Hypocalcemia secondary to vitamin D3 (D3) depletion (D-Ca-) perturbs extra- and intracellular calcium (Ca). To study the effect of cyclic nutritional changes in the D3 and calcium (Ca) repletion state, we investigated the lasting effects of calcium or D3 repletion on calcium and bone metabolism using a novel depletion-repletion-redepletion protocol. D-Ca- rats presenting osteomalacia without rickets and a significant impairment in whole body mineral content (BMC) accretion were repleted with either calcium alone [3% (Ca+3) or 0.5% (Ca+0.5)] or D3 and then switched back to the original D-Ca- diet. All repletion protocols, except Ca+0.5, normalized serum (S) Ca and parathyroid hormone (PTH) but Ca+3 exhibited growth retardation and hypophosphatemia. D3 normalized BMC in D-Ca- and healed osteomalacia while Ca+0.5 led to 50% normalization. In contrast, rickets with no BMC accretion was observed in Ca+3 most likely secondary to hypophosphatemia. Upon redepletion, S Ca rapidly decreased while S PTH and phosphate increased. D3 and Ca+0.5 survived the redepletion protocols but all Ca+3 died within 5 days upon sudden Ca withdrawal whereas progressive Ca redepletion significantly delayed the death rate. Data indicate that during the calcium redepletion period, correction of hypophosphatemia in Ca+3 allowed calcification of the enlarged growth plates thus resulting in an increased demand for calcium. It is postulated that this increased demand for calcium, in conjunction with low dietary calcium and the bone calcium reservoir incapacity to provide sufficient calcium to sustain S Ca, led to the observed acute hypocalcemia which was most likely the cause of death. This hypothesis is further supported by the observation that Ca+3 submitted to a progressive Ca deprivation exhibited a delay in death rate, a progressive involution of rickets and survival only upon return to the D-Ca- phenotype. Furthermore, in Ca+3, increasing dietary phosphate by 0.6% to achieve a Ca/P ratio similar to Ca+0.5 or D3 prevented the development of hypophosphatemia, slightly increased S Ca, significantly increased BMC, prevented the development of rickets and allowed 100% survival during rapid calcium withdrawal. Collectively, data clearly demonstrate the importance of the dietary Ca/P ratio to maintain S Ca/P at optimum concentrations for bone health.