Targeted therapies inhibiting the MAPK pathway have been a breakthrough in advanced melanoma management. Two BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, have been approved in Europe in 2012 and 2013, respectively, for BRAF-mutated advanced melanoma. Combination of BRAFi with a MEK inhibitor (MEKi) is now the standard of care for these patients. Furthermore, MEKis were recently shown to improve progression-free survival in NRAS-mutated advanced melanoma.
Many adverse events (AEs) have been described with BRAFi and MEKi, either combined or used as a single agent. Main MEKi AEs include gastrointestinal AEs, cutaneous AEs, elevated creatine phosphokinase, hepatitis, edema, cardiovascular, and ophthalmologic AEs 1. Prolonged overall survival among patients treated with MEKi highlights other unrecognized AEs such as osteopenia.
We describe herein two patients with advanced melanoma controlled by long-term MEKi or combination of BRAF and MEK inhibitors, who developed fractures related to severe osteopenia.
A nonmenopausal 48-year-old woman, with no past medical history and no known risk factor for osteoporosis, was diagnosed with a BRAF, NRAS, and c-KIT wild-type acrolentiginous melanoma in July 2007. Tumor relapsed in May 2009 with multiple pulmonary metastases. Melanoma progressed despite dacarbazine followed by fotemustine chemotherapy.
In February 2010, the patient received off label a selective MEK1/2i, pimasertib, 120 mg/day. During MEKi therapy, she experienced grade 1 AEs (acneiform rash, diarrhea, and serous retinal detachment) and asymptomatic 10% decreased left ventricular ejection fraction requiring dose de-escalation. She achieved sustained partial response until September 2015 when histologically proven pulmonary relapse was observed, after 6 years of pimasertib treatment.
Pembrolizumab 200 mg every 3 weeks was introduced on mid-August 2015.
In January 2016, 4 months after MEKi was stopped, she suddenly complained of spontaneous buttock and back pain. Pelvis radiographs and bone scintigraphy combined with MRI concluded to thoraco-lumbar spine, both sacral alae and left superior and inferior rami fractures, whereas 18F-FDG PET examination ruled out any bone metastatic lesion (Fig. 1).
A DEXA scan revealed osteopenia [lumbar spine and femoral neck bone mineral densities (BMDs) were −1.6 and −2.3, respectively]. Bone architecture was assessed by µCT-scanner (Scanco, Xtreme CT) at the ultradistal radius and tibia bones; bone resorption and cortical porosity were within normal limits 2. Individual FRAX score (https://www.sheffield.ac.uk/FRAX/) was 4.8% probable of severe fracture at 10 years ahead, compared with a FRAX score of less than 5% in the youngest postmenopausal French women, suggesting a similar risk 3,4.
Blood analyses are summarized in Table 1. They display increased serum level of bone alkaline phosphatase and vitamin D deficiency. There was no hormonal dysfunction of any pituitary axes.
Zoledronic acid 4 mg at one infusion, cholecalciferol (vitamin D3) 100 000 UI every 15 days for 1 month and then every 3 months, oral calcium 1000 mg/day, and appropriate analgesics, were started. Pain resumed, and no further bone event occurred in the following year. After 9 months, BMD measurement remained stable. No spine immobilization was needed, in absence of functional consequence.
A 42-year-old man, with past medical history of nephrectomy for congenital malformation and no osteoporosis risk factors, was diagnosed with a BRAF V600E-mutated superficial spreading melanoma of the right chest in August 2009 with macroscopic axillar node involvement. He underwent excision and radical axillary node dissection. Tumor relapsed in 2010 (stage IV) with subcutaneous and bone metastasis of the left tibia medial condyle. At that time, the patient received 1 month of dacarbazine and then 37 months of vemurafenib monotherapy.
A combination of BRAFi (dabrafenib 300 mg/day) and MEKi (trametinib 2 mg/day) was introduced on July 2015 according to guidelines for BRAF-mutated melanoma management. BRAF alone and then combined with MEKi led to sustained control of melanoma with no significant AEs.
In January 2016, after 6 months of BRAFi/MEKi combined treatment, the patient complained of mechanical right buttock and thigh pain. MRI and PET scanner revealed a pelvis fracture of the left acetabular rim, without evidence of bone metastasis.
DEXA scan revealed slight osteopenia (BMD at lumbar spine and femoral neck were −1.4 and −0.7, respectively). Individual FRAX score was 2.4% probable of severe fractures at 10 years, compared with less than 5% in the control group 3,4.
Blood analyses (Table 1) showed increased level of serum bone alkaline phosphatase and vitamin D deficiency associated with secondary hyperparathyroidism. There was neither hormonal dysfunction of the pituitary axes nor chronic kidney disease.
Zoledronic acid 4 mg at one infusion, cholecalciferol (vitamin D3) 100 000 UI every 15 days for 1 month and then every 3 months, oral calcium 1000 mg/day, and ad hoc analgesics, were started without immobilization, resulting in good outcome. One year later, blood analysis showed normalization of biological parameters. A DEXA scan was performed 1 year later and revealed a global stability of osteopenia.
We report on two middle-aged patients with advanced melanoma who developed spontaneous fractures with osteopenia after long-term therapy with a MEKi alone or combined with a BRAFi. These fractures are similar to fractures owing to bone insufficiency usually observed in elderly patients sustaining minimal trauma. In both patients, no osteoporosis risk factors or hormonal dysfunction, no evidence of secondary osteoporosis including corticosteroid therapy and no bone metastasis at the site of factures were elicited. Overall kinetics of signs and imaging data led us to conclude that the MEKis were imputable in the development of such a bone fragility.
Osteoporosis is a skeletal disorder characterized by a low BMD and microarchitectural deterioration leading to an increased risk of low-trauma or spontaneous fractures. It is a common condition and affects up to 30% of women and 12% of men 5. It is usually classified as primary osteoporosis when it occurs in postmenopausal women and in men in absence of an underlying disease, and as secondary osteoporosis in case of an underlying disease or medication. Some conditions are well known to be associated with osteoporosis, such as chronic inflammatory diseases, malabsorption, long-term corticosteroid therapy, alcohol overuse, tobacco and some antineoplastic treatment, such as cyclophosphamide and doxorubicin, which have a direct effect on bone metabolism, and also hormone therapies in patients with breast cancer and prostate cancer 6.
Insufficiency fractures are a type of stress fracture, which are the result of normal stresses on abnormal bone. Loss of bone trabeculae decreases bone elastic resistance. Sites frequently affected by insufficiency fractures are the pelvic bones including sacrum (H sign), the thoracic vertebra, the tibia, the fibula, and the calcaneus.
Numerous pathways are involved in the homeostasis of bone turnover, which result in a balanced activity between osteoclasts and osteoblasts. Bone cell activity is regulated by systemic and local factors, among which are cytokines, growth factors, and receptors such as PGDF-R, c-KIT, M-CSF, and RANK, which will interact with different pathways where various tyrosine kinase are involved. Each leads to different effects, revealing the complexity of bone metabolism.
The effect of tyrosine kinase inhibitors on bone metabolism has been mostly studied with imatinib. Imatinib mesylate, or imatinib, is the first tyrosine kinase inhibitor approved in hemato-oncology, and its main targets are the BCR-Abelson kinase, KIT, and PDGF-R. Changes induced by imatinib on bone metabolism are now well described, such as hypophosphatemia with concomitant increased phosphaturia, decrease in serum calcium level despite hyperparathyroidism, or also a decrease in BMD at the femoral neck 24 months after initiation of imatinib, albeit with an associated increase in trabecular bone volume. Imatinib is thought to decrease the ability of osteoclasts to resorb bone and the effect on osteoblast is unsure.
Those effects are well summarized and explained in a review by Aleman et al. 7, but it could not conclude on whether those effects are associated with altered clinical outcomes such as fracture. One premenopausal patient treated with imatinib experienced an unexplained stress fracture of the hip, without anomalies on biochemistry and bone density 7. In another case report, a bilateral subtrochanteric fractures occurred in a 60-year-old female treated for 1 year with imatinib mesylate for a chronic myeloid leukemia. BMD was normal, and biochemistry tests were within normal limits apart for serum phosphate levels, serum osteocalcin, and urinary N-telopeptide of collagen cross-links, which were decreased, and intact parathyroid hormone level, which was increased 8.
Patients treated with imatinib should then be regularly monitored for bone metabolism disorder and patients presenting those adverse events should receive an amount of calcium, vitamin D, phosphate supplements, or calcitriol, in accordance with current guidelines 9. In addition, when osteopenia, hyperparathyroidism, or hypophosphatemia are detected, the full differential diagnosis of causes should be explored.
Very little information is available on the potential effect of MEKi on bone formation, with controversial data. In 2002, a short study showed that inhibition of MEK1 and MEK2 promotes preosteoclast differentiation 10, whereas a recent study looking for osteoclast differentiation pathway found that the inhibition of MEK5/ERK5 pathways resulted in inhibiting osteoclast differentiation 11.
Concerning BRAFi, it has been shown that they impaired in vitro differentiation of peripheral blood mononuclear cells to osteoclast precursors and exerted an inhibition on osteoclast resorptive capacity 12. Until now, no osteoporosis has been described with BRAF inhibitor, but three cases of nonmetastatic bone sclerotic lesions have been reported in patients treated with BRAFi 13.
To look for other cases of osteopenia induced by MEKi or BRAFi, we examined two databases: French Pharmacovigilance database established in 1985 to record Adverse Drug Reactions reported to a network of 31 French Regional Pharmacovigilance Center, and WHO Pharmacovigilance database (VigiBase). No cases of fracture, osteopenia or osteoporosis have been reported in French Pharmacovigilance database after MEKi or BRAFi. A request of VigiBase for all cases of fracture, osteopenia or osteoporosis ‘suspected’ to have been induced by MEKi or BRAFi identified eight individual case safety reports (four cases of fracture and four cases of osteoporosis) including a case of a 9-year-old girl who developed a fracture after treatment with trametinib for a plexiform neurofibroma.
New cancer treatments, like targeted therapies, have increased the life expectancy in patients with melanoma. Long-term survival could be associated with yet underestimated adverse effects such as related fractures that could impair their quality of life, and bear a significant economic effect. Further data from national or European registries are needed to better evaluate the prevalence of osteopenia and other long-term adverse events and make recommendations on their prevention.
Conflicts of interest
There are no conflicts of interest.
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