Misconceptions (3): calcium leaves bone only by resorption and enters only by formation.

A central concept in our field is that bone undergoes turnover, which of necessity involves the mineral of bone as well as the matrix. With a representative value for total body calcium of 1000 g [1] and a representative value for wholebody bone turnover of 12%/year [2], about 330 mg of calcium is removed from bone each day by osteoclasts. With a representative value for long-term whole-body bone loss of 1%/year [3], about 300 mg of calcium is returned to bone each day by osteoblasts, a negative balance of about 30 mg/day. It is widely believed that this is the only means whereby calcium can move out of or into the skeleton. For example, “this pool is in dynamic equilibrium with calcium entering and exiting via the intestine, bone, and renal tubule. In zero balance, bone resorption and formation are equivalent at about 500 mg/day, . . .” [4]; “. . . an effective balance of calcium absorption, calcium excretion, bone formation and bone destruction” [5]; “approximately 500 mg of Ca enters and leaves the skeleton daily as a result of bone formation and resorption, respectively” [6]; and, “the input of calcium into the ECF can come only from resorption of bone mineral and absorption of gastrointestinal calcium. . . . The egress of calcium from the ECF can be either through bone formation or renal calcium excretion” [7]. None of these statements explicitly rules out other pathways of calcium movement, but their context makes clear that this is what the authors believed. The many readers of these book chapters, and indeed almost everyone who came into the field in the past 20 years, will be surprised to learn that much larger calcium fluxes between extracellular fluid (ECF) and bone than those mediated by osteoclasts and osteoblasts have been recognized for almost 50 years [8–11]. Their existence was established using radioisotopes of calcium, which led to the concept of the exchangeable or miscible pool of calcium. In addition to calcium in the ECF, this includes most of the calcium bound to soft connective tissue macromolecules and about 0.3% of the calcium in bone [11]. I shall summarize the evidence relating to this pool and its associated fluxes, including their location, magnitude, mechanisms, and homeostatic significance. But first I must clarify the ambiguity in the term “exchange.” In physical chemistry the exchange of an ion between solid and liquid phases is isoionic, preserving exact mass balance without a change in concentration, a process that cannot contribute to homeostasis [10]. But in physiology, exchange can also refer to the reciprocal translocations that reflect a reversible process which can attain dynamic equilibrium. In such a system, the net flux in either direction represents the balance between opposing fluxes of greater magnitude. Mass balance is preserved at equilibrium, but not during the transition between one equilibrium state and another [11]. The exchangeable calcium pool is the aggregate of calcium ions within which a labeled tracer equilibrates to attain the same concentration as in plasma. The apparent size of the pool depends on the time of sampling and the choice of mathematical model, but a representative value is 5000 mg, of which about 1000 mg is in ECF, about 1000 mg in soft connective tissues (some of it intracellular), and about 3000 mg in bone [9]; the remainder of the discussion will focus on the bone component of the total exchangeable pool. Examination of bone by radioautography at different times after labeled calcium administration shows immediate rapid uptake at all bone surfaces accessible to the circulation, regardless of their cellular activity or degree of mineralization [8,11]. In the long bone cortices, these surfaces are the * 4301 W. Markham, Slot 587, Little Rock, AR 72205-7199. E-mail address: endoadmin@uams.edu (A.M. Parfitt). Bone 33 (2003) 259–263 www.elsevier.com/locate/bone