Patients who are not going to have parathyroid surgery should maintain hydration at all times. Their intake of calcium should follow established nutritional guidelines. While it seems intuitive to want to restrict calcium intake in PHPT, there are reasons not to restrict dietary calcium. Calcium excretion is not substantially affected by calcium intake. There is reason to be concerned about low calcium intakes as this could be a signal for the abnormal parathyroid gland(s) to become even more active. On the other hand, one does not want to encourage high calcium intake which can be a particular problem if the 1,25- dihydroxyvitamin D3 is elevated. As is the case for subjects without PHPT, dietary sources of calcium are to be recommended instead of supplemental forms.
Phosphate
Oral phosphate is virtually never used in PHPT anymore. Concerns about GI tolerance, further increases in PTH levels, and ectopic calcifications have essentially relegated oral phosphate to a historical footnote.
Oestrogen
Studies of oestrogen in PHPT have typically been high, but lower doses have also seemed to be beneficial. Given the limited data, it is nevertheless, reasonable to consider oestrogen among postmenopausal women for whom surgery is not an option, are willing to take oestrogen, and there are no contraindications. When oestrogen is effective, the serum calcium will fall by 0.5 to 1.0 mg/ d. PTH levels will remain stable. BMD will increase in the lumbar spine and femoral neck.
Selective oestrogen Receptor Modulator (SERM)
There are very limited data on the use of SERMs in PHPT. In a small study of 18 postmenopausal women, Rubin et al. reported a significant decline in the serum calcium by about 0.5 mg/ dl after 8 weeks of raloxifene. The results were transient with return of the serum calcium and reduced bone turnover markers to baseline during the 4- week wash out period. There were no changes in PTH or urinary calcium excretion. Zanchetta and Bogado, with an even smaller number of subjects and without a blinded experimental design, showed a similar reduction in serum calcium with raloxifene.
Vitamin D
Referencing the discussion earlier in this chapter on vitamin D deficiency being related to activity of disease, the logic follows that vitamin D replacement should be associated with better control of the hyperparathyroid state. Grey et al. administered vitamin D3 to 21 patients with mild PHPT. The repletion regimen in these subjects whose 25- hydroxyvitamin levels averaged 20 ng/ ml, was 50 000 international unit (IU)s weekly for 4 weeks followed by 50 000 IU monthly for the next 11 months. After 12 months, the average 25- hydroxyvitamin D levels increased to 31 ng/ ml. The serum PTH levels fell by about 25% without any change in the serum calcium. Three subjects developed marked hypercalciuria ( >400 mg/ day). Although this report supports the idea that vitamin D insufficiency can worsen the hyperparathyroid state, it does not provide guidance as to how vitamin D should be replaced. A more reasonable approach employed 2800 IU/ day for 6 months and showed, in a randomized trial, that mean PTH levels fell by 17% without any change in the serum calcium concentration. In addition to the biochemical effects of vitamin D, muscle strength might be improved as shown by Amstrup et al.. This suggestion could not be confirmed by Rolighed et al. in a short 6- month study.
In short, the 25- hydroxyvitamin D level should be normal in PHPT. While the definition of ‘normal’ is controversial, that controversy relates to the ‘right number’ in subjects without evidence for metabolic bone diseases. Given the upside safety of vitamin D and the work of Walker et al., in which the inflection point below which the PTH level appears to rise further in PHPT, namely at around 25 ng/ ml, it seems reasonable to aim for a level greater than 30 ng/ ml (75 nmol/ L).
Bisphosphonates
The bisphosphonates are attractive in PHPT, not because they affect PTH secretion directly but because they reduce bone turnover in a disease characterized by high bone turnover. Theoretically, they could reduce serum and urinary calcium levels and increase BMD. The amino substituted bisphosphonates, in common use for osteoporosis, have been of interest. A limited but positive experience with risedronate, has been followed by more detailed studies with alendronate. Several promising studies of alendronate in PHPT have been followed by three well- controlled studies. The work of Khan et al. utilizing a randomized, double- blinded, placebo- controlled design, in 44 patients with mild, asymptomatic PHPT, showed a significant 5.3% increase in BMD of the lumbar spine, which rose further to almost 7% % by year 2 (Figure 1). Total hip BMD increased by 4.01% in year 2. As expected, bone turnover markers fell by more than 50%. Calcium, phosphorus, and PTH levels did not change. Men with PHPT have also been studied with similar results. Chow et al. have reported an experience similar to Khan et al., except that the serum calcium fell by 0.34 mg/ dl.
Fig1. The effect of alendronate on bone mineral density in primary hyperparathyroidism. With alendronate, bone mineral density increases significantly after 1 year, while the placebo group shows no change until it is crossed over to alendronate in year 2. Adapted with permission from Khan AA, Bilezikian JP, Kung AWC, Ahmed MM, Dubois SJ, Ho AYY, Schussheim D, Rubin MR, Shaikh AM, Silverberg SJ, Standish TI, Syed Z, Syed ZA: Alendronate in primary hyperparathyroidism: a double- blind, randomized, placebo- controlled trial. J Clin Endocrinol Metab 2004;89:3319– 3325. Copyright © 2004, Oxford University Press. (ref 215).
These promising results suggest that in patients with low BMD who are not candidates for parathyroid surgery, for whatever reason, might show improvements in BMD when alendronate is use. An unusual finding of increased fracture risk in those receiving alendronate compared to those who underwent successful parathyroidectomy deserves comment. The selection bias of the two groups would appear to be the best explanation for these unexpected results. Those who received alendronate were at greater risk for fracture than those who underwent parathyroid surgery. Obviously, if a patient is a candidate for parathyroid surgery, that is preferred but the body of reports with alendronate do substantiate its utility in situations where parathyroid surgery is not a consideration.
These promising results suggest that in patients with low BMD who are not candidates for parathyroid surgery, for whatever reason, might show improvements in BMD when alendronate is use. An unusual finding of increased fracture risk in those receiving alendronate compared to those who underwent successful parathyroidectomy deserves comment. The selection bias of the two groups would appear to be the best explanation for these unexpected results. Those who received alendronate were at greater risk for fracture than those who underwent parathyroid surgery. Obviously, if a patient is a candidate for parathyroid surgery, that is preferred but the body of reports with alendronate do substantiate its utility in situations where parathyroid surgery is not a consideration.
Denosumab
The use of denosumab is theoretically attractive in PHPT because it interferes with RANK L, a cytokine intimately related to a catabolic pathway utilized by PTH. In the study of Eller- Vainicher et al. (Figure 2), denosumab was shown to improve BMD to a significantly greater extent than a comparable group of postmenopausal women with osteoporosis but without PHPT. One looks forward to further controlled studies of denosumab in PHPT.
Fig2. Denosumab in primary hyperparathyroidism. 1- year changes in BMD after denosumab in osteoporotic postmenopausal women with or without primary hyperparathyroidism. The patients with primary hyperparathyroidism demonstrated significant greater increases in BMD at all sites in comparison to those without primary hyperparathyroidism. Reproduced with permission from Eller- Vainicher C, Palmieri S, Cairoli E, Goggi G, Scillitani A, Arosio M, Falchett A, Chiodini I. Protective Effect of Denosumab on Bone in Older Women with Primary Hyperparathyroidism. J Am Geriatr Soc 2018;66:518– 24. Copyright © 2018 The American Geriatrics Society. (ref 219).
calcimimetics
Different from the aforementioned pharmacological approaches to PHPT, an approach that targets the parathyroid gland secretory apparatus is most attractive. Interference with the CaSR would provide this more specific approach. Calcimimetics increase the calcium signal to the parathyroid cell and should reduce the secretion of PTH. Following promising early studies with an early calcimimetic, the phenylalkylamine (R)- N- (3- methoxy- alpha- phenylethyl)- 3- (2- chlorophenyl)- 1- propylamine [R- 568], a more potent calcimimetic, cinacalcet hydrochloride was studied and approved by the US Food and Drug Administration (FDA). The indication is for control of the serum calcium in patients with PHPT who present a challenge to control. The work of Shoback, Peacock, and their as sociates have documented the efficacy of cinacalcet in reducing the serum calcium in PHPT. The studies have been carried out for up to 5 years, demonstrating continuous control of the serum calcium. The drug has been shown to effective among a spectrum of clinical manifestations and in those with severe dis ease. One negative aspect of this drug is that BMD does not improve.
Cinacalcet has also been shown to be effective in parathyroid cancer but high doses may be required.
