Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis.
Histomorphometry and quantitative backscattered electron microscopy of iliac crest biopsies from patients with adult hypophosphatasia not only confirmed the expected enrichment of non-mineralized osteoid, but also demonstrated an altered trabecular microarchitecture, an increased number of osteoblasts, and an impaired calcium distribution within the mineralized bone matrix.


BACKGROUND
Adult hypophosphatasia is an inherited disorder of bone metabolism caused by inactivating mutations of the ALPL gene, encoding tissue non-specific alkaline phosphatase. While it is commonly accepted that the increased fracture risk of the patients is the consequence of osteomalacia, there are only few studies describing a complete histomorphometric analysis of bone biopsies from affected individuals. Therefore, we analyzed iliac crest biopsies from eight patients and set them in direct comparison to biopsies from healthy donors or from individuals with other types of osteomalacia.


METHODS
Histomorphometric analysis was performed on non-decalcified sections stained either after von Kossa/van Gieson or with toluidine blue. Bone mineral density distribution was quantified by backscattered electron microscopy.


RESULTS
Besides the well-documented enrichment of non-mineralized bone matrix in individuals suffering from adult hypophosphatasia, our histomorphometric analysis revealed alterations of the trabecular microarchitecture and an increased number of osteoblasts compared to healthy controls or to individuals with other types of osteomalacia. Moreover, the analysis of the mineralized bone matrix revealed significantly decreased calcium content in patients with adult hypophosphatasia.


CONCLUSIONS
Taken together, our data show that adult hypophosphatasia does not solely result in an enrichment of osteoid, but also in a considerable degradation of bone quality, which might contribute to the increased fracture risk of the affected individuals.
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
F
F
Barvencik
F Timo
FT
Beil
M
M
Gebauer
B
B
Busse
T
T
Koehne
S
S
Seitz
J
J
Zustin
P
P
Pogoda
T
T
Schinke
M
M
Amling
D000328:Adult; D000368:Aged; D015519:Bone Density; D001857:Bone Matrix / Q000473:pathology*; D002113:Calcification, Physiologic; D016022:Case-Control Studies; D006801:Humans; D007014:Hypophosphatasia / Q000473:pathology*; D007085:Ilium / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism; D010018:Osteomalacia / Q000473:pathology*; D055815:Young Adult
Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8
1409720
Clin Chem. 1992 Dec;38(12):2501-5
1360878
Pediatr Endocrinol Rev. 2006 Aug;3  Suppl 3:470-5
17551468
Bone. 2008 Mar;42(3):456-66
18096457
J Bone Miner Res. 1987 Dec;2(6):595-610
3455637
Clin Genet. 2008 Mar;73(3):245-50
17922851
Endocrinology. 1999 Nov;140(11):4982-7
10537122
Orphanet J Rare Dis. 2007 Oct 04;2:40
17916236
J Bone Miner Res. 2007 Dec;22 Suppl 2:V105-7
18290711
Am J Pathol. 1997 Dec;151(6):1555-61
9403706
Bone Miner. 1994 Dec;27(3):193-208
7535140
Calcif Tissue Int. 1999 Jan;64(1):8-17
9868277
J Clin Pathol. 1996 Aug;49(8):682-4
8881924
J Bone Miner Res. 2009 Aug;24(8):1493-505
19335222
J Biomed Mater Res. 1993 Jan;27(1):57-64
8420999
J Bone Miner Res. 2010 Feb;25(2):305-12
19594303
Scanning Microsc. 1995 Mar;9(1):75-86; discussion 86-8
8553027
J Bone Miner Res. 2009 Jun;24(6):1132-4
19113923
Calcif Tissue Int. 1999 Mar;64(3):185-90
10024373
Endocr Rev. 1994 Aug;15(4):439-61
7988481
Am J Hum Genet. 1990 Feb;46(2):286-92
1689104
J Bone Joint Surg Am. 1994 Dec;76(12):1840-6
7527402
BMC Med Genet. 2009 Jun 06;10:51
19500388
Am J Med Genet. 1990 May;36(1):15-22
2333903
J Bone Miner Res. 1996 Jan;11(1):36-45
8770695
Best Pract Res Clin Rheumatol. 2008 Mar;22(1):113-27
18328985
Minerva Pediatr. 2005 Oct;57(5):319-23
16205618
Clin Orthop Relat Res. 2008 Apr;466(4):990-6
18219546
Medicine (Baltimore). 1984 Jan;63(1):12-24
6690884
Bone. 1998 Oct;23(4):319-26
9763143
J Bone Miner Res. 1992 Dec;7(12):1475-82
1481733
Scan Electron Microsc. 1986;(Pt 4):1537-54
3544196
J Bone Joint Surg Am. 1986 Sep;68(7):981-90
3745261
Calcif Tissue Int. 2010 Aug;87(2):108-19
20524110
Endocrinol Metab Clin North Am. 1990 Mar;19(1):133-73
2113470
Orphanet J Rare Dis. 2009 Feb 21;4:6
19232125
Eur J Pediatr. 1982 Mar;138(2):197-9
7094944
J Clin Endocrinol Metab. 2010 Apr;95(4):1846-50
20157195
Genomics. 1997 Jun 1;42(2):364-6
9192863
Am J Med Genet. 1985 Dec;22(4):743-58
4073124
Hum Mol Genet. 1994 Sep;3(9):1683-4
7833929