Osteomalacia

Causes Hypophosphatemia FGF23 and klotho vitamin D Microscopic images Animations X-rays Therapy Phosphate supplements References

Osteomalacia means "soft bones". Osteoid is the bone protein matrix, composed primarily of type 1 collagen. When there is insufficient mineral or osteoblast dysfunction, the osteoid does not mineralize properly, and it accumulates.

When the newly formed bone of the growth plate does not mineralize, the growth plate becomes thick, wide and irregular. This results in the clinical diagnosis of rickets, and is seen only in children because adults no longer have growth plates. When the remodeled bone does not mineralize, osteomalacia occurs, and this happens in all ages. Most of the hereditary causes of osteomalacia appear during childhood and cause rickets.

New! Brownstein CA. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A 2008;105(9):3455-60.

Dentin Matrix Protein 1 (DMP1) is made in the osteocytes. Homozygous mutations in this gene on the 4th chromosome cause osteomalacia. The DMP1 somehow inhibits secretion or production of FGF23, so the mutated protein releases the inhibition. Also, the osteocytes have abnormal morphology (Feng JQ and Lorenz-Depiereux B.)

Imatinib , a drug used to treat certain cancers (CML or gastrointestinal stromal tumors) causes hypophosphatemia, renal phosphate wasting, and biochemical evidence of low bone turnover. The mechanisms are not clear - - - the authors suggested it was due to suppression of the RANK-L signalling, but other drugs which block bone turnover, or which directly block RANK-L signalling do not cause low phosphate. I wonder if this drug may interact with some of the newly discovered Klotho or other phosphatonins (Berman E).

Hypophosphatasia has a totally different pathophysiology from the other kinds of osteomalaica. It is caused by deficiency in the enzyme alkaline phosphatase. There are several isoforms of this enzyme with different functions; the bone form cleaves pyrophosphate. This is important because the pyrophosphate acts to inhibit mineralization. Without it, we would all turn into pillars of calcium-phosphate! The bone must be protected from this inhibition, and so the bone is entirely lined with linging cells that contain alkaline phosphatase. When the enzyme doesn't work, the pyrophosphatase enters the bone and prevents mineralization. In homozygous cases the disease is fatal because the bones of the ribs are so weak the children get pneumonia and breathing difficulty. Diagnosis is suspected if alkaline phosphatase is low and confirmed with elevated levels of plasma pyridoxal 5'-phosphate and urine phosphoethanolamine. New work with bone transplantation gives hope for a treatment of these children (Whyte MP). In adults, partial deficiency of alkaline phosphatase causes osteomalacia, bone pain and stress fractures. Patients also suffer from arthritis and chondrocalcinosis, as well as dental abnormalities. Lowering phosphate intake could reduce pyrophosphate levels. Calcium and vitamin D should be given carefully, and NOT in high doses, because extra calcium will make the calcinosis worse. Teriparatide might be beneficial in adults with hypophosphatasia (Whyte MP).

The bisphosphonates are analogs of pyrophosphate; when a carbon is substituted for the oxygen the molecule can enter the bones and inhibit mineralization. This is why high doses of older bisphosphonates like etidronate cause osteomalacia. Newer bisphosphonates are more potent so the doses given are not high enough to cause osteomalacia.

Microscopic images

Osteomalacia may be suspected on a clinical basis, especially when there is a family history or lab abnormalities listed on the table above. In uncertain cases, the most reliable way to establish the diagnosis is with an UNDECALCIFIED bone biopsy. Click images for larger views

	NORMAL: A photomicrograph of a biopsy from a normal postmenopausal woman showing an osteoid seam of normal width. Mineralized bone is green and osteoid is orange.
		OSTEOMALACIA: The orange-staining osteoid covers many surfaces and is thicker than normal. The second photo is from part of the biopsy that was decalcified and thus it appears normal. The osteomalacia cannot be appreciated.
	FOCAL OSTEOMALACIA: Both photos from the same section of a bone biopsy. Near the cortex is osteomalacia. This woman had been misdiagnosed as Paget's disease and had been treated with high doses of etidronate.
	ALUMINUM STAIN. This was from a dialysis patient with severe osteomalacia. Aluminum stains as a red line on the surface and in cement lines.
		VITAMIN D DEFICIENCY. The second biopsy shows resolution of the osteomalacia after treatment.

Click to view an animation of normal remodeling, then compare to osteomalacia. These are Flash animations. Use your browser's 'back' button to return.

Normal

Osteomalacia

Xrays

Click photos for enlarged view.

Here is an xray showing a pseudofracture (red arrow) from an adult who has x-linked hypophosphatemic rickets. This is a classic pseudofracture and is pathognomonic for osteomalacia.

This is an xray of a child with bowed legs due to rickets (thanks to Dr. Mike Richardson)

Closer view of a knee showing thick growth plates that appear fuzzy, and widened knee joints

Treatment

This really depends on the cause of the osteomalacia. Treatment can be as simple as vitamin D or as complex as parenteral nutrition. Orthopaedic surgery is frequently necessary. Patients with X-linked hypophosphatemic rickets usually are treated with a combination of calcitriol and phosphate supplements, and careful medical monitoring is needed.

Phosphate supplements
Name	ID	Composition	Phosphorus mg/dose
K-Phos MF (Beach)	White, 1135 round	KPO4 155 mg NaPO4 350 mg	125
K-Phos #2 (Beach)	Brown, 1134 oblong	KPO4 305 mg NaPO4 700 mg	250
K-Phos Neutral (Beach)	White, 1125 oblong	KPO4 155 mg Na2PO4 852 mg NaPO4 130 mg	250
K-Phos (Beach) "Original"	White, 1111 round	KPO4 500 mg	114
Neutra-Phos K (Alza)	powder	KPO4 and K2PO4 1450 mg	250
Neutra-Phos (Alza)	powder	NaPO4 and K PO4 1250 mg	250
Phospha-Soda (Fleet's)	solution	NaPO4	125 mg/mL
(250mg phosphorus = 8 mmol). Adult dose varies, 1000 - 2000 mg/day

X-linked Hypophosphatemia Network This is a site about hereditary hypophosphatemia with rickets, usually x-linked (previously called vitaminD resistant rickets)

More about oncogenic osteomalacia.