Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by autonomous secretion of parathyroid hormone (PTH), most often presenting with hypercalcemia. One of its most important complications is osteoporosis, which results primarily from increased bone resorption. When curative surgical treatment (parathyroidectomy) is not feasible, pharmacological therapy aimed at reducing bone resorption is indicated. Two potent antiresorptive agents used in the treatment of primary osteoporosis are zoledronic acid (zoledronate), an intravenous bisphosphonate, and denosumab, a monoclonal antibody that inhibits the RANK/RANKL pathway. Because bone loss in PHPT is largely driven by excessive activation of the RANK/RANKL system, we hypothesized that denosumab, as a targeted inhibitor of this pathway, would lead to greater increases in bone mineral density (BMD), more pronounced reductions in serum calcium, and stronger suppression of bone turnover compared with zoledronate.
Methods: We enrolled 40 postmenopausal women with PHPT and osteoporosis who were not eligible for surgical treatment. At baseline, we assessed routine biochemical parameters and bone turnover markers (BTMs), including C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I procollagen (P1NP), and bone-specific alkaline phosphatase (BAP), and measured BMD. Participants were randomly assigned in equal numbers to receive either zoledronate 5 mg intravenously once yearly (ZOL group) or denosumab 60 mg subcutaneously every 6 months (DMAB group). BMD was evaluated at baseline and after 12 and 24 months. Laboratory parameters and BTMs were measured at 3, 6, 12, 18, and 24 months. All participants received vitamin D₃ supplementation (800–1000 IU daily) and were advised to maintain a daily calcium intake of up to 1000 mg from dietary sources. Between-group comparisons of continuous variables were performed using the independent-samples t-test or the Mann–Whitney test, as appropriate. Changes over time and between-group differences in repeated measurements were analyzed using a mixed ANOVA model. Statistical analyses were conducted using SPSS.
Results: Over the two-year treatment period, increases in BMD did not differ significantly between the two groups. After 12 months, lumbar spine (LS) BMD increased significantly in both groups (DMAB: +0.038 g/cm², p < 0.001; ZOL: +0.040 g/cm², p = 0.003). Total hip (TH) BMD increased significantly only in the DMAB group (+0.036 g/cm², p = 0.006). No significant changes were observed at the femoral neck (FN) or one-third radius (1/3R) in either group during the first year. At 24 months, BMD remained significantly above baseline at the LS in both groups and at the TH in the DMAB group. No additional significant increases were observed during the second year of treatment. At 3 months, serum total calcium decreased significantly in both groups (DMAB: −0.07 mmol/L, p = 0.045; ZOL: −0.08 mmol/L, p < 0.01), with no difference between treatments. At 6 months, calcium levels remained lower than baseline (F (1,37) = 5.09, p = 0.03). However, at 12, 18, and 24 months, calcium levels no longer differed significantly from baseline, and no between-group differences were observed at any time point. Intact PTH (iPTH) increased significantly after the first administration of both drugs (3 months: F (1,37) = 10.48, p = 0.003; 6 months: F (1,37) = 7.46, p = 0.01), without differences between groups. No further increases were observed following subsequent administrations. At 3 months, CTX, P1NP, and BAP decreased significantly in both groups. The reductions in CTX and P1NP were greater in the DMAB group (CTX: −0.952 vs −0.556 μg/L, p = 0.03; P1NP: −75.45 vs −54.06 μg/L, p = 0.003). Although BAP decreased in both groups, the relative reduction was greater with DMAB (58% vs 50%, p = 0.024). Absolute CTX and P1NP values at 3 months were significantly lower in the DMAB group. At later time points, CTX remained suppressed below baseline in both groups, without significant differences between treatments. The relative reduction in P1NP remained consistently greater in the DMAB group throughout follow-up. Absolute BAP values were lower in the DMAB group at 24 months (p = 0.0425), and reductions from baseline were greater with DMAB at 12 and 24 months.
Conclusion: After two years of treatment, denosumab and zoledronate produced comparable increases in BMD. LS BMD improved significantly in both groups, while TH BMD increased significantly only with denosumab. Both treatments resulted in a modest, short-term reduction in serum calcium, with no sustained differences between groups. Denosumab produced a more pronounced suppression of bone turnover; resorption was particularly suppressed during the first three months of treatment, and formation was also suppressed in the later stages of treatment.
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