Clinical Investigations Genetic Variation and Covariation of Parathyroid Hormone Levels and Bone Density in the Human Population I. Otremski, 1 D. Karasik, 2 G. Livshits 2 1 Department of Traumatology and Orthopaedics, Ichilov Municipal Hospital, Tel Aviv, Israel 2 Research Unit—Human Population Biology, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel Received: 21 July 1998 / Accepted: 30 September 1999 Abstract. The present study was an attempt to evaluate the relative importance of familial/genetic factors in interindi- vidual variation of plasma concentrations of parathyroid hormone (PTH) and bone mineral density (BMD). We also examined to what extent common genetic and environmen- tal factors may be involved in covariation between the hor- mone concentrations and BMD levels. Ninety-five nuclear pedigrees (consisting of 187 males and 168 females, aged 18–91 and 18–86 years old, respec- tively), from several small villages in the Chuvasha Au- tonomy, Russia, were assessed for PTH, sex hormones, and BMD. PTH plasma levels were measured in duplicate by immunoradiometric assay using an N-tact PTH SP kit. Stan- dard roentgenography was done from the second and third phalanges of the middle finger on both hands for assessment of compact and cancellous bone BMD separately. The pres- ent study clearly confirmed the results of the previous ge- netic analyses of BMD which indicated that between 47% and 60% of the total variance of BMD, adjusted for sex and age effects, were attributable to genetic factors. Genetic factors also contributed significantly to interindividual variation of PTH. Constraining these additive genetic ef- fects to zero dramatically increased the likelihood ratio (P < 0.001), indicating that at least 30% of the hormone plasma variation was attributable to genetic sources. The results of bivariate decomposition analysis were not clear cut. Two types of bivariate analyses showed that PTH-BMD genetic correlations according to sex and between the opposite sexes were consistently negative, but only marginally sig- nificant. Key words: Parathyroid hormone — Bone mineral density — Variance decomposition analysis — Bivariate analysis. The major function of parathyroid hormone (PTH) is to maintain normocalcemia and to reduce plasma phosphate [1]. The main factors that regulate PTH production and secretion are calcium, phosphate, vitamin D, and the sex steroids. Circulating level of ionized calcium and phosphate acts directly on the parathyroid glands in a feedback fash- ion. Sex steroids, especially estrogen, may inhibit various intermediaries, which are released from osteoblasts in the presence of PTH to activate osteoclasts [2]. Sex steroids deficiency may be the most common cause of bone loss [3], and lowered levels of estrogen may be responsible for the secondary hyperparathyroidism and increase in bone turn- over in late postmenopausal women [4]. Bone serves as a target organ for most PTH actions. The action of PTH on osteoblasts causes the release of an un- identified osteoclast activation factor that stimulates them to attack bone. An imbalance in the PTH level may lead to several pathological conditions, such as hypo- and hyper- parathyroidism. One of the most striking features of hyper- parathyroidism is the severe demineralization of bone which may appear radiologically as osteoporosis, due to the lattice- like form of the cortical bone [5]. Increased bone mass, both in trabecular and cortical bone, was observed in hypopara- thyroid patients after thyroidectomy [6]. There are some data on ethnic differences in PTH levels. For example, serum PTH was found to be significantly higher in Afro-American than in Caucasian women [7]. However, the data concerning the contribution of genetic factors to quantitative variation of plasma/serum levels of PTH in healthy populations are very limited. Work in the field of heritable influences in PTH expression and variabil- ity were performed mainly on families with affected indi- viduals [8–11]. According to Parkinson and Thakker [8], PTH is en- coded by a single gene located on 11p15. Individual differ- ences in serum PTH concentrations in all likelihood cannot be wholly explained by its structural gene [12]. A number of other genes as well as environmental influences may deter- mine this hormone’s levels. However, no study has yet been performed to estimate the relative influence of genetic ef- fects on variability and heritability of this hormone’s levels. Moreover, whereas the relationship between hormone levels and bone mineral density (BMD) received much attention in recent years [7, 13, 14], these studies have explored only the phenotypic correlations between PTH and bone mass. The Correspondence to: G. Livshits Calcif Tissue Int (2000) 66:168–175 © 2000 Springer-Verlag New York Inc.