Osteomalacia as a Result of Vitamin D Deficiency

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.

Among the metabolic bone diseases with known pathogenic mechanisms, osteoporosis is the most common and osteomalacia is the least common disorder. Nevertheless, osteomalacia occurs with regular frequency such that it may escape recognition especially in its early stages because of the often indefinite symptoms such as vague bone pain and muscle weakness. In reality, however, osteomalacia is an end-stage bone disease of severe vitamin D or phosphate depletion of any cause with characteristic biochemical, radiological, and bone histologic features. The descriptive term osteomalacia originally referred to a generalized softening of bone leading to crippling deformities, and is almost always caused by vitamin D deficiency, and rarely by phosphate and calcium depletion. The cardinal histologic bone feature of osteomalacia is an excessive accumulation of unmineralized or poorly mineralized bone matrix. In contrast, rickets (see the article by Thandrayen and Pettifor elsewhere in this issue for further exploration of this topic) is a disease of impaired mineralization of cartilage resulting in defective enchondral bone formation. By definition, therefore, rickets occurs only in children and adolescents before epiphyseal fusion, whereas osteomalacia occurs in children and in adults. Although this is an important clinical distinction, the pathogenesis of rickets and osteomalacia is similar.

Historical perspective and scope of the problem

The first description of osteomalacia was by Gustav Pommer, a German pathologist, in the late nineteenth century who discussed the histologic differences between osteomalacia, osteoporosis, and osteitis fibrosa. One of the earliest reports of osteomalacia studied by tetracycline-based bone histomorphometry of the ribs was reported from Henry Ford Hospital in 1966. Based on current concepts of bone remodeling, Pommer’s observations can be restated as replacement of resorbed bone by the same amount of bone in healthy adults, by a lesser amount of bone in age-related osteoporosis, and by unmineralized bone matrix (or osteoid) in osteomalacia. With the realization of the critical role of vitamin D in bone and mineral metabolism in general and bone mineralization in particular, it became apparent that almost all cases of bone softening were the result of vitamin D deficiency, and osteomalacia was synonymous with bone disease that could be cured by vitamin D repletion. However, it is now clear that not all cases of osteomalacia are cured by vitamin D therapy and similarly not all individuals with vitamin D depletion develop osteomalacia. Nevertheless, it is important to bear in mind that almost all individuals with prolonged severe vitamin D depletion will eventually develop osteomalacia with irreversible cortical bone loss and increased risk of fractures for the rest of their lives. Osteomalacia manifests as a distinct metabolic bone disease with its characteristic clinical, biochemical, radiographic, and histologic bone features, that can be distinguished unambiguously from osteoporosis or any other metabolic bone disease.

Because of the lack of any systematic studies on osteomalacia it is difficult to estimate the precise prevalence of osteomalacia. A MEDLINE search from 1950 to 2009 using the MeSH term “osteomalacia” reveals several articles, but all are concerned with individual case reports or case series. Nevertheless, vitamin D deficiency is the most common cause of osteomalacia worldwide, but in the United States, gastrointestinal disorders causing vitamin D deficiency and hypophosphatemic osteomalacia are the most common. Gastric bypass surgery for morbid obesity is now emerging as the leading cause of vitamin D deficiency osteomalacia in this country. Other uncommon causes of vitamin D deficiency osteomalacia are summarized in Box 1 .

Box 1

  • Extrinsic

  • Decreased exposure to sunlight

  • Use of sunscreens (especially >8 SPF)

  • Use of a veil (or hijab)

  • Increased or dark skin pigmentation

  • Inadequate dietary intake

  • Morbid obesity

  • Intrinsic

  • Advancing age with decreased cutaneous production of vitamin D

  • Malabsorption caused by various gastrointestinal disorders

    • Gastrectomy (partial, total, or bypass procedure)

    • Small intestinal disease, resection, or bypass

    • Gluten enteropathy (celiac sprue)

    • Biliary cirrhosis (uncommon)

    • Pancreatic insufficiency including cystic fibrosis (uncommon)

  • Acquired vitamin D deficiency

  • (as a result of increased catabolism or metabolic clearance)

    • Anticonvulsants

    • Calcium deficiency with secondary hyperparathyroidism

    • Primary hyperaparathyroidism

    • Paget’s disease of bone (depletion caused by excess consumption)

Common causes of vitamin D deficiency osteomalacia

Evolution of Hypovitaminosis D Osteopathy and Osteomalacia

In its early stages, vitamin D deficiency is associated with increased serum alkaline phosphatase and parathyroid hormone (PTH) levels, increased bone turnover without mineralization defect, and irreversible cortical bone loss, which the authors defined as hypovitaminosis D osteopathy stage I (HVO-I) or preosteomalacia. Recognition of this preclinical stage is important to prevent PTH-mediated cortical bone loss and progression to frank osteomalacia. In the next stage, hypovitaminosis D osteopathy stage II (HVO-II), there is progressive accumulation of unmineralized matrix (or osteoid) with some preservation of mineralization. In the last stage, hypovitaminosis D osteopathy stage III (HVO-III), there is complete cessation of mineralization with no tetracycline uptake, conforming to the traditional descriptions of osteomalacia. The distinguishing histologic bone features of osteomalacia and osteoporosis along with reference ranges are summarized in Table 1 . Osteoporosis is characterized by a quantum decrease in bone volume without mineralization defect, whereas osteomalacia is associated with a decrease in bone volume and excess osteoid accumulation. The extent of bone mineralization is either near normal or slightly reduced in osteoporosis, whereas it is always absent in osteomalacia. Secondary hyperparathyroidism, an inevitable consequence of chronic vitamin D deficiency, in rare cases is associated with bone marrow fibrosis, similar to that found in primary hyperparathyroidism. In osteomalacia, osteoid volume, thickness, and surface are all increased, whereas in osteitis fibrosa, only the osteoid volume and surface but not the thickness are increased and usually not to the same extent as in osteomalacia (see Table 1 ). A mineralization lag time (MLT) of more than 100 days separates osteomalacia unambiguously from all other conditions with increased osteoid indices as a result of increased bone turnover, such as hyperparathyroidism, hyperthyroidism, and Paget disease of bone (see Table 1 ). Thus a combination of increased osteoid thickness greater than 15 μm and an MLT more than 100 days should be used as diagnostic criteria for osteomalacia of any cause including vitamin D deficiency osteomalacia.

Table 1

Representative bone histomorphometric and bone density measurements in patients with osteoporosis and osteomalacia

Measurement Normal Postmenopausal White Women a Osteoporosis (With Fractures) a Osteomalacia
Bone Histomorphometry
Osteoid surface/bone surface (%) 20.3 (4.35–39.7) 15.7 (2.78–34.5) 69 ± 13
Osteoid thickness (μm) 8.49 (5.75–12.2) 7.63 (4.74–11.5) 27 ± 9
Mineralization lag time (MLT; days) 71.2 (18.6–158) 73.8 (17.1–132) >100
Bone formation rate/bone surface (μm 3 /μm 2 /y) 15.9 (1.00–33.9) 13.0 (0.436–33.7) 0
Bone Mineral Density
Spine T-score Referrent −2.3 ± 1.8 −3.0 ± 1.6
Spine Z-score Referrent −1.2 ± 0.8 −2.0 ± 1.4
Femoral neck T-score Referrent −2.1 ± 1.6 −4.1 ± 1.0
Femoral neck Z-score Referrent −1.1 ± 0.6 −2.7 ± 0.7
Forearm Z-score Referrent −1.1 ± 1.0 −6.0 ± 2.3
Forearm T-score Referrent −0.85 ± 0.5 −3.8 ± 0.8

Note the magnitude and pattern of bone mineral deficits with more trabecular bone deficit (spine and hip) in postmenopausal osteoporosis and predominant cortical bone deficit (forearm bone mineral density) in osteomalacia.

Data from Basha B, Rao DS, Han Z-H, Parfitt AM. Osteomalacia due to vitamin D depletion in the US. Am J Med 2000;108:296–300.

a Representative data from the authors’ laboratory (published and unpublished).

Clinical manifestations of osteomalacia

Osteomalacia in its classic form manifests with a constellation of symptoms and signs that can be collectively referred to as osteomalcic syndrome. Some symptoms are vague and nonspecific and can easily escape the attention of the clinician, whereas others are highly specific and often diagnostic. Between these 2 extremes a patient may present with a combination of symptoms and signs. Therefore, a high degree of suspicion in the right clinical context is necessary to diagnose osteomalacia especially in the early stages. Because of the increase in serum alkaline phosphatase levels and dramatic appearance on bone scans, metastatic disease is often suspected leading to exhaustive, expensive, and often unnecessary testing. A recent case seen by the senior author illustrates the problem. A 59-year-old white woman with no previous history of cancer or gastrointestinal surgery was seen for a high serum alkaline phosphatase level (890–950 IU/L) that had progressively increased over a period of 1 to 2 years during which she developed vague musculoskeletal symptoms, which she described as aches and pains of getting old. A whole body bone scan showed multiple bilateral rib fractures without increased uptake elsewhere in the skeleton ( Fig. 1 ), an unusual finding in malignancy, but nevertheless referred to an oncologist for further evaluation. She underwent an exhaustive investigation for cancer and myeoloproliferative diseases including a bone marrow examination that was normal. Only when a house officer ordered measurement of serum PTH, because that was the only test that had not yet been performed, and found to be 879 pg/mL was the patient referred to a bone and mineral specialist. The house officer did not consider measurement of 25-hydroxyvitamin D. She had profound proximal myopathy, diffuse bone pain, and an undetectable level of serum 25-hydroxyvitamin D (<4 ng/mL). Bone biopsy confirmed severe osteomalacia ( Fig. 2 ) and all her symptoms improved dramatically within 3 to 4 months of vitamin repletion. This case illustrates the problems with diagnosis of osteomalacia even though much has been written on vitamin D deficiency recently.

Fig. 1

A whole body bone scan before ( A ) and after ( B ) vitamin D therapy in the patient described in the text. Complete and thorough evaluation did not reveal any cause for vitamin D deficiency other than nutritional deficiency. Note multiple bilateral hot spots in the ribs without any other discrete foci elsewhere in the body, characteristic of osteomalacia, but not of metastatic disease as was thought initially in this patient. Also, note a decreased uptake in the kidney in the absence of renal insufficiency suggesting an avid uptake and retention in the skeleton.

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Osteomalacia as a Result of Vitamin D Deficiency
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