Endocrinology Metabolism

Osteomalacia

Are you sure your patient has Osteomalacia and what should you expect to find?

Osteomalacia means softening of the bones and refers to defective or delayed mineralization of the organic matrix (osteoid) of cancellous and cortical bone. Rickets refers to impaired mineralization of the cartilaginous growth plate and abnormal endochondral bone formation and, therefore, cannot occur in adults after closure of the growth plates. Osteomalacia remains quite common. When the disorder presents with fractures, bone pain, and reduced bone mineral density (BMD), it may masquerade as osteoporosis but in striking contrast to osteoporosis, osteomalacia usually has abnormal levels of serum calcium, inorganic phosphorus, or alkaline phosphatase activity. Figure 1.

Figure 1.

In this photomicrograph of a bone biopsy specimen taken from a patient with osteomalacia, normally mineralized bone is blue and unmineralized bone matrix or osteoid is red. The excess osteoid is due to both an increase in the extent of cancellous bone surface covered with osteoid as well as to augmentation of the osteoid seam thickness. The osteoid seams are lined by flattened, pavement-like cells instead of normal, plump, cuboidal osteoblasts. (Modified Masson stain, magnification x400)

Bone disease in osteomalacia almost always manifests in the same manner regardless of its numerous possible causes listed in Table I.

Table I.

Causes of Osteomalacia

Clinical featues

Osteomalacia can present with following clinical features:

Asymptomatic:

Patients can be asymptomatic even with striking biochemical and densitometric findings of osteomalacia (eg: 29 year old women with severe vitamin D deficiency at 4 ng/ml, PTH at 100 pg/ml (range: 12-88) and low bone mineral density was evaluated for pathologic fracture. She remained clinically asymptomatic before and after normalization of her vitamin D level and improvement in her bone density).

Myopathy with proximal muscle weakness:

Can present with painful proximal muscle weakness (especially pelvic girdle), waddling gait and gait instability. Creatine kinase (CK) level is typically normal.

Bone pain and tenderness:

Usually poorly localized bone pain or tenderness. Most often, the pain is in the lower back, pelvis, and legs and is worse on weight bearing. May be worse at night and after sudden movements such as turning in bed or change from sitting to standing.

Bone tenderness is often elicited by rib cage compression or pressing on the tibiae, wrists, pubic rami, or iliac crests.

Symptoms due to low calcium and low phosphorous:

Hypocalcemia: May present with paresthesias, muscle cramps or spams, tingling or numbness or seizures. Positive Chvostek's sign and Trousseau's sign.

Hypophosphatemia: muscle weakness.

A positive Chvostek's sign range from twitching of the lip to spasm of all ipsilateral facial muscles by tapping over the facial nerve just in front of the ear (tap on the imaginary line connecting the zygomatic bone (cheekbone) to angle of the jaw). To elicit the sign use a short, soft rubber handle when patient is aware of the procedure and is in a relaxed state.

The Trousseau's sign is positive if carpopedal spasm is produced by inflation of a blood pressure cuff above systolic blood pressure for three minutes. Carpopedal spasm is characterized by flexion of the wrist, adduction of the thumb, flexion of the metacarpophalangeal joints and extension of the interphalangeal joints.

Pathologic fractures:

A major clue is bilaterally symmetrical fractures with slow healing. Most involve the appendicular skeleton and pelvis.

Abnormal serum concentrations of calcium, phosphorous, alkaline phosphatase, 25-hydroxyvitamin D and PTH:

Biochemical changes depend on the stage of the disease and its etiology.

Laboratory abnormalities may include:

  1. Decreased 25-hydroxyvitamin D with or without secondary hyperparathyroidism

  2. Hypophosphatemia

  3. Hypocalcemia

  4. Hypocalciuria

  5. Increase in alkaline phosphatase/ bone specific alkaline phosphatase

The serum 25-hydroxyvitamin D levels are often < 10-15 ng/ml. In contrast, serum 1,25-dihydroxyvitamin D levels are usually elevated owing to the concomitant hyperparathyroidism and do not contribute to the diagnosis of osteomalacia except in the rare abnormalities of vitamin D resistance [when 1,25-dihydroxyvitamin D levels are extraordinarily high] or when 1-alpha hydroxylation is defective [and 1,25-dihydroxyvitamin D levels are low or undetectable].

Hypophosphatemia usually precedes and is more severe than hypocalcemia and is due to secondary hyperparathyroidism, intestinal phosphate malabsorption and lack of action of vitamin D metabolites on renal phosphate conservation.

Hypocalcemia is due to impaired action of parathyroid hormone (PTH) on the calcium homeostatic system in osteoid-covered bone and intestinal malabsorption of calcium. Hypocalcemia may also be aggravated by the presence of hypomagnesemia.

Hypocalciuria is due to the low circulating calcium level and the increase in tubular reabsorption of calcium as a result of secondary hyperparathyroidism but hypercalciuria may occur with osteomalacia in renal tubular acidosis, phosphate depletion, or acquired Fanconi syndrome.

Increased serum alkaline phosphatase or bone specific alkaline phosphatase activity is classically associated with osteomalacia due to vitamin D deficiency but is not an early or reliable clue because some patients may have normal or only borderline elevated levels. To infer the origin of the increased serum alkaline phosphatase [ie, bone rather than liver] use gamma glutamyl transpeptidase, which is normal in bone disease and increased in hepatobiliary disease or medication-induced increased alkaline phosphatase.

The inherited disease of bone metabolism, hypophosphatasia, presents with normal serum 25-hydroxyvitamin D and calcium, high normal or elevated phosphorus and subnormal alkaline phosphatase.

Classic radiologic features may be present:

Radiographic features may be absent with early osteomalacia, and only blurred margins of the cancellous bone with thin cortices may be noted. The presence of bilateral, thin (2-3 mm), radiolucent bands known as pseudofractures (sometimes called Looser's zones or Milkman's fractures) found perpendicular to the periosteal surface in ribs, pubic and ischial rami, the neck of the femur, metatarsals, and below the glenoid fossa on the outer border of the scapulae are generally considered to be pathognomonic of osteomalacia. (Figure 2)

Figure 2.

Radioisotope bone scanning shows increased uptake at sites of pseudofractures and may be mistaken for metastatic disease.

These pseudofractures show increased uptake on bone scans and may lead to an inappropriate search for a primary malignancy. (Figure 3)

Figure 3.

Radiographic evidence of a pseudofracture is generally considered a reliable diagnostic feature of osteomalacia but may be seen in disorders without excess osteoid.

Decreased bone density from defective mineralization:

Bone mineral density T-scores may be as low as -3 to -4, with the radial diaphyseal density (the distal 1/3 radial site) lower than that of the lumbar spine or total proximal femur.

However, a bone mineral density determination is not required for the diagnosis of osteomalacia and reduced bone mineral density does not differentiate osteomalacia from osteoporosis.

What are the causes of Osteomalacia?

See Table I. Causes of Osteomalacia

Which individuals are most at risk for developing osteomalacia?

  • Malnutrition

  • Malabsorption / Postgastrectomy

  • Renal defects - impairment of 1-alpha hydroxylase can occur because of loss of renal mass or in the renal tubular disorders such as Fanconi syndrome

  • Decreased solar exposure

  • Geriatric patients

  • Institutionalized patients

  • Medications as listed in Table I

What are the indications for Vitamin D testing?

Measurement of 25-hydroxyvitamin D is beneficial in following conditions:

  1. Symptoms of bone pain and proximal muscle weakness

  2. Increased falls

  3. Advanced age

  4. History of gastric surgery or malabsorption

  5. Before drug treatment for osteoporosis

  6. Abnormal bone mineral density

  7. Elevated serum alkaline phosphatase or PTH levels

  8. Low serum calcium or phosphorus levels

Look for the right cause of osteomalacia

Patients may have more than one possible explanation for osteomalacia and need further work up for the right diagnosis.

A patient presents with a pathologic fracture and low bone mineral density. There was a history of HIV and treatment with Tenofovir which is known to cause hypophosphatemic osteomalacia. However, work up revealed normal serum phosphorus levels and severe vitamin D deficiency. With a diagnosis of vitamin D deficient osteomalacia, the patient was started on replacement therapy and was able to continue to receive the benefit of the Tenofovir.

Consider other conditions that can mimic Osteomalacia

Osteoporosis:

Patients are usually asymptomatic until fractures occur. Loss of height is common.

Differentiating features include normal circulating levels of PTH, calcium and phosphorus. Alkaline phosphatase is usually normal but may be slightly elevated, especially following fracture.

Hypophosphatemia due to hyperparathyroidism:

Patients may present with a history of renal stones, polyuria, muscle weakness, fatigue, bone pain, normal or elevated alkaline phosphate, high urine phosphate, elevated or high normal PTH levels and the sine qua non of primary hyperparathyroidism, hypercalcemia.

Hypocalcemia due to hypoparathyroidism:

Patients may present with a history of tetany, carpopedal spasms, tingling of lips and hands, muscle and abdominal cramps, psychological changes and a positive Chvostek's sign and Trousseau's test. Differentiating features include hyperphosphatemia, low or low-normal PTH level, and normal or low-normal alkaline phosphatase.

Renal osteodystrophy:

A disorder of bone and mineral metabolism associated with chronic renal disease and secondary hyperparathyroidism. Usually seen with frankly abnormal serum calcium, phosphorus, creatinine, alkaline phosphatase and PTH levels.

Multiple myeloma or metastatic cancer:

Bone pain most common in back, hip, or ribs. May present as pathologic fractures with hypercalcemia and azotemia.

When do you need bone biopsy in the diagnosis of osteomalacia?

Bone biopsy can give a definitive histomorphometric diagnosis of osteomalacia.

A clinician can manage most metabolic bone diseases without the aid of a bone biopsy. It may be useful in evaluating patients with complaints of unusual bone pain or progressive loss of bone mineral density, unexplained pathologic fractures, relative youth, particularly when the results of the physical examination, radiographs, and biochemical findings are ambiguous.

Bone biopsy is also indicated in patients with unexplained chronic hypophosphatemia.

When biopsy is necessary and if local pathologist is not familiar with the preparation of an undecalcified, plastic-embedded, bone specimen to identify defective mineralization, the best solution is to refer the patient to a bone histomorphometry center for biopsy.

How do you identify delay or defect in bone mineralization?

Mineralization requires the availability of sufficient calcium and phosphorus at the remodeling site [the predominant function of Vitamin D], the presence of a normal bone collagen matrix, the absence of inhibitors of mineralization, and adequate amount of skeletal alkaline phosphatase activity.

Normally, up to 70% of the mineralization of the osteoid deposited by the osteoblasts start within 4 to 12 days and proceeds at about 1 um per day; but in osteomalacia, mineral deposition in the osteoid slows or stops completely, while the osteoblasts continue to make osteoid and alkaline phosphatase, which then accumulates in excessive amounts.

Normal osteoid width is about 4 to 12 um, but in osteomalacia, the osteoid width may become dramatically augmented (see Figure 1).

The histomorphometric diagnosis of osteomalacia requires the simultaneous presence of three findings:

  1. Excessive osteoid [osteoid area greater than 10%; normal is less than 4%],

  2. Augmentation of the osteoid width [more than 15 um; normal is 4-12 um], and

  3. Prolongation of the mineralization lag time [greater than 100 days; normal is 9-20 days], as determined by the osteoid width divided by the distance between and linear extent of double tetracycline labels observed in the bone after the patient receives two time-spaced courses of oral tetracycline.

How to interpret results of bone biopsy using double tetracycline labeling?

Tetracycline is deposited early in the course of hydroxyapatite crystal formation and generates bright stripes at the interface of mineralized bone and osteoid when viewed with fluorescent microscopy.

If two time-spaced courses of tetracycline [1 g/day for 3 days] are separated by a 14-day interval, the rate of mineralization [um/day] can be calculated by measuring the average distance between the double labels divided by the number of days between the two courses. (Figure 4)

Figure 4.

The distance between the two bright yellow tetracycline labels divided by the days between the oral courses of tetracycline is the mineral appositional rate in microns per day. (Magnification x200)

When the double labels are numerous and widely spaced, mineralization is intact, and if excess osteoid is present, it is due to increased bone turnover.

A paucity of tetracycline labels that are narrowly spaced indicates that if excessive osteoid is present, it must be due to delayed or ceased mineralization.

How do you manage Osteomalacia due to Vitamin D disorders?

Osteomalacia management includes advice on appropriate nutrition and sun exposure when indicated, discontinuation of offending drugs and treating or reversal of the underlying cause.

Vitamin D and Calcium replacement:

1) Vitamin D2 / D3 replacement:

Replacement doses depend on the serum 25-hydroxyvitamin D level, as shown in the Table II. The goal is to raise the serum 25-hydroxyvitamin D level well above 30 ng/ml and restore the elevated parathyroid hormone concentrations to normal without hypercalcemia or hypercalciuria.

Table II.

25-Hydroxyvitamin D level Ergocalciferol (D2) or Cholecalciferol (D3) dose recommended
25(OH)D = 20 - 30 ng/ml 50,000 IU once a week for 10 weeks and once a month thereafter
25(OH)D = 10 - 19 ng/ml 50,000 IU twice a week for 10 weeks and twice a month thereafter
25(OH)D < 10 ng/ml 50,000 IU three times a week for 10 weeks and three times a month thereafter

Maintenance dose:

The optimal vitamin D maintenance dose is not clear, but most bone and mineral problems are avoided by 50,000 IU of ergocalciferol or cholecalciferol given once monthly. Notable exceptions occur in patients with celiac disease, malabsorption, gastric surgery, or bypass for obesity, who often require much larger amounts.

2) Calcitriol (1,25-Dihydroxyvitamin D) replacement:

The onset and offset of action of calcitriol are much more rapid than with any other compounds. More frequent monitoring of serum calcium is necessary during the early phases of treatment while the dose is being titrated.

It should be considered in patients with severe malabsorption or when there is defect in 1-alpha hydroxylation such as in vitamin D dependent rickets type I or chronic renal failure.

The dose is usually in the range of 0.25 to 1.5 ug daily in divided doses. Toxicity with calcitriol should be avoided by frequent monitoring.

3) Calcium replacement:

Patients with severe disease usually require vitamin D and calcium supplementation.

Usually 1-1.5 gm per day of oral elemental calcium is a reasonable initial dose. Frequent small doses (three times a day are more effective and tolerable than fewer larger ones. The absorbability of calcium supplements is enhanced with meals. Calcium preparations such as calcium carbonate (40% calcium as in Os-Cal or the equivalent) can be used. Some patients with adverse gastrointestinal side effects with above preparations prefer using chocolate- or coffee- flavored formulations known as Viactiv (500 mg calcium per tablet). PPIs or H2 blocking drugs do not impair calcium absorption.

Monitoring:

An increase in the serum alkaline phosphatase activity [the healing "flare"] and a small increase in the serum and urine calcium levels are the earliest signs of effective treatment.

In some patients with severe osteomalacia, bone pain and paresthesias may increase and the serum calcium levels decrease during first week of therapy due to increased skeletal avidity for mineral during healing, indicating the need for additional calcium supplementation.

At the start of therapy, serum calcium levels should be measured at weekly intervals. If hypoalbuminemia is present, serum ionized calcium determinations may be more useful. When therapy appears stabilized, biweekly or monthly intervals are usually sufficient for the first 3 or 4 months, but even with long term therapy, measurements should be at least three times a year.

Urinary calcium excretion should be monitored when treatment has normalized the serum calcium levels. The urinary calcium-to-creatinine ratio (mg/mg) should be kept in between 0.02-0.22.

What is the target goal for 25-Hydroxyvitamin D level?

25-Hydroxyvitamin D level: It would be appropriate to use a range from 30 - 80 ng/ml for most patients as an optimal and safe range.

For many patients, 1000-2000 IU daily or 50,000 IU once monthly of ergocalciferol or cholecalciferol, is required to maintain a 25-Hydroxyvitamin D level above 30 ng/ml.

Does hypophosphatemic osteomalacia need replacement with phosphate?

Management includes advice on appropriate nutrition when indicated, discontinuation of offending drugs and treating or reversal of the underlying cause.

Phosphorous replacement:

Therapy for chronic hypophosphatemia is aimed at maintaining normal concentration of serum phosphorus without inducing secondary hyperparathyroidism or nephrocalcinosis.

Use divided doses of phosphorus supplements 1-3 g/day and calcitriol 1-4 ug/day to increase the absorption of phosphorus and prevent the phosphorus-induced increase in parathyroid hormone. If phosphorus-induced secondary hyperparathyroidism develops, the phosphorus supplements are rapidly excreted, and therapy not only is futile but also causes the additional bone burden of hyperparathyroidism.

Monitoring:

Baseline and yearly renal ultrasound examinations are necessary to recognize early nephrocalcinosis or nephrolithiasis. The need for phosphorus supplementation may be life long.

How do you manage Oncogenic osteomalacia?

Oncogenic osteomalacia: A syndrome seen in association with mesenchymal tumors and rarely with prostate cancer.

These tumors may be small, obscurely situated, difficult to identify and secrete phosphaturic proteins. Fibroblast growth factor 23 [FGF 23] is the most documented protein, but others have also been incriminated.

The bone pain, muscle pain, proximal muscle weakness, fractures, waddling gait, and osteomalacia characteristics of this syndrome are due to hypophosphatemia which is made worse by inappropriately low levels of 1,25-dihydroxyvitamin D. Alkaline phosphatase activity is often elevated. Levels of calcium are typically normal, and in some cases PTH levels are mildly elevated.

Oncogenic osteomalacia is treated with phosphorus supplementation and calcitriol until the offending tumor can be located and resected. Surgical correction of the bony deformities should be postponed until medical management achieves persistently normal levels of calcium, phosphorus, and alkaline phosphatase activity. An exception to this rule is an acute fracture of the femoral neck. Prompt surgical repair may be essential to avoid osteonecrosis.

The biochemical abnormalities remit and the osteomalacia heals when the tumor responsible is removed.

Is it possible to have osteomalacia and osteoporosis at the same time?

About 20% of North American women receiving treatment for osteoporosis have 25-Hydroxyvitamin D levels < 20 ng/ml and 8% have levels < 15 ng/ml, indicating at the least, impaired bone mineralization could be a confounding factor and, at worst osteomalacia is the correct diagnosis rather than osteoporosis. (Figure 5)

Figure 5.

When a patient with osteoporosis (a reduced amount of normally mineralized bone) also becomes severely vitamin D deficient and developes osteomalacia (defective bone mineralization), the concurrent diagnoses may only be made with an undecalcified bone biopsy specimen. (Modified Masson stain, blue is mineralized bone and red is osteoid, magnification x100)

If osteomalacia is mistaken for osteoporosis and treatment is started with a bisphosphonate, the patient may experience new-onset paresthesias, muscle cramps, palpitations, and seizures. This not uncommon scenario occurs because the antiresorptive treatment interferes with the compensatory secondary hyperparathyroidism and aggravates the hypocalcemia. In this setting, bisphosphonates also may further increase the PTH levels and prompt an additional search for other causes of secondary hyperparathyroidism.

To avoid the above complication, patients with osteomalacia associated with osteoporosis should undergo treatment for osteomalacia first and, afterwards (6-12 months later), osteoporosis should be re-evaluated and treated appropriately.

Is it possible to have vitamin D deficiency coexisting with primary hyperparathyroidism?

Some patients with primary hyperparathyroidism have coexisting vitamin D deficiency and present with normocalcemia or hypercalcemia, elevated or inappropriately normal PTH level and low 25-hydroxyvitamin D level. Urinary calcium may be low or normal, but may increase with vitamin D repletion.

Regardless or the clinical severity of primary hyperparathyroidism, the disease seems to be more severe in those with concomitant vitamin D deficiency. Treatment with vitamin D as needed is suggested (see Table II). Serum and urine calcium levels should be monitored.

What should you tell the patient and the family about prognosis?

The response to appropriate treatment in most forms of osteomalacia is usually excellent. Stopping the offending drug or treating the underlying cause usually reverses the osteomalacia. Medications used are relatively inexpensive and are safe if monitored appropriately.

Improvements in bone pain and muscle weakness usually occur within weeks to months and healing of skeletal lesions within 6-9 months.

What’s the evidence?/References

Leboff, MS, Kohlmeier, L, Hurwitz, S. "Occult vitamin D deficiency in postmenopausal US women with acute hip fracture". JAMA. vol. 281. 1999. pp. 1505-1511.

(An often overlooked but treatable problem.)

Thomas, MK, Lloyd-Jones, DM, Thadhani, RI. "Hypovitaminosis D in medical inpatients". N Engl J Med. vol. 338. 1998. pp. 777-783.

(A common problem.)

Holick, MF. "Vitamin D deficiency". N Engl J Med. vol. 357. 2007. pp. 266-281.

(A comprehensive review of vitamin D deficiency.)

Parfitt, AM, Avioli, LV, Krane, SM. "Osteomalacia and Related Disorders". Metabolic Bone Disease. vol. 1997. WB Saunders. pp. 328-386.

(The definitive work on osteomalacia and a detailed review of bone remodeling dynamics.)

Quarles, LD. "Endocrine functions of bone in mineral metabolism regulation". J Clin Invest. vol. 118. 2008. pp. 3820-3828.

(A review of new signaling pathways for phosphate excretion and vitamin D metabolism.)

Weinstein, RS, Bryce, GF, Sappington, LJ. "Decreased serum ionized calcium and vitamin D metabolite levels with anticonvulsant drug treatment". J Clin Endocrinol Metab. vol. 58. 1984. pp. 1003-1009.

(Tetracycline-labeled bone biopsy specimens obtained from patients receiving long term anticonvulsant drug therapy indicated that secondary hyperparathyroidism was present rather than osteomalacia.)

Tali Cukierman. "A Fractured Diagnosis". N Engl J Med. vol. 353. 2005. pp. 509-514.

(A case report of a young patient with osteomalacia masquerading as osteoporosis.)
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