Poster Presentation ANZBMS-MEPSA-ANZORS 2022

Clinical Case
A 22 year old woman, CG, presented with an atraumatic right distal femur fracture following two weeks of leg pain. X-ray confirmed transverse metaphyseal fracture (Figure 1). CT and MRI suggested stress fracture (Figure 2). She was otherwise healthy with no history of renal calculi or coeliac disease. Her past medical history includes previous intra-articular distal radius fracture after falling on outstretched hand, mild seasonal asthma and acne vulgaris requiring previous antibiotic use. She reports a normal developmental history with menarche occurring at age 12. She is nulliparous and takes levonorgestrol 150mcg/ethinyloestradiol 30mcg for menorrhagia. She is on no other regular medications or supplements. Her mother was diagnosed with ER positive breast cancer at age 48. There is no other family history of malignancy nor parathyroid disease, pituitary dysfunction or osteoporosis. CG works in an office-based job. She is a non-smoker and consumes alcohol rarely. Her diet is dairy inclusive, high in fibre and relatively low in meat. She does not participate in excessive physical activity.

On examination sclera were normal, there was no evidence of Cushingoid features, palpable lymphadenopathy or hyper-flexibility other than elbow hyper-flexion. She had normal dentition and palate.

Intra-operative bone biopsy from the fracture site was consistent with chronic inflammation without evidence of malignancy. Further imaging was attended including x-ray of the left femur given history of prodromal pain which identified stromal reaction to left distal femur in a similar location to that of the right (Figure 3). Thoracic and lumbrosacral spine x-rays were unremarkable. Bone scan revealed previous second and ninth rib fractures. Bone mineral density (BMD) was very low for age (Z scores: L2-L4 -3.3, right femoral neck -1.6 and left femoral neck -1.6).

 Investigations for secondary causes of osteoporosis were unremarkable:

CG subsequently attended prophylactic fixation of the left femur. Bone biopsy was attended with single labelled tetracycline labelling which demonstrated severe osteoporosis with reduced trabecular bone area and ‘islands’ of bone as well as reduced osteoid surfaces and thickness, reduced bone formation and osteoclast surfaces. Interestingly bone turnover markers were low despite recent fracture. CG represented with bilateral ankle pain. X-rays confirmed healing fracture in the right distal metaphysis of the tibia.

Genetic studies excluded osteogenesis imperfecta, Gaucher disease and homocystinuria. There are no plans to proceed to whole genome sequencing. Her mother and brother attended BMD which demonstrated osteopenia and low bone mineral density although not osteoporotic respectively. Management to date includes calcium supplementation and observation including annual BMD in keeping with CG’s wishes to not commence Teriparatide at this time.

Literature Review
Osteoporosis is characterised by low bone mass and changes within the microarchitecture of bone resulting in increased risk of fragility fractures. Less commonly this occurs in pre-menopausal women. In this population there is often an underlying cause resulting in secondary osteoporosis. When no secondary cause is found in an otherwise healthy individual with normal gonadal function this is termed “idiopathic osteoporosis” (IOP).

Contributing factors may include low body weight, tobacco consumption and low calcium intake¹, however, there is a large genetic predisposition and family history of osteoporosis is more common in patients with IOP1 ¹. Despite studies involving whole exome sequencing the genetic aetiology is not identified in the majority of women (89%)². This suggests the pathogenesis of idiopathic osteoporosis is heterogeneous which is further supported by the variety of clinical presentations and evidence of patients with high, normal and low bone turnover markers.

Uncoupling between resorption and formation results in net bone loss¹. There is decreased initiation of remodelling cycles with more time in the resorption phase. In the formation phase, matrix is formed at a reduced rate with osteoid mineralisation occurring more slowly³. Osteoclast function is further implicated by the finding of elevated Tartrate-resistant acid phosphatase isoform 5b (TRAP5b), a specific osteoclast marker that correlates to either the number or the activity of differentiated osteoblasts and is independent to C-telopeptide (CTx) and N-telopeptides (NTx)¹. Microcomputed tomography and microfinite element analysis has identified structural change within the microarchitecture contributing to reduced stiffness in both patients with IOP and those with idiopathic low bone mineral density^4,5.   

IOP with high bone turnover have a biochemical pattern resembling idiopathic hypercalciuria, while microarchitectural deficits and reduced stiffness are most severe in those with the lowest bone formation ratio⁴. IOP with low bone turnover also had higher serum IGF-1 levels which suggests primary osteoblast dysfunction with resistance to IGF-1⁴.

Treatment of IOP often includes an anabolic agent such as Teriparatide⁶. Interestingly, approximately 20% of patients demonstrate minimal response to Teriparatide. These patients generally have low bone turnover markers^7,8, which may implicate osteoblast dysfunction in the attenuation of the response to Teriparatide⁹. Response to Teriparatide is correlated to the increase of expression of the IGF-1 receptor (IGF-1R) on the surface of circulating osteoblast progenitor cells while lower IGF-1R expression is associated with higher body fat and lower BMD response¹⁰. Alternate treatment strategies such as combination therapy, romosozumab and the implications of future pregnancy will be reviewed in further detail.

Take home points:

• IOP is a heterogenous disease including different levels of bone turnover activity and underlying pathogenesis
• Microarchitectural deficits contribute to reduced density and stiffness in both patients with fractures and those with idiopathic low bone mineral density
• In those with low bone turnover IOP, pathogenesis may be implicated by osteoblast dysfunction due to IGF-1 resistance