Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). The oropharyngeal epithelium differs from the mucosal epithelium at other commonly HPV16-infected sites (i.e., cervix and anogenital region) in that it is juxtaposed with the underlying lymphatic tissue, serving a key immunologic function in the surveillance of inhaled and ingested pathogens. Therefore, the natural history of infection and immune response to HPV at this site may differ from that at other anatomic locations. This review summarizes the literature concerning the adaptive immune response against HPV in the context of HNSCC, with a focus on the T-cell response. Recent studies have shown that a broad repertoire of tumorinfiltrating HPV-specific T-cells are found in nearly all patients with HPV-positive tumors. A systemic response is found in only a proportion of these. Furthermore, the local response is more frequent in OPSCC patients than in cervical cancer patients and HPV-negative OPSCC patients. Despite this, tumor persistence may be facilitated by abnormalities in antigen processing, a skewed T-helper cell response, and an increased local prevalence of T-regulatory cells. Nonetheless, the immunologic profile of HPV-positive vs. HPV-negative HNSCC is associated with a significantly better outcome, and the HPV-specific immune response is suggested to play a role in the significantly better response to therapy of HPV-positive patients. Immunoprofiling may prove a valuable prognostic tool, and immunotherapy trials targeting HPV are underway, providing hope for decreasing treatment-related toxicity.

Discontinuing denosumab is associated with bone loss and possibly increased fracture risk. We investigated if treatment with zoledronate (ZOL) could prevent bone loss and if the timing of the ZOL infusion influenced the outcome. We report on a 2-year randomized, open label, interventional study including 61 patients with osteopenia, discontinuing denosumab after 4.6 AE 1.6 years. We administrated ZOL 6 months (6M group, n = 20) or 9 months (9M group, n = 20) after the last denosumab injection or when bone turnover had increased (OBS group, n = 21). We monitored the patients with DXA and bone turnover markers. Our primary endpoints were change in lumbar spine BMD (LSBMD) 6 months after ZOL and the proportion of patients who failed to maintain BMD. The study is ongoing (clinicaltrials.gov; NCT03087851). We included 61 participants and 59 patients completed follow-up 12 months after ZOL. Six months after ZOL, LSBMD had decreased significantly by (mean AE SE) 2.1% AE 0.9%, 4.3% AE 1.1%, and 3.0% AE 1.1% in the 6M, 9M, and OBS groups, respectively, and by 4.8% AE 0.7%, 4.1% AE 1.1%, and 4.7% AE 1.2% 12 months after ZOL in the 6M, 9M, and OBS groups, respectively (p < .02, no between-group differences). BMD loss above the least significant change was seen in all groups; at the spine: 6M, n = 6 (30%); 9M, n = 9 (45%); and OBS, n = 9 (47%); and at the total hip: 6M, n = 1 (5%); 9M, n = 5 (25%); and OBS, n = 2 (11%). In the 6M group p-crosslinked C-terminal telopeptide (p-CTX) decreased initially, but increased rapidly thereafter, and 6 months after ZOL, p-CTX was 0.60 AE 0.08 g/L. p-CTX increased rapidly in the 9M and OBS groups, was suppressed by ZOL but increased again thereafter; p-CTX was 0.47 AE 0.05 μg/L and 0.47 AE 0.05 μg/L in the 9M and OBS groups 6 months after ZOL, respectively. Incident vertebral fractures were seen in two women in the 9M group. Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients discontinuing denosumab.

The hypercalcemia and associated hypercalciuria seems to be due to an intestinal hyperabsorption of calcium. It remains to be elucidated, whether an increased calcitriol synthesis within granulomas is the only (main) mechanism by which intestinal calcium absorption is increased. Glucocorticoids seem most appropriate as the first choice for treatment. Bodybuilders should be warned against use of intramuscular oil injections (and other substances), as this may have severe adverse health consequences.

The glycoprotein sclerostin inhibits activation of the canonical Wnt pathway and thereby suppresses bone formation by inhibiting the osteoblasts. Additionally, sclerostin increases bone resorption by stimulating the production of receptor activator of nuclear factor kappa-β-ligand (RANKL). Romosozumab (ROMO) is a monoclonal antibody against sclerostin. Phase III clinical trials in postmenopausal women with osteoporosis have shown that ROMO increases bone mineral density at the lumbar spine and hip and reduces the risk of vertebral and clinical fractures in comparison with placebo. In women with severe osteoporosis, ROMO reduces the risk of vertebral, nonvertebral and clinical fractures in comparison with alendronate. ROMO is the first treatment for osteoporosis with dual action, and may become a valuable tool for improving the treatment of osteoporosis. At present, the approval of ROMO by the authorities is awaiting further investigations of a potential increased risk of cardiovascular events associated with ROMO treatment.

Increased bone turnover and rapid bone loss follow discontinuation of denosumab. We investigated the long-term efficacy of zoledronate (ZOL) in maintaining bone mineral density (BMD) after discontinuation of denosumab. In this randomized, open-label, interventional study, we included 61 postmenopausal women and men older than 50 years discontinuing denosumab after 4.6 AE 1.6 years. We administered ZOL 6 months (6 M) or 9 months (9 M) after the last denosumab or when bone turnover had increased (observation group [OBS]). ZOL was readministrated if p-cross-linked C-terminal telopeptide (p-CTX) increased ≥1.26 μg/L or BMD decreased ≥5%. The results after 12 months have previously been published; here we report the outcome after 24 months (ClinicalTrials NCT03087851). Fifty-eight patients completed the study. From 12 to 24 months after the initial ZOL, lumbar spine (LS) BMD was maintained: 0.9 AE 0.9%, 0.4 AE 0.8%, and 0.3 AE 0.7% in the 6 M, 9 M, and OBS groups, respectively (p > .05, no between-group differences). Similarly, total hip (TH) and femoral neck (FN) BMD did not change in any group during year 2. From baseline to 24 months after ZOL, LS BMD decreased by 4.0 AE 0.8%, 4.1 AE 0.8%, and 4.3 AE 1.5% in the 6 M, 9 M, and OBS groups, respectively (p < .001, no between-group differences). Significant bone loss (LS, TH, or FN) was found in all groups 24 months after ZOL: 6 M group: n = 12 (60%), 9 M group: n = 7 (37%), and OBS group: n = 10 (53%). P-CTX did not change significantly during the second year (p > .05, no between-group differences). No patient fulfilled the CTX or fracture criteria for retreatment during year 2; however, 9 patients were retreated at M24 due to BMD loss ≥5%. Two patients sustained a non-vertebral fracture during year 2. Treatment with ZOL subsequent to long-term denosumab did not fully prevent increased bone turnover and bone loss during the first year; however, CTX remained with the reference range and BMD was maintained during the second year.

In this case report, we describe increased BTMs and hypercalcemia associated with discontinuation of 10 years treatment with denosumab. The increase in BTMs is assumed to be temporary and normalization is expected. Since denosumab is commonly used, there is an urgent need for evidence-based guidelines on discontinuation of long-term treatment, avoiding side effects and preserving anti-fracture efficacy.

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