Clinical case
A 76 year old woman was referred to metabolic bone clinic for further management of bisphosphonate-associated right atypical femoral fracture (AFF). She initially presented in April 2020 with sudden, severe, atraumatic hip pain with imaging confirming markedly displaced transverse subtrochanteric fracture of the right femur. Magnetic resonance imaging (MRI) of the left hip excluded AFF on the contralateral side. Post-intramedullary (IM) nail insertion, she was mobilising with minimal pain using a 4-wheel frame.
Her medical history was significant for multiple myeloma (MM) diagnosed in 2007. Induction therapy comprised melphalan, prednisolone and zoledronic acid. Due to progression of disease in December 2014, she commenced bortezomib and dexamethasone before proceeding to have an autologous stem cell transplant. She subsequently received monthly intravenous zoledronic acid infusions for 12 months then the frequency was reduced to every three months. In May 2019, she commenced third-line treatment with lenalidomide and dexamethasone. Zoledronic acid was ceased with the diagnosis of AFF.
Her other comorbidities included ischemic heart disease, chronic kidney disease, chronic pulmonary embolism, paroxysmal atrial fibrillation and hypertension. She lived at home with her husband and was independent with activities of daily living. She was not known to have significant vitamin D deficiency and had not sustained any other minimal trauma fractures.
Laboratory and medical imaging findings
Initial biochemistry revealed vitamin D level 55 nmol/L, creatinine 138 umol/L, corrected calcium 2.31 mmol/L, phosphate 0.73 mmol/L, and parathyroid hormone 114 pg/mL (15-68). Fasting C-telopeptide (CTX) level was 138 ng/L and procollagen type 1 N-terminal propeptide (P1NP) was 24 ug/L, reflective of long-term anti-resorptive therapy. Dual-energy x-ray absorptiometry (DEXA) scan revealed lumbar spine bone mineral density (BMD) of 1.226g/cm2 with T-score of 0.4 and left femoral neck BMD of 0.950g/cm2 with T-score 0.3.
Plain film radiography of the right hip 18-months post-IM nail insertion showed minimal interval bone remodelling without evidence of union. Computed tomography (CT) scan showed medial cortex union, and partial union at posterior cortex. 22-months post-operatively, repeat x-ray demonstrated persistent non-union of right AFF and new left femoral stress fracture with beaking of the lateral cortex of left femur.
Progress
Given persistent non-union of her right AFF, the orthopaedic team was hesitant to pursue surgical management of the left stress fracture. In consultation with her haematology team, she was commenced on teriparatide subcutaneous injections 20mcg daily for six months via compassionate access.
Brief outline of the literature
This case raises several interesting issues:
MM is a haematological malignancy characterised by clonal expansion of plasma cells.1 Features include hypercalcemia, renal impairment, anaemia and diffuse osteopenia or focal lytic lesions.1 Myeloma bone disease (MBD) is present in more than 80% patients with MM and results from plasma cell activation of osteoclast and suppression of osteoblast activity.2 Intravenous bisphosphonates remain the standard of care for treatment and prevention of MBD and are administered every 3 to 4 weeks for 1-2 years.2
Long term bisphosphonate use is known to contribute to the development of AFF.3 Most cases are treated surgically with intramedullary nailing however the procedure is associated with complications such as non-union and delayed union.3 Currently there are no pharmacologic treatments approved for use in non-union. Several studies and case series have reported teriparatide, recombinant human parathyroid hormone, can enhance fracture healing time and union of AFF.4
There are however theoretical concerns about using teriparatide in MM. The use of teriparatide treatment for osteoporosis has previously been contraindicated in malignant bone disorders due to the increased incidence in osteosarcoma in rats in preclinical data.5 Post-clinical studies have since found the incidence of osteosarcoma in patients using teriparatide is equivalent to incidence rates of osteosarcoma in the general population.5
There is also thought to be a potential role of parathyroid hormone–related protein (PTHrP) in MM pathogenesis and progression through osteoclast activation.6 Whilst there is no evidence to demonstrate a direct causal link, there have been a small number of case reports of teriparatide use and MM development or recurrence. In one case report a patient presented with monoclonal gammopathy of uncertain significance (MGUS) and developed malignant melanoma post-teriparatide treatment.7 In another case report MM was diagnosed soon after discontinuation of teriparatide treatment.8 This association was disputed in a 12 month open label pilot study of 12 myeloma patients with previous bisphosphonate use who received subcutaneous teriparatide 20mcg daily. The results showed positive anabolic bone effects without an increase in myeloma disease activity or hypercalcemia.9
Take home messages
1) Teriparatide may be considered to improve fracture healing in AFF.
2) Despite theoretical concerns, early studies have shown that use of teriparatide for 12 months in patients with MM may have positive anabolic bone effects and does not appear to increase disease activity.