At a Glance

This chapter discusses primary metabolic osteomalacia presenting in adults. Osteomalacia as a complication of renal failure and disorders of Vitamin D metabolism are not discussed.

Osteomalacia is the presence of excessive nonmineralized bone (also called osteoid). In adults, it presents as bone pain and incomplete fractures.

Osteomalacia, as an acquired metabolic disease, can be divided into disorders preventing bone mineralization (mainly vitamin D deficiency) and disorders with excessive mineral loss and metabolic acidosis (mainly renal tubular acidosis). Some of the vitamin D-related causes are secondary to toxic effects of drugs (commonly anti-seizure medications). Occasionally, osteomalacia can be caused by environmental toxins, including aluminum. However, it is unusual for toxins to accumulate enough to cause osteomalacia unless there is also renal impairment. There are many subtypes of renal tubular acidosis, including a variety of transporter defects and metabolic challenges that may lead to odd presentations of osteomalacia.

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There are also other rare causes of primary metabolic osteomalacia that do not fall into the categories above. This chapter focuses on osteomalacia secondary to Vitamin D deficiency and renal tubular acidosis (RTA).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Initial workup generally includes radiology of pelvis and any positions in which bone pain occurs; informing the radiologist that pseudofractures/osteomalacia is a consideration may be helpful. Absolute diagnosis of osteomalacia requires a bone biopsy with analysis of undecalcified sections (different from a regular bone marrow, which is decalcified so that undecalcified bone cannot be determined). This is the only way that osteoid can be measured.

Several laboratory tests, such as serum electrolytes, calcium, phosphate, parathyroid hormone, and 25-hydoxy-Vitamin D, may support the specific cause of osteomalacia, and bone biopsy may be unnecessary if a common and treatable cause is identified. However, bone biopsy is not dangerous or particularly expensive and is advisable in any case with unusual features or diagnostic problems.

Serum electrolytes, blood gases (variable findings but usually hypokalemia, metabolic acidosis, and normal anion gap), serum alkaline phosphatase, parathyroid hormone (PTH; increased), calcium, phosphorus, and 25 hydroxyvitamin D (variably decreased) are helpful laboratory tests. Specifically, metabolic acidosis indicates work-up for renal tubular acidosis, whereas low vitamin D suggests work-up of vitamin D deficiency induced osteomalacia (outlined in Table 1).

Table 1.
25 Hydroxyvitamin D Urine pH Urine Bicarbonate Excretion
Very low result (<10 ng/mL) is consistent with vitamin D deficiency-induced osteomalacia Inability to acidify to <pH 5.5 despite metabolic acidosis in addition to bicarbonate excretion >5% of bicarbonate during loading indicated proximal RTA Urine Bicarbonate Excretion >15% of bicarbonate during loading in addition to lack of acidification to <pH 5.5 indicates proximal RTA

The serum electrolytes and PTH are important to make other findings interpretable and to avoid pitfalls, such as osteomalacia with abnormal phosphate management. If phosphate and creatinine are increased, phosphate retention with early renal failure should be considered rather than a primary metabolic osteomalacia. Hypophosphatemia, typically genetic and with several specific etiologies, will cause osteomalacia due to insufficiency of phosphate to allow mineralization, whereas elevated PTH allows calcium to remain normal. The specific types of inherited phosphate wasting are generally appropriate for referral to academic pediatric specialists and are not considered here.

A 25-hydroxy-Vitamin D less than 10 ng/mL suggests osteomalacia secondary to severe Vitamin D deficiency.

Low urine pH (<5.5) and urine bicarbonate excretion greater than 15% of bicarbonate during loading is consistent with proximal RTA. If there are findings of renal tubular acidosis presenting in an adult, many drugs may trigger the event, including antibiotics, so history is important, as are major dietary changes.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Consider that osteomalacia may occur as side effects of drugs, commonly seizure medications, but many other drugs may also alter renal tubular function.

Liver failure and related metabolic insufficiency may cause secondary osteomalacia, although in these cases the primary disease is usually the main concern and not a diagnostic problem, although management may be challenging.

If the cause is not readily apparent on initial analysis, further consideration should include detailed analysis of diet or the possibility that toxins, including aluminum intoxication. Aluminum intoxication is easily diagnosed on bone biopsy.

Other toxic metals occasionally also present with osteomalacia, including acute iron overload in adults. This is also easily diagnosed by bone biopsy.

There is a variety of consensus publications suggesting that vitamin D below approximately 40 ng/ml is a deficiency. However, 25-hydroxyvitamin D of 20-30 ng/mL is prevalent in subjects in good health with high sun exposure. This may reflect, in part, that serum 25-hydroxy D in healthy subjects with strong sun exposure is mainly natural D3, which is highly active. The recommendations to maintain Vitamin D reflect that vitamin D2 administration is largely nontoxic and most physicians recommend dietary D2 to avoid deficiency, even though this may have minimal effects. Regardless, only levels less than 10 are associated with osteomalacia.

Overall understanding of the role of vitamin D in health is not particularly good, and, to further complicate interpretation, some laboratory tests are not very reliable or repeatable. 25 hydroxyvitamin D2 and D3 have different activity. D3, the prohormone produced in the skin with sun exposure, is approximately twice as potent. 1,25 dihydroxyvitamin D is the form that activates gene transcription, and 24,25 dihydroxyvitamin D has effects on fracture healing and probably other metabolism. If total 25 hydroxyvitamin D results do not fit well with the clinical condition, LC-MS/MS testing can provide separate measurement of D2 and D3.

In adults with acquired osteomalacia secondary to vitamin D insufficiency, the existence of a vitamin D metabolizing condition, mainly sarcoidosis or skin tumors, should be considered. In addition, other rare tumors can cause osteomalacia (as a group, called oncogenic osteomalacia), and some may do so by alternative mechanisms, such as phosphaturia.

What Lab Results Are Absolutely Confirmatory?

A bone biopsy with analysis of undecalcified sections confirms osteomalacia. If a treatable cause is apparent, a bone biopsy may not be required. However, in persistent osteomalacia without a clear cause, a bone biopsy is indicated to determine the causes, such as aluminum intoxication or systemic mastocytosis.

Correction after potassium citrate or, when required, bicarbonate administration can be confirmatory.

Correction after treatment of conditions that degrade vitamin D is also confirmatory.