Short summary

Osteoporosis affects 11% of the Danish population, increasing fracture risk and mortality. Alendronate is a first-line treatment but due to rare, serious longterm side effects, treatment pauses are recommended to selected patients. Data on fracture risk following discontinuation are limited. This study seeks to fill this gap by investigating fracture risk and predictors during an alendronate treatment pause.

Rationale

Osteoporosis is a common disease that increases fracture risk, morbidity and mortality. The Danish Health Board estimates that up to 650,000 or 11% of the Danish population has osteoporosis. Alendronate has been first line treatment since early nineties, is generally well tolerated and has a low cost. However, the long-term effects of treatment beyond 10 years are largely unknown. The risk of serious side effects, such as osteonecrosis of the jaw and atypical femur fractures, rises with prolonged use but declines rapidly after cessation. This has led many guidelines, including the Danish, to recommend a treatment pause for selected patients, although some guidelines emphasize the increased fracture risk during the pause. The existing data on fracture risk during treatment pause are conflicting. The best-designed study (RCT) showed increased risk of clinical vertebral fractures, but not non-vertebral fractures. Additionally, hip BMD decreased gradually and reached pretreatment levels after five years. In this previous study, prevalent vertebral fracture and low BMD were strong predictors for vertebral fractures during five years of follow up. A large cohort study found a modest increased risk of all fractures (RR 0.92) in patients on treatment pause and no difference in hip fracture risk. A recent Danish register based study found no difference between long and short times users according to fracture risk. Vertebral fractures, especially multiple fractures, can cause pain, disability, and significantly increase mortality, which remains elevated for the rest of a patient's life. In contrast, mortality after hip fractures increases only for 2-3 years before returning to baseline. In this three-year, multicenter, single-blinded, randomized controlled trial we aim to investigate fracture risk and potential predictors of fractures and bone loss in an alendronate treatment pause.

Description of the cohort

This study will include 1400 women with postmenopausal osteoporosis, who have been treated with alendronate for at least three years without prior fractures in the last three years. Participants will be randomized to either continue alendronate treatment or cessation of treatment.

Data and biological material

Primary endpoint - Incidence of fragility fractures during the study period (Fx assesment) Secondary endpoints - Changes in BMD spine and hip (DXA-scans) - Changes in Bone Turnover Markers CTX and P1NP (blood samples) - Proportion of patients having to restart treatment - Adverse events. Exploratory endpoints - Clinical and paraclinical determinants of fracture and bone loss during Alendronate (ALN) discontinuation. For most patients this will include available data on BMD at (prestudy) treatment start and during prestudy treatment. - Histological, cellular and molecular predictors for pronounced bone loss after discontinuation

Collaborating researchers and departments

Department of internal medicin, Esbjerg Hospital

• Jeppe Gram

Department of endocrinology, Hvidovre Hospital

• Jens-Erik Bech Jensen

Department of endocrinology, Bispebjerg Hospital

• Pia Eiken

Department of internal medicine, Herlev Hospital

• Jakob Præst Holm

Department of Internal medicine, Nordsjællands Hospital

• Louise Tjelum

Department of endocrinology, Århus Universityhospital

• Bente Langdahl