Poster Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Case
A 24-year-old female presented with more than 30 fractures throughout her childhood and adult life. Her risk factors for osteoporosis included long-term prednisolone use, minimal calcium intake, low vitamin D and oligomenorrhoea.

Her past medical history was significant for chronic constipation identified in early infancy. She previously had a cecostomy tube, and multiple electronic stimulations with no benefit. She currently managed with two litres of colonLYTLEY daily via a nasogastric tube.

Other past medical history included chronic eczema, on high dose prednisolone (25-50mg daily) for 6 years, and she had lost contact with dermatology. She was obese, with a BMI of 56, with limited response to very low energy diets or phentermine, and financial restrictions prohibited commencement of a GLP-1 analogue.

At presentation, her medications included prednisolone 25mg daily, colonLYTLEY 2L daily, topiramate 50mg BD, and an implanon in-situ. She was a non-smoker, with no family history of osteoporosis.

Her obese BMI precluded a DXA attainment at the spine and hip, but wrist bone density was normal.  Initial management included dietary optimisation and restoration of vitamin D levels. Given her significant fracture history and risk factors, zoledronic acid was administered, but was complicated by significant extravasation. This resulted in early cessation of the infusion, and later cellulitis. Bone turnover markers pre- and post-infusion showed a mild reduction, indicating some degree of bone suppression from the partial zoledronic acid dose.

Consent for genetic testing was taken, and showed an autosomal dominant heterozygous mutation in the LRP5 gene, a likely de novo pathogenic mutation. After expert discussion, an application was made for compassionate access romosozumab for further management of her bone health.

Re-engagement and review by dermatology led to reduction in prednisolone to 7.5mg daily, and bariatric review allowed commencement of hospital funded semaglutide for weight-loss.

Her relevant investigations at presentation are listed below:

Bone Density Scan GE Lunar
-Right forearm BMD is 0.909grams/cm²
-Z-score +0.2, T-score +0.2

Thoracolumbar x-ray
-no fractures

Discussion

The Wnt signalling pathway plays a critical role in bone metabolism [1,2,3]. The Wnt ligand binds to LRP5/6 and Fzd receptors on the cell surface, inducing an intracellular signalling cascade causing increased beta-catenin in the nucleus [3,4]. Beta-catenin promotes the progression of mesenchymal stem cells from osteoblastic precursor cells into mature osteoblasts, while suppressing differentiation into adipogenic and chondrogenic lineages [1,2,4,5]. (See Figure 1).

A mutation in the LRP5 gene causes a defect in the Wnt signalling cascade, resulting in decreased osteoblasts, and thus decreased bone formation [3]. Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of severe juvenile osteoporosis and congenital blindness, due to biallelic mutations in the LRP5 gene [3].

Heterozygous LRP5 loss-of-function mutations cause juvenile onset osteoporosis and familial exudative vitreoretinopathy. Although a less severe phenotype than OPPG, it still results in increased fractures from childhood, and patients are at risk of blindness due to premature arrest of the retinal vasculature [5].

Treatment for patients with LRP5 mutations is not well established, limited to case reports and series.

Bisphosphonates appear safe and effective in this cohort [6]. A case series in children with OPPG demonstrates improvement in bone density in 4 patients treated with oral bisphosphonates over a 1.5-6-year period [6]. They had increases in Z-scores and decreased fractures, with 3 patients having normalisation of bone density. 

Denosumab is uncommonly used due to the young age of patients, although theoretically will have similar effects to bisphosphonates. A case report of a 19-year-old with OPPG showed increased bone density of 26.4% in the lumbar spine after 12-months of denosumab therapy [7].

Teriparatide is a PTH analogue which stimulates osteoblastic function [8]. Theoretically, osteoanabolic therapy may be more successful than anti-resorptive therapy in patients with LRP5 mutations, given the principal defect is reduced bone formation. Again, the research is limited to case studies. A 19-year-old with OPPG completed 24-months of teriparatide therapy, after 6 years of bisphosphonate treatment. He had an ensuing 10% increase in bone density, with no fractures on therapy [9].

Romosozumab is a humanised monoclonal sclerostin-neutralising antibody that binds to and inhibits sclerostin. Sclerostin is a Wnt antagonists, binding to LRP5/6, thus resulting in inhibition of bone formation [6]. It has been proposed that romosozumab may be less effective in patients with LRP5 mutations, whereby sclerostin already does not effectively bind the receptor.

However, a study found dual LRP5 and sclerostin knock-out mice had stronger bones than mice solely lacking the LRP5 gene. The LRP5 deficient mice were then treated with anti-sclerostin therapy for 3-weeks, and showed improvement in bone density [10]. The hypothesis being without LRP5, the anabolic effects of sclerostin depletion occur via other receptors (such as LRP4/6).

Novel therapies for osteoporosis include antibodies targeting the LRP6 receptor, resulting in stimulation of the Wnt signaling pathway, and anti-DKK therapy (DKK being another Wnt antagonist). A study in mice with and without multiple myeloma showed improvements in trabecular bone volume after LRP6 antibody treatment. The combination treatment of LRP6 antibodies and anti-DKK therapy more than doubled trabecular bone volume [11].
This is a promising area for patients with LRP5 mutations, as they are likely more reliant on LRP6. By increasing the activity of the Wnt pathway via LRP6, these patients may have significant gains in bone density.

Take Home Messages

• The Wnt pathway plays a critical role in bone remodelling, and is already targeted for anti-osteoporosis therapy (romosozumab)
• The optimal therapy for patients with LRP5 mutations causing osteoporosis is yet to be determined, currently most evidence for safety and efficacy lies with bisphosphonates
• Romosozumab may be beneficial in these patients given alternate receptors involved in the Wnt signaling pathway
• Novel therapies such as LRP6 antibodies may be particularly useful in this cohort
• Other osteoporosis risk factors including long-term steroid use, and suboptimal vitamin D levels are significant contributors to this patient’s osteoporosis, and thus should be managed as a priority

Figure 1 The Wnt signalling pathway, showing potential therapeutic targets [1].