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

Introduction:

The extent to which metabolic abnormalities of diabetes impact bone health are complex and frequently underestimated, as the identification and management of fracture risk in diabetic patients remains challenging. The prevalence and severity of osteoporosis in patients with type 1 diabetes (T1DM) is increased compared to non-diabetic patients[1]. The pathophysiology of bone disease is mediated by multiple complex pathways, including the deficiency of insulin and insulin-like growth factors, accumulation of advanced glycation end-products in bone collagen, microangiopathy, increased bone marrow adiposity[2] and release of inflammatory cytokines. Together these may affect osteoblast recruitment and proliferation, collagen formation and osteocyte function, which contribute to reduced bone quality and bone strength[1-3]. Furthermore, abnormalities in bone turnover and uncoupling of bone remodeling[4] may be affected by the complications of diabetes such as renal impairment. The association of T1DM with other autoimmune malabsorptive conditions, such as coeliac disease, may also result in osteoporosis and is not uncommon[5]. However, the co-existence of pancreatic exocrinopathy and T1DM leading to osteoporosis is exceptionally rare.

Case:

 A 29-year-old Caucasian female sustained an atraumatic left tibial fracture, prompting further investigation. This is on a background of a 10-year history of suboptimally controlled T1DM (GAD182U/mL) with previous significant weight loss due to chronic malabsorption and prolonged vitamin D deficiency from severe pancreatic exocrinopathy. This is on a prolonged history of an elevated HbA1c (10.1-14.7%) suffering microvascular complications of proliferative retinopathy, polyneuropathy, nephropathy with an elevated u-AER (534mg/mmol creat) and autonomic neuropathy including gastroparesis and postural hypotension with erect BP decline of 20mmHg. She also had a 4-year history of amenorrhea due to weight-related hypothalamic hypogonadism (low FSH <1IU/L, LH <0.1IU/L and estradiol <70pmol/L).

Physical examination revealed sustained left ankle swelling as well as reduced muscle strength. Body composition confirmed very low skeletal muscle mass (19.2kg) but an elevated fat mass (25.5kg).

Spinal x-rays demonstrated osteofragility fractures with 20% anterior compression fractures of T7 and T8 vertebral bodies. A dual-energy X-ray absorptiometry scan further confirmed a low peak bone mass/osteoporosis with significantly reduced total hip bone mineral density of 0.60g/cm² (t-score of -3.4).

Laboratory investigations revealed chronic malabsorption with a low serum 25-vitamin D (15nmol/L), ferritin (8μmol/L), vitamin B12 (12pmol/L) as well as pancreatic exocrine insufficiency with a low faecal elastase (42mcg/g). She had a low-normal ionised serum calcium (1.19mmol/L), normal total serum calcium (2.14mmol/L), secondary hyperparathyroidism with an elevated PTH (10.8pmol/L) and 24-hour urine excretion revealed a low calcium level (0.6mmol/day). Coeliac serology and cystic fibrosis transmembrane conductance regulator genetic testing were negative, excluding coeliac disease and cystic fibrosis as contributing factors to her chronic malabsorption. Her bone turnover markers were elevated with P1NP (88mcg/L) and CTx (560mcg/L).

Treatment:

Intensive diabetic management was achieved using a Medtronic-770G insulin pump and dietary adjustments. Therapy was initiated with oral cholecalciferol 5000IU daily, calcium citrate 250mg TDS and Creon pancreatic enzyme capsules 75,000IU TDS. The benefits of parenteral bisphosphonates were considered.

Discussion:

Long-term exposure to a diabetic environment with microvascular disease may affect bone microvasculature and bone marrow microenvironment where bone progenitor cells reside. This shifts production to adipocytes, and away from osteoblasts, resulting in an increase in bone marrow adiposity[6]. These changes predispose the bone to increased fracture risk and impaired osseus healing. In addition, microvascular complications, including neuropathy, retinopathy and postural orthostatic hypotension increase falls risk, which may also partially account for increased fracture risk[8], which is paramount to address in our patient’s ongoing management.

 Our patient’s poor metabolic control, the effects of her chronic weight-related hypogonadism and malabsorptive state from the exocrinopathy causing a severe vitamin D and B12 deficiencies contributed to her metabolic bone disorder, low skeletal muscle mass and BMD and resulted in osteoporosis and osteofragility fractures. The fracture risk assessment tools (FRAX) which can accurately determine fracture risk in patients living with diabetes was not used since this has limitations in individuals aged under forty[8]. Although a bone biopsy was not performed, she most likely had features of both osteoporosis and osteomalacia.

 The management of our patient required a multidisciplinary approach and the correction of all metabolic abnormalities and deficiency states. A diabetes team was essential for improving her glycaemia and reducing her hypoglycaemia risk (regarded as higher than normal due to her hypoglycaemia unawareness from autonomic neuropathy and the most likely combined insulin/glucagon deficiency from her pancreatic endo/exocrinopathy). Dietary advice and a muscle strengthening program was important to reduce her falls risk and optimal treatment of hypogonadism, pancreatic malabsorption and multi-vitamin deficiency state were required to restore normal bone remodelling.

 Currently, no therapeutic guidelines exist relating to optimal anti-osteoporotic agents in diabetic patients. A systematic review evaluating the efficacy of risedronate, alendronate, raloxifene, and teriparatide in diabetic patients with osteoporosis reported similar increases in bone density as well as fracture risk reductions in vertebral (alendronate, raloxifene) and nonvertebral (teriparatide) fractures in patients with and without diabetes[9]. Newly developed osteoporotic drugs, such as sclerostin inhibitors, specifically improve osteocyte function, cortical bone microstructure and bone stiffness, which may be a promising therapy to improve bone strength specifically in diabetic patients[1, 10].

Conclusion:

This case highlights the complex nature of osteofragility fractures in a young individual with T1DM and highlights the need for a comprehensive investigation of potential contributing factors. Continual follow-up and coordination among specialists are vital to ensure the patient's long-term skeletal health and overall well-being. Further research is warranted to better understand the presentation, early detection and mechanism of osteofragility fractures in T1DM-related pancreatic exocrinopathy.

Learning points:

1. Patients with T1DM are at increased risk of developing severe osteoporosis due to reduced bone mineralisation attributed to insulin deficiency, chronic hyperglycaemia, and autoimmune inflammation necessitating regular bone health assessments.
2. Exocrine pancreatic abnormalities often occur in T1DM as well as an increased association of other autoimmune malabsorptive conditions, which can contribute to osteoporotic risk, which clinicians should screen.
3. Management of diabetic-related osteofragility fractures requires a multifactorial approach for correction of all metabolic abnormalities and early identification of contributing co-morbidities.