Effectiveness of anti-osteoporotic treatment after successful parathyroidectomy for primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

Primary hyperparathyroidism (pHPT) affects bone metabolism by advancing turnover through increase in both bone formation and resorption, resulting in a net decrease in bone mineral density (BMD) and strength [1, 2]. In the literature, the incidence of osteopenia or osteoporosis in patients with pHPT has been estimated at 39% to 59%, affecting BMD at all sites measured (lumbar spine, femur, and radius) [3‐5]. The fracture risk, especially in vertebral spine, is thus increased up to fivefold [6‐8] and is associated with low BMD [9]. Parathyroidectomy (PTX) is the only causal treatment for pHPT and is recommended even in patients without severe symptoms, yet reduced BMD [10].

Only three randomized trials have addressed the effect of PTX on BMD vs. observation alone. PTX resulted in a minor but significant increase in BMD of 0.5% to 4% after 1 year [11, 12] and a 3.3% increase only at the lumbar spine after 5 years [13] in patients with mild disease. Improvement of BMD is not found in all patients, as another prospective trial showed no improvement whatsoever following PTX in more than half of postmenopausal women [14]. Thus, the fracture risk is increased by up to 10 or more years following successful surgery [6, 15, 16]. No investigations have so far focused on patients with pHPT and preoperatively diagnosed osteoporosis or osteopenia, who generally are at an advanced risk of fractures, especially not for their postoperative change in BMD and bone turnover.

To our knowledge, no trial has as yet addressed the potentially positive influence of treatment with anti-osteoporotic medication on BMD and bone metabolism after PTX. Basically, these medications can have two physiological effects: they either reduce bone resorption or increase bone formation. While the main effect of bisphosphonate therapy is the reduction of bone resorption, it seems more reasonable to stimulate bone formation to advance the increase in BMD after PTX. Strontium ranelate (SR) is one of the few osteoporosis-specific medications that both stimulate osteoblasts and thereby bone formation and inhibit osteoclasts (reducing bone resorption) [17, 18], leading to a decrease in vertebral and non-vertebral fractures [19, 20]. A meta-analysis of four trials has substantiated the positive effect of 2 g SR daily on the fracture risk in primary osteoporosis [21], [22]. Improved bone microarchitecture [23] may at least partially account for this effect.

Although the use of SR has been restricted (for the potentially elevated risk of thromboembolism and cardiovascular events), it at least continues to serve as an example of an anti-osteoporotic medication for patients with low BMD after successful PTX. The rationale is to stimulate bone formation, re-improve bone strength, increase BMD to the largest extent and as quickly as possible, and thus potentially prevent fractures.

Another new target of pharmacological intervention to increase bone formation is the Wnt signaling pathway, measured by the biochemical parameters sclerostin (SOST) and Dickkopf-1 (DKK-1). Although there is evidence that this pathway is important for the effects of parathyroid hormone (PTH) on bone metabolism [24], the dynamics of SOST and DKK-1 after PTX for PHPT have not yet been investigated. This pathway is of special interest, as the novel therapeutic agent romosozumab, an antibody against SOST, has shown potent anti-osteoporotic effects [25].

Thus, the aim of this study was to focus on osteopenic and osteoporotic patients after PTX for pHPT in an attempt to investigate the effect of an anti-osteoporotic medication with an anabolic effect on the change of BMD and on classical biochemical markers of bone metabolism. Additionally, the parameters SOST and DKK-1 were analyzed as potential future targets of intervention for stimulating bone formation.

This is the first prospective, randomized, double-blind trial to investigate the effect of anti-osteoporotic treatment on the postoperative course of BMD and bone metabolism after successful PTX, focusing only on patients with preoperatively advanced bone involvement (diagnosed osteoporosis or osteopenia). The rationale of this intervention was to enhance the speed and extent of bone density normalization in the early postoperative course. With intervention, the percentage of BMD increase at the lumbar spine was more than twofold higher in the treatment group than in the placebo group and the percentage of patients with osteopenia or osteoporosis declined from 69.0 to 37.9%. The additional effect of 6% lumbar-spine BMD change (PG: 3.94%; SG: 9.94%) shown in this study was equal to the 1-year baseline change after SR intake found in patients with primary osteoporosis but without pHPT (postmenopausal women and men). This treatment effect has been seen to reduce both vertebral and non-vertebral fractures [19, 20, 30]. As the fracture risk is prolonged up to 10 or more years following successful PTX in patients with pHPT [6, 15, 16], this effect seems preferable. The data presented here thus demonstrate that an anti-osteoporotic medication may additionally and positively influence bone remineralization, while producing similar effects as in patients without preceding PTX for pHPT. The effect on lumbar-spine BMD seems to be of even greater importance, as this site appears to be more strongly affected by pHPT [31, 32].

Although statistically not significant, a tendency towards a more pronounced gain in BMD at all sites was observed in females compared to males in either group (see Table 2). Especially for postmenopausal women who per se are at an elevated risk of fractures, any positive effect on bone stability seems important, since this trial showed that surgical cure of pHPT without additional treatment failed to reduce the proportion of patients with osteoporosis or osteopenia 1 year after PTX at any site in spite of adequate vitamin D and calcium supplementation. In a prospective and another retrospective trial, a further decrease in BMD was even documented in 15% to 31% [14, 33].

The information on biochemical markers presented here offers a broad insight into postoperative changes following PTX. Basically, the levels of Ca⁺⁺ at diagnosis were only slightly elevated (1.39 and 1.41 mmol/L in the SG and PG, respectively; normal range 1.16–1.32 mmol/L) as consequence to earlier diagnoses in Western countries due to screening programs with more frequently asymptomatic patients [31]. Nevertheless, alterations in markers of bone metabolism were documented in all patients demonstrating relevant bone involvement, albeit with a high level of variability (thus suggesting individual differences in pHPT-induced bone affection). The serum levels of CTX, a bone resorption marker, as well as those of the bone formation markers OC and P1NP significantly declined in all subjects at follow-up compared to baseline (Table 3). Additionally, the two antagonists of the Wnt signaling pathway (“antagonists” of bone formation)—SOST and DKK-1—that have not yet been evaluated following PTX, slightly increased in both treatment groups over the 1-year follow-up. Both the increase in SOST and DKK-1 and the reduction of “classical” markers of bone metabolism suggest that PTX reduces bone resorption as well as bone formation. These findings are in line with our previous study, also showing reduced bone turnover after PTX surgery [34, 35]. Therefore, it seems unreasonable to postoperatively apply a mainly antiresorptive treatment such as bisphosphonates that have even shown to bear potentially negative effects in pHPT-related bone involvement [36]. Although SR was limited in its use in 2017 (due to an advanced risk of thromboembolism and cardiovascular events), it seems reasonable to consider other anti-osteoporotic medications stimulating bone formation to improve BMD after PTX. Alternatively, the Wnt signaling pathway may be an interesting starting point for further investigation, as both SOST and DKK-1 levels were seen to increase postoperatively in this trial. Romosozumab, an antibody against SOST, is a promising new therapeutic agent against osteoporosis, improving bone formation, and microarchitecture [25]. It was recently approved by the FDA and might be another potential pharmacological option. This assumption is in line with findings that expression of SOST in bone is enhanced after PTX for secondary (renal) HPT [37].

In addition to the effect of PTH in pHPT, low BMD may also be caused by such other factors as primary osteoporosis, especially in postmenopausal women. We therefore attempted to establish markers of bone metabolism that may potentially reflect bone involvement by pHPT. OC and CTX were strongly correlated (as strongly as Ca⁺⁺) with preoperative PTH levels, and both markers, yet not PTH, showed a correlation with postoperative increase in BMD at the lumbar spine. These findings are in accordance with the study authored by Hansen et al., showing a correlation between increase in volumetric BMD and CTX (no data for OC) [38], but contradict the findings of Rolighed et al. who detected a positive association between preoperative PTH levels and postoperative BMD increase [39]. Preoperative biochemical markers may help to identify patients in whom a pronounced positive effect of successful PTX on postoperative BMD may be expected. They may also assist in differentiating such patients from those in whom primary osteoporosis and other factors may additionally strongly affect bone quality and who are less likely to improve after cure of pHPT, thus requiring immediate additional therapy.

Essentially, our investigation had several strengths: it was the first to investigate the effect of an anti-osteoporotic treatment immediately after successful PTX. Apart from its prospective, randomized, and double-blind design, the study population was very homogeneous, including only osteopenic and osteoporotic patients. Moreover, all patients were supplied with adequate standardized vitamin D and calcium doses, as shown to be important after PTX for pHPT [40].

A limitation of this trial is that SR was restricted in its use at the end of patient recruitment. Some of the measured effect of SR is likely caused by the overestimation of BMD in DXA scans of patients treated with SR (due to the higher atomic number of strontium compared to calcium [41]). However, even if 25% of the additional effect (approx. 6%) in the SG was caused by overestimation of BMD, the increase would still be 3.5% higher than in the PG (3.94% vs. SG: 7.47%; p = 0.01).

In conclusion, this randomized, double-blind, placebo-controlled trial indicated that the treatment of osteopenic or osteoporotic patients following PTX increases BMD mainly at the lumbar spine. The rationale of this trial was emphasized by the fact that without treatment, nearly all patients remained osteoporotic or at least osteopenic even with an adequate supply of vitamin D and calcium. In patients with high levels of OC and CTX, an increase in BMD is more likely than in those with low markers of bone metabolism. Thus, at least patients with osteoporosis/osteopenia with a lower probability of improvement after PTX should either be monitored closely for improvement in bone density or even receive bone-specific treatment immediately after PTX to reduce the risk of potential complications. As strontium ranelate was restricted in its use, other medications with positive effects on bone formation should be evaluated and the Wnt pathway may be another target for therapy.