Osteoprotegerin in Primary Hyperparathyroidism

Dear Editor,

We appreciate the comments of Minisola et al. [1] regarding the role of osteoprotegerin (OPG) and ligand of receptor activator of nuclear factor κB (RANKL) in patients with primary hyperparathyroidism (PHPT) treated with parathyroidectomy (PTX) or alendronate.

Baseline serum levels of OPG among our patients with PHPT [2] were in line with the results of previous PHPT studies [3] [4] and they were significantly higher than in the control group. The conditions of studies in cellular and animal models and in humans treated with PTH analogues do not correspond precisely with the conditions of chronic PTH excess in PHPT. The findings of several publications regarding OPG or RANKL in humans with PHPT do not indicate an OPG serum change after parathyroidectomy, which would seem to confirm our observations ([Table 1], [2] [3] [4] [5] [6]). It may be supposed that the elevated OPG serum concentration, which remained unchanged one year after PTX, is linked to continuous bone reconstruction and increased BMD which, while most vigorous during early months, continues to occur for many years following PTX [7] [8].

Table 1 Results for OPG and RANKL estimations in clinical trials for primary parathyroidism in humans.

Authors	Baseline serum level			Deviation from serum baseline 12 months after parathyroidectomy
	OPG	RANKL	n	OPG	RANKL	n
Stilgren et al. [5]				↔		20
Nakchbandi et al. [3]	↔ a	↑a	29
Kerschan-Schindl et al. [4]				↔		52
Szymczak et al. [2]	↑b	↑b	63	↔	↓	29
Stilgren et al. [6]				↑ mRNA in bone biopsies	↓ mRNA in bone biopsies	27

↔: “normal”, “unchanged”; ↑: higher; ↓: lower

^aIn comparison with range of norm

^bIn comparison with healthy control group

We did not examine the early changes of bone turnover markers after PTX. The only clear and recurrent correlation between bone turnover markers and the OPG/RANK/RANKL system was the positive correlation between OPG and bone resorption marker ICTP, which was observed in the entire group both prior to treatment (r=0.29, p=0.02) and in the 12^th month of treatment (r=0.36, p=0.0066). OPG-ICTP correlation was additionally observed when assessed separately for a group treated with alendronate and another with PXT. This suggests that OPG is produced to counteract bone damage independently of its cause. In recent years, it has also been discovered that OPG is expressed in response to canonical Wnt/β-catenin signaling pathway [9].

This important bone involvement is typical for PHPT, especially in patients qualified for PTX. The mean vitamin 25(OH)D serum concentration in PHPT group was (30.9±21.5 pg/ml) and did not vary with control group (31.4±15.1 pg/ml). No significant differences in clinical manifestations of PHPT were observed between patients with low (less than 20 ng/ml) or normal 25(OH)D serum concentrations, though the concentration of 25(OH)D negatively correlated with PTH and ICTP, which would suggest that vitamin D deficiency increases PTH secretion. There was no correlation between the values for vitamin 25(OH)D and OPG, RANKL or OPG/RANKL.

We should, of course, remain aware that OPG and RANKL are produced by many tissues and that their serum concentrations only partially reflect the local bone micro-environment. Conversely, serum concentrations of OPG and RANKL are likely to more connected with bone production in PHPT than in other diseases with lower bone turnover. From a technical point of view the quality of OPG assay used in our study, while seeming to be quite good, still requires larger controlled trials under different biological conditions.

• References

• 1 Minisola S, Cipriani C, Piemonte S, Colangelo L, Pepe J, Romagnoli E. Osteoprotegerin serum levels in primary hyperparathyroidism and changes following surgery. Horm Metab Res 2014; Jan 10 [Epub ahead of print]
• 2 Szymczak J, Bohdanowicz-Pawlak A. Osteoprotegerin, RANKL, and bone turnover in primary hyperparathyroidism: the effect of parathyroidectomy and treatment with alendronate. Horm Metab Res 2013; 45: 759-764
• 3 Nakchbandi IA, Lang R, Kinder B, Insogna KL. The role of the receptor activator of nuclear factor-κB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. J Clin Endocrinol Metab 2008; 93: 967-973
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