching treatment will offer additional reduction in risk of nonvertebral fracture. (4,(39)(40)(41)(42)(43)(44) Based on studies from patients who are not receiving treatment, the increase in risk of fracture associated with an incident nonvertebral fracture may be greatest in the first 5 years after the fracture occurs and then wane with time. (24)(25)(26)(27)(28)(29)(30)(31) Furthermore, in patients receiving zoledronic acid, incident nonvertebral fracture is an important risk factor for future nonvertebral fractures over the next 3 years if therapy is discontinued.…”

An Essential Warning

“…Additionally, it is very clear that switching from denosumab to the anabolic agent teriparatide, and presumably abaloparatide as well, should be avoided because this transition is associated with even more extensive skeletal remodeling and even greater bone loss than that observed when denosumab is discontinued without a drug transition. (14) Finally, although not addressing the issue directly, this report raises questions concerning the optimal timing of bisphosphonate administration when used after denosumab. Given bisphosphonates' mechanism of action and preferential deposition at sites of active bone remodeling, (15) it is plausible that if exposure occurs while denosumab's antiresorptive effects are still maximal, the drug will be considerably less effective than if given to a patient with ongoing robust bone turnover.…”

Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis

“…(18)(19)(20)(21)(22)(23) This is certainly true of TPTD and PTH. (24)(25)(26)(27)(28)(29)(30) BMD responses to initial TPTD/PTH followed by potent antiresorptive therapy are substantial in both spine and hip sites as a result of the effects of both components of the treatment sequence. (28,(31)(32)(33)(34) In contrast, several studies have indicated that hip BMD responses to TPTD are lower in patients who have already been pretreated with potent antiresorptive therapies and consistently decline transiently for the first year or even longer.…”

“…(24)(25)(26)(27)(28)(29)(30) BMD responses to initial TPTD/PTH followed by potent antiresorptive therapy are substantial in both spine and hip sites as a result of the effects of both components of the treatment sequence. (28,(31)(32)(33)(34) In contrast, several studies have indicated that hip BMD responses to TPTD are lower in patients who have already been pretreated with potent antiresorptive therapies and consistently decline transiently for the first year or even longer. (24)(25)(26)(27)(28)30) Although there are no fracture endpoint trials in these antiresorptive pretreated patients, the substantial differences in BMD outcome, particularly for the hip region, suggest that TPTD effects against fracture could also differ in these pretreated patients.…”