Osteomalacia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
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Overview
Pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Ibrahim Elkhayat, M.B.B.Ch.[3]
Osteomalacia is characterized by defective mineralization of newly formed bone matrix (osteoid), resulting in accumulation of unmineralized osteoid. The fundamental abnormality is failure to establish or maintain the local biochemical conditions required for hydroxyapatite formation. Mechanistically, osteomalacia can result from inadequate calcium availability, inadequate phosphate availability, or abnormalities in local inhibitors and promoters of mineralization.[1][2]
Normal bone mineralization
Bone mineralization occurs on an organic matrix composed predominantly of type I collagen. Mineralization requires an adequate local concentration of calcium and phosphate and appropriate regulation of inhibitors and promoters of hydroxyapatite formation.
Matrix vesicles participate in the initiation of mineralization by concentrating calcium and phosphate. The local balance between pyrophosphate, a potent inhibitor of hydroxyapatite formation, and phosphate is particularly important. ENPP1 contributes to extracellular pyrophosphate generation, whereas tissue-nonspecific alkaline phosphatase (TNSALP), encoded by ALPL, hydrolyzes pyrophosphate and increases the availability of inorganic phosphate, thereby favoring hydroxyapatite formation.[2][3]
Thus, normal mineralization depends not simply on the circulating concentrations of calcium and phosphate, but on their local availability at the mineralization front and on the balance between mineralization-promoting and mineralization-inhibiting factors.[2]
Defective mineralization and osteoid accumulation
When mineralization is impaired, osteoid continues to be produced but fails to mineralize normally. The resulting accumulation of osteoid is the defining structural lesion of osteomalacia. Histomorphometry may demonstrate increased osteoid volume and surface, thick osteoid seams, a reduced or absent mineralization front, and prolonged mineralization lag time.[4]
A classic histomorphometric description of osteomalacia includes osteoid comprising more than 10% of total bone, osteoid seams covering more than 25% of trabecular surface and exceeding five lamellae, together with a decreased mineralization front. Normal mean mineral apposition is approximately 0.7 µm/day. The presence of excess osteoid alone is not sufficient to establish a mineralization defect because osteoid accumulation may also occur in high- or low-turnover states.[4][5][6]
Calcipenic pathway
Severe vitamin D deficiency reduces intestinal calcium absorption and can produce hypocalcemia or a tendency toward hypocalcemia. The resulting secondary hyperparathyroidism increases renal phosphate excretion and thereby decreases the calcium-phosphate product available for skeletal mineralization. Low calcium intake can produce a similar pathway through stimulation of parathyroid hormone (PTH) and increased phosphaturia.[7][1]
Secondary hyperparathyroidism also increases bone turnover and promotes cortical bone loss, particularly through increased endosteal resorption and cortical porosity. Consequently, low bone mineral density in vitamin D-related osteomalacia may reflect both increased bone turnover and loss of mineralized bone in addition to the accumulation of unmineralized osteoid.[7]
The histologic evolution of hypovitaminosis D osteopathy can be conceptualized as a continuum. In HVOi, secondary hyperparathyroidism and increased bone turnover cause increased osteoid accumulation without established mineralization failure (preosteomalacia). HVOii is characterized by delayed mineralization, whereas in HVOiii newly formed matrix may fail to mineralize. HVOia represents an early phase in which osteoid accumulation is attributable predominantly to secondary hyperparathyroidism and increased turnover rather than a primary mineralization defect.[8]
Phosphopenic and FGF23-mediated pathway
Chronic hypophosphatemia directly impairs hydroxyapatite formation and can therefore produce osteomalacia even when calcium availability is adequate.[9]
Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate homeostasis. Excess FGF23 acts through FGFR-Klotho signaling in the renal proximal tubule to reduce expression of sodium-phosphate cotransporters, particularly NaPi-IIa and NaPi-IIc, thereby increasing urinary phosphate excretion. FGF23 also suppresses renal CYP27B1 activity and promotes CYP24A1-mediated vitamin D catabolism, reducing circulating 1,25-dihydroxyvitamin D and consequently reducing intestinal phosphate absorption.[9][10]
In FGF23-mediated disorders such as X-linked hypophosphatemia (XLH), the mineralization defect is not explained solely by systemic hypophosphatemia. Local accumulation of PHEX-dependent phospho-ASARM peptides and osteopontin can inhibit mineralization, while osteocyte-derived FGF23 signaling can locally suppress TNSALP activity and increase pyrophosphate at the mineralization front. Serum alkaline phosphatase may remain elevated because of increased bone turnover despite impaired local mineralization.[11][2][12][13]
In hereditary hypophosphatemic rickets with hypercalciuria (HHRH), phosphate wasting is FGF23-independent and associated with appropriately elevated 1,25-dihydroxyvitamin D. Histomorphometric evidence demonstrates that hypophosphatemia itself can produce osteomalacia, supporting phosphate deficiency as a direct determinant of mineralization.[14][15]
Mineralization-inhibitor and matrix pathway
Defects in local promoters and inhibitors of mineralization can produce osteomalacia independently of systemic calcium or phosphate deficiency. In hypophosphatasia, deficient TNSALP activity results in accumulation of inorganic pyrophosphate and other mineralization inhibitors, impairing hydroxyapatite formation. A low serum alkaline phosphatase activity in the appropriate clinical context reflects this underlying enzymatic defect.[3][2]
Other acquired disturbances of the mineralization process can similarly impair hydroxyapatite formation through accumulation or exposure to mineralization-inhibiting substances. These mechanisms are distinct from disorders in which the primary abnormality is calcium or phosphate availability.
Pathophysiologic biochemical patterns
| Mechanistic pathway | Principal biochemical abnormality | Effect on mineralization |
|---|---|---|
| Calcipenic | Reduced calcium availability, often with secondary hyperparathyroidism and phosphate wasting | Reduced calcium-phosphate availability at the mineralization front |
| FGF23-mediated phosphopenic | Renal phosphate wasting with reduced 1,25-dihydroxyvitamin D | Chronic hypophosphatemia and impaired phosphate availability |
| FGF23-independent phosphopenic | Renal or systemic phosphate depletion without primary FGF23 excess | Direct impairment of hydroxyapatite formation |
| Mineralization-inhibitor/matrix defect | Increased local pyrophosphate or other inhibitors of mineralization | Inhibition of hydroxyapatite nucleation and propagation |
Clinical implications of the pathophysiology
The final common pathway of osteomalacia is inadequate mineralization of osteoid. The calcium-phosphate product available at the mineralization front is a major determinant of whether hydroxyapatite can form, but local matrix regulators can independently modify mineralization.[2]
Secondary hyperparathyroidism contributes to cortical bone loss and increased bone turnover, helping explain reduced bone mineral density and skeletal fragility in calcipenic osteomalacia.[7]
An inappropriately low or normal 1,25-dihydroxyvitamin D concentration in the presence of hypophosphatemia supports an FGF23-mediated mechanism, whereas appropriately elevated 1,25-dihydroxyvitamin D in hypophosphatemia suggests an FGF23-independent phosphate-wasting pathway.[9][14]
A low alkaline phosphatase activity in a patient with a suspected mineralization disorder should raise consideration of hypophosphatasia, whereas elevated alkaline phosphatase can occur in osteomalacia associated with increased bone turnover.[3][11]
References
- ↑ 1.0 1.1 Sam A; Meeran K; Hill N (2023). Osteomalacia. Endocrinology and Diabetes.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Collins MT; Marcucci G; Anders HJ; et al. (2022). "Skeletal and extraskeletal disorders of biomineralization". Nat Rev Endocrinol. 18 (8): 473–489. doi:10.1038/s41574-022-00682-7.
- ↑ 3.0 3.1 3.2 Whyte MP (2016). "Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 12 (4): 233–246. doi:10.1038/nrendo.2016.14.
- ↑ 4.0 4.1 Bain B; Clark D; Wilkins B (2019). "Diseases of Bone". Bone Marrow Pathology (5th ed.).
- ↑ Recker RR; Kimmel DB; Parfitt AM; et al. (1988). "Static and tetracycline-based bone histomorphometric data from 34 normal postmenopausal females". J Bone Miner Res. 3 (2): 133–144. doi:10.1002/jbmr.5650030203.
- ↑ Jha S; Chapman M; Roszko K (2019). "When Low Bone Mineral Density and Fractures Is Not Osteoporosis". Curr Osteoporos Rep. 17 (5): 324–332. doi:10.1007/s11914-019-00529-7.
- ↑ 7.0 7.1 7.2 Christodoulou S; Goula T; Ververidis A; Drosos G (2013). "Vitamin D and Bone Disease". BioMed Res Int. 2013: 396541. doi:10.1155/2013/396541.
- ↑ Parfitt AM; Qiu S; Rao DS (2004). "The Mineralization Index--a New Approach to the Histomorphometric Appraisal of Osteomalacia". Bone. 35 (1): 320–325. doi:10.1016/j.bone.2004.02.016.
- ↑ 9.0 9.1 9.2 Agoro R; White KE (2023). "Regulation of FGF23 production and phosphate metabolism by bone–kidney interactions". Nat Rev Nephrol. 19 (3): 185–193. doi:10.1038/s41581-022-00665-x.
- ↑ Edmonston D; Wolf M (2020). "FGF23 at the crossroads of phosphate, iron economy and erythropoiesis". Nat Rev Nephrol. 16 (1): 7–19. doi:10.1038/s41581-019-0189-5.
- ↑ 11.0 11.1 Kamenický P; Briot K; Munns CF; Linglart A (2024). "X-Linked Hypophosphataemia". Lancet. 404 (10455): 887–901. doi:10.1016/S0140-6736(24)01305-9.
- ↑ Barros NM; Hoac B; Neves RL; et al. (2013). "Proteolytic Processing of Osteopontin by PHEX and Accumulation of Osteopontin Fragments in Hyp Mouse Bone, the Murine Model of X-Linked Hypophosphatemia". J Bone Miner Res. 28 (3): 688–699. doi:10.1002/jbmr.1766.
- ↑ Hoac B; Østergaard M; Wittig NK; et al. (2020). "Genetic Ablation of Osteopontin in Osteomalacic Hyp Mice Partially Rescues the Deficient Mineralization Without Correcting Hypophosphatemia". J Bone Miner Res. 35 (10): 2032–2048. doi:10.1002/jbmr.4101.
- ↑ 14.0 14.1 Bergwitz C; Miyamoto KI (2019). "Hereditary Hypophosphatemic Rickets With Hypercalciuria: Pathophysiology, Clinical Presentation, Diagnosis and Therapy". Pflugers Arch. 471 (1): 149–163. doi:10.1007/s00424-018-2184-2.
- ↑ Gazit D; Tieder M; Liberman UA; Passi-Even L; Bab IA (1991). "Osteomalacia in Hereditary Hypophosphatemic Rickets With Hypercalciuria: A Correlative Clinical-Histomorphometric Study". J Clin Endocrinol Metab. 72 (1): 229–235. doi:10.1210/jcem-72-1-229.