Endocrine Abstracts

JOINT1334

Introduction: As molecular genetic testing became more available, we are now able to better identify different molecular causes of monogenic osteoporosis. Unfortunately, their treatment remains uncertain.

Clinical case: An 18-year-old male presented in our clinic with a history of multiple fractures preceded by medium intensity traumas, occurring from age seven. Although none of them were classic fragility fractures, their frequency prompted further investigation. He had normal development and no other clinical features. Endocrine work-up was normal, except for a mild functional hyperprolactinemia. Serum osteocalcin and beta-crosslaps were within range. He had a low bone mineral density for age and sex, with Z scores of -2.5 DS (lumbar) and -2.9 DS (left femoral neck). We suspected osteogenesis imperfecta, advised genetic consult and recommended oral bisphosphonates (not administered due to poor compliance). Five years later, the patient managed to obtain a genetic test, showing a heterozygote mutation of WNT1 gene, consistent with autosomal dominant early onset osteoporosis. No new fractures occurred since last visit. Repeated osseous metabolism markers showed a slightly elevated alkaline phosphatase and normal, though in the lower range, osteocalcin and beta-crosslaps. He had a slight leukopenia and no other notably endocrine or metabolic disturbances with stationary BMD.

Discussion: Fratzl-Zelman et al¹ demonstrated that this mutation is associated with low bone turnover osteoporosis, rendering bisphosphonate treatment inefficient, in line with other reports² of bisphosphonates showing no effects in these patients. Moreover, they showed that teriparatide treatment produced little to no improvement. Other study showed a positive effect of teriparatide, although rising questions regarding increased bone marrow adiposity in these patients³. Romosozumab could be a potential targeted treatment.

Case resolution and conclusions: Lifestyle modification was advised and given the stable clinical and densitometric evaluation, treatment initiation was postponed. As more cases of monogenic WNT1 osteoporosis are recognized, more studies are necessary to find an appropriate treatment plan. So far, different treatment choices have conflicting outcomes.

References: 1. Fratzl-Zelman N et al. Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations. Bone. 2021;146:115900. doi:10.1016/j.bone.2021.115900. 2. Turin CG et al. Heterozygous variant in WNT1 gene in two brothers with early onset osteoporosis. Bone Rep. 2021;15:101118. doi:10.1016/j.bonr.2021.101118. 3. Välimäki VV et al. Teriparatide treatment in patients with WNT1 or PLS3 mutation-related early-onset osteoporosis: A pilot study. J Clin Endocrinol Metab. 2017;102(2):535–44. doi:10.1210/jc.2016-2423.