(80 days)
Osteomark® is a urinary assay that provides a quantitative measure of the excretion of crosslinked N-telopeptides of type I collagen (NTx) as an indicator of human bone resorption. Elevated levels of urinary NTx indicate elevated human bone resorption. Measurement of NTx is intended for use in:
A. Predicting skeletal response (bone mineral density) to hormonal antiresorptive therapy in postmenopausal women
B. Therapeutic monitoring of:
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- anti-resorptive therapies in postmenopausal women
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- anti-resorptive therapies in individuals diagnosed with osteoporosis
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- anti-resorptive therapies in individuals diagnosed with Paget's disease of bone
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- estrogen-suppressing therapies
The measurement range of Osteomark is 20 to 3000 nM Bone Collagen Equivalents (BCE) of NTx.
Osteomark is a competitive enzyme-linked immunosorbent assay (ELISA) which utilizes a horseradish peroxidase labeled monoclonal antibody directed against the cross-linked Ntelopeptides (NTx) present in urine specimens. An Osteomark® kit is comprised of the following reagents:
Antigen Coated 96-Well Plate Calibrators: 1 nM BCE 30 nM BCE 100 nM BCE 300 nM BCE 1000 nM BCE 3000 nM BCE Antibody Conjugate Concentrate Antibody Conjugate Diluent Level I and Level II Urine Controls 30X Wash Concentrate Buffered Substrate Chromogen Reagent Stopping Reagent
The solid phase utilizes microwells onto which NTx has been adsorbed. NTx in the specimen or Calibrator competes with the solid phase NTx for antibody binding sites. The resulting amount of Antibody Conjugate bound to the solid phase is indirectly proportional to the amount of NTx in the specimen or Calibrator. The quantity of NTx in the specimen is determined from a standard calibration curve using reagents supplied in the kit. Assay values are standardized to an equivalent amount of bone collagen, and are expressed in nanomole bone collagen equivalents per liter (nM BCE). BCE reflects the amount of immunoreactive NTx, as measured by Ostcomark, liberated from human bone collagen following digestion with bacterial collagenase, as measured by hydroxyproline by high performance liquid chromatography (HPLC).
Acceptance Criteria and Device Performance for Osteomark®
This response synthesizes information from the provided text to describe the acceptance criteria and the studies that prove the Osteomark® device meets these criteria.
1. Table of Acceptance Criteria and Reported Device Performance
Given that Osteomark is a diagnostic assay, acceptance criteria typically revolve around its analytical and clinical performance in fulfilling its intended use. Here's a table based on the provided data:
| Acceptance Criterion | Reported Device Performance |
|---|---|
| Analytical Performance | |
| Lower Limit of Detection (LLOD) | 20 nM BCE |
| Intra-assay Variability | Average 8% CV (range 5-19% CV) |
| Inter-assay Variability | Average 4% CV (range 3-5% CV) |
| Antigen Recovery | Average 105% (over 200-2500 nM BCE range) |
| Dilutional Linearity | Correlation coefficients of r=0.999 to 1.000 (over 44-2940 nM BCE range) |
| Clinical Performance (Predicting Skeletal Response to HRT) | |
| Sensitivity for >30% decrease in Osteomark predicting positive BMD response | 80% (95% C.I. 70%, 88%) |
| Specificity for >30% decrease in Osteomark predicting positive BMD response | 59% (95% C.I. 36%, 79%) |
| Predictive Value Positive (PVP) for 30% change (at 80% prevalence) | 88.6% |
| Predictive Value Negative (PVN) for 30% change (at 80% prevalence) | 42.4% |
| Association between baseline Osteomark and risk of BMD loss without HRT | High baseline Osteomark (≥67 nM BCE/mM creatinine) indicated 17.3 times higher risk of spine BMD loss without HRT. |
| Clinical Performance (Monitoring Estrogen Suppressing Therapy) | |
| Mean increase in Osteomark during estrogen suppression | 68% increase from baseline (correlated with -3.7% decrease in lumbar spine BMD) |
| Percentage of subjects with ≥30% increase in Osteomark during estrogen suppression | 63% (55/88) |
| Clinical Performance (Monitoring Anti-Resorptive Therapy in Paget's Disease) | |
| Clinically significant change (≥30%) in Osteomark achieved (all therapies) | Yes, at each timepoint (Month 1, 3, 6) |
| Correlation with total alkaline phosphatase | High positive correlation at baseline and 6 months (r=0.72-0.88, p=0.0001-0.0003) |
| Earlier assessment of therapeutic response compared to total alkaline phosphatase | Osteomark showed 19% responders at Month 1 vs. 2% for total alkaline phosphatase |
| Clinical Performance (Monitoring Anti-Resorptive Therapy in Osteoporosis) | |
| Percentage of alendronate group with Osteomark 40% decrease at 3 months | 87% (76/87) |
2. Sample Sizes and Data Provenance
The document provides details for several studies:
- Reference Range Determination (Premenopausal Women):
- Sample Size: 258 women
- Data Provenance: Multi-center, cross-sectional study; likely prospective for urine collection after study definition.
- Reference Range Determination (Men):
- Sample Size: 81 men
- Data Provenance: Study conducted at a large reference laboratory. Implied prospective since it's for reference range establishment.
- Within-Subject Variability:
- Sample Size: 8 healthy subjects
- Data Provenance: Urine specimens collected every 2-3 days over 2 months. Prospective.
- Intra-assay Variability:
- Sample Size: 8 urine specimens, each tested in replicates of 10.
- Data Provenance: Not specified, likely internal lab testing.
- Inter-assay Variability:
- Sample Size: 3 urine specimens, each tested in duplicate over 20 separate assay runs.
- Data Provenance: Not specified, likely internal lab testing.
- Antigen Recovery:
- Sample Size: 3 normal urine specimens.
- Data Provenance: Not specified, likely internal lab testing.
- Dilutional Linearity:
- Sample Size: 4 urine specimens.
- Data Provenance: Not specified, likely internal lab testing.
- Clinical Study: Predicting Skeletal Response & Monitoring HRT in Postmenopausal Women:
- Sample Size (completed study): 227 women (109 HRT group, 118 calcium group)
- Data Provenance: Multi-center, randomized, prospective clinical trial. (Campodarve et. al., 1995)
- Clinical Study: Monitoring Estrogen Suppressing Therapy:
- Sample Size: Not explicitly stated for all analyses, but for percent change analysis: 88 subjects (55/88 had ≥30% change, 33/88 had
§ 862.1400 Hydroxyproline test system.
(a)
Identification. A hydroxyproline test system is a device intended to measure the amino acid hydroxyproline in urine. Hydroxyproline measurements are used in the diagnosis and treatment of various collagen (connective tissue) diseases, bone disease such as Paget's disease, and endocrine disorders such as hyperparathyroidism and hyperthyroidism.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.