Severe early-onset osteoporosis due to heterozygous WNT1 variants in adults - a clinical and therapeutic challenge

Sep 29, 2026

Early-onset osteoporosis (EOOP) is recognized in premenopausal adults with low DXA-derived BMD plus fragility fracture or chronic disease, requiring prompt identification of underlying causes. This report describes two adults with WNT1-related osteoporosis who developed symptoms only in adulthood, with progressive kyphosis and multiple vertebral fragility fractures. Biochemistry for calcium and phosphate metabolism was largely normal, while bone biopsies showed low bone turnover and impaired bone metabolism. Genetic testing confirmed heterozygous pathogenic WNT1 variants, highlighting care challenges and the need for anabolic long-term strategies with an exit plan.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages6

Reading Time15 min

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Vignette

Case description

Journal of Bone and Mineral Research, 2026, 41,85–90 [https://doi.org/10.1093/jbmr/zjaf150](https://doi.org/10.1093/jbmr/zjaf150) Advance access publication: November 8, 2025 Complex Clinical Challenges Severe early-onset osteoporosis due to heterozygous WNT1 variants in adults: a clinical and therapeutic challenge Eeva M. Ryhänen1 , Riikka E. Mäkitie2 ,3 , Tuula Pekkarinen1 , Heikki Kröger4 ,5 , Xiaoyu Tong4 , Liisa Kerttula6 , Outi Mäkitie7 ,8 ,9 , 10 , * , Camilla Schalin-Jäntti1 1 Department of Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), 00290 Helsinki, Finland 2 Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland 3 Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland 4 Kuopio Musculoskeletal Research Unit (KMRU), Institute of Clinical Medicine, University of Eastern Finland, 70029 Kuopio, Finland 5 Department of Orthopedics, Kuopio University Hospital, 70029 Kuopio, Finland 6 Diagnostic Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland 7 Children’s Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland 8 Research Program Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland 9 Genetics Research Program, Folkhälsan Research Center, 00014 Helsinki, Finland 10 Department of Molecular Medicine and Surgery, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, 171 77 Stockholm, Sweden *Corresponding author: Outi Mäkitie, Folkhälsan Research Center, University of Helsinki, P. O. Box 63, FI-00014 Helsinki, Finland (outi. makitie@helsinki.ﬁ) . Vignette Early-onset osteoporosis (EOOP) is diagnosed in premenopausal women or men under 50 yr of age when DXA-derived BMD is low (Zscore ≤ −2 .0 or T-score ≤ −2 . 5) in the presence of a fragility fracture or a chronic disease. In young adult patients, it is essential to recognize EOOP and identify the underlying cause, including possible genetic defects, to optimize tailored treatments. Among monogenic causes, WNT1-related osteoporosis has been described in children and adults. We present two adults, a 27-yr-old male and his mother, who had no skeletal symptoms in childhood but presented as adults with back pain. Further studies revealed low BMD and multiple spinal fragility fractures, leading to rapid height loss and progressive kyphosis. Biochemistry was largely normal, but bone biopsies showed impaired bone metabolism with low bone turnover. Both were found to harbor a previously described pathogenic heterozygous variant in WNT1, which leads to impaired WNT signaling. We describe the challenges in their clinical care, sequence of treatments, and outcome. These patients highlight the value of a correct genetic diagnosis to better understand the mechanisms behind low bone mass and to enable early intervention. Furthermore, our study emphasizes the need for anabolic treatment options for both males and females with EOOP, and the importance of long-term treatment planning, including an exit strategy. Keywords: Monogenic osteoporosis, vertebral fracture, WNTsignalling pathway, romosozumab, P4HB Lay Summary: A 27-yr-old male presented with back pain and multiple vertebral fractures; he had lost 7. 5 cm of his height within 6 mo. DXA showed severely impaired BMD. In the absence of a secondary cause for osteoporosis, genetic testing was undertaken and revealed a heterozygous disease-causing variant in WNT1 . His mother, presenting with back pain and severe kyphosis, was found to carry the same mutation. In both subjects, osteoporosis progressed rapidly causing several additional vertebral fractures. Biochemistry on calcium and phosphate metabo

FAQs

What diagnostic criteria define early-onset osteoporosis in this article?

EOOP is diagnosed in adults under 50 years with low DXA-derived BMD (Z-score ≤ −2.0 or T-score ≤ −2.5) in the presence of a fragility fracture or a chronic disease.

What did genetic testing show in the two reported adults?

Both the 27-year-old male and his mother were found to carry a previously described pathogenic heterozygous variant in WNT1, implicating impaired WNT signaling.

Why was treatment challenging and how was therapy adjusted?

Despite initially normal calcium/phosphate biochemistry, osteoporosis progressed rapidly with additional fractures. Both started with denosumab; after new fractures, the mother’s treatment was changed to include anabolic therapy to promote WNT signaling and a longer-term plan.

Sep 29, 2026

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