Beware of bone pain with bisphosphonates

Abstract

A 71-year-old woman who had been taking ibandronate for 10 years presented to an Endocrinology Department with persistent mid-thigh pain. Pelvic X-ray showed bilateral femoral cortical expansion, indicating impending atypical femoral fractures (AFFs). AFFs have been linked to long-term bisphosphonate therapy and have morbidity and mortality similar to that of hip fractures. Such fractures can be averted by regular reviews of bisphosphonate therapy and vigilance for prodromal symptoms. This patient’s bisphosphonate therapy was stopped, and fractures were avoided by treatment with vitamin D and parathyroid hormone.

Background

It has been estimated that osteoporosis affects 2.8 million people in the UK. Bisphosphonates can reduce the risk of hip fractures by 30%–50% and vertebral fractures by 30%–70%.¹ Paradoxically, bisphosphonate therapy has recently been associated with an increase in risk of one particular type of fracture, namely a transverse femoral diaphyseal fracture that tends to occur with minimal trauma, the so-called ‘atypical femoral fracture’ (AFF). These result in morbidity and mortality similar to that of hip fractures. AFFs are often preceded by a typical prodromal thigh pain so doctors should therefore be vigilant for prodromal symptoms of AFFs in patients on bisphosphonate therapy and adopt an appropriate therapeutic approach.²

Case presentation

A 71-year-old vegetarian woman of Indian origin presented to the Norfolk & Norwich University Hospital Endocrinology Department in 2012 with generalised aches and pains. Her medical history included osteoporosis diagnosed in 1999 on a DEXA scan, bilateral Colles’ fractures in 2008 and pernicious anaemia. Her regular medications were calcium carbonate 2500 mg one tablet daily (Calcichew Forte), calcitriol (1,25-dihydroxyvitamin D) 500 ng daily, diclofenac 100 mg daily, ibandronic acid 150 mg monthly, started in 2002, and vitamin B₁₂ injections. The ibandronic acid was started for osteoporosis and was chosen for the convenience of a once monthly oral preparation. The calcitriol had been prescribed for vitamin D deficiency.

Investigations

• DEXA (12 January 2011): T-scores −0.9 in the lumbar spine, −1.8 in the left hip and −1.6 left femoral neck (Z-scores of 1,–0.5 and 0 respectively)

Blood tests (21 May 2012):

• 25-OH vitamin D 13 nmol/L (50–120).

• Adjusted calcium 2.33 mmol/L (2.10–2.60).

• Alkaline phosphatase 63 U/L (38–126).

Blood tests (20 November 2012):

• Parathyroid hormone 3.7 pmol/L (1.6–6.9).

• 25-OH vitamin D 53 nmol/L (50–120).

• Plasma C-terminal telopeptide of type-1 collagen (CTX) 0.13 μg/L (0.10–0.50).

• Serum procollagen type-1 amino terminal peptide 14 μg/L (19–69).

• Radiographs of hips and pelvis 10 December 2013: no bone or joint abnormality reported.

Differential diagnosis

Osteopenia with vitamin D deficiency.

Treatment

The patient was given 150 000 IU of intramuscular vitamin D (ergocalciferol) and continued ibandronic acid 150 mg monthly. Calcichew Forte was changed to Calcichew D3 Forte one daily. The generalised bone pain initially resolved but vitamin D insufficiency recurred (25-OH vitamin D 36 nmol/L) and right hip pain was present over the next year. Cholecalciferol 20 000 IU (vitamin D) oral once weekly was administered commencing December 2013 for 8 months.

Outcome and follow-up

In August 2014, the patient now complained specifically of mid-thigh pain. Investigation results were as follows:

• Plasma C-terminal telopeptide of type-1 collagen 0.23 μg/L (0.10–0.50).

• Serum procollagen type-1 amino terminal peptide 24 μg/L (19–69).

• 25-OH vitamin D 82 nmol/L (optimal 50–120).

• Plain X-ray femurs: bilateral femoral cortical expansion (figures 1 and 2).

Figure 1.

Pelvic radiograph demonstrating bilateral femoral cortical expansion at the proximal third of the femora (arrows).

Figure 2.

Left femoral radiograph showing periosteal stress reaction (arrow).

Urgent bilateral femoral nailing was recommended following orthopaedic review, but the patient did not want this treatment and after discussion the initial therapy was conservative management:

• Ibandronic acid was stopped.

• Teriparatide (PTH1–34, ‘Forsteo’) injections were commenced 20 μg once daily, subcutaneous, for 2 years.

• The patient was still receiving calcitriol at this stage as it had alleviated some of her musculoskeletal pain and this was continued for the duration of her Teriparatide therapy.

• Vitamin D₃ (cholecalciferol) dose was reduced to 1000 IU daily for 1 year.

• After completion of Teriparatide therapy, the thigh pain was much improved bilaterally and follow-up radiographs showed that the femoral cortical expansion was significantly improved and the impending fractures had almost completely healed.

Discussion

The lifelong risk of having a fracture related to osteoporosis is approximately one in two for women and one in four for men.² Bisphosphonates have successfully been used to reduce this risk by increasing bone strength and stiffness but reduce bone remodelling and have been associated with AFFs if used for more than 3 years.^{2 3} The patient in this case study had been on ibandronate for 10 years. Her bone marker results reflected low bone remodelling with CTX in keeping with decreased collagen resorption in response to ibandronate while her low serum procollagen type-1 amino-terminal peptide result reflected decreased type-1 collagen synthesis. The relative risk of AFFs associated with bisphosphonate use has been estimated from 1.70 (95% CI: 1.22 to 2.37) to 55 (95% CI: 39 to 79) corresponding to an absolute risk of 11 (95% CI: 7 to 14) fractures per 10 000 person-years of use.^{4 5} These fractures are rare compared with typical osteoporotic fractures and so less of a public health concern but their impact on the individual warrants vigilance.⁴ Mortality following AFFs has been estimated to be 14% at 12 months and 25% at 24 months and morbidity is similar to that for hip fractures.^{2 3}

AFFs are thought to be insufficiency fractures arising from a fatigue mechanism associated with repetitive loading.⁶ Possible risk factors for AFFs during bisphosphonate therapy include use of multiple antiresorptive medications, glucocorticoids or proton-pump inhibitors, younger age when starting bisphosphonates, low pretreatment bone turnover and normal bone mineral density.^{3 7} The relative risk of AFFs on alendronate compared with risedronate has been estimated as 1.9 (95% CI: 1.1 to 3.3).⁵ Following cessation of bisphosphonate therapy, the risk of AFFs has been estimated to reduce by 70% per year.⁵ Clinical features of AFFs include prodromal pain for weeks to months, no significant trauma and bilateral fractures in some patients.^{2 7} Radiographic features include periosteal stress reaction, complete or incomplete, non-comminuted, transverse or short oblique subtrochanteric fractures, usually starting laterally and extending medially, proximal to the supracondylar flare with (often bilateral) thickening of the lateral femoral cortices.^{2 3} Intramedullary nails are recommended for repair of complete fractures and symptomatic incomplete fractures.

Asymptomatic incomplete fractures can be managed conservatively with non-weight-bearing and re-evaluated after 2–3 months.³ Imaging based on prodromal pain enabled cortical expansion to be identified in this patient before identifiable fractures occurred. Concentrations of bone-remodelling markers changed after bisphosphonate therapy was stopped and parathyroid hormone therapy was commenced (figure 3). Our report of a case with an impending AFF that healed with medical/conservative management is consistent with other reports in the literature⁶ and adds support to the hypothesis that a partial AFF may be arrested and reversed before it has propagated through the cortex. Teriparatide therapy has been associated with increasing the speed of the healing process but good clinical trial evidence of this is lacking.

Figure 3.

Graphs of markers of calcium and bone metabolic indices (25-OH vitamin D; 1,25 di-OH vitamin D; plasma C-terminal telopeptide of type-1 collagen (CTX) and serum procollagen type-1 amino terminal peptide (P1NP)) changes between 2012 and 2015. Ibandronic acid therapy was stopped in August 2014.

Learning points.

• Bisphosphonate therapy should be re-evaluated periodically after the first 5 years of use and stopping or pausing (drug holiday) should be considered for patients with low fracture risk and T-scores > −2.5.

• Patients on bisphosphonate therapy should be counselled to be vigilant for persistent thigh or groin pain.

• X-rays of the entire femur are essential for symptomatic patients. If X-rays are normal, consider MRI or radionuclide bone scintigraphy.

• If an atypical femoral fracture is confirmed, the contralateral femur should be evaluated radiologically.

• Femoral cortical expansion secondary to prolonged bisphosphonate therapy can sometimes be successfully managed medically without surgical intervention.