Osteomalacia, rickets, and renal osteodystrophy

Introduction

Osteomalacia, by definition, means that osteoblasts have laid down a collagen matrix but there is a defect in its ability to be mineralized. In children, a defect in mineralization of osteoid in long bones leads to osteomalacia. The accompanying hypophosphatemia leads to impaired apoptosis of the most mature chondrocytes of the growth plate, leading to the classic skeletal deformities of rickets.

Calcium, Phosphorous, and Vitamin D Metabolism

The major skeletal mineral components are calcium and phosphate. Thus any alteration in the calcium-phosphate product in the circulation can result in a mineralization defect in the skeleton. Vitamin D plays a critical role in maintaining both serum calcium and phosphate concentrations. Vitamin D is obtained by exposure of the skin to sunlight or from the diet. ( Fig. 204.1 ). (Vitamin D refers to either vitamin D ₂ or D ₃ .)

Upon exposure to ultraviolet irradiation, the vitamin D precursor 7-dehydrocholesterol present in the skin is cleaved to form pre–vitamin D ₃ , which then undergoes a temperature-sensitive molecular rearrangement to form vitamin D ₃ (cholecalciferol). The biologically inactive vitamin D ₃ is transported in the blood bound to the vitamin D binding protein (DBP) and then hydroxylated in the liver by vitamin D-25-hydroxylase (25-OHase) to form the major circulating form of vitamin D: 25-hydroxyvitamin D (25[OH]D). 25(OH)D is, however, biologically inert and requires hydroxylation in the kidneys on carbon 1 by 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1, 1-OHase) to form 1α,25-dihydroxyvitamin D (1,25[OH] ₂ D), the biologically active form of vitamin D responsible for regulating calcium and phosphorus homeostasis. In the kidneys, the 24-hydroxylase enzyme (CYP24A1) can decrease the amount of 25[OH]D available by hydroxylating the carbon 24 on 25[OH]D to form 24, 25 dihydroxyvitamin D (24,25[OH] ₂ D ₃ ). CYP24A1 also hydroxylates 1,25[OH] ₂ D to decrease the circulating concentrations of biologically active vitamin D.

Interaction of 1,25(OH) ₂ D with its vitamin D nuclear receptor (VDR) in the small intestine results in an increase in the efficiency of intestinal calcium absorption. Both proximal and distal segments of the intestine are necessary for optimal intestinal calcium absorption. Though most studies demonstrate the role of 1,25(OH) ₂ D in regulating calcium transport in the duodenum, studies also suggest that 1,25(OH) ₂ D modulates calcium transport in the distal gut. In the kidneys, approximately 65% of the filtered calcium is passively reabsorbed in the proximal tubules, while 1,25(OH) ₂ D and parathyroid hormone (PTH) act to increase calcium reabsorption in the distal renal tubules.

Phosphate is absorbed in the small intestine by the sodium-dependent phosphate cotransporter type IIb (NPT2b, SLC34A2 ) and filtered by the kidney. About 60% to 65% of dietary intake of phosphate is absorbed by the small intestine, and approximately 70% of the renal filtered load is reabsorbed in the proximal convoluted tubule. Renal reabsorption of phosphate is mediated by the brush border sodium-dependent (Na ⁺ ) phosphate (Pi) transporters, including Type I Na/Pi cotransporter (NPT1, SLC17A1 ) and Type II Na/Pi cotransporters Type IIa (NPT2a, SLC34A1 ) and Type IIc (NPT2c, SLC24A3 ). PTH promotes renal phosphate excretion by enhancing the rapid internalization of NPT2a and its subsequent lysosomal degradation. 1,25(OH) ₂ D stimulates renal phosphate reabsorption by increasing renal NPT2a expression directly and also by decreasing PTH levels. The hormone fibroblast growth factor 23 (FGF23), produced by osteoblasts and osteocytes in bone, is a major regulator of phosphate homeostasis. FGF23 increases renal phosphate excretion by decreasing the brush border localization of NPT2a/c in the proximal tubules of the kidneys. FGF23 also modulates 1,25(OH) ₂ D levels by downregulating expression of C y p27 b1 and upregulating expression of Cyp24a1 .

Effect of Vitamin D on Bone Metabolism

The calcium × phosphate product in the circulation and in the extravascular space plays a major role in normal mineralization of the osteoid laid down by osteoblasts. It is known that vitamin D is not required for mineralization of the osteoid matrix. Patients with vitamin D–resistant rickets have a mutation in their VDR leading to severe rickets and osteomalacia. When these patients were infused with calcium and phosphorus to maintain a normal calcium-phosphate product, the unmineralized osteoid was mineralized. Furthermore, mice lacking the VDR fed a rescue high calcium, high phosphate diet do not develop rickets or osteocmalacia.

Interaction of 1,25(OH) ₂ D with its VDR in osteoblasts increases the expression of alkaline phosphatase (ALP) and receptor activator of nuclear factor κB ligand (RANKL). The ALP produced by osteoblasts is important in bone mineralization because patients with a decrease in bone-specific ALP, known as hypophosphatasia , have a mineralization defect in osteoid.

When expressed on the surface of an osteoblast or released into the extracellular space, RANKL interacts with its receptor RANK on osteoclast precursor cells of the monocyte lineage, leading to signal the formation of multinucleated mature osteoclasts These osteoclasts, under the direction of a variety of cytokines, including interleukin-1 (IL-1) and IL-6, increase resorption of bone by releasing hydrochloric acid to dissolve the mineral and collagenases, including cathepsin K, to dissolve the matrix.

Causes of Osteomalacia and Rickets

There are several different causes for osteomalacia and rickets, and these are listed in Box 204.1 . The pathophysiology of these disparate causes varies, and the principal ones are discussed in detail next.