The Parathyroid Hormone D-Lema

Michael F. Holick

Vitamin D, Skin, and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine Boston University School of Medicine Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Michael F. Holick, M.D., Ph.D., Vitamin D, Skin, and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.

Much has been written on what a normal level of 25-hydroxyvitamin D [25(OH)D] is (1, 2, 3, 4). A normal range represents the mean value ± 2 SDs in blood samples from healthy subjects. The problem with this analysis is the assumption that the collection of blood was obtained from healthy normal volunteers. It is now clear that adults in all age groups are at risk of vitamin D deficiency (1, 2, 3, 4) and, therefore, many of the so-called normal volunteers most likely were vitamin D insufficient or deficient, which when taken into account lowered the mean as well as the lower limit of normal. Typically, many of the commercial assays use the lower limit of normal for 25(OH)D to be between 10 and 15 ng/ml. On the other hand, Heaney et al. (5) have reported that 25(OH)D levels needed to be at least 32.4 ng/ml to maximize intestinal calcium absorption.

Chapuy et al. (1) plotted 25(OH)D vs. PTH concentrations and concluded that a 25(OH)D of 31.2 ng/ml (78 nmol/liter) or lower should be considered to be vitamin D deficient. Vieth et al. (6) replotted the data using a LOWESS plot and reported that there was no plateau relationship between PTH and 25(OH)D. They concluded that if lower PTH is a goal, then a higher 25(OH)D concentration will always lower PTH further.

In this issue of JCEM, Souberbielle et al. (7) report that the upper limit of the normative value for PTH in vitamin D-sufficient subjects is more than 30% lower than what is generally accepted as the upper limit of the normal range for the commonly used immunoradiometric assay in the United States, namely 65 pg/ml. The authors have provided retrospective evidence from a chart review analysis that the upper limit of normal for PTH should be 46 pg/ml, not 65 pg/ml. They assume in their review that the patients were uniformly vitamin D sufficient. This is doubtful at best. In addition, the 708 patients who were 59 ± 13 yr old, were either osteopenic or osteoporotic. These individuals are not, therefore, the ideal cohort to use to establish a normative range. None had normal bone density. Moreover, the authors used an in-house assay for 25(OH)D that they admitted reads about 40% lower than the commercial assays [i.e. their 25(OH)D of 12 ng/ml equaled 20 ng/ml when performed by an established commercial assay], another point that confounds interpretation of their study.

PTH levels increase with age and are independent of renal function. This age-dependent increase has been ascribed to an alteration in the PTH-1,25(OH)2D axis. It is equally plausible that because men and women over the age of 50 yr are often vitamin D deficient, that this has influenced the measurement of normative PTH levels in this age group. Clearly, there needs to be a rigorous establishment of the normal range for PTH in all age groups in subjects who are both vitamin D sufficient [i.e. 25(OH)D>20 ng/ml, and without metabolic bone disease]. This goal has not been achieved in the study of Souberbielle et al. (7).

If 46 pg/ml is going to become the new upper range of normal, the issue becomes what to do with PTHs above that number. The authors found patients with a normal serum calcium concentration and a PTH above 46 pg/ml who had surgically proven primary hyperparathyroidism (PHPT). Unfortunately, they do not report on what was found at surgery. It is possible that those patients with surgically proven PHPT were suffering from secondary hyperparathyroidism due to either chronic vitamin D deficiency or periodic (seasonal) vitamin D deficiency. There is evidence that the parathyroid gland can produce 1,25(OH)2D locally, which in turn regulates the proliferation and differentiation of parathyroid cells (8). Thus, during vitamin D deficiency, the parathyroid cells become hyperplastic. This can also increase the probability of a somatic mutation that could lead to adenoma (9). Indeed, it is likely that the cause in many patients found to have subtle mild PHPT with hyperplasia is due to vitamin D deficiency. The finding of hyperplastic glands in the subjects who underwent parathyroid surgery with normal calcium concentrations would strengthen this viewpoint. Malabanan et al. (2) reported that giving pharmacological doses of vitamin D (50,000 IU vitamin D2 once per week for 8 wk) and calcium supplementation to patients with low normal 25(OH)D levels (between 11 and 19 ng/ml) led to a dramatic reduction in their PTH concentrations when their 25(OH)D levels increased by more than 100% (17.0 ± 10 to 35.0 ± 10 ng/ml). Fifty-five and 35% of patients with normal 25(OH)D levels of 10.1–14.9 and 15.0–19.9 ng/ml had secondary hyperparathyroidism [i.e. PTH > 65 ng/liter (pg/ml)]. In patients with PTH levels above 46 pg/ml and a normal serum calcium concentration it would be prudent to give a trial of vitamin D (50,000 IU once per week for 4–8 wk) with calcium to see whether the PTH substantially decreases to return within the normal range. The effect can be dramatic (10, 11). This advice pertains to the patient with normal serum calcium levels, not to the patient who has hypercalcemia. Another scenario could result, however, in the patient with vitamin D deficiency and normal serum calcium concentration, namely that the primary hyperparathyroidism is unmasked with an increase in serum calcium after vitamin D. In patients who do not have PHPT but rather secondary hyperparathyroidism due to vitamin D deficiency, correction of secondary hyperparathyroidism with vitamin D and calcium can result with as much as a 25% increase in bone mineral density and 100% decrease in PTH within 2 yr (11). Of course, recommendations for surgery in patients with normal serum calcium levels and persistently elevated PTH, after vitamin D repletion, should be based upon the most recent guidelines (12).

Bottom line: do not think about normal levels of 25(OH)D and PTH, but think about healthy levels. Do not interpret a single elevated PTH value with a normal serum calcium as necessarily indicative of PHPT but rather possibly due to secondary causes the most likely being vitamin D deficiency. In the absence of sun exposure, it is estimated that 1000 IU vitamin D is required to maximize bone health and to keep PTH levels normal (13, 14).

Received June 12, 2003.

Accepted June 12, 2003.

References

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